Neocortical glial cell numbers in human brains

DEFF Research Database (Denmark)

Pelvig, D.P.; Pakkenberg, H.; Stark, A.K.

2008-01-01

Stereological cell counting was applied to post-mortem neocortices of human brains from 31 normal individuals, age 18-93 years, 18 females (average age 65 years, range 18-93) and 13 males (average age 57 years, range 19-87). The cells were differentiated in astrocytes, oligodendrocytes, microglia...... while the total astrocyte number is constant through life; finally males have a 28% higher number of neocortical glial cells and a 19% higher neocortical neuron number than females. The overall total number of neocortical neurons and glial cells was 49.3 billion in females and 65.2 billion in males...... and neurons and counting were done in each of the four lobes. The study showed that the different subpopulations of glial cells behave differently as a function of age; the number of oligodendrocytes showed a significant 27% decrease over adult life and a strong correlation to the total number of neurons...

Resection of individually identified high-rate high-frequency oscillations region is associated with favorable outcome in neocortical epilepsy

Czech Academy of Sciences Publication Activity Database

Cho, J.R.; Koo, D.L.; Joo, E.Y.; Seo, D.W.; Hong, S.-Ch.; Jiruška, Přemysl; Hong, S.B.

2014-01-01

Roč. 55, č. 11 (2014), s. 1872-1883 ISSN 0013-9580 R&D Projects: GA MZd(CZ) NT14489 Institutional support: RVO:67985823 Keywords : epilepsy surgery * high-frequency oscillations * neocortical epilepsy Subject RIV: FH - Neurology Impact factor: 4.571, year: 2014

Cell Type-specific Intrinsic Perithreshold Oscillations in Hippocampal GABAergic Interneurons.

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Kang, Young-Jin; Lewis, Hannah Elisabeth Smashey; Young, Mason William; Govindaiah, Gubbi; Greenfield, Lazar John; Garcia-Rill, Edgar; Lee, Sang-Hun

2018-04-15

The hippocampus plays a critical role in learning, memory, and spatial processing through coordinated network activity including theta and gamma oscillations. Recent evidence suggests that hippocampal subregions (e.g., CA1) can generate these oscillations at the network level, at least in part, through GABAergic interneurons. However, it is unclear whether specific GABAergic interneurons generate intrinsic theta and/or gamma oscillations at the single-cell level. Since major types of CA1 interneurons (i.e., parvalbumin-positive basket cells (PVBCs), cannabinoid type 1 receptor-positive basket cells (CB 1 BCs), Schaffer collateral-associated cells (SCAs), neurogliaform cells and ivy cells) are thought to play key roles in network theta and gamma oscillations in the hippocampus, we tested the hypothesis that these cells generate intrinsic perithreshold oscillations at the single-cell level. We performed whole-cell patch-clamp recordings from GABAergic interneurons in the CA1 region of the mouse hippocampus in the presence of synaptic blockers to identify intrinsic perithreshold membrane potential oscillations. The majority of PVBCs (83%), but not the other interneuron subtypes, produced intrinsic perithreshold gamma oscillations if the membrane potential remained above -45 mV. In contrast, CB 1 BCs, SCAs, neurogliaform cells, ivy cells, and the remaining PVBCs (17%) produced intrinsic theta, but not gamma, oscillations. These oscillations were prevented by blockers of persistent sodium current. These data demonstrate that the major types of hippocampal interneurons produce distinct frequency bands of intrinsic perithreshold membrane oscillations. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

PET imaging of neocortical monoaminergic terminals in Parkinson's disease

International Nuclear Information System (INIS)

Marie, R.M.; Barre, L.; Rioux, P.; Allain, P.; Lechevalier, B.; Baron, J.C.

1995-01-01

Post-mortem neurochemical studies in Parkinson's disease (PD) have shown that, in addition to the typical nigro-striatal dopamine denervation, there exists a concomitant neocortical monoamine fibre deafferentation (of variable severity) whose role in motor, and especially in associated cognitive and affective impairment, remains elusive. We have extensively examined whether PET imaging with 11 C-S-Nomifensine ( 11 C-NMF), a radioligand of the dopamine and norepinephrine presynaptic reuptake sites which has been used so far to investigate the striatum, could provide a method for assessing in vivo the neocortical monoamine terminal loss in PD; previously, this has been a little addressed and controversial issue. To this end, we prospectively selected a highly homogeneous sample of nine non-demented, non-depressed idiopathic PD patients with mild to marked side-to-side asymmetry in motor impairment. In addition to recovering the previously-reported correlations with putaminal 11 C-NMF specific uptake asymmetries, the clinical motor asymmetries also significantly correlated in the clinically expected direction to neocortical (especially frontal) 11 C-NMF asymmetries. suggesting the monoamine neocortical denervation might play a direct role in motor impairment in PD. These results demonstrate that it is possible to assess in vivo the neocortical monoamine terminal loss. and to elucidate its potential role in the complex cognitive and affective impairment, in both PD and atypical degenerative parkinsonism. (author)

Statistical mechanics of neocortical interactions: A scaling paradigm applied to electroencephalography

Science.gov (United States)

Ingber, Lester

1991-09-01

A series of papers has developed a statistical mechanics of neocortical interactions (SMNI), deriving aggregate behavior of experimentally observed columns of neurons from statistical electrical-chemical properties of synaptic interactions. While not useful to yield insights at the single-neuron level, SMNI has demonstrated its capability in describing large-scale properties of short-term memory and electroencephalographic (EEG) systematics. The necessity of including nonlinear and stochastic structures in this development has been stressed. In this paper, a more stringent test is placed on SMNI: The algebraic and numerical algorithms previously developed in this and similar systems are brought to bear to fit large sets of EEG and evoked-potential data being collected to investigate genetic predispositions to alcoholism and to extract brain ``signatures'' of short-term memory. Using the numerical algorithm of very fast simulated reannealing, it is demonstrated that SMNI can indeed fit these data within experimentally observed ranges of its underlying neuronal-synaptic parameters, and the quantitative modeling results are used to examine physical neocortical mechanisms to discriminate high-risk and low-risk populations genetically predisposed to alcoholism. Since this study is a control to span relatively long time epochs, similar to earlier attempts to establish such correlations, this discrimination is inconclusive because of other neuronal activity which can mask such effects. However, the SMNI model is shown to be consistent with EEG data during selective attention tasks and with neocortical mechanisms describing short-term memory previously published using this approach. This paper explicitly identifies similar nonlinear stochastic mechanisms of interaction at the microscopic-neuronal, mesoscopic-columnar, and macroscopic-regional scales of neocortical interactions. These results give strong quantitative support for an accurate intuitive picture, portraying

The Genetic Association Between Neocortical Volume and General Cognitive Ability Is Driven by Global Surface Area Rather Than Thickness.

Science.gov (United States)

Vuoksimaa, Eero; Panizzon, Matthew S; Chen, Chi-Hua; Fiecas, Mark; Eyler, Lisa T; Fennema-Notestine, Christine; Hagler, Donald J; Fischl, Bruce; Franz, Carol E; Jak, Amy; Lyons, Michael J; Neale, Michael C; Rinker, Daniel A; Thompson, Wesley K; Tsuang, Ming T; Dale, Anders M; Kremen, William S

2015-08-01

Total gray matter volume is associated with general cognitive ability (GCA), an association mediated by genetic factors. It is expectable that total neocortical volume should be similarly associated with GCA. Neocortical volume is the product of thickness and surface area, but global thickness and surface area are unrelated phenotypically and genetically in humans. The nature of the genetic association between GCA and either of these 2 cortical dimensions has not been examined. Humans possess greater cognitive capacity than other species, and surface area increases appear to be the primary driver of the increased size of the human cortex. Thus, we expected neocortical surface area to be more strongly associated with cognition than thickness. Using multivariate genetic analysis in 515 middle-aged twins, we demonstrated that both the phenotypic and genetic associations between neocortical volume and GCA are driven primarily by surface area rather than thickness. Results were generally similar for each of 4 specific cognitive abilities that comprised the GCA measure. Our results suggest that emphasis on neocortical surface area, rather than thickness, could be more fruitful for elucidating neocortical-GCA associations and identifying specific genes underlying those associations. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A Method to Culture GABAergic Interneurons Derived from the Medial Ganglionic Eminence

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Sira A. Franchi

2018-01-01

Full Text Available Understanding the mechanisms guiding interneuron development is a central aspect of the current research on cortical/hippocampal interneurons, which is highly relevant to brain function and pathology. In this methodological study we have addressed the setup of protocols for the reproducible culture of dissociated cells from murine medial ganglionic eminences (MGEs, to provide a culture system for the analysis of interneurons in vitro. This study includes the detailed protocols for the preparation of the dissociated cells, and for their culture on optimal substrates for cell migration or differentiation. These cultures enriched in interneurons may allow the investigation of the migratory behavior of interneuron precursors and their differentiation in vitro, up to the formation of morphologically identifiable GABAergic synapses. Live imaging of MGE–derived cells plated on proper substrates shows that they are useful to study the migratory behavior of the precursors, as well as the behavior of growth cones during the development of neurites. Most MGE-derived precursors develop into polarized GABAergic interneurons as determined by axonal, dendritic, and GABAergic markers. We present also a comparison of cells from WT and mutant mice as a proof of principle for the use of these cultures for the analysis of the migration and differentiation of GABAergic cells with different genetic backgrounds. The culture enriched in interneurons described here represents a useful experimental system to examine in a relatively easy and fast way the morpho-functional properties of these cells under physiological or pathological conditions, providing a powerful tool to complement the studies in vivo.

Neocortical electrical stimulation for epilepsy : Closed-loop versus open-loop

NARCIS (Netherlands)

Vassileva, Albena; van Blooijs, Dorien; Leijten, Frans; Huiskamp, Geertjan

2018-01-01

The aim of this review is to evaluate whether open-loop or closed-loop neocortical electrical stimulation should be the preferred approach to manage seizures in intractable epilepsy. Twenty cases of open-loop neocortical stimulation with an implanted device have been reported, in 5 case studies.

Neocortical glial cell numbers in human brains.

Science.gov (United States)

Pelvig, D P; Pakkenberg, H; Stark, A K; Pakkenberg, B

2008-11-01

Stereological cell counting was applied to post-mortem neocortices of human brains from 31 normal individuals, age 18-93 years, 18 females (average age 65 years, range 18-93) and 13 males (average age 57 years, range 19-87). The cells were differentiated in astrocytes, oligodendrocytes, microglia and neurons and counting were done in each of the four lobes. The study showed that the different subpopulations of glial cells behave differently as a function of age; the number of oligodendrocytes showed a significant 27% decrease over adult life and a strong correlation to the total number of neurons while the total astrocyte number is constant through life; finally males have a 28% higher number of neocortical glial cells and a 19% higher neocortical neuron number than females. The overall total number of neocortical neurons and glial cells was 49.3 billion in females and 65.2 billion in males, a difference of 24% with a high biological variance. These numbers can serve as reference values in quantitative studies of the human neocortex.

Anatomical and Electrophysiological Clustering of Superficial Medial Entorhinal Cortex Interneurons

Science.gov (United States)

2017-01-01

Abstract Local GABAergic interneurons regulate the activity of spatially-modulated principal cells in the medial entorhinal cortex (MEC), mediating stellate-to-stellate connectivity and possibly enabling grid formation via recurrent inhibitory circuitry. Despite the important role interneurons seem to play in the MEC cortical circuit, the combination of low cell counts and functional diversity has made systematic electrophysiological studies of these neurons difficult. For these reasons, there remains a paucity of knowledge on the electrophysiological profiles of superficial MEC interneuron populations. Taking advantage of glutamic acid decarboxylase 2 (GAD2)-IRES-tdTomato and PV-tdTomato transgenic mice, we targeted GABAergic interneurons for whole-cell patch-clamp recordings and characterized their passive membrane features, basic input/output properties and action potential (AP) shape. These electrophysiologically characterized cells were then anatomically reconstructed, with emphasis on axonal projections and pial depth. K-means clustering of interneuron anatomical and electrophysiological data optimally classified a population of 106 interneurons into four distinct clusters. The first cluster is comprised of layer 2- and 3-projecting, slow-firing interneurons. The second cluster is comprised largely of PV+ fast-firing interneurons that project mainly to layers 2 and 3. The third cluster contains layer 1- and 2-projecting interneurons, and the fourth cluster is made up of layer 1-projecting horizontal interneurons. These results, among others, will provide greater understanding of the electrophysiological characteristics of MEC interneurons, help guide future in vivo studies, and may aid in uncovering the mechanism of grid field formation. PMID:29085901

Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties.

Science.gov (United States)

Casale, Amanda E; Foust, Amanda J; Bal, Thierry; McCormick, David A

2015-11-25

The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast-spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca(2+)-activated K(+) channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons contain three main

Neocortical Development in Brain of Young Children

DEFF Research Database (Denmark)

Kjaer, Majken; Fabricius, Katrine; Sigaard, Rasmus Krarup

2017-01-01

The early postnatal development of neuron and glia numbers is poorly documented in human brain. Therefore we estimated using design-based stereological methods the regional volumes of neocortex and the numbers of neocortical neurons and glial cells for 10 children (4 girls and 6 boys), ranging from...... neonate to 3 years of age. The 10 infants had a mean of 20.7 × 109 neocortical neurons (range 18.0-24.8 × 109) estimated with a coefficient of variation (CV) = 0.11; this range is similar to adult neuron numbers. The glia populations were 10.5 × 109 oligodendrocytes (range 5.0-16.0 × 109; CV = 0.40); 5...

Functional Maps of Neocortical Local Circuitry

Science.gov (United States)

Thomson, Alex M.; Lamy, Christophe

2007-01-01

This review aims to summarize data obtained with different techniques to provide a functional map of the local circuit connections made by neocortical neurones, a reference for those interested in cortical circuitry and the numerical information required by those wishing to model the circuit. A brief description of the main techniques used to study circuitry is followed by outline descriptions of the major classes of neocortical excitatory and inhibitory neurones and the connections that each layer makes with other cortical and subcortical regions. Maps summarizing the projection patterns of each class of neurone within the local circuit and tables of the properties of these local circuit connections are provided. This review relies primarily on anatomical studies that have identified the classes of neurones and their local and long distance connections and on paired intracellular and whole-cell recordings which have documented the properties of the connections between them. A large number of different types of synaptic connections have been described, but for some there are only a few published examples and for others the details that can only be obtained with paired recordings and dye-filling are lacking. A further complication is provided by the range of species, technical approaches and age groups used in these studies. Wherever possible the range of available data are summarised and compared. To fill some of the more obvious gaps for the less well-documented cases, data obtained with other methods are also summarized. PMID:18982117

Synaptic integration of transplanted interneuron progenitor cells into native cortical networks.

Science.gov (United States)

Howard, MacKenzie A; Baraban, Scott C

2016-08-01

Interneuron-based cell transplantation is a powerful method to modify network function in a variety of neurological disorders, including epilepsy. Whether new interneurons integrate into native neural networks in a subtype-specific manner is not well understood, and the therapeutic mechanisms underlying interneuron-based cell therapy, including the role of synaptic inhibition, are debated. In this study, we tested subtype-specific integration of transplanted interneurons using acute cortical brain slices and visualized patch-clamp recordings to measure excitatory synaptic inputs, intrinsic properties, and inhibitory synaptic outputs. Fluorescently labeled progenitor cells from the embryonic medial ganglionic eminence (MGE) were used for transplantation. At 5 wk after transplantation, MGE-derived parvalbumin-positive (PV+) interneurons received excitatory synaptic inputs, exhibited mature interneuron firing properties, and made functional synaptic inhibitory connections to native pyramidal cells that were comparable to those of native PV+ interneurons. These findings demonstrate that MGE-derived PV+ interneurons functionally integrate into subtype-appropriate physiological niches within host networks following transplantation. Copyright © 2016 the American Physiological Society.

SDF1 Reduces Interneuron Leading Process Branching through Dual Regulation of Actin and Microtubules

Science.gov (United States)

Lysko, Daniel E.; Putt, Mary

2014-01-01

Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process. PMID:24695713

SDF1 reduces interneuron leading process branching through dual regulation of actin and microtubules.

Science.gov (United States)

Lysko, Daniel E; Putt, Mary; Golden, Jeffrey A

2014-04-02

Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process.

Convergent microRNA actions coordinate neocortical development.

Science.gov (United States)

Barca-Mayo, Olga; De Pietri Tonelli, Davide

2014-08-01

Neocortical development is a complex process that, at the cellular level, involves tight control of self-renewal, cell fate commitment, survival, differentiation and delamination/migration. These processes require, at the molecular level, the precise regulation of intrinsic signaling pathways and extrinsic factors with coordinated action in a spatially and temporally specific manner. Transcriptional regulation plays an important role during corticogenesis; however, microRNAs (miRNAs) are emerging as important post-transcriptional regulators of various aspects of central nervous system development. miRNAs are a class of small, single-stranded noncoding RNA molecules that control the expression of the majority of protein coding genes (i.e., targets). How do different miRNAs achieve precise control of gene networks during neocortical development? Here, we critically review all the miRNA-target interactions validated in vivo, with relevance to the generation and migration of pyramidal-projection glutamatergic neurons, and for the initial formation of cortical layers in the embryonic development of rodent neocortex. In particular, we focus on convergent miRNA actions, which are still a poorly understood layer of complexity in miRNA signaling, but potentially one of the keys to disclosing how miRNAs achieve the precise coordination of complex biological processes such as neocortical development.

CLASP2 Links Reelin to the Cytoskeleton during Neocortical Development.

Science.gov (United States)

Dillon, Gregory M; Tyler, William A; Omuro, Kerilyn C; Kambouris, John; Tyminski, Camila; Henry, Shawna; Haydar, Tarik F; Beffert, Uwe; Ho, Angela

2017-03-22

The Reelin signaling pathway plays a crucial role in regulating neocortical development. However, little is known about how Reelin controls the cytoskeleton during neuronal migration. Here, we identify CLASP2 as a key cytoskeletal effector in the Reelin signaling pathway. We demonstrate that CLASP2 has distinct roles during neocortical development regulating neuron production and controlling neuron migration, polarity, and morphogenesis. We found downregulation of CLASP2 in migrating neurons leads to mislocalized cells in deeper cortical layers, abnormal positioning of the centrosome-Golgi complex, and aberrant length/orientation of the leading process. We discovered that Reelin regulates several phosphorylation sites within the positively charged serine/arginine-rich region that constitute consensus GSK3β phosphorylation motifs of CLASP2. Furthermore, phosphorylation of CLASP2 regulates its interaction with the Reelin adaptor Dab1 and this association is required for CLASP2 effects on neurite extension and motility. Together, our data reveal that CLASP2 is an essential Reelin effector orchestrating cytoskeleton dynamics during brain development. Copyright © 2017 Elsevier Inc. All rights reserved.

Hilar GABAergic interneuron activity controls spatial learning and memory retrieval.

Directory of Open Access Journals (Sweden)

Yaisa Andrews-Zwilling

Full Text Available Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD, the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear.We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0--a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity.Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD.

Identification of Inhibitory Premotor Interneurons Activated at a Late Phase in a Motor Cycle during Drosophila Larval Locomotion.

Directory of Open Access Journals (Sweden)

Yuki Itakura

Full Text Available Rhythmic motor patterns underlying many types of locomotion are thought to be produced by central pattern generators (CPGs. Our knowledge of how CPG networks generate motor patterns in complex nervous systems remains incomplete, despite decades of work in a variety of model organisms. Substrate borne locomotion in Drosophila larvae is driven by waves of muscular contraction that propagate through multiple body segments. We use the motor circuitry underlying crawling in larval Drosophila as a model to try to understand how segmentally coordinated rhythmic motor patterns are generated. Whereas muscles, motoneurons and sensory neurons have been well investigated in this system, far less is known about the identities and function of interneurons. Our recent study identified a class of glutamatergic premotor interneurons, PMSIs (period-positive median segmental interneurons, that regulate the speed of locomotion. Here, we report on the identification of a distinct class of glutamatergic premotor interneurons called Glutamatergic Ventro-Lateral Interneurons (GVLIs. We used calcium imaging to search for interneurons that show rhythmic activity and identified GVLIs as interneurons showing wave-like activity during peristalsis. Paired GVLIs were present in each abdominal segment A1-A7 and locally extended an axon towards a dorsal neuropile region, where they formed GRASP-positive putative synaptic contacts with motoneurons. The interneurons expressed vesicular glutamate transporter (vGluT and thus likely secrete glutamate, a neurotransmitter known to inhibit motoneurons. These anatomical results suggest that GVLIs are premotor interneurons that locally inhibit motoneurons in the same segment. Consistent with this, optogenetic activation of GVLIs with the red-shifted channelrhodopsin, CsChrimson ceased ongoing peristalsis in crawling larvae. Simultaneous calcium imaging of the activity of GVLIs and motoneurons showed that GVLIs' wave-like activity lagged

Hilar GABAergic Interneuron Activity Controls Spatial Learning and Memory Retrieval

Science.gov (United States)

Andrews-Zwilling, Yaisa; Gillespie, Anna K.; Kravitz, Alexxai V.; Nelson, Alexandra B.; Devidze, Nino; Lo, Iris; Yoon, Seo Yeon; Bien-Ly, Nga; Ring, Karen; Zwilling, Daniel; Potter, Gregory B.; Rubenstein, John L. R.; Kreitzer, Anatol C.; Huang, Yadong

2012-01-01

Background Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear. Methodology and Principal Findings We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0)—a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity. Conclusions and Significance Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD. PMID:22792368

Spatiotemporal dynamics of rhythmic spinal interneurons measured with two-photon calcium imaging and coherence analysis.

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Kwan, Alex C; Dietz, Shelby B; Zhong, Guisheng; Harris-Warrick, Ronald M; Webb, Watt W

2010-12-01

In rhythmic neural circuits, a neuron often fires action potentials with a constant phase to the rhythm, a timing relationship that can be functionally significant. To characterize these phase preferences in a large-scale, cell type-specific manner, we adapted multitaper coherence analysis for two-photon calcium imaging. Analysis of simulated data showed that coherence is a simple and robust measure of rhythmicity for calcium imaging data. When applied to the neonatal mouse hindlimb spinal locomotor network, the phase relationships between peak activity of >1,000 ventral spinal interneurons and motor output were characterized. Most interneurons showed rhythmic activity that was coherent and in phase with the ipsilateral motor output during fictive locomotion. The phase distributions of two genetically identified classes of interneurons were distinct from the ensemble population and from each other. There was no obvious spatial clustering of interneurons with similar phase preferences. Together, these results suggest that cell type, not neighboring neuron activity, is a better indicator of an interneuron's response during fictive locomotion. The ability to measure the phase preferences of many neurons with cell type and spatial information should be widely applicable for studying other rhythmic neural circuits.

Zebrafish Mnx proteins specify one motoneuron subtype and suppress acquisition of interneuron characteristics

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Seredick Steve D

2012-11-01

Full Text Available Abstract Background Precise matching between motoneuron subtypes and the muscles they innervate is a prerequisite for normal behavior. Motoneuron subtype identity is specified by the combination of transcription factors expressed by the cell during its differentiation. Here we investigate the roles of Mnx family transcription factors in specifying the subtypes of individually identified zebrafish primary motoneurons. Results Zebrafish has three Mnx family members. We show that each of them has a distinct and temporally dynamic expression pattern in each primary motoneuron subtype. We also show that two Mnx family members are expressed in identified VeLD interneurons derived from the same progenitor domain that generates primary motoneurons. Surprisingly, we found that Mnx proteins appear unnecessary for differentiation of VeLD interneurons or the CaP motoneuron subtype. Mnx proteins are, however, required for differentiation of the MiP motoneuron subtype. We previously showed that MiPs require two temporally-distinct phases of Islet1 expression for normal development. Here we show that in the absence of Mnx proteins, the later phase of Islet1 expression is initiated but not sustained, and MiPs become hybrids that co-express morphological and molecular features of motoneurons and V2a interneurons. Unexpectedly, these hybrid MiPs often extend CaP-like axons, and some MiPs appear to be entirely transformed to a CaP morphology. Conclusions Our results suggest that Mnx proteins promote MiP subtype identity by suppressing both interneuron development and CaP axon pathfinding. This is, to our knowledge, the first report of transcription factors that act to distinguish CaP and MiP subtype identities. Our results also suggest that MiP motoneurons are more similar to V2 interneurons than are CaP motoneurons.

Parvalbumin-expressing interneurons can act solo while somatostatin-expressing interneurons act in chorus in most cases on cortical pyramidal cells.

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Safari, Mir-Shahram; Mirnajafi-Zadeh, Javad; Hioki, Hiroyuki; Tsumoto, Tadaharu

2017-10-06

Neural circuits in the cerebral cortex consist primarily of excitatory pyramidal (Pyr) cells and inhibitory interneurons. Interneurons are divided into several subtypes, in which the two major groups are those expressing parvalbumin (PV) or somatostatin (SOM). These subtypes of interneurons are reported to play distinct roles in tuning and/or gain of visual response of pyramidal cells in the visual cortex. It remains unclear whether there is any quantitative and functional difference between the PV → Pyr and SOM → Pyr connections. We compared unitary inhibitory postsynaptic currents (uIPSCs) evoked by electrophysiological activation of single presynaptic interneurons with population IPSCs evoked by photo-activation of a mass of interneurons in vivo and in vitro in transgenic mice in which PV or SOM neurons expressed channelrhodopsin-2, and found that at least about 14 PV neurons made strong connections with a postsynaptic Pyr cell while a much larger number of SOM neurons made weak connections. Activation or suppression of single PV neurons modified visual responses of postsynaptic Pyr cells in 6 of 7 pairs whereas that of single SOM neurons showed no significant modification in 8 of 11 pairs, suggesting that PV neurons can act solo whereas most of SOM neurons may act in chorus on Pyr cells.

Inhibitory coupling between inhibitory interneurons in the spinal cord dorsal horn

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Ribeiro-da-Silva Alfredo

2009-05-01

Full Text Available Abstract Local inhibitory interneurons in the dorsal horn play an important role in the control of excitability at the segmental level and thus determine how nociceptive information is relayed to higher structures. Regulation of inhibitory interneuron activity may therefore have critical consequences on pain perception. Indeed, disinhibition of dorsal horn neuronal networks disrupts the balance between excitation and inhibition and is believed to be a key mechanism underlying different forms of pain hypersensitivity and chronic pain states. In this context, studying the source and the synaptic properties of the inhibitory inputs that the inhibitory interneurons receive is important in order to predict the impact of drug action at the network level. To address this, we studied inhibitory synaptic transmission in lamina II inhibitory interneurons identified under visual guidance in spinal slices taken from transgenic mice expressing enhanced green fluorescent protein (EGFP under the control of the GAD promoter. The majority of these cells fired tonically to a long depolarizing current pulse. Monosynaptically evoked inhibitory postsynaptic currents (eIPSCs in these cells were mediated by both GABAA and glycine receptors. Consistent with this, both GABAA and glycine receptor-mediated miniature IPSCs were recorded in all of the cells. These inhibitory inputs originated at least in part from local lamina II interneurons as verified by simultaneous recordings from pairs of EGFP+ cells. These synapses appeared to have low release probability and displayed potentiation and asynchronous release upon repeated activation. In summary, we report on a previously unexamined component of the dorsal horn circuitry that likely constitutes an essential element of the fine tuning of nociception.

Cercal sensory system and giant interneurons in Gryllodes sigillatus.

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Kanou, Masamichi; Nawae, Miyuki; Kuroishi, Hiroyuki

2006-04-01

The external morphologies of two cricket species, Gryllodes sigillatus and Gryllus bimaculatus, were investigated. Despite its small body length, G. sigillatus possessed longer cerci and longer cercal filiform hairs than G. bimaculatus. The estimated number of filiform hairs on a cercus was also larger in G. sigillatus than in G. bimaculatus. Wind-sensitive interneurons receiving sensory inputs from cercal filiform hairs and running in the ventral nerve cord (VNC) were investigated in G. sigillatus both morphologically and physiologically. By intracellular staining, these interneurons were proved to be morphologically homologous with previously identified giant interneurons (GIs 8-1, 9-1, 9-2, 9-3, 10-2, and 10-3) in G. bimaculatus and Acheta domesticus. In G. sigillatus, the intensity-response relationship (I-R curve) for each GI was investigated using a unidirectional air current stimulus. The stimulus was applied from 12 different directions, and an I-R curve was obtained for each stimulus direction. Each GI showed a characteristic I-R curve depending on stimulus direction. The directionality curve expressed in terms of threshold velocity showed that each GI had a distinctive directional characteristic. The functional properties of GIs in G. sigillatus, such as I-R curve, threshold velocity, and directional characteristics, were compared with those of homologous GIs in G. bimaculatus in Discussion.

Functional differences between neurochemically defined populations of inhibitory interneurons in the rat spinal dorsal horn ?

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Polg?r, Erika; Sardella, Thomas C.P.; Tiong, Sheena Y.X.; Locke, Samantha; Watanabe, Masahiko; Todd, Andrew J.

2013-01-01

In order to understand how nociceptive information is processed in the spinal dorsal horn we need to unravel the complex synaptic circuits involving interneurons, which constitute the vast majority of the neurons in laminae I?III. The main limitation has been the difficulty in defining functional populations among these cells. We have recently identified 4 non-overlapping classes of inhibitory interneuron, defined by expression of galanin, neuropeptide Y (NPY), neuronal nitric oxide synthase ...

Interneuron progenitor transplantation to treat CNS dysfunction

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Muhammad O Chohan

2016-08-01

Full Text Available Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field.

Neocortical development as an evolutionary platform for intragenomic conflict

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Eric eLewitus

2013-04-01

Full Text Available Embryonic development in mammals has evolved a platform for genomic conflict between mothers and embryos and, by extension, between maternal and paternal genomes. The evolutionary interests of the mother and embryo may be maximized through the promotion of sex-chromosome genes and imprinted alleles, resulting in the rapid evolution of postzygotic phenotypes preferential to either the maternal or paternal genome. In eutherian mammals, extraordinary in utero maternal investment in the brain, and neocortex especially, suggests that convergent evolution of an expanded mammalian neocortex along divergent lineages may be explained, in part, by parent-of-origin-linked gene expression arising from parent-offspring conflict. The influence of this conflict on neocortical development and evolution, however, has not been investigated at the genomic level. In this hypothesis and theory article, we provide preliminary evidence for positive selection in humans in the regions of two platforms of intragenomic conflict – chromosomes 15q11-q13 and X – and explore the potential relevance of cis-regulated imprinted domains to neocortical expansion in mammalian evolution. We present the hypothesis that maternal- and paternal-specific pressures on the developing neocortex compete intragenomically to influence neocortical expansion in mammalian evolution.

Immunohistochemical visualization of mouse interneuron subtypes

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Jensen, Simon Mølgaard; Ulrichsen, Maj; Boggild, Simon

2014-01-01

, and calretinin are also commonly used as markers to narrow down the specific interneuron subtype. Here, we describe a journey to find the necessary immunological reagents for studying GABAergic interneurons of the mouse hippocampus. Based on web searches there are several hundreds of different antibodies...... of the hippocampus where they have previously been described. Additionally, the antibodies were also tested on sections from mouse spinal cord with similar criteria for specificity of the antibodies. Using the antibodies with a high rating on pAbmAbs, stainings with high signal-to-noise ratios and location...

Radial glial dependent and independent dynamics of interneuronal migration in the developing cerebral cortex.

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Yukako Yokota

2007-08-01

Full Text Available Interneurons originating from the ganglionic eminence migrate tangentially into the developing cerebral wall as they navigate to their distinct positions in the cerebral cortex. Compromised connectivity and differentiation of interneurons are thought to be an underlying cause in the emergence of neurodevelopmental disorders such as schizophrenia. Previously, it was suggested that tangential migration of interneurons occurs in a radial glia independent manner. Here, using simultaneous imaging of genetically defined populations of interneurons and radial glia, we demonstrate that dynamic interactions with radial glia can potentially influence the trajectory of interneuronal migration and thus the positioning of interneurons in cerebral cortex. Furthermore, there is extensive local interneuronal migration in tangential direction opposite to that of pallial orientation (i.e., in a medial to lateral direction from cortex to ganglionic eminence all across the cerebral wall. This counter migration of interneurons may be essential to locally position interneurons once they invade the developing cerebral wall from the ganglionic eminence. Together, these observations suggest that interactions with radial glial scaffold and localized migration within the expanding cerebral wall may play essential roles in the guidance and placement of interneurons in the developing cerebral cortex.

Diversity and overlap of Parvalbumin and Somatostatin expressing interneurons in mouse presubiculum

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Mérie eNassar

2015-05-01

Full Text Available The presubiculum, located between hippocampus and entorhinal cortex, plays a fundamental role in representing spatial information, notably head direction. Little is known about GABAergic interneurons of this region. Here, we used three transgenic mouse lines, Pvalb-Cre, Sst-Cre and X98, to examine distinct interneurons labeled with tdTomato or green fluorescent protein. The distribution of interneurons in presubicular lamina for each animal line was compared to that in the GAD67-GFP knock-in animal line. Labelling was specific in the Pvalb-Cre line with 87% of labeled interneurons immunopositive for (PV. Immunostaining for somatostatin (SOM revealed good specificity in the X98 line with 89% of fluorescent cells, but a lesser specificity in Sst-Cre animals where only 71% of labeled cells were immunopositive. A minority of ~ 6% of interneurons co-expressed PV and SOM in the presubiculum of Sst-Cre animals. The electrophysiological and morphological properties of fluorescent interneurons from Pvalb-Cre, Sst-Cre and X98 mice differed. Distinct physiological groups of presubicular interneurons were resolved by unsupervised cluster analysis of parameters describing passive properties, firing patterns and AP shapes. One group consisted of SOM-positive, Martinotti type neurons with a low firing threshold (cluster 1. Fast spiking basket cells, mainly from the Pvalb-Cre line, formed a distinct group (cluster 3. Another group (cluster 2 contained interneurons of intermediate electrical properties and basket-cell like morphologies. These labeled neurons were recorded from both Sst-Cre and Pvalb-Cre animals. Thus, our results reveal a wide variation in anatomical and physiological properties for these interneurons, a real overlap of interneurons immuno-positive for both PV and SOM as well as an off-target recombination in the Sst-Cre line, possibly linked to maternal cre inheritance.

Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease

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Lax, Nichola Z.; Grady, John; Laude, Alex; Chan, Felix; Hepplewhite, Philippa D.; Gorman, Grainne; Whittaker, Roger G.; Ng, Yi; Cunningham, Mark O.

2015-01-01

Aims Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ‐aminobutyric acid (GABA)‐ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease. Methods Histochemical, immunohistochemical and immunofluorescent assays were performed on post‐mortem brain tissue from 10 patients and 10 age‐matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABAergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring. Results We observed significant, global reductions in complex I expression within GABAergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344A>G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABAergic cell density showed a dramatic reduction in cell density suggesting interneurone loss. Conclusions We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease. PMID:25786813

Disrupted Co-activation of Interneurons and Hippocampal Network after Focal Kainate Lesion

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Lim-Anna Sieu

2017-11-01

Full Text Available GABAergic interneurons are known to control activity balance in physiological conditions and to coordinate hippocampal networks during cognitive tasks. In temporal lobe epilepsy interneuron loss and consecutive network imbalance could favor pathological hypersynchronous epileptic discharges. We tested this hypothesis in mice by in vivo unilateral epileptogenic hippocampal kainate lesion followed by in vitro recording of extracellular potentials and patch-clamp from GFP-expressing interneurons in CA3, in an optimized recording chamber. Slices from lesioned mice displayed, in addition to control synchronous events, larger epileptiform discharges. Despite some ipsi/contralateral and layer variation, interneuron density tended to decrease, average soma size to increase. Their membrane resistance decreased, capacitance increased and contralateral interneuron required higher current intensity to fire action potentials. Examination of synchronous discharges of control and larger amplitudes, revealed that interneurons were biased to fire predominantly with the largest population discharges. Altogether, these observations suggest that the overall effect of reactive cell loss, hypertrophy and reduced contralateral excitability corresponds to interneuron activity tuning to fire with larger population discharges. Such cellular and network mechanisms may contribute to a runaway path toward epilepsy.

Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate

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Timothy J. Petros

2015-11-01

Full Text Available Fate determination in the mammalian telencephalon, with its diversity of neuronal subtypes and relevance to neuropsychiatric disease, remains a critical area of study in neuroscience. Most studies investigating this topic focus on the diversity of neural progenitors within spatial and temporal domains along the lateral ventricles. Often overlooked is whether the location of neurogenesis within a fate-restricted domain is associated with, or instructive for, distinct neuronal fates. Here, we use in vivo fate mapping and the manipulation of neurogenic location to demonstrate that apical versus basal neurogenesis influences the fate determination of major subgroups of cortical interneurons derived from the subcortical telencephalon. Somatostatin-expressing interneurons arise mainly from apical divisions along the ventricular surface, whereas parvalbumin-expressing interneurons originate predominantly from basal divisions in the subventricular zone. As manipulations that shift neurogenic location alter interneuron subclass fate, these results add an additional dimension to the spatial-temporal determinants of neuronal fate determination.

Effects of gap junction blockers on human neocortical synchronization.

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Gigout, S; Louvel, J; Kawasaki, H; D'Antuono, M; Armand, V; Kurcewicz, I; Olivier, A; Laschet, J; Turak, B; Devaux, B; Pumain, R; Avoli, M

2006-06-01

Field potentials and intracellular recordings were obtained from human neocortical slices to study the role of gap junctions (GJ) in neuronal network synchronization. First, we examined the effects of GJ blockers (i.e., carbenoxolone, octanol, quinine, and quinidine) on the spontaneous synchronous events (duration = 0.2-1.1 s; intervals of occurrence = 3-27 s) generated by neocortical slices obtained from temporal lobe epileptic patients during application of 4-aminopyridine (4AP, 50 muM) and glutamatergic receptor antagonists. The synchronicity of these potentials (recorded at distances up to 5 mm) was decreased by GJ blockers within 20 min of application, while prolonged GJ blockers treatment at higher doses made them disappear with different time courses. Second, we found that slices from patients with focal cortical dysplasia (FCD) could generate in normal medium spontaneous synchronous discharges (duration = 0.4-8 s; intervals of occurrence = 0.5-90 s) that were (i) abolished by NMDA receptor antagonists and (ii) slowed down by carbenoxolone. Finally, octanol or carbenoxolone blocked 4AP-induced ictal-like discharges (duration = up to 35 s) in FCD slices. These data indicate that GJ play a role in synchronizing human neocortical networks and may implement epileptiform activity in FCD.

Functional characterization of dI6 interneurons in the neonatal mouse spinal cord.

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Dyck, Jason; Lanuza, Guillermo M; Gosgnach, Simon

2012-06-01

Our understanding of the neural control of locomotion has been greatly enhanced by the ability to identify and manipulate genetically defined populations of interneurons that comprise the locomotor central pattern generator (CPG). To date, the dI6 interneurons are one of the few populations that settle in the ventral region of the postnatal spinal cord that have not been investigated. In the present study, we utilized a novel transgenic mouse line to electrophysiologically characterize dI6 interneurons located close to the central canal and study their function during fictive locomotion. The majority of dI6 cells investigated were found to be rhythmically active during fictive locomotion and could be divided into two electrophysiologically distinct populations of interneurons. The first population fired rhythmic trains of action potentials that were loosely coupled to ventral root output and contained several intrinsic membrane properties of rhythm-generating neurons, raising the possibility that these cells may be involved in the generation of rhythmic activity in the locomotor CPG. The second population fired rhythmic trains of action potentials that were tightly coupled to ventral root output and lacked intrinsic oscillatory mechanisms, indicating that these neurons may be driven by a rhythm-generating network. Together these results indicate that dI6 neurons comprise an important component of the locomotor CPG that participate in multiple facets of motor behavior.

Computational modeling of distinct neocortical oscillations driven by cell-type selective optogenetic drive: Separable resonant circuits controlled by low-threshold spiking and fast-spiking interneurons

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Dorea Vierling-Claassen

2010-11-01

Full Text Available Selective optogenetic drive of fast spiking interneurons (FS leads to enhanced local field potential (LFP power across the traditional gamma frequency band (20-80Hz; Cardin et al., 2009. In contrast, drive to regular-spiking pyramidal cells (RS enhances power at lower frequencies, with a peak at 8 Hz. The first result is consistent with previous computational studies emphasizing the role of FS and the time constant of GABAA synaptic inhibition in gamma rhythmicity. However, the same theoretical models do not typically predict low-frequency LFP enhancement with RS drive. To develop hypotheses as to how the same network can support these contrasting behaviors, we constructed a biophysically principled network model of primary somatosensory neocortex containing FS, RS and low-threshold-spiking (LTS interneurons. Cells were modeled with detailed cell anatomy and physiology, multiple dendritic compartments, and included active somatic and dendritic ionic currents. Consistent with prior studies, the model demonstrated gamma resonance during FS drive, dependent on the time-constant of GABAA inhibition induced by synchronous FS activity. Lower frequency enhancement during RS drive was replicated only on inclusion of an inhibitory LTS population, whose activation was critically dependent on RS synchrony and evoked longer-lasting inhibition. Our results predict that differential recruitment of FS and LTS inhibitory populations is essential to the observed cortical dynamics and may provide a means for amplifying the natural expression of distinct oscillations in normal cortical processing.

Cortical interneurons from human pluripotent stem cells: prospects for neurological and psychiatric disease

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Charles Edward Arber

2013-03-01

Full Text Available Cortical interneurons represent 20% of the cells in the cortex. These cells are local inhibitory neurons whose function is to modulate the firing activities of the excitatory projection neurons. Cortical interneuron dysfunction is believed to lead to runaway excitation underlying (or implicated in seizure-based diseases, such as epilepsy, autism and schizophrenia. The complex development of this cell type and the intricacies involved in defining the relative subtypes are being increasingly well defined. This has led to exciting experimental cell therapy in model organisms, whereby fetal-derived interneuron precursors can reverse seizure severity and reduce mortality in adult epileptic rodents. These proof-of-principle studies raise hope for potential interneuron-based transplantation therapies for treating epilepsy. On the other hand, cortical neurons generated from patient iPSCs serve as a valuable tool to explore genetic influences of interneuron development and function. This is a fundamental step in enhancing our understanding of the molecular basis of neuropsychiatric illnesses and the development of targeted treatments. Protocols are currently being developed for inducing cortical interneuron subtypes from mouse and human pluripotent stem cells. This review sets out to summarize the progress made in cortical interneuron development, fetal tissue transplantation and the recent advance in stem cell differentiation towards interneurons.

The neocortical network representing associative memory reorganizes with time in a process engaging the anterior temporal lobe.

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Nieuwenhuis, Ingrid L C; Takashima, Atsuko; Oostenveld, Robert; McNaughton, Bruce L; Fernández, Guillén; Jensen, Ole

2012-11-01

During encoding, the distributed neocortical representations of memory components are presumed to be associatively linked by the hippocampus. With time, a reorganization of brain areas supporting memory takes place, which can ultimately result in memories becoming independent of the hippocampus. While it is theorized that with time, the neocortical representations become linked by higher order neocortical association areas, this remains to be experimentally supported. In this study, 24 human participants encoded sets of face-location associations, which they retrieved 1 or 25 h later ("recent" and "remote" conditions, respectively), while their brain activity was recorded using whole-head magnetoencephalography. We investigated changes in the functional interactions between the neocortical representational areas emerging over time. To assess functional interactions, trial-by-trial high gamma (60-140 Hz) power correlations were calculated between the neocortical representational areas relevant to the encoded information, namely the fusiform face area (FFA) and posterior parietal cortex (PPC). With time, both the FFA and the PPC increased their functional interactions with the anterior temporal lobe (ATL). Given that the ATL is involved in semantic representation of paired associates, our results suggest that, already within 25 h after acquiring new memory associations, neocortical functional links are established via higher order semantic association areas.

Responses of Withdrawal Interneurons to Serotonin Applications in Naïve and Learned Snails Are Different

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Tatiana K. Bogodvid

2017-12-01

Full Text Available Long-term changes in membrane potential after associative training were described previously in identified premotor interneurons for withdrawal of the terrestrial snail Helix. Serotonin was shown to be a major transmitter involved in triggering the long-term changes in mollusks. In the present study we compared the changes in electrophysiological characteristics of identifiable premotor interneurons for withdrawal in response to bath applications of serotonin (5-HT or serotonin precursor 5-hydroxytryptophan (5-HTP in preparations from naïve, neurotoxin-injected or associatively trained snails. It was found that 5-HT or 5-HTP applications caused a significant decrease of membrane potential in premotor interneurons of naïve snails, associatively trained snails and snails with impaired serotonergic system by injection of a selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT 1 week before the experiments. Applications of 5-HT or 5-HTP did not cause significant changes in the action potential (AP threshold potential of these neurons in naïve snails. Conversely, applications of 5-HT or 5-HTP to the premotor interneurons of previously trained or 5,7-DHT-injected snails caused a significant increase in the firing threshold potential in spite of a depolarizing shift of the resting membrane potential. Results demonstrate that responsiveness of premotor interneurons to extracellularly applied 5-HT or 5-HTP changes for days after the associative training or serotonin depletion. Similarity of the effects in trained and 5,7-DHT-injected animals may be due to massive release of serotonin elicited by 5,7-DHT injection. Our results suggest that serotonin release due to aversive conditionining or elicited by the neurotoxin administration triggers similar changes in resting membrane potential and AP threshold in response to bath applications of 5-HT or its precursor 5-HTP.

Enhancement of Neocortical-Medial Temporal EEG Correlations during Non-REM Sleep

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Nikolai Axmacher

2008-01-01

Full Text Available Interregional interactions of oscillatory activity are crucial for the integrated processing of multiple brain regions. However, while the EEG in virtually all brain structures passes through substantial modifications during sleep, it is still an open question whether interactions between neocortical and medial temporal EEG oscillations also depend on the state of alertness. Several previous studies in animals and humans suggest that hippocampal-neocortical interactions crucially depend on the state of alertness (i.e., waking state or sleep. Here, we analyzed scalp and intracranial EEG recordings during sleep and waking state in epilepsy patients undergoing presurgical evaluation. We found that the amplitudes of oscillations within the medial temporal lobe and the neocortex were more closely correlated during sleep, in particular during non-REM sleep, than during waking state. Possibly, the encoding of novel sensory inputs, which mainly occurs during waking state, requires that medial temporal dynamics are rather independent from neocortical dynamics, while the consolidation of memories during sleep may demand closer interactions between MTL and neocortex.

Distinct roles of SOM and VIP interneurons during cortical Up states

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Garrett T. Neske

2016-07-01

Full Text Available During cortical network activity, recurrent synaptic excitation among pyramidal neurons is approximately balanced by synaptic inhibition, which is provided by a vast diversity of inhibitory interneurons. The relative contributions of different interneuron subtypes to inhibitory tone during cortical network activity is not well understood. We previously showed that many of the major interneuron subtypes in mouse barrel cortex are highly active during Up states (Neske et al., 2015; while fast-spiking (FS, parvalbumin (PV-positive cells were the most active interneuron subtype, many non-fast-spiking (NFS, PV-negative interneurons were as active or more active than neighboring pyramidal cells. This suggests that the NFS cells could play a role in maintaining or modulating Up states. Here, using optogenetic techniques, we further dissected the functional roles during Up states of two major NFS, PV-negative interneuron subtypes: somatostatin (SOM-positive cells and vasoactive intestinal peptide (VIP-positive cells. We found that while pyramidal cell excitability during Up states significantly increased when SOM cells were optogenetically silenced, VIP cells did not influence pyramidal cell excitability either upon optogenetic silencing or activation. VIP cells failed to contribute to Up states despite their ability to inhibit SOM cells strongly. We suggest that the contribution of VIP cells to the excitability of pyramidal cells may vary with cortical state.

Anatomical Recruitment of Spinal V2a Interneurons into Phrenic Motor Circuitry after High Cervical Spinal Cord Injury.

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Zholudeva, Lyandysha V; Karliner, Jordyn S; Dougherty, Kimberly J; Lane, Michael A

2017-11-01

More than half of all spinal cord injuries (SCIs) occur at the cervical level, often resulting in impaired respiration. Despite this devastating outcome, there is substantial evidence for endogenous neuroplasticity after cervical SCI. Spinal interneurons are widely recognized as being an essential anatomical component of this plasticity by contributing to novel neuronal pathways that can result in functional improvement. The identity of spinal interneurons involved with respiratory plasticity post-SCI, however, has remained largely unknown. Using a transgenic Chx10-eGFP mouse line (Strain 011391-UCD), the present study is the first to demonstrate the recruitment of excitatory interneurons into injured phrenic circuitry after a high cervical SCI. Diaphragm electromyography and anatomical analysis were used to confirm lesion-induced functional deficits and document extent of the lesion, respectively. Transneuronal tracing with pseudorabies virus (PRV) was used to identify interneurons within the phrenic circuitry. There was a robust increase in the number of PRV-labeled V2a interneurons ipsilateral to the C2 hemisection, demonstrating that significant numbers of these excitatory spinal interneurons were anatomically recruited into the phrenic motor pathway two weeks after injury, a time known to correspond with functional phrenic plasticity. Understanding this anatomical spinal plasticity and the neural substrates associated with functional compensation or recovery post-SCI in a controlled, experimental setting may help shed light onto possible cellular therapeutic candidates that can be targeted to enhance spontaneous recovery.

The Outwardly Rectifying Current of Layer 5 Neocortical Neurons that was Originally Identified as "Non-Specific Cationic" Is Essentially a Potassium Current.

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Omer Revah

Full Text Available In whole-cell patch clamp recordings from layer 5 neocortical neurons, blockade of voltage gated sodium and calcium channels leaves a cesium current that is outward rectifying. This current was originally identified as a "non-specific cationic current", and subsequently it was hypothesized that it is mediated by TRP channels. In order to test this hypothesis, we used fluorescence imaging of intracellular sodium and calcium indicators, and found no evidence to suggest that it is associated with influx of either of these ions to the cell body or dendrites. Moreover, the current is still prominent in neurons from TRPC1-/- and TRPC5-/- mice. The effects on the current of various blocking agents, and especially its sensitivity to intracellular tetraethylammonium, suggest that it is not a non-specific cationic current, but rather that it is generated by cesium-permeable delayed rectifier potassium channels.

Neocortical neuron types in Xenarthra and Afrotheria: implications for brain evolution in mammals.

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Sherwood, Chet C; Stimpson, Cheryl D; Butti, Camilla; Bonar, Christopher J; Newton, Alisa L; Allman, John M; Hof, Patrick R

2009-02-01

Interpreting the evolution of neuronal types in the cerebral cortex of mammals requires information from a diversity of species. However, there is currently a paucity of data from the Xenarthra and Afrotheria, two major phylogenetic groups that diverged close to the base of the eutherian mammal adaptive radiation. In this study, we used immunohistochemistry to examine the distribution and morphology of neocortical neurons stained for nonphosphorylated neurofilament protein, calbindin, calretinin, parvalbumin, and neuropeptide Y in three xenarthran species-the giant anteater (Myrmecophaga tridactyla), the lesser anteater (Tamandua tetradactyla), and the two-toed sloth (Choloepus didactylus)-and two afrotherian species-the rock hyrax (Procavia capensis) and the black and rufous giant elephant shrew (Rhynchocyon petersi). We also studied the distribution and morphology of astrocytes using glial fibrillary acidic protein as a marker. In all of these species, nonphosphorylated neurofilament protein-immunoreactive neurons predominated in layer V. These neurons exhibited diverse morphologies with regional variation. Specifically, high proportions of atypical neurofilament-enriched neuron classes were observed, including extraverted neurons, inverted pyramidal neurons, fusiform neurons, and other multipolar types. In addition, many projection neurons in layers II-III were found to contain calbindin. Among interneurons, parvalbumin- and calbindin-expressing cells were generally denser compared to calretinin-immunoreactive cells. We traced the evolution of certain cortical architectural traits using phylogenetic analysis. Based on our reconstruction of character evolution, we found that the living xenarthrans and afrotherians show many similarities to the stem eutherian mammal, whereas other eutherian lineages display a greater number of derived traits.

Intracerebroventricular kainic acid administration to neonatal rats alters interneuron development in the hippocampus.

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Dong, Hongxin; Csernansky, Cynthia A; Chu, Yunxiang; Csernansky, John G

2003-10-10

The effects of neonatal exposure to excitotoxins on the development of interneurons have not been well characterized, but may be relevant to the pathogenesis of neuropsychiatric disorders. In this study, the excitotoxin, kainic acid (KA) was administered to rats at postnatal day 7 (P7) by intracerebroventricular (i.c.v.) infusion. At P14, P25, P40 and P60, Nissl staining and immunohistochemical studies with the interneuron markers, glutamic acid decarboxylase (GAD-67), calbindin-D28k (CB) and parvalbumin (PV) were performed in the hippocampus. In control animals, the total number of interneurons, as well as the number of interneurons stained with GAD-67, CB and PV, was nearly constant from P14 through P60. In KA-treated rats, Nissl staining, GAD-67 staining, and CB staining revealed a progressive decline in the overall number of interneurons in the CA1 and CA3 subfields from P14 to P60. In contrast, PV staining in KA-treated rats showed initial decreases in the number of interneurons in the CA1 and CA3 subfields at P14 followed by increases that approached control levels by P60. These results suggest that, in general, early exposure to the excitotoxin KA decreases the number of hippocampal interneurons, but has a more variable effect on the specific population of interneurons labeled by PV. The functional impact of these changes may be relevant to the pathogenesis of neuropsychiatric disorders, such as schizophrenia.

Acetylcholine release and inhibitory interneuron activity in hippocampal CA1

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A. Rory McQuiston

2014-09-01

Full Text Available Acetylcholine release in the central nervous system (CNS has an important role in attention, recall and memory formation. One region influenced by acetylcholine is the hippocampus, which receives inputs from the medial septum and diagonal band of Broca complex (MS/DBB. Release of acetylcholine from the MS/DBB can directly affect several elements of the hippocampus including glutamatergic and GABAergic neurons, presynaptic terminals, postsynaptic receptors and astrocytes. A significant portion of acetylcholine’s effect likely results from the modulation of GABAergic inhibitory interneurons, which have crucial roles in controlling excitatory inputs, synaptic integration, rhythmic coordination of principal neurons and outputs in the hippocampus. Acetylcholine affects interneuron function in large part by altering their membrane potential via muscarinic and nicotinic receptor activation. This minireview describes recent data from mouse hippocampus that investigated changes in CA1 interneuron membrane potentials following acetylcholine release. The interneuron subtypes affected, the receptor subtypes activated, and the potential outcome on hippocampal CA1 network function is discussed.

Interneuronal Mechanism for Tinbergen’s Hierarchical Model of Behavioral Choice

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Pirger, Zsolt; Crossley, Michael; László, Zita; Naskar, Souvik; Kemenes, György; O’Shea, Michael; Benjamin, Paul R.; Kemenes, Ildikó

2014-01-01

Summary Recent studies of behavioral choice support the notion that the decision to carry out one behavior rather than another depends on the reconfiguration of shared interneuronal networks [1]. We investigated another decision-making strategy, derived from the classical ethological literature [2, 3], which proposes that behavioral choice depends on competition between autonomous networks. According to this model, behavioral choice depends on inhibitory interactions between incompatible hierarchically organized behaviors. We provide evidence for this by investigating the interneuronal mechanisms mediating behavioral choice between two autonomous circuits that underlie whole-body withdrawal [4, 5] and feeding [6] in the pond snail Lymnaea. Whole-body withdrawal is a defensive reflex that is initiated by tactile contact with predators. As predicted by the hierarchical model, tactile stimuli that evoke whole-body withdrawal responses also inhibit ongoing feeding in the presence of feeding stimuli. By recording neurons from the feeding and withdrawal networks, we found no direct synaptic connections between the interneuronal and motoneuronal elements that generate the two behaviors. Instead, we discovered that behavioral choice depends on the interaction between two unique types of interneurons with asymmetrical synaptic connectivity that allows withdrawal to override feeding. One type of interneuron, the Pleuro-Buccal (PlB), is an extrinsic modulatory neuron of the feeding network that completely inhibits feeding when excited by touch-induced monosynaptic input from the second type of interneuron, Pedal-Dorsal12 (PeD12). PeD12 plays a critical role in behavioral choice by providing a synaptic pathway joining the two behavioral networks that underlies the competitive dominance of whole-body withdrawal over feeding. PMID:25155505

NMDAR hypofunction and somatostatin-expressing GABAergic interneurons and receptors: A newly identified correlation and its effects in schizophrenia

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Fatemah Alherz

2017-06-01

Full Text Available This review investigates the association between N-methyl-d-Aspartate receptor (NMDAR hypofunction and somatostatin-expressing GABAergic interneurons (SST+ and how it contributes to the cognitive deficits observed in schizophrenia (SZ. This is based on evidence that NMDAR antagonists caused symptoms resembling SZ in healthy individuals. NMDAR hypofunction in GABAergic interneurons results in the modulation of the cortical network oscillation, particularly in the gamma range (30–80 Hz. These gamma-band oscillation (GBO abnormalities were found to lead to the cognitive deficits observed in the disorder. Postmortem mRNA studies have shown that SST decreased more significantly than any other biomarker in schizophrenic subjects. The functional role of Somatostatin (SST in the aetiology of SZ can be studied through its receptors. Genetic knockout studies in animal models in Huntington's disease (HD have shown that a specific SST receptor, SSTR2, is increased along with the increased NMDAR activity, with opposing patterns observed in SZ. A direct correlation between SSTR and NMDAR is hence inferred in this review with the hope of finding a potential new therapeutic target for the treatment of SZ and related neurological conditions.

Glycine Receptor α2 Subunit Activation Promotes Cortical Interneuron Migration

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Ariel Avila

2013-08-01

Full Text Available Glycine receptors (GlyRs are detected in the developing CNS before synaptogenesis, but their function remains elusive. This study demonstrates that functional GlyRs are expressed by embryonic cortical interneurons in vivo. Furthermore, genetic disruption of these receptors leads to interneuron migration defects. We discovered that extrasynaptic activation of GlyRs containing the α2 subunit in cortical interneurons by endogenous glycine activates voltage-gated calcium channels and promotes calcium influx, which further modulates actomyosin contractility to fine-tune nuclear translocation during migration. Taken together, our data highlight the molecular events triggered by GlyR α2 activation that control cortical tangential migration during embryogenesis.

Hilar Interneuron Vulnerability Distinguishes Aged Rats With Memory Impairment

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Spiegel, Amy M.; Koh, Ming Teng; Vogt, Nicholas M.; Rapp, Peter R.; Gallagher, Michela

2016-01-01

Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred, aged, male Long-Evans rats exhibit a spectrum of individual differences in hippocampal-dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67- and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory-impaired rats. Age-related decreases in GAD67- and somatostatin-immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment. PMID:23749483

Hippocampal-neocortical functional reorganization underlies children's cognitive development.

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Qin, Shaozheng; Cho, Soohyun; Chen, Tianwen; Rosenberg-Lee, Miriam; Geary, David C; Menon, Vinod

2014-09-01

The importance of the hippocampal system for rapid learning and memory is well recognized, but its contributions to a cardinal feature of children's cognitive development-the transition from procedure-based to memory-based problem-solving strategies-are unknown. Here we show that the hippocampal system is pivotal to this strategic transition. Longitudinal functional magnetic resonance imaging (fMRI) in 7-9-year-old children revealed that the transition from use of counting to memory-based retrieval parallels increased hippocampal and decreased prefrontal-parietal engagement during arithmetic problem solving. Longitudinal improvements in retrieval-strategy use were predicted by increased hippocampal-neocortical functional connectivity. Beyond childhood, retrieval-strategy use continued to improve through adolescence into adulthood and was associated with decreased activation but more stable interproblem representations in the hippocampus. Our findings provide insights into the dynamic role of the hippocampus in the maturation of memory-based problem solving and establish a critical link between hippocampal-neocortical reorganization and children's cognitive development.

Dynamic interneuron-principal cell interplay leads to a specific pattern of in vitro ictogenesis.

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Lévesque, Maxime; Chen, Li-Yuan; Hamidi, Shabnam; Avoli, Massimo

2018-07-01

Ictal discharges induced by 4-aminopyridine in the in vitro rodent entorhinal cortex present with either low-voltage fast or sudden onset patterns. The role of interneurons in initiating low-voltage fast onset ictal discharges is well established but the processes leading to sudden onset ictal discharges remain unclear. We analysed here the participation of interneurons (n = 75) and principal cells (n = 13) in the sudden onset pattern by employing in vitro tetrode wire recordings in the entorhinal cortex of brain slices from Sprague-Dawley rats. Ictal discharges emerged from a background of frequently occurring interictal spikes that were associated to a specific interneuron/principal cell interplay. High rates of interneuron firing occurred 12 ms before interictal spike onset while principal cells fired later during low interneuron firing. In contrast, the onset of sudden ictal discharges was characterized by increased firing from principal cells 627 ms before ictal onset whereas interneurons increased their firing rates 161 ms before ictal onset. Our data show that sudden onset ictogenesis is associated with frequently occurring interictal spikes resting on the interplay between interneurons and principal cells while ictal discharges stem from enhanced principal cell firing leading to increased interneuron activity. These findings indicate that specific patterns of interactions between interneurons and principal cells shape interictal and ictal discharges with sudden onset in the rodent entorhinal cortex. We propose that specific neuronal interactions lead to the generation of distinct onset patterns in focal epileptic disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

Bringing up the rear: new premotor interneurons add regional complexity to a segmentally distributed motor pattern

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Norris, Brian J.; Doloc-Mihu, Anca; Calabrese, Ronald L.

2011-01-01

Central pattern generators (CPGs) pace and pattern many rhythmic activities. We have uncovered a new module in the heartbeat CPG of leeches that creates a regional difference in this segmentally distributed motor pattern. The core CPG consists of seven identified pairs and one unidentified pair of heart interneurons of which 5 pairs are premotor and inhibit 16 pairs of heart motor neurons. The heartbeat CPG produces a side-to-side asymmetric pattern of activity of the premotor heart interneurons corresponding to an asymmetric fictive motor pattern and an asymmetric constriction pattern of the hearts with regular switches between the two sides. The premotor pattern progresses from rear to front on one side and nearly synchronously on the other; the motor pattern shows corresponding intersegmental coordination, but only from segment 15 forward. In the rearmost segments the fictive motor pattern and the constriction pattern progress from front to rear on both sides and converge in phase. Modeling studies suggested that the known inhibitory inputs to the rearmost heart motor neurons were insufficient to account for this activity. We therefore reexamined the constriction pattern of intact leeches. We also identified electrophysiologically two additional pairs of heart interneurons in the rear. These new heart interneurons make inhibitory connections with the rear heart motor neurons, are coordinated with the core heartbeat CPG, and are dye-coupled to their contralateral homologs. Their strong inhibitory connections with the rearmost heart motor neurons and the small side-to-side phase difference of their bursting contribute to the different motor and beating pattern observed in the animal's rear. PMID:21775711

Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations.

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Stark, Eran; Roux, Lisa; Eichler, Ronny; Senzai, Yuta; Royer, Sebastien; Buzsáki, György

2014-07-16

High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation, frequency control, and spatial coherence of the rhythm are poorly understood. Using multisite optogenetic manipulations in freely behaving rodents, we found that depolarization of a small group of nearby pyramidal cells was sufficient to induce high-frequency oscillations, whereas closed-loop silencing of pyramidal cells or activation of parvalbumin- (PV) or somatostatin-immunoreactive interneurons aborted spontaneously occurring ripples. Focal pharmacological blockade of GABAA receptors abolished ripples. Localized PV interneuron activation paced ensemble spiking, and simultaneous induction of high-frequency oscillations at multiple locations resulted in a temporally coherent pattern mediated by phase-locked interneuron spiking. These results constrain competing models of ripple generation and indicate that temporally precise local interactions between excitatory and inhibitory neurons support ripple generation in the intact hippocampus. Copyright © 2014 Elsevier Inc. All rights reserved.

Transcriptional and Post-Transcriptional Mechanisms of the Development of Neocortical Lamination

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Tatiana Popovitchenko

2017-11-01

Full Text Available The neocortex is a laminated brain structure that is the seat of higher cognitive capacity and responses, long-term memory, sensory and emotional functions, and voluntary motor behavior. Proper lamination requires that progenitor cells give rise to a neuron, that the immature neuron can migrate away from its mother cell and past other cells, and finally that the immature neuron can take its place and adopt a mature identity characterized by connectivity and gene expression; thus lamination proceeds through three steps: genesis, migration, and maturation. Each neocortical layer contains pyramidal neurons that share specific morphological and molecular characteristics that stem from their prenatal birth date. Transcription factors are dynamic proteins because of the cohort of downstream factors that they regulate. RNA-binding proteins are no less dynamic, and play important roles in every step of mRNA processing. Indeed, recent screens have uncovered post-transcriptional mechanisms as being integral regulatory mechanisms to neocortical development. Here, we summarize major aspects of neocortical laminar development, emphasizing transcriptional and post-transcriptional mechanisms, with the aim of spurring increased understanding and study of its intricacies.

Organization of projection-specific interneurons in the spinal cord of the red-eared turtle

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Nissen, Ulla Vig; Moldovan, Mihai; Hounsgaard, Jørn

2008-01-01

Using differential retrograde axonal tracing, we identified motoneurons (MNs) and projection-specific interneuron (IN) classes in lumbar segment D9 of the adult red-eared turtle spinal cord. We characterized the distribution of these neurons in the transverse plane, and estimated their numbers...

Is attentional blink a byproduct of neocortical attractors?

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David N Silverstein

2011-05-01

Full Text Available This study proposes a computational model for attentional blink or blink of the mind, a phenomenon where a human subject misses perception of a later expected visual pattern as two expected visual patterns are presented less than 500 ms apart. A neocortical patch modeled as an attractor network is stimulated with a sequence of 14 patterns 100 ms apart, two of which are expected targets. Patterns that become active attractors are considered recognized. A neocortical patch is represented as a square matrix of hypercolumns, each containing a set of minicolumns with synaptic connections within and across both minicolumns and hypercolumns. Each minicolumn consists of locally connected layer 2/3 pyramidal cells with interacting basket cells and layer 4 pyramidal cells for input stimulation. All neurons are implemented using the Hodgkin-Huxley multi-compartmental cell formalism and include calcium dynamics, and they interact via saturating and depressing AMPA / NMDA and GABAA synapses. Stored patterns are encoded with global connectivity of minicolumns across hypercolumns and active patterns compete as the result of lateral inhibition in the network. Stored patterns were stimulated over time intervals to create attractor interference measurable with synthetic spike traces. This setup corresponds with item presentations in human visual attentional blink studies. Stored target patterns were depolarized while distractor patterns where hyperpolarized to represent expectation of items in working memory. Additionally, studies on the inhibitory effect of benzodiazopines on attentional blink in human subjects were compared with neocortical simulations where the GABAA receptor conductance and decay time were increased. Simulations showed increases in the attentional blink duration, agreeing with observations in human studies.

Age-Related Uptake of Heavy Metals in Human Spinal Interneurons.

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Roger Pamphlett

Full Text Available Toxic heavy metals have been implicated in the loss of spinal motoneurons in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND. Motoneuron loss in the spinal anterior horn is severe in ALS/MND at the time of death, making this tissue unsuitable for examination. We therefore examined spinal cords of people without muscle weakness to look for any presence of heavy metals that could make these neurons susceptible to damage. Spinal cord samples from 50 individuals aged 1-95 y who had no clinical or histopathological evidence of spinal motoneuron loss were studied. Seven μm formalin-fixed paraffin-embedded sections were stained for heavy metals with silver nitrate autometallography (AMGHM which detects intracellular mercury, silver or bismuth. Neurons in the spinal cord were classified as interneurons or α-motoneurons based on their site and cell body diameter. Spinal interneurons containing heavy metals were present in 8 of 24 people (33% aged 61-95 y, but not at younger ages. These AMGHM interneurons were most numerous in the lumbar spinal cord, with moderate numbers in the caudal cervical cord, few in the rostral cervical cord, and almost none in the thoracic cord. All people with AMGHM interneurons had occasional AMGHM staining in α-motoneurons as well. In one man AMGHM staining was present in addition in dorsomedial nucleus and sensory neurons. In conclusion, heavy metals are present in many spinal interneurons, and in a few α-motoneurons, in a large proportion of older people. Damage to inhibitory interneurons from toxic metals in later life could result in excitotoxic injury to motoneurons and may underlie motoneuron injury or loss in conditions such as ALS/MND, multiple sclerosis, sarcopenia and calf fasciculations.

Local connections of layer 5 GABAergic interneurons to corticospinal neurons

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Yasuyo H Tanaka

2011-09-01

Full Text Available In the local circuit of the cerebral cortex, GABAergic inhibitory interneurons are considered to work in collaboration with excitatory neurons. Although many interneuron subgroups have been described in the cortex, local inhibitory connections of each interneuron subgroup are only partially understood with respect to the functional neuron groups that receive these inhibitory connections. In the present study, we morphologically examined local inhibitory inputs to corticospinal neurons (CSNs in motor areas using transgenic rats in which GABAergic neurons expressed fluorescent protein Venus. By analysis of biocytin-filled axons obtained with whole-cell recording/staining in cortical slices, we classified fast-spiking (FS neurons in layer (L 5 into two types, FS1 and FS2, by their high and low densities of axonal arborization, respectively. We then investigated the connections of FS1, FS2, somatostatin-immunopositive (SOM and other (non-FS/non-SOM interneurons to CSNs that were retrogradely labeled in a Golgi-like manner in motor areas. When close appositions between the axon boutons of the intracellularly labeled interneurons and the somata/dendrites of the retrogradely labeled CSNs were examined electron-microscopically, 74% of these appositions made symmetric synaptic contacts. The axon boutons of single FS1 neurons were 2–4-fold more frequent in appositions to the somata/dendrites of CSNs than those of FS2, SOM and non-FS/non-SOM neurons. Axosomatic appositions were most frequently formed with axon boutons of FS1 and FS2 neurons (approximately 30% and least frequently formed with those of SOM neurons (7%. In contrast, SOM neurons most extensively sent axon boutons to the apical dendrites of CSNs. These results might suggest that motor outputs are controlled differentially by the subgroups of L5 GABAergic interneurons in cortical motor areas. 

Meningeal defects alter the tangential migration of cortical interneurons in Foxc1hith/hith mice

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Zarbalis Konstantinos

2012-01-01

Full Text Available Abstract Background Tangential migration presents the primary mode of migration of cortical interneurons translocating into the cerebral cortex from subpallial domains. This migration takes place in multiple streams with the most superficial one located in the cortical marginal zone. While a number of forebrain-expressed molecules regulating this process have emerged, it remains unclear to what extent structures outside the brain, like the forebrain meninges, are involved. Results We studied a unique Foxc1 hypomorph mouse model (Foxc1hith/hith with meningeal defects and impaired tangential migration of cortical interneurons. We identified a territorial correlation between meningeal defects and disruption of interneuron migration along the adjacent marginal zone in these animals, suggesting that impaired meningeal integrity might be the primary cause for the observed migration defects. Moreover, we postulate that the meningeal factor regulating tangential migration that is affected in homozygote mutants is the chemokine Cxcl12. In addition, by using chromatin immunoprecipitation analysis, we provide evidence that the Cxcl12 gene is a direct transcriptional target of Foxc1 in the meninges. Further, we observe migration defects of a lesser degree in Cajal-Retzius cells migrating within the cortical marginal zone, indicating a less important role for Cxcl12 in their migration. Finally, the developmental migration defects observed in Foxc1hith/hith mutants do not lead to obvious differences in interneuron distribution in the adult if compared to control animals. Conclusions Our results suggest a critical role for the forebrain meninges to promote during development the tangential migration of cortical interneurons along the cortical marginal zone and Cxcl12 as the factor responsible for this property.

Effect of seizure on hippocampus in mesial temporal lobe epilepsy and neocortical epilepsy: an MRS study

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Lee, S.K.; Kim, D.W.; Kim, K.K.; Chung, C.K.; Song, I.C.; Chang, K.H.

2005-01-01

This study was performed to evaluate the effect of seizures on the bilateral hippocampus in mesial temporal lobe epilepsy (mTLE) and neocortical epilepsy by single voxel proton magnetic resonance spectroscopy (MRS). Forty-one patients with mTLE having unilateral hippocampal sclerosis and 43 patients with a neocortical epilepsy who underwent subsequent epilepsy surgery were recruited. Ninety-five percent confidence intervals of N-acetyl aspartate/choline (NAA/Cho) and NAA/creatine (NAA/Cr) ratios in 20 healthy control subjects were used as threshold values to determine abnormal NAA/Cho and NAA/Cr. NAA/Cho and NAA/Cr were significantly lower in the ipsilateral hippocampus of mTLE and neocortical epilepsy. Using asymmetry indices for patients with bilaterally abnormal ratios of NAA/Cho and NAA/Cr in addition to using unilateral abnormal ratio, the seizure focus was correctly lateralized in 65.9% of patients with mTLE and 48.8% of neocortical epilepsy patients. Bilateral NAA/Cho abnormality was significantly related to a poor surgical outcome in mTLE. No significant relationship was found between the results of NAA/Cho or NAA/Cr and surgical outcome in neocortical epilepsy. The mean contralateral NAA/Cr ratio of the hippocampus in mTLE was significantly lower in patients with a history of secondary generalized tonic-clonic seizure (SGTCS) than in those without. (orig.)

Effect of seizure on hippocampus in mesial temporal lobe epilepsy and neocortical epilepsy: an MRS study

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Lee, S.K.; Kim, D.W.; Kim, K.K. [Seoul National University College of Medicine, Seoul National University Hospital, Department of Neurology, Chongno ku, Seoul (Korea); Chung, C.K. [Seoul National University College of Medicine, Seoul National University Hospital, Department of Neurosurgery, Chongno ku, Seoul (Korea); Song, I.C.; Chang, K.H. [Seoul National University College of Medicine, Seoul National University Hospital, Department of Radiology, Chongno ku, Seoul (Korea)

2005-12-01

This study was performed to evaluate the effect of seizures on the bilateral hippocampus in mesial temporal lobe epilepsy (mTLE) and neocortical epilepsy by single voxel proton magnetic resonance spectroscopy (MRS). Forty-one patients with mTLE having unilateral hippocampal sclerosis and 43 patients with a neocortical epilepsy who underwent subsequent epilepsy surgery were recruited. Ninety-five percent confidence intervals of N-acetyl aspartate/choline (NAA/Cho) and NAA/creatine (NAA/Cr) ratios in 20 healthy control subjects were used as threshold values to determine abnormal NAA/Cho and NAA/Cr. NAA/Cho and NAA/Cr were significantly lower in the ipsilateral hippocampus of mTLE and neocortical epilepsy. Using asymmetry indices for patients with bilaterally abnormal ratios of NAA/Cho and NAA/Cr in addition to using unilateral abnormal ratio, the seizure focus was correctly lateralized in 65.9% of patients with mTLE and 48.8% of neocortical epilepsy patients. Bilateral NAA/Cho abnormality was significantly related to a poor surgical outcome in mTLE. No significant relationship was found between the results of NAA/Cho or NAA/Cr and surgical outcome in neocortical epilepsy. The mean contralateral NAA/Cr ratio of the hippocampus in mTLE was significantly lower in patients with a history of secondary generalized tonic-clonic seizure (SGTCS) than in those without. (orig.)

