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Sample records for neurochemically distinct interneuron

  1. A NOVEL FUNCTIONALLY DISTINCT SUBTYPE OF STRIATAL NPY INTERNEURON

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    Ibáñez-Sandoval, Osvaldo; Tecuapetla, Fatuel; Unal, Bengi; Shah, Fulva; Koós, Tibor; Tepper, James M.

    2011-01-01

    We investigated the properties of neostriatal neuropeptide Y (NPY)-expressing interneurons in transgenic green fluorescent protein (GFP)-NPY reporter mice. In vitro whole cell recordings and biocytin staining demonstrated the existence of a novel class of neostriatal NPY-expressing GABAergic interneurons that exhibit electrophysiological, neurochemical and morphological properties strikingly different from those of previously described NPY-containing, plateau-depolarization low-threshold spike (NPY-PLTS) interneurons. The novel NPY interneuron type (NPY-neurogliaform) differed from previously described NPY-PLTS interneurons by exhibiting a significantly lower input resistance and hyperpolarized membrane potential, regular, non-accommodating spiking in response to depolarizing current injections and an absence of plateau depolarizations or low threshold spikes. NPY-neurogliaform interneurons were also easily distinguished morphologically by their dense compact and highly branched dendritic and local axonal arborizations that contrasted sharply with the sparse and extended axonal and dendritic arborizations of NPY-PLTS interneurons. Further, NPY-neurogliaform interneurons did not express immunofluorescence for somatostatin or nitric oxide synthase that was ubiquitous in NPY-PLTS interneurons. IPSP/Cs could only rarely be elicited in spiny projection neurons (SPN) in paired recordings with NPY-PLTS interneurons. In contrast, the probability of SPN innervation by NPY-neurogliaform interneurons was extremely high, the synapse very reliable (no failures were observed), and the resulting postsynaptic response was a slow, GABAA receptor-mediated inhibitory postsynaptic current (IPSC) that has not been previously described in striatum, but that has been elicited from NPY-GABAergic neurogliaform interneurons in cortex and hippocampus. These properties suggest unique and distinctive roles for NPY-PLTS and NPY-neurogliaform interneurons in the integrative properties of the

  2. Distinct Translaminar Glutamatergic Circuits to GABAergic Interneurons in the Neonatal Auditory Cortex

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    Rongkang Deng

    2017-05-01

    Full Text Available GABAergic activity is important in neocortical development and plasticity. Because the maturation of GABAergic interneurons is regulated by neural activity, the source of excitatory inputs to GABAergic interneurons plays a key role in development. We show, by laser-scanning photostimulation, that layer 4 and layer 5 GABAergic interneurons in the auditory cortex in neonatal mice (interneurons showed two spatial patterns of translaminar connection: inputs originating predominantly from supragranular or from supragranular and infragranular layers, including the subplate, which relays early thalamocortical activity. Sensory deprivation altered the development of translaminar inputs. Thus, distinct translaminar circuits to GABAergic interneurons exist throughout development, and the maturation of excitatory synapses is input-specific. Glutamatergic signaling from subplate and intracortical sources likely plays a role in the maturation of GABAergic interneurons.

  3. Metabolomics reveals distinct neurochemical profiles associated with stress resilience

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    Brooke N. Dulka

    2017-12-01

    Full Text Available Acute social defeat represents a naturalistic form of conditioned fear and is an excellent model in which to investigate the biological basis of stress resilience. While there is growing interest in identifying biomarkers of stress resilience, until recently, it has not been feasible to associate levels of large numbers of neurochemicals and metabolites to stress-related phenotypes. The objective of the present study was to use an untargeted metabolomics approach to identify known and unknown neurochemicals in select brain regions that distinguish susceptible and resistant individuals in two rodent models of acute social defeat. In the first experiment, male mice were first phenotyped as resistant or susceptible. Then, mice were subjected to acute social defeat, and tissues were immediately collected from the ventromedial prefrontal cortex (vmPFC, basolateral/central amygdala (BLA/CeA, nucleus accumbens (NAc, and dorsal hippocampus (dHPC. Ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-HRMS was used for the detection of water-soluble neurochemicals. In the second experiment, male Syrian hamsters were paired in daily agonistic encounters for 2 weeks, during which they formed stable dominant-subordinate relationships. Then, 24 h after the last dominance encounter, animals were exposed to acute social defeat stress. Immediately after social defeat, tissue was collected from the vmPFC, BLA/CeA, NAc, and dHPC for analysis using UPLC-HRMS. Although no single biomarker characterized stress-related phenotypes in both species, commonalities were found. For instance, in both model systems, animals resistant to social defeat stress also show increased concentration of molecules to protect against oxidative stress in the NAc and vmPFC. Additionally, in both mice and hamsters, unidentified spectral features were preliminarily annotated as potential targets for future experiments. Overall, these findings

  4. Subtype-specific reduction of olfactory bulb interneurons in Pax6 heterozygous mutant mice.

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    Haba, Hasumi; Nomura, Tadashi; Suto, Fumikazu; Osumi, Noriko

    2009-09-01

    Interneurons in the olfactory bulb (OB) play essential roles in the processing of olfactory information. They are classified into several subpopulations by the expression of different neurochemical markers. Here we focused on a transcription factor Pax6, and examined its expression and function in distinct subtypes of OB interneurons. We identified Pax6 expression in specific subtypes of interneurons in the external plexiform layer (EPL). The number of these interneuron subtypes was dramatically decreased in Pax6 heterozygous mutant mice. These results indicate that Pax6 is required for differentiation and/or maintenance of EPL interneurons in the adult mouse OB.

  5. Density and neurochemical profiles of neuronal nitric oxide synthase-expressing interneuron in the mouse basolateral amygdala.

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    Wang, Xiaona; Liu, Chunhua; Wang, Xiaochen; Gao, Fei; Zhan, Ren-Zhi

    2017-05-15

    Neuronal nitric oxide synthase (nNOS)-expressing interneurons reside in the basolateral nucleus of the amygdala (BLA) of rodents. In the present study, we immunohistochemically analyzed nNOS-positive cells in the mouse BLA by focusing on their density, γ-Aminobutyric acid (GABA)ergicity, and co-localization with calcium-binding proteins and neuropeptides. The density of nNOS-containing neurons was analyzed with unbiased stereology. Experiments were conducted in both adult wild-type C57BL/6 and glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mice, in which GFP is expressed in GABAergic neurons under the control of the endogenous GAD67 gene promoter. In the BLA, the density of nNOS-positive cells was 3.92×103cells/mm3. Immunofluorescence revealed that nNOS-containing neurons constituted almost 26.93±2.36% of the GAD67-GFP neurons. Almost every nNOS-positive cell expressed glutamic acid decarboxylase 65 (GAD65). Proportions of nNOS-positive interneurons that expressed calbindin, calretinin, parvalbumin, somatostatin and neuropeptide Y were approximately 5.20%, 15.63%, 26.50%, 87.50% and 88.00%, respectively; but exhibited no co-localization with vasoactive intestinal polypeptide. By contrast, percentages of calbindin, calretinin, parvalbumin, somatostatin and neuropeptide Y-positive cells that expressed nNOS were approximately 1.93%, 7.25%, 25.25%, 80.25% and 87.50%, respectively. Together, these findings suggest that nNOS-expressing cells are a discrete interneuronal subpopulation in the mouse BLA and may play a functional role in the inhibitory circuitry of this brain region. Copyright © 2017. Published by Elsevier B.V.

  6. Independent control of gamma and theta activity by distinct interneuron networks in the olfactory bulb.

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    Fukunaga, Izumi; Herb, Jan T; Kollo, Mihaly; Boyden, Edward S; Schaefer, Andreas T

    2014-09-01

    Circuits in the brain possess the ability to orchestrate activities on different timescales, but the manner in which distinct circuits interact to sculpt diverse rhythms remains unresolved. The olfactory bulb is a classic example of a place in which slow theta and fast gamma rhythms coexist. Furthermore, inhibitory interneurons that are generally implicated in rhythm generation are segregated into distinct layers, neatly separating local and global motifs. We combined intracellular recordings in vivo with circuit-specific optogenetic interference to examine the contribution of inhibition to rhythmic activity in the mouse olfactory bulb. We found that the two inhibitory circuits controlled rhythms on distinct timescales: local, glomerular networks coordinated theta activity, regulating baseline and odor-evoked inhibition, whereas granule cells orchestrated gamma synchrony and spike timing. Notably, granule cells did not contribute to baseline rhythms or sniff-coupled odor-evoked inhibition. Thus, activities on theta and gamma timescales are controlled by separate, dissociable inhibitory networks in the olfactory bulb.