Crosstalk between intracellular and extracellular signals regulating interneuron production, migration and integration into the cortex.

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Peyre, Elise; Silva, Carla G; Nguyen, Laurent

2015-01-01

During embryogenesis, cortical interneurons are generated by ventral progenitors located in the ganglionic eminences of the telencephalon. They travel along multiple tangential paths to populate the cortical wall. As they reach this structure they undergo intracortical dispersion to settle in their final destination. At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Different levels of molecular regulation contribute to interneuron migration. These include: (1) Extrinsic guidance cues distributed along migratory streams that are sensed and integrated by migrating interneurons; (2) Intrinsic genetic programs driven by specific transcription factors that grant specification and set the timing of migration for different subtypes of interneurons; (3) Adhesion molecules and cytoskeletal elements/regulators that transduce molecular signalings into coherent movement. These levels of molecular regulation must be properly integrated by interneurons to allow their migration in the cortex. The aim of this review is to summarize our current knowledge of the interplay between microenvironmental signals and cell autonomous programs that drive cortical interneuron porduction, tangential migration, and intergration in the developing cerebral cortex.

EphA4 defines a class of excitatory locomotor-related interneurons

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Butt, S. J B; Lundfald, Line; Kiehn, Ole

2005-01-01

of these interneurons provide direct excitation to ipsilateral motor neurons as determined by spike-triggered averaging of the local ventral root DC trace. Our findings substantiate the role of EphA4-positive interneurons as significant components of the ipsilateral locomotor network and describe a group of putative...... of the role of these cells in the network. One such marker is the EphA4 axon guidance receptor. EphA4-null mice display an abnormal rabbit-like hopping gait that is thought to be the result of synchronization of the normally alternating, bilateral locomotor network via aberrant crossed connections....... In this study, we have performed whole-cell patch clamp on EphA4-positive interneurons in the flexor region (L2) of the locomotor network. We provide evidence that although EphA4 positive interneurons are not entirely a homogeneous population, most of them fire in a rhythmic manner. Moreover, a subset...

Temporal integration and 1/f power scaling in a circuit model of cerebellar interneurons.

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Maex, Reinoud; Gutkin, Boris

2017-07-01

Inhibitory interneurons interconnected via electrical and chemical (GABA A receptor) synapses form extensive circuits in several brain regions. They are thought to be involved in timing and synchronization through fast feedforward control of principal neurons. Theoretical studies have shown, however, that whereas self-inhibition does indeed reduce response duration, lateral inhibition, in contrast, may generate slow response components through a process of gradual disinhibition. Here we simulated a circuit of interneurons (stellate and basket cells) of the molecular layer of the cerebellar cortex and observed circuit time constants that could rise, depending on parameter values, to >1 s. The integration time scaled both with the strength of inhibition, vanishing completely when inhibition was blocked, and with the average connection distance, which determined the balance between lateral and self-inhibition. Electrical synapses could further enhance the integration time by limiting heterogeneity among the interneurons and by introducing a slow capacitive current. The model can explain several observations, such as the slow time course of OFF-beam inhibition, the phase lag of interneurons during vestibular rotation, or the phase lead of Purkinje cells. Interestingly, the interneuron spike trains displayed power that scaled approximately as 1/ f at low frequencies. In conclusion, stellate and basket cells in cerebellar cortex, and interneuron circuits in general, may not only provide fast inhibition to principal cells but also act as temporal integrators that build a very short-term memory. NEW & NOTEWORTHY The most common function attributed to inhibitory interneurons is feedforward control of principal neurons. In many brain regions, however, the interneurons are densely interconnected via both chemical and electrical synapses but the function of this coupling is largely unknown. Based on large-scale simulations of an interneuron circuit of cerebellar cortex, we

HERC 1 ubiquitin ligase mutation affects neocortical, CA3 hippocampal and spinal cord projection neurons. An ultrastructural study

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Rocío eRuiz

2016-04-01

Full Text Available The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and, hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

Response characteristics of vibration-sensitive interneurons related to Johnston's organ in the honeybee, Apis mellifera.

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Ai, Hiroyuki; Rybak, Jürgen; Menzel, Randolf; Itoh, Tsunao

2009-07-10

Honeybees detect airborne vibration by means of Johnston's organ (JO), located in the pedicel of each antenna. In this study we identified two types of vibration-sensitive interneurons with arborizations in the primary sensory area of the JO, namely, the dorsal lobe-interneuron 1 (DL-Int-1) and dorsal lobe-interneuron 2 (DL-Int-2) using intracellular recordings combined with intracellular staining. For visualizing overlapping areas between the JO sensory terminals and the branches of these identified interneurons, the three-dimensional images of the individual neurons were registered into the standard atlas of the honeybee brain (Brandt et al. [2005] J Comp Neurol 492:1-19). Both DL-Int-1 and DL-Int-2 overlapped with the central terminal area of receptor neurons of the JO in the DL. For DL-Int-1 an on-off phasic excitation was elicited by vibrational stimuli applied to the JO when the spontaneous spike frequency was low, whereas tonic inhibition was induced when it was high. Moreover, current injection into a DL-Int-1 led to changes of the response pattern from on-off phasic excitation to tonic inhibition, in response to the vibratory stimulation. Although the vibration usually induced on-off phasic excitation in DL-Int-1, vibration applied immediately after odor stimulation induced tonic inhibition in it. DL-Int-2 responded to vibration stimuli applied to the JO by a tonic burst and were most sensitive to 265 Hz vibration, which is coincident with the strongest frequency of airborne vibrations arising during the waggle dance. These results suggest that DL-Int-1 and DL-Int-2 are related to coding of the duration of the vibration as sensed by the JO. Copyright 2009 Wiley-Liss, Inc.

Hilar somatostatin interneuron loss reduces dentate gyrus inhibition in a mouse model of temporal lobe epilepsy.

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Hofmann, Gabrielle; Balgooyen, Laura; Mattis, Joanna; Deisseroth, Karl; Buckmaster, Paul S

2016-06-01

In patients with temporal lobe epilepsy, seizures usually start in the hippocampus, and dentate granule cells are hyperexcitable. Somatostatin interneurons are a major subpopulation of inhibitory neurons in the dentate gyrus, and many are lost in patients and animal models. However, surviving somatostatin interneurons sprout axon collaterals and form new synapses, so the net effect on granule cell inhibition remains unclear. The present study uses optogenetics to activate hilar somatostatin interneurons and measure the inhibitory effect on dentate gyrus perforant path-evoked local field potential responses in a mouse model of temporal lobe epilepsy. In controls, light activation of hilar somatostatin interneurons inhibited evoked responses up to 40%. Epileptic pilocarpine-treated mice exhibited loss of hilar somatostatin interneurons and less light-induced inhibition of evoked responses. These findings suggest that severe epilepsy-related loss of hilar somatostatin interneurons can overwhelm the surviving interneurons' capacity to compensate by sprouting axon collaterals. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Crosstalk between intracellular and extracellular signals regulating interneuron production migration and integration into the cortex

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Elise ePeyre

2015-04-01

Full Text Available During embryogenesis, cortical interneurons are generated by ventral progenitors located in the ganglionic eminences of the telencephalon. They travel along multiple tangential paths to populate the cortical wall. As they reach this structure they undergo intracortical dispersion to settle in their final destination. At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Different levels of molecular regulation contribute to interneuron migration. These include: 1/ Extrinsic guidance cues distributed along migratory streams that are sensed and integrated by migrating interneurons; 2/ Intrinsic genetic programs driven by specific transcription factors that grant specification and set the timing of migration for different subtypes of interneurons; 3/ Adhesion molecules and cytoskeletal elements/regulators that transduce molecular signalings into coherent movement. These levels of molecular regulation must be properly integrated by interneurons to allow their migration in the cortex. The aim of this review is to summarize our current knowledge of the interplay between microenvironmental signals and cell autonomous programs that drive cortical interneuron porduction, tangential migration, and intergration in the developing cerebral cortex.

Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice.

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Toia, Alyssa R; Cuoco, Joshua A; Esposito, Anthony W; Ahsan, Jawad; Joshi, Alok; Herron, Bruce J; Torres, German; Bolivar, Valerie J; Ramos, Raddy L

2017-01-18

Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1 A/J /NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction.

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Zou, D; Chen, L; Deng, D; Jiang, D; Dong, F; McSweeney, C; Zhou, Y; Liu, L; Chen, G; Wu, Y; Mao, Y

2016-01-01

Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PVpositive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3DGq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

Circuit variability interacts with excitatory-inhibitory diversity of interneurons to regulate network encoding capacity.

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Tsai, Kuo-Ting; Hu, Chin-Kun; Li, Kuan-Wei; Hwang, Wen-Liang; Chou, Ya-Hui

2018-05-23

Local interneurons (LNs) in the Drosophila olfactory system exhibit neuronal diversity and variability, yet it is still unknown how these features impact information encoding capacity and reliability in a complex LN network. We employed two strategies to construct a diverse excitatory-inhibitory neural network beginning with a ring network structure and then introduced distinct types of inhibitory interneurons and circuit variability to the simulated network. The continuity of activity within the node ensemble (oscillation pattern) was used as a readout to describe the temporal dynamics of network activity. We found that inhibitory interneurons enhance the encoding capacity by protecting the network from extremely short activation periods when the network wiring complexity is very high. In addition, distinct types of interneurons have differential effects on encoding capacity and reliability. Circuit variability may enhance the encoding reliability, with or without compromising encoding capacity. Therefore, we have described how circuit variability of interneurons may interact with excitatory-inhibitory diversity to enhance the encoding capacity and distinguishability of neural networks. In this work, we evaluate the effects of different types and degrees of connection diversity on a ring model, which may simulate interneuron networks in the Drosophila olfactory system or other biological systems.

Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons.

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Canetta, S; Bolkan, S; Padilla-Coreano, N; Song, L J; Sahn, R; Harrison, N L; Gordon, J A; Brown, A; Kellendonk, C

2016-07-01

Abnormalities in prefrontal gamma aminobutyric acid (GABA)ergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders, including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, resulted from a decrease in release probability and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to MIA, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders.

Serotonin inhibits low-threshold spike interneurons in the striatum

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Cains, Sarah; Blomeley, Craig P; Bracci, Enrico

2012-01-01

Low-threshold spike interneurons (LTSIs) are important elements of the striatal architecture and the only known source of nitric oxide in this nucleus, but their rarity has so far prevented systematic studies. Here, we used transgenic mice in which green fluorescent protein is expressed under control of the neuropeptide Y (NPY) promoter and striatal NPY-expressing LTSIs can be easily identified, to investigate the effects of serotonin on these neurons. In sharp contrast with its excitatory action on other striatal interneurons, serotonin (30 μm) strongly inhibited LTSIs, reducing or abolishing their spontaneous firing activity and causing membrane hyperpolarisations. These hyperpolarisations persisted in the presence of tetrodotoxin, were mimicked by 5-HT2C receptor agonists and reversed by 5-HT2C antagonists. Voltage-clamp slow-ramp experiments showed that serotonin caused a strong increase in an outward current activated by depolarisations that was blocked by the specific M current blocker XE 991. In current-clamp experiments, XE 991 per se caused membrane depolarisations in LTSIs and subsequent application of serotonin (in the presence of XE 991) failed to affect these neurons. We concluded that serotonin strongly inhibits striatal LTSIs acting through postsynaptic 5-HT2C receptors and increasing an M type current. PMID:22495583

Presynaptic miniature GABAergic currents in developing interneurons.

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Trigo, Federico F; Bouhours, Brice; Rostaing, Philippe; Papageorgiou, George; Corrie, John E T; Triller, Antoine; Ogden, David; Marty, Alain

2010-04-29

Miniature synaptic currents have long been known to represent random transmitter release under resting conditions, but much remains to be learned about their nature and function in central synapses. In this work, we describe a new class of miniature currents ("preminis") that arise by the autocrine activation of axonal receptors following random vesicular release. Preminis are prominent in gabaergic synapses made by cerebellar interneurons during the development of the molecular layer. Unlike ordinary miniature postsynaptic currents in the same cells, premini frequencies are strongly enhanced by subthreshold depolarization, suggesting that the membrane depolarization they produce belongs to a feedback loop regulating neurotransmitter release. Thus, preminis could guide the formation of the interneuron network by enhancing neurotransmitter release at recently formed synaptic contacts. Copyright 2010 Elsevier Inc. All rights reserved.

Development of calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in cultured neocortical neurons visualized by cobalt staining

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Jensen, J B; Schousboe, A; Pickering, D S

1998-01-01

The developmental expression of calcium (Ca2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in cultured neocortical neurons was evaluated by using cobalt uptake, a histochemical method that identifies cells expressing Ca2+-permeable, non-N-methyl-D-aspartate...

Locally Applied Valproate Enhances Survival in Rats after Neocortical Treatment with Tetanus Toxin and Cobalt Chloride

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Dirk-Matthias Altenmüller

2013-01-01

Full Text Available Purpose. In neocortical epilepsies not satisfactorily responsive to systemic antiepileptic drug therapy, local application of antiepileptic agents onto the epileptic focus may enhance treatment efficacy and tolerability. We describe the effects of focally applied valproate (VPA in a newly emerging rat model of neocortical epilepsy induced by tetanus toxin (TeT plus cobalt chloride (CoCl2. Methods. In rats, VPA ( or sodium chloride (NaCl ( containing polycaprolactone (PCL implants were applied onto the right motor cortex treated before with a triple injection of 75 ng TeT plus 15 mg CoCl2. Video-EEG monitoring was performed with intracortical depth electrodes. Results. All rats randomized to the NaCl group died within one week after surgery. In contrast, the rats treated with local VPA survived significantly longer (. In both groups, witnessed deaths occurred in the context of seizures. At least of the rats surviving the first postoperative day developed neocortical epilepsy with recurrent spontaneous seizures. Conclusions. The novel TeT/CoCl2 approach targets at a new model of neocortical epilepsy in rats and allows the investigation of local epilepsy therapy strategies. In this vehicle-controlled study, local application of VPA significantly enhanced survival in rats, possibly by focal antiepileptic or antiepileptogenic mechanisms.

MGE-derived nNOS+ interneurons promote fear acquisition in nNOS-/- mice.

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Zhang, Lin; Yuan, Hong-Jin; Cao, Bo; Kong, Cheng-Cheng; Yuan, Fang; Li, Jun; Ni, Huan-Yu; Wu, Hai-Yin; Chang, Lei; Liu, Yan; Luo, Chun-Xia

2017-12-02

Neuronal nitric oxide synthase (nNOS) 1 , mainly responsible for NO release in central nervous system (CNS) 2 , plays a significant role in multiple physiological functions. However, the function of nNOS + interneurons in fear learning has not been much explored. Here we focused on the medial ganglionic eminences (MGE) 3 -derived nNOS + interneurons in fear learning. To determine the origin of nNOS + interneurons, we cultured neurons in vitro from MGE, cortex, lateral ganglionic eminence (LGE) 4 , caudal ganglionic eminences (CGE) 5 and preoptic area (POA) 6 . The results showed that MGE contained the most abundant precursors of nNOS + interneurons. Moreover, donor cells from E12.5 embryos demonstrated the highest positive rate of nNOS + interneurons compared with other embryonic periods (E11.5, E12, E13, E13.5 and E14). Additionally, these cells from E12.5 embryos showed long axonal and abundant dendritic arbors after 10 days culture, indicating the capability to disperse and integrate in host neural circuits after transplantation. To investigate the role of MGE-derived nNOS + interneurons in fear learning, donor MGE cells were transplanted into dentate gyrus (DG) 7 of nNOS knock-out (nNOS -/- ) or wild-type mice. Results showed that the transplantation of MGE cells promoted the acquisition of nNOS -/- but not the wild-type mice, suggesting the importance of nNOS + neurons in fear acquisition. Moreover, we transplanted MGE cells from nNOS -/- mice or wild-type mice into DG of the nNOS -/- mice and found that only MGE cells from wild-type mice but not the nNOS -/- mice rescued the deficit in acquisition of the nNOS -/- mice, further confirming the positive role of nNOS + neurons in fear learning. Copyright © 2017 Elsevier Inc. All rights reserved.

NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons

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Marta Perez-Rando

2017-06-01

Full Text Available N-methyl-D-aspartate receptors (NMDARs are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty-four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB. We have also used entorhino-hippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders.

Facilitation of neocortical presynaptic terminal development by NMDA receptor activation

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Sceniak Michael P

2012-02-01

Full Text Available Abstract Background Neocortical circuits are established through the formation of synapses between cortical neurons, but the molecular mechanisms of synapse formation are only beginning to be understood. The mechanisms that control synaptic vesicle (SV and active zone (AZ protein assembly at developing presynaptic terminals have not yet been defined. Similarly, the role of glutamate receptor activation in control of presynaptic development remains unclear. Results Here, we use confocal imaging to demonstrate that NMDA receptor (NMDAR activation regulates accumulation of multiple SV and AZ proteins at nascent presynaptic terminals of visual cortical neurons. NMDAR-dependent regulation of presynaptic assembly occurs even at synapses that lack postsynaptic NMDARs. We also provide evidence that this control of presynaptic terminal development is independent of glia. Conclusions Based on these data, we propose a novel NMDAR-dependent mechanism for control of presynaptic terminal development in excitatory neocortical neurons. Control of presynaptic development by NMDARs could ultimately contribute to activity-dependent development of cortical receptive fields.

Differential regulation of microtubule severing by APC underlies distinct patterns of projection neuron and interneuron migration

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Eom, Tae-Yeon; Stanco, Amelia; Guo, Jiami; Wilkins, Gary; Deslauriers, Danielle; Yan, Jessica; Monckton, Chase; Blair, Josh; Oon, Eesim; Perez, Abby; Salas, Eduardo; Oh, Adrianna; Ghukasyan, Vladimir; Snider, William D.; Rubenstein, John L. R.; Anton, E. S.

2014-01-01

Coordinated migration of distinct classes of neurons to appropriate positions leads to the formation of functional neuronal circuitry in the cerebral cortex. Two major classes of cortical neurons, interneurons and projection neurons, utilize distinctly different modes (radial vs. tangential) and routes of migration to arrive at their final positions in the cerebral cortex. Here, we show that adenomatous polyposis coli (APC) modulates microtubule (MT) severing in interneurons to facilitate tangential mode of interneuron migration, but not the glial-guided, radial migration of projection neurons. APC regulates the stability and activity of the MT severing protein p60-katanin in interneurons to promote the rapid remodeling of neuronal processes necessary for interneuron migration. These findings reveal how severing and restructuring of MTs facilitate distinct modes of neuronal migration necessary for laminar organization of neurons in the developing cerebral cortex. PMID:25535916

Molecular and Electrophysiological Characterization of GABAergic Interneurons Expressing the Transcription Factor COUP-TFII in the Adult Human Temporal Cortex

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Varga, Csaba; Tamas, Gabor; Barzo, Pal; Olah, Szabolcs; Somogyi, Peter

2015-01-01

Transcription factors contribute to the differentiation of cortical neurons, orchestrate specific interneuronal circuits, and define synaptic relationships. We have investigated neurons expressing chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), which plays a role in the migration of GABAergic neurons. Whole-cell, patch-clamp recording in vitro combined with colocalization of molecular cell markers in the adult cortex differentiates distinct interneurons. The majority of strongly COUP-TFII-expressing neurons were in layers I–III. Most calretinin (CR) and/or cholecystokinin- (CCK) and/or reelin-positive interneurons were also COUP-TFII-positive. CR-, CCK-, or reelin-positive neurons formed 80%, 20%, or 17% of COUP-TFII-positive interneurons, respectively. About half of COUP-TFII-/CCK-positive interneurons were CR-positive, a quarter of them reelin-positive, but none expressed both. Interneurons positive for COUP-TFII fired irregular, accommodating and adapting trains of action potentials (APs) and innervated mostly small dendritic shafts and rarely spines or somata. Paired recording showed that a calretinin-/COUP-TFII-positive interneuron elicited inhibitory postsynaptic potentials (IPSPs) in a reciprocally connected pyramidal cell. Calbindin, somatostatin, or parvalbumin-immunoreactive interneurons and most pyramidal cells express no immunohistochemically detectable COUP-TFII. In layers V and VI, some pyramidal cells expressed a low level of COUP-TFII in the nucleus. In conclusion, COUP-TFII is expressed in a diverse subset of GABAergic interneurons predominantly innervating small dendritic shafts originating from both interneurons and pyramidal cells. PMID:25787832

Anatomical and electrophysiological changes in striatal TH interneurons after loss of the nigrostriatal dopaminergic pathway.

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Ünal, Bengi; Shah, Fulva; Kothari, Janish; Tepper, James M

2015-01-01

Using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the tyrosine hydroxylase (TH) promoter, we have previously shown that there are approximately 3,000 striatal EGFP-TH interneurons per hemisphere in mice. Here, we report that striatal TH-EGFP interneurons exhibit a small, transient but significant increase in number after unilateral destruction of the nigrostriatal dopaminergic pathway. The increase in cell number is accompanied by electrophysiological and morphological changes. The intrinsic electrophysiological properties of EGFP-TH interneurons ipsilateral to 6-OHDA lesion were similar to those originally reported in intact mice except for a significant reduction in the duration of a characteristic depolarization induced plateau potential. There was a significant change in the distribution of the four previously described electrophysiologically distinct subtypes of striatal TH interneurons. There was a concomitant increase in the frequency of both spontaneous excitatory and inhibitory post-synaptic currents, while their amplitudes did not change. Nigrostriatal lesions did not affect somatic size or dendritic length or branching, but resulted in an increase in the density of proximal dendritic spines and spine-like appendages in EGFP-TH interneurons. The changes indicate that electrophysiology properties and morphology of striatal EGFP-TH interneurons depend on endogenous levels of dopamine arising from the nigrostriatal pathway. Furthermore, these changes may serve to help compensate for the changes in activity of spiny projection neurons that occur following loss of the nigrostriatal innervation in experimental or in early idiopathic Parkinson's disease by increasing feedforward GABAergic inhibition exerted by these interneurons.

Oscillation-Driven Spike-Timing Dependent Plasticity Allows Multiple Overlapping Pattern Recognition in Inhibitory Interneuron Networks

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Garrido, Jesús A.; Luque, Niceto R.; Tolu, Silvia

2016-01-01

The majority of operations carried out by the brain require learning complex signal patterns for future recognition, retrieval and reuse. Although learning is thought to depend on multiple forms of long-term synaptic plasticity, the way this latter contributes to pattern recognition is still poorly...... and at the inhibitory interneuron-interneuron synapses, the interneurons rapidly learned complex input patterns. Interestingly, induction of plasticity required that the network be entrained into theta-frequency band oscillations, setting the internal phase-reference required to drive STDP. Inhibitory plasticity...... effectively distributed multiple patterns among available interneurons, thus allowing the simultaneous detection of multiple overlapping patterns. The addition of plasticity in intrinsic excitability made the system more robust allowing self-adjustment and rescaling in response to a broad range of input...

Differential expression of parvalbumin interneurons in neonatal phencyclidine treated rats and socially isolated rats

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Kaalund, Sanne Simone; Riise, Jesper; Broberg, Brian

2013-01-01

of parvalbumin-positive interneurons (PV(+) interneurons). In this study we examined PV(+) expression in two rat models of cognitive dysfunction in schizophrenia, the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical...

Intermittent Theta-Burst Transcranial Magnetic Stimulation Alters Electrical Properties of Fast-Spiking Neocortical Interneurons in an Age-Dependent Fashion

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Kathrin eHoppenrath

2016-03-01

Full Text Available Modulation of human cortical excitability by repetitive transcranial magnetic stimulation (rTMS appears to be in part related to changed activity of inhibitory systems. Our own studies showed that intermittent theta-burst stimulation (iTBS applied via rTMS to rat cortex primarily affects the parvalbumin-expressing (PV fast-spiking interneurons (FSIs, evident via a strongly reduced PV expression. We further found the iTBS effect on PV to be age-dependent since no reduction in PV could be induced before the perineuronal nets (PNNs of FSIs start to grow around postnatal day 30. To elucidate possible iTBS-induced changes in the electrical properties of FSIs and cortical network activity during cortical critical period, we performed ex vivo – in vitro whole-cell patch clamp recordings from pre-labelled FSIs in the current study. FSIs of verum iTBS-treated rats displayed a higher excitability than sham-treated controls at PD29-38, evident as higher rates of induced action potential firing at low current injections (100-200 pA and a more depolarized resting membrane potential. This effect was absent in younger (PD26-28 and older animals (PD40-62. Slices of verum iTBS-treated rats further showed higher rates of spontaneous EPSCs. Based on these and previous findings we conclude that FSIs are particularly sensitive to theta-burst stimulation during early cortical development, when FSIs show an activity-driven step of maturation which is paralleled by intense growth of the PNNs and subsequent closure of the cortical critical period. Although to be proven further, rTMS may be a possible early intervention to compensate for hypo-activity related mal-development of cortical neuronal circuits.

Intermittent Theta-Burst Transcranial Magnetic Stimulation Alters Electrical Properties of Fast-Spiking Neocortical Interneurons in an Age-Dependent Fashion.

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Hoppenrath, Kathrin; Härtig, Wolfgang; Funke, Klaus

2016-01-01

Modulation of human cortical excitability by repetitive transcranial magnetic stimulation (rTMS) appears to be in part related to changed activity of inhibitory systems. Our own studies showed that intermittent theta-burst stimulation (iTBS) applied via rTMS to rat cortex primarily affects the parvalbumin-expressing (PV) fast-spiking interneurons (FSIs), evident via a strongly reduced PV expression. We further found the iTBS effect on PV to be age-dependent since no reduction in PV could be induced before the perineuronal nets (PNNs) of FSIs start to grow around postnatal day (PD) 30. To elucidate possible iTBS-induced changes in the electrical properties of FSIs and cortical network activity during cortical critical period, we performed ex vivo-in vitro whole-cell patch clamp recordings from pre-labeled FSIs in the current study. FSIs of verum iTBS-treated rats displayed a higher excitability than sham-treated controls at PD29-38, evident as higher rates of induced action potential firing at low current injections (100-200 pA) and a more depolarized resting membrane potential. This effect was absent in younger (PD26-28) and older animals (PD40-62). Slices of verum iTBS-treated rats further showed higher rates of spontaneous excitatory postsynaptic currents (sEPSCs). Based on these and previous findings we conclude that FSIs are particularly sensitive to TBS during early cortical development, when FSIs show an activity-driven step of maturation which is paralleled by intense growth of the PNNs and subsequent closure of the cortical critical period. Although to be proven further, rTMS may be a possible early intervention to compensate for hypo-activity related mal-development of cortical neuronal circuits.

Local dynamics of gap-junction-coupled interneuron networks

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Lau, Troy; Zochowski, Michal; Gage, Gregory J; Berke, Joshua D

2010-01-01

Interneurons coupled by both electrical gap-junctions (GJs) and chemical GABAergic synapses are major components of forebrain networks. However, their contributions to the generation of specific activity patterns, and their overall contributions to network function, remain poorly understood. Here we demonstrate, using computational methods, that the topological properties of interneuron networks can elicit a wide range of activity dynamics, and either prevent or permit local pattern formation. We systematically varied the topology of GJ and inhibitory chemical synapses within simulated networks, by changing connection types from local to random, and changing the total number of connections. As previously observed we found that randomly coupled GJs lead to globally synchronous activity. In contrast, we found that local GJ connectivity may govern the formation of highly spatially heterogeneous activity states. These states are inherently temporally unstable when the input is uniformly random, but can rapidly stabilize when the network detects correlations or asymmetries in the inputs. We show a correspondence between this feature of network activity and experimental observations of transient stabilization of striatal fast-spiking interneurons (FSIs), in electrophysiological recordings from rats performing a simple decision-making task. We suggest that local GJ coupling enables an active search-and-select function of striatal FSIs, which contributes to the overall role of cortical-basal ganglia circuits in decision-making

Selective Reduction of AMPA Currents onto Hippocampal Interneurons Impairs Network Oscillatory Activity

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Le Magueresse, Corentin; Monyer, Hannah

2012-01-01

Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4HC−/− mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125–250 Hz) in the CA1 region of GluA4HC−/− mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4HC−/− mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance. PMID:22675480

A Subtype of Inhibitory Interneuron with Intrinsic Persistent Activity in Human and Monkey Neocortex

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Bo Wang

2015-03-01

Full Text Available A critical step in understanding the neural basis of human cognitive functions is to identify neuronal types in the neocortex. In this study, we performed whole-cell recording from human cortical slices and found a distinct subpopulation of neurons with intrinsic persistent activity that could be triggered by single action potentials (APs but terminated by bursts of APs. This persistent activity was associated with a depolarizing plateau potential induced by the activation of a persistent Na+ current. Single-cell RT-PCR revealed that these neurons were inhibitory interneurons. This type of neuron was found in different cortical regions, including temporal, frontal, occipital, and parietal cortices in human and also in frontal and temporal lobes of nonhuman primate but not in rat cortical tissues, suggesting that it could be unique to primates. The characteristic persistent activity in these inhibitory interneurons may contribute to the regulation of pyramidal cell activity and participate in cortical processing.

Influence of Pyrethroid Insecticides on Sodium and Calcium Influx in Neocortical Neurons

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Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Using murine neocortical neurons in primary culture, we have compared the ability of 11 structurally diverse pyrethroid insecticides to evoke Na+ ...

A pair of interneurons influences the choice between feeding and locomotion in Drosophila

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Mann, Kevin; Gordon, Michael D.; Scott, Kristin

2013-01-01

The decision to engage in one behavior often precludes the selection of others, suggesting cross-inhibition between incompatible behaviors. For example, the likelihood to initiate feeding might be influenced by an animal’s commitment to other behaviors. Here, we examine the modulation of feeding behavior in the fruit fly, Drosophila melanogaster, and identify a pair of interneurons in the ventral nerve cord that is activated by stimulation of mechanosensory neurons and inhibits feeding initia...

An essential role for neuregulin-4 in the growth and elaboration of developing neocortical pyramidal dendrites.

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Paramo, Blanca; Wyatt, Sean; Davies, Alun M

2018-04-01

Neuregulins, with the exception of neuregulin-4 (NRG4), have been shown to be extensively involved in many aspects of neural development and function and are implicated in several neurological disorders, including schizophrenia, depression and bipolar disorder. Here we provide the first evidence that NRG4 has a crucial function in the developing brain. We show that both the apical and basal dendrites of neocortical pyramidal neurons are markedly stunted in Nrg4 -/- neonates in vivo compared with Nrg4 +/+ littermates. Neocortical pyramidal neurons cultured from Nrg4 -/- embryos had significantly shorter and less branched neurites than those cultured from Nrg4 +/+ littermates. Recombinant NRG4 rescued the stunted phenotype of embryonic neocortical pyramidal neurons cultured from Nrg4 -/- mice. The majority of cultured wild type embryonic cortical pyramidal neurons co-expressed NRG4 and its receptor ErbB4. The difference between neocortical pyramidal dendrites of Nrg4 -/- and Nrg4 +/+ mice was less pronounced, though still significant, in juvenile mice. However, by adult stages, the pyramidal dendrite arbors of Nrg4 -/- and Nrg4 +/+ mice were similar, suggesting that compensatory changes in Nrg4 -/- mice occur with age. Our findings show that NRG4 is a major novel regulator of dendritic arborisation in the developing cerebral cortex and suggest that it exerts its effects by an autocrine/paracrine mechanism. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

V1 and v2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion.

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Zhang, Jingming; Lanuza, Guillermo M; Britz, Olivier; Wang, Zhi; Siembab, Valerie C; Zhang, Ying; Velasquez, Tomoko; Alvarez, Francisco J; Frank, Eric; Goulding, Martyn

2014-04-02

Reciprocal activation of flexor and extensor muscles constitutes the fundamental mechanism that tetrapod vertebrates use for locomotion and limb-driven reflex behaviors. This aspect of motor coordination is controlled by inhibitory neurons in the spinal cord; however, the identity of the spinal interneurons that serve this function is not known. Here, we show that the production of an alternating flexor-extensor motor rhythm depends on the composite activities of two classes of ventrally located inhibitory neurons, V1 and V2b interneurons (INs). Abrogating V1 and V2b IN-derived neurotransmission in the isolated spinal cord results in a synchronous pattern of L2 flexor-related and L5 extensor-related locomotor activity. Mice lacking V1 and V2b inhibition are unable to articulate their limb joints and display marked deficits in limb-driven reflex movements. Taken together, these findings identify V1- and V2b-derived neurons as the core interneuronal components of the limb central pattern generator (CPG) that coordinate flexor-extensor motor activity. Copyright © 2014 Elsevier Inc. All rights reserved.

Patterns of hippocampal-neocortical interactions in the retrieval of episodic autobiographical memories across the entire life-span of aged adults

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Viard, Armelle; Lebreton, Karine; Chételat, Gaël; Desgranges, Béatrice; Landeau, Brigitte; Young, Alan; De La Sayette, Vincent; Eustache, Francis; Piolino, Pascale

2010-01-01

We previously demonstrated that Episodic Autobiographical Memories (EAMs) rely on a network of brain regions comprising the medial temporal lobe (MTL) and distributed neocortical regions regardless of their remoteness. The findings supported the model of memory consolidation which proposes a permanent role of MTL during EAM retrieval (Multiple-Trace Theory or MTT) rather than a temporary role (standard model). Our present aim was to expand the results by examining the interactions between the MTL and neocortical regions (or MTL-neocortical links) during EAM retrieval with varying retention intervals. We used an experimental paradigm specially designed to engage aged participants in the recollection of EAMs, extracted from five different time-periods, covering their whole life-span, in order to examine correlations between activation in the MTL and neocortical regions. The nature of the memories was checked at debriefing by means of behavioral measures to control the degree of episodicity and properties of memories. Targeted correlational analyses carried out on the MTL, frontal, lateral temporal and posterior regions revealed strong links between the MTL and neocortex during the retrieval of both recent and remote EAMs, challenging the standard model of memory consolidation and supporting MTT instead. Further confirmation was given by results showing that activation in the left and right hippocampi significantly correlated during the retrieval of both recent and remote memories. Correlations among extra-MTL neocortical regions also emerged for all time-periods, confirming the critical role of the prefrontal, temporal (lateral temporal cortex and temporal pole), precuneus and posterior cingulate regions in EAM retrieval. Overall, this paper emphasizes the role of a bilateral network of MTL and neocortical areas whose activation correlate during the recollection of rich phenomenological recent and remote EAMs. PMID:19338022

Functional α7β2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid β peptides

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Liu Qiang

2012-12-01

Full Text Available Abstract Background β-amyloid (Aβ accumulation is described as a hallmark of Alzheimer’s disease (AD. Aβ perturbs a number of synaptic components including nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs, which are abundantly expressed in the hippocampus and found on GABAergic interneurons. We have previously demonstrated the existence of a novel, heteromeric α7β2-nAChR in basal forebrain cholinergic neurons that exhibits high sensitivity to acute Aβ exposure. To extend our previous work, we evaluated the expression and pharmacology of α7β2-nAChRs in hippocampal interneurons and their sensitivity to Aβ. Results GABAergic interneurons in the CA1 subregion of the hippocampus expressed functional α7β2-nAChRs, which were characterized by relatively slow whole-cell current kinetics, pharmacological sensitivity to dihydro-β-erythroidine (DHβE, a nAChR β2* subunit selective blocker, and α7 and β2 subunit interaction using immunoprecipitation assay. In addition, α7β2-nAChRs were sensitive to 1 nM oligomeric Aβ. Similar effects were observed in identified hippocampal interneurons prepared from GFP-GAD mice. Conclusion These findings suggest that Aβ modulation of cholinergic signaling in hippocampal GABAergic interneurons via α7β2-nAChRs could be an early and critical event in Aβ-induced functional abnormalities of hippocampal function, which may be relevant to learning and memory deficits in AD.

Incorporating rapid neocortical learning of new schema-consistent information into complementary learning systems theory.

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McClelland, James L

2013-11-01

The complementary learning systems theory of the roles of hippocampus and neocortex (McClelland, McNaughton, & O'Reilly, 1995) holds that the rapid integration of arbitrary new information into neocortical structures is avoided to prevent catastrophic interference with structured knowledge representations stored in synaptic connections among neocortical neurons. Recent studies (Tse et al., 2007, 2011) showed that neocortical circuits can rapidly acquire new associations that are consistent with prior knowledge. The findings challenge the complementary learning systems theory as previously presented. However, new simulations extending those reported in McClelland et al. (1995) show that new information that is consistent with knowledge previously acquired by a putatively cortexlike artificial neural network can be learned rapidly and without interfering with existing knowledge; it is when inconsistent new knowledge is acquired quickly that catastrophic interference ensues. Several important features of the findings of Tse et al. (2007, 2011) are captured in these simulations, indicating that the neural network model used in McClelland et al. has characteristics in common with neocortical learning mechanisms. An additional simulation generalizes beyond the network model previously used, showing how the rate of change of cortical connections can depend on prior knowledge in an arguably more biologically plausible network architecture. In sum, the findings of Tse et al. are fully consistent with the idea that hippocampus and neocortex are complementary learning systems. Taken together, these findings and the simulations reported here advance our knowledge by bringing out the role of consistency of new experience with existing knowledge and demonstrating that the rate of change of connections in real and artificial neural networks can be strongly prior-knowledge dependent. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Humans and great apes share increased neocortical neuropeptide Y innervation compared to other haplorhine primates

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Mary Ann eRaghanti

2014-02-01

Full Text Available Neuropeptide Y (NPY plays a role in a variety of basic physiological functions and has also been implicated in regulating cognition, including learning and memory. A decrease in neocortical NPY has been reported for Alzheimer’s disease, schizophrenia, bipolar disorder, and depression, potentially contributing to associated cognitive deficits. The goal of the present analysis was to examine variation in neocortical NPY-immunoreactive axon and varicosity density among haplorhine primates (monkeys, apes, and humans. Stereologic methods were used to measure the ratios of NPY-expressing axon length density to total neuron density (ALv/Nv and NPY-immunoreactive varicosity density to neuron density (Vv/Nv, as well as the mean varicosity spacing in neocortical areas 10, 24, 44, and 22 (Tpt of humans, African great apes, New World monkeys, and Old World monkeys. Humans and great apes showed increased cortical NPY innervation relative to monkey species for ALv/Nv and Vv/Nv. Furthermore, humans and great apes displayed a conserved pattern of varicosity spacing across cortical areas and layers, with no differences between cortical layers or among cortical areas. These phylogenetic differences may be related to shared life history variables and may reflect specific cognitive abilities.

Disinhibition in learning and memory circuits: New vistas for somatostatin interneurons and long-term synaptic plasticity.

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Artinian, Julien; Lacaille, Jean-Claude

2017-11-23

Neural circuit functions involve finely controlled excitation/inhibition interactions that allow complex neuronal computations and support high order brain functions such as learning and memory. Disinhibition, defined as a transient brake on inhibition that favors excitation, recently appeared to be a conserved circuit mechanism implicated in various functions such as sensory processing, learning and memory. Although vasoactive intestinal polypeptide (VIP) interneurons are considered to be the main disinhibitory cells, recent studies highlighted a pivotal role of somatostatin (SOM) interneurons in inhibiting GABAergic interneurons and promoting principal cell activation. Interestingly, long-term potentiation of excitatory input synapses onto hippocampal SOM interneurons is proposed as a lasting mechanism for regulation of disinhibition of principal neurons. Such regulation of network metaplasticity may be important for hippocampal-dependent learning and memory. Copyright © 2017 Elsevier Inc. All rights reserved.

Differential regulation of the excitability of prefrontal cortical fast-spiking interneurons and pyramidal neurons by serotonin and fluoxetine.

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Ping Zhong

2011-02-01

Full Text Available Serotonin exerts a powerful influence on neuronal excitability. In this study, we investigated the effects of serotonin on different neuronal populations in prefrontal cortex (PFC, a major area controlling emotion and cognition. Using whole-cell recordings in PFC slices, we found that bath application of 5-HT dose-dependently increased the firing of FS (fast spiking interneurons, and decreased the firing of pyramidal neurons. The enhancing effect of 5-HT in FS interneurons was mediated by 5-HT₂ receptors, while the reducing effect of 5-HT in pyramidal neurons was mediated by 5-HT₁ receptors. Fluoxetine, the selective serotonin reuptake inhibitor, also induced a concentration-dependent increase in the excitability of FS interneurons, but had little effect on pyramidal neurons. In rats with chronic fluoxetine treatment, the excitability of FS interneurons was significantly increased, while pyramidal neurons remained unchanged. Fluoxetine injection largely occluded the enhancing effect of 5-HT in FS interneurons, but did not alter the reducing effect of 5-HT in pyramidal neurons. These data suggest that the excitability of PFC interneurons and pyramidal neurons is regulated by exogenous 5-HT in an opposing manner, and FS interneurons are the major target of Fluoxetine. It provides a framework for understanding the action of 5-HT and antidepressants in altering PFC network activity.

Characterization of reliability of spike timing in spinal interneurons during oscillating inputs

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Beierholm, Ulrik; Nielsen, Carsten D.; Ryge, Jesper

2001-01-01

that interneurons can respond with a high reliability of spike timing, but only by combining fast and slow oscillations is it possible to obtain a high reliability of firing during rhythmic locomotor movements. Theoretical analysis of the rotation number provided new insights into the mechanism for obtaining......The spike timing in rhythmically active interneurons in the mammalian spinal locomotor network varies from cycle to cycle. We tested the contribution from passive membrane properties to this variable firing pattern, by measuring the reliability of spike timing, P, in interneurons in the isolated...... the analysis we used a leaky integrate and fire (LIF) model with a noise term added. The LIF model was able to reproduce the experimentally observed properties of P as well as the low-pass properties of the membrane. The LIF model enabled us to use the mathematical theory of nonlinear oscillators to analyze...

Artificial spatiotemporal touch inputs reveal complementary decoding in neocortical neurons.

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Oddo, Calogero M; Mazzoni, Alberto; Spanne, Anton; Enander, Jonas M D; Mogensen, Hannes; Bengtsson, Fredrik; Camboni, Domenico; Micera, Silvestro; Jörntell, Henrik

2017-04-04

Investigations of the mechanisms of touch perception and decoding has been hampered by difficulties in achieving invariant patterns of skin sensor activation. To obtain reproducible spatiotemporal patterns of activation of sensory afferents, we used an artificial fingertip equipped with an array of neuromorphic sensors. The artificial fingertip was used to transduce real-world haptic stimuli into spatiotemporal patterns of spikes. These spike patterns were delivered to the skin afferents of the second digit of rats via an array of stimulation electrodes. Combined with low-noise intra- and extracellular recordings from neocortical neurons in vivo, this approach provided a previously inaccessible high resolution analysis of the representation of tactile information in the neocortical neuronal circuitry. The results indicate high information content in individual neurons and reveal multiple novel neuronal tactile coding features such as heterogeneous and complementary spatiotemporal input selectivity also between neighboring neurons. Such neuronal heterogeneity and complementariness can potentially support a very high decoding capacity in a limited population of neurons. Our results also indicate a potential neuroprosthetic approach to communicate with the brain at a very high resolution and provide a potential novel solution for evaluating the degree or state of neurological disease in animal models.

The Performance of Ictal Brain SPECT Localizing for Epileptogenic Zone in Neocortical Epilepsy

International Nuclear Information System (INIS)

Kim, Eun Sik; Lee, Dong Soo; Hyun, In Young; Chung, June Key; Lee, Myung Chul; Koh, Chang Soon; Lee, Sang Kun; Chang, Kee Hyun

1995-01-01

The epileptogenic zones should be localized precisely before surgical resection of these zones in intractable epilepsy. The localization is more difficult in patients with neocortical epilepsy than in patients with temporal lobe epilepsy. This study aimed at evaluation of the usefulness of ictal brain perfusion SPECT for the localization of epileptogenic zones in neocortical epilepsy. We compared the performance of ictal SPECT with MRI referring to ictal scalp electroencephalography (sEEG). Ictal 99m Tc-HMPAO SPECT were done in twenty-one patients. Ictal EEG were also obtained during video monitoring. MRI were reviewed. According to the ictal sEEG and semiology, 8 patients were frontal lobe epilepsy, 7 patients were lateral temporal lobe epilepsy, 2 patients were parietal lobe epilepsy, and 4 patients were occipital lobe epilepsy. Ictal SPECT showed hyperperfusion in 14 patients(67%) in the zones which were suspected to be epileptogenic according to ictal EEG and semiology. MRI found morphologic abnormalities in 9 patients(43%). Among the 12 patients, in whom no epileptogenic zones were revealed by MR1, ictal SPECT found zones of hyperperfusion concordant with ictal sEEG in 9 patients(75%). However, no zones of hyperperfusion were found in 4 among 9 patients who were found to have cerebromalacia, abnormal calcification and migration anomaly in MRI. We thought that ictal SPECT was useful for localization of epileptogenic zones in neocortical epilepsy and especially in patients with negative findings in MRI.

Striatal fast-spiking interneurons: from firing patterns to postsynaptic impact

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Andreas eKlaus

2011-07-01

Full Text Available In the striatal microcircuit, fast-spiking (FS interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization, do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.

Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia

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Zhihong eJiang

2013-09-01

Full Text Available Schizophrenia etiology is thought to involve an interaction between genetic and environmental factors during postnatal brain development. However, there is a fundamental gap in our understanding of the molecular mechanisms by which environmental factors interact with genetic susceptibility to trigger symptom onset and disease progression. In this review, we summarize the most recent findings implicating oxidative stress as one mechanism by which environmental insults, especially early life social stress, impact the development of schizophrenia. Based on a review of the literature and the results of our own animal model, we suggest that environmental stressors such as social isolation render parvalbumin-positive interneurons vulnerable to oxidative stress. We previously reported that social isolation stress exacerbates many of the schizophrenia-like phenotypes seen in a conditional genetic mouse model of schizophrenia in which NMDARs are selectively ablated in half of cortical and hippocampal interneurons during early postnatal development (Belforte et al., 2010. We have since revealed that this social isolation-induced effect is caused by impairments in the antioxidant defense capacity in the parvalbumin-positive interneurons in which NMDARs are ablated. We propose that this effect is mediated by the down-regulation of PGC-1α, a master regulator of mitochondrial energy metabolism and anti-oxidant defense, following the deletion of NMDARs (Jiang et al, 2013. Other potential molecular mechanisms underlying redox dysfunction upon gene and environmental interaction will be discussed, with a focus on the unique properties of parvalbumin-positive interneurons.

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives.

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Fee, Corey; Banasr, Mounira; Sibille, Etienne

2017-10-15

The functional integration of external and internal signals forms the basis of information processing and is essential for higher cognitive functions. This occurs in finely tuned cortical microcircuits whose functions are balanced at the cellular level by excitatory glutamatergic pyramidal neurons and inhibitory gamma-aminobutyric acidergic (GABAergic) interneurons. The balance of excitation and inhibition, from cellular processes to neural network activity, is characteristically disrupted in multiple neuropsychiatric disorders, including major depressive disorder (MDD), bipolar disorder, anxiety disorders, and schizophrenia. Specifically, nearly 3 decades of research demonstrate a role for reduced inhibitory GABA level and function across disorders. In MDD, recent evidence from human postmortem and animal studies suggests a selective vulnerability of GABAergic interneurons that coexpress the neuropeptide somatostatin (SST). Advances in cell type-specific molecular genetics have now helped to elucidate several important roles for SST interneurons in cortical processing (regulation of pyramidal cell excitatory input) and behavioral control (mood and cognition). Here, we review evidence for altered inhibitory function arising from GABAergic deficits across disorders and specifically in MDD. We then focus on properties of the cortical microcircuit, where SST-positive GABAergic interneuron deficits may disrupt functioning in several ways. Finally, we discuss the putative origins of SST cell deficits, as informed by recent research, and implications for therapeutic approaches. We conclude that deficits in SST interneurons represent a contributing cellular pathology and therefore a promising target for normalizing altered inhibitory function in MDD and other disorders with reduced SST cell and GABA functions. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Drosophila ovipositor extension in mating behavior and egg deposition involves distinct sets of brain interneurons.

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Ken-ichi Kimura

Full Text Available Oviposition is a female-specific behavior that directly affects fecundity, and therefore fitness. If a fertilized female encounters another male that she has evaluated to be of better quality than her previous mate, it would be beneficial for her to remate with this male rather than depositing her eggs. Females who decided not to remate exhibited rejection behavior toward a courting male and engaged in oviposition. Although recent studies of Drosophila melanogaster identified sensory neurons and putative second-order ascending interneurons that mediate uterine afferents affecting female reproductive behavior, little is known about the brain circuitry that selectively activates rejection versus oviposition behaviors. We identified the sexually dimorphic pC2l and female-specific pMN2 neurons, two distinct classes of doublesex (dsx-expressing neurons that can initiate ovipositor extension associated with rejection and oviposition behavior, respectively. pC2l interneurons, which induce ovipositor extrusion for rejection in females, have homologues that control courtship behavior in males. Activation of these two classes of neurons appears to be mutually exclusive and each governs hierarchical control of the motor program in the VNC either for rejection or oviposition, contributing centrally to the switching on or off of the alternative motor programs.

Normalization for sparse encoding of odors by a wide-field interneuron.

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Papadopoulou, Maria; Cassenaer, Stijn; Nowotny, Thomas; Laurent, Gilles

2011-05-06

Sparse coding presents practical advantages for sensory representations and memory storage. In the insect olfactory system, the representation of general odors is dense in the antennal lobes but sparse in the mushroom bodies, only one synapse downstream. In locusts, this transformation relies on the oscillatory structure of antennal lobe output, feed-forward inhibitory circuits, intrinsic properties of mushroom body neurons, and connectivity between antennal lobe and mushroom bodies. Here we show the existence of a normalizing negative-feedback loop within the mushroom body to maintain sparse output over a wide range of input conditions. This loop consists of an identifiable "giant" nonspiking inhibitory interneuron with ubiquitous connectivity and graded release properties.

Perineuronal Net Protein Neurocan Inhibits NCAM/EphA3 Repellent Signaling in GABAergic Interneurons.

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Sullivan, Chelsea S; Gotthard, Ingo; Wyatt, Elliott V; Bongu, Srihita; Mohan, Vishwa; Weinberg, Richard J; Maness, Patricia F

2018-04-18

Perineuronal nets (PNNs) are implicated in closure of critical periods of synaptic plasticity in the brain, but the molecular mechanisms by which PNNs regulate synapse development are obscure. A receptor complex of NCAM and EphA3 mediates postnatal remodeling of inhibitory perisomatic synapses of GABAergic interneurons onto pyramidal cells in the mouse frontal cortex necessary for excitatory/inhibitory balance. Here it is shown that enzymatic removal of PNN glycosaminoglycan chains decreased the density of GABAergic perisomatic synapses in mouse organotypic cortical slice cultures. Neurocan, a key component of PNNs, was expressed in postnatal frontal cortex in apposition to perisomatic synapses of parvalbumin-positive interneurons. Polysialylated NCAM (PSA-NCAM), which is required for ephrin-dependent synapse remodeling, bound less efficiently to neurocan than mature, non-PSA-NCAM. Neurocan bound the non-polysialylated form of NCAM at the EphA3 binding site within the immunoglobulin-2 domain. Neurocan inhibited NCAM/EphA3 association, membrane clustering of NCAM/EphA3 in cortical interneuron axons, EphA3 kinase activation, and ephrin-A5-induced growth cone collapse. These studies delineate a novel mechanism wherein neurocan inhibits NCAM/EphA3 signaling and axonal repulsion, which may terminate postnatal remodeling of interneuron axons to stabilize perisomatic synapses in vivo.

Interneuron Deficit Associates Attenuated Network Synchronization to Mismatch of Energy Supply and Demand in Aging Mouse Brains

DEFF Research Database (Denmark)

Jessen, Sanne Barsballe; Mathiesen, Claus; Lind, Barbara Lykke

2017-01-01

Higher cognitive functions depend critically on synchronized network activity in the gamma range (30-100 Hz), which results from activity of fast-spiking parvalbumin-positive (PV) interneurons. Here, we examined synaptic activity in the gamma band in relation to PV interneuron activity, stimulati...

Experience-Dependent Regulation of Presynaptic NMDARs Enhances Neurotransmitter Release at Neocortical Synapses

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Urban-Ciecko, Joanna; Wen, Jing A.; Parekh, Puja K.; Barth, Alison L.

2015-01-01

Sensory experience can selectively alter excitatory synaptic strength at neocortical synapses. The rapid increase in synaptic strength induced by selective whisker stimulation (single-row experience/SRE, where all but one row of whiskers has been removed from the mouse face) is due, at least in part, to the trafficking of AMPA receptors (AMPARs)…

Conical expansion of the outer subventricular zone and the role of neocortical folding in evolution and development

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Eric eLewitus

2013-08-01

Full Text Available There is a basic rule to mammalian neocortical expansion: as it expands, so does it fold. The degree to which it folds, however, cannot strictly be attributed to its expansion. Across species, cortical volume does not keep pace with cortical surface area, but rather folds appear more rapidly than expected. As a result, larger brains quickly become disproportionately more convoluted than smaller brains. Both the absence (lissencephaly and presence (gyrencephaly of cortical folds is observed in all mammalian orders and, while there is likely some phylogenetic signature to the evolutionary appearance of gyri and sulci, there are undoubtedly universal trends to the acquisition of folds in an expanding neocortex. Whether these trends are governed by conical expansion of neocortical germinal zones, the distribution of cortical connectivity, or a combination of growth- and connectivity-driven forces remains an open question. But the importance of cortical folding for evolution of the uniquely mammalian neocortex, as well as for the incidence of neuropathologies in humans, is undisputed. In this hypothesis and theory article, we will summarize the development of cortical folds in the neocortex, consider the relative influence of growth- versus connectivity-driven forces for the acquisition of cortical folds between and within species, assess the genetic, cell-biological, and mechanistic implications for neocortical expansion, and discuss the significance of these implications for human evolution, development, and disease. We will argue that evolutionary increases in the density of neuron production, achieved via maintenance of a basal proliferative niche in the neocortical germinal zones, drive the conical migration of neurons towards the cortical surface and ultimately lead to the establishment of cortical folds in large-brained mammal species.

Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

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Hedrich, Ulrike B S; Liautard, Camille; Kirschenbaum, Daniel; Pofahl, Martin; Lavigne, Jennifer; Liu, Yuanyuan; Theiss, Stephan; Slotta, Johannes; Escayg, Andrew; Dihné, Marcel; Beck, Heinz; Mantegazza, Massimo; Lerche, Holger

2014-11-05

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation. Copyright © 2014 the authors 0270-6474/14/3414874-16$15.00/0.

Crosstalk between intracellular and extracellular signals regulating interneuron production, migration and integration into the cortex

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Peyre, Elise; Silva, Carla G.; Nguyen, Laurent

2015-01-01

During embryogenesis, cortical interneurons are generated by ventral progenitors located in the ganglionic eminences of the telencephalon. They travel along multiple tangential paths to populate the cortical wall. As they reach this structure they undergo intracortical dispersion to settle in their final destination. At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Differe...

Neocortical layers I and II of the hedgehog (Erinaceus europaeus). I. Intrinsic organization.

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Valverde, F; Facal-Valverde, M V

1986-01-01

The intrinsic organization and interlaminar connections in neocortical layers I and II have been studied in adult hedgehogs (Erinaceus europaeus) using the Golgi method. Layer I contains a dense plexus of horizontal fibers, the terminal dendritic bouquets of pyramidal cells of layer II and of underlying layers, and varieties of intrinsic neurons. Four main types of cells were found in layer I. Small horizontal cells represent most probably persisting foetal horizontal cells described for other mammals. Large horizontal cells, tufted cells, and spinous horizontal cells were also found in this layer. Layer II contains primitive pyramidal cells representing the most outstanding feature of the neocortex of the hedgehog. Most pyramidal cells in layer II have two, three or more apical dendrites, richly covered by spines predominating over the basal dendrites. These cells resemble pyramidal cells found in the piriform cortex, hippocampus and other olfactory areas. It is suggested that the presence of these neurons reflects the retention of a primitive character in neocortical evolution. Cells with intrinsic axons were found among pyramidal cells in layer II. These have smooth dendrites penetrating layer I and local axons forming extremely complex terminal arborizations around the bodies and proximal dendritic portions of pyramidal cells. They most probably effect numerous axo-somatic contacts resembling basket cells. The similarity of some axonal terminals with the chandelier type of axonal arborization is discussed. Other varieties of cells located in deep cortical layers and having ascending axons for layers I and II were also studied. It is concluded that the two first neocortical layers represent a level of important integration in this primitive mammal.

A defined network of fast-spiking interneurons in orbitofrontal cortex: responses to behavioral contingencies and ketamine administration

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Michael C Quirk

2009-11-01

Full Text Available Orbitofrontal cortex (OFC is a region of prefrontal cortex implicated in the motivational control of behavior and in related abnormalities seen in psychosis and depression. It has been hypothesized that a critical mechanism in these disorders is the dysfunction of GABAergic interneurons that normally regulate prefrontal information processing. Here, we studied a subclass of interneurons isolated in rat OFC using extracellular waveform and spike train analysis. During performance of a goal-directed behavioral task, the firing of this class of putative fast-spiking (FS interneurons showed robust temporal correlations indicative of a functionally coherent network. FS cell activity also co-varied with behavioral response latency, a key indicator of motivational state. Systemic administration of ketamine, a drug that can mimic psychosis, preferentially inhibited this cell class. Together, these results support the idea that OFC-FS interneurons form a critical link in the regulation of motivation by prefrontal circuits during normal and abnormal brain and behavioral states.

Expression of gastrin-releasing peptide by excitatory interneurons in the mouse superficial dorsal horn.

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Gutierrez-Mecinas, Maria; Watanabe, Masahiko; Todd, Andrew J

2014-12-11

Gastrin-releasing peptide (GRP) and its receptor have been shown to play an important role in the sensation of itch. However, although GRP immunoreactivity has been detected in the spinal dorsal horn, there is debate about whether this originates from primary afferents or local excitatory interneurons. We therefore examined the relation of GRP immunoreactivity to that seen with antibodies that label primary afferent or excitatory interneuron terminals. We tested the specificity of the GRP antibody by preincubating with peptides with which it could potentially cross-react. We also examined tissue from a mouse line in which enhanced green fluorescent protein (EGFP) is expressed under control of the GRP promoter. GRP immunoreactivity was seen in both primary afferent and non-primary glutamatergic axon terminals in the superficial dorsal horn. However, immunostaining was blocked by pre-incubation of the antibody with substance P, which is present at high levels in many nociceptive primary afferents. EGFP+ cells in the GRP-EGFP mouse did not express Pax2, and their axons contained the vesicular glutamate transporter 2 (VGLUT2), indicating that they are excitatory interneurons. In most cases, their axons were also GRP-immunoreactive. Multiple-labelling immunocytochemical studies indicated that these cells did not express either of the preprotachykinin peptides, and that they generally lacked protein kinase Cγ, which is expressed by a subset of the excitatory interneurons in this region. These results show that GRP is expressed by a distinct population of excitatory interneurons in laminae I-II that are likely to be involved in the itch pathway. They also suggest that the GRP immunoreactivity seen in primary afferents in previous studies may have resulted from cross-reaction of the GRP antibody with substance P or the closely related peptide neurokinin A.

Patterned sensory nerve stimulation enhances the reactivity of spinal Ia inhibitory interneurons.

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Kubota, Shinji; Hirano, Masato; Morishita, Takuya; Uehara, Kazumasa; Funase, Kozo

2015-03-25

Patterned sensory nerve stimulation has been shown to induce plastic changes in the reciprocal Ia inhibitory circuit. However, the mechanisms underlying these changes have not yet been elucidated in detail. The aim of the present study was to determine whether the reactivity of Ia inhibitory interneurons could be altered by patterned sensory nerve stimulation. The degree of reciprocal Ia inhibition, the conditioning effects of transcranial magnetic stimulation (TMS) on the soleus (SOL) muscle H-reflex, and the ratio of the maximum H-reflex amplitude versus maximum M-wave (H(max)/M(max)) were examined in 10 healthy individuals. Patterned electrical nerve stimulation was applied to the common peroneal nerve every 1 s (100 Hz-5 train) at the motor threshold intensity of tibialis anterior muscle to induce activity changes in the reciprocal Ia inhibitory circuit. Reciprocal Ia inhibition, the TMS-conditioned H-reflex amplitude, and H(max)/M(max) were recorded before, immediately after, and 15 min after the electrical stimulation. The patterned electrical nerve stimulation significantly increased the degree of reciprocal Ia inhibition and decreased the amplitude of the TMS-conditioned H-reflex in the short-latency inhibition phase, which was presumably mediated by Ia inhibitory interneurons. However, it had no effect on H(max)/M(max). Our results indicated that patterned sensory nerve stimulation could modulate the activity of Ia inhibitory interneurons, and this change may have been caused by the synaptic modification of Ia inhibitory interneuron terminals. These results may lead to a clearer understanding of the spinal cord synaptic plasticity produced by repetitive sensory inputs. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Diversity in the neuronal machine: order and variability in interneuronal microcircuits

National Research Council Canada - National Science Library

Soltesz, Ivan

2006-01-01

... Disorders 42 3: Order in Diversity: From Phenomenology to Function 45 Diversity at Multiple Levels of Neuronal Organization 45 Linnean Order in Diversity: A Modern Compendium of Interneuronal Spe...

Bio-physically plausible visualization of highly scattering fluorescent neocortical models for in silico experimentation

KAUST Repository

Abdellah, Marwan

2017-02-15

Background We present a visualization pipeline capable of accurate rendering of highly scattering fluorescent neocortical neuronal models. The pipeline is mainly developed to serve the computational neurobiology community. It allows the scientists to visualize the results of their virtual experiments that are performed in computer simulations, or in silico. The impact of the presented pipeline opens novel avenues for assisting the neuroscientists to build biologically accurate models of the brain. These models result from computer simulations of physical experiments that use fluorescence imaging to understand the structural and functional aspects of the brain. Due to the limited capabilities of the current visualization workflows to handle fluorescent volumetric datasets, we propose a physically-based optical model that can accurately simulate light interaction with fluorescent-tagged scattering media based on the basic principles of geometric optics and Monte Carlo path tracing. We also develop an automated and efficient framework for generating dense fluorescent tissue blocks from a neocortical column model that is composed of approximately 31000 neurons. Results Our pipeline is used to visualize a virtual fluorescent tissue block of 50 μm3 that is reconstructed from the somatosensory cortex of juvenile rat. The fluorescence optical model is qualitatively analyzed and validated against experimental emission spectra of different fluorescent dyes from the Alexa Fluor family. Conclusion We discussed a scientific visualization pipeline for creating images of synthetic neocortical neuronal models that are tagged virtually with fluorescent labels on a physically-plausible basis. The pipeline is applied to analyze and validate simulation data generated from neuroscientific in silico experiments.

Statistical mechanics of neocortical interactions. Derivation of short-term-memory capacity

OpenAIRE

Ingber, Lester

1984-01-01

A theory developed by the author to describe macroscopic neocortical interactions demonstrates that empirical values of chemical and electrical parameters of synaptic interactions establish several minima of the path-integral Lagrangian as a function of excitatory and inhibitory columnar firings. The number of possible minima, their time scales of hysteresis and probable reverberations, and their nearest-neighbor columnar interactions are all consistent with well-established empirical rules o...

Genetic Ablation of V2a Ipsilateral Interneurons Disrupts Left-Right Locomotor Coordination in Mammalian Spinal Cord

DEFF Research Database (Denmark)

Crone, Steven A.; Quinlan, Katharina A.; Zagoraiou, Laskaro

2008-01-01

The initiation and coordination of activity in limb muscles are the main functions of neural circuits that control locomotion. Commissural neurons connect locomotor circuits on the two sides of the spinal cord, and represent the known neural substrate for left-right coordination. Here we......-extensor coordination is unaffected. Anatomical tracing studies reveal a direct excitatory input of V2a interneurons onto commissural interneurons, including a set of molecularly defined V0 neurons that drive left-right alternation. Our findings imply that the neural substrate for left-right coordination consists...... of at least two components; commissural neurons and a class of ipsilateral interneurons that activate commissural pathways....

Modulation of Apoptosis Controls Inhibitory Interneuron Number in the Cortex

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Myrto Denaxa

2018-02-01

Full Text Available Cortical networks are composed of excitatory projection neurons and inhibitory interneurons. Finding the right balance between the two is important for controlling overall cortical excitation and network dynamics. However, it is unclear how the correct number of cortical interneurons (CIs is established in the mammalian forebrain. CIs are generated in excess from basal forebrain progenitors, and their final numbers are adjusted via an intrinsically determined program of apoptosis that takes place during an early postnatal window. Here, we provide evidence that the extent of CI apoptosis during this critical period is plastic and cell-type specific and can be reduced in a cell-autonomous manner by acute increases in neuronal activity. We propose that the physiological state of the emerging neural network controls the activity levels of local CIs to modulate their numbers in a homeostatic manner.

LTS and FS inhibitory interneurons, short-term synaptic plasticity, and cortical circuit dynamics.

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Itai Hayut

2011-10-01

Full Text Available Somatostatin-expressing, low threshold-spiking (LTS cells and fast-spiking (FS cells are two common subtypes of inhibitory neocortical interneuron. Excitatory synapses from regular-spiking (RS pyramidal neurons to LTS cells strongly facilitate when activated repetitively, whereas RS-to-FS synapses depress. This suggests that LTS neurons may be especially relevant at high rate regimes and protect cortical circuits against over-excitation and seizures. However, the inhibitory synapses from LTS cells usually depress, which may reduce their effectiveness at high rates. We ask: by which mechanisms and at what firing rates do LTS neurons control the activity of cortical circuits responding to thalamic input, and how is control by LTS neurons different from that of FS neurons? We study rate models of circuits that include RS cells and LTS and FS inhibitory cells with short-term synaptic plasticity. LTS neurons shift the RS firing-rate vs. current curve to the right at high rates and reduce its slope at low rates; the LTS effect is delayed and prolonged. FS neurons always shift the curve to the right and affect RS firing transiently. In an RS-LTS-FS network, FS neurons reach a quiescent state if they receive weak input, LTS neurons are quiescent if RS neurons receive weak input, and both FS and RS populations are active if they both receive large inputs. In general, FS neurons tend to follow the spiking of RS neurons much more closely than LTS neurons. A novel type of facilitation-induced slow oscillations is observed above the LTS firing threshold with a frequency determined by the time scale of recovery from facilitation. To conclude, contrary to earlier proposals, LTS neurons affect the transient and steady state responses of cortical circuits over a range of firing rates, not only during the high rate regime; LTS neurons protect against over-activation about as well as FS neurons.

Amelioration of improper differentiation of somatostatin-positive interneurons by triiodothyronine in a growth-retarded hypothyroid mouse strain.

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Uchida, Katsuya; Taguchi, Yusuke; Sato, Chika; Miyazaki, Hidetaka; Kobayashi, Kenichi; Kobayashi, Tetsuya; Itoi, Keiichi

2014-01-24

Thyroid hormone (TH) plays an important role in brain development, and TH deficiency during pregnancy or early postnatal periods leads to neurological disorders such as cretinism. Hypothyroidism reduces the number of parvalbumin (PV)-positive interneurons in the neocortex and hippocampus. Here we used a mouse strain (growth-retarded; grt) that shows growth retardation and hypothyroidism to examine whether somatostatin (Sst)-positive interneurons that are generated from the same pool of neural progenitor cells as PV-positive cells are also altered by TH deficiency. The number of PV-positive interneurons was significantly decreased in the neocortex and hippocampus of grt mice as compared with normal control mice. In contrast to the decrease in the number of PV neurons, the number of Sst-positive interneurons in grt mice was increased in the stratum oriens of the hippocampus and the hilus of the dentate gyrus, although their number was unchanged in the neocortex. These changes were reversed by triiodothyronine administration from postnatal day (PD) 0 to 20. TH supplementation that was initiated after PD21 did not, however, affect the number of PV- or Sst-positive cells. These results suggest that during the first three postnatal weeks, TH may be critical for the generation of subpopulations of interneurons. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Stuttering interneurons generate fast and robust inhibition onto projection neurons with low capacity of short term modulation in mouse lateral amygdala.

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Chen Song

Full Text Available The stuttering interneurons (STi represent one minor subset of interneuron population and exhibit characteristic stuttering firing upon depolarization current injection. While it has been long held that the GABAergic inhibitory transmission largely varies with the subtype identity of presynaptic interneurons, whether such a rule also applies to STi is largely unknown. Here, by paired recording of interneuron and their neighboring projection neuron in lateral amygdala, we found that relative to the fast spiking and late spiking interneurons, the STi-evoked unitary postsynaptic currents onto the projection neurons had markedly larger amplitude, shorter onset latency and faster rising and decay kinetics. The quantal content and the number of vesicles in the readily releasable pool were also larger in synapses made by STi versus other interneurons. Moreover, the short-term plasticity, as reflected by the paired pulse depression and depolarization-induced suppression of inhibition, was the least prominent in the output synapses of STi. Thus, the fast and robust inhibition together with its low capacity of short term modulation may suggest an important role for STi in preventing the overexcitation of the projection neurons and thus gating the information traffic in amygdala.

The Onecut Transcription Factors Regulate Differentiation and Distribution of Dorsal Interneurons during Spinal Cord Development

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Karolina U. Kabayiza

2017-05-01

Full Text Available During embryonic development, the dorsal spinal cord generates numerous interneuron populations eventually involved in motor circuits or in sensory networks that integrate and transmit sensory inputs from the periphery. The molecular mechanisms that regulate the specification of these multiple dorsal neuronal populations have been extensively characterized. In contrast, the factors that contribute to their diversification into smaller specialized subsets and those that control the specific distribution of each population in the developing spinal cord remain unknown. Here, we demonstrate that the Onecut transcription factors, namely Hepatocyte Nuclear Factor-6 (HNF-6 (or OC-1, OC-2 and OC-3, regulate the diversification and the distribution of spinal dorsal interneuron (dINs. Onecut proteins are dynamically and differentially distributed in spinal dINs during differentiation and migration. Analyzes of mutant embryos devoid of Onecut factors in the developing spinal cord evidenced a requirement in Onecut proteins for proper production of a specific subset of dI5 interneurons. In addition, the distribution of dI3, dI5 and dI6 interneuron populations was altered. Hence, Onecut transcription factors control genetic programs that contribute to the regulation of spinal dIN diversification and distribution during embryonic development.

HDAC2 expression in parvalbumin interneurons regulates synaptic plasticity in the mouse visual cortex

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Alexi Nott

2015-01-01

Full Text Available An experience-dependent postnatal increase in GABAergic inhibition in the visual cortex is important for the closure of a critical period of enhanced synaptic plasticity. Although maturation of the subclass of parvalbumin (Pv–expressing GABAergic interneurons is known to contribute to critical period closure, the role of epigenetics on cortical inhibition and synaptic plasticity has not been explored. The transcription regulator, histone deacetylase 2 (HDAC2, has been shown to modulate synaptic plasticity and learning processes in hippocampal excitatory neurons. We found that genetic deletion of HDAC2 specifically from Pv interneurons reduces inhibitory input in the visual cortex of adult mice and coincides with enhanced long-term depression that is more typical of young mice. These findings show that HDAC2 loss in Pv interneurons leads to a delayed closure of the critical period in the visual cortex and supports the hypothesis that HDAC2 is a key negative regulator of synaptic plasticity in the adult brain.

HDAC2 expression in parvalbumin interneurons regulates synaptic plasticity in the mouse visual cortex.

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Nott, Alexi; Cho, Sukhee; Seo, Jinsoo; Tsai, Li-Huei

2015-01-01

An experience-dependent postnatal increase in GABAergic inhibition in the visual cortex is important for the closure of a critical period of enhanced synaptic plasticity. Although maturation of the subclass of Parvalbumin (Pv)-expressing GABAergic interneurons is known to contribute to critical period closure, the role of epigenetics on cortical inhibition and synaptic plasticity has not been explored. The transcription regulator, histone deacetylase 2 (HDAC2), has been shown to modulate synaptic plasticity and learning processes in hippocampal excitatory neurons. We found that genetic deletion of HDAC2 specifically from Pv-interneurons reduces inhibitory input in the visual cortex of adult mice, and coincides with enhanced long-term depression (LTD) that is more typical of young mice. These findings show that HDAC2 loss in Pv-interneurons leads to a delayed closure of the critical period in the visual cortex and supports the hypothesis that HDAC2 is a key negative regulator of synaptic plasticity in the adult brain.

Striatal fast-spiking interneurons selectively modulate circuit output and are required for habitual behavior.

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O'Hare, Justin K; Li, Haofang; Kim, Namsoo; Gaidis, Erin; Ade, Kristen; Beck, Jeff; Yin, Henry; Calakos, Nicole

2017-09-05

Habit formation is a behavioral adaptation that automates routine actions. Habitual behavior correlates with broad reconfigurations of dorsolateral striatal (DLS) circuit properties that increase gain and shift pathway timing. The mechanism(s) for these circuit adaptations are unknown and could be responsible for habitual behavior. Here we find that a single class of interneuron, fast-spiking interneurons (FSIs), modulates all of these habit-predictive properties. Consistent with a role in habits, FSIs are more excitable in habitual mice compared to goal-directed and acute chemogenetic inhibition of FSIs in DLS prevents the expression of habitual lever pressing. In vivo recordings further reveal a previously unappreciated selective modulation of SPNs based on their firing patterns; FSIs inhibit most SPNs but paradoxically promote the activity of a subset displaying high fractions of gamma-frequency spiking. These results establish a microcircuit mechanism for habits and provide a new example of how interneurons mediate experience-dependent behavior.

Thalamocortical Projection Neuron and Interneuron Numbers in the Visual Thalamic Nuclei of the Adult C57BL/6 Mouse.

Science.gov (United States)

Evangelio, Marian; García-Amado, María; Clascá, Francisco

2018-01-01

A key parameter to constrain predictive, bottom-up circuit models of a given brain domain is the number and position of the neuronal populations involved. These include not only the neurons whose bodies reside within the domain, but also the neurons in distant regions that innervate the domain. The mouse visual cortex receives its main subcortical input from the dorsal lateral geniculate nucleus (dLGN) and the lateral posterior (LP) complex of the thalamus. The latter consists of three different nuclei: lateral posterior lateral (LPL), lateral posterior medial rostral (LPMR), and lateral posterior medial caudal (LPMC), each exhibiting specific patterns of connections with the various visual cortical areas. Here, we have determined the number of thalamocortical projection neurons and interneurons in the LP complex and dLGN of the adult C57BL/6 male mouse. We combined Nissl staining and histochemical and immunolabeling methods for consistently delineating nuclei borders, and applied unbiased stereological cell counting methods. Thalamic interneurons were identified using GABA immunolabeling. The C57BL/6 dLGN contains ∼21,200 neurons, while LP complex contains ∼31,000 total neurons. The dLGN and LP are the only nuclei of the mouse dorsal thalamus containing substantial numbers GABA-immunoreactive interneurons. These interneurons, however, are scarcer than previously estimated; they are 5.6% of dLGN neurons and just 1.9% of the LP neurons. It can be thus inferred that the dLGN contains ∼20,000 and the LP complex ∼30,400 thalamocortical projection neurons (∼12,000 in LPL, 15,200 in LPMR, and 4,200 in LPMC). The present dataset is relevant for constraining models of mouse visual thalamocortical circuits, as well as for quantitative comparisons between genetically modified mouse strains, or across species.

Serotonin receptor 3A controls interneuron migration into the neocortex

NARCIS (Netherlands)

Murthy, S.; Niquille, M.; Hurni, N.; Limoni, G.; Frazer, S.; Chameau, P.; van Hooft, J.A.; Vitalis, T.; Dayer, A.

2014-01-01

Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic

Functional diversity of supragranular GABAergic neurons in the barrel cortex

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Luc J Gentet

2012-08-01

Full Text Available Although the neocortex forms a distributed system comprised of several functional areas, its vertical columnar organization is largely conserved across areas and species, suggesting the existence of a canonical neocortical microcircuit. In order to elucidate the principles governing the organization of such a cortical diagram, a detailed understanding of the dynamics binding different types of cortical neurons into a coherent algorithm is essential. Within this complex circuitry, GABAergic interneurons, while forming approximately only 15-20% of all cortical neurons, appear critical in maintaining a dynamic balance between excitation and inhibition. Despite their importance, cortical GABAergic neurons have not been extensively studied in vivo and their precise role in shaping the local microcircuit sensory response still remains to be determined. Their paucity, combined with their molecular, anatomical and physiological diversity, has made it difficult to even establish a consensual nomenclature.However, recent technological advances in microscopy and mouse genetics have fostered a renewed interest in neocortical interneurons by putting them within visible reach of experimenters. The anatomically well-defined whisker-to-barrel pathway of the rodent is particularly amenable to studies attempting to link cortical circuit dynamics to behavior. To each whisker corresponds a discrete cortical unit equivalent to a single column, specialized in the encoding and processing of the sensory information it receives. In this review, we will focus on the functional role that each subtype of supragranular GABAergic neuron embedded within such a single neocortical unit may play in shaping the dynamics of the local circuit during somatosensory integration.

Probing phase- and frequency-dependent characteristics of cortical interneurons using combined transcranial alternating current stimulation and transcranial magnetic stimulation.

Science.gov (United States)

Hussain, Sara J; Thirugnanasambandam, Nivethida

2017-06-01

Paired-pulse transcranial magnetic stimulation (TMS) and peripheral stimulation combined with TMS can be used to study cortical interneuronal circuitry. By combining these procedures with concurrent transcranial alternating current stimulation (tACS), Guerra and colleagues recently showed that different cortical interneuronal populations are differentially modulated by the phase and frequency of tACS-imposed oscillations (Guerra A, Pogosyan A, Nowak M, Tan H, Ferreri F, Di Lazzaro V, Brown P. Cerebral Cortex 26: 3977-2990, 2016). This work suggests that different cortical interneuronal populations can be characterized by their phase and frequency dependency. Here we discuss how combining TMS and tACS can reveal the frequency at which cortical interneuronal populations oscillate, the neuronal origins of behaviorally relevant cortical oscillations, and how entraining cortical oscillations could potentially treat brain disorders. Copyright © 2017 the American Physiological Society.

Caudal Ganglionic Eminence Precursor Transplants Disperse and Integrate as Lineage-Specific Interneurons but Do Not Induce Cortical Plasticity

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Phillip Larimer

2016-08-01

Full Text Available The maturation of inhibitory GABAergic cortical circuits regulates experience-dependent plasticity. We recently showed that the heterochronic transplantation of parvalbumin (PV or somatostatin (SST interneurons from the medial ganglionic eminence (MGE reactivates ocular dominance plasticity (ODP in the postnatal mouse visual cortex. Might other types of interneurons similarly induce cortical plasticity? Here, we establish that caudal ganglionic eminence (CGE-derived interneurons, when transplanted into the visual cortex of neonatal mice, migrate extensively in the host brain and acquire laminar distribution, marker expression, electrophysiological properties, and visual response properties like those of host CGE interneurons. Although transplants from the anatomical CGE do induce ODP, we found that this plasticity reactivation is mediated by a small fraction of MGE-derived cells contained in the transplant. These findings demonstrate that transplanted CGE cells can successfully engraft into the postnatal mouse brain and confirm the unique role of MGE lineage neurons in the induction of ODP.

Large variability in synaptic N-methyl-D-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus.

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Nyíri, G; Stephenson, F A; Freund, T F; Somogyi, P

2003-01-01

Pyramidal cells receive input from several types of GABA-releasing interneurons and innervate them reciprocally. Glutamatergic activation of interneurons involves both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) type glutamate receptors expressed in type I synapses, mostly on their dendritic shafts. On average, the synaptic AMPA receptor content is several times higher on interneurons than in the spines of pyramidal cells. To compare the NMDA receptor content of synapses, we used a quantitative postembedding immunogold technique on serial electron microscopic sections, and analysed the synapses on interneuron dendrites and pyramidal cell spines in the CA1 area. Because all NMDA receptors contain the obligatory NR1 subunit, receptor localisation was carried out using antibodies recognising all splice variants of the NR1 subunit. Four populations of synapse were examined: i). on spines of pyramidal cells in stratum (str.) radiatum and str. oriens; ii). on parvalbumin-positive interneuronal dendritic shafts in str. radiatum; iii). on randomly found dendritic shafts in str. oriens and iv). on somatostatin-positive interneuronal dendritic shafts and somata in str. oriens. On average, the size of the synapses on spines was about half of those on interneurons. The four populations of synapse significantly differed in labelling for the NR1 subunit. The median density of NR1 subunit labelling was highest on pyramidal cell spines. It was lowest in the synapses on parvalbumin-positive dendrites in str. radiatum, where more than half of these synapses were immunonegative. In str. oriens, synapses on interneurons had a high variability of receptor content; some dendrites were similar to those in str. radiatum, including the proximal synapses of somatostatin-positive cells, whereas others had immunoreactivity for the NR1 subunit similar to or higher than synapses on pyramidal cell spines. These results show that synaptic NMDA

Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice

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Leung, Laura; Andrews-Zwilling, Yaisa; Yoon, Seo Yeon; Jain, Sachi; Ring, Karen; Dai, Jessica; Wang, Max Mu; Tong, Leslie; Walker, David; Huang, Yadong

2012-01-01

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive–but not NPY- or parvalbumin-positive–interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype. PMID:23300939

The Sub-Regional Functional Organization of Neocortical Irritative Epileptic Networks in Pediatric Epilepsy

Czech Academy of Sciences Publication Activity Database

Janča, R.; Kršek, P.; Ježdík, P.; Čmejla, R.; Tomášek, M.; Komárek, V.; Marusič, P.; Jiruška, Přemysl

2018-01-01

Roč. 9, Mar 23 (2018), č. článku 184. ISSN 1664-2295 R&D Projects: GA MZd(CZ) NV15-29835A Institutional support: RVO:67985823 Keywords : interictal epileptiform discharges * brain networks * epilepsy surgery * irritative zone * propagation * neocortical epilepsy Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology Impact factor: 3.552, year: 2016

Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Aβ accumulation.

Science.gov (United States)

Tong, Leslie M; Djukic, Biljana; Arnold, Christine; Gillespie, Anna K; Yoon, Seo Yeon; Wang, Max M; Zhang, Olivia; Knoferle, Johanna; Rubenstein, John L R; Alvarez-Buylla, Arturo; Huang, Yadong

2014-07-16

Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases. Copyright © 2014 the authors 0270-6474/14/349506-10$15.00/0.

A Cyfip2-Dependent Excitatory Interneuron Pathway Establishes the Innate Startle Threshold.

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Marsden, Kurt C; Jain, Roshan A; Wolman, Marc A; Echeverry, Fabio A; Nelson, Jessica C; Hayer, Katharina E; Miltenberg, Ben; Pereda, Alberto E; Granato, Michael

2018-04-17

Sensory experiences dynamically modify whether animals respond to a given stimulus, but it is unclear how innate behavioral thresholds are established. Here, we identify molecular and circuit-level mechanisms underlying the innate threshold of the zebrafish startle response. From a forward genetic screen, we isolated five mutant lines with reduced innate startle thresholds. Using whole-genome sequencing, we identify the causative mutation for one line to be in the fragile X mental retardation protein (FMRP)-interacting protein cyfip2. We show that cyfip2 acts independently of FMRP and that reactivation of cyfip2 restores the baseline threshold after phenotype onset. Finally, we show that cyfip2 regulates the innate startle threshold by reducing neural activity in a small group of excitatory hindbrain interneurons. Thus, we identify a selective set of genes critical to establishing an innate behavioral threshold and uncover a circuit-level role for cyfip2 in this process. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro.

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Hassel, Bjørnar; Elsais, Ahmed; Frøland, Anne-Sofie; Taubøll, Erik; Gjerstad, Leif; Quan, Yi; Dingledine, Raymond; Rise, Frode

2015-05-01

Fructose reacts spontaneously with proteins in the brain to form advanced glycation end products (AGE) that may elicit neuroinflammation and cause brain pathology, including Alzheimer's disease. We investigated whether fructose is eliminated by oxidative metabolism in neocortex. Injection of [(14) C]fructose or its AGE-prone metabolite [(14) C]glyceraldehyde into rat neocortex in vivo led to formation of (14) C-labeled alanine, glutamate, aspartate, GABA, and glutamine. In isolated neocortical nerve terminals, [(14) C]fructose-labeled glutamate, GABA, and aspartate, indicating uptake of fructose into nerve terminals and oxidative fructose metabolism in these structures. This was supported by high expression of hexokinase 1, which channels fructose into glycolysis, and whose activity was similar with fructose or glucose as substrates. By contrast, the fructose-specific ketohexokinase was weakly expressed. The fructose transporter Glut5 was expressed at only 4% of the level of neuronal glucose transporter Glut3, suggesting transport across plasma membranes of brain cells as the limiting factor in removal of extracellular fructose. The genes encoding aldose reductase and sorbitol dehydrogenase, enzymes of the polyol pathway that forms glucose from fructose, were expressed in rat neocortex. These results point to fructose being transported into neocortical cells, including nerve terminals, and that it is metabolized and thereby detoxified primarily through hexokinase activity. We asked how the brain handles fructose, which may react spontaneously with proteins to form 'advanced glycation end products' and trigger inflammation. Neocortical cells took up and metabolized extracellular fructose oxidatively in vivo, and isolated nerve terminals did so in vitro. The low expression of fructose transporter Glut5 limited uptake of extracellular fructose. Hexokinase was a main pathway for fructose metabolism, but ketohexokinase (which leads to glyceraldehyde formation) was

Differentiation and functional incorporation of embryonic stem cell-derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy.

Science.gov (United States)

Maisano, Xu; Litvina, Elizabeth; Tagliatela, Stephanie; Aaron, Gloster B; Grabel, Laura B; Naegele, Janice R

2012-01-04

Cell therapies for neurological disorders require an extensive knowledge of disease-associated neuropathology and procedures for generating neurons for transplantation. In many patients with severe acquired temporal lobe epilepsy (TLE), the dentate gyrus exhibits sclerosis and GABAergic interneuron degeneration. Mounting evidence suggests that therapeutic benefits can be obtained by transplanting fetal GABAergic progenitors into the dentate gyrus in rodents with TLE, but the scarcity of human fetal cells limits applicability in patient populations. In contrast, virtually limitless quantities of neural progenitors can be obtained from embryonic stem (ES) cells. ES cell-based therapies for neurological repair in TLE require evidence that the transplanted neurons integrate functionally and replace cell types that degenerate. To address these issues, we transplanted mouse ES cell-derived neural progenitors (ESNPs) with ventral forebrain identities into the hilus of the dentate gyrus of mice with TLE and evaluated graft differentiation, mossy fiber sprouting, cellular morphology, and electrophysiological properties of the transplanted neurons. In addition, we compared electrophysiological properties of the transplanted neurons with endogenous hilar interneurons in mice without TLE. The majority of transplanted ESNPs differentiated into GABAergic interneuron subtypes expressing calcium-binding proteins parvalbumin, calbindin, or calretinin. Global suppression of mossy fiber sprouting was not observed; however, ESNP-derived neurons formed dense axonal arborizations in the inner molecular layer and throughout the hilus. Whole-cell hippocampal slice electrophysiological recordings and morphological analyses of the transplanted neurons identified five basic types; most with strong after-hyperpolarizations and smooth or sparsely spiny dendritic morphologies resembling endogenous hippocampal interneurons. Moreover, intracellular recordings of spontaneous EPSCs indicated that

Effects of active conductance distribution over dendrites on the synaptic integration in an identified nonspiking interneuron.

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Akira Takashima

Full Text Available The synaptic integration in individual central neuron is critically affected by how active conductances are distributed over dendrites. It has been well known that the dendrites of central neurons are richly endowed with voltage- and ligand-regulated ion conductances. Nonspiking interneurons (NSIs, almost exclusively characteristic to arthropod central nervous systems, do not generate action potentials and hence lack voltage-regulated sodium channels, yet having a variety of voltage-regulated potassium conductances on their dendritic membrane including the one similar to the delayed-rectifier type potassium conductance. It remains unknown, however, how the active conductances are distributed over dendrites and how the synaptic integration is affected by those conductances in NSIs and other invertebrate neurons where the cell body is not included in the signal pathway from input synapses to output sites. In the present study, we quantitatively investigated the functional significance of active conductance distribution pattern in the spatio-temporal spread of synaptic potentials over dendrites of an identified NSI in the crayfish central nervous system by computer simulation. We systematically changed the distribution pattern of active conductances in the neuron's multicompartment model and examined how the synaptic potential waveform was affected by each distribution pattern. It was revealed that specific patterns of nonuniform distribution of potassium conductances were consistent, while other patterns were not, with the waveform of compound synaptic potentials recorded physiologically in the major input-output pathway of the cell, suggesting that the possibility of nonuniform distribution of potassium conductances over the dendrite cannot be excluded as well as the possibility of uniform distribution. Local synaptic circuits involving input and output synapses on the same branch or on the same side were found to be potentially affected under

The HIV-1 viral protein Tat increases glutamate and decreases GABA exocytosis from human and mouse neocortical nerve endings.

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Musante, Veronica; Summa, Maria; Neri, Elisa; Puliti, Aldamaria; Godowicz, Tomasz T; Severi, Paolo; Battaglia, Giuseppe; Raiteri, Maurizio; Pittaluga, Anna

2010-08-01

Human immunodeficiency virus-1 (HIV-1)-encoded transactivator of transcription (Tat) potentiated the depolarization-evoked exocytosis of [(3)H]D-aspartate ([(3)H]D-ASP) from human neocortical terminals. The metabotropic glutamate (mGlu) 1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) prevented this effect, whereas the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) was ineffective. Western blot analysis showed that human neocortex synaptosomes possess mGlu1 and mGlu5 receptors. Tat potentiated the K(+)-evoked release of [(3)H]D-ASP or of endogenous glutamate from mouse neocortical synaptosomes in a CPCCOEt-sensitive and MPEP-insensitive manner. Deletion of mGlu1 receptors (crv4/crv4 mice) or mGlu5 receptors (mGlu5(-/-)mouse) silenced Tat effects. Tat enhanced inositol 1,4,5-trisphosphate production in human and mouse neocortical synaptosomes, consistent with the involvement of group I mGlu receptors. Tat inhibited the K(+)-evoked release of [(3)H]gamma-aminobutyric acid ([(3)H]GABA) from human synaptosomes and that of endogenous GABA or [(3)H]GABA from mouse nerve terminals; the inhibition was insensitive to CPCCOEt or MPEP. Tat-induced effects were retained by Tat(37-72) but not by Tat(48-85). In mouse neocortical slices, Tat facilitated the K(+)- and the veratridine-induced release of [(3)H]D-ASP in a CPCCOEt-sensitive manner and was ineffective in crv4/crv4 mouse slices. These observations are relevant to the comprehension of the pathophysiological effects of Tat in central nervous system and may suggest new potential therapeutic approaches to the cure of HIV-1-associated dementia.

Determination of the phospholipid precursor of anandamide and other N- acylethanolamine phospholipids before and after sodium azide-induced toxicity in cultured neocortical neurons

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Hansen, H.H.; Schousboe, A.; Hansen, Harald S.

2000-01-01

Phospholipase D-mediated hydrolysis of N-acylethanolamine phospholipids (NAPEs) releases anandamide and other N-acylethanolamines, resulting in different actions at cellular targets in the CNS. Recently, we have demonstrated that these N-acyl lipids accumulate in cultured neocortical neurons subj...... method, neuronal NAPE species can be identified and quantified with respect to N-acyl composition, including a trans-isomer of the anandamide precursor. The anandamide precursor is up-regulated to the same extent as other NAPEs upon neuronal injury....

Characterization of focal cortical dysplasia with balloon cells by layer-specific markers: Evidence for differential vulnerability of interneurons.

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Nakagawa, Julia M; Donkels, Catharina; Fauser, Susanne; Schulze-Bonhage, Andreas; Prinz, Marco; Zentner, Josef; Haas, Carola A

2017-04-01

Focal cortical dysplasia (FCD) is a major cause of pharmacoresistant focal epilepsy. Little is known about the pathomechanisms underlying the characteristic cytoarchitectural abnormalities associated with FCD. In the present study, a broad panel of markers identifying layer-specific neuron subpopulations was applied to characterize dyslamination and structural alterations in FCD with balloon cells (FCD 2b). Pan-neuronal neuronal nuclei (NeuN) and layer-specific protein expression (Reelin, Calbindin, Calretinin, SMI32 (nonphosphorylated neurofilament H), Parvalbumin, transducin-like enhancer protein 4 (TLE4), and Vimentin) was studied by immunohistochemistry on paraffin sections of FCD2b cases (n = 22) and was compared to two control groups with (n = 7) or without epilepsy (n = 4 postmortem cases). Total and layer-specific neuron densities were systematically quantified by cell counting considering age at surgery and brain region. We show that in FCD2b total neuron densities across all six cortical layers were not significantly different from controls. In addition, we present evidence that a basic laminar arrangement of layer-specific neuron subtypes was preserved despite the severe disturbance of cortical structure. SMI32-positive pyramidal neurons showed no significant difference in total numbers, but a reduction in layers III and V. The densities of supragranular Calbindin- and Calretinin-positive interneurons in layers II and III were not different from controls, whereas Parvalbumin-expressing interneurons, primarily located in layer IV, were significantly reduced in numbers when compared to control cases without epilepsy. In layer VI, the density of TLE4-positive projection neurons was significantly increased. Altogether, these data show that changes in cellular composition mainly affect deep cortical layers in FCD2b. The application of a broad panel of markers defining layer-specific neuronal subpopulations revealed that in FCD2b neuronal diversity and a basic

The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor.

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Sanders, Jarred; Nagy, Stanislav; Fetterman, Graham; Wright, Charles; Treinin, Millet; Biron, David

2013-12-17

To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this protective behavioral response. ALA was required for the inhibition of egg-laying in response to a strong (picking-like) mechanical stimulus, characteristic of routine handling of the animals. Moreover, ALA did not respond physiologically to less intense touch stimuli, but exhibited distinct physiological responses to anterior and posterior picking-like touch, suggesting that it could distinguish between spatially separated stimuli. These responses required neither neurotransmitter nor neuropeptide release from potential upstream neurons. In contrast, the long, bilaterally symmetric processes of ALA itself were required for producing its physiological responses; when they were severed, responses to stimuli administered between the cut and the cell body were unaffected, while responses to stimuli administered posterior to the cut were abolished. C. elegans neurons are typically classified into three major groups: sensory neurons with specialized sensory dendrites, interneurons, and motoneurons with neuromuscular junctions. Our findings suggest that ALA can autonomously sense intense touch and is thus a dual-function neuron, i.e., an interneuron as well as a novel high-threshold mechanosensor.

Axonal regeneration and development of de novo axons from distal dendrites of adult feline commissural interneurons after a proximal axotomy

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Fenrich, Keith K; Skelton, Nicole; MacDermid, Victoria E

2007-01-01

Following proximal axotomy, several types of neurons sprout de novo axons from distal dendrites. These processes may represent a means of forming new circuits following spinal cord injury. However, it is not know whether mammalian spinal interneurons, axotomized as a result of a spinal cord injury......, develop de novo axons. Our goal was to determine whether spinal commissural interneurons (CINs), axotomized by 3-4-mm midsagittal transection at C3, form de novo axons from distal dendrites. All experiments were performed on adult cats. CINs in C3 were stained with extracellular injections of Neurobiotin...... at 4-5 weeks post injury. The somata of axotomized CINs were identified by the presence of immunoreactivity for the axonal growth-associated protein-43 (GAP-43). Nearly half of the CINs had de novo axons that emerged from distal dendrites. These axons lacked immunoreactivity for the dendritic protein...

Immune Regulator MCPIP1 Modulates TET Expression during Early Neocortical Development

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Huihui Jiang

2016-09-01

Full Text Available MCPIP1 is a recently identified immune regulator that plays critical roles in preventing immune disorders, and is also present in the brain. Currently an unresolved question remains as to how MCPIP1 performs its non-immune functions in normal brain development. Here, we report that MCPIP1 is abundant in neural progenitor cells (NPCs and newborn neurons during the early stages of neurogenesis. The suppression of MCPIP1 expression impairs normal neuronal differentiation, cell-cycle exit, and concomitant NPC proliferation. MCPIP1 is important for maintenance of the NPC pool. Notably, we demonstrate that MCPIP1 reduces TET (TET1/TET2/TET3 levels and then decreases 5-hydroxymethylcytosine levels. Furthermore, the MCPIP1 interaction with TETs is involved in neurogenesis and in establishing the proper number of NPCs in vivo. Collectively, our findings not only demonstrate that MCPIP1 plays an important role in early cortical neurogenesis but also reveal an unexpected link between neocortical development, immune regulators, and epigenetic modification.

Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers.

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Lanjakornsiripan, Darin; Pior, Baek-Jun; Kawaguchi, Daichi; Furutachi, Shohei; Tahara, Tomoaki; Katsuyama, Yu; Suzuki, Yutaka; Fukazawa, Yugo; Gotoh, Yukiko

2018-04-24

Non-pial neocortical astrocytes have historically been thought to comprise largely a nondiverse population of protoplasmic astrocytes. Here we show that astrocytes of the mouse somatosensory cortex manifest layer-specific morphological and molecular differences. Two- and three-dimensional observations revealed that astrocytes in the different layers possess distinct morphologies as reflected by differences in cell orientation, territorial volume, and arborization. The extent of ensheathment of synaptic clefts by astrocytes in layer II/III was greater than that by those in layer VI. Moreover, differences in gene expression were observed between upper-layer and deep-layer astrocytes. Importantly, layer-specific differences in astrocyte properties were abrogated in reeler and Dab1 conditional knockout mice, in which neuronal layers are disturbed, suggesting that neuronal layers are a prerequisite for the observed morphological and molecular differences of neocortical astrocytes. This study thus demonstrates the existence of layer-specific interactions between neurons and astrocytes, which may underlie their layer-specific functions.

Nox-2-mediated phenotype loss of hippocampal parvalbumin interneurons might contribute to postoperative cognitive decline in aging mice

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lili qiu

2016-10-01

Full Text Available Postoperative cognitive decline (POCD is a common complication following anesthesia and surgery, especially in elderly patients; however, the precise mechanisms of POCD remain unclear. Here, we investigated whether nicotinamide adenine dinucleotide phosphate (NADPH oxidase mediated-abnormalities in parvalbumin (PV interneurons play an important role in the pathophysiology of POCD. The animal model was established using isoflurane anesthesia and exploratory laparotomy in sixteen-month-old male C57BL/6 mice. For interventional experiments, mice were chronically treated with the NADPH oxidase inhibitor apocynin (APO. Open field and fear conditioning behavioral tests were performed on day 6 and 7 post-surgery, respectively. In a separate experiment, brain tissue was harvested and subjected to biochemical analysis. Primary hippocampal neurons challenged with lipopolysaccharide in vitro were used to investigate the mechanisms underlying the oxidative stress-induced abnormalities in PV interneurons. Our results showed that anesthesia and surgery induced significant hippocampus-dependent memory impairment, which was accompanied by PV interneuron phenotype loss and increased expression of interleukin-1β, markers of oxidative stress, and NADPH oxidase 2 (Nox2 in the hippocampus. In addition, lipopolysaccharide exposure increased Nox2 level and decreased the expression of PV and the number of excitatory synapses onto PV interneurons in the primary hippocampal neurons. Notably, treatment with APO reversed these abnormalities. Our study suggests that Nox2-derived ROS production triggers, at least in part, anesthesia- and surgery-induced hippocampal PV interneuron phenotype loss and consequent cognitive impairment in aging mice.

Aberrant Epigenetic Gene Regulation in GABAergic Interneuron Subpopulations in the Hippocampal Dentate Gyrus of Mouse Offspring Following Developmental Exposure to Hexachlorophene.

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Watanabe, Yousuke; Abe, Hajime; Nakajima, Kota; Ideta-Otsuka, Maky; Igarashi, Katsuhide; Woo, Gye-Hyeong; Yoshida, Toshinori; Shibutani, Makoto

2018-05-01

Maternal hexachlorophene (HCP) exposure causes transient disruption of hippocampal neurogenesis in mouse offspring. We examined epigenetically hypermethylated and downregulated genes related to this HCP-induced disrupted neurogenesis. Mated female mice were dietary exposed to 0 or 100 ppm HCP from gestational day 6 to postnatal day (PND) 21 on weaning. The hippocampal dentate gyrus of male offspring was subjected to methyl-capture sequencing and real-time reverse transcription-polymerase chain reaction analyses on PND 21. Validation analyses on methylation identified three genes, Dlx4, Dmrt1, and Plcb4, showing promoter-region hypermethylation. Immunohistochemically, DLX4+, DMRT1+, and PLCB4+ cells in the dentate hilus co-expressed GAD67, a γ-aminobutyric acid (GABA)ergic neuron marker. HCP decreased all of three subpopulations as well as GAD67+ cells on PND 21. PLCB4+ cells also co-expressed the metabotropic glutamate receptor, GRM1. HCP also decreased transcript level of synaptic plasticity-related genes in the dentate gyrus and immunoreactive granule cells for synaptic plasticity-related ARC. On PND 77, all immunohistochemical cellular density changes were reversed, whereas the transcript expression of the synaptic plasticity-related genes fluctuated. Thus, HCP-exposed offspring transiently reduced the number of GABAergic interneurons. Among them, subpopulations expressing DLX4, DMRT1, or PLCB4 were transiently reduced in number through an epigenetic mechanism. Considering the role of the Dlx gene family in GABAergic interneuron migration and differentiation, the decreased number of DLX4+ cells may be responsible for reducing those GABAergic interneurons regulating neurogenesis. The effect on granule cell synaptic plasticity was sustained until the adult stage, and reduced GABAergic interneurons active in GRM1-PLCB4 signaling may be responsible for the suppression on weaning.

Structural-functional connectivity deficits of neocortical circuits in the Fmr1 (-/y) mouse model of autism

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Haberl, M.G.; Zerbi, V.; Veltien, A.A.; Ginger, M.; Heerschap, A.; Frick, A.

2015-01-01

Fragile X syndrome (FXS), the most common inherited form of intellectual disability disorder and a frequent cause of autism spectrum disorder (ASD), is characterized by a high prevalence of sensory symptoms. Perturbations in the anatomical connectivity of neocortical circuits resulting in their

Somatostatin-expressing inhibitory interneurons in cortical circuits

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Iryna Yavorska

2016-09-01

Full Text Available Cortical inhibitory neurons exhibit remarkable diversity in their morphology, connectivity, and synaptic properties. Here, we review the function of somatostatin-expressing (SOM inhibitory interneurons, focusing largely on sensory cortex. SOM neurons also comprise a number of subpopulations that can be distinguished by their morphology, input and output connectivity, laminar location, firing properties, and expression of molecular markers. Several of these classes of SOM neurons show unique dynamics and characteristics, such as facilitating synapses, specific axonal projections, intralaminar input, and top-down modulation, which suggest possible computational roles. SOM cells can be differentially modulated by behavioral state depending on their class, sensory system, and behavioral paradigm. The functional effects of such modulation have been studied with optogenetic manipulation of SOM cells, which produces effects on learning and memory, task performance, and the integration of cortical activity. Different classes of SOM cells participate in distinct disinhibitory circuits with different inhibitory partners and in different cortical layers. Through these disinhibitory circuits, SOM cells help encode the behavioral relevance of sensory stimuli by regulating the activity of cortical neurons based on subcortical and intracortical modulatory input. Associative learning leads to long-term changes in the strength of connectivity of SOM cells with other neurons, often influencing the strength of inhibitory input they receive. Thus despite their heterogeneity and variability across cortical areas, current evidence shows that SOM neurons perform unique neural computations, forming not only distinct molecular but also functional subclasses of cortical inhibitory interneurons.

Statistical mechanics of neocortical interactions: Constraints on 40-Hz models of short-term memory

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Ingber, Lester

1995-10-01

Calculations presented in L. Ingber and P.L. Nunez, Phys. Rev. E 51, 5074 (1995) detailed the evolution of short-term memory in the neocortex, supporting the empirical 7+/-2 rule of constraints on the capacity of neocortical processing. These results are given further support when other recent models of 40-Hz subcycles of low-frequency oscillations are considered.

Reduced cell number in the neocortical part of the human fetal brain in Down syndrome

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Larsen, K.B.; Laursen, H.; Graem, N.

2008-01-01

Mental retardation is seen in all individuals with Down syndrome (DS) and different brain abnormalities are reported. The aim of this study was to investigate if mental retardation at least in part is a result of a lower cell number in the neocortical part of the human fetal forebrain. We therefore...

Deriving Dorsal Spinal Sensory Interneurons from Human Pluripotent Stem Cells

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Sandeep Gupta

2018-02-01

Full Text Available Summary: Cellular replacement therapies for neurological conditions use human embryonic stem cell (hESC- or induced pluripotent stem cell (hiPSC-derived neurons to replace damaged or diseased populations of neurons. For the spinal cord, significant progress has been made generating the in-vitro-derived motor neurons required to restore coordinated movement. However, there is as yet no protocol to generate in-vitro-derived sensory interneurons (INs, which permit perception of the environment. Here, we report on the development of a directed differentiation protocol to derive sensory INs for both hESCs and hiPSCs. Two developmentally relevant factors, retinoic acid in combination with bone morphogenetic protein 4, can be used to generate three classes of sensory INs: the proprioceptive dI1s, the dI2s, and mechanosensory dI3s. Critical to this protocol is the competence state of the neural progenitors, which changes over time. This protocol will facilitate developing cellular replacement therapies to reestablish sensory connections in injured patients. : In this article, Gupta and colleagues describe a robust protocol to derive spinal dorsal sensory interneurons from human pluripotent stem cells using the sequential addition of RA and BMP4. They find that neural progenitors must be in the correct competence state to respond to RA/BMP4 as dorsalizing signals. This competence state changes over time and determines the efficiency of the protocol. Keywords: spinal cord, neurons, sensory interneurons, proprioception, mechanosensation, human embryonic stem cells, induced pluripotent stem cells, directed differentiation, primate spinal cord, mouse spinal cord

Active action potential propagation but not initiation in thalamic interneuron dendrites

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Casale, Amanda E.; McCormick, David A.

2012-01-01

Inhibitory interneurons of the dorsal lateral geniculate nucleus of the thalamus modulate the activity of thalamocortical cells in response to excitatory input through the release of inhibitory neurotransmitter from both axons and dendrites. The exact mechanisms by which release can occur from dendrites are, however, not well understood. Recent experiments using calcium imaging have suggested that Na/K based action potentials can evoke calcium transients in dendrites via local active conductances, making the back-propagating action potential a candidate for dendritic neurotransmitter release. In this study, we employed high temporal and spatial resolution voltage-sensitive dye imaging to assess the characteristics of dendritic voltage deflections in response to Na/K action potentials in interneurons of the mouse dorsal lateral geniculate nucleus. We found that trains or single action potentials elicited by somatic current injection or local synaptic stimulation led to action potentials that rapidly and actively back-propagated throughout the entire dendritic arbor and into the fine filiform dendritic appendages known to release GABAergic vesicles. Action potentials always appeared first in the soma or proximal dendrite in response to somatic current injection or local synaptic stimulation, and the rapid back-propagation into the dendritic arbor depended upon voltage-gated sodium and TEA-sensitive potassium channels. Our results indicate that thalamic interneuron dendrites integrate synaptic inputs that initiate action potentials, most likely in the axon initial segment, that then back-propagate with high-fidelity into the dendrites, resulting in a nearly synchronous release of GABA from both axonal and dendritic compartments. PMID:22171033

Voronoi-based spatial analysis reveals selective interneuron changes in the cortex of FALS mice.

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Minciacchi, Diego; Kassa, Roman M; Del Tongo, Claudia; Mariotti, Raffaella; Bentivoglio, Marina

2009-01-01

The neurodegenerative disease amyotrophic lateral sclerosis affects lower motoneurons and corticospinal cells. Mice expressing human mutant superoxide dismutase (SOD)1 provide widely investigated models of the familial form of disease, but information on cortical changes in these mice is still limited. We here analyzed the spatial organization of interneurons characterized by parvalbumin immunoreactivity in the motor, somatosensory, and visual cortical areas of SOD1(G93A) mice. Cell number and sociological spatial behavior were assessed by digital charts of cell location in cortical samples, cell counts, and generation of two-dimensional Voronoi diagrams. In end-stage SOD1-mutant mice, an increase of parvalbumin-containing cortical interneurons was found in the motor and somatosensory areas (about 35% and 20%, respectively) with respect to wild-type littermates. Changes in cell spatial distribution, as documented by Voronoi-derived coefficients of variation, indicated increased tendency of parvalbumin cells to aggregate into clusters in the same areas of the SOD1-mutant cortex. Counts and coefficients of variation of parvalbumin cells in the visual cortex gave instead similar results in SOD1-mutant and wild-type mice. Analyses of motor and somatosensory areas in presymptomatic SOD1-mutant mice provided findings very similar to those obtained at end-stage, indicating early changes of interneurons in these cortical areas during the pathology. Altogether the data reveal in the SOD1-mutant mouse cortex an altered architectonic pattern of interneurons, which selectively affects areas involved in motor control. The findings, which can be interpreted as pathogenic factors or early disease-related adaptations, point to changes in the cortical regulation and modulation of the motor circuit during motoneuron disease.

GABAergic interneuron to astrocyte signalling: a neglected form of cell communication in the brain.

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Losi, Gabriele; Mariotti, Letizia; Carmignoto, Giorgio

2014-10-19

GABAergic interneurons represent a minority of all cortical neurons and yet they efficiently control neural network activities in all brain areas. In parallel, glial cell astrocytes exert a broad control of brain tissue homeostasis and metabolism, modulate synaptic transmission and contribute to brain information processing in a dynamic interaction with neurons that is finely regulated in time and space. As most studies have focused on glutamatergic neurons and excitatory transmission, our knowledge of functional interactions between GABAergic interneurons and astrocytes is largely defective. Here, we critically discuss the currently available literature that hints at a potential relevance of this specific signalling in brain function. Astrocytes can respond to GABA through different mechanisms that include GABA receptors and transporters. GABA-activated astrocytes can, in turn, modulate local neuronal activity by releasing gliotransmitters including glutamate and ATP. In addition, astrocyte activation by different signals can modulate GABAergic neurotransmission. Full clarification of the reciprocal signalling between different GABAergic interneurons and astrocytes will improve our understanding of brain network complexity and has the potential to unveil novel therapeutic strategies for brain disorders. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Plateau properties in mammalian spinal interneurons during transmitter-induced locomotor activity

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Kiehn, O.; Johnson, B. R.; Raastad, M.

1996-01-01

We examined the organization of spinal networks controlling locomotion in the isolated spinal cord of the neonatal rat, and in this study we provide the first demonstration of plateau and bursting mechanisms in mammalian interneurons that show locomotor-related activity. Using tight-seal whole...

Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus.

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Hájos, N; Papp, E C; Acsády, L; Levey, A I; Freund, T F

1998-01-01

In previous studies m2 muscarinic acetylcholine receptor-immunoreactive interneurons and various types of m2-positive axon terminals have been described in the hippocampal formation. The aim of the present study was to identify the types of interneurons expressing m2 receptor and to examine whether the somadendritic and axonal m2 immunostaining labels the same or distinct cell populations. In the CA1 subfield, neurons immunoreactive for m2 have horizontal dendrites, they are located at the stratum oriens/alveus border and have an axon that project to the dendritic region of pyramidal cells. In the CA3 subfield and the hilus, m2-positive neurons are multipolar and are scattered in all layers except stratum lacunosum-moleculare. In stratum pyramidale of the CA1 and CA3 regions, striking axon terminal staining for m2 was observed, surrounding the somata and axon initial segments of pyramidal cells in a basket-like manner. The co-localization of m2 with neurochemical markers and GABA was studied using the "mirror" technique and fluorescent double-immunostaining at the light microscopic level and with double-labelling using colloidal gold-conjugated antisera and immunoperoxidase reaction (diaminobenzidine) at the electron microscopic level. GABA was shown to be present in the somata of most m2-immunoreactive interneurons, as well as in the majority of m2-positive terminals in all layers. The calcium-binding protein parvalbumin was absent from practically all m2-immunoreactive cell bodies and dendrites. In contrast, many of the terminals synapsing on pyramidal cell somata and axon initial segments co-localized parvalbumin and m2, suggesting a differential distribution of m2 receptor immunoreactivity on the axonal and somadendritic membrane of parvalbumin-containing basket and axo-axonic cells. The co-existence of m2 receptors with the calcium-binding protein calbindin and the neuropeptides cholecystokinin and vasoactive intestinal polypeptide was rare throughout the

Neocortical gamma oscillations in idiopathic generalized epilepsy

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Benedek, Krisztina; Berenyi, Antal; Gombkoto, Peter

2016-01-01

Objective: Absence seizures in patients with idiopathic generalized epilepsy (IGE) may in part be explained by a decrease in phasic GABAA (type-A c-aminobutyric acid) receptor function, but the mechanisms are only partly understood. Here we studied the relation between ictal and interictal spike......-wave discharges (SWDs) and electroencephalography (EEG) gamma oscillatory activity (30-60 Hz) in patients with IGE. Methods: EEG recordings were obtained of 14 children with IGE (mean age, 8.5 +/- 5 years) and 14 age-and sex-matched controls. Time-frequency analysis of each seizure and seizure-free control epochs...... was performed and cross-coherences of neocortical gamma oscillations were calculated to describe interictal and ictal characteristics of generalized seizures. Results: SWDs were characterized with an abrupt increase of oscillatory activity of 34 and 13-60 Hz, peaking at 3-4 and 30-60 Hz, and with a simultaneous...

Predictive values of F-18-FDG PET and ictal SPECT to find epileptogenic zones in cryptogenic neocortical epilepsies

International Nuclear Information System (INIS)

Lee, D. S.; Lee, S. K.; Jeong, Z. K.; Kim, H. Z.; Lee, M. C.; Ko, C. S.

1997-01-01

Though cumulated reported sensitivity were 33% (F-18-FDG PET) and 81%(ictal SPECT) in neocortical epilepsy, positive predictive values rather than sensitivity should be referred if we wish to know the reliability of positive findings to predict epileptogenic zones. In cryptogenic neocortical epilepsy which did not have structural lesions on MR, we tried to find performance of F-18-FDG PET and ictal SPECT to find epileptogenic zones. In 77 patients who had no lesion on MR and who were suspected to have neocortical epilepsy on video monitored EEG, ictal SPECT were done in 44 patients and F-18-FDG PET were done in 70 patients. Invasive study and operation was done in 24 patients. The most hyper perfused area or prominently hypometabolic area was suspected to be epileptogenic on ictal SPECT or F-18-FDG PET, respectively. We could find zones of ictal hyperperfusion in 34/44(78%) patients. Positive predictive values of ictal hyperperfusion were 58%, 60%, and 12.5% in frontal lobes (n=12), lateral temporal lobes (20), and parietal lobes (8). We could find hypometabolic areas in 50/70(76%) patients. Positive predictive values of hypometabolism were 78%, 71%, 33%, and 25% in frontal lobes (9), lateral temporal lobes (28), parietal lobes (3) and occipital lobes (4). Among 24 patients who were operated, 17 patients were followed up more than 7 months (15 ± 5). Thirteen patients improved (10 : Engel class I or II, 2: 90% reduction, 1: 75% reduction but multifocal). Five among 11 PET studies were correct, 3 among 10 SPECT studies, and 6 among 11 PET/SPECT studies (55%) were correct for localization. In conclusion, three fourths of patients gave positive results to localized epileptogenic zones in cryptogenic neocortical epilepsy, and predictive values of ictal hyperperfusion or interictal hypometabolism were highest in frontal or lateral temporal lobes if these lobes were found to be culprit though rapid ictal propagation of cortical hyperperfusion confounded the exact

Transmission to interneurons is via slow excitatory synaptic potentials mediated by P2Y(1 receptors during descending inhibition in guinea-pig ileum.

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Peter D J Thornton

Full Text Available BACKGROUND: The nature of synaptic transmission at functionally distinct synapses in intestinal reflex pathways has not been fully identified. In this study, we investigated whether transmission between interneurons in the descending inhibitory pathway is mediated by a purine acting at P2Y receptors to produce slow excitatory synaptic potentials (EPSPs. METHODOLOGY/PRINCIPAL FINDINGS: Myenteric neurons from guinea-pig ileum in vitro were impaled with intracellular microelectrodes. Responses to distension 15 mm oral to the recording site, in a separately perfused stimulation chamber and to electrical stimulation of local nerve trunks were recorded. A subset of neurons, previously identified as nitric oxide synthase immunoreactive descending interneurons, responded to both stimuli with slow EPSPs that were reversibly abolished by a high concentration of PPADS (30 μM, P2 receptor antagonist. When added to the central chamber of a three chambered organ bath, PPADS concentration-dependently depressed transmission through that chamber of descending inhibitory reflexes, measured as inhibitory junction potentials in the circular muscle of the anal chamber. Reflexes evoked by distension in the central chamber were unaffected. A similar depression of transmission was seen when the specific P2Y(1 receptor antagonist MRS 2179 (10 μM was in the central chamber. Blocking either nicotinic receptors (hexamethonium 200 μM or 5-HT(3 receptors (granisetron 1 μM together with P2 receptors had no greater effect than blocking P2 receptors alone. CONCLUSIONS/SIGNIFICANCE: Slow EPSPs mediated by P2Y(1 receptors, play a primary role in transmission between descending interneurons of the inhibitory reflexes in the guinea-pig ileum. This is the first demonstration for a primary role of excitatory metabotropic receptors in physiological transmission at a functionally identified synapse.

Molecular layer interneurons of the cerebellum: developmental and morphological aspects.

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Sotelo, Constantino

2015-10-01

During the past 25 years, our knowledge on the development of basket and stellate cells (molecular layer interneurons [MLIs]) has completely changed, not only regarding their origin from the ventricular zone, corresponding to the primitive cerebellar neuroepithelium, instead of the external granular layer, but above all by providing an almost complete account of the genetic regulations (transcription factors and other genes) involved in their differentiation and synaptogenesis. Moreover, it has been shown that MLIs' precursors (dividing neuroblasts) and not young postmitotic neurons, as in other germinal neuroepithelia, leave the germinative zone and migrate all along a complex and lengthy path throughout the presumptive cerebellar white matter, which provides suitable niches exerting epigenetic influences on their ultimate neuronal identities. Recent studies carried out on the anatomical-functional properties of adult MLIs emphasize the importance of these interneurons in regulating PC inhibition, and point out the crucial role played by electrical synaptic transmission between MLIs as well as ephaptic interactions between them and Purkinje cells at the pinceaux level, in the regulation of this inhibition.

Trajectory of the main GABAergic interneuron populations from early development to old age in the rat primary auditory cortex

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Lydia eOuellet

2014-06-01

Full Text Available In both humans and rodents, decline in cognitive function is a hallmark of the aging process, the basis for this decrease has yet to be fully characterized. However, using aged rodent models, deficits in auditory processing have been associated with significant decreases in inhibitory signaling attributed to a loss of GABAergic interneurons. Not only are these interneurons crucial for pattern detection and other large-scale population dynamics, but they have also been linked to mechanisms mediating plasticity and learning, making them a prime candidate for study and modelling of modifications to cortical communication pathways in neurodegenerative diseases. Using the rat primary auditory cortex (A1 as a model, we probed the known markers of GABAergic interneurons with immunohistological methods, using antibodies against gamma aminobutyric acid (GABA, parvalbumin (PV, somatostatin (SOM, calretinin (CR, vasoactive intestinal peptide (VIP, choline acetyltransferase (ChAT, neuropeptide Y (NPY and cholecystokinin (CCK to document the changes observed in interneuron populations across the rat’s lifespan. This analysis provided strong evidence that several but not all GABAergic neurons were affected by the aging process, showing most dramatic changes in expression of parvalbumin (PV and somatostatin (SOM expression. With this evidence, we show how understanding these trajectories of cell counts may be factored into a simple model to quantify changes in inhibitory signalling across the course of life, which may be applied as a framework for creating more advanced simulations of interneuronal implication in normal cerebral processing, normal aging, or pathological processes.

The many tunes of perisomatic targeting interneurons in the hippocampal network

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Tommas J Ellender

2010-07-01

Full Text Available The axonal targets of perisomatic targeting interneurons make them ideally suited to synchronise excitatory neurons. As such they have been implicated in rhythm generation of network activity in many brain regions including the hippocampus. However, several recent publications indicate that their roles extend beyond that of rhythm generation. Firstly, it has been shown that, in addition to rhythm generation, GABAergic perisomatic inhibition also serves as a current generator contributing significantly to hippocampal oscillatory EEG signals. Furthermore, GABAergic interneurons have a hitherto unexpected role in the initiation of hippocampal population bursts, both in the developing and adult hippocampus. In this review, we describe these new observations in detail and discuss the implications they have for our understanding of the mechanisms underlying physiological and pathological hippocampal network activities. This review is part of the Frontiers in Cellular Neuroscience's special topic entitled GABA signalling in health and disease based on the meeting at the CNCR Amsterdam.

Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.

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Do-Ha, Dzung; Buskila, Yossi; Ooi, Lezanne

2018-02-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K + concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.

GABA action in immature neocortical neurons directly depends on the availability of ketone bodies.

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Rheims, Sylvain; Holmgren, Carl D; Chazal, Genevieve; Mulder, Jan; Harkany, Tibor; Zilberter, Tanya; Zilberter, Yuri

2009-08-01

In the early postnatal period, energy metabolism in the suckling rodent brain relies to a large extent on metabolic pathways alternate to glucose such as the utilization of ketone bodies (KBs). However, how KBs affect neuronal excitability is not known. Using recordings of single NMDA and GABA-activated channels in neocortical pyramidal cells we studied the effects of KBs on the resting membrane potential (E(m)) and reversal potential of GABA-induced anionic currents (E(GABA)), respectively. We show that during postnatal development (P3-P19) if neocortical brain slices are adequately supplied with KBs, E(m) and E(GABA) are both maintained at negative levels of about -83 and -80 mV, respectively. Conversely, a KB deficiency causes a significant depolarization of both E(m) (>5 mV) and E(GABA) (>15 mV). The KB-mediated shift in E(GABA) is largely determined by the interaction of the NKCC1 cotransporter and Cl(-)/HCO3 transporter(s). Therefore, by inducing a hyperpolarizing shift in E(m) and modulating GABA signaling mode, KBs can efficiently control the excitability of neonatal cortical neurons.

Co-localization of glycine and gaba immunoreactivity in interneurons in Macaca monkey cerebellar cortex.

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Crook, J; Hendrickson, A; Robinson, F R

2006-09-15

Previous work demonstrates that the cerebellum uses glycine as a fast inhibitory neurotransmitter [Ottersen OP, Davanger S, Storm-Mathisen J (1987) Glycine-like immunoreactivity in the cerebellum of rat and Senegalese baboon, Papio papio: a comparison with the distribution of GABA-like immunoreactivity and with [3H]glycine and [3H]GABA uptake. Exp Brain Res 66(1):211-221; Ottersen OP, Storm-Mathisen J, Somogyi P (1988) Colocalization of glycine-like and GABA-like immunoreactivities in Golgi cell terminals in the rat cerebellum: a postembedding light and electron microscopic study. Brain Res 450(1-2):342-353; Dieudonne S (1995) Glycinergic synaptic currents in Golgi cells of the rat cerebellum. Proc Natl Acad Sci U S A 92:1441-1445; Dumoulin A, Triller A, Dieudonne S (2001) IPSC kinetics at identified GABAergic and mixed GABAergic and glycinergic synapses onto cerebellar Golgi cells. J Neurosci 21(16):6045-6057; Dugue GP, Dumoulin A, Triller A, Dieudonne S (2005) Target-dependent use of coreleased inhibitory transmitters at central synapses. J Neurosci 25(28):6490-6498; Zeilhofer HU, Studler B, Arabadzisz D, Schweizer C, Ahmadi S, Layh B, Bosl MR, Fritschy JM (2005) Glycinergic neurons expressing enhanced green fluorescent protein in bacterial artificial chromosome transgenic mice. J Comp Neurol 482(2):123-141]. In the rat cerebellum glycine is not released by itself but is released together with GABA by Lugaro cells onto Golgi cells [Dumoulin A, Triller A, Dieudonne S (2001) IPSC kinetics at identified GABAergic and mixed GABAergic and glycinergic synapses onto cerebellar Golgi cells. J Neurosci 21(16):6045-6057] and by Golgi cells onto unipolar brush and granule cells [Dugue GP, Dumoulin A, Triller A, Dieudonne S (2005) Target-dependent use of coreleased inhibitory transmitters at central synapses. J Neurosci 25(28):6490-6498]. Here we report, from immunolabeling evidence in Macaca cerebellum, that interneurons in the granular cell layer are glycine+ at a density

c-Fos expression is elevated in GABAergic interneurons of the gustatory cortex following novel taste learning.

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Doron, Guy; Rosenblum, Kobi

2010-07-01

Long-term sensory memories are considered to be stored in the relevant cortical region subserving the given modality. We and others have recently identified a series of molecular alterations in the gustatory cortex (GC) of the rat at different time intervals following novel taste learning. Some of these correlative modifications were also necessary for taste memory acquisition and/or consolidation. However, very little is known about the localization of these molecular modifications within the GC or about the functional activation of the GC hours after novel taste learning. Here, we hypothesize that inhibitory interneurons are activated in the GC on a scale of hours following learning and used c-Fos expression and confocal microscopy with different markers to test this hypothesis. We found that GABAergic interneurons are activated in the GC in correlation with novel taste learning. The activation was evident in the deep but not superficial layers of the dysgranular insular cortex. These results suggest that the GABAergic machinery in the deep layers of the GC participates in the processing of taste information hours after learning, and provide evidence for the involvement of a local cortical circuit not only during acquisition of new information but also during off-line processing and consolidation of taste information.

In Vivo Study of Dynamics and Stability of Dendritic Spines on Olfactory Bulb Interneurons in Xenopus laevis Tadpoles.

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Yu-Bin Huang

Full Text Available Dendritic spines undergo continuous remodeling during development of the nervous system. Their stability is essential for maintaining a functional neuronal circuit. Spine dynamics and stability of cortical excitatory pyramidal neurons have been explored extensively in mammalian animal models. However, little is known about spiny interneurons in non-mammalian vertebrate models. In the present study, neuronal morphology was visualized by single-cell electroporation. Spiny neurons were surveyed in the Xenopus tadpole brain and observed to be widely distributed in the olfactory bulb and telencephalon. DsRed- or PSD95-GFP-expressing spiny interneurons in the olfactory bulb were selected for in vivo time-lapse imaging. Dendritic protrusions were classified as filopodia, thin, stubby, or mushroom spines based on morphology. Dendritic spines on the interneurons were highly dynamic, especially the filopodia and thin spines. The stubby and mushroom spines were relatively more stable, although their stability significantly decreased with longer observation intervals. The 4 spine types exhibited diverse preferences during morphological transitions from one spine type to others. Sensory deprivation induced by severing the olfactory nerve to block the input of mitral/tufted cells had no significant effects on interneuron spine stability. Hence, a new model was established in Xenopus laevis tadpoles to explore dendritic spine dynamics in vivo.

Persistent barrage firing in cortical interneurons can be induced in vivo and may be important for the suppression of epileptiform activity

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Norimitsu eSuzuki

2014-03-01

Full Text Available Neural circuits are typically maintained in a state of dynamic equilibrium by balanced synaptic excitation and inhibition. However, brain regions that are particularly susceptible to epilepsy may have evolved additional specialized mechanisms for inhibiting overexcitation. Here we identify one such possible mechanism in the cerebral cortex and hippocampus of mice. Recently it was reported that some types of GABAergic interneurons can slowly integrate excitatory inputs until eventually they fire persistently in the absence of the original stimulus. This property, called persistent firing or retroaxonal barrage firing, is of unknown physiological importance. We show that two common types of interneurons in cortical regions, neurogliaform cells and fast-spiking multipolar cells, are unique in exhibiting barrage firing in acute slices (~85% and ~23% success rate for induction, respectively. Barrage firing can also be induced in vivo, although the success rate for induction is lower (~60% in neurogliaform cells. In slices, barrage firing could reliably be triggered by trains of excitatory synaptic input, as well as by exposure to proconvulsant bath solutions (elevated extracellular K+, blockade of GABAA receptors. Using pair recordings in slices, we confirmed that barrage-firing neurogliaform cells can produce synaptic inhibition of nearby pyramidal neurons, and that this inhibition outlasts the original excitation. The ubiquity of neurogliaform and fast-spiking cells, together with their ability to fire persistently following excessive excitation, suggests that these interneurons may function as cortical sentinels, imposing an activity-dependent brake on undesirable neuronal hyperexcitability.

Somatostatin-positive interneurons in the dentate gyrus of mice provide local- and long-range septal synaptic inhibition.

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Yuan, Mei; Meyer, Thomas; Benkowitz, Christoph; Savanthrapadian, Shakuntala; Ansel-Bollepalli, Laura; Foggetti, Angelica; Wulff, Peer; Alcami, Pepe; Elgueta, Claudio; Bartos, Marlene

2017-04-03

Somatostatin-expressing-interneurons (SOMIs) in the dentate gyrus (DG) control formation of granule cell (GC) assemblies during memory acquisition. Hilar-perforant-path-associated interneurons (HIPP cells) have been considered to be synonymous for DG-SOMIs. Deviating from this assumption, we show two functionally contrasting DG-SOMI-types. The classical feedback-inhibitory HIPPs distribute axon fibers in the molecular layer. They are engaged by converging GC-inputs and provide dendritic inhibition to the DG circuitry. In contrast, SOMIs with axon in the hilus, termed hilar interneurons (HILs), provide perisomatic inhibition onto GABAergic cells in the DG and project to the medial septum. Repetitive activation of glutamatergic inputs onto HIPP cells induces long-lasting-depression (LTD) of synaptic transmission but long-term-potentiation (LTP) of synaptic signals in HIL cells. Thus, LTD in HIPPs may assist flow of spatial information from the entorhinal cortex to the DG, whereas LTP in HILs may facilitate the temporal coordination of GCs with activity patterns governed by the medial septum.

Default activity patterns at the neocortical microcircuit level

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Artur eLuczak

2012-06-01

Full Text Available Even in absence of sensory stimuli cortical networks exhibit complex, self-organized activity patterns. While the function of those spontaneous patterns of activation remains poorly understood, recent studies both in vivo and in vitro have demonstrated that neocortical neurons activate in a surprisingly similar sequential order both spontaneously and following input into cortex. For example, neurons that tend to fire earlier within spontaneous bursts of activity also fire earlier than other neurons in response to sensory stimuli. These 'default patterns' can last hundreds of milliseconds and are strongly conserved under a variety of conditions. In this paper we will review recent evidence for these default patterns at the local cortical level. We speculate that cortical architecture imposes common constraints on spontaneous and evoked activity flow, which result in the similarity of the patterns.

Identification of Arx targets unveils new candidates for controlling cortical interneuron migration and differentiation

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Gaelle M Friocourt

2011-12-01

Full Text Available Mutations in the homeobox transcription factor ARX have been found to be responsible for a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of intellectual disabilities without apparent brain abnormalities, but with associated features of dystonia and epilepsy. Arx expression is mainly restricted to populations of GABA-containing neurons. Studies of the effects of ARX loss of function, either in humans or mutant mice, revealed varying defects, suggesting multiple roles of this gene in brain patterning, neuronal proliferation and migration, cell maturation and differentiation, as well as axonal outgrowth and connectivity. However, to date, little is known about how Arx functions as a transcription factor or which genes it binds and regulates. Recently, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified approximately 1000 gene promoters bound by Arx in transfected neuroblastoma N2a cells and mouse embryonic brain. To narrow the analysis of Arx targets to those most likely to control cortical interneuron migration and/or differentiation, we compare here our data to previously published studies searching for genes enriched or down-regulated in cortical interneurons between E13.5 and E15.5. We thus identified 14 Arx-target genes enriched (Cxcr7, Meis1, Ppap2a, Slc12a5, Ets2, Phlda1, Zif268, Igf1, Lmo3, Sema6, Lgi1, Alk, Tgfb3, Napb and 5 genes specifically down-regulated (Hmgn3, Lmo1, Ebf3, Rasgef1b and Slit2 in cortical migrating neurons. In this review, we present these genes and discuss how their possible regulation by Arx may lead to the dysfunction of GABAergic neurons, resulting in mental retardation and epilepsy.

Multiple non-cell-autonomous defects underlie neocortical callosal dysgenesis in Nfib-deficient mice

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Sunn Nana

2009-12-01

Full Text Available Abstract Background Agenesis of the corpus callosum is associated with many human developmental syndromes. Key mechanisms regulating callosal formation include the guidance of axons arising from pioneering neurons in the cingulate cortex and the development of cortical midline glial populations, but their molecular regulation remains poorly characterised. Recent data have shown that mice lacking the transcription factor Nfib exhibit callosal agenesis, yet neocortical callosal neurons express only low levels of Nfib. Therefore, we investigate here how Nfib functions to regulate non-cell-autonomous mechanisms of callosal formation. Results Our investigations confirmed a reduction in glial cells at the midline in Nfib-/- mice. To determine how this occurs, we examined radial progenitors at the cortical midline and found that they were specified correctly in Nfib mutant mice, but did not differentiate into mature glia. Cellular proliferation and apoptosis occurred normally at the midline of Nfib mutant mice, indicating that the decrease in midline glia observed was due to deficits in differentiation rather than proliferation or apoptosis. Next we investigated the development of callosal pioneering axons in Nfib-/- mice. Using retrograde tracer labelling, we found that Nfib is expressed in cingulate neurons and hence may regulate their development. In Nfib-/- mice, neuropilin 1-positive axons fail to cross the midline and expression of neuropilin 1 is diminished. Tract tracing and immunohistochemistry further revealed that, in late gestation, a minor population of neocortical axons does cross the midline in Nfib mutants on a C57Bl/6J background, forming a rudimentary corpus callosum. Finally, the development of other forebrain commissures in Nfib-deficient mice is also aberrant. Conclusion The formation of the corpus callosum is severely delayed in the absence of Nfib, despite Nfib not being highly expressed in neocortical callosal neurons. Our

Statistical mechanics of neocortical interactions. Derivation of short-term-memory capacity

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Ingber, Lester

1984-06-01

A theory developed by the author to describe macroscopic neocortical interactions demonstrates that empirical values of chemical and electrical parameters of synaptic interactions establish several minima of the path-integral Lagrangian as a function of excitatory and inhibitory columnar firings. The number of possible minima, their time scales of hysteresis and probable reverberations, and their nearest-neighbor columnar interactions are all consistent with well-established empirical rules of human short-term memory. Thus, aspects of conscious experience are derived from neuronal firing patterns, using modern methods of nonlinear nonequilibrium statistical mechanics to develop realistic explicit synaptic interactions.

skn-1 is required for interneuron sensory integration and foraging behavior in Caenorhabditis elegans.

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Wilson, Mark A; Iser, Wendy B; Son, Tae Gen; Logie, Anne; Cabral-Costa, Joao V; Mattson, Mark P; Camandola, Simonetta

2017-01-01

Nrf2/skn-1, a transcription factor known to mediate adaptive responses of cells to stress, also regulates energy metabolism in response to changes in nutrient availability. The ability to locate food sources depends upon chemosensation. Here we show that Nrf2/skn-1 is expressed in olfactory interneurons, and is required for proper integration of multiple food-related sensory cues in Caenorhabditis elegans. Compared to wild type worms, skn-1 mutants fail to perceive that food density is limiting, and display altered chemo- and thermotactic responses. These behavioral deficits are associated with aberrant AIY interneuron morphology and migration in skn-1 mutants. Both skn-1-dependent AIY autonomous and non-autonomous mechanisms regulate the neural circuitry underlying multisensory integration of environmental cues related to energy acquisition.

Synaptic targets of commissural interneurons in the lumbar spinal cord of neonatal rats

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Birinyi, András; Viszokay, Kornél; Wéber, Ildikó

2003-01-01

dextran amine (BDA) into the lateral motor column to retrogradely label commissural interneurons that may have direct projections to motor neurons. Stained neurons were recovered in the ventromedial areas of the contralateral gray matter in substantial numbers. In the second experiment BDA was injected...... into the ventromedial gray matter on one side of the lumbar spinal cord, whereas motor neurons were simultaneously labeled on the opposite side by applying biocytin onto the ventral roots. BDA injections into the ventromedial gray matter labeled a strong axon bundle that arose from the site of injection, crossed...... the midline in the ventral commissure, and extensively arborized in the contralateral ventral gray matter. Many of these axons made close appositions with dendrites and somata of motor neurons and also with commissural interneurons retrogradely labeled with BDA. The results suggest that commissural...

Anatomical and electrophysiological characterization of a population of dI6 interneurons in the neonatal mouse spinal cord.

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Griener, Anna; Zhang, Wei; Kao, Henry; Haque, Farhia; Gosgnach, Simon

2017-10-24

The locomotor central pattern generator is a neural network located in the ventral aspect of the caudal spinal cord that underlies stepping in mammals. While many genetically defined interneurons that are thought to comprise this neural network have been identified and characterized, the dI6 cells- which express the transcription factors WT1 and/or DMRT3- are one population that settle in this region, are active during locomotion, whose function is poorly understood. These cells were originally hypothesized to be commissural premotor interneurons, however evidence in support of this is sparse. Here we characterize this population of cells using the TgDbx1 Cre ;R26 EFP ;Dbx1 LacZ transgenic mouse line, which has been shown to be an effective marker of dI6 interneurons. We show dI6 cells to be abundant in laminae VII and VIII along the entire spinal cord and provide evidence that subtypes outside the WT1/DMRT3 expressing dI6 cells may exist. Retrograde tracing experiments indicate that the majority of dI6 cells project descending axons, and some make monosynaptic or disynaptic contacts onto motoneurons on either side of the spinal cord. Analysis of their activity during non-resetting deletions, which occur during bouts of fictive locomotion, suggests that these cells are involved in both locomotor rhythm generation and pattern formation. This study provides a thorough characterization of the dI6 cells labeled in the TgDbx1 Cre ;R26 EFP ;Dbx1 LacZ transgenic mouse, and supports previous work suggesting that these cells play multiple roles during locomotor activity. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Volumetric MRI for evaluation of regional pattern and progression of neocortical degeneration in Alzheimer's disease

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Leinsinger, G.; Teipel, S.; Pruessner, J.; Hampel, H.; Wismueller, A.; Born, C.; Meindl, T.; Flatz, W.; Schoenberg, S.; Reiser, M.

2003-01-01

Volumetric analysis of the corpus callosum and hippocampus using MRI in Alzheimer's disease (AD) to evaluate the regional pattern and progression of neocortical neurodegeneration. In subsequent studies we investigated patients with AD and healthy controls. Volumetry was based on MRI-data from a sagittal 3D T1w-gradient echo sequence. The corpus callosum (CC) was measured in a midsagittal slice, and subdivided into 5 subregions. Volumetry of the hippocampus/amygdala-formation (HAF) was performed by segmentation in coronary reoriented slices. In AD patients we found a significant atrophy in the rostrum und splenium of CC. The atrophy was correlated with the severity of dementia, but no correlation was found with the load of white matter lesions. In comparison with 18 FDG-PET, we found a significant correlation of regional CC-atrophy with the regional decline of cortical glucose metabolism. A ROC-analysis demonstrated no significant differences in the diagostic accuracy of HAF volumetry and regional CC volumetry of the splenium (region C5) even in mild stages of dementia. Regional atrophy of CC can be used as a marker of neocortical degeneration even in early stages of dementia in AD. (orig.) [de

Spinal Hb9::Cre-derived excitatory interneurons contribute to rhythm generation in the mouse

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Caldeira, Vanessa; Dougherty, Kimberly J.; Borgius, Lotta

2017-01-01

Rhythm generating neurons are thought to be ipsilaterally-projecting excitatory neurons in the thoracolumbar mammalian spinal cord. Recently, a subset of Shox2 interneurons (Shox2 non-V2a INs) was found to fulfill these criteria and make up a fraction of the rhythm-generating population. Here we...... than in cords from controls. Collectively, our findings indicate that excitatory Hb9::Cre-derived INs constitute a distinct population of neurons that participates in the rhythm generating kernel for spinal locomotion....... use Hb9::Cre mice to genetically manipulate Hb9::Cre-derived excitatory interneurons (INs) in order to determine the role of these INs in rhythm generation. We demonstrate that this line captures a consistent population of spinal INs which is mixed with respect to neurotransmitter phenotype...

skn-1 is required for interneuron sensory integration and foraging behavior in Caenorhabditis elegans.

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Mark A Wilson

Full Text Available Nrf2/skn-1, a transcription factor known to mediate adaptive responses of cells to stress, also regulates energy metabolism in response to changes in nutrient availability. The ability to locate food sources depends upon chemosensation. Here we show that Nrf2/skn-1 is expressed in olfactory interneurons, and is required for proper integration of multiple food-related sensory cues in Caenorhabditis elegans. Compared to wild type worms, skn-1 mutants fail to perceive that food density is limiting, and display altered chemo- and thermotactic responses. These behavioral deficits are associated with aberrant AIY interneuron morphology and migration in skn-1 mutants. Both skn-1-dependent AIY autonomous and non-autonomous mechanisms regulate the neural circuitry underlying multisensory integration of environmental cues related to energy acquisition.

Roles for multifunctional and specialized spinal interneurons during motor pattern generation in tadpoles, zebrafish larvae, and turtles

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Ari Berkowitz

2010-06-01

Full Text Available The hindbrain and spinal cord can produce multiple forms of locomotion, escape, and withdrawal behaviors and (in limbed vertebrates site-specific scratching. Until recently, the prevailing view was that the same classes of CNS neurons generate multiple kinds of movements, either through reconfiguration of a single, shared network or through an increase in the number of neurons recruited within each class. The mechanisms involved in selecting and generating different motor patterns have recently been explored in detail in some non-mammalian, vertebrate model systems. Work on the hatchling Xenopus tadpole, the larval zebrafish, and the adult turtle has now revealed that distinct kinds of motor patterns are actually selected and generated by combinations of multifunctional and specialized spinal interneurons. Multifunctional interneurons may form a core, multipurpose circuit that generates elements of coordinated motor output utilized in multiple behaviors, such as left-right alternation. But, in addition, specialized spinal interneurons including separate glutamatergic and glycinergic classes are selectively activated during specific patterns: escape-withdrawal, swimming and struggling in tadpoles and zebrafish, and limb withdrawal and scratching in turtles. These specialized neurons can contribute by changing the way central pattern generator (CPG activity is initiated and by altering CPG composition and operation. The combined use of multifunctional and specialized neurons is now established as a principle of organization across a range of vertebrates. Future research may reveal common patterns of multifunctionality and specialization among interneurons controlling diverse movements and whether similar mechanisms exist in higher-order brain circuits that select among a wider array of complex movements.

Histamine H3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons.

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Varaschin, Rafael Koerich; Osterstock, Guillaume; Ducrot, Charles; Leino, Sakari; Bourque, Marie-Josée; Prado, Marco A M; Prado, Vania Ferreira; Salminen, Outi; Rannanpää Née Nuutinen, Saara; Trudeau, Louis-Eric

2018-04-15

Histamine H 3 receptors are widely distributed G i -coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H 3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. Acute brain slices from C57BL/6 or channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine transients evoked either electrically or optogenetically were measured by fast-scan cyclic voltammetry. The H 3 agonist α-methylhistamine significantly reduced electrically- evoked dopamine overflow, an effect blocked by the nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, suggesting involvement of cholinergic interneurons. None of the drug treatments targeting H 3 receptors affected optogenetically evoked dopamine overflow, indicating that direct H 3 -modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H 3 receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H 3 receptors by α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the ventral, but not in the dorsal striatum. Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H 3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons. Copyright © 2018 IBRO

Ivy and neurogliaform interneurons are a major target of μ opioid receptor modulation

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Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

2011-01-01

Mu opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform cells are not only numerous, but also have unique properties, including promiscuous gap junctions formed with various interneuronal subtypes, volume transmission, and the ability to produce a postsynaptic GABAB response after a single presynaptic spike. Using a mouse line expressing green fluorescent protein under the neuropeptide Y promoter, we find that across all layers of CA1, activation of μORs hyperpolarizes Ivy and neurogliaform cells. Further, paired recordings between synaptically coupled Ivy and pyramidal cells show that Ivy cell terminals are dramatically inhibited by μOR-activation. Effects in Ivy and neurogliaform cells are seen at similar concentrations of agonist as those producing inhibition in fast-spiking PV basket cells. We also report that Ivy cells display the recently described phenomenon of persistent firing, a state of continued firing in the absence of continued input, and that induction of persistent firing is inhibited by μOR-activation. Together these findings identify a major, previously unrecognized, target of μOR-modulation. Given the prominence of this cell type in and beyond CA1, as well as its unique role in microcircuitry, opioid modulation of neurogliaform cells has wide implications. PMID:22016519

Ivy and neurogliaform interneurons are a major target of μ-opioid receptor modulation.

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Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

2011-10-19

μ-Opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin-expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform cells are not only numerous but also have unique properties, including promiscuous gap junctions formed with various interneuronal subtypes, volume transmission, and the ability to produce a postsynaptic GABA(B) response after a single presynaptic spike. Using a mouse line expressing green fluorescent protein under the neuropeptide Y promoter, we find that, across all layers of CA1, activation of μORs hyperpolarizes Ivy and neurogliaform cells. Furthermore, paired recordings between synaptically coupled Ivy and pyramidal cells show that Ivy cell terminals are dramatically inhibited by μOR activation. Effects in Ivy and neurogliaform cells are seen at similar concentrations of agonist as those producing inhibition in fast-spiking parvalbumin basket cells. We also report that Ivy cells display the recently described phenomenon of persistent firing, a state of continued firing in the absence of continued input, and that induction of persistent firing is inhibited by μOR activation. Together, these findings identify a major, previously unrecognized, target of μOR modulation. Given the prominence of this cell type in and beyond CA1, as well as its unique role in microcircuitry, opioid modulation of neurogliaform cells has wide implications.

Synaptic Changes in AMPA Receptor Subunit Expression in Cortical Parvalbumin Interneurons in the Stargazer Model of Absence Epilepsy

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Nadia K. Adotevi

2017-12-01

Full Text Available Feedforward inhibition is essential to prevent run away excitation within the brain. Recent evidence suggests that a loss of feed-forward inhibition in the corticothalamocortical circuitry may underlie some absence seizures. However, it is unclear if this aberration is specifically linked to loss of synaptic excitation onto local fast-spiking parvalbumin-containing (PV+ inhibitory interneurons, which are responsible for mediating feedforward inhibition within cortical networks. We recently reported a global tissue loss of AMPA receptors (AMPARs, and a specific mistrafficking of these AMPARs in PV+ interneurons in the stargazer somatosensory cortex. The current study was aimed at investigating if cellular changes in AMPAR expression were translated into deficits in receptors at specific synapses in the feedforward inhibitory microcircuit. Using western blot immunolabeling on biochemically isolated synaptic fractions, we demonstrate a loss of AMPAR GluA1–4 subunits in the somatosensory cortex of stargazers compared to non-epileptic control mice. Furthermore, using double post-embedding immunogold-cytochemistry, we show a loss of GluA1–4-AMPARs at excitatory synapses onto cortical PV+ interneurons. Altogether, these data indicate a loss of synaptic AMPAR-mediated excitation of cortical PV+ inhibitory neurons. As the cortex is considered the site of initiation of spike wave discharges (SWDs within the corticothalamocortical circuitry, loss of AMPARs at cortical PV+ interneurons likely impairs feed-forward inhibitory output, and contributes to the generation of SWDs and absence seizures in stargazers.

Corollary discharge inhibition of wind-sensitive cercal giant interneurons in the singing field cricket

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Hedwig, Berthold

2014-01-01

Crickets carry wind-sensitive mechanoreceptors on their cerci, which, in response to the airflow produced by approaching predators, triggers escape reactions via ascending giant interneurons (GIs). Males also activate their cercal system by air currents generated due to the wing movements underlying sound production. Singing males still respond to external wind stimulation, but are not startled by the self-generated airflow. To investigate how the nervous system discriminates sensory responses to self-generated and external airflow, we intracellularly recorded wind-sensitive afferents and ventral GIs of the cercal escape pathway in fictively singing crickets, a situation lacking any self-stimulation. GI spiking was reduced whenever cercal wind stimulation coincided with singing motor activity. The axonal terminals of cercal afferents showed no indication of presynaptic inhibition during singing. In two ventral GIs, however, a corollary discharge inhibition occurred strictly in phase with the singing motor pattern. Paired intracellular recordings revealed that this inhibition was not mediated by the activity of the previously identified corollary discharge interneuron (CDI) that rhythmically inhibits the auditory pathway during singing. Cercal wind stimulation, however, reduced the spike activity of this CDI by postsynaptic inhibition. Our study reveals how precisely timed corollary discharge inhibition of ventral GIs can prevent self-generated airflow from triggering inadvertent escape responses in singing crickets. The results indicate that the responsiveness of the auditory and wind-sensitive pathway is modulated by distinct CDIs in singing crickets and that the corollary discharge inhibition in the auditory pathway can be attenuated by cercal wind stimulation. PMID:25318763

Taurine activates GABAergic networks in the neocortex of immature mice

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Bogdan Aurel Sava

2014-02-01

Full Text Available Although it has been suggested that taurine is the main endogenous neurotransmitter acting on glycine receptors, the implications of glycine receptor-mediated taurine actions on immature neocortical networks have not been addressed yet. To investigate the influence of taurine on the excitability of neuronal networks in the immature neocortex, we performed whole-cell patch-clamp recordings from visually identified pyramidal neurons and interneurons in coronal slices from C57Bl/6 and GAD67-GFP transgenic mice (postnatal days 2-4. In 46 % of the pyramidal neurons bath-application of taurine at concentrations ≥ 300 mM significantly enhanced the frequency of postsynaptic currents (PSCs by 744.3 ± 93.8 % (n = 120 cells. This taurine-induced increase of PSC frequency was abolished by 0.2 mM tetrodotoxine, 1 mM strychnine or 3 mM gabazine, but was unaffected by the glutamatergic antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX and (± R(--3-(2-carboxypiperazine-4-yl-propyl-1-phosphonic acid (CPP, suggesting that taurine specifically activates GABAergic network activity projecting to pyramidal neurons. Cell-attached recordings revealed that taurine enhanced the frequency of action potentials in pyramidal neurons, indicating an excitatory action of the GABAergic PSCs. In order to identify the presynaptic targets of taurine we demonstrate that bath application of taurine induced in GAD67-GFP labeled interneurons an inward current that is mainly mediated by glycine receptors and can generate action potentials in these cells. We conclude from these results that taurine can enhance network excitability in the immature neocortex by selectively activating GABAergic interneurons via interactions with glycine receptors.