  7. The gyri of the octopus vertical lobe have distinct neurochemical identities.

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    Shigeno, Shuichi; Ragsdale, Clifton W

    2015-06-15

    The cephalopod vertical lobe is the largest learning and memory structure known in invertebrate nervous systems. It is part of the visual learning circuit of the central brain, which also includes the superior frontal and subvertical lobes. Despite the well-established functional importance of this system, little is known about neuropil organization of these structures and there is to date no evidence that the five longitudinal gyri of the vertical lobe, perhaps the most distinctive morphological feature of the octopus brain, differ in their connections or molecular identities. We studied the histochemical organization of these structures in hatchling and adult Octopus bimaculoides brains with immunostaining for serotonin, octopus gonadotropin-releasing hormone (oGNRH), and octopressin-neurophysin (OP-NP). Our major finding is that the five lobules forming the vertical lobe gyri have distinct neurochemical signatures. This is most prominent in the hatchling brain, where the median and mediolateral lobules are enriched in OP-NP fibers, the lateral lobule is marked by oGNRH innervation, and serotonin immunostaining heavily labels the median and lateral lobules. A major source of input to the vertical lobe is the superior frontal lobe, which is dominated by a neuropil of interweaving fiber bundles. We have found that this neuropil also has an intrinsic neurochemical organization: it is partitioned into territories alternately enriched or impoverished in oGNRH-containing fascicles. Our findings establish that the constituent lobes of the octopus superior frontal-vertical system have an intricate internal anatomy, one likely to reflect the presence of functional subsystems within cephalopod learning circuitry. © 2015 Wiley Periodicals, Inc.

  8. Distinct Neurochemical Profiles of Spinocerebellar Ataxias 1, 2, 6, and Cerebellar Multiple System Atrophy

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    Öz, Gülin; Iltis, Isabelle; Hutter, Diane; Thomas, William; Bushara, Khalaf O.; Gomez, Christopher M.

    2011-01-01

    Hereditary and sporadic neurodegenerative ataxias are movement disorders that affect the cerebellum. Robust and objective biomarkers are critical for treatment trials of ataxias. In addition, such biomarkers may help discriminate between ataxia subtypes because these diseases display substantial overlap in clinical presentation and conventional MRI. Profiles of 10–13 neurochemical concentrations obtained in vivo by high field proton magnetic resonance spectroscopy (1H MRS) can potentially provide ataxia-type specific biomarkers. We compared cerebellar and brainstem neurochemical profiles measured at 4 T from 26 patients with spinocerebellar ataxias (SCA1, N=9; SCA2, N=7; SCA6, N=5) or cerebellar multiple system atrophy (MSA-C, N=5) and 15 age-matched healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA) was used to assess disease severity. The patterns of neurochemical alterations relative to controls differed between ataxia types. Myo-inositol levels in the vermis, myo-inositol, total N-acetylaspartate, total creatine, glutamate, glutamine in the cerebellar hemispheres and myo-inositol, total N-acetylaspartate, glutamate in the pons were significantly different between patient groups (Bonferroni corrected pataxia types. Studies with higher numbers of patients and other ataxias are warranted to further investigate the clinical utility of neurochemical levels as measured by high-field MRS as ataxia biomarkers. PMID:20838948

  9. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex.

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    Kvitsiani, D; Ranade, S; Hangya, B; Taniguchi, H; Huang, J Z; Kepecs, A

    2013-06-20

    Neurons in the prefrontal cortex exhibit diverse behavioural correlates, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically defined inhibitory interneuron classes, the perisomatically targeting parvalbumin (PV) and the dendritically targeting somatostatin (SOM) neurons in anterior cingulate cortex of mice performing a reward foraging task. Here we show that PV and a subtype of SOM neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory effects and behavioural correlates. Out of several events pertaining to behaviour, a subtype of SOM neurons selectively responded at reward approach, whereas PV neurons responded at reward leaving and encoded preceding stay duration. These behavioural correlates of PV and SOM neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to the anterior cingulate cortex. Furthermore, PV neurons could fire in millisecond synchrony, exerting fast and powerful inhibition on principal cell firing, whereas the inhibitory effect of SOM neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of, and inputs to, principal neurons. These results suggest a connection between the circuit-level function of different interneuron types in regulating the flow of information and the behavioural functions served by the cortical circuits. Moreover, these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity.

  10. Location matters: distinct DNA methylation patterns in GABAergic interneuronal populations from separate microcircuits within the human hippocampus.

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    Ruzicka, W Brad; Subburaju, Sivan; Coyle, Joseph T; Benes, Francine M

    2018-01-15

    Recent studies describe distinct DNA methylomes among phenotypic subclasses of neurons in the human brain, but variation in DNA methylation between common neuronal phenotypes distinguished by their function within distinct neural circuits remains an unexplored concept. Studies able to resolve epigenetic profiles at the level of microcircuits are needed to illuminate chromatin dynamics in the regulation of specific neuronal populations and circuits mediating normal and abnormal behaviors. The Illumina HumanMethylation450 BeadChip was used to assess genome-wide DNA methylation in stratum oriens GABAergic interneurons sampled by laser-microdissection from two discrete microcircuits along the trisynaptic pathway in postmortem human hippocampus from eight control, eight schizophrenia, and eight bipolar disorder subjects. Data were analysed using the minfi Bioconductor package in R software version 3.3.2. We identified 11 highly significant differentially methylated regions associated with a group of genes with high construct-validity, including multiple zinc finger of the cerebellum gene family members and WNT signaling factors. Genomic locations of differentially methylated regions were highly similar between diagnostic categories, with a greater number of differentially methylated individual cytosine residues between circuit locations in bipolar disorder cases than in schizophrenia or control (42, 7, and 7 differentially methylated positions, respectively). These findings identify distinct DNA methylomes among phenotypically similar populations of GABAergic interneurons functioning within separate hippocampal subfields. These data compliment recent studies describing diverse epigenotypes among separate neuronal subclasses, extending this concept to distinct epigenotypes within similar neuronal phenotypes from separate microcircuits within the human brain. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email

  11. 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.

  12. Excitation-transcription coupling in parvalbumin-positive interneurons employs a novel CaM Kinase-dependent pathway distinct from excitatory neurons

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    Cohen, Samuel M.; Ma, Huan; Kuchibhotla, Kishore V.; Watson, Brendon O.; Buzsáki, György; Froemke, Robert C.; Tsien, Richard W.

    2016-01-01

    Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. Here, we report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease. PMID:27041500

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

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    Matamales, Miriam; Götz, Jürgen; Bertran-Gonzalez, Jesus

    2016-01-01

    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 striatum.

  14. 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

  15. Social Stress Engages Neurochemically-Distinct Afferents to the Rat Locus Coeruleus Depending on Coping Strategy123

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    Reyes, Beverly A. S.; Zitnik, Gerard; Foster, Celia; Van Bockstaele, Elisabeth J.

    2015-01-01

    Abstract Stress increases vulnerability to psychiatric disorders, partly by affecting brain monoamine systems, such as the locus coeruleus (LC)-norepinephrine system. During stress, LC activity is coregulated by corticotropin-releasing factor (CRF) and endogenous opioids. This study identified neural circuitry that regulates LC activity of intruder rats during the resident–intruder model of social stress. LC afferents were retrogradely labeled with Fluorogold (FG) and rats were subjected to one or five daily exposures to an aggressive resident. Sections through the nucleus paragigantocellularis (PGi) and central amygdalar nucleus (CNA), major sources of enkephalin (ENK) and CRF LC afferents, respectively, were immunocytochemically processed to detect c-fos, FG, and CRF or ENK. In response to a single exposure, intruder rats assumed defeat with a relatively short latency (SL). LC neurons, PGI-ENK LC afferents, and CNA-CRF LC afferents were activated in these rats as indicated by increased c-fos expression. With repeated stress, rats exhibited either a SL or long latency (LL) to defeat and these strategies were associated with distinct patterns of neuronal activation. In SL rats, LC neurons were activated, as were CNA-CRF LC afferents but not PGI-ENK LC afferents. LL rats had an opposite pattern, maintaining activation of PGi-ENK LC afferents but not CNA-CRF LC afferents or LC neurons. Together, these results indicate that the establishment of different coping strategies to social stress is associated with changes in the circuitry that regulates activity of the brain norepinephrine system. This may underlie differential vulnerability to the consequences of social stress that characterize these different coping strategies. PMID:26634226

  16. Major amyloid-β-degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex.

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    Pacheco-Quinto, Javier; Eckman, Christopher B; Eckman, Elizabeth A

    2016-12-01

    Impaired clearance of amyloid-β peptide (Aβ) has been postulated to significantly contribute to the amyloid accumulation typical of Alzheimer's disease. Among the enzymes known to degrade Aβ in vivo are endothelin-converting enzyme (ECE)-1, ECE-2, and neprilysin (NEP), and evidence suggests that they regulate independent pools of Aβ that may be functionally significant. To better understand the differential regulation of Aβ concentration by its physiological degrading enzymes, we characterized the cell and region-specific expression pattern of ECE-1, ECE-2, and NEP by in situ hybridization and immunohistochemistry in brain areas relevant to Alzheimer's disease. In contrast to the broader distribution of ECE-1, ECE-2 and NEP were found enriched in GABAergic neurons. ECE-2 was majorly expressed by somatostatin-expressing interneurons and was active in isolated synaptosomes. NEP messenger RNA was found mainly in parvalbumin-expressing interneurons, with NEP protein localized to perisomatic parvalbuminergic synapses. The identification of somatostatinergic and parvalbuminergic synapses as hubs for Aβ degradation is consistent with the possibility that Aβ may have a physiological function related to the regulation of inhibitory signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Distinct Neurochemical Adaptations Within the Nucleus Accumbens Produced by a History of Self-Administered vs Non-Contingently Administered Intravenous Methamphetamine

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    Lominac, Kevin D; Sacramento, Arianne D; Szumlinski, Karen K; Kippin, Tod E