Differential antiepileptic effects of the organic calcium antagonists verapamil and flunarizine in neurons of organotypic neocortical explants from newborn rats

NARCIS (Netherlands)

Bingmann, D; Speckmann, E J; Baker, R E; Ruijter, J; de Jong, B. M.

1988-01-01

Effects of the organic calcium antagonists verapamil and flunarizine on pentylenetetrazol induced paroxysmal depolarizations were tested in organotypic neocortical explants taken from neonatal rats. In these in vitro experiments the papaverin derivative verapamil depressed, and finally abolished,

Phenotype of V2-derived interneurons and their relationship to the axon guidance molecule EphA4 in the developing mouse spinal cord

DEFF Research Database (Denmark)

Lundfald, Line; Restrepo, C. Ernesto; Butt, Simon J B

2007-01-01

, we demonstrated that a large proportion of V2 interneurons expressed the axon guidance molecule EphA4, a molecule previously shown to be important for correct organization of locomotor networks. We also showed that V2 interneurons and motor neurons alone did not account for all EphA4-expressing...

Mild prenatal protein malnutrition increases alpha2C-adrenoceptor density in the cerebral cortex during postnatal life and impairs neocortical long-term potentiation and visuo-spatial performance in rats.

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Soto-Moyano, Rubén; Valladares, Luis; Sierralta, Walter; Pérez, Hernán; Mondaca, Mauricio; Fernández, Victor; Burgos, Héctor; Hernández, Alejandro

2005-06-01

Mild reduction in the protein content of the mother's diet from 25 to 8% casein, calorically compensated by carbohydrates, does not alter body and brain weights of rat pups at birth, but leads to significant enhancements in the concentration and release of cortical noradrenaline during early postnatal life. Since central noradrenaline and some of its receptors are critically involved in long-term potentiation (LTP) and memory formation, this study evaluated the effect of mild prenatal protein malnutrition on the alpha2C-adrenoceptor density in the frontal and occipital cortices, induction of LTP in the same cortical regions and the visuo-spatial memory. Pups born from rats fed a 25% casein diet throughout pregnancy served as controls. At day 8 of postnatal age, prenatally malnourished rats showed a threefold increase in neocortical alpha2C-adrenoceptor density. At 60 days-of-age, alpha2C-adrenoceptor density was still elevated in the neocortex, and the animals were unable to maintain neocortical LTP and presented lower visuo-spatial memory performance. Results suggest that overexpression of neocortical alpha2C-adrenoceptors during postnatal life, subsequent to mild prenatal protein malnutrition, could functionally affect the synaptic networks subserving neocortical LTP and visuo-spatial memory formation.

Tuning afferent synapses of hippocampal interneurons by neuropeptide Y

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Ledri, Marco; Sørensen, Andreas Toft; Erdelyi, Ferenc

2011-01-01

Cholecystokinin (CCK)-expressing basket cells encompass a subclass of inhibitory GABAergic interneurons that regulate memory-forming oscillatory network activity of the hippocampal formation in accordance to the emotional and motivational state of the animal, conveyed onto these cells by respective...... are modulated by neuropeptide Y (NPY), one of the major local neuropeptides that strongly inhibits hippocampal excitability and has significant effect on its memory function. Here, using GAD65-GFP transgenic mice for prospective identification of CCK basket cells and whole-cell patch-clamp recordings, we show...

Medial Olivocochlear Reflex Interneurons Are Located in the Posteroventral Cochlear Nucleus: A Kainic Acid Lesion Study in Guinea Pigs

OpenAIRE

De VENECIA, RONALD K.; LIBERMAN, M. CHARLES; GUINAN, JOHN J.; BROWN, M. CHRISTIAN

2005-01-01

The medial olivocochlear (MOC) reflex arc is probably a three-neuron pathway consisting of type I spiral ganglion neurons, reflex interneurons in the cochlear nucleus, and MOC neurons that project to the outer hair cells of the cochlea. We investigated the identity of MOC reflex interneurons in the cochlear nucleus by assaying their regional distribution using focal injections of kainic acid. Our reflex metric was the amount of change in the distortion product otoacoustic emission (at 2f1–f2)...

A combined electrophysiological and morphological study of neuropeptide Y?expressing inhibitory interneurons in the spinal dorsal horn of the mouse

OpenAIRE

Iwagaki, Noboru; Ganley, Robert P.; Dickie, Allen C.; Polg?r, Erika; Hughes, David I.; Del Rio, Patricia; Revina, Yulia; Watanabe, Masahiko; Todd, Andrew J.; Riddell, John S.

2015-01-01

Abstract The spinal dorsal horn contains numerous inhibitory interneurons that control transmission of somatosensory information. Although these cells have important roles in modulating pain, we still have limited information about how they are incorporated into neuronal circuits, and this is partly due to difficulty in assigning them to functional populations. Around 15% of inhibitory interneurons in laminae I-III express neuropeptide Y (NPY), but little is known about this population. We th...

Cryptic organisation within an apparently irregular rostrocaudal distribution of interneurons in the embryonic zebrafish spinal cord

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Wells, Simon, E-mail: simon.wells@adelaide.edu.au [Discipline of Genetics, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); The Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia 5005 (Australia); Conran, John G., E-mail: john.conran@adelaide.edu.au [Ecology and Evolutionary Biology, School of Earth and Environmental Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); Tamme, Richard, E-mail: rtamme@ttu.ee [Discipline of Genetics, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); Gaudin, Arnaud, E-mail: a.gaudin@uq.edu.au [School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072 (Australia); Webb, Jonathan, E-mail: jonathan.webb@worc.ox.ac.uk [Discipline of Genetics, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); Lardelli, Michael, E-mail: michael.lardelli@adelaide.edu.au [Discipline of Genetics, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); The Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia 5005 (Australia)

2010-11-15

The molecules and mechanisms involved in patterning the dorsoventral axis of the developing vertebrate spinal cord have been investigated extensively and many are well known. Conversely, knowledge of mechanisms patterning cellular distributions along the rostrocaudal axis is relatively more restricted. Much is known about the rostrocaudal distribution of motoneurons and spinal cord cells derived from neural crest but there is little known about the rostrocaudal patterning of most of the other spinal cord neurons. Here we report data from our analyses of the distribution of dorsal longitudinal ascending (DoLA) interneurons in the developing zebrafish spinal cord. We show that, although apparently distributed irregularly, these cells have cryptic organisation. We present a novel cell-labelling technique that reveals that DoLA interneurons migrate rostrally along the dorsal longitudinal fasciculus of the spinal cord during development. This cell-labelling strategy may be useful for in vivo analysis of factors controlling neuron migration in the central nervous system. Additionally, we show that DoLA interneurons persist in the developing spinal cord for longer than previously reported. These findings illustrate the need to investigate factors and mechanisms that determine 'irregular' patterns of cell distribution, particularly in the central nervous system but also in other tissues of developing embryos.

Quantitative assessment of CA1 local circuits: knowledge base for interneuron-pyramidal cell connectivity.

Science.gov (United States)

Bezaire, Marianne J; Soltesz, Ivan

2013-09-01

In this work, through a detailed literature review, data-mining, and extensive calculations, we provide a current, quantitative estimate of the cellular and synaptic constituents of the CA1 region of the rat hippocampus. Beyond estimating the cell numbers of GABAergic interneuron types, we calculate their convergence onto CA1 pyramidal cells and compare it with the known input synapses on CA1 pyramidal cells. The convergence calculation and comparison are also made for excitatory inputs to CA1 pyramidal cells. In addition, we provide a summary of the excitatory and inhibitory convergence onto interneurons. The quantitative knowledge base assembled and synthesized here forms the basis for data-driven, large-scale computational modeling efforts. Additionally, this work highlights specific instances where the available data are incomplete, which should inspire targeted experimental projects toward a more complete quantification of the CA1 neurons and their connectivity. Copyright © 2013 Wiley Periodicals, Inc.

Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions

DEFF Research Database (Denmark)

Hervig, Mona E; Thomsen, Morten S; Kalló, Imre

2016-01-01

and thalamus of rats. A single dose of PCP (10mg/kg, s.c.) significantly increased total number of c-Fos-IR in: (1) the prelimbic, infralimbic, anterior cingulate, ventrolateral orbital, motor, somatosensory and retrosplenial cortices as well as the nucleus accumbens (NAc), field CA1 of the hippocampus (CA1......) field of hippocampus and mediodorsal thalamus (MD); (2) PV-IR cells in the ventrolateral orbitofrontal and retrosplenial cortices and CA1 field of hippocampus; and (3) CB-IR cells in the motor cortex. Overall, our data indicate that PCP activates a wide range of cortical and subcortical brain regions...... and subcortical areas, but whether such induction occurs in specific populations of GABAergic interneuron subtypes still remains to be established. We performed an immunohistochemical analysis of the PCP-induced c-Fos-immunoreactivity (IR) in parvalbumin (PV) and calbindin (CB) interneuron subtypes in the cortex...

Damaged Neocortical Perineuronal Nets Due to Experimental Focal Cerebral Ischemia in Mice, Rats and Sheep

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Wolfgang Härtig

2017-08-01

Full Text Available As part of the extracellular matrix (ECM, perineuronal nets (PNs are polyanionic, chondroitin sulfate proteoglycan (CSPG-rich coatings of certain neurons, known to be affected in various neural diseases. Although these structures are considered as important parts of the neurovascular unit (NVU, their role during evolution of acute ischemic stroke and subsequent tissue damage is poorly understood and only a few preclinical studies analyzed PNs after acute ischemic stroke. By employing three models of experimental focal cerebral ischemia, this study was focused on histopathological alterations of PNs and concomitant vascular, glial and neuronal changes according to the NVU concept. We analyzed brain tissues obtained 1 day after ischemia onset from: (a mice after filament-based permanent middle cerebral artery occlusion (pMCAO; (b rats subjected to thromboembolic MACO; and (c sheep at 14 days after electrosurgically induced focal cerebral ischemia. Multiple fluorescence labeling was applied to explore simultaneous alterations of NVU and ECM. Serial mouse sections labeled with the net marker Wisteria floribunda agglutinin (WFA displayed largely decomposed and nearly erased PNs in infarcted neocortical areas that were demarcated by up-regulated immunoreactivity for vascular collagen IV (Coll IV. Subsequent semi-quantitative analyses in mice confirmed significantly decreased WFA-staining along the ischemic border zone and a relative decrease in the directly ischemia-affected neocortex. Triple fluorescence labeling throughout the three animal models revealed up-regulated Coll IV and decomposed PNs accompanied by activated astroglia and altered immunoreactivity for parvalbumin, a calcium-binding protein in fast-firing GABAergic neurons which are predominantly surrounded by neocortical PNs. Furthermore, ischemic neocortical areas in rodents simultaneously displayed less intense staining of WFA, aggrecan, the net components neurocan, versican and the

Medial olivocochlear reflex interneurons are located in the posteroventral cochlear nucleus: a kainic acid lesion study in guinea pigs.

Science.gov (United States)

de Venecia, Ronald K; Liberman, M Charles; Guinan, John J; Brown, M Christian

2005-07-11

The medial olivocochlear (MOC) reflex arc is probably a three-neuron pathway consisting of type I spiral ganglion neurons, reflex interneurons in the cochlear nucleus, and MOC neurons that project to the outer hair cells of the cochlea. We investigated the identity of MOC reflex interneurons in the cochlear nucleus by assaying their regional distribution using focal injections of kainic acid. Our reflex metric was the amount of change in the distortion product otoacoustic emission (at 2f(1)-f(2)) just after onset of the primary tones. This metric for MOC reflex strength has been shown to depend on an intact reflex pathway. Lesions involving the posteroventral cochlear nucleus (PVCN), but not the other subdivisions, produced long-term decreases in MOC reflex strength. The degree of cell loss within the dorsal part of the PVCN was a predictor of whether the lesion affected MOC reflex strength. We suggest that multipolar cells within the PVCN have the distribution and response characteristics appropriate to be the MOC reflex interneurons. (c) 2005 Wiley-Liss, Inc.

A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development.

Science.gov (United States)

Deng, Dazhi; Jian, Chongdong; Lei, Ling; Zhou, Yijing; McSweeney, Colleen; Dong, Fengping; Shen, Yilun; Zou, Donghua; Wang, Yonggang; Wu, Yuan; Zhang, Limin; Mao, Yingwei

2017-10-17

Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 ( DISC1 ), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects.

The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor

OpenAIRE

Sanders, Jarred; Nagy, Stanislav; Fetterman, Graham; Wright, Charles; Treinin, Millet; Biron, David

2013-01-01

Background To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this pr...

Melatonin administration impairs visuo-spatial performance and inhibits neocortical long-term potentiation in rats.

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Soto-Moyano, Rubén; Burgos, Héctor; Flores, Francisco; Valladares, Luis; Sierralta, Walter; Fernández, Victor; Pérez, Hernán; Hernández, Paula; Hernández, Alejandro

2006-10-01

Melatonin has been shown to inhibit long-term potentiation (LTP) in hippocampal slices of rats. Since LTP may be one of the main mechanisms by which memory traces are encoded and stored in the central nervous system, it is possible that melatonin could modulate cognitive performance by interfering with the cellular and/or molecular mechanisms involved in LTP. We investigated in rats the effects of intraperitoneally-administered melatonin (0.1, 1 and 10 mg/kg), its saline-ethanol solvent, or saline alone, on the acquisition of visuo-spatial memory as well as on the ability of the cerebral cortex to develop LTP in vivo. Visuo-spatial performance was assessed daily in rats, for 10 days, in an 8-arm radial maze, 30 min after they received a single daily dose of melatonin. Visual cortex LTP was determined in sodium pentobarbital anesthetized rats (65 mg/kg i.p.), by potentiating transcallosal evoked responses with a tetanizing train (312 Hz, 500 ms duration) 30 min after administration of a single dose of melatonin. Results showed that melatonin impaired visuo-spatial performance in rats, as revealed by the greater number of errors committed and time spent to solve the task in the radial maze. Melatonin also prevented the induction of neocortical LTP. It is concluded that melatonin, at the doses utilized in this study, could alter some forms of neocortical plasticity involved in short- and long-term visuo-spatial memories in rats.

Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice

Science.gov (United States)

Sherman, Maxwell A.; Lee, Shane; Law, Robert; Haegens, Saskia; Thorn, Catherine A.; Hämäläinen, Matti S.; Moore, Christopher I.; Jones, Stephanie R.

2016-01-01

Human neocortical 15–29-Hz beta oscillations are strong predictors of perceptual and motor performance. However, the mechanistic origin of beta in vivo is unknown, hindering understanding of its functional role. Combining human magnetoencephalography (MEG), computational modeling, and laminar recordings in animals, we present a new theory that accounts for the origin of spontaneous neocortical beta. In our MEG data, spontaneous beta activity from somatosensory and frontal cortex emerged as noncontinuous beta events typically lasting drive targeting proximal and distal dendrites of pyramidal neurons, where the defining feature of a beta event was a strong distal drive that lasted one beta period (∼50 ms). This beta mechanism rigorously accounted for the beta event profiles; several other mechanisms did not. The spatial location of synaptic drive in the model to supragranular and infragranular layers was critical to the emergence of beta events and led to the prediction that beta events should be associated with a specific laminar current profile. Laminar recordings in somatosensory neocortex from anesthetized mice and awake monkeys supported these predictions, suggesting this beta mechanism is conserved across species and recording modalities. These findings make several predictions about optimal states for perceptual and motor performance and guide causal interventions to modulate beta for optimal function. PMID:27469163

Dopamine D4 receptor activation increases hippocampal gamma oscillations by enhancing synchronization of fast-spiking interneurons.

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Richard Andersson

Full Text Available BACKGROUND: Gamma oscillations are electric activity patterns of the mammalian brain hypothesized to serve attention, sensory perception, working memory and memory encoding. They are disrupted or altered in schizophrenic patients with associated cognitive deficits, which persist in spite of treatment with antipsychotics. Because cognitive symptoms are a core feature of schizophrenia it is relevant to explore signaling pathways that potentially regulate gamma oscillations. Dopamine has been reported to decrease gamma oscillation power via D1-like receptors. Based on the expression pattern of D4 receptors (D4R in hippocampus, and pharmacological effects of D4R ligands in animals, we hypothesize that they are in a position to regulate gamma oscillations as well. METHODOLOGY/PRINCIPAL FINDINGS: To address this hypothesis we use rat hippocampal slices and kainate-induced gamma oscillations. Local field potential recordings as well as intracellular recordings of pyramidal cells, fast-spiking and non-fast-spiking interneurons were carried out. We show that D4R activation with the selective ligand PD168077 increases gamma oscillation power, which can be blocked by the D4R-specific antagonist L745,870 as well as by the antipsychotic drug Clozapine. Pyramidal cells did not exhibit changes in excitatory or inhibitory synaptic current amplitudes, but inhibitory currents became more coherent with the oscillations after application of PD168077. Fast-spiking, but not non-fast spiking, interneurons, increase their action potential phase-coupling and coherence with regard to ongoing gamma oscillations in response to D4R activation. Among several possible mechanisms we found that the NMDA receptor antagonist AP5 also blocks the D4R mediated increase in gamma oscillation power. CONCLUSIONS/SIGNIFICANCE: We conclude that D4R activation affects fast-spiking interneuron synchronization and thereby increases gamma power by an NMDA receptor-dependent mechanism. This

Prdm8 regulates the morphological transition at multipolar phase during neocortical development.

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Mayuko Inoue

Full Text Available Here, we found that the PR domain protein Prdm8 serves as a key regulator of the length of the multipolar phase by controlling the timing of morphological transition. We used a mouse line with expression of Prdm8-mVenus reporter and found that Prdm8 is predominantly expressed in the middle and upper intermediate zone during both the late and terminal multipolar phases. Prdm8 expression was almost coincident with Unc5D expression, a marker for the late multipolar phase, although the expression of Unc5D was found to be gradually down-regulated to the point at which mVenus expression was gradually up-regulated. This expression pattern suggests the possible involvement of Prdm8 in the control of the late and terminal multipolar phases, which controls the timing for morphological transition. To test this hypothesis, we performed gain- and loss-of-function analysis of neocortical development by using in utero electroporation. We found that the knockdown of Prdm8 results in premature change from multipolar to bipolar morphology, whereas the overexpression of Prdm8 maintained the multipolar morphology. Additionally, the postnatal analysis showed that the Prdm8 knockdown stimulated the number of early born neurons, and differentiated neurons located more deeply in the neocortex, however, majority of those cells could not acquire molecular features consistent with laminar location. Furthermore, we found the candidate genes that were predominantly utilized in both the late and terminal multipolar phases, and these candidate genes included those encoding for guidance molecules. In addition, we also found that the expression level of these guidance molecules was inhibited by the introduction of the Prdm8 expression vector. These results indicate that the Prdm8-mediated regulation of morphological changes that normally occur during the late and terminal multipolar phases plays an important role in neocortical development.

Immunohistochemical visualization of mouse interneuron subtypes [v1; ref status: indexed, http://f1000r.es/4em

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Simon Molgaard

2014-10-01

Full Text Available The activity of excitatory neurons is controlled by a small, but highly diverse population of inhibitory interneurons. These cells show a high level of physiological, morphological and neurochemical heterogeneity, and play highly specific roles in neuronal circuits. In the mammalian hippocampus, these are divided into 21 different subtypes of GABAergic interneurons based on their expression of different markers, morphology and their electrophysiological properties. Ideally, all can be marked using an antibody directed against the inhibitory neurotransmitter GABA, but parvalbumin, calbindin, somatostatin, and calretinin are also commonly used as markers to narrow down the specific interneuron subtype. Here, we describe a journey to find the necessary immunological reagents for studying GABAergic interneurons of the mouse hippocampus. Based on web searches there are several hundreds of different antibodies on the market directed against these four markers. Searches in the literature databases allowed us to narrow it down to a subset of antibodies most commonly used in publications. However, in our hands the most cited ones did not work for immunofluorescence stainings of formaldehyde fixed tissue sections and cultured hippocampal neurons, and we had to immunostain our way through thirteen different commercial antibodies before finally finding a suitable antibody for each of the four markers. The antibodies were evaluated based on signal-to-noise ratios as well as if positive cells were found in layers of the hippocampus where they have previously been described. Additionally, the antibodies were also tested on sections from mouse spinal cord with similar criteria for specificity of the antibodies. Using the antibodies with a high rating on pAbmAbs, stainings with high signal-to-noise ratios and location of the immunostained cells in accordance with the literature could be obtained, making these antibodies suitable choices for studying the

Interneuronal systems of the cervical spinal cord assessed with BOLD imaging at 1.5 T

International Nuclear Information System (INIS)

Stracke, C.P.; Schoth, F.; Moeller-Hartmann, W.; Krings, T.; Pettersson, L.G.

2005-01-01

The purpose of this study was to investigate if functional activity with spinal cord somatosensory stimulation can be visualized using BOLD fMRI. We investigated nine healthy volunteers using a somatosensory stimulus generator. The stimuli were applied in three different runs at the first, third, and fifth finger tip of the right hand, respectively, corresponding to dermatomes c6, c7, and c8. The stimuli gave an increase of BOLD signal (activation) in three different locations of the spinal cord and brain stem. First, activations could be seen in the spinal segment corresponding to the stimulated dermatome in seven out of nine volunteers for c6 stimulation, two out of eight for c7, and three out of eight for c8. These activations were located close to the posterior margin of the spinal cord, presumably reflecting synaptic transmission to dorsal horn interneurons. Second, activation in the medulla oblongata was evident in four subjects, most likely corresponding to the location of the nucleus cuneatus. The third location of activation, which was the strongest and most reliable observed was inside the spinal cord in the c3 and c4 segments. Activation at these spinal levels was almost invariably observed independently of the dermatome stimulated (9/9 for c6, 8/8 for c7, and 7/8 for c8 stimulation). These activations may pertain to an interneuronal system at this spinal level. The results are discussed in relation to neurophysiological studies on cervical spinal interneuronal pathways in animals and humans. (orig.)

PV Interneurons: Critical Regulators of E/I Balance for Prefrontal Cortex-Dependent Behavior and Psychiatric Disorders

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Brielle R. Ferguson

2018-05-01

Full Text Available Elucidating the prefrontal cortical microcircuit has been challenging, given its role in multiple complex behaviors, including working memory, cognitive flexibility, attention, social interaction and emotional regulation. Additionally, previous methodological limitations made it difficult to parse out the contribution of certain neuronal subpopulations in refining cortical representations. However, growing evidence supports a fundamental role of fast-spiking parvalbumin (PV GABAergic interneurons in regulating pyramidal neuron activity to drive appropriate behavioral responses. Further, their function is heavily diminished in the prefrontal cortex (PFC in numerous psychiatric diseases, including schizophrenia and autism. Previous research has demonstrated the importance of the optimal balance of excitation and inhibition (E/I in cortical circuits in maintaining the efficiency of cortical information processing. Although we are still unraveling the mechanisms of information representation in the PFC, the E/I balance seems to be crucial, as pharmacological, chemogenetic and optogenetic approaches for disrupting E/I balance induce impairments in a range of PFC-dependent behaviors. In this review, we will explore two key hypotheses. First, PV interneurons are powerful regulators of E/I balance in the PFC, and help optimize the representation and processing of supramodal information in PFC. Second, diminishing the function of PV interneurons is sufficient to generate an elaborate symptom sequelae corresponding to those observed in a range of psychiatric diseases. Then, using this framework, we will speculate on whether this circuitry could represent a platform for the development of therapeutic interventions in disorders of PFC function.

Adenosine A2A Receptors Control Glutamatergic Synaptic Plasticity in Fast Spiking Interneurons of the Prefrontal Cortex

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Amber Kerkhofs

2018-03-01

Full Text Available Adenosine A2A receptors (A2AR are activated upon increased synaptic activity to assist in the implementation of long-term plastic changes at synapses. While it is reported that A2AR are involved in the control of prefrontal cortex (PFC-dependent behavior such as working memory, reversal learning and effort-based decision making, it is not known whether A2AR control glutamatergic synapse plasticity within the medial PFC (mPFC. To elucidate that, we tested whether A2AR blockade affects long-term plasticity (LTP of excitatory post-synaptic potentials in pyramidal neurons and fast spiking (FS interneurons in layer 5 of the mPFC and of population spikes. Our results show that A2AR are enriched at mPFC synapses, where their blockade reversed the direction of plasticity at excitatory synapses onto layer 5 FS interneurons from LTP to long-term depression, while their blockade had no effect on the induction of LTP at excitatory synapses onto layer 5 pyramidal neurons. At the network level, extracellularly induced LTP of population spikes was reduced by A2AR blockade. The interneuron-specificity of A2AR in controlling glutamatergic synapse LTP may ensure that during periods of high synaptic activity, a proper excitation/inhibition balance is maintained within the mPFC.

Data on characterizing the gene expression patterns of neuronal ceroid lipofuscinosis genes: CLN1, CLN2, CLN3, CLN5 and their association to interneuron and neurotransmission markers: Parvalbumin and Somatostatin

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Helena M. Minye

2016-09-01

Full Text Available The article contains raw and analyzed data related to the research article “Neuronal ceroid lipofuscinosis genes, CLN2, CLN3, CLN5 are spatially and temporally co-expressed in a developing mouse brain” (Fabritius et al., 2014 [1]. The processed data gives an understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN1, CLN2, CLN3 and CLN5 genes in a murine model. The data shows relationship between the expression pattern of these genes during neural development. Immunohistochemistry was used to identify known interneuronal markers for neurotransmission and cell proliferation: parvalbumin, somatostatin subpopulations of interneurons. Non-radioactive in-situ hybridization detected CLN5 mRNA in the hippocampus. Throughout the development strong expression of CLN genes were identified in the germinal epithelium and in ventricle regions, cortex, hippocampus, and cerebellum. This provides supportive evidence that CLN1, CLN2, CLN3 and CLN5 genes may be involved in synaptic pruning.

Oscillatory activity in neocortical networks during tactile discrimination near the limit of spatial acuity.

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Adhikari, Bhim M; Sathian, K; Epstein, Charles M; Lamichhane, Bidhan; Dhamala, Mukesh

2014-05-01

Oscillatory interactions within functionally specialized but distributed brain regions are believed to be central to perceptual and cognitive functions. Here, using human scalp electroencephalography (EEG) recordings combined with source reconstruction techniques, we study how oscillatory activity functionally organizes different neocortical regions during a tactile discrimination task near the limit of spatial acuity. While undergoing EEG recordings, blindfolded participants felt a linear three-dot array presented electromechanically, under computer control, and reported whether the central dot was offset to the left or right. The average brain response differed significantly for trials with correct and incorrect perceptual responses in the timeframe approximately between 130 and 175ms. During trials with correct responses, source-level peak activity appeared in the left primary somatosensory cortex (SI) at around 45ms, in the right lateral occipital complex (LOC) at 130ms, in the right posterior intraparietal sulcus (pIPS) at 160ms, and finally in the left dorsolateral prefrontal cortex (dlPFC) at 175ms. Spectral interdependency analysis of activity in these nodes showed two distinct distributed networks, a dominantly feedforward network in the beta band (12-30Hz) that included all four nodes and a recurrent network in the gamma band (30-100Hz) that linked SI, pIPS and dlPFC. Measures of network activity in both bands were correlated with the accuracy of task performance. These findings suggest that beta and gamma band oscillatory networks coordinate activity between neocortical regions mediating sensory and cognitive processing to arrive at tactile perceptual decisions. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons

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Nakajima, Miho; Görlich, Andreas; Heintz, Nathaniel

2014-01-01

SUMMARY Human imaging studies have revealed that intranasal administration of the “prosocial” hormone oxytocin (OT) activates the frontal cortex, and that this action of OT correlates with enhanced brain function in autism. Here we report the discovery of a population of somatostatin (Sst) positive, regular spiking interneurons that express the oxytocin receptor (OxtrINs). Silencing of OxtrINs in the medial prefrontal cortex (mPFC) of female mice resulted in loss of social interest in male mice specifically during the sexually receptive phase of the estrous cycle. This sociosexual deficit was also present in mice in which the Oxtr gene was conditionally deleted from the mPFC, and in control mice infused with an Oxtr antagonist. Our data demonstrate a gender, cell type and state specific role for OT/Oxtr signaling in the mPFC, and identify a latent cortical circuit element that may modulate other complex social behaviors in response to OT. PMID:25303526

Newborn Interneurons in the Accessory Olfactory Bulb Promote Mate Recognition in Female Mice

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Livio eOboti

2011-09-01

Full Text Available In the olfactory bulb of adult rodents, local interneurons are constantly replaced by immature precursors derived from the subventricular zone. Whether any olfactory sensory process specifically relies on this cell renewal remains largely unclear. By using the well-known model of mating-induced imprinting, we demonstrate that this olfactory memory formation critically depends on the presence of newborn granule neurons in the accessory olfactory bulb. Accordingly, we show that, in adult female mice, exposure to male pheromones increases the number of new granule cells surviving in the accessory olfactory bulb. This neuronal addition depends on the detection of sensory cues by the vomeronasal organ and requires centrifugal feedback activity from the amygdala. The stimuli affecting neuronal survival are contained in the low molecular weight fraction of urine and are implied in pheromonal recognition during mating. By chemical depletion of newly generated bulbar interneurons, we show a direct role of renewed granule cells in the accessory olfactory bulb in preventing pregnancy block by mating male odours. Taken together, our results indicate that adult neurogenesis is essential for specific brain functions such as persistent odour learning and mate recognition.

GABA-mediated synchronization in the human neocortex: elevations in extracellular potassium and presynaptic mechanisms.

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Louvel, J; Papatheodoropoulos, C; Siniscalchi, A; Kurcewicz, I; Pumain, R; Devaux, B; Turak, B; Esposito, V; Villemeure, J G; Avoli, M

2001-01-01

Field potential and extracellular [K(+)] ([K(+)](o)) recordings were made in the human neocortex in an in vitro slice preparation to study the synchronous activity that occurs in the presence of 4-aminopyridine (50 microM) and ionotropic excitatory amino acid receptor antagonists. Under these experimental conditions, negative or negative-positive field potentials accompanied by rises in [K(+)](o) (up to 4.1 mM from a baseline of 3.25 mM) occurred spontaneously at intervals of 3-27 s. Both field potentials and [K(+)](o) elevations were largest at approximately 1000 microm from the pia. Similar events were induced by neocortical electrical stimuli. Application of medium containing low [Ca(2+)]/high [Mg(2+)] (n=3 slices), antagonism of the GABA(A) receptor (n=7) or mu-opioid receptor activation (n=4) abolished these events. Hence, they represented network, GABA-mediated potentials mainly reflecting the activation of type A receptors following GABA release from interneurons. The GABA(B) receptor agonist baclofen (10-100 microM, n=11) reduced and abolished the GABA-mediated potentials (ID(50)=18 microM). Baclofen effects were antagonized by the GABA(B) receptor antagonist CGP 35348 (0.1-1 mM, n=6; ID(50)=0.19 mM). CGP 38345 application to control medium increased the amplitude of the GABA-mediated potentials and the concomitant [K(+)](o) rises without modifying their rate of occurrence. The GABA-mediated potentials were not influenced by the broad-spectrum metabotropic glutamate agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (100 microM, n=10), but decreased in rate with the group I receptor agonist (S)-3,5-dihydroxyphenylglycine (10-100 microM, n=9). Our data indicate that human neocortical networks challenged with 4-aminopyridine generate glutamatergic-independent, GABA-mediated potentials that are modulated by mu-opioid and GABA(B) receptors presumably located on interneuron terminals. These events are associated with [K(+)](o) elevations that may

Unsupervised classification of neocortical activity patterns in neonatal and pre-juvenile rodents

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Nicole eCichon

2014-05-01

Full Text Available Flexible communication within the brain, which relies on oscillatory activity, is not confined to adult neuronal networks. Experimental evidence has documented the presence of discontinuous patterns of oscillatory activity already during early development. Their highly variable spatial and time-frequency organization has been related to region specificity. However, it might be equally due to the absence of unitary criteria for classifying the early activity patterns, since they have been mainly characterized by visual inspection. Therefore, robust and unbiased methods for categorizing these discontinuous oscillations are needed for increasingly complex data sets from different labs. Here, we introduce an unsupervised detection and classification algorithm for the discontinuous activity patterns of rodents during early development. For this, firstly time windows with discontinuous oscillations vs. epochs of network silence were identified. In a second step, the major features of detected events were identified and processed by principal component analysis for deciding on their contribution to the classification of different oscillatory patterns. Finally, these patterns were categorized using an unsupervised cluster algorithm. The results were validated on manually characterized neonatal spindle bursts, which ubiquitously entrain neocortical areas of rats and mice, and prelimbic nested gamma spindle bursts. Moreover, the algorithm led to satisfactory results for oscillatory events that, due to increased similarity of their features, were more difficult to classify, e.g. during the pre-juvenile developmental period. Based on a linear classification, the optimal number of features to consider increased with the difficulty of detection. This algorithm allows the comparison of neonatal and pre-juvenile oscillatory patterns in their spatial and temporal organization. It might represent a first step for the unbiased elucidation of activity patterns

Dual role for DOCK7 in tangential migration of interneuron precursors in the postnatal forebrain.

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Nakamuta, Shinichi; Yang, Yu-Ting; Wang, Chia-Lin; Gallo, Nicholas B; Yu, Jia-Ray; Tai, Yilin; Van Aelst, Linda

2017-12-04

Throughout life, stem cells in the ventricular-subventricular zone generate neuroblasts that migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into local interneurons. Although progress has been made toward identifying extracellular factors that guide the migration of these cells, little is known about the intracellular mechanisms that govern the dynamic reshaping of the neuroblasts' morphology required for their migration along the RMS. In this study, we identify DOCK7, a member of the DOCK180-family, as a molecule essential for tangential neuroblast migration in the postnatal mouse forebrain. DOCK7 regulates the migration of these cells by controlling both leading process (LP) extension and somal translocation via distinct pathways. It controls LP stability/growth via a Rac-dependent pathway, likely by modulating microtubule networks while also regulating F-actin remodeling at the cell rear to promote somal translocation via a previously unrecognized myosin phosphatase-RhoA-interacting protein-dependent pathway. The coordinated action of both pathways is required to ensure efficient neuroblast migration along the RMS. © 2017 Nakamuta et al.

Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid

DEFF Research Database (Denmark)

Rinaldi, Tania; Silberberg, Gilad; Markram, Henry

2008-01-01

Exposure to valproic acid (VPA) during embryogenesis can cause several teratogenic effects, including developmental delays and in particular autism in humans if exposure occurs during the third week of gestation. We examined the postnatal effects of embryonic exposure to VPA on microcircuit...... properties of juvenile rat neocortex using in vitro electrophysiology. We found that a single prenatal injection of VPA on embryonic day 11.5 causes a significant enhancement of the local recurrent connectivity formed by neocortical pyramidal neurons. The study of the biophysical properties...... of these connections revealed weaker excitatory synaptic responses. A marked decrease of the intrinsic excitability of pyramidal neurons was also observed. Furthermore, we demonstrate a diminished number of putative synaptic contacts in connection between layer 5 pyramidal neurons. Local hyperconnectivity may render...

Intermittent Hypoxia Enhances Functional Connectivity of Midcervical Spinal Interneurons

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Streeter, Kristi A.; Sunshine, Michael D.; Patel, Shreya; Gonzalez-Rothi, Elisa J.; Reier, Paul J.

2017-01-01

Brief, intermittent oxygen reductions [acute intermittent hypoxia (AIH)] evokes spinal plasticity. Models of AIH-induced neuroplasticity have focused on motoneurons; however, most midcervical interneurons (C-INs) also respond to hypoxia. We hypothesized that AIH would alter the functional connectivity between C-INs and induce persistent changes in discharge. Bilateral phrenic nerve activity was recorded in anesthetized and ventilated adult male rats and a multielectrode array was used to record C4/5 spinal discharge before [baseline (BL)], during, and 15 min after three 5 min hypoxic episodes (11% O2, H1–H3). Most C-INs (94%) responded to hypoxia by either increasing or decreasing firing rate. Functional connectivity was examined by cross-correlating C-IN discharge. Correlograms with a peak or trough were taken as evidence for excitatory or inhibitory connectivity between C-IN pairs. A subset of C-IN pairs had increased excitatory cross-correlations during hypoxic episodes (34%) compared with BL (19%; p phrenic motoneurons and excitatory inputs to these “pre-phrenic” cells increased during AIH. We conclude that AIH alters connectivity of the midcervical spinal network. To our knowledge, this is the first demonstration that AIH induces plasticity within the propriospinal network. SIGNIFICANCE STATEMENT Acute intermittent hypoxia (AIH) can trigger spinal plasticity associated with sustained increases in respiratory, somatic, and/or autonomic motor output. The impact of AIH on cervical spinal interneuron (C-IN) discharge and connectivity is unknown. Our results demonstrate that AIH recruits excitatory C-INs into the spinal respiratory (phrenic) network. AIH also enhances excitatory and reduces inhibitory connections among the C-IN network. We conclude that C-INs are part of the respiratory, somatic, and/or autonomic response to AIH, and that propriospinal plasticity may contribute to sustained increases in motor output after AIH. PMID:28751456

Reduction in cortical parvalbumin expression due to intermittent theta-burst stimulation correlates with maturation of the perineuronal nets in young rats.

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Mix, Annika; Hoppenrath, Kathrin; Funke, Klaus

2015-01-01

We recently showed that intermittent theta-burst stimulation (iTBS) using transcranial magnetic stimulation strongly reduces the number of rat neocortical interneurons expressing glutamic acid decarboxylase 67 kDa (GAD67) and parvalbumin (PV), indicating changed activity of fast-spiking (FS) interneurons. In advance of in vitro studies intended to characterize changes in electrical properties of FS interneurons under these conditions, we tested whether the iTBS effect is age-dependent. Conscious Sprague-Dawley rats aged between 28 and 90 days received three blocks of iTBS at 15 min intervals. We found that iTBS-related reduction in PV+ cells was absent up to an age of 32 days, then gradually increased, and approached a maximum of about 40% reduction at an age of about 40 days. The relative number of cells expressing PV (PV+, 8-9%) did not change with age in sham-controls and also the increase in cortical c-Fos expression induced by iTBS was not principally age-dependent. However, a prominent growth of the perineuronal nets, typically surrounding the PV+ cells, exactly paralleled the increase in the iTBS effect. Based on these findings, we conclude that the functional development of the inhibitory network of PV+ interneurons with regard to intracortical synaptic connectivity is not sufficiently matured in rats younger than 35 d to enable activity-dependent modifications during iTBS. Outgrowth of the perineuronal nets and associated maturation of excitatory cortical inputs, as is characteristic for the critical cortical period, may take place before PV+ interneurons can be sufficiently activated via repetitive transcranial magnetic stimulation, allowing plastic changes of molecular phenotype and likely also synaptic plasticity. © 2014 Wiley Periodicals, Inc.

Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia.

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Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A; Quik, Maryka

2016-12-01

Tardive dyskinesia (TD) is a drug-induced movement disorder that arises with antipsychotics. These drugs are the mainstay of treatment for schizophrenia and bipolar disorder, and are also prescribed for major depression, autism, attention deficit hyperactivity, obsessive compulsive and post-traumatic stress disorder. There is thus a need for therapies to reduce TD. The present studies and our previous work show that nicotine administration decreases haloperidol-induced vacuous chewing movements (VCMs) in rodent TD models, suggesting a role for the nicotinic cholinergic system. Extensive studies also show that D2 dopamine receptors are critical to TD. However, the precise involvement of striatal cholinergic interneurons and D2 medium spiny neurons (MSNs) in TD is uncertain. To elucidate their role, we used optogenetics with a focus on the striatum because of its close links to TD. Optical stimulation of striatal cholinergic interneurons using cholineacetyltransferase (ChAT)-Cre mice expressing channelrhodopsin2-eYFP decreased haloperidol-induced VCMs (~50%), with no effect in control-eYFP mice. Activation of striatal D2 MSNs using Adora2a-Cre mice expressing channelrhodopsin2-eYFP also diminished antipsychotic-induced VCMs, with no change in control-eYFP mice. In both ChAT-Cre and Adora2a-Cre mice, stimulation or mecamylamine alone similarly decreased VCMs with no further decline with combined treatment, suggesting nAChRs are involved. Striatal D2 MSN activation in haloperidol-treated Adora2a-Cre mice increased c-Fos + D2 MSNs and decreased c-Fos + non-D2 MSNs, suggesting a role for c-Fos. These studies provide the first evidence that optogenetic stimulation of striatal cholinergic interneurons and GABAergic MSNs modulates VCMs, and thus possibly TD. Moreover, they suggest nicotinic receptor drugs may reduce antipsychotic-induced TD. Copyright © 2016 Elsevier Inc. All rights reserved.

Multiple distinct subtypes of GABAergic neurons in mouse visual cortex identified by triple immunostaining

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Yuri Gonchar

2008-03-01

Full Text Available The majority of cortical interneurons use GABA (gamma amino butyric acid as inhibitory neurotransmitter. GABAergic neurons are morphologically, connectionally, electrically and chemically heterogeneous. In rat cerebral cortex three distinct groups of GABAergic interneurons have been identifi ed by the expression of parvalbumin (PV, calretinin (CR and somatostatin (SOM. Recent studies in mouse cerebral cortex have revealed a different organization in which the CR and SOM populations are partially overlapping. Because CR and SOM neurons derive from different progenitors located in different embryonic structures, the coexpression of CR + SOM suggests that the chemical differentiation of interneurons is regulated postmitotically. Here, we have taken an important fi rst step towards understanding this process by triple immunostaining mouse visual cortex with a panel of antibodies, which has been used extensively for classifying developing interneurons. We have found at least 13 distinct groups of GABAergic neurons which include PV, CR, SOM, CCK (cholecystokinin, CR + SOM, CR + NPY (neuropeptide Y, CR + VIP (vasointestinal polypeptide, SOM + NPY, SOM + VIP, VIP + ChAT (choline acetyltransferase, CCK + NPY, CR + SOM + NPY and CR + SOM + VIP expressing cells. Triple immunostaining with PV, CR and SOM antibodies during postnatal development further showed that PV is never colocalized with CR and SOM. Importantly, expression of SOM and CR + SOM developed after the percentage of CR cells that do not express SOM has reached the mature level, suggesting that the chemical differentiation of SOM and CR + SOM neurons is a postnatal event, which may be controlled by transcriptional regulation.

Ivy and neurogliaform interneurons are a major target of μ opioid receptor modulation

OpenAIRE

Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

2011-01-01

Mu opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform ...

Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome.

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Nomura, Toshihiro; Musial, Timothy F; Marshall, John J; Zhu, Yiwen; Remmers, Christine L; Xu, Jian; Nicholson, Daniel A; Contractor, Anis

2017-11-22

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is a leading cause of inherited intellectual disability, and the most common known cause of autism spectrum disorder. FXS is broadly characterized by sensory hypersensitivity and several developmental alterations in synaptic and circuit function have been uncovered in the sensory cortex of the mouse model of FXS ( Fmr1 KO). GABA-mediated neurotransmission and fast-spiking (FS) GABAergic interneurons are central to cortical circuit development in the neonate. Here we demonstrate that there is a delay in the maturation of the intrinsic properties of FS interneurons in the sensory cortex, and a deficit in the formation of excitatory synaptic inputs on to these neurons in neonatal Fmr1 KO mice. Both these delays in neuronal and synaptic maturation were rectified by chronic administration of a TrkB receptor agonist. These results demonstrate that the maturation of the GABAergic circuit in the sensory cortex is altered during a critical developmental period due in part to a perturbation in BDNF-TrkB signaling, and could contribute to the alterations in cortical development underlying the sensory pathophysiology of FXS. SIGNIFICANCE STATEMENT Fragile X (FXS) individuals have a range of sensory related phenotypes, and there is growing evidence of alterations in neuronal circuits in the sensory cortex of the mouse model of FXS ( Fmr1 KO). GABAergic interneurons are central to the correct formation of circuits during cortical critical periods. Here we demonstrate a delay in the maturation of the properties and synaptic connectivity of interneurons in Fmr1 KO mice during a critical period of cortical development. The delays both in cellular and synaptic maturation were rectified by administration of a TrkB receptor agonist, suggesting reduced BDNF-TrkB signaling as a contributing factor. These results provide evidence that the function of fast-spiking interneurons is disrupted due to a deficiency in neurotrophin

Closed Loop Brain Model of Neocortical Information Based Exchange

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James eKozloski

2016-01-01

Full Text Available Here we describe an information based exchange' model of brain function that ascribes to neocortex, basal ganglia, and thalamus distinct network functions. The model allows us to analyze whole brain system set point measures, such as the rate and heterogeneity of transitions in striatum and neocortex, in the context of neuromodulation and other perturbations. Our closed-loop model is grounded in neuroanatomical observations, proposing a novel Grand Loop through neocortex, and invokes different forms of plasticity at specific tissue interfaces and their principle cell synapses to achieve these transitions. By implementing a system for maximum information based exchange of action potentials between modeled neocortical areas, we observe changes to these measures in simulation. We hypothesize that similar dynamic set points and modulations exist in the brain's resting state activity, and that different modifications to information based exchange may shift the risk profile of different component tissues, resulting in different neurodegenerative diseases. This model is targeted for further development using IBM's Neural Tissue Simulator, which allows scalable elaboration of networks, tissues, and their neural and synaptic components towards ever greater complexity and biological realism.

Singing modulates parvalbumin interneurons throughout songbird forebrain vocal control circuitry

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Zengin-Toktas, Yildiz

2017-01-01

Across species, the performance of vocal signals can be modulated by the social environment. Zebra finches, for example, adjust their song performance when singing to females (‘female-directed’ or FD song) compared to when singing in isolation (‘undirected’ or UD song). These changes are salient, as females prefer the FD song over the UD song. Despite the importance of these performance changes, the neural mechanisms underlying this social modulation remain poorly understood. Previous work in finches has established that expression of the immediate early gene EGR1 is increased during singing and modulated by social context within the vocal control circuitry. Here, we examined whether particular neural subpopulations within those vocal control regions exhibit similar modulations of EGR1 expression. We compared EGR1 expression in neurons expressing parvalbumin (PV), a calcium buffer that modulates network plasticity and homeostasis, among males that performed FD song, males that produced UD song, or males that did not sing. We found that, overall, singing but not social context significantly affected EGR1 expression in PV neurons throughout the vocal control nuclei. We observed differences in EGR1 expression between two classes of PV interneurons in the basal ganglia nucleus Area X. Additionally, we found that singing altered the amount of PV expression in neurons in HVC and Area X and that distinct PV interneuron types in Area X exhibited different patterns of modulation by singing. These data indicate that throughout the vocal control circuitry the singing-related regulation of EGR1 expression in PV neurons may be less influenced by social context than in other neuron types and raise the possibility of cell-type specific differences in plasticity and calcium buffering. PMID:28235074

Statistical mechanics of neocortical interactions: Path-integral evolution of short-term memory

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Ingber, Lester

1994-05-01

Previous papers in this series of statistical mechanics of neocortical interactions (SMNI) have detailed a development from the relatively microscopic scales of neurons up to the macroscopic scales as recorded by electroencephalography (EEG), requiring an intermediate mesocolumnar scale to be developed at the scale of minicolumns (~=102 neurons) and macrocolumns (~=105 neurons). Opportunity was taken to view SMNI as sets of statistical constraints, not necessarily describing specific synaptic or neuronal mechanisms, on neuronal interactions, on some aspects of short-term memory (STM), e.g., its capacity, stability, and duration. A recently developed c-language code, pathint, provides a non-Monte Carlo technique for calculating the dynamic evolution of arbitrary-dimension (subject to computer resources) nonlinear Lagrangians, such as derived for the two-variable SMNI problem. Here, pathint is used to explicitly detail the evolution of the SMNI constraints on STM.

Ablation of fast-spiking interneurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome, produces anxiety and elevated grooming.

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Xu, M; Li, L; Pittenger, C

2016-06-02

Tic disorders, including Tourette syndrome (TS), are thought to involve pathology of cortico-basal ganglia loops, but their pathology is not well understood. Post-mortem studies have shown a reduced number of several populations of striatal interneurons, including the parvalbumin-expressing fast-spiking interneurons (FSIs), in individuals with severe, refractory TS. We tested the causal role of this interneuronal deficit by recapitulating it in an otherwise normal adult mouse using a combination transgenic-viral cell ablation approach. FSIs were reduced bilaterally by ∼40%, paralleling the deficit found post-mortem. This did not produce spontaneous stereotypies or tic-like movements, but there was increased stereotypic grooming after acute stress in two validated paradigms. Stereotypy after amphetamine, in contrast, was not elevated. FSI ablation also led to increased anxiety-like behavior in the elevated plus maze, but not to alterations in motor learning on the rotorod or to alterations in prepulse inhibition, a measure of sensorimotor gating. These findings indicate that a striatal FSI deficit can produce stress-triggered repetitive movements and anxiety. These repetitive movements may recapitulate aspects of the pathophysiology of tic disorders. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Tcf3 represses Wnt-β-catenin signaling and maintains neural stem cell population during neocortical development.

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Atsushi Kuwahara

Full Text Available During mouse neocortical development, the Wnt-β-catenin signaling pathway plays essential roles in various phenomena including neuronal differentiation and proliferation of neural precursor cells (NPCs. Production of the appropriate number of neurons without depletion of the NPC population requires precise regulation of the balance between differentiation and maintenance of NPCs. However, the mechanism that suppresses Wnt signaling to prevent premature neuronal differentiation of NPCs is poorly understood. We now show that the HMG box transcription factor Tcf3 (also known as Tcf7l1 contributes to this mechanism. Tcf3 is highly expressed in undifferentiated NPCs in the mouse neocortex, and its expression is reduced in intermediate neuronal progenitors (INPs committed to the neuronal fate. We found Tcf3 to be a repressor of Wnt signaling in neocortical NPCs in a reporter gene assay. Tcf3 bound to the promoter of the proneural bHLH gene Neurogenin1 (Neurog1 and repressed its expression. Consistent with this, Tcf3 repressed neuronal differentiation and increased the self-renewal activity of NPCs. We also found that Wnt signal stimulation reduces the level of Tcf3, and increases those of Tcf1 (also known as Tcf7 and Lef1, positive mediators of Wnt signaling, in NPCs. Together, these results suggest that Tcf3 antagonizes Wnt signaling in NPCs, thereby maintaining their undifferentiated state in the neocortex and that Wnt signaling promotes the transition from Tcf3-mediated repression to Tcf1/Lef1-mediated enhancement of Wnt signaling, constituting a positive feedback loop that facilitates neuronal differentiation.

Spillover-mediated feedforward-inhibition functionally segregates interneuron activity

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Coddington, Luke T.; Rudolph, Stephanie; Lune, Patrick Vande; Overstreet-Wadiche, Linda; Wadiche, Jacques I.

2013-01-01

Summary Neurotransmitter spillover represents a form of neural transmission not restricted to morphologically defined synaptic connections. Communication between climbing fibers (CFs) and molecular layer interneurons (MLIs) in the cerebellum is mediated exclusively by glutamate spillover. Here, we show how CF stimulation functionally segregates MLIs based on their location relative to glutamate release. Excitation of MLIs that reside within the domain of spillover diffusion coordinates inhibition of MLIs outside the diffusion limit. CF excitation of MLIs is dependent on extrasynaptic NMDA receptors that enhance the spatial and temporal spread of CF signaling. Activity mediated by functionally segregated MLIs converges onto neighboring Purkinje cells (PCs) to generate a long-lasting biphasic change in inhibition. These data demonstrate how glutamate release from single CFs modulates excitability of neighboring PCs, thus expanding the influence of CFs on cerebellar cortical activity in a manner not predicted by anatomical connectivity. PMID:23707614

Calretinin and parvalbumin immunoreactive interneurons in the retrosplenial cortex of the rat brain: Qualitative and quantitative analyses

Czech Academy of Sciences Publication Activity Database

Salaj, M.; Druga, Rastislav; Cerman, J.; Kubová, Hana; Barinka, F.

2015-01-01

Roč. 1627, Nov 19 (2015), s. 201-215 ISSN 0006-8993 R&D Projects: GA ČR(CZ) GBP304/12/G069 Institutional support: RVO:67985823 Keywords : retrosplenial cortex * calretinin * parvalbumin * interneurons * calcium-binding proteins * perirhinal cortex Subject RIV: FH - Neurology Impact factor: 2.561, year: 2015

The Role of Interneurons in Autism and Tourette Syndrome.

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Rapanelli, Maximiliano; Frick, Luciana Romina; Pittenger, Christopher

2017-07-01

The brain includes multiple types of interconnected excitatory and inhibitory neurons that together allow us to move, think, feel, and interact with the environment. Inhibitory interneurons (INs) comprise a small, heterogeneous fraction, but they exert a powerful and tight control over neuronal activity and consequently modulate the magnitude of neuronal output and, ultimately, information processing. IN abnormalities are linked to two pediatric psychiatric disorders with high comorbidity: autism spectrum disorder (ASD) and Tourette syndrome (TS). Studies probing the basis of this link have been contradictory regarding whether the causative mechanism is a reduction in number, dysfunction, or gene aberrant expression (or a combination thereof). Here, we integrate different theories into a more comprehensive view of INs as responsible for the symptomatology observed in these disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: implications for autism and epilepsy.

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Gant, John C; Thibault, Oliver; Blalock, Eric M; Yang, Jun; Bachstetter, Adam; Kotick, James; Schauwecker, Paula E; Hauser, Kurt F; Smith, George M; Mervis, Ron; Li, YanFang; Barnes, Gregory N

2009-04-01

Clinically, perturbations in the semaphorin signaling system have been associated with autism and epilepsy. The semaphorins have been implicated in guidance, migration, differentiation, and synaptic plasticity of neurons. The semaphorin 3F (Sema3F) ligand and its receptor, neuropilin 2 (NPN2) are highly expressed within limbic areas. NPN2 signaling may intimately direct the apposition of presynaptic and postsynaptic locations, facilitating the development and maturity of hippocampal synaptic function. To further understand the role of NPN2 signaling in central nevous system (CNS) plasticity, structural and functional alterations were assessed in NPN2 deficient mice. In NPN2 deficient mice, we measured seizure susceptibility after kainic acid or pentylenetetrazol, neuronal excitability and synaptic throughput in slice preparations, principal and interneuron cell counts with immunocytochemical protocols, synaptosomal protein levels with immunoblots, and dendritic morphology with Golgi-staining. NPN2 deficient mice had shorter seizure latencies, increased vulnerability to seizure-related death, were more likely to develop spontaneous recurrent seizure activity after chemical challenge, and had an increased slope on input/output curves. Principal cell counts were unchanged, but GABA, parvalbumin, and neuropeptide Y interneuron cell counts were significantly reduced. Synaptosomal NPN2 protein levels and total number of GABAergic synapses were decreased in a gene dose-dependent fashion. CA1 pyramidal cells showed reduced dendritic length and complexity, as well as an increased number of dendritic spines. These data suggest the novel hypothesis that the Sema 3F signaling system's role in appropriate placement of subsets of hippocampal interneurons has critical downstream consequences for hippocampal function, resulting in a more seizure susceptible phenotype.

Calretinin and parvalbumin immunoreactive interneurons in the retrosplenial cortex of the rat brain: Qualitative and quantitative analyses.

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Salaj, Martin; Druga, Rastislav; Cerman, Jiří; Kubová, Hana; Barinka, Filip

2015-11-19

The retrosplenial cortex (RSC) is a mesocortical region broadly involved with memory and navigation. It shares many characteristics with the perirhinal cortex (PRC), both of which appear to be significantly involved in the spreading of epileptic activity. We hypothesized that RSC possesses an interneuronal composition similar to that of PRC. To prove the hypothesis we studied the general pattern of calretinin (CR) and parvalbumin (PV) immunoreactivity in the RSC of the rat brain, its optical density as well as the morphological features and density of CR- and PV-immunoreactive (CR+ and PV+) interneurons. We also analyzed the overall neuronal density on Nissl-stained sections in RSC. Finally, we compared our results with our earlier analysis of PRC (Barinka et al., 2012). Compared to PRC, RSC was observed to have a higher intensity of PV staining and lower intensity of CR staining of neuropil. Vertically-oriented bipolar neurons were the most common morphological type among CR+ neurons. The staining pattern did not allow for a similarly detailed analysis of somatodendritic morphology of PV+ neurons. RSC possessed lower absolute (i.e., neurons/mm(3)) and relative (i.e., percentage of the overall neuronal population) densities of CR+ neurons and similar absolute and lower relative densities of PV+ neurons relative to PRC. CR: PV neuronal ratio in RSC (1:2 in area 29 and 1:2.2 in area 30) differed from PRC (1:1.2 in area 35 and 1:1.7 in area 36). In conclusion, RSC, although similar in many aspects to PRC, differs strikingly in the interneuronal composition relative to PRC. Copyright © 2015 Elsevier B.V. All rights reserved.

MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.

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Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K

2015-08-15

MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. Copyright © 2015 Elsevier B.V. All rights reserved.

Localization and pharmacological characterization of voltage dependent calcium channels in cultured neocortical neurons

DEFF Research Database (Denmark)

Timmermann, D B; Lund, Trine Meldgaard; Belhage, B

2001-01-01

The physiological significance and subcellular distribution of voltage dependent calcium channels was defined using calcium channel blockers to inhibit potassium induced rises in cytosolic calcium concentration in cultured mouse neocortical neurons. The cytosolic calcium concentration was measured...... channels were differentially distributed in somata, neurites and nerve terminals. omega-conotoxin MVIIC (omega-CgTx MVIIC) inhibited approximately 40% of the Ca(2+)-rise in both somata and neurites and 60% of the potassium induced [3H]GABA release, indicating that the Q-type channel is the quantitatively...... most important voltage dependent calcium channel in all parts of the neuron. After treatment with thapsigargin the increase in cytosolic calcium was halved, indicating that calcium release from thapsigargin sensitive intracellular calcium stores is an important component of the potassium induced rise...

An intracellular study on low-frequency acoustic signal processing in locust——Structure and function of the cercus-to-giant interneuron system

Institute of Scientific and Technical Information of China (English)

沈钧贤; 徐智敏

1995-01-01

The structure and function of the cercus-to-giant interneuron system,relevant to the receptionof low-frequency sound,within the terminal abdominal ganglion of the locust Locusta migratoria were revealedby using intracellular electrophysiological recording and dye labeling technique.This system consists of 4 bilater-al pairs of the giant interneurons(GIs 1—4).Each GI has distinct dendritic branching fields,position of thesoma,and location and orientation of its major axon.The characteristics of the system in responseto low-frequency sound,such as discharge patterns,the relationships between response threshold-frequency,in-tensity curves,and encoding of stimulus frequency,were also studied.The role of the system in low-frequencysound communication was discussed.

Spectroscopic evidence of hippocampal abnormalities in neocortical epilepsy

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Mueller, S. G.; Laxer, K. D.; Cashdollar, N.; Lopez, R. C.; Weiner, M. W.

2009-01-01

Lesional neocortical epilepsy (NE) can be associated with hippocampal sclerosis or hippocampal spectroscopic abnormalities without atrophy (dual pathology). In this study, magnetic resonance spectroscopic imaging (MRSI) was used to determine the frequency of hippocampal damage/dysfunction in NE with and without structural lesion. Sixteen patients with NE [seven temporal NE (NE-T), nine extratemporal (NE-ET)] and 16 controls were studied with a 2D MRSI sequence (Repetition time/echo time (TR/TE) = 1800/135 ms) covering both hippocampi. Seven NE patients had MR visible lesions (NE-Les), nine had normal MRI (NE-no). In each hippocampus, 12 voxels were uniformly selected. In controls, mean (± SD) NAA/(Cr + Cho) values for each voxel were calculated and voxels with NAA/(Cr + Cho) ≤ (mean in controls – 2SD in controls) were defined as ‘pathological’ in patients. Eight of 16 NE patients had at least two ‘pathological’ voxel (mean 2.5, range 2–5) in one hippocampus. Four were NE-Les and four NE-no. Three (43%) NE-T patients, had evidence for hippocampal damage/dysfunction and five (56%) had NE-ET. The ipsilateral hippocampus was affected in six of eight NE patients. Evidence for unilateral hippocampal damage/dysfunction was demonstrated in 50% of the NE patients. The type of NE, i.e. NE-Les or NE-no, NE-T or NE-ET, had no influence on the occurrence of hippocampal damage/dysfunction. PMID:16618342

P1 interneurons promote a persistent internal state that enhances inter-male aggression in Drosophila

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Hoopfer, Eric D; Jung, Yonil; Inagaki, Hidehiko K; Rubin, Gerald M; Anderson, David J

2015-01-01

How brains are hardwired to produce aggressive behavior, and how aggression circuits are related to those that mediate courtship, is not well understood. A large-scale screen for aggression-promoting neurons in Drosophila identified several independent hits that enhanced both inter-male aggression and courtship. Genetic intersections revealed that 8-10 P1 interneurons, previously thought to exclusively control male courtship, were sufficient to promote fighting. Optogenetic experiments indicated that P1 activation could promote aggression at a threshold below that required for wing extension. P1 activation in the absence of wing extension triggered persistent aggression via an internal state that could endure for minutes. High-frequency P1 activation promoted wing extension and suppressed aggression during photostimulation, whereas aggression resumed and wing extension was inhibited following photostimulation offset. Thus, P1 neuron activation promotes a latent, internal state that facilitates aggression and courtship, and controls the overt expression of these social behaviors in a threshold-dependent, inverse manner. DOI: http://dx.doi.org/10.7554/eLife.11346.001 PMID:26714106

Oxytocin Depolarizes Fast-Spiking Hilar Interneurons and Induces GABA Release onto Mossy Cells of the Rat Dentate Gyrus

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Harden, Scott W.; Frazier, Charles J.

2016-01-01

Delivery of exogenous oxytocin (OXT) to central oxytocin receptors (OXT-Rs) is currently being investigated as a potential treatment for conditions such as post-traumatic stress disorder (PTSD), depression, social anxiety, and autism spectrum disorder (ASD). Despite significant research implicating central OXT signaling in modulation of mood, affect, social behavior, and stress response, relatively little is known about the cellular and synaptic mechanisms underlying these complex actions, particularly in brain regions which express the OXT-R but lie outside of the hypothalamus (where OXT-synthesizing neurons reside). We report that bath application of low concentrations of the selective OXT-R agonist Thr4,Gly7-OXT (TGOT) reliably and robustly drives GABA release in the dentate gyrus in an action potential dependent manner. Additional experiments led to identification of a small subset of small hilar interneurons that are directly depolarized by acute application of TGOT. From a physiological perspective, TGOT-responsive hilar interneurons have high input resistance, rapid repolarization velocity during an action potential, and a robust afterhyperpolarization. Further, they fire irregularly (or stutter) in response to moderate depolarization, and fire quickly with minimal spike frequency accommodation in response to large current injections. From an anatomical perspective, TGOT responsive hilar interneurons have dense axonal arborizations in the hilus that were found close proximity with mossy cell somata and/or proximal dendrites, and also invade the granule cell layer. Further, they have primary dendrites that always extend into the granule cell layer, and sometimes have clear arborizations in the molecular layer. Overall, these data reveal a novel site of action for OXT in an important limbic circuit, and represent a significant step towards better understanding how endogenous OXT may modulate flow of information in hippocampal networks. PMID:27068005

Synaptic reorganization of inhibitory hilar interneuron circuitry after traumatic brain injury in mice

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Hunt, Robert F.; Scheff, Stephen W.; Smith, Bret N.

2011-01-01

Functional plasticity of synaptic networks in the dentate gyrus has been implicated in the development of posttraumatic epilepsy and in cognitive dysfunction after traumatic brain injury, but little is known about potentially pathogenic changes in inhibitory circuits. We examined synaptic inhibition of dentate granule cells and excitability of surviving GABAergic hilar interneurons 8–13 weeks after cortical contusion brain injury in transgenic mice that express enhanced green fluorescent protein in a subpopulation of inhibitory neurons. Whole-cell voltage-clamp recordings in granule cells revealed a reduction in spontaneous and miniature IPSC frequency after head injury; no concurrent change in paired-pulse ratio was found in granule cells after paired electrical stimulation of the hilus. Despite reduced inhibitory input to granule cells, action potential and EPSC frequencies were increased in hilar GABA neurons from slices ipsilateral to the injury, versus those from control or contralateral slices. Further, increased excitatory synaptic activity was detected in hilar GABA neurons ipsilateral to the injury after glutamate photostimulation of either the granule cell or CA3 pyramidal cell layers. Together, these findings suggest that excitatory drive to surviving hilar GABA neurons is enhanced by convergent input from both pyramidal and granule cells, but synaptic inhibition of granule cells is not fully restored after injury. This rewiring of circuitry regulating hilar inhibitory neurons may reflect an important compensatory mechanism, but it may also contribute to network destabilization by increasing the relative impact of surviving individual interneurons in controlling granule cell excitability in the posttraumatic dentate gyrus. PMID:21543618

Representation of the body in the lateral striatum of the freely moving rat: Fast Spiking Interneurons respond to stimulation of individual body parts.

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Kulik, Julianna M; Pawlak, Anthony P; Kalkat, Manraj; Coffey, Kevin R; West, Mark O

2017-02-15

Numerous studies have shown that certain types of striatal interneurons play a crucial role in selection and regulation of striatal output. Striatal Fast-Spiking Interneurons (FSIs) are parvalbumin positive, GABAergic interneurons that constitute less than 1% of the total striatal population. It is becoming increasingly evident that these sparsely distributed neurons exert a strong inhibitory effect on Medium Spiny projection Neurons (MSNs). MSNs in lateral striatum receive direct synaptic input from regions of cortex representing discrete body parts, and show phasic increases in activity during touch or movement of specific body parts. In the present study, we sought to determine whether lateral striatal FSIs identified by their electrophysiological properties, i.e., short-duration spike and fast firing rate (FR), display body part sensitivity similar to that exhibited by MSNs. During video recorded somatosensorimotor exams, each individual body part was stimulated and responses of single neurons were observed and quantified. Individual FSIs displayed patterns of activity related selectively to stimulation of a discrete body part. Most patterns of activity were similar to those exhibited by typical MSNs, but some phasic decreases were observed. These results serve as evidence that some striatal FSIs process information related to discrete body parts and participate in sensorimotor processing by striatal networks that contribute to motor output. Parvalbumin positive, striatal FSIs are hypothesized to play an important role in behavior by inhibiting MSNs. We asked a fundamental question regarding information processed during behavior by FSIs: whether FSIs, which preferentially occupy the sensorimotor portion of the striatum, process activity of discrete body parts. Our finding that they do, in a selective manner similar to MSNs, begins to reveal the types of phasic signals that FSI feed forward to projection neurons during striatal processing of cortical input

Spinal Hb9::Cre-derived excitatory interneurons contribute to rhythm generation in the mouse.

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Caldeira, Vanessa; Dougherty, Kimberly J; Borgius, Lotta; Kiehn, Ole

2017-01-27

Rhythm generating neurons are thought to be ipsilaterally-projecting excitatory neurons in the thoracolumbar mammalian spinal cord. Recently, a subset of Shox2 interneurons (Shox2 non-V2a INs) was found to fulfill these criteria and make up a fraction of the rhythm-generating population. Here we use Hb9::Cre mice to genetically manipulate Hb9::Cre-derived excitatory interneurons (INs) in order to determine the role of these INs in rhythm generation. We demonstrate that this line captures a consistent population of spinal INs which is mixed with respect to neurotransmitter phenotype and progenitor domain, but does not overlap with the Shox2 non-V2a population. We also show that Hb9::Cre-derived INs include the comparatively small medial population of INs which continues to express Hb9 postnatally. When excitatory neurotransmission is selectively blocked by deleting Vglut2 from Hb9::Cre-derived INs, there is no difference in left-right and/or flexor-extensor phasing between these cords and controls, suggesting that excitatory Hb9::Cre-derived INs do not affect pattern generation. In contrast, the frequencies of locomotor activity are significantly lower in cords from Hb9::Cre-Vglut2 Δ/Δ mice than in cords from controls. Collectively, our findings indicate that excitatory Hb9::Cre-derived INs constitute a distinct population of neurons that participates in the rhythm generating kernel for spinal locomotion.

Interplay of intrinsic and synaptic conductances in the generation of high-frequency oscillations in interneuronal networks with irregular spiking.

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Fabiano Baroni

2014-05-01

Full Text Available High-frequency oscillations (above 30 Hz have been observed in sensory and higher-order brain areas, and are believed to constitute a general hallmark of functional neuronal activation. Fast inhibition in interneuronal networks has been suggested as a general mechanism for the generation of high-frequency oscillations. Certain classes of interneurons exhibit subthreshold oscillations, but the effect of this intrinsic neuronal property on the population rhythm is not completely understood. We study the influence of intrinsic damped subthreshold oscillations in the emergence of collective high-frequency oscillations, and elucidate the dynamical mechanisms that underlie this phenomenon. We simulate neuronal networks composed of either Integrate-and-Fire (IF or Generalized Integrate-and-Fire (GIF neurons. The IF model displays purely passive subthreshold dynamics, while the GIF model exhibits subthreshold damped oscillations. Individual neurons receive inhibitory synaptic currents mediated by spiking activity in their neighbors as well as noisy synaptic bombardment, and fire irregularly at a lower rate than population frequency. We identify three factors that affect the influence of single-neuron properties on synchronization mediated by inhibition: i the firing rate response to the noisy background input, ii the membrane potential distribution, and iii the shape of Inhibitory Post-Synaptic Potentials (IPSPs. For hyperpolarizing inhibition, the GIF IPSP profile (factor iii exhibits post-inhibitory rebound, which induces a coherent spike-mediated depolarization across cells that greatly facilitates synchronous oscillations. This effect dominates the network dynamics, hence GIF networks display stronger oscillations than IF networks. However, the restorative current in the GIF neuron lowers firing rates and narrows the membrane potential distribution (factors i and ii, respectively, which tend to decrease synchrony. If inhibition is shunting instead

Interplay of intrinsic and synaptic conductances in the generation of high-frequency oscillations in interneuronal networks with irregular spiking.

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Baroni, Fabiano; Burkitt, Anthony N; Grayden, David B

2014-05-01

High-frequency oscillations (above 30 Hz) have been observed in sensory and higher-order brain areas, and are believed to constitute a general hallmark of functional neuronal activation. Fast inhibition in interneuronal networks has been suggested as a general mechanism for the generation of high-frequency oscillations. Certain classes of interneurons exhibit subthreshold oscillations, but the effect of this intrinsic neuronal property on the population rhythm is not completely understood. We study the influence of intrinsic damped subthreshold oscillations in the emergence of collective high-frequency oscillations, and elucidate the dynamical mechanisms that underlie this phenomenon. We simulate neuronal networks composed of either Integrate-and-Fire (IF) or Generalized Integrate-and-Fire (GIF) neurons. The IF model displays purely passive subthreshold dynamics, while the GIF model exhibits subthreshold damped oscillations. Individual neurons receive inhibitory synaptic currents mediated by spiking activity in their neighbors as well as noisy synaptic bombardment, and fire irregularly at a lower rate than population frequency. We identify three factors that affect the influence of single-neuron properties on synchronization mediated by inhibition: i) the firing rate response to the noisy background input, ii) the membrane potential distribution, and iii) the shape of Inhibitory Post-Synaptic Potentials (IPSPs). For hyperpolarizing inhibition, the GIF IPSP profile (factor iii)) exhibits post-inhibitory rebound, which induces a coherent spike-mediated depolarization across cells that greatly facilitates synchronous oscillations. This effect dominates the network dynamics, hence GIF networks display stronger oscillations than IF networks. However, the restorative current in the GIF neuron lowers firing rates and narrows the membrane potential distribution (factors i) and ii), respectively), which tend to decrease synchrony. If inhibition is shunting instead of

Prenatal phencyclidine treatment induces behavioral deficits through impairment of GABAergic interneurons in the prefrontal cortex.

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Toriumi, Kazuya; Oki, Mika; Muto, Eriko; Tanaka, Junko; Mouri, Akihiro; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

2016-06-01

We previously reported that prenatal treatment with phencyclidine (PCP) induces glutamatergic dysfunction in the prefrontal cortex (PFC), leading to schizophrenia-like behavioral deficits in adult mice. However, little is known about the prenatal effect of PCP treatment on other types of neurons. We focused on γ-aminobutyric acid (GABA)-ergic interneurons and evaluated the effect of prenatal PCP exposure on the neurodevelopment of GABAergic interneurons in the PFC. PCP was administered at the dose of 10 mg/kg/day to pregnant dams from embryonic day 6.5 to 18.5. After the pups were reared to adult, we analyzed their GABAergic system in the PFC using immunohistological, biochemical, and behavioral analyses in adulthood. The prenatal PCP treatment decreased the density of parvalbumin-positive cells and reduced the expression level of glutamic acid decarboxylase 67 (GAD67) and GABA content of the PFC in adults. Additionally, prenatal PCP treatment induced behavioral deficits in adult mice, such as hypersensitivity to PCP and prepulse inhibition (PPI) deficits. These behavioral deficits were ameliorated by pretreatment with the GABAB receptor agonist baclofen. Furthermore, the density of c-Fos-positive cells was decreased after the PPI test in the PFC of mice treated with PCP prenatally, and this effect was ameliorated by pretreatment with baclofen. These findings suggest that prenatal treatment with PCP induced GABAergic dysfunction in the PFC, which caused behavioral deficits.

Corrigendum to “Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain" [Neurosci.Lett. 580 (2014) 12–16] A possible new animal model of autism

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Sabers, Anne; Bertelsen, Freja C B; Scheel-Krüger, Jørgen

2015-01-01

The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20 mg/kg or 100 mg/kg) continuously during the last 9......–12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fraction at or and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups....... Pups exposed to 100 mg/kg, but not to 20 mg/kg VPA displayed a significant (p brain development by disturbing neocortical organization...