    2012-01-01

    Methamphetamine is a highly addictive psychomotor stimulant yet the neurobiological consequences of methamphetamine self-administration remain under-characterized. Thus, we employed microdialysis in rats trained to self-administer intravenous (IV) infusions of methamphetamine (METH-SA) or saline (SAL) and a group of rats receiving non-contingent IV infusions of methamphetamine (METH-NC) at 1 or 21 days withdrawal to determine the dopamine and glutamate responses in the nucleus accumbens (NAC) to a 2 mg/kg methamphetamine intraperitoneal challenge. Furthermore, basal NAC extracellular glutamate content was assessed employing no net-flux procedures in these three groups at both time points. At both 1- and 21-day withdrawal points, methamphetamine elicited a rise in extracellular dopamine in SAL animals and this effect was sensitized in METH-NC rats. However, METH-SA animals showed a much greater sensitized dopamine response to the drug challenge compared with the other groups. Additionally, acute methamphetamine decreased extracellular glutamate in both SAL and METH-NC animals at both time-points. In contrast, METH-SA rats exhibited a modest and delayed rise in glutamate at 1-day withdrawal and this rise was sensitized at 21 days withdrawal. Finally, no net-flux microdialysis revealed elevated basal glutamate and increased extraction fraction at both withdrawal time-points in METH-SA rats. Although METH-NC rats exhibited no change in the glutamate extraction fraction, they exhibited a time-dependent elevation in basal glutamate levels. These data illustrate for the first time that a history of methamphetamine self-administration produces enduring changes in NAC neurotransmission and that non-pharmacological factors have a critical role in the expression of these methamphetamine-induced neurochemical adaptations. PMID:22030712

  18. 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.

  19. Neurochemical aspects of childhood autism

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    R.B. Minderaa (Ruud)

    1985-01-01

    textabstractThe topic of this thesis is neurochemical aspects of infantile autism. The experimental work is centered around the most robust and consistant neurochemical finding in child psychiatry, namely that group mean whole blood serotonin (5-Hydroxytryptamine, 5-HT) values are

  20. Suicide: Neurochemical Approaches

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    Ritabrata Banerjee

    2013-10-01

    Full Text Available Despite the devastating effect of suicide on numerous lives, there is still a dearthof knowledge concerning its neurochemical aspects. There is increasing evidence that brain-derived neurotrophic factor (BDNF and Nerve growth factor (NGF are involved in the pathophysiology and treatment of depression through binding and activating their cognate receptors trk B and trk A respectively. The present study was performed to examine whether the expression profiles of BDNF and/or trk B as well as NGF and/or trk A were altered in postmortem brain in subjects who commitsuicide and whether these alterations were associated with specific psychopathologic conditions. These studies were performed in hippocampus obtained 21 suicide subjects and 19 non-psychiatric control subjects. The protein and mRNA levels of BDNF, trk B and NGF, trk A were determined with Sandwich ELISA, Western Blot and RT PCR respectively. Given the importance of BDNFand NGF along with their cognate receptors in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF, Trk B and NGF, Trk A in both protein and mRNA levels of postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.

  1. 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.

  2. Classification of neocortical interneurons using affinity propagation

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    Roberto eSantana

    2013-12-01

    Full Text Available In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. Neuronal classification has been a difficult problem because it is unclear what a neuronal cell class actually is and what are the best characteristics are to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological or molecular characteristics, when applied to selected datasets, have provided quantitative and unbiased identification of distinct neuronal subtypes. However, better and more robust classification methods are needed for increasingly complex and larger datasets. We explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. In fact, using a combined anatomical/physiological dataset, our algorithm differentiated parvalbumin from somatostatin interneurons in 49 out of 50 cases. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits.

  3. Postnatal Migration of Cerebellar Interneurons

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    Ludovic Galas

    2017-06-01

    Full Text Available Due to its continuing development after birth, the cerebellum represents a unique model for studying the postnatal orchestration of interneuron migration. The combination of fluorescent labeling and ex/in vivo imaging revealed a cellular highway network within cerebellar cortical layers (the external granular layer, the molecular layer, the Purkinje cell layer, and the internal granular layer. During the first two postnatal weeks, saltatory movements, transient stop phases, cell-cell interaction/contact, and degradation of the extracellular matrix mark out the route of cerebellar interneurons, notably granule cells and basket/stellate cells, to their final location. In addition, cortical-layer specific regulatory factors such as neuropeptides (pituitary adenylate cyclase-activating polypeptide (PACAP, somatostatin or proteins (tissue-type plasminogen activator (tPA, insulin growth factor-1 (IGF-1 have been shown to inhibit or stimulate the migratory process of interneurons. These factors show further complexity because somatostatin, PACAP, or tPA have opposite or no effect on interneuron migration depending on which layer or cell type they act upon. External factors originating from environmental conditions (light stimuli, pollutants, nutrients or drug of abuse (alcohol also alter normal cell migration, leading to cerebellar disorders.

  4. The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity.

    Science.gov (United States)

    Scheyltjens, Isabelle; Arckens, Lutgarde

    2016-01-01

    The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning.

  5. The vulnerability of calretinin-containing hippocampal interneurons in temporal lobe epilepsy

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    Zsofia eMagloczky

    2014-09-01

    Full Text Available This review focuses on the vulnerability of a special interneuron type – the calretinin (CR-containing interneurons – in temporal lobe epilepsy (TLE.CR is a calcium-binding protein expressed mainly by GABAergic interneurons in the hippocampus. Despite their morphological heterogeneity, CR-containing interneurons form a distinct subpopulation of inhibitory cells, innervating other interneurons in rodents and to some extent principal cells in the human. Their dendrites are strongly connected by zona adherentiae and presumably by gap junctions both in rats and humans. CR-containing interneurons are suggested to play a key role in the hippocampal inhibitory network, since they can effectively synchronize dendritic inhibitory interneurons.The sensitivity of CR-expressing interneurons to epilepsy was discussed in several reports, both in animal models and in humans. In the sclerotic hippocampus the density of CR-immunopositive cells is decreased significantly. In the non-sclerotic hippocampus, the CR-containing interneurons are preserved, but their dendritic tree is varicose, segmented, and zona-adherentia-type contacts can be less frequently observed among dendrites.Therefore, the dendritic inhibition of pyramidal cells may be less effective in TLE. This can be partially explained by the impairment of the CR-containing interneuron ensemble in the epileptic hippocampus, which may result in an asynchronous and thus less effective dendritic inhibition of the principal cells. This phenomenon, together with the sprouting of excitatory pathway axons and enhanced innervation of principal cells, may be involved in seizure generation.Preventing the loss of CR-positive cells and preserving the integrity of CR-positive dendrite gap junctions may have antiepileptic effects, maintaining proper inhibitory function and helping to protect principal cells in epilepsy.

  6. Vibration-processing interneurons in the honeybee brain

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    Hiroyuki Ai

    2010-01-01

    Full Text Available The afferents of the Johnston’s organ (JO in the honeybee brain send their axons to three distinct areas, the dorsal lobe, the dorsal subesophageal ganglion (DL-dSEG, and the posterior protocerebral lobe (PPL, suggesting that vibratory signals detected by the JO are processed differentially in these primary sensory centers. The morphological and physiological characteristics of interneurons arborizing in these areas were studied by intracellular recording and staining. DL-Int-1 and DL-Int-2 have dense arborizations in the DL-dSEG and respond to vibratory stimulation applied to the JO in either tonic excitatory, on-off-phasic excitatory, or tonic inhibitory patterns. PPL-D-1 has dense arborizations in the PPL, sends axons into the ventral nerve cord (VNC, and responds to vibratory stimulation and olfactory stimulation simultaneously applied to the antennae in long-lasting excitatory pattern. These results show that there are at least two parallel pathways for vibration processing through the DL-dSEG and the PPL. In this study, Honeybee Standard Brain was used as the common reference, and the morphology of two types of interneurons (DL-Int-1 and DL-Int-2 and JO afferents was merged into the standard brain based on the boundary of several neuropiles, greatly supporting the understanding of the spatial relationship between these identified neurons and JO afferents. The visualization of the region where the JO afferents are closely appositioned to these DL interneurons demonstrated the difference in putative synaptic regions between the JO afferents and these DL interneurons (DL-Int-1 and DL-Int-2 in the DL. The neural circuits related to the vibration-processing interneurons are discussed.

  7. Extended Interneuronal Network of the Dentate Gyrus

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    Gergely G. Szabo

    2017-08-01

    Full Text Available Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.

  8. 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.