Parvalbumin- and vasoactive intestinal polypeptide-expressing neocortical interneurons impose differential inhibition on Martinotti cells

NARCIS (Netherlands)

Walker, F.; Mock, M.; Feyerabend, M.; Guy, J.; Wagener, R.J.; Schubert, D.; Staiger, J.F.; Witte, M. de

2016-01-01

Disinhibition of cortical excitatory cell gate information flow through and between cortical columns. The major contribution of Martinotti cells (MC) is providing dendritic inhibition to excitatory neurons and therefore they are a main component of disinhibitory connections. Here we show by means of

The sodium channel activator Lu AE98134 normalizes the altered firing properties of fast spiking interneurons in Dlx5/6+/- mice

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von Schoubye, Nadia Lybøl; Frederiksen, Kristen; Kristiansen, Uffe

2018-01-01

Mental disorders such as schizophrenia are associated with impaired firing properties of fast spiking inhibitory interneurons (FSINs) causing reduced task-evoked gamma-oscillation in prefrontal cortex. The voltage-gated sodium channel NaV1.1 is highly expressed in PV-positive interneurons, but only...... at low levels in principal cells. Positive modulators of Nav1.1 channels are for this reason considered potential candidates for the treatment of cognitive disorders. Here we examined the effect of the novel positive modulator of voltage-gated sodium channels Lu AE98134. We found that Lu AE98134...... facilitated the sodium current mediated by NaV1.1 expressed in HEK cells by shifting its activation to more negative values, decreasing its inactivation kinetics and promoting a persistent inward current. In a slice preparation from the brain of adult mice, Lu AE98134 promoted the excitability of fast spiking...

Neocortical inhibitory activities and long-range afferents contribute to the synchronous onset of silent states of the neocortical slow oscillation.

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Lemieux, Maxime; Chauvette, Sylvain; Timofeev, Igor

2015-02-01

During slow-wave sleep, neurons of the thalamocortical network are engaged in a slow oscillation (<1 Hz), which consists of an alternation between the active and the silent states. Several studies have provided insights on the transition from the silent, which are essentially periods of disfacilitation, to the active states. However, the conditions leading to the synchronous onset of the silent state remain elusive. We hypothesized that a synchronous input to local inhibitory neurons could contribute to the transition to the silent state in the cat suprasylvian gyrus during natural sleep and under ketamine-xylazine anesthesia. After partial and complete deafferentation of the cortex, we found that the silent state onset was more variable among remote sites. We found that the transition to the silent state was preceded by a reduction in excitatory postsynaptic potentials and firing probability in cortical neurons. We tested the impact of chloride-mediated inhibition in the silent-state onset. We uncovered a long-duration (100-300 ms) inhibitory barrage occurring about 250 ms before the silent state onset in 3-6% of neurons during anesthesia and in 12-15% of cases during natural sleep. These inhibitory activities caused a decrease in cortical firing that reduced the excitatory drive in the neocortical network. That chain reaction of disfacilitation ends up on the silent state. Electrical stimuli could trigger a network silent state with a maximal efficacy in deep cortical layers. We conclude that long-range afferents to the neocortex and chloride-mediated inhibition play a role in the initiation of the silent state. Copyright © 2015 the American Physiological Society.

Statistical mechanics of neocortical interactions: Stability and duration of the 7±2 rule of short-term-memory capacity

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Ingber, Lester

1985-02-01

This paper is an essential addendum to a previous paper [L. Ingber, Phys. Rev. A 29, 3346 (1984)]. Calculations are presented here to support the claim made in the previous paper that there exists an approximate one-dimensional solution to the two-dimensional neocortical Fokker-Planck equation. This solution is extremely useful, not only for obtaining a closed algebraic expression for the time of first passage, but also for establishing that minima of the associated path-integral stationary Lagrangian are indeed stable points of the transient dynamic system. Also, a relatively nontechnical summary is given of the basic theory.

Pauses in Striatal Cholinergic Interneurons: What is Revealed by Their Common Themes and Variations?

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Yan-Feng Zhang

2017-10-01

Full Text Available Striatal cholinergic interneurons, the so-called tonically active neurons (TANs, pause their firing in response to sensory cues and rewards during classical conditioning and instrumental tasks. The respective pause responses observed can demonstrate many commonalities, such as constant latency and duration, synchronous occurrence in a population of cells, and coincidence with phasic activities of midbrain dopamine neurons (DANs that signal reward predictions and errors. Pauses can however also show divergent properties. Pause latencies and durations can differ in a given TAN between appetitive vs. aversive outcomes in classical conditioning, initial excitation can be present or absent, and a second pause can variably follow a rebound. Despite more than 20 years of study, the functions of these pause responses are still elusive. Our understanding of pause function is hindered by an incomplete understanding of how pauses are generated. In this mini-review article, we compare pause types, as well as current key hypotheses for inputs underlying pauses that include dopamine-induced inhibition through D2-receptors, a GABA input from ventral tegmental area, and a prolonged afterhyperpolarization induced by excitatory input from the cortex or from the thalamus. We review how each of these mechanisms alone explains some but not all aspects of pause responses. These mechanisms might need to operate in specific but variable sets of sequences to generate a full range of pause responses. Alternatively, these mechanisms might operate in conjunction with an underlying control mechanism within cholinergic interneurons which could potentially provide a framework to generate the common themes and variations seen amongst pause responses.

Fate of Cajal-Retzius neurons in the postnatal mouse neocortex

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Tara G Chowdhury

2010-03-01

Full Text Available Cajal-Retzius (CR neurons play a critical role in cortical neuronal migration, but their exact fate after the completion of neocortical lamination remains a mystery. Histological evidence has been unable to unequivocally determine whether these cells die or undergo a phenotypic transformation to become resident interneurons of Layer 1 in the adult neocortex. To determine their ultimate fate, we performed chronic in vivo two-photon imaging of identified CR neurons during postnatal development in mice that express the green fluorescent protein (GFP under the control of the early B-cell factor 2 (Ebf2 promoter. We find that, after birth, virtually all CR neurons in mouse neocortex express Ebf2. Although postnatal CR neurons undergo dramatic morphological transformations, they do not migrate to deeper layers. Instead, their gradual disappearance from the cortex is due to apoptotic death during the second postnatal week. A small fraction of CR neurons present at birth survive into adulthood. We conclude that, in addition to orchestrating cortical layering, a subset of CR neurons must play other roles beyond the third postnatal week.

For things needing your attention: the role of neocortical gamma in sensory perception.

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Pritchett, Dominique L; Siegle, Joshua H; Deister, Christopher A; Moore, Christopher I

2015-04-01

Two general classes of hypotheses for the role for gamma oscillations in sensation are those that predict gamma facilitates signal amplification through local synchronization of a distinct ensemble, and those that predict gamma modulates fine temporal relationships between neurons to represent information. Correlative evidence has been offered for and against these hypotheses. A recent study in which gamma was optogenetically entrained by driving fast-spiking interneurons showed enhanced sensory detection of harder-to-perceive stimuli, those that benefit most from attention, in agreement with the amplification hypotheses. These findings are supported by similar studies employing less specific optogenetic patterns or single neuron stimulation, but contrast with findings based on direct optogenetic stimulation of pyramidal neurons. Key next steps for this topic are described. Copyright © 2015 Elsevier Ltd. All rights reserved.

A cortical attractor network with Martinotti cells driven by facilitating synapses.

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Pradeep Krishnamurthy

Full Text Available The population of pyramidal cells significantly outnumbers the inhibitory interneurons in the neocortex, while at the same time the diversity of interneuron types is much more pronounced. One acknowledged key role of inhibition is to control the rate and patterning of pyramidal cell firing via negative feedback, but most likely the diversity of inhibitory pathways is matched by a corresponding diversity of functional roles. An important distinguishing feature of cortical interneurons is the variability of the short-term plasticity properties of synapses received from pyramidal cells. The Martinotti cell type has recently come under scrutiny due to the distinctly facilitating nature of the synapses they receive from pyramidal cells. This distinguishes these neurons from basket cells and other inhibitory interneurons typically targeted by depressing synapses. A key aspect of the work reported here has been to pinpoint the role of this variability. We first set out to reproduce quantitatively based on in vitro data the di-synaptic inhibitory microcircuit connecting two pyramidal cells via one or a few Martinotti cells. In a second step, we embedded this microcircuit in a previously developed attractor memory network model of neocortical layers 2/3. This model network demonstrated that basket cells with their characteristic depressing synapses are the first to discharge when the network enters an attractor state and that Martinotti cells respond with a delay, thereby shifting the excitation-inhibition balance and acting to terminate the attractor state. A parameter sensitivity analysis suggested that Martinotti cells might, in fact, play a dominant role in setting the attractor dwell time and thus cortical speed of processing, with cellular adaptation and synaptic depression having a less prominent role than previously thought.

Amelioration of oxidative stress-induced phenotype loss of parvalbumin interneurons might contribute to the beneficial effects of environmental enrichment in a rat model of post-traumatic stress disorder.

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Sun, Xiao R; Zhang, Hui; Zhao, Hong T; Ji, Mu H; Li, Hui H; Wu, Jing; Li, Kuan Y; Yang, Jian J

2016-10-01

Post-traumatic stress disorder (PTSD) is a common psychiatric disease following exposure to a severe traumatic event or physiological stress, which is characterized by anxiety- and depression-like behaviors and cognitive impairment. However, the underlying mechanisms remain elusive. Parvalbumin (PV) interneurons that are susceptible to oxidative stress are a subset of inhibitory GABAergic neurons regulating the excitability of pyramidal neurons, while dysfunction of PV interneurons is casually linked to many mental disorders including PTSD. We therefore hypothesized that environmental enrichment (EE), a method of enhanced cognitive, sensory and motor stimulation, can reverse the behavioral impairments by normalizing PV interneurons in a rat model of PTSD induced by inescapable foot shocks (IFS). Behavioral changes were determined by the open field, elevated plus maze, fear conditioning, and Morris water maze tests. The levels of nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), NOX4, PV, glutamic acid decarboxylase 67 (GAD-67), and 8-hydroxy-2-deoxyguanosine (8-OH-dG) in the hippocampus and prefrontal cortex were determined. Our results showed that in this PTSD model, rats displayed the anxiety-like behavior, enhanced fear learning behavior, and hippocampus- dependent spatial memory deficit, which were accompanied by the up-regulation of NOX2, 8-OH-dG, and down-regulation of PV and GAD-67. Notably, EE reversed all these abnormalities. These results suggest that restoration of PV interneurons by inhibiting oxidative stress in the hippocampus and prefrontal cortex might represent a mechanism through which EE reverses the behavioral impairments in a rat model of PTSD induced by IFS. Copyright © 2016 Elsevier B.V. All rights reserved.

Npas4 Regulates Mdm2 and thus Dcx in Experience-Dependent Dendritic Spine Development of Newborn Olfactory Bulb Interneurons

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Sei-ichi Yoshihara

2014-08-01

Full Text Available Sensory experience regulates the development of various brain structures, including the cortex, hippocampus, and olfactory bulb (OB. Little is known about how sensory experience regulates the dendritic spine development of OB interneurons, such as granule cells (GCs, although it is well studied in mitral/tufted cells. Here, we identify a transcription factor, Npas4, which is expressed in OB GCs immediately after sensory input and is required for dendritic spine formation. Npas4 overexpression in OB GCs increases dendritic spine density, even under sensory deprivation, and rescues reduction of dendrite spine density in the Npas4 knockout OB. Furthermore, loss of Npas4 upregulates expression of the E3-ubiquitin ligase Mdm2, which ubiquitinates a microtubule-associated protein Dcx. This leads to reduction in the dendritic spine density of OB GCs. Together, these findings suggest that Npas4 regulates Mdm2 expression to ubiquitinate and degrade Dcx during dendritic spine development in newborn OB GCs after sensory experience.

Primary cellular meningeal defects cause neocortical dysplasia and dyslamination

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Hecht, Jonathan H.; Siegenthaler, Julie A.; Patterson, Katelin P.; Pleasure, Samuel J.

2010-01-01

Objective Cortical malformations are important causes of neurological morbidity, but in many cases their etiology is poorly understood. Mice with Foxc1 mutations have cellular defects in meningeal development. We use hypomorphic and null alleles of Foxc1 to study the effect of meningeal defects on neocortical organization. Methods Embryos with loss of Foxc1 activity were generated using the hypomorphic Foxc1hith allele and the null Foxc1lacZ allele. Immunohistologic analysis was used to assess cerebral basement membrane integrity, marginal zone heterotopia formation, neuronal overmigration, meningeal defects, and changes in basement membrane composition. Dysplasia severity was quantified using two measures. Results Cortical dysplasia resembling cobblestone cortex, with basement membrane breakdown and lamination defects, is seen in Foxc1 mutants. As Foxc1 activity was reduced, abnormalities in basement membrane integrity, heterotopia formation, neuronal overmigration, and meningeal development appeared earlier in gestation and were more severe. Surprisingly, the basement membrane appeared intact at early stages of development in the face of severe deficits in meningeal development. Prominent defects in basement membrane integrity appeared as development proceeded. Molecular analysis of basement membrane laminin subunits demonstrated that loss of the meninges led to changes in basement membrane composition. Interpretation Cortical dysplasia can be caused by cellular defects in the meninges. The meninges are not required for basement membrane establishment but are needed for remodeling as the brain expands. Specific changes in basement membrane composition may contribute to subsequent breakdown. Our study raises the possibility that primary meningeal defects may cortical dysplasia in some cases. PMID:20976766

Overproduction of Upper-Layer Neurons in the Neocortex Leads to Autism-like Features in Mice

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Wei-Qun Fang

2014-12-01

Full Text Available Summary: The functional integrity of the neocortex depends upon proper numbers of excitatory and inhibitory neurons; however, the consequences of dysregulated neuronal production during the development of the neocortex are unclear. As excess cortical neurons are linked to the neurodevelopmental disorder autism, we investigated whether the overproduction of neurons leads to neocortical malformation and malfunction in mice. We experimentally increased the number of pyramidal neurons in the upper neocortical layers by using the small molecule XAV939 to expand the intermediate progenitor population. The resultant overpopulation of neurons perturbs development of dendrites and spines of excitatory neurons and alters the laminar distribution of interneurons. Furthermore, these phenotypic changes are accompanied by dysregulated excitatory and inhibitory synaptic connection and balance. Importantly, these mice exhibit behavioral abnormalities resembling those of human autism. Thus, our findings collectively suggest a causal relationship between neuronal overproduction and autism-like features, providing developmental insights into the etiology of autism. : Fang et al. generated a mouse model with excessive excitatory neurons in the neocortex by manipulating embryonic neurogenesis. Overproduction of neurons results in autism-like anatomical and behavioral features. These findings suggest a causal relationship between overproduction of neurons and cortical malfunction and provide developmental insights into the etiology of autism.

The Mechanisms of Repetitive Spike Generation in an Axonless Retinal Interneuron

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Mark S. Cembrowski

2012-02-01

Full Text Available Several types of retinal interneurons exhibit spikes but lack axons. One such neuron is the AII amacrine cell, in which spikes recorded at the soma exhibit small amplitudes (5 ms. Here, we used electrophysiological recordings and computational analysis to examine the mechanisms underlying this atypical spiking. We found that somatic spikes likely represent large, brief action potential-like events initiated in a single, electrotonically distal dendritic compartment. In this same compartment, spiking undergoes slow modulation, likely by an M-type K conductance. The structural correlate of this compartment is a thin neurite that extends from the primary dendritic tree: local application of TTX to this neurite, or excision of it, eliminates spiking. Thus, the physiology of the axonless AII is much more complex than would be anticipated from morphological descriptions and somatic recordings; in particular, the AII possesses a single dendritic structure that controls its firing pattern.

Sparing of descending axons rescues interneuron plasticity in the lumbar cord to allow adaptive learning after thoracic spinal cord injury

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Christopher Nelson Hansen

2016-03-01

Full Text Available This study evaluated the role of spared axons on structural and behavioral neuroplasticity in the lumbar enlargement after a thoracic spinal cord injury (SCI. Previous work has demonstrated that recovery in the presence of spared axons after an incomplete lesion increases behavioral output after a subsequent complete spinal cord transection (TX. This suggests that spared axons direct adaptive changes in below-level neuronal networks of the lumbar cord. In response to spared fibers, we postulate that lumbar neuron networks support behavioral gains by preventing aberrant plasticity. As such, the present study measured histological and functional changes in the isolated lumbar cord after complete TX or incomplete contusion (SCI. To measure functional plasticity in the lumbar cord, we used an established instrumental learning paradigm. In this paradigm, neural circuits within isolated lumbar segments demonstrate learning by an increase in flexion duration that reduces exposure to a noxious leg shock. We employed this model using a proof-of-principle design to evaluate the role of sparing on lumbar learning and plasticity early (7 days or late (42 days after midthoracic SCI in a rodent model. Early after SCI or TX at 7d, spinal learning was unattainable regardless of whether the animal recovered with or without axonal substrate. Failed learning occurred alongside measures of cell soma atrophy and aberrant dendritic spine expression within interneuron populations responsible for sensorimotor integration and learning. Alternatively, exposure of the lumbar cord to a small amount of spared axons for 6 weeks produced near-normal learning late after SCI. This coincided with greater cell soma volume and fewer aberrant dendritic spines on interneurons. Thus, an opportunity to influence activity-based learning in locomotor networks depends on spared axons limiting maladaptive plasticity. Together, this work identifies a time dependent interaction between

The PKA-C3 catalytic subunit is required in two pairs of interneurons for successful mating of Drosophila.

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Cassar, Marlène; Sunderhaus, Elizabeth; Wentzell, Jill S; Kuntz, Sara; Strauss, Roland; Kretzschmar, Doris

2018-02-06

Protein kinase A (PKA) has been shown to play a role in a plethora of cellular processes ranging from development to memory formation. Its activity is mediated by the catalytic subunits whereby many species express several paralogs. Drosophila encodes three catalytic subunits (PKA-C1-3) and whereas PKA-C1 has been well studied, the functions of the other two subunits were unknown. PKA-C3 is the orthologue of mammalian PRKX/Pkare and they are structurally more closely related to each other than to other catalytic subunits within their species. PRKX is expressed in the nervous system in mice but its function is also unknown. We now show that the loss of PKA-C3 in Drosophila causes copulation defects, though the flies are active and show no defects in other courtship behaviours. This phenotype is specifically due to the loss of PKA-C3 because PKA-C1 cannot replace PKA-C3. PKA-C3 is expressed in two pairs of interneurons that send projections to the ventro-lateral protocerebrum and the mushroom bodies and that synapse onto motor neurons in the ventral nerve cord. Rescue experiments show that expression of PKA-C3 in these interneurons is sufficient for copulation, suggesting a role in relaying information from the sensory system to motor neurons to initiate copulation.

Neocortical dynamics at multiple scales: EEG standing waves, statistical mechanics, and physical analogs.

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Ingber, Lester; Nunez, Paul L

2011-02-01

The dynamic behavior of scalp potentials (EEG) is apparently due to some combination of global and local processes with important top-down and bottom-up interactions across spatial scales. In treating global mechanisms, we stress the importance of myelinated axon propagation delays and periodic boundary conditions in the cortical-white matter system, which is topologically close to a spherical shell. By contrast, the proposed local mechanisms are multiscale interactions between cortical columns via short-ranged non-myelinated fibers. A mechanical model consisting of a stretched string with attached nonlinear springs demonstrates the general idea. The string produces standing waves analogous to large-scale coherent EEG observed in some brain states. The attached springs are analogous to the smaller (mesoscopic) scale columnar dynamics. Generally, we expect string displacement and EEG at all scales to result from both global and local phenomena. A statistical mechanics of neocortical interactions (SMNI) calculates oscillatory behavior consistent with typical EEG, within columns, between neighboring columns via short-ranged non-myelinated fibers, across cortical regions via myelinated fibers, and also derives a string equation consistent with the global EEG model. Copyright © 2010 Elsevier Inc. All rights reserved.

Morphology and kainate-receptor immunoreactivity of identified neurons within the entorhinal cortex projecting to superior temporal sulcus in the cynomolgus monkey

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Good, P. F.; Morrison, J. H.; Bloom, F. E. (Principal Investigator)

1995-01-01

Projections of the entorhinal cortex to the hippocampus are well known from the classical studies of Cajal (Ramon y Cajal, 1904) and Lorente de No (1933). Projections from the entorhinal cortex to neocortical areas are less well understood. Such connectivity is likely to underlie the consolidation of long-term declarative memory in neocortical sites. In the present study, a projection arising in layer V of the entorhinal cortex and terminating in a polymodal association area of the superior temporal gyrus has been identified with the use of retrograde tracing. The dendritic arbors of neurons giving rise to this projection were further investigated by cell filling and confocal microscopy with computer reconstruction. This analysis demonstrated that the dendritic arbor of identified projection neurons was largely confined to layer V, with the exception of a solitary, simple apical dendrite occasionally ascending to superficial laminae but often confined to the lamina dissecans (layer IV). Finally, immunoreactivity for glutamate-receptor subunit proteins GluR 5/6/7 of the dendritic arbor of identified entorhinal projection neurons was examined. The solitary apical dendrite of identified entorhinal projection neurons was prominently immunolabeled for GluR 5/6/7, as was the dendritic arbor of basilar dendrites of these neurons. The restriction of the large bulk of the dendritic arbor of identified entorhinal projection neurons to layer V implies that these neurons are likely to be heavily influenced by hippocampal output arriving in the deep layers of the entorhinal cortex. Immunoreactivity for GluR 5/6/7 throughout the dendritic arbor of such neurons indicates that this class of glutamate receptor is in a position to play a prominent role in mediating excitatory neurotransmission within hippocampal-entorhinal circuits.

Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expression of neuregulin-1.

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Radonjić, Nevena V; Jakovcevski, Igor; Bumbaširević, Vladimir; Petronijević, Nataša D

2013-06-01

Perinatal phencyclidine (PCP) administration in rat blocks the N-methyl D-aspartate receptor (NMDAR) and causes symptoms reminiscent of schizophrenia in human. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) interneuron neurotransmission may be associated with schizophrenia. Neuregulin-1 (NRG-1) is a trophic factor important for neurodevelopment, synaptic plasticity, and wiring of GABA circuits. The aim of this study was to determine the long-term effects of perinatal PCP administration on the projection and local circuit neurons and NRG-1 expression in the cortex and hippocampus. Rats were treated on postnatal day 2 (P2), P6, P9, and P12 with either PCP (10 mg/kg) or saline. Morphological studies and determination of NRG-1 expression were performed at P70. We demonstrate reduced densities of principal neurons in the CA3 and dentate gyrus (DG) subregions of the hippocampus and a reduction of major interneuronal populations in all cortical and hippocampal regions studied in PCP-treated rats compared with controls. For the first time, we show the reduced density of reelin- and somatostatin-positive cells in the cortex and hippocampus of animals perinatally treated with PCP. Furthermore, an increase in the numbers of perisomatic inhibitory terminals around the principal cells was observed in the motor cortex and DG. We also show that perinatal PCP administration leads to an increased NRG-1 expression in the cortex and hippocampus. Taken together, our findings demonstrate that perinatal PCP administration increases NRG-1 expression and reduces the number of projecting and local circuit neurons, revealing complex consequences of NMDAR blockade.

Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801

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Bygrave, A M; Masiulis, S; Nicholson, E; Berkemann, M; Barkus, C; Sprengel, R; Harrison, P J; Kullmann, D M; Bannerman, D M; Kätzel, D

2016-01-01

It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1ΔPV mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1ΔPV mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1ΔPVmice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1ΔPVmice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1ΔPVmice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease. PMID:27070406

Current and calcium responses to local activation of axonal NMDA receptors in developing cerebellar molecular layer interneurons.

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Bénédicte Rossi

Full Text Available In developing cerebellar molecular layer interneurons (MLIs, NMDA increases spontaneous GABA release. This effect had been attributed to either direct activation of presynaptic NMDA receptors (preNMDARs or an indirect pathway involving activation of somato-dendritic NMDARs followed by passive spread of somatic depolarization along the axon and activation of axonal voltage dependent Ca(2+ channels (VDCCs. Using Ca(2+ imaging and electrophysiology, we searched for preNMDARs by uncaging NMDAR agonists either broadly throughout the whole field or locally at specific axonal locations. Releasing either NMDA or glutamate in the presence of NBQX using short laser pulses elicited current transients that were highly sensitive to the location of the spot and restricted to a small number of varicosities. The signal was abolished in the presence of high Mg(2+ or by the addition of APV. Similar paradigms yielded restricted Ca(2+ transients in interneurons loaded with a Ca(2+ indicator. We found that the synaptic effects of NMDA were not inhibited by blocking VDCCs but were impaired in the presence of the ryanodine receptor antagonist dantrolene. Furthermore, in voltage clamped cells, bath applied NMDA triggers Ca(2+ elevations and induces neurotransmitter release in the axonal compartment. Our results suggest the existence of preNMDARs in developing MLIs and propose their involvement in the NMDA-evoked increase in GABA release by triggering a Ca(2+-induced Ca(2+ release process mediated by presynaptic Ca(2+ stores. Such a mechanism is likely to exert a crucial role in various forms of Ca(2+-mediated synaptic plasticity.

Lack of Cdkl5 disrupts the organization of excitatory and inhibitory synapses and parvalbumin interneurons in the primary visual cortex

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Riccardo Pizzo

2016-11-01

Full Text Available CDKL5 (cyclin-dependent kinase-like 5 mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (CDKL5 disorder. CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1 of Cdkl5-/y mice. We found a severe reduction of c-fos expression in V1 of Cdkl5-/y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5-/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period. The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience-dependent refinement of cortical circuits during the critical period of development.

Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex.

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Pizzo, Riccardo; Gurgone, Antonia; Castroflorio, Enrico; Amendola, Elena; Gross, Cornelius; Sassoè-Pognetto, Marco; Giustetto, Maurizio

2016-01-01

Cyclin-dependent kinase-like 5 (CDKL5) mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (RTT; CDKL5 disorder). CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1) of Cdkl5 -/y mice. We found a severe reduction of c-Fos expression in V1 of Cdkl5 -/y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5 -/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period (CP). The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience-dependent refinement of cortical circuits during the CP of development.

Electroconvulsive therapy and structural neuroplasticity in neocortical, limbic and paralimbic cortex

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Pirnia, T; Joshi, S H; Leaver, A M; Vasavada, M; Njau, S; Woods, R P; Espinoza, R; Narr, K L

2016-01-01

Electroconvulsive therapy (ECT) is a highly effective and rapidly acting treatment for severe depression. To understand the biological bases of therapeutic response, we examined variations in cortical thickness from magnetic resonance imaging (MRI) data in 29 patients scanned at three time points during an ECT treatment index series and in 29 controls at two time points. Changes in thickness across time and with symptom improvement were evaluated at high spatial resolution across the cortex and within discrete cortical regions of interest. Patients showed increased thickness over the course of ECT in the bilateral anterior cingulate cortex (ACC), inferior and superior temporal, parahippocampal, entorhinal and fusiform cortex and in distributed prefrontal areas. No changes across time occurred in controls. In temporal and fusiform regions showing significant ECT effects, thickness differed between patients and controls at baseline and change in thickness related to therapeutic response in patients. In the ACC, these relationships occurred in treatment responders only, and thickness measured soon after treatment initiation predicted the overall ECT response. ECT leads to widespread neuroplasticity in neocortical, limbic and paralimbic regions and changes relate to the extent of antidepressant response. Variations in ACC thickness, which discriminate treatment responders and predict response early in the course of ECT, may represent a biomarker of overall clinical outcome. Because post-mortem studies show focal reductions in glial density and neuronal size in patients with severe depression, ECT-related increases in thickness may be attributable to neuroplastic processes affecting the size and/or density of neurons and glia and their connections. PMID:27271858

Fluctuating inhibitory inputs promote reliable spiking at theta frequencies in hippocampal interneurons

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Duluxan eSritharan

2012-05-01

Full Text Available Theta frequency (4-12 Hz rhythms in the hippocampus play important roles in learning and memory. CA1 interneurons located at the stratum lacunosum-moleculare and radiatum junction (LM/RAD are thought to contribute to hippocampal theta population activities by rhythmically pacing pyramidal cells with inhibitory postsynaptic potentials. This implies that LM/RAD cells need to fire reliably at theta frequencies in vivo. To determine whether this could occur, we use biophysically-based LM/RAD model cells and apply different cholinergic and synaptic inputs to simulate in vivo-like network environments. We assess spike reliabilities and spiking frequencies, identifying biophysical properties and network conditions that best promote reliable theta spiking. We find that synaptic background activities that feature large inhibitory, but not excitatory, fluctuations are essential. This suggests that strong inhibitory input to these cells is vital for them to be able to contribute to population theta activities. Furthermore, we find that Type I-like oscillator models produced by augmented persistent sodium currents (INap or diminished A type potassium currents (IA enhance reliable spiking at lower theta frequencies. These Type I-like models are also the most responsive to large inhibitory fluctuations and can fire more reliably under such conditions. In previous work, we showed that INap and IA are largely responsible for establishing LM/RAD cells’ subthreshold activities. Taken together with this study, we see that while both these currents are important for subthreshold theta fluctuations and reliable theta spiking, they contribute in different ways – INap to reliable theta spiking and subthreshold activity generation, and IA to subthreshold activities at theta frequencies. This suggests that linking subthreshold and suprathreshold activities should be done with consideration of both in vivo contexts and biophysical specifics.

Brainlab: A Python Toolkit to Aid in the Design, Simulation, and Analysis of Spiking Neural Networks with the NeoCortical Simulator.

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Drewes, Rich; Zou, Quan; Goodman, Philip H

2009-01-01

Neuroscience modeling experiments often involve multiple complex neural network and cell model variants, complex input stimuli and input protocols, followed by complex data analysis. Coordinating all this complexity becomes a central difficulty for the experimenter. The Python programming language, along with its extensive library packages, has emerged as a leading "glue" tool for managing all sorts of complex programmatic tasks. This paper describes a toolkit called Brainlab, written in Python, that leverages Python's strengths for the task of managing the general complexity of neuroscience modeling experiments. Brainlab was also designed to overcome the major difficulties of working with the NCS (NeoCortical Simulator) environment in particular. Brainlab is an integrated model-building, experimentation, and data analysis environment for the powerful parallel spiking neural network simulator system NCS.

Recent Advances in the Pathogenesis of Syndromic Autisms

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A. Benvenuto

2009-01-01

Full Text Available Background. Current advances in genetic technology continue to expand the list of medical conditions associated with autism. Clinicians have to identify specific autistic-related syndromes, and to provide tailored counseling. The aim of this study is to elucidate recent advances in autism research that offer important clues into pathogenetic mechanisms of syndromic autism and relevant implications for clinical practice. Data Sources. The PubMed database was searched with the keywords “autism” and “chromosomal abnormalities,” “metabolic diseases,” “susceptibility loci.” Results. Defined mutations, genetic syndromes, and metabolic diseases account for up to 20% of autistic patients. Metabolic and mitochondrial defects may have toxic effects on the brain cells, causing neuronal loss and altered modulation of neurotransmission systems. Alterations of the neocortical excitatory/inhibitory balance and perturbations of interneurons' development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in Fragile X-Syndrome and Tuberous Sclerosis Complex. Chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections, brain growth, and synaptic/dendritic morphology. Conclusion. Metabolic testing may be appropriate if specific symptoms are present. High-resolution chromosome analysis may be recommended if a specific diagnosis is suspected because of obvious dysmorphisms. Identifying cryptic chromosomal abnormalities by whole genome microarray analysis can increase the understanding of the neurobiological pathways to autism.

Medial temporal and neocortical contributions to remote memory for semantic narratives: evidence from amnesia.

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Verfaellie, Mieke; Bousquet, Kathryn; Keane, Margaret M

2014-08-01

Studies of remote memory for semantic facts and concepts suggest that hippocampal lesions lead to a temporally graded impairment that extends no more than ten years prior to the onset of amnesia. Such findings have led to the notion that once consolidated, semantic memories are represented neocortically and are no longer dependent on the hippocampus. Here, we examined the fate of well-established semantic narratives following medial temporal lobe (MTL) lesions. Seven amnesic patients, five with lesions restricted to the MTL and two with lesions extending into lateral temporal cortex (MTL+), were asked to recount fairy tales and bible stories that they rated as familiar. Narratives were scored for number and type of details, number of main thematic elements, and order in which the main thematic elements were recounted. In comparison to controls, patients with MTL lesions produced fewer details, but the number and order of main thematic elements generated was intact. By contrast, patients with MTL+ lesions showed a pervasive impairment, affecting not only the generation of details, but also the generation and ordering of main steps. These findings challenge the notion that, once consolidated, semantic memories are no longer dependent on the hippocampus for retrieval. Possible hippocampal contributions to the retrieval of detailed semantic narratives are discussed. Published by Elsevier Ltd.

POMT1-associated walker-warburg syndrome: a disorder of dendritic development of neocortical neurons.

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Judas, M; Sedmak, G; Rados, M; Sarnavka, V; Fumić, K; Willer, T; Gross, C; Hehr, U; Strahl, S; Cuk, M; Barić, I

2009-02-01

We have analyzed the morphology and dendritic development of neocortical neurons in a 2.5-month-old infant with Walker-Warburg syndrome homozygotic for a novel POMT1 gene mutation, by Golgi methods. We found that pyramidal neurons frequently displayed abnormal (oblique, horizontal, or inverted) orientation. A novel finding of this study is that members of the same population of pyramidal neurons display different stages of development of their dendritic arborizations: some neurons had poorly developed dendrites and thus resembled pyramidal neurons of the late fetal cortex; for some neurons, the level of differentiation corresponded to that in the newborn cortex; finally, some neurons had quite elaborate dendritic trees as expected for the cortex of 2.5-month-old infant. In addition, apical dendrites of many pyramidal neurons were conspiciously bent to one side, irrespective to the general orientation of the pyramidal neuron. These findings suggest that Walker-Warburg lissencephaly is characterized by two hitherto unnoticed pathogenetic changes in the cerebral cortex: (a) heterochronic decoupling of dendritic maturation within the same neuronal population (with some members significantly lagging behind the normal maturational schedule) and (b) anisotropically distorted shaping of dendritic trees, probably caused by patchy displacement of molecular guidance cues for dendrites in the malformed cortex. Copyright Georg Thieme Verlag KG Stuttgart New York.

Environmental enrichment as a therapeutic avenue for anxiety in aged Wistar rats: Effect on cat odor exposition and GABAergic interneurons.

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Sampedro-Piquero, P; Castilla-Ortega, E; Zancada-Menendez, C; Santín, L J; Begega, A

2016-08-25

The use of more ethological animal models to study the neurobiology of anxiety has increased in recent years. We assessed the effect of an environmental enrichment (EE) protocol (24h/day over a period of two months) on anxiety-related behaviors when aged Wistar rats (21months old) were confronted with cat odor stimuli. Owing to the relationship between GABAergic interneurons and the anxiety-related neuronal network, we examined changes in the expression of Parvalbumin (PV) and 67kDa form of glutamic acid decarboxylase (GAD-67) immunoreactive cells in different brain regions involved in stress response. Behavioral results revealed that enriched rats traveled further and made more grooming behaviors during the habituation session. In the cat odor session, they traveled longer distances and they showed more active interaction with the odor stimuli and less time in freezing behavior. Zone analysis revealed that the enriched group spent more time in the intermediate zone according to the proximity of the predator odor. Regarding the neurobiological data, the EE increased the expression of PV-positive cells in some medial prefrontal regions (cingulate (Cg) and prelimbic (PL) cortices), whereas the GAD-67 expression in the basolateral amygdala was reduced in the enriched group. Our results suggest that EE is able to reduce anxiety-like behaviors in aged animals even when ethologically relevant stimuli are used. Moreover, GABAergic interneurons could be involved in mediating this resilient behavior. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Population-specific regulation of Chmp2b by Lbx1 during onset of synaptogenesis in lateral association interneurons.

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Jun Xu

Full Text Available Chmp2b is closely related to Vps2, a key component of the yeast protein complex that creates the intralumenal vesicles of multivesicular bodies. Dominant negative mutations in Chmp2b cause autophagosome accumulation and neurodegenerative disease. Loss of Chmp2b causes failure of dendritic spine maturation in cultured neurons. The homeobox gene Lbx1 plays an essential role in specifying postmitotic dorsal interneuron populations during late pattern formation in the neural tube. We have discovered that Chmp2b is one of the most highly regulated cell-autonomous targets of Lbx1 in the embryonic mouse neural tube. Chmp2b was expressed and depended on Lbx1 in only two of the five nascent, Lbx1-expressing, postmitotic, dorsal interneuron populations. It was also expressed in neural tube cell populations that lacked Lbx1 protein. The observed population-specific expression of Chmp2b indicated that only certain population-specific combinations of sequence specific transcription factors allow Chmp2b expression. The cell populations that expressed Chmp2b corresponded, in time and location, to neurons that make the first synapses of the spinal cord. Chmp2b protein was transported into neurites within the motor- and association-neuropils, where the first synapses are known to form between E11.5 and E12.5 in mouse neural tubes. Selective, developmentally-specified gene expression of Chmp2b may therefore be used to endow particular neuronal populations with the ability to mature dendritic spines. Such a mechanism could explain how mammalian embryos reproducibly establish the disynaptic cutaneous reflex only between particular cell populations.

Cornu Ammonis Regions–Antecedents of Cortical Layers?

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Mercer, Audrey; Thomson, Alex M.

2017-01-01

Studying neocortex and hippocampus in parallel, we are struck by the similarities. All three to four layered allocortices and the six layered mammalian neocortex arise in the pallium. All receive and integrate multiple cortical and subcortical inputs, provide multiple outputs and include an array of neuronal classes. During development, each cell positions itself to sample appropriate local and distant inputs and to innervate appropriate targets. Simpler cortices had already solved the need to transform multiple coincident inputs into serviceable outputs before neocortex appeared in mammals. Why then do phylogenetically more recent cortices need multiple pyramidal cell layers? A simple answer is that more neurones can compute more complex functions. The dentate gyrus and hippocampal CA regions—which might be seen as hippocampal antecedents of neocortical layers—lie side by side, albeit around a tight bend. Were the millions of cells of rat neocortex arranged in like fashion, the surface area of the CA pyramidal cell layers would be some 40 times larger. Even if evolution had managed to fold this immense sheet into the space available, the distances between neurones that needed to be synaptically connected would be huge and to maintain the speed of information transfer, massive, myelinated fiber tracts would be needed. How much more practical to stack the “cells that fire and wire together” into narrow columns, while retaining the mechanisms underlying the extraordinary precision with which circuits form. This demonstrably efficient arrangement presents us with challenges, however, not the least being to categorize the baffling array of neuronal subtypes in each of five “pyramidal layers.” If we imagine the puzzle posed by this bewildering jumble of apical dendrites, basal dendrites and axons, from many different pyramidal and interneuronal classes, that is encountered by a late-arriving interneurone insinuating itself into a functional circuit, we can

Outcome of intracranial electroencephalography monitoring and surgery in magnetic resonance imaging-negative temporal lobe epilepsy.

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Lee, Ricky W; Hoogs, Marietta M; Burkholder, David B; Trenerry, Max R; Drazkowski, Joseph F; Shih, Jerry J; Doll, Karey E; Tatum, William O; Cascino, Gregory D; Marsh, W Richard; Wirrell, Elaine C; Worrell, Gregory A; So, Elson L

2014-07-01

We evaluated the outcomes of intracranial electroencephalography (iEEG) recording and subsequent resective surgery in patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE). Thirty-two patients were identified from the Mayo Clinic Epilepsy Surgery Database (Arizona, Florida, and Minnesota). Eight (25.0%) had chronic iEEG monitoring that recorded neocortical temporal seizure onsets; 12 (37.5%) had mesial temporal seizure onsets; 5 (15.6%) had independent neocortical and mesial temporal seizure onsets; and 7 (21.9%) had simultaneous neocortical and mesial seizure onsets. Neocortical temporal lobe seizure semiology was the only factor significantly associated with neocortical temporal seizure onsets on iEEG. Only 33.3% of patients who underwent lateral temporal neocorticectomy had an Engel class 1 outcome, whereas 76.5% of patients with iEEG-guided anterior temporal lobectomy that included the amygdala and the hippocampus had an Engel class 1 outcome. Limitations in cohort size precluded statistical analysis of neuropsychological test data. Copyright © 2014 Elsevier B.V. All rights reserved.

Closed-loop response properties of a visual interneuron involved in fly optomotor control

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Naveed eEjaz

2013-03-01

Full Text Available Due to methodological limitations neural function is mostly studied under open-loop conditions. Normally, however, nervous systems operate in closed-loop where sensory input is processed to generate behavioural outputs, which again change the sensory input. Here, we investigate the closed-loop responses of an identified visual interneuron, the blowfly H1-cell, that is part of a neural circuit involved in optomotor flight and gaze control. Those behaviours may be triggered by attitude changes during flight in turbulent air. The fly analyses the resulting retinal image shifts and performs compensatory body and head rotations to regain its default attitude. We developed a fly-robot interface to study H1-cell responses in a 1 degree-of-freedom image stabilization task. Image shifts, induced by externally forced rotations, modulate the cell’s spike rate that controls counter rotations of a mobile robot to minimize relative motion between the robot and its visual surroundings. A feedback controller closed the loop between neural activity and the rotation of the robot. Under these conditions we found the following H1-cell response properties: (i the peak spike rate decreases when the mean image velocity is increased, (ii the relationship between spike rate and image velocity depends on the standard deviation of the image velocities suggesting adaptive scaling of the cell’s signalling range, and (iii the cell’s gain decreases linearly with increasing image accelerations.Our results reveal a remarkable qualitative similarity between the response dynamics of the H1-cell under closed-loop conditions with those obtained in previous open-loop experiments. Finally, we show that the adaptive scaling of the H1-cell’s responses, while maximizing information on image velocity, decreases the cell’s sensitivity to image accelerations. Understanding such trade-offs in biological vision systems may advance the design of smart vision sensors for autonomous

Brainlab: a Python toolkit to aid in the design, simulation, and analysis of spiking neural networks with the NeoCortical Simulator

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Richard P Drewes

2009-05-01

Full Text Available Neuroscience modeling experiments often involve multiple complex neural network and cell model variants, complex input stimuli and input protocols, followed by complex data analysis. Coordinating all this complexity becomes a central difficulty for the experimenter. The Python programming language, along with its extensive library packages, has emerged as a leading ``glue'' tool for managing all sorts of complex programmatictasks. This paper describes a toolkit called Brainlab, written in Python, that leverages Python's strengths for the task of managing the general complexity of neuroscience modeling experiments. Brainlab was also designed to overcome the major difficulties of working with the NCS environment in particular. Brainlab is an integrated model building, experimentation, and data analysis environment for the powerful parallel spiking neural network simulator system NCS (the NeoCortical Simulator.

Balanced plasticity and stability of the electrical properties of a molluscan modulatory interneuron after classical conditioning: a computational study

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Dimitris Vavoulis

2010-05-01

Full Text Available The Cerebral Giant Cells (CGCs are a pair of identified modulatory interneurons in the Central Nervous System of the pond snail Lymnaea stagnalis with an important role in the expression of both unconditioned and conditioned feeding behavior. Following single-trial food-reward classical conditioning, the membrane potential of the CGCs becomes persistently depolarized. This depolarization contributes to the conditioned response by facilitating sensory cell to command neuron synapses, which results in the activation of the feeding network by the conditioned stimulus. Despite the depolarization of the membrane potential, which enables the CGGs to play a key role in learning-induced network plasticity, there is no persistent change in the tonic firing rate or shape of the action potentials, allowing these neurons to retain their normal network function in feeding. In order to understand the ionic mechanisms of this novel combination of plasticity and stability of intrinsic electrical properties, we first constructed and validated a Hodgkin-Huxley-type model of the CGCs. We then used this model to elucidate how learning-induced changes in a somal persistent sodium and a delayed rectifier potassium current lead to a persistent depolarization of the CGCs whilst maintaining their firing rate. Including in the model an additional increase in the conductance of a high-voltage-activated calcium current allowed the spike amplitude and spike duration also to be maintained after conditioning. We conclude therefore that a balanced increase in three identified conductances is sufficient to explain the electrophysiological changes found in the CGCs after classical conditioning.

Fast-Spiking Interneurons Supply Feedforward Control of Bursting, Calcium, and Plasticity for Efficient Learning.

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Owen, Scott F; Berke, Joshua D; Kreitzer, Anatol C

2018-02-08

Fast-spiking interneurons (FSIs) are a prominent class of forebrain GABAergic cells implicated in two seemingly independent network functions: gain control and network plasticity. Little is known, however, about how these roles interact. Here, we use a combination of cell-type-specific ablation, optogenetics, electrophysiology, imaging, and behavior to describe a unified mechanism by which striatal FSIs control burst firing, calcium influx, and synaptic plasticity in neighboring medium spiny projection neurons (MSNs). In vivo silencing of FSIs increased bursting, calcium transients, and AMPA/NMDA ratios in MSNs. In a motor sequence task, FSI silencing increased the frequency of calcium transients but reduced the specificity with which transients aligned to individual task events. Consistent with this, ablation of FSIs disrupted the acquisition of striatum-dependent egocentric learning strategies. Together, our data support a model in which feedforward inhibition from FSIs temporally restricts MSN bursting and calcium-dependent synaptic plasticity to facilitate striatum-dependent sequence learning. Copyright © 2018 Elsevier Inc. All rights reserved.

Quantitative Imaging of Cholinergic Interneurons Reveals a Distinctive Spatial Organization and a Functional Gradient across the Mouse Striatum.

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Miriam Matamales

Full Text Available Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood. Here, we systematically mapped and digitally reconstructed the entire ensemble of CINs in the mouse striatum and quantitatively assessed differences in densities, spatial arrangement and neuropil content across striatal functional territories. This approach demonstrated that the rostral portion of the striatum contained a higher concentration of CINs than the caudal striatum and that the cholinergic content in the core of the ventral striatum was significantly lower than in the rest of the regions. Additionally, statistical comparison of spatial point patterns in the striatal cholinergic ensemble revealed that only a minor portion of CINs (17% aggregated into cluster and that they were predominantly organized in a random fashion. Furthermore, we used a fluorescence reporter to estimate the activity of over two thousand CINs in naïve mice and found that there was a decreasing gradient of CIN overall function along the dorsomedial-to-ventrolateral axis, which appeared to be independent of their propensity to aggregate within the striatum. Altogether this work suggests that the regulation of striatal function by acetylcholine across the striatum is highly heterogeneous, and that signals originating in external afferent systems may be principally determining the function of CINs in the

Optogenetic activation of neocortical neurons in vivo with a sapphire-based micro-scale LED probe

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Niall eMcAlinden

2015-05-01

Full Text Available Optogenetics has proven to be a revolutionary technology in neuroscience and has advanced continuously over the past decade. However, optical stimulation technologies for in vivo need to be developed to match the advances in genetics and biochemistry that have driven this field. In particular, conventional approaches for in vivo optical illumination have a limitation on the achievable spatio-temporal resolution. Here we utilize a sapphire-based microscale gallium nitride light-emitting diode (µLED probe to activate neocortical neurons in vivo. The probes were designed to contain independently controllable multiple µLEDs, emitting at 450 nm wavelength with an irradiance of up to 2 W/mm2. Monte-Carlo stimulations predicted that optical stimulation using a µLED can modulate neural activity within a localized region. To validate this prediction, we tested this probe in the mouse neocortex that expressed channelrhodopsin-2 (ChR2 and compared the results with optical stimulation through a fiber at the cortical surface. We confirmed that both approaches reliably induced action potentials in cortical neurons and that the µLED probe evoked strong responses in deep neurons. Due to the possibility to integrate many optical stimulation sites onto a single shank, the µLED probe is thus a promising approach to control neurons locally in vivo.

Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing

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Roger Cachope

2012-07-01

Full Text Available Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior.

Novel AAV-based rat model of forebrain synucleinopathy shows extensive pathologies and progressive loss of cholinergic interneurons.

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Patrick Aldrin-Kirk

Full Text Available Synucleinopathies, characterized by intracellular aggregation of α-synuclein protein, share a number of features in pathology and disease progression. However, the vulnerable cell population differs significantly between the disorders, despite being caused by the same protein. While the vulnerability of dopamine cells in the substantia nigra to α-synuclein over-expression, and its link to Parkinson's disease, is well studied, animal models recapitulating the cortical degeneration in dementia with Lewy-bodies (DLB are much less mature. The aim of this study was to develop a first rat model of widespread progressive synucleinopathy throughout the forebrain using adeno-associated viral (AAV vector mediated gene delivery. Through bilateral injection of an AAV6 vector expressing human wild-type α-synuclein into the forebrain of neonatal rats, we were able to achieve widespread, robust α-synuclein expression with preferential expression in the frontal cortex. These animals displayed a progressive emergence of hyper-locomotion and dysregulated response to the dopaminergic agonist apomorphine. The animals receiving the α-synuclein vector displayed significant α-synuclein pathology including intra-cellular inclusion bodies, axonal pathology and elevated levels of phosphorylated α-synuclein, accompanied by significant loss of cortical neurons and a progressive reduction in both cortical and striatal ChAT positive interneurons. Furthermore, we found evidence of α-synuclein sequestered by IBA-1 positive microglia, which was coupled with a distinct change in morphology. In areas of most prominent pathology, the total α-synuclein levels were increased to, on average, two-fold, which is similar to the levels observed in patients with SNCA gene triplication, associated with cortical Lewy body pathology. This study provides a novel rat model of progressive cortical synucleinopathy, showing for the first time that cholinergic interneurons are vulnerable

Synaptic Conductance Estimates of the Connection Between Local Inhibitor Interneurons and Pyramidal Neurons in Layer 2/3 of a Cortical Column

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Hoffmann, Jochen H.O.; Meyer, H. S.; Schmitt, Arno C.; Straehle, Jakob; Weitbrecht, Trinh; Sakmann, Bert; Helmstaedter, Moritz

2015-01-01

Stimulation of a principal whisker yields sparse action potential (AP) spiking in layer 2/3 (L2/3) pyramidal neurons in a cortical column of rat barrel cortex. The low AP rates in pyramidal neurons could be explained by activation of interneurons in L2/3 providing inhibition onto L2/3 pyramidal neurons. L2/3 interneurons classified as local inhibitors based on their axonal projection in the same column were reported to receive strong excitatory input from spiny neurons in L4, which are also the main source of the excitatory input to L2/3 pyramidal neurons. Here, we investigated the remaining synaptic connection in this intracolumnar microcircuit. We found strong and reliable inhibitory synaptic transmission between intracolumnar L2/3 local-inhibitor-to-L2/3 pyramidal neuron pairs [inhibitory postsynaptic potential (IPSP) amplitude −0.88 ± 0.67 mV]. On average, 6.2 ± 2 synaptic contacts were made by L2/3 local inhibitors onto L2/3 pyramidal neurons at 107 ± 64 µm path distance from the pyramidal neuron soma, thus overlapping with the distribution of synaptic contacts from L4 spiny neurons onto L2/3 pyramidal neurons (67 ± 34 µm). Finally, using compartmental simulations, we determined the synaptic conductance per synaptic contact to be 0.77 ± 0.4 nS. We conclude that the synaptic circuit from L4 to L2/3 can provide efficient shunting inhibition that is temporally and spatially aligned with the excitatory input from L4 to L2/3. PMID:25761638

Time organization of frontal-motor cortex interneuron interactions in the cat neocortex in conditions of different levels of food motivation.

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Merzhanova, G Kh; Dolbakyan, E E

1997-01-01

Studies were carried out in conscious cats with recording of multicellular activity in moderate hunger and after 24-h food deprivation. Cross-correlation analysis was used to assess statistical interneuron interactions between closely-located neurons in the frontal and sensorimotor regions of the neocortex (local networks), and between the cells of these regions (distributed networks). One-day food deprivation increased the number of interactions formed within both local and distributed neuron networks. Increases in intercortical connections between the frontal and motor regions was seen at all time intervals studied (0-100 msec), though the most significant changes occurred at time intervals of up to 30 msec.

Neocortical concentrations of neuropeptides in senile dementia of the Alzheimer and Lewy body type: comparison with Parkinson's disease and severity correlations.

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Leake, A; Perry, E K; Perry, R H; Jabeen, S; Fairbairn, A F; McKeith, I G; Ferrier, I N

1991-02-15

Corticotropin releasing hormone (CRH), somatostatin (SRIF), and arginine vasopressin (AVP) concentrations were estimated using radioimmunoassay in the temporal and occipital cortices in postmortem brain from patients clinically and neuropathologically diagnosed as senile dementia of the Lewy body type (SDLT), senile dementia of the Alzheimer type (SDAT), and Parkinson's disease (PD) and from neurologically normal controls. The concentration of temporal and occipital neocortical CRH was diminished in both SDAT and SDLT compared to control values, whereas SRIF was reduced only in temporal cortex in both these conditions. In contrast, the concentrations of both CRH and SRIF were unaltered in PD. The concentrations of AVP in SDLT, SDAT, and PD were similar to those found in the control groups. The decrement in SRIF, but not CRH, was found to be correlated with some indices of severity of illness in SDAT; a similar but nonsignificant trend for SRIF was observed in SDLT.

Microglia Modulate Wiring of the Embryonic Forebrain

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Paola Squarzoni

2014-09-01

Full Text Available Dysfunction of microglia, the tissue macrophages of the brain, has been associated with the etiology of several neuropsychiatric disorders. Consistently, microglia have been shown to regulate neurogenesis and synaptic maturation at perinatal and postnatal stages. However, microglia invade the brain during mid-embryogenesis and thus could play an earlier prenatal role. Here, we show that embryonic microglia, which display a transiently uneven distribution, regulate the wiring of forebrain circuits. Using multiple mouse models, including cell-depletion approaches and cx3cr1−/−, CR3−/−, and DAP12−/− mutants, we find that perturbing microglial activity affects the outgrowth of dopaminergic axons in the forebrain and the laminar positioning of subsets of neocortical interneurons. Since defects in both dopamine innervation and cortical networks have been linked to neuropsychiatric diseases, our study provides insights into how microglial dysfunction can impact forebrain connectivity and reveals roles for immune cells during normal assembly of brain circuits.

BDNF Up-Regulates α7 Nicotinic Acetylcholine Receptor Levels on Subpopulations of Hippocampal Interneurons

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Massey, Kerri A.; Zago, Wagner M.; Berg, Darwin K.

2006-01-01

In the hippocampus, brain-derived neurotrophic factor (BDNF) regulates a number of synaptic components. Among these are nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs), which are interesting because of their relative abundance in the hippocampus and their high relative calcium permeability. We show here that BDNF elevates surface and intracellular pools of α7-nAChRs on cultured hippocampal neurons and that glutamatergic activity is both necessary and sufficient for the effect. Blocking transmission through NMDA receptors with APV blocked the BDNF effect; increasing spontaneous excitatory activity with the GABAA receptor antagonist bicuculline replicated the BDNF effect. BDNF antibodies blocked the BDNF-mediated increase but not the bicuculline one, consistent with enhanced glutamatergic activity acting downstream from BDNF. Increased α7-nAChR clusters were most prominent on interneuron subtypes known to innervate directly excitatory neurons. The results suggest that BDNF, acting through glutamatergic transmission, can modulate hippocampal output in part by controlling α7-nAChR levels. PMID:17029981

Nitric oxide synthase-I containing cortical interneurons co-express antioxidative enzymes and anti-apoptotic Bcl-2 following focal ischemia: evidence for direct and indirect mechanisms towards their resistance to neuropathology.

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Bidmon, H J; Emde, B; Kowalski, T; Schmitt, M; Mayer, B; Kato, K; Asayama, K; Witte, O W; Zilles, K

2001-09-01

Neuronal nitric oxide-I is constitutively expressed in approximately 2% of cortical interneurons and is co-localized with gamma-amino butric acid, somatostatin or neuropeptide Y. These interneurons additionally express high amounts of glutamate receptors which mediate the glutamate-induced hyperexcitation following cerebral injury, under these conditions nitric oxide production increases contributing to a potentiation of oxidative stress. However, perilesional nitric oxide synthase-I containing neurons are known to be resistant to ischemic and excitotoxic injury. In vitro studies show that nitrosonium and nitroxyl ions inactivate N-methyl-D-aspartate receptors, resulting in neuroprotection. The question remains of how these cells are protected against their own high intracellular nitric oxide production after activation. In this study, we investigated immunocytochemically nitric oxide synthase-I containing cortical neurons in rats after unilateral, cortical photothrombosis. In this model of focal ischemia, perilesional, constitutively nitric oxide synthase-I containing neurons survived and co-expressed antioxidative enzymes, such as manganese- and copper-zinc-dependent superoxide dismutases, heme oxygenase-2 and cytosolic glutathione peroxidase. This enhanced antioxidant expression was accompanied by a strong perinuclear presence of the antiapoptotic Bcl-2 protein. No colocalization was detectable with upregulated heme oxygenase-1 in glia and the superoxide and prostaglandin G(2)-producing cyclooxygenase-2 in neurons. These results suggest that nitric oxide synthase-I containing interneurons are protected against intracellular oxidative damage and apoptosis by Bcl-2 and several potent antioxidative enzymes. Since nitric oxide synthase-I positive neurons do not express superoxide-producing enzymes such as cyclooxygenase-1, xanthine oxidase and cyclooxygenase-2 in response to injury, this may additionally contribute to their resistance by reducing their internal

beta1 integrin maintains integrity of the embryonic neocortical stem cell niche.

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Karine Loulier

2009-08-01

to the ventricular surface and maintaining the physical integrity of the neocortical niche, with even transient perturbations resulting in long-lasting cortical defects.

A central pattern generator producing alternative outputs: pattern, strength, and dynamics of premotor synaptic input to leech heart motor neurons.

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Norris, Brian J; Weaver, Adam L; Wenning, Angela; García, Paul S; Calabrese, Ronald L

2007-11-01

The central pattern generator (CPG) for heartbeat in medicinal leeches consists of seven identified pairs of segmental heart interneurons and one unidentified pair. Four of the identified pairs and the unidentified pair of interneurons make inhibitory synaptic connections with segmental heart motor neurons. The CPG produces a side-to-side asymmetric pattern of intersegmental coordination among ipsilateral premotor interneurons corresponding to a similarly asymmetric fictive motor pattern in heart motor neurons, and asymmetric constriction pattern of the two tubular hearts, synchronous and peristaltic. Using extracellular recordings from premotor interneurons and voltage-clamp recordings of ipsilateral segmental motor neurons in 69 isolated nerve cords, we assessed the strength and dynamics of premotor inhibitory synaptic output onto the entire ensemble of heart motor neurons and the associated conduction delays in both coordination modes. We conclude that premotor interneurons establish a stereotypical pattern of intersegmental synaptic connectivity, strengths, and dynamics that is invariant across coordination modes, despite wide variations among preparations. These data coupled with a previous description of the temporal pattern of premotor interneuron activity and relative phasing of motor neuron activity in the two coordination modes enable a direct assessment of how premotor interneurons through their temporal pattern of activity and their spatial pattern of synaptic connectivity, strengths, and dynamics coordinate segmental motor neurons into a functional pattern of activity.

Increasing proportions of tyrosine hydroxylase-immunoreactive interneurons colocalize with choline acetyltransferase or vasoactive intestinal peptide in the developing rat cerebral cortex

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Asmus, Stephen E.; Cocanougher, Benjamin T.; Allen, Donald L.; Boone, John B.; Brooks, Elizabeth A.; Hawkins, Sarah M.; Hench, Laura A.; Ijaz, Talha; Mayfield, Meredith N.

2011-01-01

Cortical interneurons are critical for information processing, and their dysfunction has been implicated in neurological disorders. One subset of this diverse cell population expresses tyrosine hydroxylase (TH) during postnatal rat development. Cortical TH-immunoreactive neurons appear at postnatal day (P) 16. The number of TH cells sharply increases between P16 and P20 and subsequently decreases to adult values. The absence of apoptotic markers in these cells suggests that the reduction in cell number is not due to cell death but is due to a decline in TH production. Cortical TH cells lack all additional catecholaminergic enzymes, and many coexpress GABA and calretinin, but little else is known about their phenotype or function. Because interneurons containing choline acetyltransferase (ChAT) or vasoactive intestinal peptide (VIP) share characteristics with cortical TH neurons, the coexpression of TH with ChAT or VIP was examined throughout the neocortex at P16, P20, and P30. The proportions of TH cell profiles double-labeled for ChAT or VIP significantly increased between P16 and P30. Based on their proximity to blood vessels, intrinsic cholinergic and VIPergic cells have been hypothesized to regulate cortical microcirculation. Labeling with the gliovascular marker aquaporin-4 revealed that at least half of the TH cells were apposed to microvessels at these ages, and many of these cells contained ChAT or VIP. Cortical TH neurons did not coproduce nitric oxide synthase. These results suggest that increasing proportions of cortical TH neurons express ChAT or VIP developmentally and that a subset of these TH neurons may regulate local blood flow. PMID:21295554

Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro.

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Nobuhara, Chloe K; DeVos, Sarah L; Commins, Caitlin; Wegmann, Susanne; Moore, Benjamin D; Roe, Allyson D; Costantino, Isabel; Frosch, Matthew P; Pitstick, Rose; Carlson, George A; Hock, Christoph; Nitsch, Roger M; Montrasio, Fabio; Grimm, Jan; Cheung, Anne E; Dunah, Anthone W; Wittmann, Marion; Bussiere, Thierry; Weinreb, Paul H; Hyman, Bradley T; Takeda, Shuko

2017-06-01

The clinical progression of Alzheimer disease (AD) is associated with the accumulation of tau neurofibrillary tangles, which may spread throughout the cortex by interneuronal tau transfer. If so, targeting extracellular tau species may slow the spreading of tau pathology and possibly cognitive decline. To identify suitable target epitopes, we tested the effects of a panel of tau antibodies on neuronal uptake and aggregation in vitro. Immunodepletion was performed on brain extract from tau-transgenic mice and postmortem AD brain and added to a sensitive fluorescence resonance energy transfer-based tau uptake assay to assess blocking efficacy. The antibodies reduced tau uptake in an epitope-dependent manner: N-terminal (Tau13) and middomain (6C5 and HT7) antibodies successfully prevented uptake of tau species, whereas the distal C-terminal-specific antibody (Tau46) had little effect. Phosphorylation-dependent (40E8 and p396) and C-terminal half (4E4) tau antibodies also reduced tau uptake despite removing less total tau by immunodepletion, suggesting specific interactions with species involved in uptake. Among the seven antibodies evaluated, 6C5 most efficiently blocked uptake and subsequent aggregation. More important, 6C5 also blocked neuron-to-neuron spreading of tau in a unique three-chamber microfluidic device. Furthermore, 6C5 slowed down the progression of tau aggregation even after uptake had begun. Our results imply that not all antibodies/epitopes are equally robust in terms of blocking tau uptake of human AD-derived tau species. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Onset Dynamics of Action Potentials in Rat Neocortical Neurons and Identified Snail Neurons: Quantification of the Difference

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Volgushev, Maxim; Malyshev, Aleksey; Balaban, Pavel; Chistiakova, Marina; Volgushev, Stanislav; Wolf, Fred

2008-01-01

The generation of action potentials (APs) is a key process in the operation of nerve cells and the communication between neurons. Action potentials in mammalian central neurons are characterized by an exceptionally fast onset dynamics, which differs from the typically slow and gradual onset dynamics seen in identified snail neurons. Here we describe a novel method of analysis which provides a quantitative measure of the onset dynamics of action potentials. This method captures the...

Persistent schema-dependent hippocampal-neocortical connectivity during memory encoding and postencoding rest in humans.

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van Kesteren, Marlieke T R; Fernández, Guillén; Norris, David G; Hermans, Erno J

2010-04-20

The hippocampus is thought to promote gradual incorporation of novel information into long-term memory by binding, reactivating, and strengthening distributed cortical-cortical connections. Recent studies implicate a key role in this process for hippocampally driven crosstalk with the (ventro)medial prefrontal cortex (vmPFC), which is proposed to become a central node in such representational networks over time. The existence of a relevant prior associative network, or schema, may moreover facilitate this process. Thus, hippocampal-vmPFC crosstalk may support integration of new memories, particularly in the absence of a relevant prior schema. To address this issue, we used functional magnetic resonance imaging (fMRI) and prior schema manipulation to track hippocampal-vmPFC connectivity during encoding and postencoding rest. We manipulated prior schema knowledge by exposing 30 participants to the first part of a movie that was temporally scrambled for 15 participants. The next day, participants underwent fMRI while encoding the movie's final 15 min in original order and, subsequently, while resting. Schema knowledge and item recognition performance show that prior schema was successfully and selectively manipulated. Intersubject synchronization (ISS) and interregional partial correlation analyses furthermore show that stronger prior schema was associated with more vmPFC ISS and less hippocampal-vmPFC interregional connectivity during encoding. Notably, this connectivity pattern persisted during postencoding rest. These findings suggest that additional crosstalk between hippocampus and vmPFC is required to compensate for difficulty integrating novel information during encoding and provide tentative support for the notion that functionally relevant hippocampal-neocortical crosstalk persists during off-line periods after learning.

A central pattern generator producing alternative outputs: phase relations of leech heart motor neurons with respect to premotor synaptic input.

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Norris, Brian J; Weaver, Adam L; Wenning, Angela; García, Paul S; Calabrese, Ronald L

2007-11-01

The central pattern generator (CPG) for heartbeat in leeches consists of seven identified pairs of segmental heart interneurons and one unidentified pair. Four of the identified pairs and the unidentified pair of interneurons make inhibitory synaptic connections with segmental heart motor neurons. The CPG produces a side-to-side asymmetric pattern of intersegmental coordination among ipsilateral premotor interneurons corresponding to a similarly asymmetric fictive motor pattern in heart motor neurons, and asymmetric constriction pattern of the two tubular hearts: synchronous and peristaltic. Using extracellular techniques, we recorded, in 61 isolated nerve cords, the activity of motor neurons in conjunction with the phase reference premotor heart interneuron, HN(4), and another premotor interneuron that allowed us to assess the coordination mode. These data were then coupled with a previous description of the temporal pattern of premotor interneuron activity in the two coordination modes to synthesize a global phase diagram for the known elements of the CPG and the entire motor neuron ensemble. These average data reveal the stereotypical side-to-side asymmetric patterns of intersegmental coordination among the motor neurons and show how this pattern meshes with the activity pattern of premotor interneurons. Analysis of animal-to-animal variability in this coordination indicates that the intersegmental phase progression of motor neuron activity in the midbody in the peristaltic coordination mode is the most stereotypical feature of the fictive motor pattern. Bilateral recordings from motor neurons corroborate the main features of the asymmetric motor pattern.

Cited2 Regulates Neocortical Layer II/III Generation and Somatosensory Callosal Projection Neuron Development and Connectivity.

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Fame, Ryann M; MacDonald, Jessica L; Dunwoodie, Sally L; Takahashi, Emi; Macklis, Jeffrey D

2016-06-15

The neocortex contains hundreds to thousands of distinct subtypes of precisely connected neurons, allowing it to perform remarkably complex tasks of high-level cognition. Callosal projection neurons (CPN) connect the cerebral hemispheres via the corpus callosum, integrating cortical information and playing key roles in associative cognition. CPN are a strikingly diverse set of neuronal subpopulations, and development of this diversity requires precise control by a complex, interactive set of molecular effectors. We have found that the transcriptional coregulator Cited2 regulates and refines two stages of CPN development. Cited2 is expressed broadly by progenitors in the embryonic day 15.5 subventricular zone, during the peak of superficial layer CPN birth, with a progressive postmitotic refinement in expression, becoming restricted to CPN of the somatosensory cortex postnatally. We generated progenitor-stage and postmitotic forebrain-specific Cited2 conditional knock-out mice, using the Emx1-Cre and NEX-Cre mouse lines, respectively. We demonstrate that Cited2 functions in progenitors, but is not necessary postmitotically, to regulate both (1) broad generation of layer II/III CPN and (2) acquisition of precise area-specific molecular identity and axonal/dendritic connectivity of somatosensory CPN. This novel CPN subtype-specific and area-specific control from progenitor action of Cited2 adds yet another layer of complexity to the multistage developmental regulation of neocortical development. This study identifies Cited2 as a novel subtype-specific and area-specific control over development of distinct subpopulations within the broad population of callosal projection neurons (CPN), whose axons connect the two cerebral hemispheres via the corpus callosum (CC). Currently, how the remarkable diversity of CPN subtypes is specified, and how they differentiate to form highly precise and specific circuits, are largely unknown. We found that Cited2 functions within

The opposite effects of nandrolone decanoate and exercise on anxiety levels in rats may involve alterations in hippocampal parvalbumin-positive interneurons.

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Dragica Selakovic

Full Text Available The aim of this study was to evaluate the behavioral effects of chronic (six weeks nandrolone decanoate (ND, 20 mg/kg, s.c., weekly in single dose administration (in order to mimic heavy human abuse, and exercise (swimming protocol of 60 minutes a day, five days in a row/two days break, applied alone and simultaneously with ND, in male rats (n = 40. Also, we evaluated the effects of those protocols on hippocampal parvalbumin (PV content and the possible connection between the alterations in certain parts of hippocampal GABAergic system and behavioral patterns. Both ND and exercise protocols induced increase in testosterone, dihydrotestosterone and estradiol blood levels. Our results confirmed anxiogenic effects of ND observed in open field (OF test (decrease in the locomotor activity, as well as in frequency and cumulative duration in the centre zone and in elevated plus maze (EPM test (decrease in frequency and cumulative duration in open arms, and total exploratory activity, that were accompanied with a mild decrease in the number of PV interneurons in hippocampus. Chronic exercise protocol induced significant increase in hippocampal PV neurons (dentate gyrus and CA1 region, followed by anxiolytic-like behavioral changes, observed in both OF and EPM (increase in all estimated parameters, and in evoked beam-walking test (increase in time to cross the beam, compared to ND treated animals. The applied dose of ND was sufficient to attenuate beneficial effects of exercise in rats by means of decreased exercise-induced anxiolytic effect, as well as to reverse exercise-induced augmentation in number of PV immunoreactive neurons in hippocampus. Our results implicate the possibility that alterations in hippocampal PV interneurons (i.e. GABAergic system may be involved in modulation of anxiety level induced by ND abuse and/or extended exercise protocols.

The opposite effects of nandrolone decanoate and exercise on anxiety levels in rats may involve alterations in hippocampal parvalbumin-positive interneurons.

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Selakovic, Dragica; Joksimovic, Jovana; Zaletel, Ivan; Puskas, Nela; Matovic, Milovan; Rosic, Gvozden

2017-01-01

The aim of this study was to evaluate the behavioral effects of chronic (six weeks) nandrolone decanoate (ND, 20 mg/kg, s.c., weekly in single dose) administration (in order to mimic heavy human abuse), and exercise (swimming protocol of 60 minutes a day, five days in a row/two days break), applied alone and simultaneously with ND, in male rats (n = 40). Also, we evaluated the effects of those protocols on hippocampal parvalbumin (PV) content and the possible connection between the alterations in certain parts of hippocampal GABAergic system and behavioral patterns. Both ND and exercise protocols induced increase in testosterone, dihydrotestosterone and estradiol blood levels. Our results confirmed anxiogenic effects of ND observed in open field (OF) test (decrease in the locomotor activity, as well as in frequency and cumulative duration in the centre zone) and in elevated plus maze (EPM) test (decrease in frequency and cumulative duration in open arms, and total exploratory activity), that were accompanied with a mild decrease in the number of PV interneurons in hippocampus. Chronic exercise protocol induced significant increase in hippocampal PV neurons (dentate gyrus and CA1 region), followed by anxiolytic-like behavioral changes, observed in both OF and EPM (increase in all estimated parameters), and in evoked beam-walking test (increase in time to cross the beam), compared to ND treated animals. The applied dose of ND was sufficient to attenuate beneficial effects of exercise in rats by means of decreased exercise-induced anxiolytic effect, as well as to reverse exercise-induced augmentation in number of PV immunoreactive neurons in hippocampus. Our results implicate the possibility that alterations in hippocampal PV interneurons (i.e. GABAergic system) may be involved in modulation of anxiety level induced by ND abuse and/or extended exercise protocols.

Different AMPA receptor subtypes mediate the distinct kinetic components of a biphasic EPSC in hippocampal interneurons

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Todd eStincic

2015-05-01

Full Text Available CA1 hippocampal interneurons at the border between stratum radiatum and stratum lacunosum-moleculare have AMPA receptor (AMPAR-mediated excitatory postsynaptic currents (EPSCs that consist of two distinct phases: a typical fast component (FC, and a highly unusual slow component (SC that persists for hundreds of milliseconds. To determine whether these kinetically distinct components of the EPSC are mediated by distinct AMPAR subpopulations, we examined the relative contributions of GluA2-containing and –lacking AMPARs to the SC. GluA2-containing AMPARs mediated the majority of the FC whereas GluA2-lacking AMPARs preferentially generated the SC. When glutamate uptake through the glial glutamate transporter EAAT1 was inhibited, spill over-mediated AMPAR activation recruited an even slower third kinetic component that persisted for several seconds; however, this spillover-mediated current was mediated predominantly by GluA2-containing AMPARs and therefore was clearly distinct from the SC when uptake is intact. Thus, different AMPAR subpopulations that vary in GluA2 content mediate the distinct components of the AMPAR EPSC. The SC is developmentally downregulated in mice, declining after the second postnatal week. This downregulation affects both GluA2-containing and GluA2-lacking AMPARs mediating the SC, and is not accompanied by developmental changes in the GluA2 content of AMPARs underlying the FC. Thus, the downregulation of the SC appears to be independent of synaptic GluA2 expression, suggesting the involvement of another AMPAR subunit or an auxiliary protein. Our results therefore identify GluA2-dependent and GluA2-independent determinants of the SC: GluA2-lacking AMPARs preferentially contribute to the SC, while the developmental downregulation of the SC is independent of GluA2 content.

The complex contribution of NOS interneurons in the physiology of cerebrovascular regulation

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Sonia eDuchemin

2012-08-01

Full Text Available Following the discovery of the vasorelaxant properties of nitric oxide (NO by Furchgott and Ignarro, the finding by Bredt and coll. of a constitutively expressed NO synthase in neurons (nNOS led to the presumption that neuronal NO may control cerebrovascular functions. Consequently, numerous studies have sought to determine whether neuraly-derived NO is involved in the regulation of cerebral blood flow. Anatomically, axons, dendrites or somata of NO neurons have been found to contact the basement membrane of blood vessels or perivascular astrocytes in all segments of the cortical microcirculation. Functionally, various experimental approaches support a role of neuronal NO in the maintenance of resting cerebral blood flow as well as in the vascular response to neuronal activity. Since decades, it has been assumed that neuronal NO simply diffuses to the local blood vessels and produce vasodilation through a cGMP-PKG dependent mechanism. However, NO is not the sole mediator of vasodilation in the cerebral microcirculation and is known to interact with a myriad of signaling pathways also involved in vascular control. In addition, cerebrovascular regulation is the result of a complex orchestration between all components of the neurovascular unit (i.e. neuronal, glial and vascular cells also known to produce NO. In this review article, the role of NO interneuron in the regulation of cortical microcirculation will be discussed in the context of the neurovascular unit.

[Pathological neocortical findings in patients with medication-resistant medial temporal lobe epilepsy submitted to surgery].