  9. Classification of neocortical interneurons using affinity propagation

    Science.gov (United States)

    Santana, Roberto; McGarry, Laura M.; Bielza, Concha; Larrañaga, Pedro; Yuste, Rafael

    2013-01-01

    In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. In fact, neuronal classification is a difficult problem because it is unclear how to designate a neuronal cell class and what are the best characteristics to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological, or molecular characteristics, have provided quantitative and unbiased identification of distinct neuronal subtypes, when applied to selected datasets. However, better and more robust classification methods are needed for increasingly complex and larger datasets. Here, we explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. Affinity propagation outperformed Ward's method, a current standard clustering approach, in classifying the neurons into 4 subtypes. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits. PMID:24348339

  10. Subcellular Targeting of VIP Boutons in Mouse Barrel Cortex is Layer-Dependent and not Restricted to Interneurons.

    Science.gov (United States)

    Zhou, Xiaojuan; Rickmann, Michael; Hafner, Georg; Staiger, Jochen F

    2017-11-01

    Neocortical vasoactive intestinal polypeptide (VIP) expressing cells are a diverse subpopulation of GABAergic interneurons issuing distinct axonal projections. They are known to inhibit other types of interneurons as well as excitatory principal neurons and possess a disinhibitory net effect in cortical circuits. In order to elucidate their targeting specificity, the output connectivity of VIP interneurons was studied at the subcellular level in barrel cortex of interneuron-specific Cre-driver mice, using pre- and postembedding electron microscopy. Systematically sampling VIP boutons across all layers, we found a substantial proportion of the innervated subcellular structures were dendrites (80%), with somata (13%), and spines (7%) being much less targeted. In layer VI, a high proportion of axosomatic synapses was found (39%). GABA-immunopositive ratio was quantified among the targets using statistically validated thresholds: only 37% of the dendrites, 7% of the spines, and 26% of the somata showed above-threshold immunogold labeling. For the main target structure "dendrite", a higher proportion of GABAergic subcellular profiles existed in deep than in superficial layers. In conclusion, VIP interneurons innervate non-GABAergic excitatory neurons and interneurons at their subcellular domains with layer-dependent specificity. This suggests a diverse output of VIP interneurons, which predicts multiple functionality in cortical circuitry beyond disinhibition. © The Author 2017. Published by Oxford University Press.

  11. Simultaneous wireless electrophysiological and neurochemical monitoring

    Science.gov (United States)

    Murari, Kartikeya; Mollazadeh, Mohsen; Thakor, Nitish; Cauwenberghs, Gert

    2008-08-01

    Information processing and propagation in the central nervous system is mostly electrical in nature. At synapses, electrical signals cause the release of neurotransmitters like dopamine, glutamate etc., that are sensed by post-synaptic neurons resulting in signal propagation or inhibition. It can be very informative to monitor electrical and neurochemical signals simultaneously to understand the mechanisms underlying normal or abnormal brain function. We present an integrated system for the simultaneous wireless acquisition of neurophysiological and neurochemical activity. Applications of the system to neuroscience include monitoring EEG and glutamate in rat somatosensory cortex following global ischemia.

  12. 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.

  13. Single dendrite-targeting interneurons generate branch-specific inhibition.

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    Caleb eStokes

    2014-11-01

    Full Text Available Microcircuits composed of dendrite-targeting inhibitory interneurons and pyramidal cells are fundamental elements of cortical networks, however, the impact of individual interneurons on pyramidal dendrites is unclear. Here, we combine paired recordings and calcium imaging to determine the spatial domain over which single dendrite-targeting interneurons influence pyramidal cells in olfactory cortex. We show that a major action of individual interneurons is to inhibit dendrites in a branch-specific fashion.

  14. 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.

  15. Neurochemical measurements in the zebrafish brain

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    Lauren eJones

    2015-09-01

    Full Text Available The zebrafish is an ideal model organism for behavioural genetics and neuroscience. The high conservation of genes and neurotransmitter pathways between zebrafish and other vertebrates permits the translation of research between species. Zebrafish behaviour can be studied at both larval and adult stages and recent research has begun to establish zebrafish models for human disease. Fast scan cyclic voltammetry (FSCV is an electrochemical technique that permits the detection of neurotransmitter release and reuptake. In this study we have used in vitro FSCV to measure the release of analytes in the adult zebrafish telencephalon. We compare different stimulation methods and present a characterisation of neurochemical changes in the wild-type zebrafish brain. This study represents the first FSCV recordings in zebrafish, thus paving the way for neurochemical analysis of the fish brain.

  16. Neurochemical measurements in the zebrafish brain

    Science.gov (United States)

    Jones, Lauren J.; McCutcheon, James E.; Young, Andrew M. J.; Norton, William H. J.

    2015-01-01

    The zebrafish is an ideal model organism for behavioral genetics and neuroscience. The high conservation of genes and neurotransmitter pathways between zebrafish and other vertebrates permits the translation of research between species. Zebrafish behavior can be studied at both larval and adult stages and recent research has begun to establish zebrafish models for human disease. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the detection of neurotransmitter release and reuptake. In this study we have used in vitro FSCV to measure the release of analytes in the adult zebrafish telencephalon. We compare different stimulation methods and present a characterization of neurochemical changes in the wild-type zebrafish brain. This study represents the first FSCV recordings in zebrafish, thus paving the way for neurochemical analysis of the fish brain. PMID:26441575

  17. SOME NEUROCHEMICAL DISTURBANCES IN MULTIPLE SCLEROSIS

    OpenAIRE

    Vladimir V. Markelov; Maxim V. Trushin

    2006-01-01

    ABSTRACTThe data presented in this manuscript suggest a pivotal role of the central nervous system (CNS) in the regulation of immune status. We describe here that some neurochemical disturbances may provoke development of various diseases including multiple sclerosis. Some theoretic and practical backgrounds, how to improve the multiple sclerosis sufferers and patients with other autoimmune disorders, are also given.RESUMENLos datos que presentamos en este manuscrito, sugieren un papel guia d...

  18. Differential distribution and function of GABABRs in somato-dendritic and axonal compartments of principal cells and interneurons in cortical circuits.

    Science.gov (United States)

    Kulik, Ákos; Booker, Sam A; Vida, Imre

    2017-10-14

    GABABRs are highly expressed in cortical circuits, controlling neuronal excitability and synaptic transmission in both principal cells and inhibitory interneurons. Light and electron microscopic studies confirmed the wide distribution of receptors and revealed cell type-specific quantitative differences in their cellular and subcellular distributions. At the subcellular level, GABABRs are abundant at the peri- and extrasynaptic membrane of somato-dendritic compartments and to lower levels in the axon terminals of both cortical excitatory principal cells and inhibitory interneurons. Differences in the surface densities are particularly prominent between neurochemically-defined interneuron types. Whole-cell recordings further demonstrated that GABABRs differentially mediate post- and presynaptic inhibition in principal cells and various GABAergic interneurons by preferentially modulating postsynaptic G-protein-coupled inwardly rectifying K+ (Kir3) channels and presynaptic high voltage-activated Ca2+ (Cav) channels. These data convergently indicate that GABABRs not only control the overall level of neuronal excitability and activity, but can also fine tune the activation and interactions of excitatory and inhibitory neurons in cortical circuits. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Neurochemical alterations associated with borderline personality disorder.

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    Atmaca, Murad; Karakoc, Tevfik; Mermi, Osman; Gurkan Gurok, M; Yildirim, Hanefi

    2015-01-01

    In neuroimaging on borderline personality disorder, prior studies focused on the hippocampus and amygdala, as mentioned above. However, no study investigated whether there were neurochemical changes in the patients with borderline personality disorder. Therefore, in the present study, we aimed to investigate neurochemical change of patients diagnosed with borderline disorder and hypothesized that neurochemicals would change in the hippocampus region of these patients. Seventeen patients and the same number of healthy control subjects were analyzed by using a 1.5 Tesla GE Signa Imaging System. N-acetylaspartate (NAA), choline compounds (CHO), and creatine (CRE) values of hippocampal region were measured. The mean NAA/CRE ratio in the hippocampus region was significantly reduced in the patients with borderline personality disorder compared to that of healthy control subjects, In addition, NAA/CHO ratio of the patients with borderline personality disorder was also significantly reduced when compared to that of healthy subjects. There was no difference in the ratio of CHO/CRE. In summary, we present evidence for reduced NAA in the patients with borderline personality disorder. © 2015, The Author(s).

  20. Immunofluorescent visualization of mouse interneuron subtypes [v2; ref status: indexed, http://f1000r.es/4qq

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    Simon Molgaard

    2014-11-01

    Full Text Available The activity of excitatory neurons is controlled by a 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, an antibody review database, 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

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

    Directory of Open Access Journals (Sweden)

    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

  2. Presynaptic miniature GABAergic currents in developing interneurons.

    Science.gov (United States)

    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.

  3. Sox5 controls dorsal progenitor and interneuron specification in the spinal cord.

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    Quiroga, Alejandra C; Stolt, C Claus; Diez del Corral, Ruth; Dimitrov, Spas; Pérez-Alcalá, Siro; Sock, Elisabeth; Barbas, Julio A; Wegner, Michael; Morales, Aixa V

    2015-05-01

    The basic organization of somatosensory circuits in the spinal cord is already setup during the initial patterning of the dorsal neural tube. Extrinsic signals, such as Wnt and TGF-β pathways, activate combinatorial codes of transcription factors that are responsible for generating a pattern of discrete domains of dorsal progenitors (dp). These progenitors will give rise to distinct dorsal interneurons (dI). The Wnt/ βcatenin signaling pathway controls specification of dp/dI1-3 progenitors and interneurons. According to the current model in the field, Wnt/βcatenin activity seems to act in a graded fashion in the spinal cord, as different relative levels determine the identity of adjacent progenitors. However, it is not clear how this activity gradient is controlled and how the identities of dI1-3 are differentially regulated by Wnt signalling. We have determined that two SoxD transcription factors, Sox5 and Sox6, are expressed in restricted domains of dorsal progenitors in the neural tube. Using gain- and loss-of function approaches in chicken embryos, we have established that Sox5 controls cell fate specification of dp2 and dp3 progenitors and, as a result, controls the correct number of the corresponding dorsal interneurons (dI2 and dI3). Furthermore, Sox5 exerts its function by restricting dorsally Wnt signaling activity via direct transcriptional induction of the negative Wnt pathway regulator Axin2. By that way, Sox5 acts as a Wnt pathway modulator that contributes to sharpen the dorsal gradient of Wnt/βcatenin activity to control the distinction of two functionally distinct types of interneurons, dI2 and dI3 involved in the somatosensory relay. © 2014 Wiley Periodicals, Inc.

  4. Behavioral metabolomics analysis identifies novel neurochemical signatures in methamphetamine sensitization

    OpenAIRE

    Adkins, Daniel E.; McClay, Joseph L.; VUNCK, SARAH A.; Batman, Angela M.; Vann, Robert E.; Clark, Shaunna L.; SOUZA,RENAN P. DE; Crowley, James J.; Sullivan, Patrick F; van den Oord, Edwin J.C.G.; Beardsley, Patrick M.

    2013-01-01

    Behavioral sensitization has been widely studied in animal models and is theorized to reflect neural modifications associated with human psychostimulant addiction. While the mesolimbic dopaminergic pathway is known to play a role, the neurochemical mechanisms underlying behavioral sensitization remain incompletely understood. In the present study, we conducted the first metabolomics analysis to globally characterize neurochemical differences associated with behavioral sensitization. Methamphe...

  5. Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties

    Science.gov (United States)

    Casale, Amanda E.; Foust, Amanda J.; Bal, Thierry

    2015-01-01

    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 Ca2+-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. SIGNIFICANCE STATEMENT 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

  6. SOME NEUROCHEMICAL DISTURBANCES IN MULTIPLE SCLEROSIS

    Directory of Open Access Journals (Sweden)

    Vladimir V. Markelov

    2006-04-01

    Full Text Available ABSTRACTThe data presented in this manuscript suggest a pivotal role of the central nervous system (CNS in the regulation of immune status. We describe here that some neurochemical disturbances may provoke development of various diseases including multiple sclerosis. Some theoretic and practical backgrounds, how to improve the multiple sclerosis sufferers and patients with other autoimmune disorders, are also given.RESUMENLos datos que presentamos en este manuscrito, sugieren un papel guia del sistema nervioso central (SNC en la regulación del estado inmune. Describimos aquí que varias alteraciones neuroquímicas pueden provocar el desarrollo de varias enfermedades, incluyendo esclerosis múltiple. También se comenta acerca del trasfondo teórico y práctico, y cómo mejorar a víctimas y pacientes con esclerosis múltiple y otras alteraciones autoinmunes.

  7. Adolescent GBR12909 exposure induces oxidative stress, disrupts parvalbumin-positive interneurons, and leads to hyperactivity and impulsivity in adult mice.

    Science.gov (United States)

    Khan, Asma; de Jong, Loek A W; Kamenski, Mary E; Higa, Kerin K; Lucero, Jacinta D; Young, Jared W; Behrens, M Margarita; Powell, Susan B

    2017-03-14

    The adolescent period in mammals is a critical period of brain maturation and thus represents a time of susceptibility to environmental insult, e.g. psychosocial stress and/or drugs of abuse, which may cause lasting impairments in brain function and behavior and even precipitate symptoms in at-risk individuals. One likely effect of these environmental insults is to increase oxidative stress in the developing adolescent brain. Indeed, there is increasing evidence that redox dysregulation plays an important role in the development of schizophrenia and other neuropsychiatric disorders and that GABA interneurons are particularly susceptible to alterations in oxidative stress. The current study sought to model this adolescent neurochemical "stress" by exposing mice to the dopamine transporter inhibitor GBR12909 (5mg/kg; IP) during adolescence (postnatal day 35-44) and measuring the resultant effect on locomotor behavior and probabilistic reversal learning as well as GABAergic interneurons and oxidative stress in adulthood. C57BL6/J mice exposed to GBR12909 showed increased activity in a novel environment and increased impulsivity as measured by premature responding in the probabilistic reversal learning task. Adolescent GBR12909-exposed mice also showed decreased parvalbumin (PV) immunoreactivity in the prefrontal cortex, which was accompanied by increased oxidative stress in PV+ neurons. These findings indicate that adolescent exposure to a dopamine transporter inhibitor results in loss of PV in GABAergic interneurons, elevations in markers of oxidative stress, and alterations in behavior in adulthood. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Immunostaining of Biocytin-filled and Processed Sections for Neurochemical Markers.

    Science.gov (United States)

    Swietek, Bogumila; Gupta, Akshay; Proddutur, Archana; Santhakumar, Vijayalakshmi

    2016-12-31

    Electrophysiological recordings of cells using the patch clamp technique have allowed for the identification of different neuronal types based on firing patterns. The inclusion of biocytin/neurobiotin in the recording electrode permits post-hoc recovery of morphological details, which are necessary to determine the dendritic arborization and the regions targeted by the axons of the recorded neurons. However, given the presence of morphologically similar neurons with distinct neurochemical identities and functions, immunohistochemical staining for cell-type-specific proteins is essential to definitively identify neurons. To maintain network connectivity, brain sections for physiological recordings are prepared at a thickness of 300 µm or greater. However, this thickness often hinders immunohistological postprocessing due to issues with antibody penetration, necessitating the resectioning of the tissue. Resectioning of slices is a challenging art, often resulting in the loss of tissue and morphology of the cells from which electrophysiological data was obtained, rendering the data unusable. Since recovery of morphology would limit data loss and guide in the selection of neuronal markers, we have adopted a strategy of recovering cell morphology first, followed by secondary immunostaining. We introduce a practical approach to biocytin filling during physiological recordings and subsequent serial immunostaining for the recovery of morphology, followed by the restaining of sections to determine the neurochemical identity. We report that sections that were filled with biocytin, fixed with paraformaldehyde (PFA), stained, and coverslipped can be removed and restained with a second primary antibody days later. This restaining involves the removal of the coverslip, the washing of sections in a buffer solution, and the incubation of primary and secondary antibodies to reveal the neurochemical identity. The method is advantageous for eliminating data loss due to an inability

  9. Hilar GABAergic interneuron activity controls spatial learning and memory retrieval.

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    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.

  10. Genetics and Function of Neocortical GABAergic Interneurons in Neurodevelopmental Disorders

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    E. Rossignol

    2011-01-01

    Full Text Available A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders.

  11. Autism and Fragile X: Is There a Neurochemical Link?

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    Nagwa A. Meguid

    2014-12-01

    CONCLUSIONS: Autism and Fragile X syndrome share some neurochemical similarities with regards of high Glutamate and GABA levels while Serotonin was significantly different in the 2 disorders and may be used a unique biomarker for autism.

  12. Co-expression of VAL- and TMT-opsins uncovers ancient photosensory interneurons and motorneurons in the vertebrate brain.

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    Ruth M Fischer

    Full Text Available The functional principle of the vertebrate brain is often paralleled to a computer: information collected by dedicated devices is processed and integrated by interneuron circuits and leads to output. However, inter- and motorneurons present in today's vertebrate brains are thought to derive from neurons that combined sensory, integration, and motor function. Consistently, sensory inter-motorneurons have been found in the simple nerve nets of cnidarians, animals at the base of the evolutionary lineage. We show that light-sensory motorneurons and light-sensory interneurons are also present in the brains of vertebrates, challenging the paradigm that information processing and output circuitry in the central brain is shielded from direct environmental influences. We investigated two groups of nonvisual photopigments, VAL- and TMT-Opsins, in zebrafish and medaka fish; two teleost species from distinct habitats separated by over 300 million years of evolution. TMT-Opsin subclasses are specifically expressed not only in hypothalamic and thalamic deep brain photoreceptors, but also in interneurons and motorneurons with no known photoreceptive function, such as the typeXIV interneurons of the fish optic tectum. We further show that TMT-Opsins and Encephalopsin render neuronal cells light-sensitive. TMT-Opsins preferentially respond to blue light relative to rhodopsin, with subclass-specific response kinetics. We discovered that tmt-opsins co-express with val-opsins, known green light receptors, in distinct inter- and motorneurons. Finally, we show by electrophysiological recordings on isolated adult tectal slices that interneurons in the position of typeXIV neurons respond to light. Our work supports "sensory-inter-motorneurons" as ancient units for brain evolution. It also reveals that vertebrate inter- and motorneurons are endowed with an evolutionarily ancient, complex light-sensory ability that could be used to detect changes in ambient light spectra

  13. Central Neurochemical Ultradian Variability in Depression

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    Ronald M. Salomon

    2006-01-01

    Full Text Available Depression is characterized by blunted behavior and neuroendocrine function that generally improve with antidepressant treatment. This study examined intrinsic variability in brain neurotransmitter function, since it may be a source of blunted behavior and neuroendocrine function in depression and a marker for the illness, and has not previously been analyzed using wavelet decomposition. To measure variability in monoamine metabolites, lumbar cerebrospinal fluid (CSF was collected in serial samples in depressed patients before and after treatment. We hypothesized that changes in variability would be observed after treatment. Mechanisms that control such variability may be critical to the pathophysiology of depression. Method: Time series data was obtained from serial ten-min sampling over a 24-hr period (N = 144 from thirteen depressed patients, with a repeat collection after 5 weeks of antidepressant (sertraline or bupropion treatment. Concentrations of tryptophan (TRP, the monoamine metabolites 5-HIAA (metabolite of serotonin and HVA (metabolite of dopamine, and the HVA:5HIAA ratio were transformed to examine power in slowly (160 min/cycle to rapidly (20 min/cycle occurring events. Power, the sum of the squares of the coefficients in each d (detail wavelet, reflects variability within a limited frequency bandwidth for that wavelet. Pre-treatment to post-treatment comparisons were conducted with repeated measures ANOVA. Results: Antidepressant treatment was associated with increased power in the d2 wavelet from the HVA (p = 0.03 and the HVA:5-HIAA ratio (p = 0.03 series. The d1 and d3 wavelets showed increased power following antidepressant treatment for the ratio series (d1, p = 0.01; d3, p = 0.05. Significant changes in power were not observed for the 5-HIAA data series. Power differences among analytes suggest that the findings are specific to each system. Conclusion: The wavelet transform analysis shows changes in neurochemical signal

  14. The interesting interplay between interneurons and adult hippocampal neurogenesis

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    Masiulis, Irene; Yun, Sanghee; Eisch, Amelia J.