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Estupiñán-Díaz, B; Morales-Chacón, L M; Lorigados-Pedre, L; García-Maeso, I; Bender-del Busto, J E; Trápaga-Quincoses, O; Hidalgo-Portal, L; García-Navarro, M E; Sánchez-Coroneaux, A; Orozco-Suárez, S

The dual pathology consisting of hippocampal sclerosis plus focal cortical dysplasia (FCD) is often reported in patients with medication-resistant medial temporal lobe epilepsy (MTLE). To determine the histopathological changes that take place in the neocortex of patients with medication-resistant MTLE submitted to surgery and to evaluate the relation between the histopathological changes, pathological background and the clinical course of patients who had received surgical treatment. Tissue obtained by en bloc resection from the neocortex of 18 patients with MTLE refractory to medical treatment was processed histologically and a tailored temporal lobectomy was performed with electrocorticography. Dual pathology was diagnosed in 13 patients (72.2%). Imaging studies confirmed the existence of mesial sclerosis of the temporal in 100% of cases and there was no evidence of neocortical lesions. Histologically, 46.15% and 38.46% of the patients were diagnosed as belonging to FCD type 1a and FCD type 1b, respectively. Only one patient presented FCD type 2a. A statistically significant relation was found between the presence of dual pathology and the existence of an early precipitating injury (p = 0.04). One year after surgery, 72.7% (8/11) patients with dual pathology were classified as belonging to Engel class I. In patients with MTLE there are microscopic FCD-type alterations in the neocortex. There is an association between these alterations and the existence of an initial precipitating injury. Complete resection of the epileptogenic area, which is guaranteed by the lobectomy tailored by electrocorticography, allows patients to enjoy a favourable post-surgical progression one year after surgery.

Effect of Prenatal Protein Malnutrition on Long-Term Potentiation and BDNF Protein Expression in the Rat Entorhinal Cortex after Neocortical and Hippocampal Tetanization

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Alejandro Hernández

2008-01-01

Full Text Available Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC in the adult progeny. Unlike normal eutrophic controls, 55–60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals.

Effect of prenatal protein malnutrition on long-term potentiation and BDNF protein expression in the rat entorhinal cortex after neocortical and hippocampal tetanization.

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Hernández, Alejandro; Burgos, Héctor; Mondaca, Mauricio; Barra, Rafael; Núñez, Héctor; Pérez, Hernán; Soto-Moyano, Rubén; Sierralta, Walter; Fernández, Victor; Olivares, Ricardo; Valladares, Luis

2008-01-01

Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP) of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC) in the adult progeny. Unlike normal eutrophic controls, 55-60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF) in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals.

Chronic ketamine reduces the peak frequency of gamma oscillations in mouse prefrontal cortex ex vivo

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James M. McNally

2013-09-01

Full Text Available Abnormalities in EEG gamma band oscillations (GBO, 30-80 Hz serve as a prominent biomarker of schizophrenia (Sz, associated with positive, negative and cognitive symptoms. Chronic, subanesthetic administration of antagonists of N-methyl-D-aspartate receptors (NMDAR, such as ketamine, elicits behavioral effects and alterations in cortical interneurons similar to those observed in Sz. However, the chronic effects of ketamine on neocortical GBO are poorly understood. Thus, here we examine the effects of chronic (5 daily i.p. injections application of ketamine (5 and 30 mg/kg and the more specific NMDAR antagonist, MK-801 (0.02, 0.5, and 2 mg/kg, on neocortical GBO ex vivo. Oscillations were generated by focal application of the glutamate receptor agonist, kainate, in coronal brain slices containing the prelimbic cortex. This region constitutes the rodent analogue of the human dorsolateral prefrontal cortex, a brain region strongly implicated in Sz-pathophysiology. Here we report the novel finding that chronic ketamine elicits a reduction in the peak oscillatory frequency of kainate-elicited oscillations (from 47 to 40 Hz at 30 mg/kg. Moreover, the power of GBO in the 40-50 Hz band was reduced. These findings are reminiscent of both the reduced resonance frequency and power of cortical oscillations observed in Sz clinical studies. Surprisingly, MK-801 had no significant effect, suggesting care is needed when equating Sz-like behavioral effects elicited by different NMDAR antagonists to alterations in GBO activity. We conclude that chronic ketamine in the mouse mimics GBO abnormalities observed in Sz patients. Use of this ex vivo slice model may be useful in testing therapeutic compounds which rescue these GBO abnormalities.

A spiking network model of cerebellar Purkinje cells and molecular layer interneurons exhibiting irregular firing

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William eLennon

2014-12-01

Full Text Available While the anatomy of the cerebellar microcircuit is well studied, how it implements cerebellar function is not understood. A number of models have been proposed to describe this mechanism but few emphasize the role of the vast network Purkinje cells (PKJs form with the molecular layer interneurons (MLIs – the stellate and basket cells. We propose a model of the MLI-PKJ network composed of simple spiking neurons incorporating the major anatomical and physiological features. In computer simulations, the model reproduces the irregular firing patterns observed in PKJs and MLIs in vitro and a shift toward faster, more regular firing patterns when inhibitory synaptic currents are blocked. In the model, the time between PKJ spikes is shown to be proportional to the amount of feedforward inhibition from an MLI on average. The two key elements of the model are: (1 spontaneously active PKJs and MLIs due to an endogenous depolarizing current, and (2 adherence to known anatomical connectivity along a parasagittal strip of cerebellar cortex. We propose this model to extend previous spiking network models of the cerebellum and for further computational investigation into the role of irregular firing and MLIs in cerebellar learning and function.

A convergent and essential interneuron pathway for Mauthner-cell-mediated escapes.

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Lacoste, Alix M B; Schoppik, David; Robson, Drew N; Haesemeyer, Martin; Portugues, Ruben; Li, Jennifer M; Randlett, Owen; Wee, Caroline L; Engert, Florian; Schier, Alexander F

2015-06-01

The Mauthner cell (M-cell) is a command-like neuron in teleost fish whose firing in response to aversive stimuli is correlated with short-latency escapes [1-3]. M-cells have been proposed as evolutionary ancestors of startle response neurons of the mammalian reticular formation [4], and studies of this circuit have uncovered important principles in neurobiology that generalize to more complex vertebrate models [3]. The main excitatory input was thought to originate from multisensory afferents synapsing directly onto the M-cell dendrites [3]. Here, we describe an additional, convergent pathway that is essential for the M-cell-mediated startle behavior in larval zebrafish. It is composed of excitatory interneurons called spiral fiber neurons, which project to the M-cell axon hillock. By in vivo calcium imaging, we found that spiral fiber neurons are active in response to aversive stimuli capable of eliciting escapes. Like M-cell ablations, bilateral ablations of spiral fiber neurons largely eliminate short-latency escapes. Unilateral spiral fiber neuron ablations shift the directionality of escapes and indicate that spiral fiber neurons excite the M-cell in a lateralized manner. Their optogenetic activation increases the probability of short-latency escapes, supporting the notion that spiral fiber neurons help activate M-cell-mediated startle behavior. These results reveal that spiral fiber neurons are essential for the function of the M-cell in response to sensory cues and suggest that convergent excitatory inputs that differ in their input location and timing ensure reliable activation of the M-cell, a feedforward excitatory motif that may extend to other neural circuits. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hippocampal "cholinergic interneurons" visualized with the choline acetyltransferase promoter: anatomical distribution, intrinsic membrane properties, neurochemical characteristics, and capacity for cholinergic modulation.

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Yi, Feng; Catudio-Garrett, Elizabeth; Gábriel, Robert; Wilhelm, Marta; Erdelyi, Ferenc; Szabo, Gabor; Deisseroth, Karl; Lawrence, Josh

2015-01-01

Release of acetylcholine (ACh) in the hippocampus (HC) occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB) is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa) mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-positive structures, some of which were Neurotrace/DAPI-negative and likely represent large axon terminals. In the HC of ChAT-Rosa mice, ChAT-YFP cells were Neurotrace-positive and more abundant in CA3 and dentate gyrus than CA1 with partial overlap with calretinin/VIP. Moreover, an anti-ChAT antibody consistently showed ChAT immunoreactivity in ChAT-YFP cells from MS-DBB but rarely from HC. Furthermore, ChAT-YFP cells from CA1 stratum radiatum/stratum lacunosum moleculare (SR/SLM) exhibited a stuttering firing phenotype but a delayed firing phenotype in stratum pyramidale (SP) of CA3. Input resistance and capacitance were also different between CA1 SR/LM and CA3 SP ChAT-YFP cells. Bath application of ACh increased firing frequency in all ChAT-YFP cells; however, cholinergic modulation was larger in CA1 SR/SLM than CA3 SP ChAT-YFP cells. Finally, CA3 SP ChAT-YFP cells exhibited a wider AP half-width and weaker cholinergic modulation than YFP-negative CA3 pyramidal cells. Consistent with CRE expression in a subpopulation of principal cells, optogenetic stimulation evoked glutamatergic postsynaptic currents in CA1 SR/SLM interneurons. In conclusion, the presence of fluorescently labeled hippocampal cells common to both ChAT-tauGFP and ChAT-Rosa mice are in good agreement with previous reports on the existence of cholinergic interneurons, but both transgenic mouse lines exhibited unexpected anatomical features that departed considerably from earlier observations.

Hippocampal cholinergic interneurons visualized with the choline acetyltransferase promoter: anatomical distribution, intrinsic membrane properties, neurochemical characteristics, and capacity for cholinergic modulation

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Feng eYi

2015-03-01

Full Text Available Release of acetylcholine (ACh in the hippocampus (HC occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-positive structures, some of which were Neurotrace/DAPI-negative and likely represent large axon terminals. In the HC of ChAT-Rosa mice, ChAT-YFP cells were Neurotrace-positive and more abundant in CA3 and dentate gyrus than CA1 with partial overlapping with calretinin/VIP. Moreover, an anti-ChAT antibody consistently showed ChAT immunoreactivity in ChAT-YFP cells from MS-DBB but rarely from HC. Furthermore, ChAT-YFP cells from CA1 stratum radiatum/stratum lacunosum moleculare (SR/SLM exhibited a stuttering firing phenotype but a delayed firing phenotype in stratum pyramidale (SP of CA3. Input resistance and capacitance were also different between CA1 SR/LM and CA3 SP ChAT-YFP cells. Bath application of ACh increased firing frequency in all ChAT-YFP cells; however, cholinergic modulation was larger in CA1 SR/SLM than CA3 SP ChAT-YFP cells. Finally, CA3 SP ChAT-YFP cells exhibited a wider AP half-width and weaker cholinergic modulation than YFP-negative CA3 pyramidal cells. Consistent with CRE expression in a subpopulation of principal cells, optogenetic stimulation evoked glutamatergic postsynaptic currents in CA1 SR/SLM interneurons. In conclusion, the presence of fluorescently labeled hippocampal cells common to both ChAT-Rosa and ChAT-tauGFP mice are in good agreement with previous reports on the existence of cholinergic interneurons, but both transgenic mouse lines exhibited unexpected anatomical features that departed considerably from earlier observations.

Distribution and function of HCN channels in the apical dendritic tuft of neocortical pyramidal neurons.

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Harnett, Mark T; Magee, Jeffrey C; Williams, Stephen R

2015-01-21

The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons receives substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch recordings demonstrated that the amplitude and properties of ensemble HCN channel activity were uniform in patches excised from distal apical dendritic trunk and tuft sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamic-clamp experiments revealed that these compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B pyramidal neurons. Copyright © 2015 the authors 0270-6474/15/351024-14$15.00/0.

[A surgical case of mesial temporal lobe epilepsy associated with hippocampal sclerosis and traumatic neocortical lesion].

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Kitazawa, Yu; Jin, Kazutaka; Iwasaki, Masaki; Suzuki, Hiroyoshi; Tanaka, Fumiaki; Nakasato, Nobukazu

2017-11-25

A 26-year-old right-handed woman, with a history of left temporal lobe contusion caused by a fall at the age of 9 months, started to have complex partial seizures with oral automatism at the age of 7 years. The seizures occurred once or twice a month despite combination therapy with several antiepileptic agents. Her history and imaging studies suggested the diagnosis of epilepsy arising from traumatic neocortical temporal lesion. Comprehensive assessment including long-term video EEG monitoring, MRI, FDG-PET, MEG, and neuropsychological evaluation was performed at the age of 26 years. The diagnosis was left mesial temporal lobe epilepsy associated with hippocampal atrophy and traumatic temporal cortical lesion. The patient was readmitted for surgical treatment at the age of 27 years. Intracranial EEG monitoring showed that ictal discharges started in the left hippocampus and spread to the traumatic lesion in the left posterior superior temporal gyrus 10 seconds after the onset. This case could not be classified as dual pathology exactly, because the traumatic left temporal cortical lesion did not show independent epileptogenicity. However, the traumatic lesion was highly likely to be the source of the epileptogenicity, and she had right hemispheric dominance for language and functional deterioration in the whole temporal cortex. Therefore, left amygdalo-hippocampectomy and left temporal lobectomy including the traumatic lesion were performed according to the diagnosis of dual pathology. Subsequently, she remained seizure-free for 3 years. Comprehensive assessment of seizure semiology, neurophysiology, neuroradiology, and neuropsychology is important to determine the optimum therapeutic strategies for drug-resistant epilepsy.

Transplanted Human Stem Cell-Derived Interneuron Precursors Mitigate Mouse Bladder Dysfunction and Central Neuropathic Pain after Spinal Cord Injury.

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Fandel, Thomas M; Trivedi, Alpa; Nicholas, Cory R; Zhang, Haoqian; Chen, Jiadong; Martinez, Aida F; Noble-Haeusslein, Linda J; Kriegstein, Arnold R

2016-10-06

Neuropathic pain and bladder dysfunction represent significant quality-of-life issues for many spinal cord injury patients. Loss of GABAergic tone in the injured spinal cord may contribute to the emergence of these symptoms. Previous studies have shown that transplantation of rodent inhibitory interneuron precursors from the medial ganglionic eminence (MGE) enhances GABAergic signaling in the brain and spinal cord. Here we look at whether transplanted MGE-like cells derived from human embryonic stem cells (hESC-MGEs) can mitigate the pathological effects of spinal cord injury. We find that 6 months after transplantation into injured mouse spinal cords, hESC-MGEs differentiate into GABAergic neuron subtypes and receive synaptic inputs, suggesting functional integration into host spinal cord. Moreover, the transplanted animals show improved bladder function and mitigation of pain-related symptoms. Our results therefore suggest that this approach may be a valuable strategy for ameliorating the adverse effects of spinal cord injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Propensity for Bistability of Bursting and Silence in the Leech Heart Interneuron

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Tatiana Dashevskiy

2018-02-01

Full Text Available The coexistence of neuronal activity regimes has been reported under normal and pathological conditions. Such multistability could enhance the flexibility of the nervous system and has many implications for motor control, memory, and decision making. Multistability is commonly promoted by neuromodulation targeting specific membrane ionic currents. Here, we investigated how modulation of different ionic currents could affect the neuronal propensity for bistability. We considered a leech heart interneuron model. It exhibits bistability of bursting and silence in a narrow range of the leak current parameters, conductance (gleak and reversal potential (Eleak. We assessed the propensity for bistability of the model by using bifurcation diagrams. On the diagram (gleak, Eleak, we mapped bursting and silent regimes. For the canonical value of Eleak we determined the range of gleak which supported the bistability. We use this range as an index of propensity for bistability. We investigated how this index was affected by alterations of ionic currents. We systematically changed their conductances, one at a time, and built corresponding bifurcation diagrams in parameter planes of the maximal conductance of a given current and the leak conductance. We found that conductance of only one current substantially affected the index of propensity; the increase of the maximal conductance of the hyperpolarization-activated cationic current increased the propensity index. The second conductance with the strongest effect was the conductance of the low-threshold fast Ca2+ current; its reduction increased the propensity index although the effect was about two times smaller in magnitude. Analyzing the model with both changes applied simultaneously, we found that the diagram (gleak, Eleak showed a progressively expanded area of bistability of bursting and silence.

Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease.

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Ztaou, Samira; Maurice, Nicolas; Camon, Jeremy; Guiraudie-Capraz, Gaëlle; Kerkerian-Le Goff, Lydia; Beurrier, Corinne; Liberge, Martine; Amalric, Marianne

2016-08-31

Over the last decade, striatal cholinergic interneurons (ChIs) have reemerged as key actors in the pathophysiology of basal-ganglia-related movement disorders. However, the mechanisms involved are still unclear. In this study, we address the role of ChI activity in the expression of parkinsonian-like motor deficits in a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion model using optogenetic and pharmacological approaches. Dorsal striatal photoinhibition of ChIs in lesioned ChAT(cre/cre) mice expressing halorhodopsin in ChIs reduces akinesia, bradykinesia, and sensorimotor neglect. Muscarinic acetylcholine receptor (mAChR) blockade by scopolamine produces similar anti-parkinsonian effects. To decipher which of the mAChR subtypes provides these beneficial effects, systemic and intrastriatal administration of the selective M1 and M4 mAChR antagonists telenzepine and tropicamide, respectively, were tested in the same model of Parkinson's disease. The two compounds alleviate 6-OHDA lesion-induced motor deficits. Telenzepine produces its beneficial effects by blocking postsynaptic M1 mAChRs expressed on medium spiny neurons (MSNs) at the origin of the indirect striatopallidal and direct striatonigral pathways. The anti-parkinsonian effects of tropicamide were almost completely abolished in mutant lesioned mice that lack M4 mAChRs specifically in dopamine D1-receptor-expressing neurons, suggesting that postsynaptic M4 mAChRs expressed on direct MSNs mediate the antiakinetic action of tropicamide. The present results show that altered cholinergic transmission via M1 and M4 mAChRs of the dorsal striatum plays a pivotal role in the occurrence of motor symptoms in Parkinson's disease. The striatum, where dopaminergic and cholinergic systems interact, is the pivotal structure of basal ganglia involved in pathophysiological changes underlying Parkinson's disease. Here, using optogenetic and pharmacological approaches, we investigated the involvement of striatal

Identifying crucial parameter correlations maintaining bursting activity.

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Anca Doloc-Mihu

2014-06-01

Full Text Available Recent experimental and computational studies suggest that linearly correlated sets of parameters (intrinsic and synaptic properties of neurons allow central pattern-generating networks to produce and maintain their rhythmic activity regardless of changing internal and external conditions. To determine the role of correlated conductances in the robust maintenance of functional bursting activity, we used our existing database of half-center oscillator (HCO model instances of the leech heartbeat CPG. From the database, we identified functional activity groups of burster (isolated neuron and half-center oscillator model instances and realistic subgroups of each that showed burst characteristics (principally period and spike frequency similar to the animal. To find linear correlations among the conductance parameters maintaining functional leech bursting activity, we applied Principal Component Analysis (PCA to each of these four groups. PCA identified a set of three maximal conductances (leak current, [Formula: see text]Leak; a persistent K current, [Formula: see text]K2; and of a persistent Na+ current, [Formula: see text]P that correlate linearly for the two groups of burster instances but not for the HCO groups. Visualizations of HCO instances in a reduced space suggested that there might be non-linear relationships between these parameters for these instances. Experimental studies have shown that period is a key attribute influenced by modulatory inputs and temperature variations in heart interneurons. Thus, we explored the sensitivity of period to changes in maximal conductances of [Formula: see text]Leak, [Formula: see text]K2, and [Formula: see text]P, and we found that for our realistic bursters the effect of these parameters on period could not be assessed because when varied individually bursting activity was not maintained.

[Interneuronal relationships in the basolateral amygdala of cats trained for choice in the quality of food reinforcement].

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Merzhanova, G Kh; Dolbakian, E E; Partev, A Z

1997-01-01

The alimentary instrumental conditioned bar-pressing reflex was elaborated in cats by the method of "active choice" of either short-delayed reinforcement with bread-meat mixture of delayed more valuable reinforcement with meat. The animals differed in behavior strategy: some animals preferred bar-pressing with the long delay (the so-called "self-control" group), other animals pressed the bar with short delay (the so-called "impulsive" group). The multiunit activity in the basolateral amygdala was recorded with chronically implanted nichrome microelectrodes. The interactions between the spike trains of the neighbouring neurons selected from the multiunit activity were evaluated by means of statistical crosscorrelation analysis. It was shown that the number of correlations between the discharges of neurons was significantly higher in the "impulsive" cats. In both groups the number of cross-correlations was maximal in cases of a difficult choice, i.e., during the omission of the conditioned bar-pressing response. In "impulsive" cats the number of interneuronal correlations was highest with the latencies in the range of 0-30 msec. We suggest that the basolateral amygdala is involved in the system of structures which determine the individual-typological characteristics of animals.

Spatial coherence resonance and spatial pattern transition induced by the decrease of inhibitory effect in a neuronal network

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Tao, Ye; Gu, Huaguang; Ding, Xueli

2017-10-01

Spiral waves were observed in the biological experiment on rat brain cortex with the application of carbachol and bicuculline which can block inhibitory coupling from interneurons to pyramidal neurons. To simulate the experimental spiral waves, a two-dimensional neuronal network composed of pyramidal neurons and inhibitory interneurons was built. By decreasing the percentage of active inhibitory interneurons, the random-like spatial patterns change to spiral waves and to random-like spatial patterns or nearly synchronous behaviors. The spiral waves appear at a low percentage of inhibitory interneurons, which matches the experimental condition that inhibitory couplings of the interneurons were blocked. The spiral waves exhibit a higher order or signal-to-noise ratio (SNR) characterized by spatial structure function than both random-like spatial patterns and nearly synchronous behaviors, which shows that changes of the percentage of active inhibitory interneurons can induce spatial coherence resonance-like behaviors. In addition, the relationship between the coherence degree and the spatial structures of the spiral waves is identified. The results not only present a possible and reasonable interpretation to the spiral waves observed in the biological experiment on the brain cortex with disinhibition, but also reveal that the spiral waves exhibit more ordered degree in spatial patterns.

Intrinsic neuromodulation in the Tritonia swim CPG: serotonin mediates both neuromodulation and neurotransmission by the dorsal swim interneurons.

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Katz, P S; Frost, W N

1995-12-01

1. Neuromodulation has previously been shown to be intrinsic to the central pattern generator (CPG) circuit that generates the escape swim of the nudibranch mollusk Tritonia diomedea; the dorsal swim interneurons (DSIs) make conventional monosynaptic connections and evoke neuromodulatory effects within the swim motor circuit. The conventional synaptic potentials evoked by a DSI onto cerebral neuron 2 (C2) and onto the dorsal flexion neurons (DFNs) consist of a fast excitatory postsynaptic potential (EPSP) followed by a prolonged slow EPSP. In their neuromodulatory role, the DSIs produce an enhancement of the monosynaptic connections made by C2 onto other CPG circuit interneurons and onto efferent flexion neurons. Previous work showed that the DSIs are immunoreactive for serotonin. Here we provide evidence that both the neurotransmission and the neuromodulation evoked by the DSIs are produced by serotonin, and that these effects may be pharmacologically separable. 2. Previously it was shown that bath-applied serotonin both mimics and occludes the modulation of the C2 synapses by the DSIs. Here we find that pressure-applied puffs of serotonin mimic both the fast and slow EPSPs evoked by a DSI onto a DFN, whereas high concentrations of bath-applied serotonin occlude both of these synaptic components. 3. Consistent with the hypothesis that serotonin mediates the actions of the DSIs, the serotonin reuptake inhibitor imipramine prolongs the duration of the fast DSI-DFN EPSP, increases the amplitude of the slow DSI-DFN EPSP, and increases both the amplitude and duration of the modulation of the C2-DFN synapse by the DSIs. 4. Two serotonergic antagonists were found that block the actions of the DSIs. Gramine blocks the fast DSI-DFN EPSP, and has far less of an effect on the slow EPSP and the modulation. Gramine also diminishes the depolarization evoked by pressure-applied serotonin, showing that it is a serotonin antagonist in this system. In contrast, methysergide greatly

Imaging Cajal's neuronal avalanche: how wide-field optical imaging of the point-spread advanced the understanding of neocortical structure-function relationship.

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Frostig, Ron D; Chen-Bee, Cynthia H; Johnson, Brett A; Jacobs, Nathan S

2017-07-01

This review brings together a collection of studies that specifically use wide-field high-resolution mesoscopic level imaging techniques (intrinsic signal optical imaging; voltage-sensitive dye optical imaging) to image the cortical point spread (PS): the total spread of cortical activation comprising a large neuronal ensemble evoked by spatially restricted (point) stimulation of the sensory periphery (e.g., whisker, pure tone, point visual stimulation). The collective imaging findings, combined with supporting anatomical and electrophysiological findings, revealed some key aspects about the PS including its very large (radius of several mm) and relatively symmetrical spatial extent capable of crossing cytoarchitectural borders and trespassing into other cortical areas; its relationship with underlying evoked subthreshold activity and underlying anatomical system of long-range horizontal projections within gray matter, both also crossing borders; its contextual modulation and plasticity; the ability of its relative spatiotemporal profile to remain invariant to major changes in stimulation parameters; its potential role as a building block for integrative cortical activity; and its ubiquitous presence across various cortical areas and across mammalian species. Together, these findings advance our understanding about the neocortex at the mesoscopic level by underscoring that the cortical PS constitutes a fundamental motif of neocortical structure-function relationship.

Neuropeptide Y as a possible homeostatic element for changes in cortical excitability induced by repetitive transcranial magnetic stimulation.

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Jazmati, Danny; Neubacher, Ute; Funke, Klaus

2018-02-24

Repetitive transcranial magnetic stimulation (rTMS) is able to modify cortical excitability. Rat rTMS studies revealed a modulation of inhibitory systems, in particular that of the parvalbumin-expressing (PV+) interneurons, when using intermittent theta-burst stimulation (iTBS). The potential disinhibitory action of iTBS raises the questions of how neocortical circuits stabilize excitatory-inhibitory balance within a physiological range. Neuropeptide Y (NPY) appears to be one candidate. Analysis of cortical expression of PV, NPY and vesicular glutamate transporter type 1 (vGluT1) by immunohistochemical means at the level of cell counts, mean neuropil expression and single cell pre-/postsynaptic expression, with and without intraventricular NPY-injection. Our results show that iTBS not only reduced the number of neurons with high-PV expression in a dose-dependent fashion, but also increased the cortical expression of NPY, discussed to reduce glutamatergic transmission, and this was further associated with a reduced vGluT1 expression, an indicator of glutamateric presynaptic activity. Interneurons showing a low-PV expression exhibit less presynaptic vGluT1 expression compared to those with a high-PV expression. Intraventricular application of NPY prior to iTBS prevented the iTBS-induced reduction in the number of high-PV neurons, the reduction in tissue vGluT1 level and that presynaptic to high-PV cells. We conclude that NPY, possibly via a global but also slow homeostatic control of glutamatergic transmission, modulates the strength and direction of the iTBS effects, likely preventing pathological imbalance of excitatory and inhibitory cortical activity but still allowing enough disinhibition beneficial for plastic changes as during learning. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Persistent discharges in dentate gyrus perisoma-inhibiting interneurons require hyperpolarization-activated cyclic nucleotide-gated channel activation.

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Elgueta, Claudio; Köhler, Johannes; Bartos, Marlene

2015-03-11

Parvalbumin (PV)-expressing perisoma-inhibiting interneurons (PIIs) of the dentate gyrus integrate rapidly correlated synaptic inputs and generate short-duration action potentials that propagate along the axon to their output synapses, supporting fast inhibitory signaling onto their target cells. Here we show that PV-PIIs in rat and mouse dentate gyrus (DG) integrate their intrinsic activity over time and can turn into a persistent firing mode characterized by the ability to generate long-lasting trains of action potentials at ∼50 Hz in the absence of additional inputs. Persistent firing emerges in the axons remote from the axon initial segment and markedly depends on hyperpolarization-activated cyclic nucleotide-gated channel (HCNC) activation. Persistent firing properties are modulated by intracellular Ca(2+) levels and somatic membrane potential. Detailed computational single-cell PIIs models reveal that HCNC-mediated conductances can contribute to persistent firing during conditions of a shift in their voltage activation curve to more depolarized potentials. Paired recordings from PIIs and their target granule cells show that persistent firing supports strong inhibitory output signaling. Thus, persistent firing may emerge during conditions of intense activation of the network, thereby providing silencing to the circuitry and the maintenance of sparse activity in the dentate gyrus. Copyright © 2015 the authors 0270-6474/15/354131-09$15.00/0.

A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens.

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Wright, William J; Schlüter, Oliver M; Dong, Yan

2017-04-01

The nucleus accumbens (NAc) gates motivated behaviors through the functional output of principle medium spiny neurons (MSNs), whereas dysfunctional output of NAc MSNs contributes to a variety of psychiatric disorders. Fast-spiking interneurons (FSIs) are sparsely distributed throughout the NAc, forming local feedforward inhibitory circuits. It remains elusive how FSI-based feedforward circuits regulate the output of NAc MSNs. Here, we investigated a distinct subpopulation of NAc FSIs that express the cannabinoid receptor type-1 (CB1). Using a combination of paired electrophysiological recordings and pharmacological approaches, we characterized and compared feedforward inhibition of NAc MSNs from CB1 + FSIs and lateral inhibition from recurrent MSN collaterals. We observed that CB1 + FSIs exerted robust inhibitory control over a large percentage of nearby MSNs in contrast to local MSN collaterals that provided only sparse and weak inhibitory input to their neighboring MSNs. Furthermore, CB1 + FSI-mediated feedforward inhibition was preferentially suppressed by endocannabinoid (eCB) signaling, whereas MSN-mediated lateral inhibition was unaffected. Finally, we demonstrated that CB1 + FSI synapses onto MSNs are capable of undergoing experience-dependent long-term depression in a voltage- and eCB-dependent manner. These findings demonstrated that CB1 + FSIs are a major source of local inhibitory control of MSNs and a critical component of the feedforward inhibitory circuits regulating the output of the NAc.

A novel role of dendritic gap junction and mechanisms underlying its interaction with thalamocortical conductance in fast spiking inhibitory neurons

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Sun Qian-Quan

2009-10-01

Full Text Available Abstract Background Little is known about the roles of dendritic gap junctions (GJs of inhibitory interneurons in modulating temporal properties of sensory induced responses in sensory cortices. Electrophysiological dual patch-clamp recording and computational simulation methods were used in combination to examine a novel role of GJs in sensory mediated feed-forward inhibitory responses in barrel cortex layer IV and its underlying mechanisms. Results Under physiological conditions, excitatory post-junctional potentials (EPJPs interact with thalamocortical (TC inputs within an unprecedented few milliseconds (i.e. over 200 Hz to enhance the firing probability and synchrony of coupled fast-spiking (FS cells. Dendritic GJ coupling allows fourfold increase in synchrony and a significant enhancement in spike transmission efficacy in excitatory spiny stellate cells. The model revealed the following novel mechanisms: 1 rapid capacitive current (Icap underlies the activation of voltage-gated sodium channels; 2 there was less than 2 milliseconds in which the Icap underlying TC input and EPJP was coupled effectively; 3 cells with dendritic GJs had larger input conductance and smaller membrane response to weaker inputs; 4 synchrony in inhibitory networks by GJ coupling leads to reduced sporadic lateral inhibition and increased TC transmission efficacy. Conclusion Dendritic GJs of neocortical inhibitory networks can have very powerful effects in modulating the strength and the temporal properties of sensory induced feed-forward inhibitory and excitatory responses at a very high frequency band (>200 Hz. Rapid capacitive currents are identified as main mechanisms underlying interaction between two transient synaptic conductances.

Sequential generation of olfactory bulb glutamatergic neurons by Neurog2-expressing precursor cells

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Brill Monika S

2011-04-01

Full Text Available Abstract Background While the diversity and spatio-temporal origin of olfactory bulb (OB GABAergic interneurons has been studied in detail, much less is known about the subtypes of glutamatergic OB interneurons. Results We studied the temporal generation and diversity of Neurog2-positive precursor progeny using an inducible genetic fate mapping approach. We show that all subtypes of glutamatergic neurons derive from Neurog2 positive progenitors during development of the OB. Projection neurons, that is, mitral and tufted cells, are produced at early embryonic stages, while a heterogeneous population of glutamatergic juxtaglomerular neurons are generated at later embryonic as well as at perinatal stages. While most juxtaglomerular neurons express the T-Box protein Tbr2, those generated later also express Tbr1. Based on morphological features, these juxtaglomerular cells can be identified as tufted interneurons and short axon cells, respectively. Finally, targeted electroporation experiments provide evidence that while the majority of OB glutamatergic neurons are generated from intrabulbar progenitors, a small portion of them originate from extrabulbar regions at perinatal ages. Conclusions We provide the first comprehensive analysis of the temporal and spatial generation of OB glutamatergic neurons and identify distinct populations of juxtaglomerular interneurons that differ in their antigenic properties and time of origin.

Direct Induction and Functional Maturation of Forebrain GABAergic Neurons from Human Pluripotent Stem Cells

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Alfred Xuyang Sun

2016-08-01

Full Text Available Gamma-aminobutyric acid (GABA-releasing interneurons play an important modulatory role in the cortex and have been implicated in multiple neurological disorders. Patient-derived interneurons could provide a foundation for studying the pathogenesis of these diseases as well as for identifying potential therapeutic targets. Here, we identified a set of genetic factors that could robustly induce human pluripotent stem cells (hPSCs into GABAergic neurons (iGNs with high efficiency. We demonstrated that the human iGNs express neurochemical markers and exhibit mature electrophysiological properties within 6–8 weeks. Furthermore, in vitro, iGNs could form functional synapses with other iGNs or with human-induced glutamatergic neurons (iENs. Upon transplantation into immunodeficient mice, human iGNs underwent synaptic maturation and integration into host neural circuits. Taken together, our rapid and highly efficient single-step protocol to generate iGNs may be useful to both mechanistic and translational studies of human interneurons.

Types and three-dimensional distribution of neuronal ectopias in the brain of mice prenatally subjected to X-irradiation

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Sun, Xue-Zhi; Takahashi, Sentaro; Kubota, Yoshihisa; Sato, Hiroshi [National Inst. of Radiological Sciences, Chiba (Japan); Cui, Chun; Fukui, Yoshihiro [Tokushima Univ. (Japan). School of Medicine; Inouye, Minoru [Shin Nippon Biomedical Lab., Ltd., Miyanoura, Kagoshima (Japan)

2002-03-01

The types and three-dimensional distribution of neocortical ectopias following prenatal exposure to X-irradiation were studied by a histological examination and computer reconstruction techniques. Pregnant ICR mice were subjected to X-irradiation at a dose of 1.5 Gy on embryonic day 13. The brains from 30-day-old mice were serially sectioned on the frontal plane at 15 {mu}m, stained with HE and observed with a microscope. The image data for the sections were input to a computer, and then reconstructed to three-dimensional brain structures using the Magellan 3.6 program. Sectional images were then drawn on a computer display at 240 {mu}m intervals, and the positions of the different types of neocortical ectopias were marked using color coding. Three types of neocortical ectopias were recognized in the irradiated brains. Neocortical Lay I ectopias were identified as small patches in the caudal occipital cortex, and were located more laterally in the neocortex in caudal sections than in the rostral sections. Periventricular ectopias were located more rostrally than Lay I ectopias, and were found from the most caudal extent of the presumed motor cortex to the most caudal extent of the lateral ventricle. Hippocampal ectopias appeared as continuous linear bands, and were frequently associated with the anterior parts of the periventricular ectopias. (author)

Proper development of relay somatic sensory neurons and D2/D4 interneurons requires homeobox genes Rnx/Tlx-3 and Tlx-1.

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Qian, Ying; Shirasawa, Senji; Chen, Chih-Li; Cheng, Leping; Ma, Qiufu

2002-05-15

Trigeminal nuclei and the dorsal spinal cord are first-order relay stations for processing somatic sensory information such as touch, pain, and temperature. The origins and development of these neurons are poorly understood. Here we show that relay somatic sensory neurons and D2/D4 dorsal interneurons likely derive from Mash1-positive neural precursors, and depend on two related homeobox genes, Rnx and Tlx-1, for proper formation. Rnx and Tlx-1 maintain expression of Drg11, a homeobox gene critical for the development of pain circuitry, and are essential for the ingrowth of trkA+ nociceptive/thermoceptive sensory afferents to their central targets. We showed previously that Rnx is necessary for proper formation of the nucleus of solitary tract, the target for visceral sensory afferents. Together, our studies demonstrate a central role for Rnx and Tlx-1 in the development of two major classes of relay sensory neurons, somatic and visceral.

Local changes in neocortical circuit dynamics coincide with the spread of seizures to thalamus in a model of epilepsy.

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Neubauer, Florian B; Sederberg, Audrey; MacLean, Jason N

2014-01-01

During the generalization of epileptic seizures, pathological activity in one brain area recruits distant brain structures into joint synchronous discharges. However, it remains unknown whether specific changes in local circuit activity are related to the aberrant recruitment of anatomically distant structures into epileptiform discharges. Further, it is not known whether aberrant areas recruit or entrain healthy ones into pathological activity. Here we study the dynamics of local circuit activity during the spread of epileptiform discharges in the zero-magnesium in vitro model of epilepsy. We employ high-speed multi-photon imaging in combination with dual whole-cell recordings in acute thalamocortical (TC) slices of the juvenile mouse to characterize the generalization of epileptic activity between neocortex and thalamus. We find that, although both structures are exposed to zero-magnesium, the initial onset of focal epileptiform discharge occurs in cortex. This suggests that local recurrent connectivity that is particularly prevalent in cortex is important for the initiation of seizure activity. Subsequent recruitment of thalamus into joint, generalized discharges is coincident with an increase in the coherence of local cortical circuit activity that itself does not depend on thalamus. Finally, the intensity of population discharges is positively correlated between both brain areas. This suggests that during and after seizure generalization not only the timing but also the amplitude of epileptiform discharges in thalamus is entrained by cortex. Together these results suggest a central role of neocortical activity for the onset and the structure of pathological recruitment of thalamus into joint synchronous epileptiform discharges.

Memory-guided sensory comparisons in the prefrontal cortex: contribution of putative pyramidal cells and interneurons.

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Hussar, Cory R; Pasternak, Tatiana

2012-02-22

Comparing two stimuli that occur at different times demands the coordination of bottom-up and top-down processes. It has been hypothesized that the dorsolateral prefrontal (PFC) cortex, the likely source of top-down cortical influences, plays a key role in such tasks, contributing to both maintenance and sensory comparisons. We examined this hypothesis by recording from the PFC of monkeys comparing directions of two moving stimuli, S1 and S2, separated by a memory delay. We determined the contribution of the two principal cell types to these processes by classifying neurons into broad-spiking (BS) putative pyramidal cells and narrow-spiking (NS) putative local interneurons. During the delay, BS cells were more likely to exhibit anticipatory modulation and represent the remembered direction. While this representation was transient, appearing at different times in different neurons, it weakened when direction was not task relevant, suggesting its utility. During S2, both putative cell types showed comparison-related activity modulations. These modulations were of two types, each carried by different neurons, which either preferred trials with stimuli moving in the same direction or trials with stimuli of different directions. These comparison effects were strongly correlated with choice, suggesting their role in circuitry underlying decision making. These results provide the first demonstration of distinct contributions made by principal cell types to memory-guided perceptual decisions. During sensory stimulation both cell types represent behaviorally relevant stimulus features contributing to comparison and decision-related activity. However in the absence of sensory stimulation, putative pyramidal cells dominated, carrying information about the elapsed time and the preceding direction.

Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons.

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Battefeld, Arne; Tran, Baouyen T; Gavrilis, Jason; Cooper, Edward C; Kole, Maarten H P

2014-03-05

Rapid energy-efficient signaling along vertebrate axons is achieved through intricate subcellular arrangements of voltage-gated ion channels and myelination. One recently appreciated example is the tight colocalization of K(v)7 potassium channels and voltage-gated sodium (Na(v)) channels in the axonal initial segment and nodes of Ranvier. The local biophysical properties of these K(v)7 channels and the functional impact of colocalization with Na(v) channels remain poorly understood. Here, we quantitatively examined K(v)7 channels in myelinated axons of rat neocortical pyramidal neurons using high-resolution confocal imaging and patch-clamp recording. K(v)7.2 and 7.3 immunoreactivity steeply increased within the distal two-thirds of the axon initial segment and was mirrored by the conductance density estimates, which increased from ~12 (proximal) to 150 pS μm(-2) (distal). The axonal initial segment and nodal M-currents were similar in voltage dependence and kinetics, carried by K(v)7.2/7.3 heterotetramers, 4% activated at the resting membrane potential and rapidly activated with single-exponential time constants (~15 ms at 28 mV). Experiments and computational modeling showed that while somatodendritic K(v)7 channels are strongly activated by the backpropagating action potential to attenuate the afterdepolarization and repetitive firing, axonal K(v)7 channels are minimally recruited by the forward-propagating action potential. Instead, in nodal domains K(v)7.2/7.3 channels were found to increase Na(v) channel availability and action potential amplitude by stabilizing the resting membrane potential. Thus, K(v)7 clustering near axonal Na(v) channels serves specific and context-dependent roles, both restraining initiation and enhancing conduction of the action potential.

Subtype-Specific Genes that Characterize Subpopulations of Callosal Projection Neurons in Mouse Identify Molecularly Homologous Populations in Macaque Cortex.

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Fame, Ryann M; Dehay, Colette; Kennedy, Henry; Macklis, Jeffrey D

2017-03-01

Callosal projection neurons (CPN) interconnect the neocortical hemispheres via the corpus callosum and are implicated in associative integration of multimodal information. CPN have undergone differential evolutionary elaboration, leading to increased diversity of cortical neurons-and more extensive and varied connections in neocortical gray and white matter-in primates compared with rodents. In mouse, distinct sets of genes are enriched in discrete subpopulations of CPN, indicating the molecular diversity of rodent CPN. Elements of rodent CPN functional and organizational diversity might thus be present in the further elaborated primate cortex. We address the hypothesis that genes controlling mouse CPN subtype diversity might reflect molecular patterns shared among mammals that arose prior to the divergence of rodents and primates. We find that, while early expression of the examined CPN-enriched genes, and postmigratory expression of these CPN-enriched genes in deep layers are highly conserved (e.g., Ptn, Nnmt, Cited2, Dkk3), in contrast, the examined genes expressed by superficial layer CPN show more variable levels of conservation (e.g., EphA3, Chn2). These results suggest that there has been evolutionarily differential retraction and elaboration of superficial layer CPN subpopulations between mouse and macaque, with independent derivation of novel populations in primates. Together, these data inform future studies regarding CPN subpopulations that are unique to primates and rodents, and indicate putative evolutionary relationships. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Microscopic mild focal cortical dysplasia in temporal lobe dual pathology: an electrocorticography study.

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Morales Chacón, L; Estupiñán, B; Lorigados Pedre, L; Trápaga Quincoses, O; García Maeso, I; Sanchez, A; Bender del Busto, J; Garcia, M E; Baez Martin, M; Zaldivar, M; Gómez, A; Orozco, S; Rocha Arrieta, L

2009-10-01

Associations between electrophysiological and histological findings might provide an insight into the epileptogenicity of mild focal cortical dysplasia (FCD) in patients with temporal lobe epilepsy (TLE) and a dual pathology. A total of 22 patients with pharmacoresistant TLE were included in the study, 16 of them with histologically confirmed hippocampal sclerosis (HS) associated with neocortical temporal mild Palmini Type-I FCD subtypes and 6 with HS. Intraoperative electrocorticography (ECoG) recordings were analysed for epileptiform discharge frequency and morphology. Associations between histological, and electrocorticography pattern findings in these patients were analysed. Electroclinical outcomes in these patients were also evaluated. Neocortical areas with mild Palmini Type-I FCD showed a significantly higher spike frequency (SF) recorded in the inferior temporal gyrus than those neocortical areas in patients with HS. There was a tendency to higher spike frequency and lower amplitude in neocortical areas with histopathologic subtype IB FCD in relation with IA during intraoperative ECoG. Post-SF excision and amplitude were significantly lower during neocortical post-excision intraoperative ECoG than during neocortical pre-excision recording. There was no difference found in the clinical outcome between patients with and without FCD. Intraoperative electrocorticographic interictal spike frequency recorded in the neocortical inferior temporal gyrus may help to characterize the histopathologic subtypes of mild Palmini Type-I FCD in patients with temporal lobe epilepsy (TLE) and a dual pathology. Our data support the epileptogenicity of neocortical mild FCD in TLE and assessments of ECoG patterns are relevant to determine the extent of the resection in these patients which can influence the electroclinical outcome.

The subcellular distribution of T-type Ca2+ channels in interneurons of the lateral geniculate nucleus.

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Allken, Vaneeda; Chepkoech, Joy-Loi; Einevoll, Gaute T; Halnes, Geir

2014-01-01

Inhibitory interneurons (INs) in the lateral geniculate nucleus (LGN) provide both axonal and dendritic GABA output to thalamocortical relay cells (TCs). Distal parts of the IN dendrites often enter into complex arrangements known as triadic synapses, where the IN dendrite plays a dual role as postsynaptic to retinal input and presynaptic to TC dendrites. Dendritic GABA release can be triggered by retinal input, in a highly localized process that is functionally isolated from the soma, but can also be triggered by somatically elicited Ca(2+)-spikes and possibly by backpropagating action potentials. Ca(2+)-spikes in INs are predominantly mediated by T-type Ca(2+)-channels (T-channels). Due to the complex nature of the dendritic signalling, the function of the IN is likely to depend critically on how T-channels are distributed over the somatodendritic membrane (T-distribution). To study the relationship between the T-distribution and several IN response properties, we here run a series of simulations where we vary the T-distribution in a multicompartmental IN model with a realistic morphology. We find that the somatic response to somatic current injection is facilitated by a high T-channel density in the soma-region. Conversely, a high T-channel density in the distal dendritic region is found to facilitate dendritic signalling in both the outward direction (increases the response in distal dendrites to somatic input) and the inward direction (the soma responds stronger to distal synaptic input). The real T-distribution is likely to reflect a compromise between several neural functions, involving somatic response patterns and dendritic signalling.

Local Optogenetic Induction of Fast (20-40 Hz Pyramidal-Interneuron Network Oscillations in the In Vitro and In Vivo CA1 Hippocampus: Modulation by CRF and Enforcement of Perirhinal Theta Activity

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Julien eDine

2016-04-01

Full Text Available The neurophysiological processes that can cause theta-to-gamma frequency range (4-80 Hz network oscillations in the rhinal cortical-hippocampal system and the potential connectivity-based interactions of such forebrain rhythms are a topic of intensive investigation. Here, using selective Channelrhodopsin-2 (ChR2 expression in mouse forebrain glutamatergic cells, we were able to locally, temporally precisely, and reliably induce fast (20-40 Hz field potential oscillations in hippocampal area CA1 in vitro (at 25°C and in vivo (i.e., slightly anaesthetized NEX-Cre-ChR2 mice. As revealed by pharmacological analyses and patch-clamp recordings from pyramidal cells and GABAergic interneurons in vitro, these light-triggered oscillations can exclusively arise from sustained suprathreshold depolarization (~200 ms or longer and feedback inhibition of CA1 pyramidal neurons, as being mandatory for prototypic pyramidal-interneuron network (P-I oscillations. Consistently, the oscillations comprised rhythmically occurring population spikes (generated by pyramidal cells and their frequency increased with increasing spectral power. We further demonstrate that the optogenetically driven CA1 oscillations, which remain stable over repeated evocations, are impaired by the stress hormone corticotropin-releasing factor (CRF, 125 nM in vitro and, even more remarkably, found that they are accompanied by concurrent states of enforced theta activity in the memory-associated perirhinal cortex (PrC in vivo. The latter phenomenon most likely derives from neurotransmission via a known, but poorly studied excitatory CA1PrC pathway. Collectively, our data provide evidence for the existence of a prototypic (CRF-sensitive P-I gamma rhythm generator in area CA1 and suggest that CA1 P-I oscillations can rapidly up-regulate theta activity strength in hippocampus-innervated rhinal networks, at least in the PrC.

Local Optogenetic Induction of Fast (20-40 Hz) Pyramidal-Interneuron Network Oscillations in the In Vitro and In Vivo CA1 Hippocampus: Modulation by CRF and Enforcement of Perirhinal Theta Activity.

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Dine, Julien; Genewsky, Andreas; Hladky, Florian; Wotjak, Carsten T; Deussing, Jan M; Zieglgänsberger, Walter; Chen, Alon; Eder, Matthias

2016-01-01

The neurophysiological processes that can cause theta-to-gamma frequency range (4-80 Hz) network oscillations in the rhinal cortical-hippocampal system and the potential connectivity-based interactions of such forebrain rhythms are a topic of intensive investigation. Here, using selective Channelrhodopsin-2 (ChR2) expression in mouse forebrain glutamatergic cells, we were able to locally, temporally precisely, and reliably induce fast (20-40 Hz) field potential oscillations in hippocampal area CA1 in vitro (at 25°C) and in vivo (i.e., slightly anesthetized NEX-Cre-ChR2 mice). As revealed by pharmacological analyses and patch-clamp recordings from pyramidal cells and GABAergic interneurons in vitro, these light-triggered oscillations can exclusively arise from sustained suprathreshold depolarization (~200 ms or longer) and feedback inhibition of CA1 pyramidal neurons, as being mandatory for prototypic pyramidal-interneuron network (P-I) oscillations. Consistently, the oscillations comprised rhythmically occurring population spikes (generated by pyramidal cells) and their frequency increased with increasing spectral power. We further demonstrate that the optogenetically driven CA1 oscillations, which remain stable over repeated evocations, are impaired by the stress hormone corticotropin-releasing factor (CRF, 125 nM) in vitro and, even more remarkably, found that they are accompanied by concurrent states of enforced theta activity in the memory-associated perirhinal cortex (PrC) in vivo. The latter phenomenon most likely derives from neurotransmission via a known, but poorly studied excitatory CA1→PrC pathway. Collectively, our data provide evidence for the existence of a prototypic (CRF-sensitive) P-I gamma rhythm generator in area CA1 and suggest that CA1 P-I oscillations can rapidly up-regulate theta activity strength in hippocampus-innervated rhinal networks, at least in the PrC.

Volumetric MRI for evaluation of regional pattern and progression of neocortical degeneration in Alzheimer's disease; MR-Volumetrie zur Darstellung von Verteilung und zeitlicher Abfolge neokortikaler Degeneration bei Morbus Alzheimer

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Leinsinger, G. [Institut fuer Klinische Radiologie, Klinikum der Ludwig-Maximilians-Universitaet Muenchen, Muenchen (Germany); Institut fuer Klinische Radiologie, LMU Muenchen, Ziemssenstrasse 1, 80336, Muenchen (Germany); Teipel, S.; Pruessner, J.; Hampel, H. [Klinik fuer Psychiatrie, Ludwig-Maximilians-Universitaet Muenchen, Muenchen (Germany); Wismueller, A.; Born, C.; Meindl, T.; Flatz, W.; Schoenberg, S.; Reiser, M. [Institut fuer Klinische Radiologie, Klinikum der Ludwig-Maximilians-Universitaet Muenchen, Muenchen (Germany)

2003-07-01

Volumetric analysis of the corpus callosum and hippocampus using MRI in Alzheimer's disease (AD) to evaluate the regional pattern and progression of neocortical neurodegeneration. In subsequent studies we investigated patients with AD and healthy controls. Volumetry was based on MRI-data from a sagittal 3D T1w-gradient echo sequence. The corpus callosum (CC) was measured in a midsagittal slice, and subdivided into 5 subregions. Volumetry of the hippocampus/amygdala-formation (HAF) was performed by segmentation in coronary reoriented slices. In AD patients we found a significant atrophy in the rostrum und splenium of CC. The atrophy was correlated with the severity of dementia, but no correlation was found with the load of white matter lesions. In comparison with {sup 18}FDG-PET, we found a significant correlation of regional CC-atrophy with the regional decline of cortical glucose metabolism. A ROC-analysis demonstrated no significant differences in the diagostic accuracy of HAF volumetry and regional CC volumetry of the splenium (region C5) even in mild stages of dementia. Regional atrophy of CC can be used as a marker of neocortical degeneration even in early stages of dementia in AD. (orig.) [German] Volumetrische Analyse des Corpus callosum und Hippokampus mittels MRT bei der Alzheimer-Erkrankung (AD), mit dem Ziel die regionale Verteilung und Progression der neokortikalen relativ zur allokortikalen Neurodegeneration zu erfassen. In mehreren Studienabschnitten wurden Patienten mit AD und gesunde Kontrollen untersucht. Als Grundlage fuer die Volumetrie diente eine sagittale 3D-T1w-Gradientenechosequenz. Die Vermessung des Corpus callosum (CC) erfolgte in der mittsagittalen Schicht, wobei 5 Subregionen definiert wurden. Die Volumetrie des Hippokampus-Amygdala-Komplexes (HAK) wurde durch Segmentierung an koronar reorientierten Schichten durchgefuehrt. Bei Patienten mit AD fand sich eine signifikante Atrophie in Rostrum und Splenium des CC. Dabei zeigte sich

Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load and Cognitive Performance in Cognitively Normal Elderly Participants.

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Chatterjee, Pratishtha; Goozee, Kathryn; Sohrabi, Hamid R; Shen, Kaikai; Shah, Tejal; Asih, Prita R; Dave, Preeti; ManYan, Candice; Taddei, Kevin; Chung, Roger; Zetterberg, Henrik; Blennow, Kaj; Martins, Ralph N

2018-01-01

The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood. Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-β load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults. Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65- 90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51, nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment Clinic- Questionnaire. Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOEɛ4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC. Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD.

Synaptic and functional linkages between spinal premotor interneurons and hand-muscle activity during precision grip

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Tomohiko eTakei

2013-04-01

Full Text Available Grasping is a highly complex movement that requires the coordination of a number of hand joints and muscles. Previous studies showed that spinal premotor interneurons (PreM-INs in the primate cervical spinal cord have divergent synaptic effects on hand motoneurons and that they might contribute to hand-muscle synergies. However, the extent to which these PreM-IN synaptic connections functionally contribute to modulating hand-muscle activity is not clear. In this paper, we explored the contribution of spinal PreM-INs to hand-muscle activation by quantifying the synaptic linkage (SL and functional linkage (FL of the PreM-INs with hand-muscle activities. The activity of 23 PreM-INs was recorded from the cervical spinal cord (C6–T1, with EMG signals measured simultaneously from hand and arm muscles in two macaque monkeys performing a precision grip task. Spike-triggered averages (STAs of rectified EMGs were compiled for 456 neuron–muscle pairs; 63 pairs showed significant post-spike effects (i.e., SL. Conversely, 231 of 456 pairs showed significant cross-correlations between the IN firing rate and rectified EMG (i.e., FL. Importantly, a greater proportion of the neuron–muscle pairs with SL showed FL (43/63 pairs, 68% compared with the pairs without SL (203/393, 52%, and the presence of SL was significantly associated with that of FL. However, a significant number of pairs had SL without FL (SL∩!FL, n = 20 or FL without SL (!SL∩FL, n = 203, and the proportions of these incongruities exceeded the number expected by chance. These results suggested that spinal PreM-INs function to significantly modulate hand-muscle activity during precision grip, but the contribution of other neural structures is also needed to recruit an adequate combination of hand-muscle motoneurons.

Firing properties of identified interneuron populations in the mammalian hindlimb central pattern generator

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Butt, S. J B; Harris-Warrick, Ronald M.; Kiehn, Ole

2002-01-01

a heterogenous population with neurons that fired in all phases of the locomotor cycle and exhibited varying degrees of rhythmicity, from strongly rhythmic to nonrhythmic. Among the rhythmic, putative CPG dCINs were populations that fired inphase with the ipsilateral or with the contralateral L2 locomotorlike......, with little direct contribution from the intrinsic pacemaker hyperpolarization-activated inward current. For both ipsilaterally and contralaterally firing dCINs the dominant synaptic drive was in-phase with the ipsilateral L2 motor activity. This study provides the first characterization of putative CPG...

Utah optrode array customization using stereotactic brain atlases and 3-D CAD modeling for optogenetic neocortical interrogation in small rodents and nonhuman primates.

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Boutte, Ronald W; Merlin, Sam; Yona, Guy; Griffiths, Brandon; Angelucci, Alessandra; Kahn, Itamar; Shoham, Shy; Blair, Steve

2017-10-01

As the optogenetic field expands, the need for precise targeting of neocortical circuits only grows more crucial. This work demonstrates a technique for using Solidworks ® computer-aided design (CAD) and readily available stereotactic brain atlases to create a three-dimensional (3-D) model of the dorsal region of area visual cortex 4 (V4D) of the macaque monkey ( Macaca fascicularis ) visual cortex. The 3-D CAD model of the brain was used to customize an [Formula: see text] Utah optrode array (UOA) after it was determined that a high-density ([Formula: see text]) UOA caused extensive damage to marmoset ( Callithrix jacchus ) primary visual cortex as assessed by electrophysiological recording of spiking activity through a 1.5-mm-diameter through glass via. The [Formula: see text] UOA was customized for optrode length ([Formula: see text]), optrode width ([Formula: see text]), optrode pitch ([Formula: see text]), backplane thickness ([Formula: see text]), and overall form factor ([Formula: see text]). Two [Formula: see text] UOAs were inserted into layer VI of macaque V4D cortices with minimal damage as assessed in fixed tissue cytochrome oxidase staining in nonrecoverable surgeries. Additionally, two [Formula: see text] arrays were implanted in mice ( Mus musculus ) motor cortices, providing early evidence for long-term tolerability (over 6 months), and for the ability to integrate the UOA with a Holobundle light delivery system toward patterned optogenetic stimulation of cortical networks.

Activity blockade and GABAA receptor blockade produce synaptic scaling through chloride accumulation in embryonic spinal motoneurons and interneurons.

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Casie Lindsly

Full Text Available Synaptic scaling represents a process whereby the distribution of a cell's synaptic strengths are altered by a multiplicative scaling factor. Scaling is thought to be a compensatory response that homeostatically controls spiking activity levels in the cell or network. Previously, we observed GABAergic synaptic scaling in embryonic spinal motoneurons following in vivo blockade of either spiking activity or GABAA receptors (GABAARs. We had determined that activity blockade triggered upward GABAergic scaling through chloride accumulation, thus increasing the driving force for these currents. To determine whether chloride accumulation also underlies GABAergic scaling following GABAAR blockade we have developed a new technique. We expressed a genetically encoded chloride-indicator, Clomeleon, in the embryonic chick spinal cord, which provides a non-invasive fast measure of intracellular chloride. Using this technique we now show that chloride accumulation underlies GABAergic scaling following blockade of either spiking activity or the GABAAR. The finding that GABAAR blockade and activity blockade trigger scaling via a common mechanism supports our hypothesis that activity blockade reduces GABAAR activation, which triggers synaptic scaling. In addition, Clomeleon imaging demonstrated the time course and widespread nature of GABAergic scaling through chloride accumulation, as it was also observed in spinal interneurons. This suggests that homeostatic scaling via chloride accumulation is a common feature in many neuronal classes within the embryonic spinal cord and opens the possibility that this process may occur throughout the nervous system at early stages of development.

Mapping to mouse chromosome 3 of the gene encoding latexin (Lxn) expressed in neocortical neurons in a region-specific manner

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Jin, Ming-hao; Uratani, Yoshihiko; Arimatsu, Yasuyoshi [Mitsubishi Kasei Institute of Life Sciences, Tokyo (Japan)

1997-02-01

Latexin was first found as a 29-kDa antigen expressed in a subset of neurons in infragranular layers of lateral, but not dorsal, neocortical areas in the rat using a monoclonal antibody PC3.1. It was found that the vast majority of latexin-expressing neurons in both layers V and VI within the lateral neocortex were generated concurrently at Embryonic Day 15, demonstrating a strict correlation between the molecular identity of neurons and the time of their generation. Since neurons expressing latexin are located in the restricted part of the neocortex, latexin has been used as a useful molecular marker to elucidate the mechanism underlying cortical regional specification. The latexin cDNA isolated from a cDNA library of the rat cerebral cortex encodes a protein composed of 223-amino-acid residues containing two potential Ca{sup 2+}/calmodulin-dependent protein kinase sites and one cGMP-dependent protein kinase phosphorylation site. The absence of any signal peptide or potential transmembrane domain is consistent with the apparent cytosolic localization of latexin in the rat brain. The transcripts of latexin were expressed in not only neutral but also nonneural tissues (e.g., lung, spleen, kidney, heart, and digestive tracts). Recently, it has been demonstrated that latexin purified from the rat brain has inhibitory activity against carboxypeptidase A1, carboxypeptidase A2, and mast cell carboxypeptidase A, with less carboxypeptidase B-inhibiting activity. The amino acid sequence deduced from the rat latexin cDNA has no strict homology to any sequences so far known. Genomic Southern blot analysis using a cDNA probe of rat latexin suggested that the gene encoding latexin in the rat has homologues in other mammalian species and in the chicken, but not in the nematode, fly, or frog. 9 refs., 1 fig.

Neuronal activity in the isolated mouse spinal cord during spontaneous deletions in fictive locomotion: insights into locomotor central pattern generator organization

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Zhong, Guisheng; Shevtsova, Natalia A; Rybak, Ilya A; Harris-Warrick, Ronald M

2012-01-01

We explored the organization of the spinal central pattern generator (CPG) for locomotion by analysing the activity of spinal interneurons and motoneurons during spontaneous deletions occurring during fictive locomotion in the isolated neonatal mouse spinal cord, following earlier work on locomotor deletions in the cat. In the isolated mouse spinal cord, most spontaneous deletions were non-resetting, with rhythmic activity resuming after an integer number of cycles. Flexor and extensor deletions showed marked asymmetry: flexor deletions were accompanied by sustained ipsilateral extensor activity, whereas rhythmic flexor bursting was not perturbed during extensor deletions. Rhythmic activity on one side of the cord was not perturbed during non-resetting spontaneous deletions on the other side, and these deletions could occur with no input from the other side of the cord. These results suggest that the locomotor CPG has a two-level organization with rhythm-generating (RG) and pattern-forming (PF) networks, in which only the flexor RG network is intrinsically rhythmic. To further explore the neuronal organization of the CPG, we monitored activity of motoneurons and selected identified interneurons during spontaneous non-resetting deletions. Motoneurons lost rhythmic synaptic drive during ipsilateral deletions. Flexor-related commissural interneurons continued to fire rhythmically during non-resetting ipsilateral flexor deletions. Deletion analysis revealed two classes of rhythmic V2a interneurons. Type I V2a interneurons retained rhythmic synaptic drive and firing during ipsilateral motor deletions, while type II V2a interneurons lost rhythmic synaptic input and fell silent during deletions. This suggests that the type I neurons are components of the RG, whereas the type II neurons are components of the PF network. We propose a computational model of the spinal locomotor CPG that reproduces our experimental results. The results may provide novel insights into the

Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex.

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Ruiz-Mejias, Marcel; Martinez de Lagran, Maria; Mattia, Maurizio; Castano-Prat, Patricia; Perez-Mendez, Lorena; Ciria-Suarez, Laura; Gener, Thomas; Sancristobal, Belen; García-Ojalvo, Jordi; Gruart, Agnès; Delgado-García, José M; Sanchez-Vives, Maria V; Dierssen, Mara

2016-03-30

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified

Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABAA receptors on parvalbumin interneurons

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Isabella eFerando

2013-09-01

Full Text Available Gamma (γ oscillations (30-120 Hz, an emergent property of neuronal networks, correlate with memory, cognition and encoding. In the hippocampal CA3 region, locally generated γ oscillations emerge through feedback between inhibitory parvalbumin-positive basket cells (PV+BCs and the principal (pyramidal cells. PV+BCs express δ-subunit-containing GABAARs (-GABAARs and NMDA receptors (NMDA-Rs that balance the frequency of γ oscillations. Neuroactive steroids (NS, such as the progesterone-derived (3α,5α-3-hydroxy-pregnan-20-one (allopregnanolone; ALLO, modulate the expression of δ-GABAARs and the tonic conductance they mediate. Pregnancy produces large increases in ALLO and brain-region-specific homeostatic changes in δ-GABAARs expression. Here we show that in CA3, where most PV+ interneurons (INs express δ-GABAARs, expression of δ-GABAARs on INs diminishes during pregnancy, but reverts to control levels within 48 hours postpartum. These anatomical findings were corroborated by a pregnancy-related increase in the frequency of kainate-induced CA3 γ oscillations in vitro that could be countered by the NMDA-R antagonists D-AP5 and PPDA. Mimicking the typical hormonal conditions during pregnancy by supplementing 100 nM ALLO lowered the γ frequencies to levels found in virgin or postpartum mice. Our findings show that states of altered NS levels (e.g., pregnancy may provoke perturbations in γ oscillatory activity through direct effects on the GABAergic system, and underscore the importance of δ-GABAARs homeostatic plasticity in maintaining constant network output despite large hormonal changes. Inaccurate coupling of NS levels to δ-GABAAR expression may facilitate abnormal neurological and psychiatric conditions such as epilepsy, post-partum depression, and post-partum psychosis, thus providing insights into potential new treatments.

Excitatory Synaptic Drive and Feedforward Inhibition in the Hippocampal CA3 Circuit Are Regulated by SynCAM 1.

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Park, Kellie A; Ribic, Adema; Laage Gaupp, Fabian M; Coman, Daniel; Huang, Yuegao; Dulla, Chris G; Hyder, Fahmeed; Biederer, Thomas

2016-07-13

Select adhesion proteins control the development of synapses and modulate their structural and functional properties. Despite these important roles, the extent to which different synapse-organizing mechanisms act across brain regions to establish connectivity and regulate network properties is incompletely understood. Further, their functional roles in different neuronal populations remain to be defined. Here, we applied diffusion tensor imaging (DTI), a modality of magnetic resonance imaging (MRI), to map connectivity changes in knock-out (KO) mice lacking the synaptogenic cell adhesion protein SynCAM 1. This identified reduced fractional anisotropy in the hippocampal CA3 area in absence of SynCAM 1. In agreement, mossy fiber refinement in CA3 was impaired in SynCAM 1 KO mice. Mossy fibers make excitatory inputs onto postsynaptic specializations of CA3 pyramidal neurons termed thorny excrescences and these structures were smaller in the absence of SynCAM 1. However, the most prevalent targets of mossy fibers are GABAergic interneurons and SynCAM 1 loss unexpectedly reduced the number of excitatory terminals onto parvalbumin (PV)-positive interneurons in CA3. SynCAM 1 KO mice additionally exhibited lower postsynaptic GluA1 expression in these PV-positive interneurons. These synaptic imbalances in SynCAM 1 KO mice resulted in CA3 disinhibition, in agreement with reduced feedforward inhibition in this network in the absence of SynCAM 1-dependent excitatory drive onto interneurons. In turn, mice lacking SynCAM 1 were impaired in memory tasks involving CA3. Our results support that SynCAM 1 modulates excitatory mossy fiber inputs onto both interneurons and principal neurons in the hippocampal CA3 area to balance network excitability. This study advances our understanding of synapse-organizing mechanisms on two levels. First, the data support that synaptogenic proteins guide connectivity and can function in distinct brain regions even if they are expressed broadly

Repeated Blockade of NMDA Receptors during Adolescence Impairs Reversal Learning and Disrupts GABAergic Interneurons in Rat Medial Prefrontal Cortex

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Jitao eLi

2016-03-01

Full Text Available Adolescence is of particular significance to schizophrenia, since psychosis onset typically occurs in this critical period. Based on the N-methyl-D-aspartate (NMDA receptor hypofunction hypothesis of schizophrenia, in this study, we investigated whether and how repeated NMDA receptor blockade during adolescence would affect GABAergic interneurons in rat medial prefrontal cortex (mPFC and mPFC-mediated cognitive functions. Specifically, adolescent rats were subjected to intraperitoneal administration of MK-801 (0.1, 0.2, 0.4 mg/kg, a non-competitive NMDA receptor antagonist, for 14 days and then tested for reference memory and reversal learning in the water maze. The density of parvabumin (PV-, calbindin (CB- and calretinin (CR-positive neurons in mPFC were analyzed at either 24 hours or 7 days after drug cessation. We found that MK-801 treatment delayed reversal learning in the water maze without affecting initial acquisition. Strikingly, MK-801 treatment also significantly reduced the density of PV+ and CB+ neurons, and this effect persisted for 7 days after drug cessation at the dose of 0.2 mg/kg. We further demonstrated that the reduction in PV+ and CB+ neuron densities was ascribed to a downregulation of the expression levels of PV and CB, but not to neuronal death. These results parallel the behavioral and neuropathological changes of schizophrenia and provide evidence that adolescent NMDA receptors antagonism offers a useful tool for unraveling the etiology of the disease.

Linear and nonlinear auditory response properties of interneurons in a high-order avian vocal motor nucleus during wakefulness.

Science.gov (United States)

Raksin, Jonathan N; Glaze, Christopher M; Smith, Sarah; Schmidt, Marc F

2012-04-01

Motor-related forebrain areas in higher vertebrates also show responses to passively presented sensory stimuli. However, sensory tuning properties in these areas, especially during wakefulness, and their relation to perception, are poorly understood. In the avian song system, HVC (proper name) is a vocal-motor structure with auditory responses well defined under anesthesia but poorly characterized during wakefulness. We used a large set of stimuli including the bird's own song (BOS) and many conspecific songs (CON) to characterize auditory tuning properties in putative interneurons (HVC(IN)) during wakefulness. Our findings suggest that HVC contains a diversity of responses that vary in overall excitability to auditory stimuli, as well as bias in spike rate increases to BOS over CON. We used statistical tests to classify cells in order to further probe auditory responses, yielding one-third of neurons that were either unresponsive or suppressed and two-thirds with excitatory responses to one or more stimuli. A subset of excitatory neurons were tuned exclusively to BOS and showed very low linearity as measured by spectrotemporal receptive field analysis (STRF). The remaining excitatory neurons responded well to CON stimuli, although many cells still expressed a bias toward BOS. These findings suggest the concurrent presence of a nonlinear and a linear component to responses in HVC, even within the same neuron. These characteristics are consistent with perceptual deficits in distinguishing BOS from CON stimuli following lesions of HVC and other song nuclei and suggest mirror neuronlike qualities in which "self" (here BOS) is used as a referent to judge "other" (here CON).

Cell-Type-Specific Circuit Connectivity of Hippocampal CA1 Revealed through Cre-Dependent Rabies Tracing

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Yanjun Sun

2014-04-01

Full Text Available We developed and applied a Cre-dependent, genetically modified rabies-based tracing system to map direct synaptic connections to specific CA1 neuron types in the mouse hippocampus. We found common inputs to excitatory and inhibitory CA1 neurons from CA3, CA2, the entorhinal cortex (EC, the medial septum (MS, and, unexpectedly, the subiculum. Excitatory CA1 neurons receive inputs from both cholinergic and GABAergic MS neurons, whereas inhibitory neurons receive a great majority of inputs from GABAergic MS neurons. Both cell types also receive weaker input from glutamatergic MS neurons. Comparisons of inputs to CA1 PV+ interneurons versus SOM+ interneurons showed similar strengths of input from the subiculum, but PV+ interneurons received much stronger input than SOM+ neurons from CA3, the EC, and the MS. Thus, rabies tracing identifies hippocampal circuit connections and maps how the different input sources to CA1 are distributed with different strengths on each of its constituent cell types.

Cellular basis for singing motor pattern generation in the field cricket (Gryllus bimaculatus DeGeer)

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Schöneich, Stefan; Hedwig, Berthold

2012-01-01

The singing behavior of male crickets allows analyzing a central pattern generator (CPG) that was shaped by sexual selection for reliable production of species-specific communication signals. After localizing the essential ganglia for singing in Gryllus bimaculatus, we now studied the calling song CPG at the cellular level. Fictive singing was initiated by pharmacological brain stimulation. The motor pattern underlying syllables and chirps was recorded as alternating spike bursts of wing-opener and wing-closer motoneurons in a truncated wing nerve; it precisely reflected the natural calling song. During fictive singing, we intracellularly recorded and stained interneurons in thoracic and abdominal ganglia and tested their impact on the song pattern by intracellular current injections. We identified three interneurons of the metathoracic and first unfused abdominal ganglion that rhythmically de- and hyperpolarized in phase with the syllable pattern and spiked strictly before the wing-opener motoneurons. Depolarizing current injection in two of these opener interneurons caused additional rhythmic singing activity, which reliably reset the ongoing chirp rhythm. The closely intermeshing arborizations of the singing interneurons revealed the dorsal midline neuropiles of the metathoracic and three most anterior abdominal neuromeres as the anatomical location of singing pattern generation. In the same neuropiles, we also recorded several closer interneurons that rhythmically hyper- and depolarized in the syllable rhythm and spiked strictly before the wing-closer motoneurons. Some of them received pronounced inhibition at the beginning of each chirp. Hyperpolarizing current injection in the dendrite revealed postinhibitory rebound depolarization as one functional mechanism of central pattern generation in singing crickets. PMID:23170234

High-resolution labeling and functional manipulation of specific neuron types in mouse brain by Cre-activated viral gene expression.

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Sandra J Kuhlman

2008-04-01

Full Text Available We describe a method that combines Cre-recombinase knockin mice and viral-mediated gene transfer to genetically label and functionally manipulate specific neuron types in the mouse brain. We engineered adeno-associated viruses (AAVs that express GFP, dsRedExpress, or channelrhodopsin (ChR2 upon Cre/loxP recombination-mediated removal of a transcription-translation STOP cassette. Fluorescent labeling was sufficient to visualize neuronal structures with synaptic resolution in vivo, and ChR2 expression allowed light activation of neuronal spiking. The structural dynamics of a specific class of neocortical neuron, the parvalbumin-containing (Pv fast-spiking GABAergic interneuron, was monitored over the course of a week. We found that although the majority of Pv axonal boutons were stable in young adults, bouton additions and subtractions on axonal shafts were readily observed at a rate of 10.10% and 9.47%, respectively, over 7 days. Our results indicate that Pv inhibitory circuits maintain the potential for structural re-wiring in post-adolescent cortex. With the generation of an increasing number of Cre knockin mice and because viral transfection can be delivered to defined brain regions at defined developmental stages, this strategy represents a general method to systematically visualize the structure and manipulate the function of different cell types in the mouse brain.

The Developing, Aging Neocortex: How genetics and epigenetics influence early developmental patterning and age-related change.

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Kelly J. Huffman

2012-10-01

Full Text Available A hallmark of mammalian development is the generation of functional subdivisions within the nervous system. In humans, this regionalization creates a complex system that regulates behavior, cognition, memory and emotion. During development, specification of neocortical tissue that leads to functional sensory and motor regions results from an interplay between cortically intrinsic, molecular processes, such as gene expression, and extrinsic processes regulated by sensory input. Cortical specification in mice occurs pre- and perinatally, when gene expression is robust and various anatomical distinctions are observed alongside an emergence of physiological function. After patterning, gene expression continues to shift and axonal connections mature into an adult form. The function of adult cortical gene expression may be to maintain neocortical subdivisions that were established during early patterning. As some changes in neocortical gene expression have been observed past early development into late adulthood, gene expression may also play a role in the altered neocortical function observed in age-related cognitive decline and brain dysfunction. This review provides a discussion of how neocortical gene expression and specific patterns of neocortical sensori-motor axonal connections develop and change throughout the lifespan of the animal. We posit that a role of neocortical gene expression in neocortex is to regulate plasticity mechanisms that impact critical periods for sensory and motor plasticity in aging. We describe results from several studies in aging brain that detail changes in gene expression that may relate to microstructural changes observed in brain anatomy. We discuss the role of altered glucocorticoid signaling in age-related cognitive and functional decline, as well as how aging in the brain may result from immune system activation. We describe how caloric restriction or reduction of oxidative stress may ameliorate effects of aging

Molecular and functional definition of the developing human striatum.