    2013-01-01

    Adult neurogenesis is a unique form of plasticity found in the hippocampus, a brain region key to learning and memory formation. While many external stimuli are known to modulate the generation of new neurons in the hippocampus, little is known about the local circuitry mechanisms that regulate the process of adult neurogenesis. The neurogenic niche in the hippocampus is highly complex and consists of a heterogeneous population of cells including interneurons. Because interneurons are already highly integrated into the hippocampal circuitry, they are in a prime position to influence the proliferation, survival, and maturation of adult-generated cells in the dentate gyrus. Here we review the current state of our understanding on the interplay between interneurons and adult hippocampal neurogenesis. We focus on activity- and signaling-dependent mechanisms, as well as research on human diseases that could provide better insight into how interneurons in general might add to our comprehension of the regulation and function of adult hippocampal neurogenesis. PMID:21956642

  15. Neurochemical mechanisms underlying responses to psychostimulants

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    Volkow, N.D.; Fowler, J.S.; Hitzemann, R.; Wang, G.J. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York, Stony Brook, NY (United States)

    1994-11-01

    This study employed positron emission tomography (PET) to investigate biochemical and metabolic characteristics of the brain of individuals which could put them at risk for drug addiction. It takes advantage of the normal variability between individuals in response to psychoactive drugs to investigate relation between mental state, brain neurochemistry and metabolism and the behavioral response to drugs. We discuss its use to assess if there is an association between mental state and dompaminergic reactivity in response to the psychostimulant drug methylphenidate (MP). Changes in synaptic dopamine induced by MP were evaluated with PET and [11C]raclopride, a D{sub 2} receptor radioligand that is sensitive to endogenous dopamine. Methylpphenidate significantly decreased striatal [11C]raclopride binding. The study showed a correlation between the magnitude of the dopamine-induced changes by methylphenidate, and the mental state of the subjects. Subjects reporting high levels of anxiety and restlessness at baseline had larger changes in MP-induced dopamine changes than those that did not. Further investigations on the relation between an individual`s response to a drug and his/her mental state and personality as well as his neurochemical brain composition may enable to understand better differences in drug addiction vulnerability.

  16. Carbon Nanofiber Electrode Array for Neurochemical Monitoring

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    Koehne, Jessica E.

    2017-01-01

    A sensor platform based on vertically aligned carbon nanofibers (CNFs) has been developed. Their inherent nanometer scale, high conductivity, wide potential window, good biocompatibility and well-defined surface chemistry make them ideal candidates as biosensor electrodes. Here, we report using vertically aligned CNF as neurotransmitter recording electrodes for application in a smart deep brain stimulation (DBS) device. Our approach combines a multiplexed CNF electrode chip, developed at NASA Ames Research Center, with the Wireless Instantaneous Neurotransmitter Concentration Sensor (WINCS) system, developed at the Mayo Clinic. Preliminary results indicate that the CNF nanoelectrode arrays are easily integrated with WINCS for neurotransmitter detection in a multiplexed array format. In the future, combining CNF based stimulating and recording electrodes with WINCS may lay the foundation for an implantable smart therapeutic system that utilizes neurochemical feedback control while likely resulting in increased DBS application in various neuropsychiatric disorders. In total, our goal is to take advantage of the nanostructure of CNF arrays for biosensing studies requiring ultrahigh sensitivity, high-degree of miniaturization, and selective biofunctionalization.

  17. Striatal cholinergic interneuron regulation and circuit effects

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    Sean Austin Lim

    2014-10-01

    Full Text Available The striatum plays a central role in motor control and motor learning. Appropriate responses to environmental stimuli, including pursuit of reward or avoidance of aversive experience all require functional striatal circuits. These pathways integrate synaptic inputs from limbic and cortical regions including sensory, motor and motivational information to ultimately connect intention to action. Although many neurotransmitters participate in striatal circuitry, one critically important player is acetylcholine (ACh. Relative to other brain areas, the striatum contains exceptionally high levels of ACh, the enzymes that catalyze its synthesis and breakdown, as well as both nicotinic and muscarinic receptor types that mediate its postsynaptic effects. The principal source of striatal ACh is the cholinergic interneuron (ChI, which comprises only about 1-2% of all striatal cells yet sends dense arbors of projections throughout the striatum. This review summarizes recent advances in our understanding of the factors affecting the excitability of these neurons through acute effects and long term changes in their synaptic inputs. In addition, we discuss the physiological effects of ACh in the striatum, and how changes in ACh levels may contribute to disease states during striatal dysfunction.

  18. Neuroanatomical and Neurochemical Basis of Impulsivity

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    Kemal Yazici

    2010-08-01

    tis paradigm, the tendency to prefer small immediate rewards over larger, more delayed reinforcers is measured. İmpulsive choice is defined by a greater tendency to value or choose smaller, more immediate reinforcers. Impulsivity is a multi-faceted behaviour. This behaviour may be studied by subdividing it into different processes neuroanatomically and neurochemically. Neuroanatomical data support the suggestion that behavioral disinhibition (impulsive action / motoric impulsivity and delay-discounting (impulsive choice / decision making differ in the degree to which various components of frontostriatal loops are implicated in their regulation. The dorsal prefrontal cortex does not appear to be involved in mediating impulsive choice, yet does have some role in regulating inhibitory processes. In contrast, there appears to be a pronounced role for the orbitofrontal cortex and basolateral amygdala in controlling impulsive choice. Other structures, however, such as the nucleus accumbens and subthalamic nucleus may be common to both circuits. From the neurochemical perspective, dopamine system and dopamine- 2 (D2 receptors in particular, seems to be closely involved in making impulsive choice. When the noradrenaline system does not function optimally, it might contribute to increased impulsivity. Serotonin might act upon prefrontal cortex to decrease impulsive choices. Interactions between the serotonin and the dopamine systems are important in the regulation of impulsive behaviour. It is possible that various receptor subtypes of the serotonin system may exert differing and even contrasting effects on impulsive behaviour. Although it is very informative to study neurotransmitter systems separately, it should be kept in mind that there are very intimate interactions between the neurotransmitter systems mentioned above. Based on the fact that impulsivity is regulated through multiple neurotransmitters and even more receptors, one may suggest that pharmacotherapy of

  19. Fast-spiking interneurons of the rat ventral striatum: temporal coordination of activity with principal cells and responsiveness to reward.

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    Lansink, Carien S; Goltstein, Pieter M; Lankelma, Jan V; Pennartz, Cyriel M A

    2010-08-01

    Although previous in vitro studies revealed inhibitory synaptic connections of fast-spiking interneurons to principal cells in the striatum, uncertainty remains about the nature of the behavioural events that correlate with changes in interneuron activity and about the temporal coordination of interneuron firing with spiking of principal cells under natural conditions. Using in vivo tetrode recordings from the ventral striatum in freely moving rats, fast-spiking neurons were distinguished from putative medium-sized spiny neurons on the basis of their spike waveforms and rates. Cross-correlograms of fast-spiking and putative medium-sized spiny neuron firing patterns revealed a variety of temporal relationships, including peaks of concurrent firing and transient decrements in medium-sized spiny neuron spiking around fast-spiking unit activity. Notably, the onset of these decrements was mostly in advance of the fast-spiking unit firing. Many of these temporal relationships were dependent on the sleep-wake state. Coordinated activity was also found amongst pairs of the same phenotype, both fast-spiking units and putative medium-sized spiny neurons, which was often marked by a broad peak of concurrent firing. When studying fast-spiking neurons in a reward-searching task, they generally showed a pre-reward ramping increment in firing rate but a decrement specifically when the rat received reward. In conclusion, our data indicate that various forms of temporally coordinated activity exist amongst ventral striatal interneurons and principal cells, which cannot be explained by feed-forward inhibitory circuits alone. Furthermore, firing patterns of ventral striatal fast-spiking interneurons do not merely correlate with the general arousal state of the animal but display distinct reward-related changes in firing rate.