Science.gov (United States)

Onorati, Marco; Castiglioni, Valentina; Biasci, Daniele; Cesana, Elisabetta; Menon, Ramesh; Vuono, Romina; Talpo, Francesca; Laguna Goya, Rocio; Lyons, Paul A; Bulfamante, Gaetano P; Muzio, Luca; Martino, Gianvito; Toselli, Mauro; Farina, Cinthia; Barker, Roger A; Biella, Gerardo; Cattaneo, Elena

2014-12-01

The complexity of the human brain derives from the intricate interplay of molecular instructions during development. Here we systematically investigated gene expression changes in the prenatal human striatum and cerebral cortex during development from post-conception weeks 2 to 20. We identified tissue-specific gene coexpression networks, differentially expressed genes and a minimal set of bimodal genes, including those encoding transcription factors, that distinguished striatal from neocortical identities. Unexpected differences from mouse striatal development were discovered. We monitored 36 determinants at the protein level, revealing regional domains of expression and their refinement, during striatal development. We electrophysiologically profiled human striatal neurons differentiated in vitro and determined their refined molecular and functional properties. These results provide a resource and opportunity to gain global understanding of how transcriptional and functional processes converge to specify human striatal and neocortical neurons during development.

Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks.

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Perea, Gertrudis; Gómez, Ricardo; Mederos, Sara; Covelo, Ana; Ballesteros, Jesús J; Schlosser, Laura; Hernández-Vivanco, Alicia; Martín-Fernández, Mario; Quintana, Ruth; Rayan, Abdelrahman; Díez, Adolfo; Fuenzalida, Marco; Agarwal, Amit; Bergles, Dwight E; Bettler, Bernhard; Manahan-Vaughan, Denise; Martín, Eduardo D; Kirchhoff, Frank; Araque, Alfonso

2016-12-24

Interneurons are critical for proper neural network function and can activate Ca 2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABA A receptors, potentiation involved astrocyte GABA B receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABA B receptor ( Gabbr1 ) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.

Ovarian cycle-linked plasticity of δ-GABAA receptor subunits in hippocampal interneurons affects γ oscillations in vivo

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Albert Miklos Barth

2014-08-01

Full Text Available GABAA receptors containing δ subunits (δ-GABAARs are GABA-gated ion channels with extra- and perisynaptic localization, strong sensitivity to neurosteroids (NS, and a high degree of plasticity. In selective brain regions they are expressed on specific principal cells and interneurons (INs, and generate a tonic conductance that controls neuronal excitability and oscillations. Plasticity of δ-GABAARs in principal cells has been described during states of altered NS synthesis including acute stress, puberty, ovarian cycle, pregnancy and the postpartum period, with direct consequences on neuronal excitability and network dynamics. The defining network events implicated in cognitive function, memory formation and encoding are γ oscillations (30-120 Hz, a well-timed loop of excitation and inhibition between principal cells and PV-expressing INs (PV+INs. The δ-GABAARs of INs can modify γ oscillations, and a lower expression of δ-GABAARs on INs during pregnancy alters γ frequency recorded in vitro. The ovarian cycle is another physiological event with large fluctuations in NS levels and δ-GABAARs. Stages of the cycle are paralleled by swings in memory performance, cognitive function, and mood in both humans and rodents. Here we show δ-GABAARs changes during the mouse ovarian cycle in hippocampal cell types, with enhanced expression during diestrus in principal cells and specific INs. The plasticity of δ-GABAARs on PV-INs decreases the magnitude of γ oscillations continuously recorded in area CA1 throughout several days in vivo during diestrus and increases it during estrus. Such recurring changes in γ magnitude were not observed in non-cycling wild-type (WT females, cycling females lacking δ-GABAARs only on PV-INs (PV-Gabrd-/-, and in male mice during a time course equivalent to the ovarian cycle. Our findings may explain the impaired memory and cognitive performance experienced by women with premenstrual syndrome (PMS or premenstrual

The role of the ventromedial prefrontal cortex in memory consolidation

NARCIS (Netherlands)

Nieuwenhuis, I.L.C.; Takashima, A.

2011-01-01

System-level memory consolidation theory posits that the hippocampus initially links the neocortical representations, followed by a shift to a hippocampus-independent neocortical network. With consolidation, an increase in activity in the human subgenual ventromedial prefrontal cortex (vmPFC) has

Emergence of ultrafast sparsely synchronized rhythms and their responses to external stimuli in an inhomogeneous small-world complex neuronal network.

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Kim, Sang-Yoon; Lim, Woochang

2017-09-01

We consider an inhomogeneous small-world network (SWN) composed of inhibitory short-range (SR) and long-range (LR) interneurons, and investigate the effect of network architecture on emergence of synchronized brain rhythms by varying the fraction of LR interneurons p long . The betweenness centralities of the LR and SR interneurons (characterizing the potentiality in controlling communication between other interneurons) are distinctly different. Hence, in view of the betweenness, SWNs we consider are inhomogeneous, unlike the "canonical" Watts-Strogatz SWN with nearly the same betweenness centralities. For small p long , the load of communication traffic is much concentrated on a few LR interneurons. However, as p long is increased, the number of LR connections (coming from LR interneurons) increases, and then the load of communication traffic is less concentrated on LR interneurons, which leads to better efficiency of global communication between interneurons. Sparsely synchronized rhythms are thus found to emerge when passing a small critical value p long (c) (≃0.16). The population frequency of the sparsely synchronized rhythm is ultrafast (higher than 100 Hz), while the mean firing rate of individual interneurons is much lower (∼30 Hz) due to stochastic and intermittent neural discharges. These dynamical behaviors in the inhomogeneous SWN are also compared with those in the homogeneous Watts-Strogatz SWN, in connection with their network topologies. Particularly, we note that the main difference between the two types of SWNs lies in the distribution of betweenness centralities. Unlike the case of the Watts-Strogatz SWN, dynamical responses to external stimuli vary depending on the type of stimulated interneurons in the inhomogeneous SWN. We consider two cases of external time-periodic stimuli applied to sub-populations of the LR and SR interneurons, respectively. Dynamical responses (such as synchronization suppression and enhancement) to these two cases of

Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

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Speed, Haley E; Masiulis, Irene; Gibson, Jay R; Powell, Craig M

2015-01-01

A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C) of Neuroligin 3 (NLGN3R451C) is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I) imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs) onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs) from parvalbumin-positive (PV) or somatostatin-positive (SOM) interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at interneurons

Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

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Haley E Speed

Full Text Available A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C of Neuroligin 3 (NLGN3R451C is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs from parvalbumin-positive (PV or somatostatin-positive (SOM interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at

Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies.

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White, Lon R; Edland, Steven D; Hemmy, Laura S; Montine, Kathleen S; Zarow, Chris; Sonnen, Joshua A; Uyehara-Lock, Jane H; Gelber, Rebecca P; Ross, G Webster; Petrovitch, Helen; Masaki, Kamal H; Lim, Kelvin O; Launer, Lenore J; Montine, Thomas J

2016-03-15

To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels. The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined. Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy. Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life. © 2016 American Academy of Neurology.

What Does Neuroscience and Cognitive Psychology Tell Us about Multiple Intelligence

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Bauer, Richard H.

2009-01-01

Studies that have used noninvasive brain imaging techniques to record neocortical activity while individuals were performing cognitive intelligence tests (traditional intelligence) and social intelligence tests were reviewed. In cognitive intelligence tests 16 neocortical areas were active, whereas in social intelligence 10 areas were active.…

Hyperexcitability and cell loss in kainate-treated hippocampal slice cultures

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Benedikz, Eirikur; Casaccia-Bonnefil, P; Stelzer, A

1993-01-01

Loss of hippocampal interneurons has been reported in patients with severe temporal lobe epilepsy and in animals treated with kainate. We investigated the relationship between KA induced epileptiform discharge and loss of interneurons in hippocampal slice cultures. Application of KA (1 micro......M) produced reversible epileptiform discharge without neurotoxicity. KA (5 microM), in contrast, produced irreversible epileptiform discharge and neurotoxicity, suggesting that the irreversible epileptiform discharge was required for the neuronal loss. Loss of CA3 pyramidal cells and parvalbumin......-like immunoreactive (PV-I) interneurons preceded loss of somatostatin-like immunoreactive (SS-I) interneurons suggesting a different time course of KA neurotoxicity in these subpopulations of interneurons....

A machine learning approach for the identification of key markers involved in brain development from single-cell transcriptomic data.

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Hu, Yongli; Hase, Takeshi; Li, Hui Peng; Prabhakar, Shyam; Kitano, Hiroaki; Ng, See Kiong; Ghosh, Samik; Wee, Lawrence Jin Kiat

2016-12-22

The ability to sequence the transcriptomes of single cells using single-cell RNA-seq sequencing technologies presents a shift in the scientific paradigm where scientists, now, are able to concurrently investigate the complex biology of a heterogeneous population of cells, one at a time. However, till date, there has not been a suitable computational methodology for the analysis of such intricate deluge of data, in particular techniques which will aid the identification of the unique transcriptomic profiles difference between the different cellular subtypes. In this paper, we describe the novel methodology for the analysis of single-cell RNA-seq data, obtained from neocortical cells and neural progenitor cells, using machine learning algorithms (Support Vector machine (SVM) and Random Forest (RF)). Thirty-eight key transcripts were identified, using the SVM-based recursive feature elimination (SVM-RFE) method of feature selection, to best differentiate developing neocortical cells from neural progenitor cells in the SVM and RF classifiers built. Also, these genes possessed a higher discriminative power (enhanced prediction accuracy) as compared commonly used statistical techniques or geneset-based approaches. Further downstream network reconstruction analysis was carried out to unravel hidden general regulatory networks where novel interactions could be further validated in web-lab experimentation and be useful candidates to be targeted for the treatment of neuronal developmental diseases. This novel approach reported for is able to identify transcripts, with reported neuronal involvement, which optimally differentiate neocortical cells and neural progenitor cells. It is believed to be extensible and applicable to other single-cell RNA-seq expression profiles like that of the study of the cancer progression and treatment within a highly heterogeneous tumour.

Hypocretin (orexin) regulates glutamate input to fast-spiking interneurons in layer V of the Fr2 region of the murine prefrontal cortex.

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Aracri, Patrizia; Banfi, Daniele; Pasini, Maria Enrica; Amadeo, Alida; Becchetti, Andrea

2015-05-01

We studied the effect of hypocretin 1 (orexin A) in the frontal area 2 (Fr2) of the murine neocortex, implicated in the motivation-dependent goal-directed tasks. In layer V, hypocretin stimulated the spontaneous excitatory postsynaptic currents (EPSCs) on fast-spiking (FS) interneurons. The effect was accompanied by increased frequency of miniature EPSCs, indicating that hypocretin can target the glutamatergic terminals. Moreover, hypocretin stimulated the spontaneous inhibitory postsynaptic currents (IPSCs) on pyramidal neurons, with no effect on miniature IPSCs. This action was prevented by blocking 1) the ionotropic glutamatergic receptors; 2) the hypocretin receptor type 1 (HCRTR-1), with SB-334867. Finally, hypocretin increased the firing frequency in FS cells, and the effect was blocked when the ionotropic glutamate transmission was inhibited. Immunolocalization confirmed that HCRTR-1 is highly expressed in Fr2, particularly in layer V-VI. Conspicuous labeling was observed in pyramidal neuron somata and in VGLUT1+ glutamatergic terminals, but not in VGLUT2+ fibers (mainly thalamocortical afferents). The expression of HCRTR-1 in GABAergic structures was scarce. We conclude that 1) hypocretin regulates glutamate release in Fr2; 2) the effect presents a presynaptic component; 3) the peptide control of FS cells is indirect, and probably mediated by the regulation of glutamatergic input onto these cells. © The Author 2013. Published by Oxford University Press.

Towards deep learning with segregated dendrites.

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Guerguiev, Jordan; Lillicrap, Timothy P; Richards, Blake A

2017-12-05

Deep learning has led to significant advances in artificial intelligence, in part, by adopting strategies motivated by neurophysiology. However, it is unclear whether deep learning could occur in the real brain. Here, we show that a deep learning algorithm that utilizes multi-compartment neurons might help us to understand how the neocortex optimizes cost functions. Like neocortical pyramidal neurons, neurons in our model receive sensory information and higher-order feedback in electrotonically segregated compartments. Thanks to this segregation, neurons in different layers of the network can coordinate synaptic weight updates. As a result, the network learns to categorize images better than a single layer network. Furthermore, we show that our algorithm takes advantage of multilayer architectures to identify useful higher-order representations-the hallmark of deep learning. This work demonstrates that deep learning can be achieved using segregated dendritic compartments, which may help to explain the morphology of neocortical pyramidal neurons.

Evidence for holistic episodic recollection via hippocampal pattern completion.

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Horner, Aidan J; Bisby, James A; Bush, Daniel; Lin, Wen-Jing; Burgess, Neil

2015-07-02

Recollection is thought to be the hallmark of episodic memory. Here we provide evidence that the hippocampus binds together the diverse elements forming an event, allowing holistic recollection via pattern completion of all elements. Participants learn complex 'events' from multiple overlapping pairs of elements, and are tested on all pairwise associations. At encoding, element 'types' (locations, people and objects/animals) produce activation in distinct neocortical regions, while hippocampal activity predicts memory performance for all within-event pairs. When retrieving a pairwise association, neocortical activity corresponding to all event elements is reinstated, including those incidental to the task. Participant's degree of incidental reinstatement correlates with their hippocampal activity. Our results suggest that event elements, represented in distinct neocortical regions, are bound into coherent 'event engrams' in the hippocampus that enable episodic recollection--the re-experiencing or holistic retrieval of all aspects of an event--via a process of hippocampal pattern completion and neocortical reinstatement.

Mirror Neurons Modeled Through Spike-Timing-Dependent Plasticity are Affected by Channelopathies Associated with Autism Spectrum Disorder.

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Antunes, Gabriela; Faria da Silva, Samuel F; Simoes de Souza, Fabio M

2018-06-01

Mirror neurons fire action potentials both when the agent performs a certain behavior and watches someone performing a similar action. Here, we present an original mirror neuron model based on the spike-timing-dependent plasticity (STDP) between two morpho-electrical models of neocortical pyramidal neurons. Both neurons fired spontaneously with basal firing rate that follows a Poisson distribution, and the STDP between them was modeled by the triplet algorithm. Our simulation results demonstrated that STDP is sufficient for the rise of mirror neuron function between the pairs of neocortical neurons. This is a proof of concept that pairs of neocortical neurons associating sensory inputs to motor outputs could operate like mirror neurons. In addition, we used the mirror neuron model to investigate whether channelopathies associated with autism spectrum disorder could impair the modeled mirror function. Our simulation results showed that impaired hyperpolarization-activated cationic currents (Ih) affected the mirror function between the pairs of neocortical neurons coupled by STDP.

Gene expression profiling of two distinct neuronal populations in the rodent spinal cord.

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Jesper Ryge

Full Text Available BACKGROUND: In the field of neuroscience microarray gene expression profiles on anatomically defined brain structures are being used increasingly to study both normal brain functions as well as pathological states. Fluorescent tracing techniques in brain tissue that identifies distinct neuronal populations can in combination with global gene expression profiling potentially increase the resolution and specificity of such studies to shed new light on neuronal functions at the cellular level. METHODOLOGY/PRINCIPAL FINDINGS: We examine the microarray gene expression profiles of two distinct neuronal populations in the spinal cord of the neonatal rat, the principal motor neurons and specific interneurons involved in motor control. The gene expression profiles of the respective cell populations were obtained from amplified mRNA originating from 50-250 fluorescently identified and laser microdissected cells. In the data analysis we combine a new microarray normalization procedure with a conglomerate measure of significant differential gene expression. Using our methodology we find 32 genes to be more expressed in the interneurons compared to the motor neurons that all except one have not previously been associated with this neuronal population. As a validation of our method we find 17 genes to be more expressed in the motor neurons than in the interneurons and of these only one had not previously been described in this population. CONCLUSIONS/SIGNIFICANCE: We provide an optimized experimental protocol that allows isolation of gene transcripts from fluorescent retrogradely labeled cell populations in fresh tissue, which can be used to generate amplified aRNA for microarray hybridization from as few as 50 laser microdissected cells. Using this optimized experimental protocol in combination with our microarray analysis methodology we find 49 differentially expressed genes between the motor neurons and the interneurons that reflect the functional

A neural network to improve dim-light vision? Dendritic fields of first-order interneurons in the nocturnal bee Megalopta genalis.

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Greiner, Birgit; Ribi, Willi A; Warrant, Eric J

2005-11-01

Using the combined Golgi-electron microscopy technique, we have determined the three-dimensional dendritic fields of the short visual fibres (svf 1-3) and first-order interneurons or L-fibres (L1-4) within the first optic ganglion (lamina) of the nocturnal bee Megalopta genalis. Serial cross sections have revealed that the svf type 2 branches into one adjacent neural unit (cartridge) in layer A, the most distal of the three lamina layers A, B and C. All L-fibres, except L1-a, exhibit wide lateral branching into several neighbouring cartridges. L1-b shows a dendritic field of seven cartridges in layers A and C, dendrites of L2 target 13 cartridges in layer A, L3 branches over a total of 12 cartridges in layer A and three in layer C and L4 has the largest dendritic field size of 18 cartridges in layer C. The number of cartridges reached by the respective L-fibres is distinctly greater in the nocturnal bee than in the worker honeybee and is larger than could be estimated from our previous Golgi-light microscopy study. The extreme dorso-ventrally oriented dendritic field of L4 in M. genalis may, in addition to its potential role in spatial summation, be involved in edge detection. Thus, we have shown that the amount of lateral spreading present in the lamina provides the anatomical basis for the required spatial summation. Theoretical and future physiological work should further elucidate the roles that this lateral spreading plays to improve dim-light vision in nocturnal insects.

Spinal interneurons differentiate sequentially from those driving the fastest swimming movements in larval zebrafish to those driving the slowest ones.

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McLean, David L; Fetcho, Joseph R

2009-10-28

Studies of neuronal networks have revealed few general principles that link patterns of development with later functional roles. While investigating the neural control of movements, we recently discovered a topographic map in the spinal cord of larval zebrafish that relates the position of motoneurons and interneurons to their order of recruitment during swimming. Here, we show that the map reflects an orderly pattern of differentiation of neurons driving different movements. First, we use high-speed filming to show that large-amplitude swimming movements with bending along much of the body appear first, with smaller, regional swimming movements emerging later. Next, using whole-cell patch recordings, we demonstrate that the excitatory circuits that drive large-amplitude, fast swimming movements at larval stages are present and functional early on in embryos. Finally, we systematically assess the orderly emergence of spinal circuits according to swimming speed using transgenic fish expressing the photoconvertible protein Kaede to track neuronal differentiation in vivo. We conclude that a simple principle governs the development of spinal networks in which the neurons driving the fastest, most powerful swimming in larvae develop first with ones that drive increasingly weaker and slower larval movements layered on over time. Because the neurons are arranged by time of differentiation in the spinal cord, the result is a topographic map that represents the speed/strength of movements at which neurons are recruited and the temporal emergence of networks. This pattern may represent a general feature of neuronal network development throughout the brain and spinal cord.

Sim1 is required for the migration and axonal projections of V3 interneurons in the developing mouse spinal cord.

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Blacklaws, Jake; Deska-Gauthier, Dylan; Jones, Christopher T; Petracca, Yanina L; Liu, Mingwei; Zhang, Han; Fawcett, James P; Glover, Joel C; Lanuza, Guillermo M; Zhang, Ying

2015-09-01

V3 spinal interneurons (INs) are a group of excitatory INs that play a crucial role in producing balanced and stable gaits in vertebrate animals. In the developing mouse spinal cord, V3 INs arise from the most ventral progenitor domain and form anatomically distinctive subpopulations in adult spinal cords. They are marked by the expression of transcription factor Sim1 postmitotically, but the function of Sim1 in V3 development remains unknown. Here, we used Sim1(Cre) ;tdTomato mice to trace the fate of V3 INs in a Sim1 mutant versus control genetic background during development. In Sim1 mutants, V3 INs are produced normally and maintain a similar position and organization as in wild types before E12.5. Further temporal analysis revealed that the V3 INs in the mutants failed to migrate properly to form V3 subgroups along the dorsoventral axis of the spinal cord. At birth, in the Sim1 mutant the number of V3 INs in the ventral subgroup was normal, but they were significantly reduced in the dorsal subgroup with a concomitant increase in the intermediate subgroup. Retrograde labeling at lumbar level revealed that loss of Sim1 led to a reduction in extension of contralateral axon projections both at E14.5 and P0 without affecting ipsilateral axon projections. These results demonstrate that Sim1 is essential for proper migration and the guidance of commissural axons of the spinal V3 INs. © 2015 Wiley Periodicals, Inc.

Food deprivation and prior anoxic coma have opposite effects on the activity of a visual interneuron in the locust.

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Cross, Kevin P; Britton, Samantha; Mangulins, Rebecca; Money, Tomas G A; Robertson, R Meldrum

2017-04-01

We compared how different metabolic stressors, anoxic coma and food deprivation, affected signaling in neural tissue. We used the locust's Descending Contralateral Movement Detector (DCMD) interneuron because its large axon, high firing frequencies, and rapid conduction velocity make it energetically expensive. We exposed locusts to a 30min anoxic coma or 1day of food deprivation and found contrasting effects on signaling within the axon. After a prior anoxic coma, the DCMD fired fewer high-frequency (>200Hz) action potentials (APs) (Control: 12.4±1.6; Coma: 6.3±0.9) with a reduction in axonal conduction velocity (CV) at all frequencies (∼4-8%) when presented with a standard looming visual stimulus. Prior anoxic coma was also associated with a loss of supernormal conduction by reducing both the number of supernormal APs and the firing frequency with the highest CV. Initially, food deprivation caused a significant increase in the number of low- and high-frequency APs with no differences observed in CV. After controlling for isolation, food deprivation resulted in an increase in high-frequency APs (>200Hz: Control: 17.1±1.7; Food-deprived: 19.9±1.3) and an increase in relative conduction velocity for frequencies >150Hz (∼2%). Action potentials of food-deprived animals had a smaller half-width (Control: 0.45±0.02ms; Food-deprived: 0.40±0.01ms) and decay time (Control: 0.62±0.03ms; Food-deprived: 0.54±0.02ms). Our data indicate that the effects of metabolic stress on neural signaling can be stressor-dependent. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modelling the cognitive and neuropathological features of schizophrenia with phencyclidine.

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Reynolds, Gavin P; Neill, Joanna C

2016-11-01

Here, Reynolds and Neill describe the studies that preceded and followed publication of this paper, which reported a deficit in parvalbumin (PV), a calcium-binding protein found in GABA interneurons known to be reduced in schizophrenia patients, in conjunction with a deficit in reversal learning in an animal model for schizophrenia. This publication resulted from common research interests: Reynolds in the neurotransmitter pathology of schizophrenia, and Neill in developing animal models for schizophrenia symptomatology. The animal model, using a sub-chronic dosing regimen (sc) with the non-competitive NMDA receptor antagonist PCP (phencyclidine), evolved from previous work in rats (for PCP) and primates (for cognition). The hypothesis of a PV deficit came from emerging evidence for a GABAergic dysfunction in schizophrenia, in particular a deficit in PV-containing GABA interneurons. Since this original publication, a PV deficit has been identified in other animal models for schizophrenia, and the PV field has expanded considerably. This includes mechanistic work attempting to identify the link between oxidative stress and GABAergic dysfunction using this scPCP model, and assessment of the potential of the PV neuron as a target for new antipsychotic drugs. The latter has included development of a molecule targeting KV3.1 channels located on PV-containing GABA interneurons which can restore both PV expression and cognitive deficits in the scPCP model. © The Author(s) 2016.

The complexity of the calretinin-expressing progenitors in the human cerebral cortex

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Nevena V Radonjic

2014-08-01

Full Text Available The complex structure and function of the cerebral cortex critically depend on the balance of excitation and inhibition provided by the pyramidal projection neurons and GABAergic interneurons, respectively. The calretinin-expressing (CalR+ cell is a subtype of GABAergic cortical interneurons that is more prevalent in humans than in rodents. In rodents, CalR+ interneurons originate in the caudal ganglionic eminence (CGE from Gsx2+ progenitors, but in humans it has been suggested that a subpopulation of CalR+ cells can also be generated in the cortical ventricular/subventricular zone (VZ/SVZ. The progenitors for cortically generated CalR+ subpopulation in primates are not yet characterized. Hence, the aim of this study was to identify patterns of expression of the transcription factors (TFs that commit cortical stem cells to the CalR fate, with a focus on Gsx2. First, we studied the expression of Gsx2 and its downstream effectors, Ascl1 and Sp8 in the cortical regions of the fetal human forebrain at midgestation. Next, we established that a subpopulation of cells expressing these TFs are proliferating in the cortical SVZ, and can be co-labeled with CalR. The presence and proliferation of Gsx2+ cells, not only in the ventral telencephalon (GE as previously reported, but also in the cerebral cortex suggests cortical origin of a subpopulation of CalR+ neurons in humans. In vitro treatment of human cortical progenitors with Sonic hedgehog (Shh, an important morphogen in the specification of interneurons, decreased levels of Ascl1 and Sp8 proteins, but did not affect Gsx2 levels. Taken together, our ex-vivo and in vitro results on human fetal brain suggest complex endogenous and exogenous regulation of TFs implied in the specification of different subtypes of CalR+ cortical interneurons.

Roles of molecular layer interneurons in sensory information processing in mouse cerebellar cortex Crus II in vivo.

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Chun-Ping Chu

Full Text Available Cerebellar cortical molecular layer interneurons (MLIs play essential roles in sensory information processing by the cerebellar cortex. However, recent experimental and modeling results are questioning traditional roles for molecular layer inhibition in the cerebellum.Synaptic responses of MLIs and Purkinje cells (PCs, evoked by air-puff stimulation of the ipsilateral whisker pad were recorded from cerebellar cortex Crus II in urethane-anesthetized ICR mice by in vivo whole-cell patch-clamp recording techniques. Under current-clamp (I = 0, air-puff stimuli were found to primarily produce inhibition in PCs. In MLIs, this stimulus evoked spike firing regardless of whether they made basket-type synaptic connections or not. However, MLIs not making basket-type synaptic connections had higher rates of background activity and also generated spontaneous spike-lets. Under voltage-clamp conditions, excitatory postsynaptic currents (EPSCs were recorded in MLIs, although the predominant response of recorded PCs was an inhibitory postsynaptic potential (IPSP. The latencies of EPSCs were similar for all MLIs, but the time course and amplitude of EPSCs varied with depth in the molecular layer. The highest amplitude, shortest duration EPSCs were recorded from MLIs deep in the molecular layer, which also made basket-type synaptic connections. Comparing MLI to PC responses, time to peak of PC IPSP was significantly slower than MLI recorded EPSCs. Blocking GABA(A receptors uncovered larger EPSCs in PCs whose time to peak, half-width and 10-90% rising time were also significantly slower than in MLIs. Biocytin labeling indicated that the MLIs (but not PCs are dye-coupled.These findings indicate that tactile face stimulation evokes rapid excitation in MLIs and inhibition occurring at later latencies in PCs in mouse cerebellar cortex Crus II. These results support previous suggestions that the lack of parallel fiber driven PC activity is due to the effect

Learning-enhanced coupling between ripple oscillations in association cortices and hippocampus.

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Khodagholy, Dion; Gelinas, Jennifer N; Buzsáki, György

2017-10-20

Consolidation of declarative memories requires hippocampal-neocortical communication. Although experimental evidence supports the role of sharp-wave ripples in transferring hippocampal information to the neocortex, the exact cortical destinations and the physiological mechanisms of such transfer are not known. We used a conducting polymer-based conformable microelectrode array (NeuroGrid) to record local field potentials and neural spiking across the dorsal cortical surface of the rat brain, combined with silicon probe recordings in the hippocampus, to identify candidate physiological patterns. Parietal, midline, and prefrontal, but not primary cortical areas, displayed localized ripple (100 to 150 hertz) oscillations during sleep, concurrent with hippocampal ripples. Coupling between hippocampal and neocortical ripples was strengthened during sleep following learning. These findings suggest that ripple-ripple coupling supports hippocampal-association cortical transfer of memory traces. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Accumulation of GABAergic neurons, causing a focal ambient GABA gradient, and downregulation of KCC2 are induced during microgyrus formation in a mouse model of polymicrogyria.

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Wang, Tianying; Kumada, Tatsuro; Morishima, Toshitaka; Iwata, Satomi; Kaneko, Takeshi; Yanagawa, Yuchio; Yoshida, Sachiko; Fukuda, Atsuo

2014-04-01

Although focal cortical malformations are considered neuronal migration disorders, their formation mechanisms remain unknown. We addressed how the γ-aminobutyric acid (GABA)ergic system affects the GABAergic and glutamatergic neuronal migration underlying such malformations. A focal freeze-lesion (FFL) of the postnatal day zero (P0) glutamic acid decarboxylase-green fluorescent protein knock-in mouse neocortex produced a 3- or 4-layered microgyrus at P7. GABAergic interneurons accumulated around the necrosis including the superficial region during microgyrus formation at P4, whereas E17.5-born, Cux1-positive pyramidal neurons outlined the GABAergic neurons and were absent from the superficial layer, forming cell-dense areas in layer 2 of the P7 microgyrus. GABA imaging showed that an extracellular GABA level temporally increased in the GABAergic neuron-positive area, including the necrotic center, at P4. The expression of the Cl(-) transporter KCC2 was downregulated in the microgyrus-forming GABAergic and E17.5-born glutamatergic neurons at P4; these cells may need a high intracellular Cl(-) concentration to induce depolarizing GABA effects. Bicuculline decreased the frequency of spontaneous Ca(2+) oscillations in these microgyrus-forming cells. Thus, neonatal FFL causes specific neuronal accumulation, preceded by an increase in ambient GABA during microgyrus formation. This GABA increase induces GABAA receptor-mediated Ca(2+) oscillation in KCC2-downregulated microgyrus-forming cells, as seen in migrating cells during early neocortical development.

Dual Gamma Rhythm Generators Control Interlaminar Synchrony in Auditory Cortex

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Ainsworth, Matthew; Lee, Shane; Cunningham, Mark O.; Roopun, Anita K.; Traub, Roger D.; Kopell, Nancy J.; Whittington, Miles A.

2013-01-01

Rhythmic activity in populations of cortical neurons accompanies, and may underlie, many aspects of primary sensory processing and short-term memory. Activity in the gamma band (30 Hz up to > 100 Hz) is associated with such cognitive tasks and is thought to provide a substrate for temporal coupling of spatially separate regions of the brain. However, such coupling requires close matching of frequencies in co-active areas, and because the nominal gamma band is so spectrally broad, it may not constitute a single underlying process. Here we show that, for inhibition-based gamma rhythms in vitro in rat neocortical slices, mechanistically distinct local circuit generators exist in different laminae of rat primary auditory cortex. A persistent, 30 – 45 Hz, gap-junction-dependent gamma rhythm dominates rhythmic activity in supragranular layers 2/3, whereas a tonic depolarization-dependent, 50 – 80 Hz, pyramidal/interneuron gamma rhythm is expressed in granular layer 4 with strong glutamatergic excitation. As a consequence, altering the degree of excitation of the auditory cortex causes bifurcation in the gamma frequency spectrum and can effectively switch temporal control of layer 5 from supragranular to granular layers. Computational modeling predicts the pattern of interlaminar connections may help to stabilize this bifurcation. The data suggest that different strategies are used by primary auditory cortex to represent weak and strong inputs, with principal cell firing rate becoming increasingly important as excitation strength increases. PMID:22114273

Cortical GABAergic excitation contributes to epileptic activities around human glioma

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Pallud, Johan; Varlet, Pascale; Cresto, Noemie; Baulac, Michel; Duyckaerts, Charles; Kourdougli, Nazim; Chazal, Geneviève; Devaux, Bertrand; Rivera, Claudio; Miles, Richard; Capelle, Laurent; Huberfeld, Gilles

2015-01-01

Rationale Diffuse brain gliomas induce seizures in a majority of patients. As in most epileptic disorders, excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glial tumor cells. Thus the contribution of GABAergic mechanisms which depend on intracellular chloride and which are defective or pro-epileptic in other structural epilepsies merits closer study. Objective We studied in neocortical slices from the peritumoral security margin resected around human brain gliomas, the occurrence, networks, cells and signaling basis of epileptic activities. Results Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges. These events were synchronized, with a high frequency oscillation signature, in superficial layers of neocortex around glioma areas with tumor infiltration. Interictal-like events depended on both glutamatergic transmission and on depolarizing GABAergic signaling. About 65% of pyramidal cells were depolarized by GABA released by interneurons. This effect was related to perturbations in Chloride homeostasis, due to changes in expression of chloride co-transporters: KCC2 was reduced and expression of NKCC1 increased. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. Conclusions Epileptic activities are sustained by excitatory effects of GABA in the peritumoral human neocortex, as in temporal lobe epilepsies. Glutamate and GABA signaling are involved in oncogenesis and chloride homeostasis is perturbed. These same factors, induce an imbalance between synaptic excitatory and inhibition underly epileptic discharges in tumor patients. PMID:25009229

Regulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene Dysbindin-1.

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Yuan, Qiang; Yang, Feng; Xiao, Yixin; Tan, Shawn; Husain, Nilofer; Ren, Ming; Hu, Zhonghua; Martinowich, Keri; Ng, Julia S; Kim, Paul J; Han, Weiping; Nagata, Koh-Ichi; Weinberger, Daniel R; Je, H Shawn

2016-08-15

Genetic variations in dystrobrevin binding protein 1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in Dtnbp1 in mice disrupted both glutamatergic and gamma-aminobutyric acidergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs. However, the mechanism by which reduced dysbindin-1 activity causes inhibitory synaptic deficits remains unknown. We investigated the role of dysbindin-1 in the exocytosis of brain-derived neurotrophic factor (BDNF) from cortical excitatory neurons, organotypic brain slices, and acute slices from dysbindin-1 mutant mice and determined how this change in BDNF exocytosis transsynaptically affected the number of inhibitory synapses formed on excitatory neurons via whole-cell recordings, immunohistochemistry, and live-cell imaging using total internal reflection fluorescence microscopy. A decrease in dysbindin-1 reduces the exocytosis of BDNF from cortical excitatory neurons, and this reduction in BDNF exocytosis transsynaptically resulted in reduced inhibitory synapse numbers formed on excitatory neurons. Furthermore, application of exogenous BDNF rescued the inhibitory synaptic deficits caused by the reduced dysbindin-1 level in both cultured cortical neurons and slice cultures. Taken together, our results demonstrate that these two genes linked to risk for schizophrenia (BDNF and dysbindin-1) function together to regulate interneuron development and cortical network activity. This evidence supports the investigation of the association between dysbindin-1 and BDNF in humans with schizophrenia. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Fast gamma oscillations are generated intrinsically in CA1 without the involvement of fast-spiking basket cells.

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Craig, Michael T; McBain, Chris J

2015-02-25

Information processing in neuronal networks relies on the precise synchronization of ensembles of neurons, coordinated by the diverse family of inhibitory interneurons. Cortical interneurons can be usefully parsed by embryonic origin, with the vast majority arising from either the caudal or medial ganglionic eminences (CGE and MGE). Here, we examine the activity of hippocampal interneurons during gamma oscillations in mouse CA1, using an in vitro model where brief epochs of rhythmic activity were evoked by local application of kainate. We found that this CA1 KA-evoked gamma oscillation was faster than that in CA3 and, crucially, did not appear to require the involvement of fast-spiking basket cells. In contrast to CA3, we also found that optogenetic inhibition of pyramidal cells in CA1 did not significantly affect the power of the oscillation, suggesting that excitation may not be essential for gamma genesis in this region. We found that MGE-derived interneurons were generally more active than CGE interneurons during CA1 gamma, although a group of CGE-derived interneurons, putative trilaminar cells, were strongly phase-locked with gamma oscillations and, together with MGE-derived axo-axonic and bistratified cells, provide attractive candidates for being the driver of this locally generated, predominantly interneuron-driven model of gamma oscillations. Copyright © 2015 the authors 0270-6474/15/353616-09$15.00/0.

The role of the intrinsic cholinergic system of the striatum: What have we learned from TAN recordings in behaving animals?

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Apicella, Paul

2017-09-30

Cholinergic interneurons provide rich local innervation of the striatum and play an important role in controlling behavior, as evidenced by the variety of movement and psychiatric disorders linked to disrupted striatal cholinergic transmission. Much progress has been made in recent years regarding our understanding of how these interneurons contribute to the processing of information in the striatum. In particular, investigation of the activity of presumed striatal cholinergic interneurons, identified as tonically active neurons or TANs in behaving animals, has pointed to their role in the signaling and learning of the motivational relevance of environmental stimuli. Although the bulk of this work has been conducted in monkeys, several studies have also been carried out in behaving rats, but information remains rather disparate across studies and it is still questionable whether rodent TANs correspond to TANs described in monkeys. Consequently, our current understanding of the function of cholinergic transmission in the striatum is challenged by the rapidly growing, but often confusing literature on the relationship between TAN activity and specific behaviors. As regards the precise nature of the information conveyed by the cholinergic TANs, a recent influential view emphasized that these local circuit neurons may play a special role in the processing of contextual information that is important for reinforcement learning and selection of appropriate actions. This review provides a summary of recent progress in TAN physiology from which it is proposed that striatal cholinergic interneurons are crucial elements for flexible switching of behaviors under changing environmental conditions. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Ectopic Expression of α6 and δ GABAA Receptor Subunits in Hilar Somatostatin Neurons Increases Tonic Inhibition and Alters Network Activity in the Dentate Gyrus

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Tong, Xiaoping; Peng, Zechun; Zhang, Nianhui; Cetina, Yliana; Huang, Christine S.; Wallner, Martin; Otis, Thomas S.

2015-01-01

The role of GABAA receptor (GABAAR)-mediated tonic inhibition in interneurons remains unclear and may vary among subgroups. Somatostatin (SOM) interneurons in the hilus of the dentate gyrus show negligible expression of nonsynaptic GABAAR subunits and very low tonic inhibition. To determine the effects of ectopic expression of tonic GABAAR subtypes in these neurons, Cre-dependent viral vectors were used to express GFP-tagged GABAAR subunits (α6 and δ) selectively in hilar SOM neurons in SOM-Cre mice. In single-transfected animals, immunohistochemistry demonstrated strong expression of either the α6 or δ subunit; in cotransfected animals, both subunits were consistently expressed in the same neurons. Electrophysiology revealed a robust increase of tonic current, with progressively larger increases following transfection of δ, α6, and α6/δ subunits, respectively, indicating formation of functional receptors in all conditions and likely coassembly of the subunits in the same receptor following cotransfection. An in vitro model of repetitive bursting was used to determine the effects of increased tonic inhibition in hilar SOM interneurons on circuit activity in the dentate gyrus. Upon cotransfection, the frequency of GABAAR-mediated bursting in granule cells was reduced, consistent with a reduction in synchronous firing among hilar SOM interneurons. Moreover, in vivo studies of Fos expression demonstrated reduced activation of α6/δ-cotransfected neurons following acute seizure induction by pentylenetetrazole. The findings demonstrate that increasing tonic inhibition in hilar SOM interneurons can alter dentate gyrus circuit activity during strong stimulation and suggest that tonic inhibition of interneurons could play a role in regulating excessive synchrony within the network. SIGNIFICANCE STATEMENT In contrast to many hippocampal interneurons, somatostatin (SOM) neurons in the hilus of the dentate gyrus have very low levels of nonsynaptic GABAARs and exhibit

Citicoline. Ferrer Internacional.

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Alexandrov, A V

2001-12-01

Citicoline was originally developed and launched by Ferrer for the treatment of stroke, and is now also being investigated for the potential treatment of Alzheimer's disease (AD). In the US, the compound is being developed by Interneuron for the treatment of stroke. A US launch had been rescheduled for 2002 although a decision on future US development of citicoline was intended to be made in conjunction with Takeda, Interneuron's US licensee. Takeda had decided not to pursue development by December 2000 and was in negotiations with Interneuron for another product candidate. Interneuron stated at this time that it would explore other partnership opportunities for citicoline. In 1993, Interneuron licensed exclusive marketing and manufacturing rights to citicoline in the US and Canada from Ferrer. By September 1997, a patent application had been filed worldwide by Interneuron for the use of citicoline in the reduction of cerebral infarct volume, and in September 1998, US-05801160 was issued for citicoline relating to the protection of brain tissue from cerebral infarction following ischemic stroke. In December 1999, US rights to the commercialization of citicoline were licensed to Takeda.

Hippocampal and neocortical metabolite ratio in patients with complex partial seizure: short TE and long TE techniques using single voxel proton MR spectroscopy

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Chung, Jin Il; Kim, Dong Ik; Lee, Byung In; Lee, Seung Ik; Yoon, Pyeong Ho [Medical College, Yonsei University, Seoul (Korea, Republic of)

2000-08-01

To compare hippocampal and neocortical metabolite ratios using single-voxel proton MR spectroscopy with different echo times in patients with complex partial seizure. Using a GE Signa 1.5T scanner with STEAM and PRESS sequences, automated single voxel proton MRS was used to determine metabolite ratio differences in the hippocampus and neocortex of nine complex partial seizure patients (mesial temporal sclerosis (n=3D5), status epilepticus (n=3D1), tumor (n=3D1), cortical dysplasia (n=3D1), occipital lobe epilepsy (n=3D1)). A total of 20 examinations were performed in the region of the hippocampus (n=3D17), temporal neocortex (n=3D1), and parieto-occipital gray matter (n=3D1). Voxel size range was 5.2-17.4 cm{sup 3}. The calculated creatine (Cr) peak was employed as an internal reference and the relative ratio of N-acetylaspartate (NAA) and choline (Cho) was calculated for both short and long echo times using an automated PROBE/SV (GE Medical Systems) package. Each NAA/Cho ratio obtained using both PRESS and STEAM techniques was compared by means of statistical analysis (paired Student t-test). Using PRESS (long TE, 272 ms), NAA/Cho ratios were successfully calculated in 16 of 20 examinations; in four this was not possible due to noise levels of the Cr and Cho peaks. Using STEAM (short TE, 30 ms) NAA/Cho ratios were successfully calculated in 19 of 20 examinations; in one, the Cho peak could not be measured. Using PRESS and STEAM, mean and standard deviations for the NAA/Cho ratio were 1.22{+-}0.50 and 1.16{+-}0.36, respectively. There were no statistically significant differences in this ratio between the short and long TE method (p less than 0.01). In complex partial seizure patients, no significant metabolite differences were found between short and long echo times of single voxel proton MR spectroscopy. The metabolite ratio at different echo times can be reliably obtained using this simplified and automated PROBE/SV quantitation method. (author)

Temporal Lobe Epilepsy Surgery Failures: A Review

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Harroud, Adil; Bouthillier, Alain; Weil, Alexander G.; Nguyen, Dang Khoa

2012-01-01

Patients with temporal lobe epilepsy (TLE) are refractory to antiepileptic drugs in about 30% of cases. Surgical treatment has been shown to be beneficial for the selected patients but fails to provide a seizure-free outcome in 20–30% of TLE patients. Several reasons have been identified to explain these surgical failures. This paper will address the five most common causes of TLE surgery failure (a) insufficient resection of epileptogenic mesial temporal structures, (b) relapse on the contralateral mesial temporal lobe, (c) lateral temporal neocortical epilepsy, (d) coexistence of mesial temporal sclerosis and a neocortical lesion (dual pathology); and (e) extratemporal lobe epilepsy mimicking TLE or temporal plus epilepsy. Persistence of epileptogenic mesial structures in the posterior temporal region and failure to distinguish mesial and lateral temporal epilepsy are possible causes of seizure persistence after TLE surgery. In cases of dual pathology, failure to identify a subtle mesial temporal sclerosis or regions of cortical microdysgenesis is a likely explanation for some surgical failures. Extratemporal epilepsy syndromes masquerading as or coexistent with TLE result in incomplete resection of the epileptogenic zone and seizure relapse after surgery. In particular, the insula may be an important cause of surgical failure in patients with TLE. PMID:22934162

Short-latency crossed responses in the human biceps femoris muscle

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Stevenson, Andrew J T; Kamavuako, Ernest N; Geertsen, Svend Sparre

2015-01-01

Interlimb reflexes contribute to the central neural coordination between different limbs in both humans and animals. Although commissural interneurons have only been directly identified in animals, spinally mediated interlimb reflexes have been discovered in a number of human lower limb muscles......, indicating their existence in humans. The aim of the present study was to investigate whether short-latency crossed-spinal reflexes are present in the contralateral biceps femoris (cBF) muscle following ipsilateral knee (iKnee) joint rotations during a sitting task, where participants maintained a slight pre...... pathways (likely involving commissural interneurons) from ipsilateral afferents to common motoneurons in the contralateral leg can likely explain the perturbation direction-dependent reversal in the sign of the short-latency cBF reflex. This article is protected by copyright. All rights reserved....

Sleep spindle-related reactivation of category-specific cortical regions after learning face-scene associations

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Bergmann, Til O; Mölle, Matthias; Diedrichs, Jens

2012-01-01

Newly acquired declarative memory traces are believed to be reactivated during NonREM sleep to promote their hippocampo-neocortical transfer for long-term storage. Yet it remains a major challenge to unravel the underlying neuronal mechanisms. Using simultaneous electroencephalography (EEG......-coupled reactivation of brain regions representing the specific task stimuli was traced during subsequent NonREM sleep with EEG-informed fMRI. Relative to the control task, learning face-scene associations triggered a stronger combined activation of neocortical and hippocampal regions during subsequent sleep. Notably......) and functional magnetic resonance imaging (fMRI) recordings in humans, we show that sleep spindles play a key role in the reactivation of memory-related neocortical representations. On separate days, participants either learned face-scene associations or performed a visuomotor control task. Spindle...

Neuropeptide receptors NPR-1 and NPR-2 regulate Caenorhabditis elegans avoidance response to the plant stress hormone methyl salicylate.

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Luo, Jintao; Xu, Zhaofa; Tan, Zhiping; Zhang, Zhuohua; Ma, Long

2015-02-01

Methyl salicylate (MeSa) is a stress hormone released by plants under attack by pathogens or herbivores . MeSa has been shown to attract predatory insects of herbivores and repel pests. The molecules and neurons underlying animal response to MeSa are not known. Here we found that the nematode Caenorhabditis elegans exhibits a strong avoidance response to MeSa, which requires the activities of two closely related neuropeptide receptors NPR-1 and NPR-2. Molecular analyses suggest that NPR-1 expressed in the RMG inter/motor neurons is required for MeSa avoidance. An NPR-1 ligand FLP-18 is also required. Using a rescuing npr-2 promoter to drive a GFP transgene, we identified that NPR-2 is expressed in multiple sensory and interneurons. Genetic rescue experiments suggest that NPR-2 expressed in the AIZ interneurons is required for MeSa avoidance. We also provide evidence that the AWB sensory neurons might act upstream of RMGs and AIZs to detect MeSa. Our results suggest that NPR-2 has an important role in regulating animal behavior and that NPR-1 and NPR-2 act on distinct interneurons to affect C. elegans avoidance response to MeSa. Copyright © 2015 by the Genetics Society of America.

Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

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David Ladrón de Guevara-Miranda

2017-03-01

Full Text Available Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV+ and neuropeptide Y (NPY+ interneurons and adult neurogenesis (cell proliferation and immature neurons] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal.

Optogenetic analysis of a nociceptor neuron and network reveals ion channels acting downstream of primary sensors

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Husson, Steven J.; Costa, Wagner Steuer; Wabnig, Sebastian; Stirman, Jeffrey N.; Watson, Joseph D.; Spencer, W. Clay; Akerboom, Jasper; Looger, Loren L.; Treinin, Millet; Miller, David M.; Lu, Hang; Gottschalk, Alexander

2012-01-01

Summary Background Nociception generally evokes rapid withdrawal behavior in order to protect the tissue from harmful insults. Most nociceptive neurons responding to mechanical insults display highly branched dendrites, an anatomy shared by Caenorhabditis elegans FLP and PVD neurons, which mediate harsh touch responses. Although several primary molecular nociceptive sensors have been characterized, less is known about modulation and amplification of noxious signals within nociceptor neurons. First, we analyzed the FLP/PVD network by optogenetics and studied integration of signals from these cells in downstream interneurons. Second, we investigated which genes modulate PVD function, based on prior single neuron mRNA profiling of PVD. Results Selectively photoactivating PVD, FLP and downstream interneurons using Channelrhodopsin-2 (ChR2) enabled functionally dissecting this nociceptive network, without interfering signals by other mechanoreceptors. Forward or reverse escape behaviors were determined by PVD and FLP, via integration by command interneurons. To identify mediators of PVD function, acting downstream of primary nocisensor molecules, we knocked down PVD-specific transcripts by RNAi and quantified light-evoked PVD-dependent behavior. Cell-specific disruption of synaptobrevin or voltage-gated Ca2+-channels (VGCCs) showed that PVD signals chemically to command interneurons. Knocking down the DEG/ENaC channel ASIC-1 and the TRPM channel GTL-1 indicated that ASIC-1 may extend PVD’s dynamic range and that GTL-1 may amplify its signals. These channels act cell-autonomously in PVD, downstream of primary mechanosensory molecules. Conclusions Our work implicates TRPM channels in modifying excitability of, and DEG/ENaCs in potentiating signal output from a mechano-nociceptor neuron. ASIC-1 and GTL-1 homologues, if functionally conserved, may denote valid targets for novel analgesics. PMID:22483941

Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex.

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McGarry, Laura M; Carter, Adam G

2016-09-07

Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared

Cognitive functions of intracellular mechanisms for contextual amplification.

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Phillips, William A

2017-03-01

Evidence for the hypothesis that input to the apical tufts of neocortical pyramidal cells plays a central role in cognition by amplifying their responses to feedforward input is reviewed. Apical tufts are electrically remote from the soma, and their inputs come from diverse sources including direct feedback from higher cortical regions, indirect feedback via the thalamus, and long-range lateral connections both within and between cortical regions. This suggests that input to tuft dendrites may amplify the cell's response to basal inputs that they receive via layer 4 and which have synapses closer to the soma. ERP data supporting this inference is noted. Intracellular studies of apical amplification (AA) and of disamplification by inhibitory interneurons targeted only at tufts are reviewed. Cognitive processes that have been related to them by computational, electrophysiological, and psychopathological studies are then outlined. These processes include: figure-ground segregation and Gestalt grouping; contextual disambiguation in perception and sentence comprehension; priming; winner-take-all competition; attention and working memory; setting the level of consciousness; cognitive control; and learning. It is argued that theories in cognitive neuroscience should not assume that all neurons function as integrate-and-fire point processors, but should use the capabilities of cells with distinct sites of integration for driving and modulatory inputs. Potentially 'unifying' theories that depend upon these capabilities are reviewed. It is concluded that evolution of the primitives of AA and disamplification in neocortex may have extended cognitive capabilities beyond those built from the long-established primitives of excitation, inhibition, and disinhibition. Copyright © 2015 Elsevier Inc. All rights reserved.

TRANSGENIC STRATEGY FOR IDENTIFYING SYNAPTIC CONNECTIONS IN MICE BY FLUORESCENCE COMPLEMENTATION (GRASP

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Masahito eYamagata

2012-02-01

Full Text Available In the "GFP reconstitution across synaptic partners" (GRASP method, non-fluorescent fragments of GFP are expressed in two different neurons; the fragments self-assemble at synapses between the two to form a fluorophore. GRASP has proven useful for light microscopic identification of synapses in two invertebrate species, Caenorhabditis elegans and Drosophila melanogaster, but has not yet been applied to vertebrates. Here, we describe GRASP constructs that function in mammalian cells and implement a transgenic strategy in which a Cre-dependent gene switch leads to expression of the two fragments in mutually exclusive neuronal subsets in mice. Using a transgenic line that expresses Cre selectively in rod photoreceptors, we demonstrate labeling of synapses in the outer plexiform layer of the retina. Labeling is specific, in that synapses made by rods remain labeled for at least 6 months whereas nearby synapses made by intercalated cone photoreceptors on many of the same interneurons remain unlabeled. We also generated antisera that label reconstituted GFP but neither fragment in order to amplify the GRASP signal and thereby increase the sensitivity of the method.

Increase in cyclic AMP concentration in a cerebral giant interneuron mimics part of a memory trace for conditioned taste aversion of the pond snail.

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Otsuka, Emi; Matsunaga, Miho; Okada, Ryuichi; Yamagishi, Miki; Okuta, Akiko; Lukowiak, Ken; Ito, Etsuro

2013-01-01

Conditioned taste aversion (CTA) can be classically conditioned in the pond snail Lymnaea stagnalis and subsequently be consolidated into long-term memory (LTM). The neural trace that subserves CTA-LTM can be summarized as follows: A polysynaptic inhibitory postsynaptic potential recorded in the neuron 1 medial (N1M) cell in the conditioned snails as a result of activation of the cerebral giant cell (CGC) is larger and lasts longer than that in control snails. The N1M cell is ultimately activated by the CGC via the neuron 3 tonic (N3t) cell. That is, the inhibitory monosynaptic inputs from the N3t cell to the N1M cell are facilitated. The N1M and N3t cells are the members of feeding central pattern generator, whereas the CGC is a multimodal interneuron thought to play a key role in feeding behavior. Here we examined the involvement of a second messenger, cAMP, in the establishment of the memory trace. We injected cAMP into the CGC and monitored the potentials of the B3 motor neuron activated by the CGC. B3 activity is used as an index for the synaptic inputs from the N3t cell to the N1M cell. We found that the B3 potentials were transiently enlarged. Thus, when the cAMP concentration is increased in the CGC by taste aversion training, cAMP-induced changes may play a key role in the establishment of a memory trace in the N3t cell.

Changes in inhibitory CA1 network in dual pathology model of epilepsy.

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Ouardouz, Mohamed; Carmant, Lionel

2012-01-01

The combination of two precipitating factors appears to be more and more recognized in patients with temporal lobe epilepsy. Using a two-hit rat model, with a neonatal freeze lesion mimicking a focal cortical malformation combined with hyperthermia-induced seizures mimicking febrile seizures, we have previously reported an increase of inhibition in CA1 pyramidal cells at P20. Here, we investigated the changes affecting excitatory and inhibitory drive onto CA1 interneurons to better define the changes in CA1 inhibitory networks and their paradoxical role in epileptogenesis, using electrophysiological recordings in CA1 hippocampus from rat pups (16-20 d old). We investigated interneurons in CA1 hippocampal area located in stratum oriens (Or) and at the border of strata lacunosum and moleculare (L-M). Our results revealed an increase of the excitatory drive to both types of interneurons with no change in the inhibitory drive. The mechanisms underlying the increase of excitatory synaptic currents (EPSCs) in both types of interneurons are different. In Or interneurons, the amplitude of spontaneous and miniature EPSCs increased, while their frequency was not affected suggesting changes at the post-synaptic level. In L-M interneurons, the frequency of spontaneous EPSCs increases, but the amplitude is not affected. Analyses of miniature EPSCs showed no changes in both their frequency and amplitude. We concluded that L-M interneurons increase in excitatory drive is due to a change in Shaffer collateral axon excitability. The changes described here in CA1 inhibitory network may actually contribute to the epileptogenicity observed in this dual pathology model by increasing pyramidal cell synchronization.

Organization of left–right coordination of neuronal activity in the mammalian spinal cord: Insights from computational modelling

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Shevtsova, Natalia A; Talpalar, Adolfo E; Markin, Sergey N; Harris-Warrick, Ronald M; Kiehn, Ole; Rybak, Ilya A

2015-01-01

Different locomotor gaits in mammals, such as walking or galloping, are produced by coordinated activity in neuronal circuits in the spinal cord. Coordination of neuronal activity between left and right sides of the cord is provided by commissural interneurons (CINs), whose axons cross the midline. In this study, we construct and analyse two computational models of spinal locomotor circuits consisting of left and right rhythm generators interacting bilaterally via several neuronal pathways mediated by different CINs. The CIN populations incorporated in the models include the genetically identified inhibitory (V0D) and excitatory (V0V) subtypes of V0 CINs and excitatory V3 CINs. The model also includes the ipsilaterally projecting excitatory V2a interneurons mediating excitatory drive to the V0V CINs. The proposed network architectures and CIN connectivity allow the models to closely reproduce and suggest mechanistic explanations for several experimental observations. These phenomena include: different speed-dependent contributions of V0D and V0V CINs and V2a interneurons to left–right alternation of neural activity, switching gaits between the left–right alternating walking-like activity and the left–right synchronous hopping-like pattern in mutants lacking specific neuron classes, and speed-dependent asymmetric changes of flexor and extensor phase durations. The models provide insights into the architecture of spinal network and the organization of parallel inhibitory and excitatory CIN pathways and suggest explanations for how these pathways maintain alternating and synchronous gaits at different locomotor speeds. The models propose testable predictions about the neural organization and operation of mammalian locomotor circuits. Key points Coordination of neuronal activity between left and right sides of the mammalian spinal cord is provided by several sets of commissural interneurons (CINs) whose axons cross the midline. Genetically identified inhibitory V

Network state-dependent inhibition of identified hippocampal CA3 axo-axonic cells in vivo

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Tukker, John J; Klausberger, Thomas; Somogyi, Peter

2015-01-01

Hippocampal sharp waves are population discharges initiated by an unknown mechanism in pyramidal cell networks of CA3. Axo-axonic cells (AACs) regulate action potential generation through GABAergic synapses on the axon initial segment. We found that CA3 AACs in anesthetized rats and AACs in freely moving rats stopped firing during sharp waves, when pyramidal cells fire most. AACs fired strongly and rhythmically around the peak of theta oscillations, when pyramidal cells fire at low probability. Distinguishing AACs from other parvalbumin-expressing interneurons by their lack of detectable SATB1 transcription factor immunoreactivity, we discovered a somatic GABAergic input originating from the medial septum that preferentially targets AACs. We recorded septo-hippocampal GABAergic cells that were activated during hippocampal sharp waves and projected to CA3. We hypothesize that inhibition of AACs, and the resulting subcellular redistribution of inhibition from the axon initial segment to other pyramidal cell domains, is a necessary condition for the emergence of sharp waves promoting memory consolidation. PMID:24141313

Hippocampal and neocortical metabolite ratio in patients with complex partial seizure: short TE and long TE techniques using single voxel proton MR spectroscopy

International Nuclear Information System (INIS)

Chung, Jin Il; Kim, Dong Ik; Lee, Byung In; Lee, Seung Ik; Yoon, Pyeong Ho

2000-01-01

To compare hippocampal and neocortical metabolite ratios using single-voxel proton MR spectroscopy with different echo times in patients with complex partial seizure. Using a GE Signa 1.5T scanner with STEAM and PRESS sequences, automated single voxel proton MRS was used to determine metabolite ratio differences in the hippocampus and neocortex of nine complex partial seizure patients (mesial temporal sclerosis (n=3D5), status epilepticus (n=3D1), tumor (n=3D1), cortical dysplasia (n=3D1), occipital lobe epilepsy (n=3D1)). A total of 20 examinations were performed in the region of the hippocampus (n=3D17), temporal neocortex (n=3D1), and parieto-occipital gray matter (n=3D1). Voxel size range was 5.2-17.4 cm 3 . The calculated creatine (Cr) peak was employed as an internal reference and the relative ratio of N-acetylaspartate (NAA) and choline (Cho) was calculated for both short and long echo times using an automated PROBE/SV (GE Medical Systems) package. Each NAA/Cho ratio obtained using both PRESS and STEAM techniques was compared by means of statistical analysis (paired Student t-test). Using PRESS (long TE, 272 ms), NAA/Cho ratios were successfully calculated in 16 of 20 examinations; in four this was not possible due to noise levels of the Cr and Cho peaks. Using STEAM (short TE, 30 ms) NAA/Cho ratios were successfully calculated in 19 of 20 examinations; in one, the Cho peak could not be measured. Using PRESS and STEAM, mean and standard deviations for the NAA/Cho ratio were 1.22±0.50 and 1.16±0.36, respectively. There were no statistically significant differences in this ratio between the short and long TE method (p less than 0.01). In complex partial seizure patients, no significant metabolite differences were found between short and long echo times of single voxel proton MR spectroscopy. The metabolite ratio at different echo times can be reliably obtained using this simplified and automated PROBE/SV quantitation method. (author)

Abundant expression of guidance and synaptogenic molecules in the injured spinal cord.

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Anne Jacobi

Full Text Available BACKGROUND: Spinal interneurons have emerged as crucial targets of supraspinal input during post-injury axonal remodelling. For example, lesioned corticospinal projections use propriospinal neurons as relay stations to form intraspinal detour circuits that circumvent the lesion site and contribute to functional recovery. While a number of the molecules that determine the formation of neuronal circuits in the developing nervous system have been identified, it is much less understood which of these cues are also expressed in the injured spinal cord and can thus guide growing collaterals and initiate synaptogenesis during circuit remodelling. METHODOLOGY/PRINCIPAL FINDINGS: To address this question we characterized the expression profile of a number of guidance and synaptogenic molecules in the cervical spinal cord of healthy and spinal cord-injured mice by in situ hybridization. To assign the expression of these molecules to distinct populations of interneurons we labeled short and long propriospinal neurons by retrograde tracing and glycinergic neurons using a transgenically expressed fluorescent protein. Interestingly, we found that most of the molecules studied including members of slit-, semaphorin-, synCAM-, neuroligin- and ephrin- families as well as their receptors are also present in the adult CNS. While many of these molecules were abundantly expressed in all interneurons examined, some molecules including slits, semaphorin 7a, synCAM4 and neuroligin 1 showed preferential expression in propriospinal interneurons. Overall the expression pattern of guidance and synaptogenic molecules in the cervical spinal cord appeared to be stable over time and was not substantially altered following a midthoracic spinal cord injury. CONCLUSIONS: Taken together, our study indicates that many of the guidance and synaptogenic cues that regulate neuronal circuit formation in development are also present in the adult CNS and therefore likely contribute to the

DEVELOPMENTAL HYPOTHYROIDISM REDUCES PARVALBUMIN EXPRESSION IN GABAERGIC NEURONS OF CORTEX AND HIPPOCAMPUS: IMMUNOHISTOCHEMICAL FINDINGS AND FUNCTIONAL CORRELATES.

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GABAergic interneurons comprise the bulk of local inhibitory neuronal circuitry in cortex and hippocampus and a subpopulation of these interneurons contain the calcium binding protein, parvalbumin (PV). A previous report indicated that severe hypothyroidism reduced PV immunoreact...

Direction of Amygdala-Neocortex Interaction During Dynamic Facial Expression Processing.

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Sato, Wataru; Kochiyama, Takanori; Uono, Shota; Yoshikawa, Sakiko; Toichi, Motomi

2017-03-01

Dynamic facial expressions of emotion strongly elicit multifaceted emotional, perceptual, cognitive, and motor responses. Neuroimaging studies revealed that some subcortical (e.g., amygdala) and neocortical (e.g., superior temporal sulcus and inferior frontal gyrus) brain regions and their functional interaction were involved in processing dynamic facial expressions. However, the direction of the functional interaction between the amygdala and the neocortex remains unknown. To investigate this issue, we re-analyzed functional magnetic resonance imaging (fMRI) data from 2 studies and magnetoencephalography (MEG) data from 1 study. First, a psychophysiological interaction analysis of the fMRI data confirmed the functional interaction between the amygdala and neocortical regions. Then, dynamic causal modeling analysis was used to compare models with forward, backward, or bidirectional effective connectivity between the amygdala and neocortical networks in the fMRI and MEG data. The results consistently supported the model of effective connectivity from the amygdala to the neocortex. Further increasing time-window analysis of the MEG demonstrated that this model was valid after 200 ms from the stimulus onset. These data suggest that emotional processing in the amygdala rapidly modulates some neocortical processing, such as perception, recognition, and motor mimicry, when observing dynamic facial expressions of emotion. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

GABA FUNCTION IS ALTERED FOLLOWING DEVELOPMENTAL HYPOTHYROIDISM: NEUROANATOMICAL AND NEUROPHYSIOLOGICAL EVIDENCE.

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Thyroid hormone deficiency during development produces changes in the structure of neurons and glial cells and alters synaptic function in the hippocampus. GABAergic interneurons comprise the bulk of local inhibitory neuronal circuitry and a subpopulation of these interneurons ...

A neural command circuit for grooming movement control.

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Hampel, Stefanie; Franconville, Romain; Simpson, Julie H; Seeds, Andrew M

2015-09-07

Animals perform many stereotyped movements, but how nervous systems are organized for controlling specific movements remains unclear. Here we use anatomical, optogenetic, behavioral, and physiological techniques to identify a circuit in Drosophila melanogaster that can elicit stereotyped leg movements that groom the antennae. Mechanosensory chordotonal neurons detect displacements of the antennae and excite three different classes of functionally connected interneurons, which include two classes of brain interneurons and different parallel descending neurons. This multilayered circuit is organized such that neurons within each layer are sufficient to specifically elicit antennal grooming. However, we find differences in the durations of antennal grooming elicited by neurons in the different layers, suggesting that the circuit is organized to both command antennal grooming and control its duration. As similar features underlie stimulus-induced movements in other animals, we infer the possibility of a common circuit organization for movement control that can be dissected in Drosophila.

Causal role of thalamic interneurons on brain state transitions: a study using a neural mass model implementing synaptic kinetics

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Basabdatta Sen Bhattacharya

2016-11-01

Full Text Available Experimental studies on the Lateral Geniculate Nucleus (LGN of mammals and rodents show that the inhibitory interneurons (IN receive around 47.1% of their afferents from the retinal spiking neurons, and constitute around 20 - 25% of the LGN cell population. However, there is a definite gap in knowledge about the role and impact of IN on thalamocortical dynamics in both experimental and model-based research. We use a neural mass computational model of the LGN with three neural populations viz. IN, thalamocortical relay (TCR, thalamic reticular nucleus (TRN, to study the causality of IN on LGN oscillations and state-transitions. The synaptic information transmission in the model is implemented with kinetic modelling, facilitating the linking of low-level cellular attributes with high-level population dynamics. The model is parameterised and tuned to simulate both Local Field Potential (LFP of LGN and electroencephalogram (EEG of visual cortex in an awake resting state with eyes closed and dominant frequency within the alpha (8-13 Hz band. The results show that: First, the response of the TRN is suppressed in the presence of IN in the circuit; disconnecting the IN from the circuit effects a dramatic change in the model output, displaying high amplitude synchronous oscillations within the alpha band in both TCR and TRN. These observations conform to experimental reports implicating the IN as the primary inhibitory modulator of LGN dynamics in a cognitive state, and that reduced cognition is achieved by suppressing the TRN response. Second, the model validates steady state visually evoked potential response in humans corresponding to periodic input stimuli; however, when the IN is disconnected from the circuit, the output power spectra do not reflect the input frequency. This agrees with experimental reports underpinning the role of IN in efficient retino-geniculate information transmission. Third, a smooth transition from alpha to theta band is

Composite Biomaterial as a Carrier for Bone-Active Substances for Metaphyseal Tibial Bone Defect Reconstruction in Rats

DEFF Research Database (Denmark)

Horstmann, Peter Frederik; Raina, Deepak Bushan; Isaksson, Hanna

2017-01-01

grouped according to defect filling: (1) Empty, (2) Allograft, (3) GBM, (4) GBM + ZA, and (5) GBM + ZA + BMP-2. In vivo microcomputed tomography (micro-CT) images at 4 weeks showed significantly higher mineralized tissue volume (MV) in the intramedullary defect region and the neocortical/callus region...... in all GBM-treated groups. After euthanization at 8 weeks, ex vivo micro-CT showed that addition of ZA (GBM + ZA) and BMP-2 (GBM + ZA + BMP-2) mainly increased the neocortical and callus formation, with the highest MV in the combined ZA and BMP-2-treated group. Qualitative histological analysis......, verifying the increased neocortical/callus thickness and finding of trabecular bone in all GBM-treated groups, supported that the differences in MV measured with micro-CT in fact represented bone tissue. In conclusion, GBM can serve as a carrier for ZA and BMP-2 leading to increased MV in the neocortex...

Cadherin 2/4 signaling via PTP1B and catenins is crucial for nucleokinesis during radial neuronal migration in the neocortex.

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Martinez-Garay, Isabel; Gil-Sanz, Cristina; Franco, Santos J; Espinosa, Ana; Molnár, Zoltán; Mueller, Ulrich

2016-06-15

Cadherins are crucial for the radial migration of excitatory projection neurons into the developing neocortical wall. However, the specific cadherins and the signaling pathways that regulate radial migration are not well understood. Here, we show that cadherin 2 (CDH2) and CDH4 cooperate to regulate radial migration in mouse brain via the protein tyrosine phosphatase 1B (PTP1B) and α- and β-catenins. Surprisingly, perturbation of cadherin-mediated signaling does not affect the formation and extension of leading processes of migrating neocortical neurons. Instead, movement of the cell body and nucleus (nucleokinesis) is disrupted. This defect is partially rescued by overexpression of LIS1, a microtubule-associated protein that has previously been shown to regulate nucleokinesis. Taken together, our findings indicate that cadherin-mediated signaling to the cytoskeleton is crucial for nucleokinesis of neocortical projection neurons during their radial migration. © 2016. Published by The Company of Biologists Ltd.

The genesis of cerebellar GABAergic neurons: fate potential and specification mechanisms

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Ketty eLeto

2012-02-01

Full Text Available The variety of neuronal phenotypes that populate the cerebellum derives from progenitors that proliferate in two germinal neuroepithelia: the ventricular zone generates GABAergic neurons, whereas the rhombic lip is the origin of glutamatergic types. Progenitors of the ventricular zone produce GABAergic projection neurons (Purkinje cells and nucleo-olivary neurons at the onset of cerebellar neurogenesis. Later on, however, these progenitors migrate into the prospective white matter, where they continue to divide up to postnatal development and generate different categories of inhibitory interneurons, according to precise spatio-temporal schedules. Projection neurons derive from discrete progenitor pools located in distinct microdomains of the ventricular zone, whereas interneurons originate from a single population of precursors, distinguished by the expression of the transcription factor Pax-2. Heterotopic/heterochronic transplantation experiments indicate that interneuron progenitors maintain full developmental potentialities up to the end of cerebellar development and acquire mature phenotypes under the influence of environmental cues present in the prospective white matter. Furthermore, the final fate choice occurs in postmitotic cells, rather than dividing progenitors. Extracerebellar cells grafted to the postnatal cerebellum are not responsive to local neurogenic cues and fail to adopt clear cerebellar identities. On the other hand, cerebellar cells grafted to extracerebellar regions retain typical phenotypes of cerebellar GABAergic interneurons, but acquire specific traits under the influence of local cues. These findings indicate that interneuron progenitors are multipotent and sensitive to spatio-temporally patterned environmental signals that regulate the genesis of different categories of interneurons, in precise quantities and at defined times and places.

[Extinction and Reconsolidation of Memory].

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Zuzina, A B; Balaban, P M

2015-01-01

Retrieval of memory followed by reconsolidation can strengthen a memory, while retrieval followed by extinction results in a decrease of memory performance due to weakening of existing memory or formation of a competing memory. In our study we analyzed the behavior and responses of identified neurons involved in the network underlying aversive learning in terrestrial snail Helix, and made an attempt to describe the conditions in which the retrieval of memory leads either to extinction or reconsolidation. In the network underlying the withdrawal behavior, sensory neurons, premotor interneurons, motor neurons, and modulatory for this network serotonergic neurons are identified and recordings from representatives of these groups were made before and after aversive learning. In the network underlying feeding behavior, the premotor modulatory serotonergic interneurons and motor neurons involved in motor program of feeding are identified. Analysis of changes in neural activity after aversive learning showed that modulatory neurons of feeding behavior do not demonstrate any changes (sometimes a decrease of responses to food was observed), while responses to food in withdrawal behavior premotor interneurons changed qualitatively, from under threshold EPSPs to spike discharges. Using a specific for serotonergic neurons neurotoxin 5,7-DiHT it was shown previously that the serotonergic system is necessary for the aversive learning, but is not necessary for maintenance and retrieval of this memory. These results suggest that the serotonergic neurons that are necessary as part of a reinforcement for developing the associative changes in the network may be not necessary for the retrieval of memory. The hypothesis presented in this review concerns the activity of the "reinforcement" serotonergic neurons that is suggested to be the gate condition for the choice between extinction/reconsolidation triggered by memory retrieval: if these serotonergic neurons do not respond during the

Brain-wide Maps Reveal Stereotyped Cell-Type-Based Cortical Architecture and Subcortical Sexual Dimorphism.

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Kim, Yongsoo; Yang, Guangyu Robert; Pradhan, Kith; Venkataraju, Kannan Umadevi; Bota, Mihail; García Del Molino, Luis Carlos; Fitzgerald, Greg; Ram, Keerthi; He, Miao; Levine, Jesse Maurica; Mitra, Partha; Huang, Z Josh; Wang, Xiao-Jing; Osten, Pavel

2017-10-05

The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitative brain-wide (qBrain) mapping platform to document the stereotyped distributions of mainly inhibitory cell types. We discover an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating parvalbumin-positive interneurons, whereas association, including frontal, areas are dominated by input-modulating somatostatin-positive interneurons. Furthermore, we identify local cell type distributions with more cells in the female brain in 10 out of 11 sexually dimorphic subcortical areas, in contrast to the overall larger brains in males. The qBrain resource can be further mined to link stereotyped aspects of neuronal distributions to known and unknown functions of diverse brain regions. Copyright © 2017 Elsevier Inc. All rights reserved.

Charting Monosynaptic Connectivity Maps by Two-Color Light-Sheet Fluorescence Microscopy

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Christian J. Niedworok

2012-11-01

Full Text Available Cellular resolution three-dimensional (3D visualization of defined, fluorescently labeled long-range neuronal networks in the uncut adult mouse brain has been elusive. Here, a virus-based strategy is described that allowed fluorescent labeling of centrifugally projecting neuronal populations in the ventral forebrain and their directly, monosynaptically connected bulbar interneurons upon a single stereotaxic injection into select neuronal populations. Implementation of improved tissue clearing combined with light-sheet fluorescence microscopy permitted imaging of the resulting connectivity maps in a single whole-brain scan. Subsequent 3D reconstructions revealed the exact distribution of the diverse neuronal ensembles monosynaptically connected with distinct bulbar interneuron populations. Moreover, rehydratation of brains after light-sheet fluorescence imaging enabled the immunohistochemical identification of synaptically connected neurons. Thus, this study describes a method for identifying monosynaptic connectivity maps from distinct, virally labeled neuronal populations that helps in better understanding of information flow in neural systems.

Brains are not just neurons. Comment on “Toward a computational framework for cognitive biology: Unifying approaches from cognitive neuroscience and comparative cognition” by Fitch

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Huber, Ludwig

2014-09-01

This comment addresses the first component of Fitch's framework: the computational power of single neurons [3]. Although I agree that traditional models of neural computation have vastly underestimated the computational power of single neurons, I am hesitant to follow him completely. The exclusive focus on neurons is likely to underestimate the importance of other cells in the brain. In the last years, two such cell types have received appropriate attention by neuroscientists: interneurons and glia. Interneurons are small, tightly packed cells involved in the control of information processing in learning and memory. Rather than transmitting externally (like motor or sensory neurons), these neurons process information within internal circuits of the brain (therefore also called 'relay neurons'). Some specialized interneuron subtypes temporally regulate the flow of information in a given cortical circuit during relevant behavioral events [4]. In the human brain approx. 100 billion interneurons control information processing and are implicated in disorders such as epilepsy and Parkinson's.

Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features.

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Thom, Maria; Eriksson, Sofia; Martinian, Lillian; Caboclo, Luis O; McEvoy, Andrew W; Duncan, John S; Sisodiya, Sanjay M

2009-08-01

Widespread changes involving neocortical and mesial temporal lobe structures can be present in patients with temporal lobe epilepsy and hippocampal sclerosis. The incidence, pathology, and clinical significance of neocortical temporal lobe sclerosis (TLS) are not well characterized. We identified TLS in 30 of 272 surgically treated cases of hippocampal sclerosis. Temporal lobe sclerosis was defined by variable reduction of neurons from cortical layers II/III and laminar gliosis; it was typically accompanied by additional architectural abnormalities of layer II, that is, abnormal neuronal orientation and aggregation. Quantitative analysis including tessellation methods for the distribution of layer II neurons supported these observations. In 40% of cases, there was a gradient of TLS with more severe involvement toward the temporal pole, possibly signifying involvement of hippocampal projection pathways. There was a history of a febrile seizure as an initial precipitating injury in 73% of patients with TLS compared with 36% without TLS; no other clinical differences between TLS and non-TLS cases were identified. Temporal lobe sclerosis was not evident preoperatively by neuroimaging. No obvious effect of TLS on seizure outcome was noted after temporal lobe resection; 73% became seizure-free at 2-year follow-up. In conclusion, approximately 11% of surgically treated hippocampal sclerosis is accompanied by TLS. Temporal lobe sclerosis is likely an acquired process with accompanying reorganizational dysplasia and an extension of mesial temporal sclerosis rather than a separate pathological entity.

NPR-9, a Galanin-Like G-Protein Coupled Receptor, and GLR-1 Regulate Interneuronal Circuitry Underlying Multisensory Integration of Environmental Cues in Caenorhabditis elegans.

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Jason C Campbell

2016-05-01

Full Text Available C. elegans inhabit environments that require detection of diverse stimuli to modulate locomotion in order to avoid unfavourable conditions. In a mammalian context, a failure to appropriately integrate environmental signals can lead to Parkinson's, Alzheimer's, and epilepsy. Provided that the circuitry underlying mammalian sensory integration can be prohibitively complex, we analyzed nematode behavioral responses in differing environmental contexts to evaluate the regulation of context dependent circuit reconfiguration and sensorimotor control. Our work has added to the complexity of a known parallel circuit, mediated by interneurons AVA and AIB, that integrates sensory cues and is responsible for the initiation of backwards locomotion. Our analysis of the galanin-like G-protein coupled receptor NPR-9 in C. elegans revealed that upregulation of galanin signaling impedes the integration of sensory evoked neuronal signals. Although the expression pattern of npr-9 is limited to AIB, upregulation of the receptor appears to impede AIB and AVA circuits to broadly prevent backwards locomotion, i.e. reversals, suggesting that these two pathways functionally interact. Galanin signaling similarly plays a broadly inhibitory role in mammalian models. Moreover, our identification of a mutant, which rarely initiates backwards movement, allowed us to interrogate locomotory mechanisms underlying chemotaxis. In support of the pirouette model of chemotaxis, organisms that did not exhibit reversal behavior were unable to navigate towards an attractant peak. We also assessed ionotropic glutamate receptor GLR-1 cell-specifically within AIB and determined that GLR-1 fine-tunes AIB activity to modify locomotion following reversal events. Our research highlights that signal integration underlying the initiation and fine-tuning of backwards locomotion is AIB and NPR-9 dependent, and has demonstrated the suitability of C. elegans for analysis of multisensory integration

Localization of Epileptogenic Zones using Partical Volume Corrected FDG Uptake on FDG PET and Voxel Based Morphometry on MRI

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Kang, Won Jun; Lee, Ho Young; Lee, Jae Sung; Lee, Dong Soo; Lee, Sang Kun; Chung, June Key; Lee, Myung Chul [College of Medicine, Univ. of Seoul National, Seoul (Korea, Republic of)

2003-07-01

Partial volume corrected (PVC) FDG uptake yields information about regional metabolic level void of volume change, and voxel based morphometry (VBM) yields objective information regarding gray matter concentration. We investigated the roles of PVC PET and VBM to localize epileptogenic zones in medial temporal lobe epilepsy (mTLE) and non-lesional neocortical epilepsy. As a control group for PVC, 40 normal volunteers without history of neurologic or psychiatric diseases underwent FDG PET and MRI. Seventeen mTLE patients (M: F=7: 10, age=309 y) and nine neocortical epilepsy patients (M: F=6: 3, age=246, lateral temporal: 5, frontal: 3, occipital: 1) confirmed by surgery or epilepsy board meeting were enrolled. Standard VBM analysis was performed using individual MRI images compared with those of age-matched controls. For PVC, FDG PET was co-registered with its own MRI. PVC PET was obtained by dividing spillover-corrected PET by smoothed gray matter image pixel by pixel. SPAM was applied as a mask of volume of interest (VOI) to calculate gyral FDG uptake on PVC-FDG PET. Hippocampus, amygdala, superior, middle, inferior temporal gyrus and parahippocampal gyrus were the gyral SPAM VOIs in mTLE. Globally normalized PVC-FDG counts were compared with those of age-matched controls in mTLE and neocortical epilepsy patients. In mTlE, PVC-FDG PET correctly localized epileptogenic zones with the accuracy of 76% (13/17) in hippocampus and 82% (14/17) in any of six regions. VBM correctly localized 59% (10/17) in mTLE. In neocortical epilepsy, PVC-FDG PET localized epileptogenic zones in 44%, and VBM in 33%, Using VBM and PVC-FDG PET altogether, epileptogenic zones were localized in 66% (6/9). In mTLE, gyral PVC FDG uptake of temporal lobes was useful in localizing epileptogenic zones by demonstrating partial volume-void FDG concentration. In non-lesional cryptogenic neocortical epilepsy, combination of PVC-FDG PET and VBM is recommended to localize epileptogenic zones.

Microstructural imaging of human neocortex in vivo.

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Edwards, Luke J; Kirilina, Evgeniya; Mohammadi, Siawoosh; Weiskopf, Nikolaus

2018-03-24

The neocortex of the human brain is the seat of higher brain function. Modern imaging techniques, chief among them magnetic resonance imaging (MRI), allow non-invasive imaging of this important structure. Knowledge of the microstructure of the neocortex has classically come from post-mortem histological studies of human tissue, and extrapolations from invasive animal studies. From these studies, we know that the scale of important neocortical structure spans six orders of magnitude, ranging from the size of axonal diameters (microns), to the size of cortical areas responsible for integrating sensory information (centimetres). MRI presents an opportunity to move beyond classical methods, because MRI is non-invasive and MRI contrast is sensitive to neocortical microstructure over all these length scales. MRI thus allows inferences to be made about neocortical microstructure in vivo, i.e. MRI-based in vivo histology. We review recent literature that has applied and developed MRI-based in vivo histology to probe the microstructure of the human neocortex, focusing specifically on myelin, iron, and neuronal fibre mapping. We find that applications such as cortical parcellation (using R 1 maps as proxies for myelin content) and investigation of cortical iron deposition with age (using R 2 * maps) are already contributing to the frontiers of knowledge in neuroscience. Neuronal fibre mapping in the cortex remains challenging in vivo, but recent improvements in diffusion MRI hold promise for exciting applications in the near future. The literature also suggests that utilising multiple complementary quantitative MRI maps could increase the specificity of inferences about neocortical microstructure relative to contemporary techniques, but that further investment in modelling is required to appropriately combine the maps. In vivo histology of human neocortical microstructure is undergoing rapid development. Future developments will improve its specificity, sensitivity, and

Impaired neurogenesis of the dentate gyrus is associated with pattern separation deficits: A computational study.

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Faghihi, Faramarz; Moustafa, Ahmed A

2016-09-01

The separation of input patterns received from the entorhinal cortex (EC) by the dentate gyrus (DG) is a well-known critical step of information processing in the hippocampus. Although the role of interneurons in separation pattern efficiency of the DG has been theoretically known, the balance of neurogenesis of excitatory neurons and interneurons as well as its potential role in information processing in the DG is not fully understood. In this work, we study separation efficiency of the DG for different rates of neurogenesis of interneurons and excitatory neurons using a novel computational model in which we assume an increase in the synaptic efficacy between excitatory neurons and interneurons and then its decay over time. Information processing in the EC and DG was simulated as information flow in a two layer feed-forward neural network. The neurogenesis rate was modeled as the percentage of new born neurons added to the neuronal population in each time bin. The results show an important role of an optimal neurogenesis rate of interneurons and excitatory neurons in the DG in efficient separation of inputs from the EC in pattern separation tasks. The model predicts that any deviation of the optimal values of neurogenesis rates leads to different decreased levels of the separation deficits of the DG which influences its function to encode memory.

SPARQL-enabled identifier conversion with Identifiers.org.

Science.gov (United States)

Wimalaratne, Sarala M; Bolleman, Jerven; Juty, Nick; Katayama, Toshiaki; Dumontier, Michel; Redaschi, Nicole; Le Novère, Nicolas; Hermjakob, Henning; Laibe, Camille

2015-06-01

On the semantic web, in life sciences in particular, data is often distributed via multiple resources. Each of these sources is likely to use their own International Resource Identifier for conceptually the same resource or database record. The lack of correspondence between identifiers introduces a barrier when executing federated SPARQL queries across life science data. We introduce a novel SPARQL-based service to enable on-the-fly integration of life science data. This service uses the identifier patterns defined in the Identifiers.org Registry to generate a plurality of identifier variants, which can then be used to match source identifiers with target identifiers. We demonstrate the utility of this identifier integration approach by answering queries across major producers of life science Linked Data. The SPARQL-based identifier conversion service is available without restriction at http://identifiers.org/services/sparql. © The Author 2015. Published by Oxford University Press.

SPARQL-enabled identifier conversion with Identifiers.org

Science.gov (United States)

Wimalaratne, Sarala M.; Bolleman, Jerven; Juty, Nick; Katayama, Toshiaki; Dumontier, Michel; Redaschi, Nicole; Le Novère, Nicolas; Hermjakob, Henning; Laibe, Camille

2015-01-01

Motivation: On the semantic web, in life sciences in particular, data is often distributed via multiple resources. Each of these sources is likely to use their own International Resource Identifier for conceptually the same resource or database record. The lack of correspondence between identifiers introduces a barrier when executing federated SPARQL queries across life science data. Results: We introduce a novel SPARQL-based service to enable on-the-fly integration of life science data. This service uses the identifier patterns defined in the Identifiers.org Registry to generate a plurality of identifier variants, which can then be used to match source identifiers with target identifiers. We demonstrate the utility of this identifier integration approach by answering queries across major producers of life science Linked Data. Availability and implementation: The SPARQL-based identifier conversion service is available without restriction at http://identifiers.org/services/sparql. Contact: sarala@ebi.ac.uk PMID:25638809

Automated computation of arbor densities: a step toward identifying neuronal cell types

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Uygar eSümbül

2014-11-01

Full Text Available The shape and position of a neuron convey information regarding its molecular and functional identity. The identification of cell types from structure, a classic method, relies on the time-consuming step of arbor tracing. However, as genetic tools and imaging methods make data-driven approaches to neuronal circuit analysis feasible, the need for automated processing increases. Here, we first establish that mouse retinal ganglion cell types can be as precise about distributing their arbor volumes across the inner plexiform layer as they are about distributing the skeletons of the arbors. Then, we describe an automated approach to computing the spatial distribution of the dendritic arbors, or arbor density, with respect to a global depth coordinate based on this observation. Our method involves three-dimensional reconstruction of neuronal arbors by a supervised machine learning algorithm, post-processing of the enhanced stacks to remove somata and isolate the neuron of interest, and registration of neurons to each other using automatically detected arbors of the starburst amacrine interneurons as fiducial markers. In principle, this method could be generalizable to other structures of the CNS, provided that they allow sparse labeling of the cells and contain a reliable axis of spatial reference.

Network models provide insights into how oriens–lacunosum-moleculare and bistratified cell interactions influence the power of local hippocampal CA1 theta oscillations

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Katie A Ferguson

2015-08-01

Full Text Available Hippocampal theta is a 4-12 Hz rhythm associated with episodic memory, and although it has been studied extensively, the cellular mechanisms underlying its generation are unclear. The complex interactions between different interneuron types, such as those between oriens--lacunosum-moleculare (OLM interneurons and bistratified cells (BiCs, make their contribution to network rhythms difficult to determine experimentally. We created network models that are tied to experimental work at both cellular and network levels to explore how these interneuron interactions affect the power of local oscillations. Our cellular models were constrained with properties from patch clamp recordings in the CA1 region of an intact hippocampus preparation in vitro. Our network models are composed of three different types of interneurons: parvalbumin-positive (PV+ basket and axo-axonic cells (BC/AACs, PV+ BiCs, and somatostatin-positive OLM cells. Also included is a spatially extended pyramidal cell model to allow for a simplified local field potential representation, as well as experimentally-constrained, theta frequency synaptic inputs to the interneurons. The network size, connectivity, and synaptic properties were constrained with experimental data. To determine how the interactions between OLM cells and BiCs could affect local theta power, we explored a number of OLM-BiC connections and connection strengths.We found that our models operate in regimes in which OLM cells minimally or strongly affected the power of network theta oscillations due to balances that, respectively, allow compensatory effects or not. Inactivation of OLM cells could result in no change or even an increase in theta power. We predict that the dis-inhibitory effect of OLM cells to BiCs to pyramidal cell interactions plays a critical role in the power of network theta oscillations. Our network models reveal a dynamic interplay between different classes of interneurons in influencing local theta

Acute serotonin 2A receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala

DEFF Research Database (Denmark)

Hornboll, Bettina; Macoveanu, Julian; Rowe, James

2013-01-01

judging the gender of neutral, fearful and angry faces. Methods: 5-HT2A receptors were blocked with ketanserin to a variable degree across subjects by adjusting the time between ketanserin-infusion and onset of the fMRI protocol. Neocortical 5-HT2A receptor binding in terms of the binding potential (BPp...... blockade reduced the neural response to fearful faces in the medial orbitofrontal cortex (OFC), independently of 5-HT2A receptor occupancy or neocortical 5-HT2A receptor BPp . The medial OFC also showed increased functional coupling with the left amygdala during processing of fearful faces depending...

Stranger in a Strange Land: Using Heterotopic Transplantations to Study Nature vs Nurture in Brain Development

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Timothy J Petros

2018-02-01

Full Text Available The mammalian brain develops from a simple sheet of neuroepithelial cells into an incredibly complex structure containing billions of neurons with trillions of synapses. Understanding how intrinsic genetic programs interact with environmental cues to generate neuronal diversity and proper connectivity is one of the most daunting challenges in developmental biology. We recently explored this issue in forebrain GABAergic inhibitory interneurons, an extremely diverse population of neurons that are classified into distinct subtypes based on morphology, neurochemical markers, and electrophysiological properties. Immature interneurons were harvested from one brain region and transplanted into a different region, allowing us to assess how challenging cells in a new environment affected their fate. Do these grafted cells adopt characteristics of the host environment or retain features from the donor environment? We found that the proportion of interneuron subgroups is determined by the host region, but some interneuron subtypes maintain features attributable to the donor environment. In this commentary, I expound on potential mechanisms that could underlie these observations and explore the implications of these findings in a greater context of developmental neuroscience.

Stranger in a Strange Land: Using Heterotopic Transplantations to Study Nature vs Nurture in Brain Development.

Science.gov (United States)

Petros, Timothy J

2018-01-01

The mammalian brain develops from a simple sheet of neuroepithelial cells into an incredibly complex structure containing billions of neurons with trillions of synapses. Understanding how intrinsic genetic programs interact with environmental cues to generate neuronal diversity and proper connectivity is one of the most daunting challenges in developmental biology. We recently explored this issue in forebrain GABAergic inhibitory interneurons, an extremely diverse population of neurons that are classified into distinct subtypes based on morphology, neurochemical markers, and electrophysiological properties. Immature interneurons were harvested from one brain region and transplanted into a different region, allowing us to assess how challenging cells in a new environment affected their fate. Do these grafted cells adopt characteristics of the host environment or retain features from the donor environment? We found that the proportion of interneuron subgroups is determined by the host region, but some interneuron subtypes maintain features attributable to the donor environment. In this commentary, I expound on potential mechanisms that could underlie these observations and explore the implications of these findings in a greater context of developmental neuroscience.

Multiple embryonic origins of nitric oxide synthase-expressing GABAergic neurons of the neocortex

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Lorenza eMagno

2012-09-01

Full Text Available Cortical GABAergic interneurons in rodents originate in three subcortical regions: the medial ganglionic eminence (MGE, the lateral/caudal ganglionic eminence (LGE/CGE and the preoptic area (POA. Each of these neuroepithelial precursor domains contributes different interneuron subtypes to the cortex. nNOS-expressing neurons represent a heterogenous population of cortical interneurons. We examined the development of these cells in the mouse embryonic cortex and their abundance and distribution in adult animals. Using genetic lineage tracing in transgenic mice we find that nNOS type I cells originate only in the MGE whereas type II cells have a triple origin in the MGE, LGE/CGE and POA. The two populations are born at different times during development, occupy different layers in the adult cortex and have distinct neurochemical profiles. nNOS neurons are more numerous in the adult cortex than previously reported and constitute a significant proportion of the cortical interneuron population. Our data suggest that the heterogeneity of nNOS neurons in the cortex can be attributed to their multiple embryonic origins which likely impose distinct genetic specification programs.

Toward robust phase-locking in Melibe swim central pattern generator models

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Jalil, Sajiya; Allen, Dane; Youker, Joseph; Shilnikov, Andrey

2013-12-01

Small groups of interneurons, abbreviated by CPG for central pattern generators, are arranged into neural networks to generate a variety of core bursting rhythms with specific phase-locked states, on distinct time scales, which govern vital motor behaviors in invertebrates such as chewing and swimming. These movements in lower level animals mimic motions of organs in higher animals due to evolutionarily conserved mechanisms. Hence, various neurological diseases can be linked to abnormal movement of body parts that are regulated by a malfunctioning CPG. In this paper, we, being inspired by recent experimental studies of neuronal activity patterns recorded from a swimming motion CPG of the sea slug Melibe leonina, examine a mathematical model of a 4-cell network that can plausibly and stably underlie the observed bursting rhythm. We develop a dynamical systems framework for explaining the existence and robustness of phase-locked states in activity patterns produced by the modeled CPGs. The proposed tools can be used for identifying core components for other CPG networks with reliable bursting outcomes and specific phase relationships between the interneurons. Our findings can be employed for identifying or implementing the conditions for normal and pathological functioning of basic CPGs of animals and artificially intelligent prosthetics that can regulate various movements.

Vagal gustatory reflex circuits for intraoral food sorting behavior in the goldfish: cellular organization and neurotransmitters.

Science.gov (United States)

Ikenaga, Takanori; Ogura, Tatsuya; Finger, Thomas E

2009-09-20

The sense of taste is crucial in an animal's determination as to what is edible and what is not. This gustatory function is especially important in goldfish, who utilize a sophisticated oropharyngeal sorting mechanism to separate food from substrate material. The computational aspects of this detection are carried out by the medullary vagal lobe, which is a large, laminated structure combining elements of both the gustatory nucleus of the solitary tract and the nucleus ambiguus. The sensory layers of the vagal lobe are coupled to the motor layers via a simple reflex arc. Details of this reflex circuit were investigated with histology and calcium imaging. Biocytin injections into the motor layer labeled vagal reflex interneurons that have radially directed dendrites ramifying within the layers of primary afferent terminals. Axons of reflex interneurons extend radially inward to terminate onto both vagal motoneurons and small, GABAergic interneurons in the motor layer. Functional imaging shows increases in intracellular Ca++ of vagal motoneurons following electrical stimulation in the sensory layer. These responses were suppressed under Ca(++)-free conditions and by interruption of the axons bridging between the sensory and motor layers. Pharmacological experiments showed that glutamate acting via (+/-)-alpha-amino-3-hydroxy- 5-ethylisoxazole-4-propioinc acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA) receptors mediate neurotransmission between reflex interneurons and vagal motoneurons. Thus, the vagal gustatory portion of the viscerosensory complex is linked to branchiomotor neurons of the pharynx via a glutamatergic interneuronal system.

Vagal gustatory reflex circuits for intraoral food sorting behavior in the goldfish Cellular organization and neurotransmitters

Science.gov (United States)

Ikenaga, Takanori; Ogura, Tatsuya; Finger, Thomas E.

2009-01-01

The sense of taste is crucial in an animal’s determination as to what is edible and what is not. This gustatory function is especially important in goldfish who utilize a sophisticated oropharyngeal sorting mechanism to separate food from substrate material. The computational aspects of this detection are carried out by the medullary vagal lobe which is a large, laminated structure combining elements of both the gustatory nucleus of the solitary tract and the nucleus ambiguus. The sensory layers of the vagal lobe are coupled to the motor layers via a simple reflex arc. Details of this reflex circuit were investigated with histology and calcium imaging. Biocytin injections into the motor layer labeled vagal reflex interneurons which have radially-directed dendrites ramifying within the layers of primary afferent terminals. Axons of reflex interneurons extend radially inward to terminate onto both vagal motoneurons and small, GABAergic interneurons in the motor layer. Functional imaging shows increases in intracellular Ca++ of vagal motoneurons following electrical stimulation in the sensory layer. These responses were suppressed under Ca++-free conditions and by interruption of the axons bridging between the sensory and motor layers. Pharmacological experiments showed that glutamate acting via (±)-α-amino-3-hydroxy-5-ethylisoxazole-4-propioinc acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA) receptors mediates neurotransmission between reflex interneurons and vagal motoneurons. Thus the vagal gustatory portion of the viscerosensory complex is linked to branchiomotor neurons of the pharynx via a glutamatergic interneuronal system. PMID:19598285

TOR signaling pathway and autophagy are involved in the regulation of circadian rhythms in behavior and plasticity of L2 interneurons in the brain of Drosophila melanogaster.

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Kijak, Ewelina; Pyza, Elżbieta

2017-01-01

Drosophila melanogaster is a common model used to study circadian rhythms in behavior and circadian clocks. However, numerous circadian rhythms have also been detected in non-clock neurons, especially in the first optic neuropil (lamina) of the fly's visual system. Such rhythms have been observed in the number of synapses and in the structure of interneurons, which exhibit changes in size and shape in a circadian manner. Although the patterns of these changes are known, the mechanism remains unclear. In the present study, we investigated the role of the TOR signaling pathway and autophagy in regulating circadian rhythms based on the behavior and structural plasticity of the lamina L2 monopolar cell dendritic trees. In addition, we examined the cyclic expression of the TOR signaling pathway (Tor, Pi3K class 1, Akt1) and autophagy (Atg5 and Atg7) genes in the fly's brain. We observed that Tor, Atg5 and Atg7 exhibit rhythmic expressions in the brain of wild-type flies in day/night conditions (LD 12:12) that are abolished in per01 clock mutants. The silencing of Tor in per expressing cells shortens a period of the locomotor activity rhythm of flies. In addition, silencing of the Tor and Atg5 genes in L2 cells disrupts the circadian plasticity of the L2 cell dendritic trees measured in the distal lamina. In turn, silencing of the Atg7 gene in L2 cells changes the pattern of this rhythm. Our results indicate that the TOR signaling pathway and autophagy are involved in the regulation of circadian rhythms in the behavior and plasticity of neurons in the brain of adult flies.

Delineating the Diversity of Spinal Interneurons in Locomotor Circuits.

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Gosgnach, Simon; Bikoff, Jay B; Dougherty, Kimberly J; El Manira, Abdeljabbar; Lanuza, Guillermo M; Zhang, Ying

2017-11-08

Locomotion is common to all animals and is essential for survival. Neural circuits located in the spinal cord have been shown to be necessary and sufficient for the generation and control of the basic locomotor rhythm by activating muscles on either side of the body in a specific sequence. Activity in these neural circuits determines the speed, gait pattern, and direction of movement, so the specific locomotor pattern generated relies on the diversity of the neurons within spinal locomotor circuits. Here, we review findings demonstrating that developmental genetics can be used to identify populations of neurons that comprise these circuits and focus on recent work indicating that many of these populations can be further subdivided into distinct subtypes, with each likely to play complementary functions during locomotion. Finally, we discuss data describing the manner in which these populations interact with each other to produce efficient, task-dependent locomotion. Copyright © 2017 the authors 0270-6474/17/3710835-07$15.00/0.

Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease.

Science.gov (United States)

Kim, Juhyun; Hughes, Ethan G; Shetty, Ashwin S; Arlotta, Paola; Goff, Loyal A; Bergles, Dwight E; Brown, Solange P

2017-09-13

Cell type-specific changes in neuronal excitability have been proposed to contribute to the selective degeneration of corticospinal neurons in amyotrophic lateral sclerosis (ALS) and to neocortical hyperexcitability, a prominent feature of both inherited and sporadic variants of the disease, but the mechanisms underlying selective loss of specific cell types in ALS are not known. We analyzed the physiological properties of distinct classes of cortical neurons in the motor cortex of hSOD1 G93A mice of both sexes and found that they all exhibit increases in intrinsic excitability that depend on disease stage. Targeted recordings and in vivo calcium imaging further revealed that neurons adapt their functional properties to normalize cortical excitability as the disease progresses. Although different neuron classes all exhibited increases in intrinsic excitability, transcriptional profiling indicated that the molecular mechanisms underlying these changes are cell type specific. The increases in excitability in both excitatory and inhibitory cortical neurons show that selective dysfunction of neuronal cell types cannot account for the specific vulnerability of corticospinal motor neurons in ALS. Furthermore, the stage-dependent alterations in neuronal function highlight the ability of cortical circuits to adapt as disease progresses. These findings show that both disease stage and cell type must be considered when developing therapeutic strategies for treating ALS. SIGNIFICANCE STATEMENT It is not known why certain classes of neurons preferentially die in different neurodegenerative diseases. It has been proposed that the enhanced excitability of affected neurons is a major contributor to their selective loss. We show using a mouse model of amyotrophic lateral sclerosis (ALS), a disease in which corticospinal neurons exhibit selective vulnerability, that changes in excitability are not restricted to this neuronal class and that excitability does not increase

Role for astroglial α1-adrenoreceptors in gliotransmission and control of synaptic plasticity in the neocortex

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Yuriy ePankratov

2015-06-01

Full Text Available Communication between neuronal and glial cells is thought to be very important for many brain functions. Acting via release of gliotransmitters, astrocytes can modulate synaptic strength. The mechanisms underlying gliotransmission remain uncertain with exocytosis being the most intriguing and debated pathway.We demonstrate that astroglial α1-adrenoreceptors are very sensitive to noradrenaline and make a significant contribution to intracellular Ca2+-signalling in layer 2/3 neocortical astrocytes. We also show that astroglial α1-adrenoreceptors are prone to desensitization upon prolonged exposure to noradrenaline.We show that within neocortical slices, α-1adrenoreceptors can activate vesicular release of ATP and D-serine from cortical astrocytes which initiate a burst of ATP receptor-mediated currents in adjacent pyramidal neurons. These purinergic currents can be inhibited by intracellular perfusion of astrocytes with Tetanus Toxin light chain, verifying their origin via astroglial exocytosis.We show that α1 adrenoreceptor-activated release of gliotransmitters is important for the induction of synaptic plasticity in the neocortex:long-term potentiation (LTP of neocortical excitatory synaptic potentials can be abolished by the selective α1-adrenoreceptor antagonist terazosin. We show that weak sub-threshold theta-burst stimulation can induce LTP when astrocytes are additionally activated by 1 μM noradrenaline. This facilitation is dependent on the activation of neuronal ATP receptors and is abolished in neocortical slices from dn-SNARE mice which have impaired glial exocytosis. Importantly, facilitation of LTP by noradrenaline can be significantly reduced by perfusion of individual astrocytes with Tetanus Toxin. Our results strongly support the physiological importance of astroglial adrenergic signalling and exocytosis of gliotransmitters for modulation of synaptic transmission and plasticity .

Barrels XXX meeting report: Barrels in Baltimore.

Science.gov (United States)

Shin, Hyeyoung; Bitzidou, Malamati; Palaguachi, Fernando; Brumberg, Joshua C

2018-03-01

The Barrels meeting annually brings together researchers focused on the rodent whisker to cortical barrel system prior to the Society for Neuroscience meeting. The 2017 meeting focused on the classification of cortical interneurons, the role interneurons have in shaping brain dynamics, and finally on the circuitry underlying oral sensations. The meeting highlighted the latest advancements in this rapidly advancing field.

Impaired GABAergic Inhibition in the Prefrontal Cortex of Early Postnatal Phencyclidine (PCP)-Treated Rats

DEFF Research Database (Denmark)

Kjaerby, Celia; Broberg, Brian V; Kristiansen, Uffe

2014-01-01

A compromised ¿-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-d-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmissio...... postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life....

Cell-specific STORM super-resolution imaging reveals nanoscale organization of cannabinoid signaling.

Science.gov (United States)

Dudok, Barna; Barna, László; Ledri, Marco; Szabó, Szilárd I; Szabadits, Eszter; Pintér, Balázs; Woodhams, Stephen G; Henstridge, Christopher M; Balla, Gyula Y; Nyilas, Rita; Varga, Csaba; Lee, Sang-Hun; Matolcsi, Máté; Cervenak, Judit; Kacskovics, Imre; Watanabe, Masahiko; Sagheddu, Claudia; Melis, Miriam; Pistis, Marco; Soltesz, Ivan; Katona, István

2015-01-01

A major challenge in neuroscience is to determine the nanoscale position and quantity of signaling molecules in a cell type- and subcellular compartment-specific manner. We developed a new approach to this problem by combining cell-specific physiological and anatomical characterization with super-resolution imaging and studied the molecular and structural parameters shaping the physiological properties of synaptic endocannabinoid signaling in the mouse hippocampus. We found that axon terminals of perisomatically projecting GABAergic interneurons possessed increased CB1 receptor number, active-zone complexity and receptor/effector ratio compared with dendritically projecting interneurons, consistent with higher efficiency of cannabinoid signaling at somatic versus dendritic synapses. Furthermore, chronic Δ(9)-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked marked CB1 downregulation in a dose-dependent manner. Full receptor recovery required several weeks after the cessation of Δ(9)-tetrahydrocannabinol treatment. These findings indicate that cell type-specific nanoscale analysis of endogenous protein distribution is possible in brain circuits and identify previously unknown molecular properties controlling endocannabinoid signaling and cannabis-induced cognitive dysfunction.

Cell-specific STORM superresolution imaging reveals nanoscale organization of cannabinoid signaling

Science.gov (United States)

Szabó, Szilárd I.; Szabadits, Eszter; Pintér, Balázs; Woodhams, Stephen G.; Henstridge, Christopher M.; Balla, Gyula Y.; Nyilas, Rita; Varga, Csaba; Lee, Sang-Hun; Matolcsi, Máté; Cervenak, Judit; Kacskovics, Imre; Watanabe, Masahiko; Sagheddu, Claudia; Melis, Miriam; Pistis, Marco; Soltesz, Ivan; Katona, István

2014-01-01

A major challenge in neuroscience is to determine the nanoscale position and quantity of signaling molecules in a cell-type-, and subcellular compartment-specific manner. We therefore developed a novel approach combining cell-specific physiological and anatomical characterization with superresolution imaging, and studied the molecular and structural parameters shaping the physiological properties of synaptic endocannabinoid signaling in the mouse hippocampus. We found that axon terminals of perisomatically-projecting GABAergic interneurons possess increased CB1 receptor number, active-zone complexity, and receptor/effector ratio compared to dendritically-projecting interneurons, in agreement with higher efficiency of cannabinoid signaling at somatic versus dendritic synapses. Furthermore, chronic Δ9-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked dramatic CB1-downregulation in a dose-dependent manner. Full receptor recovery required several weeks after cessation of Δ9-tetrahydrocannabinol treatment. These findings demonstrate that cell-type-specific nanoscale analysis of endogenous protein distribution is possible in brain circuits, and identify novel molecular properties controlling endocannabinoid signaling and cannabis-induced cognitive dysfunction. PMID:25485758

Contesting the Equivalency of Continuous Sedation until Death and Physician-assisted Suicide/Euthanasia: A Commentary on LiPuma.

Science.gov (United States)

Raho, Joseph A; Miccinesi, Guido

2015-10-01

Patients who are imminently dying sometimes experience symptoms refractory to traditional palliative interventions, and in rare cases, continuous sedation is offered. Samuel H. LiPuma, in a recent article in this Journal, argues that continuous sedation until death is equivalent to physician-assisted suicide/euthanasia based on a higher brain neocortical definition of death. We contest his position that continuous sedation involves killing and offer four objections to the equivalency thesis. First, sedation practices are proportional in a way that physician-assisted suicide/euthanasia is not. Second, continuous sedation may not entirely abolish consciousness. Third, LiPuma's particular version of higher brain neocortical death relies on an implausibly weak construal of irreversibility--a position that is especially problematic in the case of continuous sedation. Finally, we explain why continuous sedation until death is not functionally equivalent to neocortical death and, hence, physician-assisted suicide/euthanasia. Concluding remarks review the differences between these two end-of-life practices. © The Author 2015. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Thyroid hormone-dependent development of early cortical networks: Temporal specificity and the contribution of trkB and mTOR pathways

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Sören eWesterholz

2013-08-01

Full Text Available Early in neocortical network development, triiodothyronine (T3 promotes GABAergic neurons’ population increase, their somatic growth and the formation of GABAergic synapses. In the presence of T3, GABAergic interneurons form longer axons and conspicuous axonal arborizations, with an increased number of putative synaptic boutons. Here we show that the increased GABAergic axonal growth is positively correlated with the proximity to non-GABAergic neurons. A differential innervation emerges from a T3-dependent decrease of axonal length in fields with low density of neuronal cell bodies, combined with an increased bouton formation in fields with high density of neuronal somata. T3 addition to deprived networks after the first two weeks of development did not rescue deficits in the GABAergic synaptic bouton distribution, or in the frequency and duration of spontaneous bursts. During the critical two-week-period, GABAergic signaling is depolarizing as revealed by calcium imaging experiments. Interestingly, T3 enhanced the expression of the potassium-chloride cotransporter 2 (KCC2, and accelerated the developmental shift from depolarizing to hyperpolarizing GABAergic signaling in non-GABAergic neurons.The T3-related increase of spontaneous network activity was remarkably reduced after blockade of either tropomyosin-receptor kinase B (trkB or mammalian target of rapamycin (mTOR pathways. T3-dependent increase in GABAergic neurons’ soma size was mediated mainly by mTOR signaling. Conversely, the T3-dependent selective increase of GABAergic boutons near non-GABAergic cell bodies is mediated by trkB signaling only. Both trkB and mTOR signaling mediate T3-dependent reduction of the GABAergic axon extension. The circuitry context is relevant for the interaction between T3 and trkB signaling, but not for the interactions between T3 and mTOR signaling.

Impact of cercal air currents on singing motor pattern generation in the cricket (Gryllus bimaculatus DeGeer)

Science.gov (United States)

2015-01-01

The cercal system of crickets detects low-frequency air currents produced by approaching predators and self-generated air currents during singing, which may provide sensory feedback to the singing motor network. We analyzed the effect of cercal stimulation on singing motor pattern generation to reveal the response of a singing interneuron to predator-like signals and to elucidate the possible role of self-generated air currents during singing. In fictive singing males, we recorded an interneuron of the singing network while applying air currents to the cerci; additionally, we analyzed the effect of abolishing the cercal system in freely singing males. In fictively singing crickets, the effect of short air stimuli is either to terminate prematurely or to lengthen the interchirp interval, depending on their phase in the chirp cycle. Within our stimulation paradigm, air stimuli of different velocities and durations always elicited an inhibitory postsynaptic potential in the singing interneuron. Current injection in the singing interneuron elicited singing motor activity, even during the air current-evoked inhibitory input from the cercal pathway. The disruptive effects of air stimuli on the fictive singing pattern and the inhibitory response of the singing interneuron point toward the cercal system being involved in initiating avoidance responses in singing crickets, according to the established role of cerci in a predator escape pathway. After abolishing the activity of the cercal system, the timing of natural singing activity was not significantly altered. Our study provides no evidence that self-generated cercal sensory activity has a feedback function for singing motor pattern generation. PMID:26334014

Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin.

Science.gov (United States)

Butler, Corwin R; Boychuk, Jeffery A; Smith, Bret N

2017-01-01

Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.

Targeted Ablation and Reorganization of the Principal Preplate Neurons and Their Neuroblasts Identified by Golli Promoter Transgene Expression in the Neocortex of Mice

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Yuan-Yun Xie

2009-10-01

Full Text Available The present study delineates the cellular responses of dorsal pallium to targeted genetic ablation of the principal preplate neurons of the neocortex. Ganciclovir treatment during prenatal development (E11-E13; where E is embryonic day of mice selectively killed cells with shared S-phase vulnerability and targeted expression of a GPT [golli promoter transgene, linked to HSV-TK (herpes simplex virus-thymidine kinase, τ-eGFP (τ-enhanced green fluorescent protein and lacZ (lacZ galactosidase reporters] localized in preplate neurons. Morphogenetic fates of attacked neurons and neuroblasts, and their successors, were assessed by multiple labelling in time-series comparisons between ablated (HSV-TK+/0 and control (HSV-TK0/0 littermates. During ablation generation, neocortical growth was suppressed, and compensatory reorganization of non-GPT ventricular zone progenitors of dorsal pallium produced replacements for killed GPT neuroblasts. Replacement and surviving GPT neuroblasts then produced replacements for killed GPT neurons. Near-normal restoration of their complement delayed the settlement of GPT neurons into the reconstituted preplate, which curtailed the outgrowth of pioneer corticofugal axons. Based on this evidence, we conclude that specific cell killing in ablated mice can eliminate a major fraction of GPT neurons, with insignificant bystander killing. Also, replacement GPT neurons in ablated mice originate exclusively by proliferation from intermediate progenitor GPT neuroblasts, whose complement is maintained by non-GPT progenitors for inductive regulation of the total complement of GPT neurons. Finally, GPT neurons in both normal and ablated mice meet all morphogenetic criteria, including the ‘outside-in’ vertical gradient of settlement, presently used to identify principal preplate neurons. In ablated mice, delayed organization of these neurons desynchronizes and isolates developing neocortex from the rest of the brain, and

Martinotti cells: community organizers.

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Lee, Christine K; Huguenard, John R

2011-03-24

The specificity of connections made by inhibitory interneurons in the neocortex is not well understood. In this issue of Neuron, Fino and Yuste (2011) use an enhanced version of two-photon glutamate uncaging, which preserves inhibitory synaptic transmission, to demonstrate that somatostatin-positive interneurons form densely convergent connections onto pyramidal cells in layer 2/3 of mouse frontal cortex. Copyright © 2011 Elsevier Inc. All rights reserved.

Relaxin-3 inputs target hippocampal interneurons and deletion of hilar relaxin-3 receptors in "floxed-RXFP3" mice impairs spatial memory.

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Haidar, M; Guèvremont, G; Zhang, C; Bathgate, R A D; Timofeeva, E; Smith, C M; Gundlach, A L

2017-05-01

-like behavior in light/dark box and elevated-plus maze tests, and learning and long-term memory retention in the Morris water maze. These data indicate endogenous RLN3/RXFP3 signaling can modulate hippocampal-dependent spatial reference and working memory via effects on SST interneurons, and further our knowledge of hippocampal cognitive processing. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Ginseng Rb fraction protects glia, neurons and cognitive function in a rat model of neurodegeneration.

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Kangning Xu

Full Text Available The loss and injury of neurons play an important role in the onset of various neurodegenerative diseases, while both microgliosis and astrocyte loss or dysfunction are significant causes of neuronal degeneration. Previous studies have suggested that an extract enriched panaxadiol saponins from ginseng has more neuroprotective potential than the total saponins of ginseng. The present study investigated whether a fraction of highly purified panaxadiol saponins (termed as Rb fraction was protective for both glia and neurons, especially GABAergic interneurons, against kainic acid (KA-induced excitotoxicity in rats. Rats received Rb fraction at 30 mg/kg (i.p., 40 mg/kg (i.p. or saline followed 40 min later by an intracerebroventricular injection of KA. Acute hippocampal injury was determined at 48 h after KA, and impairment of hippocampus-dependent learning and memory as well as delayed neuronal injury was determined 16 to 21 days later. KA injection produced significant acute hippocampal injuries, including GAD67-positive GABAergic interneuron loss in CA1, paralbumin (PV-positive GABAergic interneuron loss, pyramidal neuron degeneration and astrocyte damage accompanied with reactive microglia in both CA1 and CA3 regions of the hippocampus. There was also a delayed loss of GAD67-positive interneurons in CA1, CA3, hilus and dentate gyrus. Microgliosis also became more severe 21 days later. Accordingly, KA injection resulted in hippocampus-dependent spatial memory impairment. Interestingly, the pretreatment with Rb fraction at 30 or 40 mg/kg significantly protected the pyramidal neurons and GABAergic interneurons against KA-induced acute excitotoxicity and delayed injury. Rb fraction also prevented memory impairments and protected astrocytes from KA-induced acute excitotoxicity. Additionally, microglial activation, especially the delayed microgliosis, was inhibited by Rb fraction. Overall, this study demonstrated that Rb fraction protected both

Dopamine negatively modulates the NCA ion channels in C. elegans.

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Topalidou, Irini; Cooper, Kirsten; Pereira, Laura; Ailion, Michael

2017-10-01

The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.

Characterization of neurons in the cortical white matter in human temporal lobe epilepsy.

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Richter, Zsófia; Janszky, József; Sétáló, György; Horváth, Réka; Horváth, Zsolt; Dóczi, Tamás; Seress, László; Ábrahám, Hajnalka

2016-10-01

The aim of the present work was to characterize neurons in the archi- and neocortical white matter, and to investigate their distribution in mesial temporal sclerosis. Immunohistochemistry and quantification of neurons were performed on surgically resected tissue sections of patients with therapy-resistant temporal lobe epilepsy. Temporal lobe tissues of patients with tumor but without epilepsy and that from autopsy were used as controls. Neurons were identified with immunohistochemistry using antibodies against NeuN, calcium-binding proteins, transcription factor Tbr1 and neurofilaments. We found significantly higher density of neurons in the archi- and neocortical white matter of patients with temporal lobe epilepsy than in that of controls. Based on their morphology and neurochemical content, both excitatory and inhibitory cells were present among these neurons. A subset of neurons in the white matter was Tbr-1-immunoreactive and these neurons coexpressed NeuN and neurofilament marker SMI311R. No colocalization of Tbr1 was observed with the inhibitory neuronal markers, calcium-binding proteins. We suggest that a large population of white matter neurons comprises remnants of the subplate. Furthermore, we propose that a subset of white matter neurons was arrested during migration, highlighting the role of cortical maldevelopment in epilepsy associated with mesial temporal sclerosis. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

A hypothesis for the evolution of the upper layers of the neocortex through co-option of the olfactory cortex developmental program.

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Federico eLuzzati

2015-05-01

Full Text Available The neocortex is unique to mammals and its evolutionary origin is still highly debated. The neocortex is generated by the dorsal pallium ventricular zone, a germinative domain that in reptiles give rise to the dorsal cortex. Whether this latter allocortical structure contains homologues of all neocortical cell types it is unclear. Recently we described a population of DCX+/Tbr1+ cells that is specifically associated with the layer II of higher order areas of both the neocortex and of the more evolutionary conserved piriform cortex. In a reptile similar cells are present in the layer II of the olfactory cortex and the DVR but not in the dorsal cortex. These data are consistent with the proposal that the reptilian dorsal cortex is homologous only to the deep layers of the neocortex while the upper layers are a mammalian innovation. Based on our observations we extended these ideas by hypothesizing that this innovation was obtained by co-opting a lateral and/or ventral pallium developmental program. Interestingly, an analysis in the Allen brain atlas revealed a striking similarity in gene expression between neocortical layers II/III and piriform cortex. We thus propose a model in which the early neocortical column originated by the superposition of the lateral olfactory and dorsal cortex. This idea is consistent with previous hypotheses that the peri-allocortex (i.e insular and perirhinal cortex may represent the more ancient neocortical part. Our model may have also interesting implications in the study of sensory processing in both neocortex and piriform cortex. The great advances in deciphering the molecular logic of the amniote pallium developmental programs will hopefully enable to directly test our hypotheses in the next future.

Memory reactivation during rest supports upcoming learning of related content

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Schlichting, Margaret L.; Preston, Alison R.

2014-01-01

Although a number of studies have highlighted the importance of offline processes for memory, how these mechanisms influence future learning remains unknown. Participants with established memories for a set of initial face–object associations were scanned during passive rest and during encoding of new related and unrelated pairs of objects. Spontaneous reactivation of established memories and enhanced hippocampal–neocortical functional connectivity during rest was related to better subsequent learning, specifically of related content. Moreover, the degree of functional coupling during rest was predictive of neural engagement during the new learning experience itself. These results suggest that through rest-phase reactivation and hippocampal–neocortical interactions, existing memories may come to facilitate encoding during subsequent related episodes. PMID:25331890

Memory reactivation during rest supports upcoming learning of related content.

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Schlichting, Margaret L; Preston, Alison R

2014-11-04

Although a number of studies have highlighted the importance of offline processes for memory, how these mechanisms influence future learning remains unknown. Participants with established memories for a set of initial face-object associations were scanned during passive rest and during encoding of new related and unrelated pairs of objects. Spontaneous reactivation of established memories and enhanced hippocampal-neocortical functional connectivity during rest was related to better subsequent learning, specifically of related content. Moreover, the degree of functional coupling during rest was predictive of neural engagement during the new learning experience itself. These results suggest that through rest-phase reactivation and hippocampal-neocortical interactions, existing memories may come to facilitate encoding during subsequent related episodes.

Spatial integration in mouse primary visual cortex.

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Vaiceliunaite, Agne; Erisken, Sinem; Franzen, Florian; Katzner, Steffen; Busse, Laura

2013-08-01

Responses of many neurons in primary visual cortex (V1) are suppressed by stimuli exceeding the classical receptive field (RF), an important property that might underlie the computation of visual saliency. Traditionally, it has proven difficult to disentangle the underlying neural circuits, including feedforward, horizontal intracortical, and feedback connectivity. Since circuit-level analysis is particularly feasible in the mouse, we asked whether neural signatures of spatial integration in mouse V1 are similar to those of higher-order mammals and investigated the role of parvalbumin-expressing (PV+) inhibitory interneurons. Analogous to what is known from primates and carnivores, we demonstrate that, in awake mice, surround suppression is present in the majority of V1 neurons and is strongest in superficial cortical layers. Anesthesia with isoflurane-urethane, however, profoundly affects spatial integration: it reduces the laminar dependency, decreases overall suppression strength, and alters the temporal dynamics of responses. We show that these effects of brain state can be parsimoniously explained by assuming that anesthesia affects contrast normalization. Hence, the full impact of suppressive influences in mouse V1 cannot be studied under anesthesia with isoflurane-urethane. To assess the neural circuits of spatial integration, we targeted PV+ interneurons using optogenetics. Optogenetic depolarization of PV+ interneurons was associated with increased RF size and decreased suppression in the recorded population, similar to effects of lowering stimulus contrast, suggesting that PV+ interneurons contribute to spatial integration by affecting overall stimulus drive. We conclude that the mouse is a promising model for circuit-level mechanisms of spatial integration, which relies on the combined activity of different types of inhibitory interneurons.

Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy

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Buckmaster, Paul S.; Abrams, Emily; Wen, Xiling

2018-01-01

Epilepsy occurs in one of 26 people. Temporal lobe epilepsy is common and can be difficult to treat effectively. It can develop after brain injuries that damage the hippocampus. Multiple pathophysiological mechanisms involving the hippocampal dentate gyrus have been proposed. This study evaluated a mouse model of temporal lobe epilepsy to test which pathological changes in the dentate gyrus correlate with seizure frequency and help prioritize potential mechanisms for further study. FVB mice (n = 127) that had experienced status epilepticus after systemic treatment with pilocarpine 31–61 days earlier were video-monitored for spontaneous, convulsive seizures 9 hr/day every day for 24–36 days. Over 4,060 seizures were observed. Seizure frequency ranged from an average of one every 3.6 days to one every 2.1 hr. Hippocampal sections were processed for Nissl stain, Prox1-immunocytochemistry, GluR2-immunocytochemistry, Timm stain, glial fibrillary acidic protein-immunocytochemistry, glutamic acid decarboxylase in situ hybridization, and parvalbumin-immunocytochemistry. Stereological methods were used to measure hilar ectopic granule cells, mossy cells, mossy fiber sprouting, astrogliosis, and GABAergic interneurons. Seizure frequency was not significantly correlated with the generation of hilar ectopic granule cells, the number of mossy cells, the extent of mossy fiber sprouting, the extent of astrogliosis, or the number of GABAergic interneurons in the molecular layer or hilus. Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons. These findings prioritize the loss of granule cell layer interneurons for further testing as a potential cause of temporal lobe epilepsy. PMID:28425097

Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy.

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Buckmaster, Paul S; Abrams, Emily; Wen, Xiling

2017-08-01

Epilepsy occurs in one of 26 people. Temporal lobe epilepsy is common and can be difficult to treat effectively. It can develop after brain injuries that damage the hippocampus. Multiple pathophysiological mechanisms involving the hippocampal dentate gyrus have been proposed. This study evaluated a mouse model of temporal lobe epilepsy to test which pathological changes in the dentate gyrus correlate with seizure frequency and help prioritize potential mechanisms for further study. FVB mice (n = 127) that had experienced status epilepticus after systemic treatment with pilocarpine 31-61 days earlier were video-monitored for spontaneous, convulsive seizures 9 hr/day every day for 24-36 days. Over 4,060 seizures were observed. Seizure frequency ranged from an average of one every 3.6 days to one every 2.1 hr. Hippocampal sections were processed for Nissl stain, Prox1-immunocytochemistry, GluR2-immunocytochemistry, Timm stain, glial fibrillary acidic protein-immunocytochemistry, glutamic acid decarboxylase in situ hybridization, and parvalbumin-immunocytochemistry. Stereological methods were used to measure hilar ectopic granule cells, mossy cells, mossy fiber sprouting, astrogliosis, and GABAergic interneurons. Seizure frequency was not significantly correlated with the generation of hilar ectopic granule cells, the number of mossy cells, the extent of mossy fiber sprouting, the extent of astrogliosis, or the number of GABAergic interneurons in the molecular layer or hilus. Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons. These findings prioritize the loss of granule cell layer interneurons for further testing as a potential cause of temporal lobe epilepsy. © 2017 Wiley Periodicals, Inc.

Distribution and morphology of nitridergic neurons across functional domains of the rat primary somatosensory cortex

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Anaelli A Nogueira-Campos

2012-11-01

Full Text Available The rat primary somatosensory cortex (S1 is remarkable for its conspicuous vertical compartmentalization in barrels and septal columns, which are additionally stratified in horizontal layers. Whereas excitatory neurons from each of these compartments perform different types of processing, the role of interneurons is much less clear. Among the numerous types of GABAergic interneurons, those producing nitric oxide (NO are especially puzzling, since this gaseous messenger can modulate neural activity, synaptic plasticity and neurovascular coupling. We used a quantitative morphological approach to investigate whether nitrergic interneurons, which might therefore be considered both as NO volume diffusers and as elements of local circuitry, display features that could relate to barrel cortex architecture. In fixed brain sections, nitrergic interneurons can be revealed by histochemical processing for NADPH-diaphorase (NADPHd. Here, the dendritic arbors of nitrergic neurons from different compartments of area S1 were 3D reconstructed from serial 200-μm thick sections, using 100x objective and the Neurolucida system. Standard morphological parameters were extracted for all individual arbors and compared across columns and layers. Wedge analysis was used to compute dendritic orientation indices. Supragranular layers displayed the highest density of nitrergic neurons, whereas layer IV contained nitrergic neurons with largest soma area. The highest nitrergic neuronal density was found in septa, where dendrites were previously characterized as more extense and ramified than in barrels. Dendritic arbors were not confined to the boundaries of the column nor layer of their respective soma, being mostly double-tufted and vertically oriented, except in supragranular layers. These data strongly suggest that nitrergic interneurons adapt their morphology to the dynamics of processing performed by cortical compartments.

Mechanisms of memory storage in a model perirhinal network.

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Samarth, Pranit; Ball, John M; Unal, Gunes; Paré, Denis; Nair, Satish S

2017-01-01

The perirhinal cortex supports recognition and associative memory. Prior unit recording studies revealed that recognition memory involves a reduced responsiveness of perirhinal cells to familiar stimuli whereas associative memory formation is linked to increasing perirhinal responses to paired stimuli. Both effects are thought to depend on perirhinal plasticity but it is unclear how the same network could support these opposite forms of plasticity. However, a recent study showed that when neocortical inputs are repeatedly activated, depression or potentiation could develop, depending on the extent to which the stimulated neocortical activity recruited intrinsic longitudinal connections. We developed a biophysically realistic perirhinal model that reproduced these phenomena and used it to investigate perirhinal mechanisms of associative memory. These analyzes revealed that associative plasticity is critically dependent on a specific subset of neurons, termed conjunctive cells (CCs). When the model network was trained with spatially distributed but coincident neocortical inputs, CCs acquired excitatory responses to the paired inputs and conveyed them to distributed perirhinal sites via longitudinal projections. CC ablation during recall abolished expression of the associative memory. However, CC ablation during training did not prevent memory formation because new CCs emerged, revealing that competitive synaptic interactions governs the formation of CC assemblies.

Virtual endocasts of Eocene Paramys (Paramyinae): oldest endocranial record for Rodentia and early brain evolution in Euarchontoglires.

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Bertrand, Ornella C; Amador-Mughal, Farrah; Silcox, Mary T

2016-01-27

Understanding the pattern of brain evolution in early rodents is central to reconstructing the ancestral condition for Glires, and for other members of Euarchontoglires including Primates. We describe the oldest virtual endocasts known for fossil rodents, which pertain to Paramys copei (Early Eocene) and Paramys delicatus (Middle Eocene). Both specimens of Paramys have larger olfactory bulbs and smaller paraflocculi relative to total endocranial volume than later occurring rodents, which may be primitive traits for Rodentia. The encephalization quotients (EQs) of Pa. copei and Pa. delicatus are higher than that of later occurring (Oligocene) Ischyromys typus, which contradicts the hypothesis that EQ increases through time in all mammalian orders. However, both species of Paramys have a lower relative neocortical surface area than later rodents, suggesting neocorticalization occurred through time in this Order, although to a lesser degree than in Primates. Paramys has a higher EQ but a lower neocortical ratio than any stem primate. This result contrasts with the idea that primates were always exceptional in their degree of overall encephalization and shows that relative brain size and neocortical surface area do not necessarily covary through time. As such, these data contradict assumptions made about the pattern of brain evolution in Euarchontoglires. © 2016 The Author(s).

Thalamocortical control of feed-forward inhibition in awake somatosensory 'barrel' cortex.

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Swadlow, Harvey A

2002-01-01

Intracortical inhibition plays a role in shaping sensory cortical receptive fields and is mediated by both feed-forward and feedback mechanisms. Feed-forward inhibition is the faster of the two processes, being generated by inhibitory interneurons driven by monosynaptic thalamocortical (TC) input. In principle, feed-forward inhibition can prevent targeted cortical neurons from ever reaching threshold when TC input is weak. To do so, however, inhibitory interneurons must respond to TC input at...

Changes in neural network homeostasis trigger neuropsychiatric symptoms.

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Winkelmann, Aline; Maggio, Nicola; Eller, Joanna; Caliskan, Gürsel; Semtner, Marcus; Häussler, Ute; Jüttner, René; Dugladze, Tamar; Smolinsky, Birthe; Kowalczyk, Sarah; Chronowska, Ewa; Schwarz, Günter; Rathjen, Fritz G; Rechavi, Gideon; Haas, Carola A; Kulik, Akos; Gloveli, Tengis; Heinemann, Uwe; Meier, Jochen C

2014-02-01

The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain-of-function GlyR in terminals of glutamatergic cells or in parvalbumin-positive interneurons persistently altered neural network excitability. The increased network excitability associated with gain-of-function GlyR expression in glutamatergic neurons resulted in recurrent epileptiform discharge, which provoked cognitive dysfunction and memory deficits without affecting bidirectional synaptic plasticity. In contrast, decreased network excitability due to gain-of-function GlyR expression in parvalbumin-positive interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or discriminative associative memory. Our animal model unveils neuron type-specific effects on cognition, formation of discriminative associative memory, and emotional behavior in vivo. Furthermore, our data identify a presynaptic disease-causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms.

Schemas and memory consolidation.

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Tse, Dorothy; Langston, Rosamund F; Kakeyama, Masaki; Bethus, Ingrid; Spooner, Patrick A; Wood, Emma R; Witter, Menno P; Morris, Richard G M

2007-04-06

Memory encoding occurs rapidly, but the consolidation of memory in the neocortex has long been held to be a more gradual process. We now report, however, that systems consolidation can occur extremely quickly if an associative "schema" into which new information is incorporated has previously been created. In experiments using a hippocampal-dependent paired-associate task for rats, the memory of flavor-place associations became persistent over time as a putative neocortical schema gradually developed. New traces, trained for only one trial, then became assimilated and rapidly hippocampal-independent. Schemas also played a causal role in the creation of lasting associative memory representations during one-trial learning. The concept of neocortical schemas may unite psychological accounts of knowledge structures with neurobiological theories of systems memory consolidation.

Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice

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Vecchia, Dania; Tottene, Angelita; van den Maagdenberg, Arn M.J.M.; Pietrobon, Daniela

2014-01-01

Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca2+] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory–inhibitory balance in FHM1. PMID:24907493

Distinct behavioral consequences of short-term and prolonged GABAergic depletion in prefrontal cortex and dorsal hippocampus

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Judith M. Reichel

2015-01-01

Full Text Available GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epileptic seizures or schizophrenia. Schizophrenia itself is clinically defined by negative- (e.g. depression and positive- (e.g. hallucinations symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved.Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs in vitro and in vivo. Given their involvement in Schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC and dorsal hippocampus (dHPC in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days and short-term (< 14 days GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories.

Histamine facilitates GABAergic transmission in the rat entorhinal cortex: Roles of H1 and H2 receptors, Na+ -permeable cation channels, and inward rectifier K+ channels.

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Cilz, Nicholas I; Lei, Saobo

2017-05-01

In the brain, histamine (HA) serves as a neuromodulator and a neurotransmitter released from the tuberomammillary nucleus (TMN). HA is involved in wakefulness, thermoregulation, energy homeostasis, nociception, and learning and memory. The medial entorhinal cortex (MEC) receives inputs from the TMN and expresses HA receptors (H 1 , H 2 , and H 3 ). We investigated the effects of HA on GABAergic transmission in the MEC and found that HA significantly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) with an EC 50 of 1.3 µM, but failed to significantly alter sIPSC amplitude. HA-induced increases in sIPSC frequency were sensitive to tetrodotoxin (TTX), required extracellular Ca 2+ , and persisted when GDP-β-S, a G-protein inactivator, was applied postsynaptically via the recording pipettes, indicating that HA increased GABA release by facilitating the excitability of GABAergic interneurons in the MEC. Recordings from local MEC interneurons revealed that HA significantly increased their excitability as determined by membrane depolarization, generation of an inward current at -65 mV, and augmentation of action potential firing frequency. Both H 1 and H 2 receptors were involved in HA-induced increases in sIPSCs and interneuron excitability. Immunohistochemical staining showed that both H 1 and H 2 receptors are expressed on GABAergic interneurons in the MEC. HA-induced depolarization of interneurons involved a mixed ionic mechanism including activation of a Na + -permeable cation channel and inhibition of a cesium-sensitive inward rectifier K + channel, although HA also inhibited the delayed rectifier K + channels. Our results may provide a cellular mechanism, at least partially, to explain the roles of HA in the brain. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex.

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Du, X; Serena, K; Hwang, W; Grech, A M; Wu, Y W C; Schroeder, A; Hill, R A

2018-04-01

Brain-derived neurotrophic factor (BDNF) is known to play a critical role early in the development of cortical GABAergic interneurons. Recently our laboratory and others have shown protracted development of specific subpopulations of GABAergic interneurons extending into adolescence. BDNF expression also changes significantly across adolescent development. However the role of BDNF in regulating GABAergic changes across adolescence remains unclear. Here, we performed a week-by-week analysis of the protein expression and cell density of three major GABAergic interneurons, parvalbumin (PV), somatostatin (SST) and calretinin (Cal) in the medial prefrontal cortex from prepubescence (week 3) to adulthood (week 12). In order to assess how BDNF and sex might influence the adolescent trajectory of GABAergic interneurons we compared WT as well as BDNF heterozygous (+/-) male and female mice. In both males and females PV expression increases during adolescent development in the mPFC. Compared to wild-types, PV expression was reduced in male but not female BDNF+/- mice throughout adolescent development. This reduction in protein expression corresponded with reduced cell density, specifically within the infralimbic prefrontal cortex. SST expression increased in early adolescent WT females and this upregulation was delayed in BDNF+/-. SST cell density also increased in early adolescent mPFC of WT female mice, with BDNF+/- again showing a reduced pattern of expression. Cal protein expression was also sex-dependently altered across adolescence with WT males showing a steady decline but that of BDNF+/- remaining unaltered. Reduced cell density in on the other hand was observed particularly in male BDNF+/- mice. In females, Cal protein expression and cell density remained largely stable. Our results show that PV, SST and calretinin interneurons are indeed still developing into early adolescence in the mPFC and that BDNF plays a critical, sex-specific role in mediating expression and

Activation of specific neuronal networks leads to different seizure onset types.

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Shiri, Zahra; Manseau, Frédéric; Lévesque, Maxime; Williams, Sylvain; Avoli, Massimo

2016-03-01

Ictal events occurring in temporal lobe epilepsy patients and in experimental models mimicking this neurological disorder can be classified, based on their onset pattern, into low-voltage, fast versus hypersynchronous onset seizures. It has been suggested that the low-voltage, fast onset pattern is mainly contributed by interneuronal (γ-aminobutyric acidergic) signaling, whereas the hypersynchronous onset involves the activation of principal (glutamatergic) cells. Here, we tested this hypothesis using the optogenetic control of parvalbumin-positive or somatostatin-positive interneurons and of calmodulin-dependent, protein kinase-positive, principal cells in the mouse entorhinal cortex in the in vitro 4-aminopyridine model of epileptiform synchronization. We found that during 4-aminopyridine application, both spontaneous seizure-like events and those induced by optogenetic activation of interneurons displayed low-voltage, fast onset patterns that were associated with a higher occurrence of ripples than of fast ripples. In contrast, seizures induced by the optogenetic activation of principal cells had a hypersynchronous onset pattern with fast ripple rates that were higher than those of ripples. Our results firmly establish that under a similar experimental condition (ie, bath application of 4-aminopyridine), the initiation of low-voltage, fast and of hypersynchronous onset seizures in the entorhinal cortex depends on the preponderant involvement of interneuronal and principal cell networks, respectively. © 2016 American Neurological Association.

Inward rectifier K+ channel and T-type Ca2+ channel contribute to enhancement of GABAergic transmission induced by β1-adrenoceptor in the prefrontal cortex.

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Luo, Fei; Zheng, Jian; Sun, Xuan; Tang, Hua

2017-02-01

The functions of prefrontal cortex (PFC) are sensitive to norepinephrine (NE). Endogenously released NE influences synaptic transmission through activation of different subtypes of adrenergic receptors in PFC including α 1 , α 2 , β 1 or β 2 -adrenoceptor. Our recent study has revealed that β 1 -adrenoceptor (β 1 -AR) activation modulates glutamatergic transmission in the PFC, whereas the roles of β 1 -AR in GABAergic transmission are elusive. In the current study, we probed the effects of the β 1 -AR agonist dobutamine (Dobu) on GABAergic transmission onto pyramidal neurons in the PFC of juvenile rats. Dobu increased both the frequency and amplitude of miniature IPSCs (mIPSCs). Ca 2+ influx through T-type voltage-gated Ca 2+ channel was required for Dobu-enhanced mIPSC frequency. We also found that Dobu facilitated GABA release probability and the number of releasable vesicles through regulating T-type Ca 2+ channel. Dobu depolarized GABAergic fast-spiking (FS) interneurons with no effects on the firing rate of action potentials (APs) of interneurons. Dobu-induced depolarization of FS interneurons required inward rectifier K + channel (Kir). Our results suggest that Dobu increase GABA release via inhibition of Kir, which further depolarizes FS interneurons resulting in Ca 2+ influx via T-type Ca 2+ channel. Copyright © 2016 Elsevier Inc. All rights reserved.

Neurog1 Genetic Inducible Fate Mapping (GIFM) Reveals the Existence of Complex Spatiotemporal Cyto-Architectures in the Developing Cerebellum.

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Obana, Edwin A; Lundell, Travis G; Yi, Kevin J; Radomski, Kryslaine L; Zhou, Qiong; Doughty, Martin L

2015-06-01

Neurog1 is a pro-neural basic helix-loop-helix (bHLH) transcription factor expressed in progenitor cells located in the ventricular zone and subsequently the presumptive white matter tracts of the developing mouse cerebellum. We used genetic inducible fate mapping (GIFM) with a transgenic Neurog1-CreER allele to characterize the contributions of Neurog1 lineages to cerebellar circuit formation in mice. GIFM reveals Neurog1-expressing progenitors are fate-mapped to become Purkinje cells and all GABAergic interneuron cell types of the cerebellar cortex but not glia. The spatiotemporal sequence of GIFM is unique to each neuronal cell type. GIFM on embryonic days (E) 10.5 to E12.5 labels Purkinje cells with different medial-lateral settling patterns depending on the day of tamoxifen delivery. GIFM on E11.5 to P7 labels interneurons and the timing of tamoxifen administration correlates with the final inside-to-outside resting position of GABAergic interneurons in the cerebellar cortex. Proliferative status and long-term BrdU retention of GIFM lineages reveals Purkinje cells express Neurog1 around the time they become post-mitotic. In contrast, GIFM labels mitotic and post-mitotic interneurons. Neurog1-CreER GIFM reveals a correlation between the timing of Neurog1 expression and the spatial organization of GABAergic neurons in the cerebellar cortex with possible implications for cerebellar circuit assembly.

Neocortical connectivity during episodic memory formation.

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Summerfield, Christopher; Greene, Matthew; Wager, Tor; Egner, Tobias; Hirsch, Joy; Mangels, Jennifer

2006-05-01

During the formation of new episodic memories, a rich array of perceptual information is bound together for long-term storage. However, the brain mechanisms by which sensory representations (such as colors, objects, or individuals) are selected for episodic encoding are currently unknown. We describe a functional magnetic resonance imaging experiment in which participants encoded the association between two classes of visual stimuli that elicit selective responses in the extrastriate visual cortex (faces and houses). Using connectivity analyses, we show that correlation in the hemodynamic signal between face- and place-sensitive voxels and the left dorsolateral prefrontal cortex is a reliable predictor of successful face-house binding. These data support the view that during episodic encoding, "top-down" control signals originating in the prefrontal cortex help determine which perceptual information is fated to be bound into the new episodic memory trace.

Neocortical connectivity during episodic memory formation.

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Christopher Summerfield

2006-05-01

Full Text Available During the formation of new episodic memories, a rich array of perceptual information is bound together for long-term storage. However, the brain mechanisms by which sensory representations (such as colors, objects, or individuals are selected for episodic encoding are currently unknown. We describe a functional magnetic resonance imaging experiment in which participants encoded the association between two classes of visual stimuli that elicit selective responses in the extrastriate visual cortex (faces and houses. Using connectivity analyses, we show that correlation in the hemodynamic signal between face- and place-sensitive voxels and the left dorsolateral prefrontal cortex is a reliable predictor of successful face-house binding. These data support the view that during episodic encoding, "top-down" control signals originating in the prefrontal cortex help determine which perceptual information is fated to be bound into the new episodic memory trace.

Cell-specific expression of calcineurin immunoreactivity within the rat basolateral amygdala complex and colocalization with the neuropeptide Y Y1 receptor.

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Leitermann, Randy J; Sajdyk, Tammy J; Urban, Janice H

2012-10-01

Neuropeptide Y (NPY) produces potent anxiolytic effects via activation of NPY Y1 receptors (Y1r) within the basolateral amygdaloid complex (BLA). The role of NPY in the BLA was recently expanded to include the ability to produce stress resilience and long-lasting reductions in anxiety-like behavior. These persistent behavioral effects are dependent upon activity of the protein phosphatase, calcineurin (CaN), which has long been associated with shaping long-term synaptic signaling. Furthermore, NPY-induced reductions in anxiety-like behavior persist months after intra-BLA delivery, which together indicate a form of neuronal plasticity had likely occurred. To define a site of action for NPY-induced CaN signaling within the BLA, we employed multi-label immunohistochemistry to determine which cell types express CaN and if CaN colocalizes with the Y1r. We have previously reported that both major neuronal cell populations in the BLA, pyramidal projection neurons and GABAergic interneurons, express the Y1r. Therefore, this current study evaluated CaN immunoreactivity in these cell types, along with Y1r immunoreactivity. Antibodies against calcium-calmodulin kinase II (CaMKII) and GABA were used to identify pyramidal neurons and GABAergic interneurons, respectively. A large population of CaN immunoreactive cells displayed Y1r immunoreactivity (90%). Nearly all (98%) pyramidal neurons displayed CaN immunoreactivity, while only a small percentage of interneurons (10%) contained CaN immunoreactivity. Overall, these anatomical findings provide a model whereby NPY could directly regulate CaN activity in the BLA via activation of the Y1r on CaN-expressing, pyramidal neurons. Importantly, they support BLA pyramidal neurons as prime targets for neuronal plasticity associated with the long-term reductions in anxiety-like behavior produced by NPY injections into the BLA. Copyright © 2012 Elsevier B.V. All rights reserved.

Expression of Kv3.1b potassium channel is widespread in macaque motor cortex pyramidal cells: A histological comparison between rat and macaque.

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Soares, David; Goldrick, Isabelle; Lemon, Roger N; Kraskov, Alexander; Greensmith, Linda; Kalmar, Bernadett

2017-06-15

There are substantial differences across species in the organization and function of the motor pathways. These differences extend to basic electrophysiological properties. Thus, in rat motor cortex, pyramidal cells have long duration action potentials, while in the macaque, some pyramidal neurons exhibit short duration "thin" spikes. These differences may be related to the expression of the fast potassium channel Kv3.1b, which in rat interneurons is associated with generation of thin spikes. Rat pyramidal cells typically lack these channels, while there are reports that they are present in macaque pyramids. Here we made a systematic, quantitative comparison of the Kv3.1b expression in sections from macaque and rat motor cortex, using two different antibodies (NeuroMab, Millipore). As our standard reference, we examined, in the same sections, Kv3.1b staining in parvalbumin-positive interneurons, which show strong Kv3.1b immunoreactivity. In macaque motor cortex, a large sample of pyramidal neurons were nearly all found to express Kv3.1b in their soma membranes. These labeled neurons were identified as pyramidal based either by expression of SMI32 (a pyramidal marker), or by their shape and size, and lack of expression of parvalbumin (a marker for some classes of interneuron). Large (Betz cells), medium, and small pyramidal neurons all expressed Kv3.1b. In rat motor cortex, SMI32-postive pyramidal neurons expressing Kv3.1b were very rare and weakly stained. Thus, there is a marked species difference in the immunoreactivity of Kv3.1b in pyramidal neurons, and this may be one of the factors explaining the pronounced electrophysiological differences between rat and macaque pyramidal neurons. © 2017 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Mapping thalamocortical network pathology in temporal lobe epilepsy.

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Bernhardt, Boris C; Bernasconi, Neda; Kim, Hosung; Bernasconi, Andrea

2012-01-10

Although experimental work has provided evidence that the thalamus is a crucial relay structure in temporal lobe epilepsy (TLE), the relation of the thalamus to neocortical pathology remains unclear. To assess thalamocortical network pathology in TLE, we mapped pointwise patterns of thalamic atrophy and statistically related them to neocortical thinning. We studied cross-sectionally 36 patients with drug-resistant TLE and 19 age- and sex-matched healthy control subjects using high-resolution MRI. To localize thalamic pathology, we converted manual labels into surface meshes using the spherical harmonic description and calculated local deformations relative to a template. In addition, we measured cortical thickness by means of the constrained Laplacian anatomic segmentation using proximity algorithm. Compared with control subjects, patients with TLE showed ipsilateral thalamic atrophy that was located along the medial surface, encompassing anterior, medial, and posterior divisions. Unbiased analysis correlating the degree of medial thalamic atrophy with cortical thickness measurements mapped bilateral frontocentral, lateral temporal, and mesiotemporal cortices. These areas overlapped with those of cortical thinning found when patients were compared with control subjects. Thalamic atrophy intensified with a longer duration of epilepsy and was more severe in patients with a history of febrile convulsions. The degree and distribution of thalamic pathology relates to the topography and extent of neocortical atrophy, lending support to the concept that the thalamus is an important hub in the pathologic network of TLE.

Modulatory Effects of Dopamine D2 Receptors on Spreading Depression in Rat Somatosensory Neocortex

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Anna Maria Haarmann

2014-11-01

Full Text Available Introduction: Spreading depression (SD is a propagating wave of depolarization followed by depression of the neuroglial activities and can modulate extracellular dopamine concentrations in the neocortex. It has been shown that the dopaminergic system plays a role in migraine. SD has been suggested as a critical phenomenon in the pathophysiology of migraine. The aim of this study was to investigate the effect of dopamine D2 receptors on the characteristic features of SD in rat neocortical tissues. Methods: The effect of dopamine D2 receptor agonist quinpirole and D2 receptor antagonist sulpiride was tested on different characteristic features (amplitude, duration and velocity of KCl-induced SD in somatosensory neocortical slices of adult rats. The effect of above-mentioned substances on production of long-term potentiation (LTP in the neocortex was also evaluated. Results: The present data revealed a dose-dependent suppression of the amplitude and duration of SD in the presence of the dopamine D2 receptor antagonist sulpiride in the neocortex. D2 dopamine receptor agonist quinpirole dose-dependently enhanced the amplitude and duration of the neocortical SD. Furthermore, application of D2 receptor antagonist significantly suppressed induction of LTP. Discussion: These results indicate that D2 receptors modulate the initiation of SD in the neocortex. This finding refers to the potential role of D2 receptor antagonist in treatment of migraine pain.