  20. Identification of DVA interneuron regulatory sequences in Caenorhabditis elegans.

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    Puckett Robinson, Carmie; Schwarz, Erich M; Sternberg, Paul W

    2013-01-01

    The identity of each neuron is determined by the expression of a distinct group of genes comprising its terminal gene battery. The regulatory sequences that control the expression of such terminal gene batteries in individual neurons is largely unknown. The existence of a complete genome sequence for C. elegans and draft genomes of other nematodes let us use comparative genomics to identify regulatory sequences directing expression in the DVA interneuron. Using phylogenetic comparisons of multiple Caenorhabditis species, we identified conserved non-coding sequences in 3 of 10 genes (fax-1, nmr-1, and twk-16) that direct expression of reporter transgenes in DVA and other neurons. The conserved region and flanking sequences in an 85-bp intronic region of the twk-16 gene directs highly restricted expression in DVA. Mutagenesis of this 85 bp region shows that it has at least four regions. The central 53 bp region contains a 29 bp region that represses expression and a 24 bp region that drives broad neuronal expression. Two short flanking regions restrict expression of the twk-16 gene to DVA. A shared GA-rich motif was identified in three of these genes but had opposite effects on expression when mutated in the nmr-1 and twk-16 DVA regulatory elements. We identified by multi-species conservation regulatory regions within three genes that direct expression in the DVA neuron. We identified four contiguous regions of sequence of the twk-16 gene enhancer with positive and negative effects on expression, which combined to restrict expression to the DVA neuron. For this neuron a single binding site may thus not achieve sufficient specificity for cell specific expression. One of the positive elements, an 8-bp sequence required for expression was identified in silico by sequence comparisons of seven nematode species, demonstrating the potential resolution of expanded multi-species phylogenetic comparisons.

  1. Wnt5a Controls Neurite Development in Olfactory Bulb Interneurons

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    Darya Pino

    2011-05-01

    Full Text Available Neurons born in the postnatal SVZ (subventricular zone must migrate a great distance before becoming mature interneurons of the OB (olfactory bulb. During migration immature OB neurons maintain an immature morphology until they reach their destination. While the morphological development of these cells must be tightly regulated, the cellular pathways responsible are still largely unknown. Our results show that the non-canonical Wnt pathway induced by Wnt5a is important for the morphological development of OB interneurons both in vitro and in vivo. Additionally, we demonstrate that non-canonical Wnt signalling works in opposition to canonical Wnt signalling in neural precursors from the SVZ in vitro. This represents a novel role for Wnt5a in the development of OB interneurons and suggests that canonical and non-canonical Wnt pathways dynamically oppose each other in the regulation of dendrite maturation.

  2. 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.

  3. Regulation of retinal interneuron subtype identity by the Iroquois homeobox gene Irx6.

    Science.gov (United States)

    Star, Erin N; Zhu, Minyan; Shi, Zhiwei; Liu, Haiquan; Pashmforoush, Mohammad; Sauve, Yves; Bruneau, Benoit G; Chow, Robert L

    2012-12-01

    Interneuronal subtype diversity lies at the heart of the distinct molecular properties and synaptic connections that shape the formation of the neuronal circuits that are necessary for the complex spatial and temporal processing of sensory information. Here, we investigate the role of Irx6, a member of the Iroquois homeodomain transcription factor family, in regulating the development of retinal bipolar interneurons. Using a knock-in reporter approach, we show that, in the mouse retina, Irx6 is expressed in type 2 and 3a OFF bipolar interneurons and is required for the expression of cell type-specific markers in these cells, likely through direct transcriptional regulation. In Irx6 mutant mice, presumptive type 3a bipolar cells exhibit an expansion of their axonal projection domain to the entire OFF region of the inner plexiform layer, and adopt molecular features of both type 2 and 3a bipolar cells, highlighted by the ectopic upregulation of neurokinin 3 receptor (Nk3r) and Vsx1. These findings reveal Irx6 as a key regulator of type 3a bipolar cell identity that prevents these cells from adopting characteristic features of type 2 bipolar cells. Analysis of the Irx6;Vsx1 double null retina suggests that the terminal differentiation of type 2 bipolar cells is dependent on the combined expression of the transcription factors Irx6 and Vsx1, but also points to the existence of Irx6;Vsx1-independent mechanisms in regulating OFF bipolar subtype-specific gene expression. This work provides insight into the generation of neuronal subtypes by revealing a mechanism in which opposing, yet interdependent, transcription factors regulate subtype identity.

  4. Genetic dissection of Gata2 selective functions during specification of V2 interneurons in the developing spinal cord.

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    Francius, Cédric; Ravassard, Philippe; Hidalgo-Figueroa, María; Mallet, Jacques; Clotman, Frédéric; Nardelli, Jeannette

    2015-07-01

    Motor activities are controlled by neural networks in the ventral spinal cord and consist in motor neurons and a set of distinct cardinal classes of spinal interneurons. These interneurons arise from distinct progenitor domains (p0-p3) delineated according to a transcriptional code. Neural progenitors of each domain express a unique combination of transcription factors (TFs) that largely contribute to determine the fate of four classes of interneurons (V0-V3) and motor neurons. In p2 domain, at least four subtypes of interneurons namely V2a, V2b, V2c, and Pax6(+) V2 are generated. Although genetic and molecular mechanisms that specify V2a and V2b are dependent on complex interplay between several TFs including Nkx6.1, Irx3, Gata2, Foxn4, and Ascl1, and signaling pathways such as Notch and TGF-β, the sequence order of the activation of these regulators and their respective contribution are not completely elucidated yet. Here, we provide evidence by loss- or gain-of-function experiments that Gata2 is necessary for the normal development of both V2a and V2b neurons. We demonstrate that Nkx6.1 and Dll4 positively regulate the activation of Gata2 and Foxn4 in p2 progenitors. Gata2 also participates in the maintenance of p2 domain by repressing motor neuron differentiation and exerting a feedback control on patterning genes. Finally, Gata2 promotes the selective activation of V2b program at the expense of V2a fate. Thus our results provide new insights on the hierarchy and complex interactions between regulators of V2 genetic program. © 2014 Wiley Periodicals, Inc.

  5. 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. 

  6. Anatomically heterogeneous populations of CB1 cannabinoid receptor-expressing interneurons in the CA3 region of the hippocampus show homogeneous input-output characteristics.

    Science.gov (United States)

    Szabó, Gergely G; Papp, Orsolya I; Máté, Zoltán; Szabó, Gábor; Hájos, Norbert

    2014-12-01

    A subpopulation of GABAergic cells in cortical structures expresses CB1 cannabinoid receptors (CB1 ) on their axon terminals. To understand the function of these interneurons in information processing, it is necessary to uncover how they are embedded into neuronal circuits. Therefore, the proportion of GABAergic terminals expressing CB1 and the morphological and electrophysiological properties of CB1 -immunoreactive interneurons should be revealed. We investigated the ratio and the origin of CB1 -expressing inhibitory boutons in the CA3 region of the hippocampus. Using immunocytochemical techniques, we estimated that ∼40% of GABAergic axon terminals in different layers of CA3 also expressed CB1 . To identify the inhibitory cell types expressing CB1 in this region, we recorded and intracellularly labeled interneurons in hippocampal slices. CB1 -expressing interneurons showed distinct axonal arborization, and were classified as basket cells, mossy-fiber-associated cells, dendritic-layer-innervating cells or perforant-path-associated cells. In each morphological category, a substantial variability in axonal projection was observed. In contrast to the diverse morphology, the active and passive membrane properties were found to be rather similar. Using paired recordings, we found that pyramidal cells displayed large and fast unitary postsynaptic currents in response to activating basket and mossy-fiber-associated cells, while they showed slower and smaller synaptic events in pairs originating from interneurons that innervate the dendritic layer, which may be due to dendritic filtering. In addition, CB1 activation significantly reduced the amplitude of the postsynaptic currents in each cell pair tested. Our data suggest that CB1 -expressing interneurons with different axonal projections have comparable physiological characteristics, contributing to a similar proportion of GABAergic inputs along the somato-dendritic axis of CA3 pyramidal cells. © 2014 Wiley Periodicals

  7. 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.

  8. 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.

  9. 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

  10. Towards a Dynamic Clamp for Neurochemical Modalities

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    Catalina Maria Rivera

    2015-05-01

    Full Text Available The classic dynamic clamp technique uses a real-time electrical interface between living cells and neural simulations in order to investigate hypotheses about neural function and structure. One of the acknowledged drawbacks of that technique is the limited control of the cells’ chemical microenvironment. In this manuscript, we use a novel combination of nanosensor and microfluidic technology and microfluidic and neural simulations to add sensing and control of chemical concentrations to the dynamic clamp technique. Specifically, we use a microfluidic lab-on-a-chip to generate distinct chemical concentration gradients (ions or neuromodulators, to register the concentrations with embedded nanosensors and use the processed signals as an input to simulations of a neural cell. The ultimate goal of this project is to close the loop and provide sensor signals to the microfluidic lab-on-a-chip to mimic the interaction of the simulated cell with other cells in its chemical environment.

  11. Encoding of tactile stimuli by mechanoreceptors and interneurons of the medicinal leech

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    Jutta Kretzberg

    2016-10-01

    Full Text Available For many animals processing of tactile information is a crucial task in behavioral contexts like exploration, foraging and stimulus avoidance. The leech, having infrequent access to food, developed an energy efficient reaction to tactile stimuli, avoiding unnecessary muscle movements: The local bend behavior moves only a small part of the body wall away from an object touching the skin, while the rest of the animal remains stationary. Amazingly, the precision of this localized behavioral response is similar to the spatial discrimination threshold of the human fingertip, although the leech skin is innervated by an order of magnitude fewer mechanoreceptors and each midbody ganglion contains only 400 individually identified neurons in total. Prior studies suggested that this behavior is controlled by a three-layered feed-forward network, consisting of four mechanoreceptors (P cells, approximately 20 interneurons and 10 individually characterized motor neurons, all of which encode tactile stimulus location by overlapping, symmetrical tuning curves. Additionally, encoding of mechanical force was attributed to three types of mechanoreceptors reacting to distinct intensity ranges: T cells for touch, P cells for pressure and N cells for strong, noxious skin stimulation. In this study, we provide evidences that tactile stimulus encoding in the leech is more complex than previously thought. Combined electrophysiological, anatomical and voltage sensitive dye approaches indicate that P and T cells both play a major role in tactile information processing resulting in local bending. Our results indicate that tactile encoding neither relies on distinct force intensity ranges of different cell types, nor location encoding is restricted to spike count tuning. Instead, we propose that P and T cells form a mixed type population, which simultaneously employs temporal response features and spike counts for multiplexed encoding of touch location and force intensity

  12. Neurochemical organization of the nucleus paramedianus dorsalis in the human

    OpenAIRE

    Baizer, Joan S.; Baker, James F.; Haas, Kristin; Lima, Raquel

    2007-01-01

    We have characterized the neurochemical organization of a small brainstem nucleus in the human brain, the nucleus paramedianus dorsalis (PMD). PMD is located adjacent and medial to the nucleus prepositus hypoglossi (PH) in the dorsal medulla, and is distinguished by the pattern of immunoreactivity of cells and fibers to several markers including calcium-binding proteins, a synthetic enzyme for nitric oxide (neuronal nitric oxide synthase, nNOS) and a nonphosphorylated neurofilament protein (a...

  13. Age-Related Neurochemical Changes in the Vestibular Nuclei

    Directory of Open Access Journals (Sweden)

    Paul eSmith

    2016-03-01

    Full Text Available There is evidence that the normal aging process is associated with impaired vestibulo-ocular (VOR and vestibulo-spinal reflexes, causing reduced visual acuity and postural instability. Nonetheless, the available evidence is not entirely consistent, especially with respect to the VOR. Some recent studies have reported that VOR gain can be intact even above 80 years of age. Similarly, although there is evidence for age-related hair cell loss and neuronal loss in Scarpa’s ganglion and the vestibular nucleus complex (VNC, it is not entirely consistent. Whatever structural and functional changes occur in the VNC as a result of aging, either to cause vestibular impairment or to compensate for it, neurochemical changes must underlie them. However, the neurochemical changes that occur in the VNC with aging are poorly understood because the available literature is very limited. This review summarises and critically evaluates the available evidence relating to the noradrenaline, serotonin, dopamine, glutamate, GABA, glycine, and nitric oxide neurotransmitter systems in the aging VNC. It is concluded that, at present, it is difficult, if not impossible, to relate the neurochemical changes observed to the function of specific VNC neurons and whether the observed changes are the cause of a functional deficit in the VNC or an effect of it. A better understanding of the neurochemical changes that occur during aging may be important for the development of potential drug treatments for age-related vestibular disorders. However, this will require the use of more sophisticated methodology such as in vivo microdialysis with single neuron recording and perhaps new technologies such as optogenetics.

  14. Age-Related Neurochemical Changes in the Vestibular Nuclei.

    Science.gov (United States)

    Smith, Paul F

    2016-01-01

    There is evidence that the normal aging process is associated with impaired vestibulo-ocular reflexes (VOR) and vestibulo-spinal reflexes, causing reduced visual acuity and postural instability. Nonetheless, the available evidence is not entirely consistent, especially with respect to the VOR. Some recent studies have reported that VOR gain can be intact even above 80 years of age. Similarly, although there is evidence for age-related hair cell loss and neuronal loss in Scarpa's ganglion and the vestibular nucleus complex (VNC), it is not entirely consistent. Whatever structural and functional changes occur in the VNC as a result of aging, either to cause vestibular impairment or to compensate for it, neurochemical changes must underlie them. However, the neurochemical changes that occur in the VNC with aging are poorly understood because the available literature is very limited. This review summarizes and critically evaluates the available evidence relating to the noradrenaline, serotonin, dopamine, glutamate, GABA, glycine, and nitric oxide neurotransmitter systems in the aging VNC. It is concluded that, at present, it is difficult, if not impossible, to relate the neurochemical changes observed to the function of specific VNC neurons and whether the observed changes are the cause of a functional deficit in the VNC or an effect of it. A better understanding of the neurochemical changes that occur during aging may be important for the development of potential drug treatments for age-related vestibular disorders. However, this will require the use of more sophisticated methodology such as in vivo microdialysis with single neuron recording and perhaps new technologies such as optogenetics.

  15. Behavioral metabolomics analysis identifies novel neurochemical signatures in methamphetamine sensitization.

    Science.gov (United States)

    Adkins, D E; McClay, J L; Vunck, S A; Batman, A M; Vann, R E; Clark, S L; Souza, R P; Crowley, J J; Sullivan, P F; van den Oord, E J C G; Beardsley, P M

    2013-11-01

    Behavioral sensitization has been widely studied in animal models and is theorized to reflect neural modifications associated with human psychostimulant addiction. While the mesolimbic dopaminergic pathway is known to play a role, the neurochemical mechanisms underlying behavioral sensitization remain incompletely understood. In this study, we conducted the first metabolomics analysis to globally characterize neurochemical differences associated with behavioral sensitization. Methamphetamine (MA)-induced sensitization measures were generated by statistically modeling longitudinal activity data for eight inbred strains of mice. Subsequent to behavioral testing, nontargeted liquid and gas chromatography-mass spectrometry profiling was performed on 48 brain samples, yielding 301 metabolite levels per sample after quality control. Association testing between metabolite levels and three primary dimensions of behavioral sensitization (total distance, stereotypy and margin time) showed four robust, significant associations at a stringent metabolome-wide significance threshold (false discovery rate, FDR biomarkers, and developing more comprehensive neurochemical models, of psychostimulant sensitization. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  16. Linking Essential Tremor to the Cerebellum: Neurochemical Evidence.

    Science.gov (United States)

    Marin-Lahoz, Juan; Gironell, Alexandre

    2016-06-01

    The pathophysiology and the exact anatomy of essential tremor (ET) is not well known. One of the pillars that support the cerebellum as the main anatomical locus in ET is neurochemistry. This review examines the link between neurochemical abnormalities found in ET and cerebellum. The review is based on published data about neurochemical abnormalities described in ET both in human and in animal studies. We try to link those findings with cerebellum. γ-aminobutyric acid (GABA) is the main neurotransmitter involved in the pathophysiology of ET. There are several studies about GABA that clearly points to a main role of the cerebellum. There are few data about other neurochemical abnormalities in ET. These include studies with noradrenaline, glutamate, adenosine, proteins, and T-type calcium channels. One single study reveals high levels of noradrenaline in the cerebellar cortex. Another study about serotonin neurotransmitter results negative for cerebellum involvement. Finally, studies on T-type calcium channels yield positive results linking the rhythmicity of ET and cerebellum. Neurochemistry supports the cerebellum as the main anatomical locus in ET. The main neurotransmitter involved is GABA, and the GABA hypothesis remains the most robust pathophysiological theory of ET to date. However, this hypothesis does not rule out other mechanisms and may be seen as the main scaffold to support findings in other systems. We clearly need to perform more studies about neurochemistry in ET to better understand the relations among the diverse systems implied in ET. This is mandatory to develop more effective pharmacological therapies.

  17. Anticholinesterases: Medical applications of neurochemical principles

    Energy Technology Data Exchange (ETDEWEB)

    Millard, C.B.; Broomfield, C.A.

    1995-12-31

    Cholinesterases form a family of serine esterases that arise in animals from at least two distinct genes. Multiple forms of these enzymes can be precisely localized and regulated by alternative mRNA splicing and by co- or posttranslational modifications. The high catalytic efficiency of the cholinesterases is quelled by certain very selective reversible and irreversible inhibitors. Owing largely to the important role of acetylcholine hydrolysis in neurotransmission, cholinesterase and its inhibitors have been studied extensively in vivo. In parallel, there has emerged an equally impressive enzyme chemistry literature. Cholinesterase inhibitors are used widely as pesticides; in this regard the compounds are beneficial with concomitant health risks. Poisoning by such compounds can result in an acute but usually manageable medical crisis and may damage the ONS and the PNS, as well as cardiac and skeletal muscle tissue. Some inhibitors have been useful for the treatment of glaucoma and myasthenia gravis, and others are in clinical trials as therapy for Alzheimer`s dementia. Concurrently, the most potent inhibitors have been developed as highly toxic chemical warfare agents. We review treatments and sequelae of exposure to selected anticholinesterases, especially organophosphorus compounds and carbamates, as they relate to recent progress in enzyme chemistry.

  18. Atypical PKC and Notch Inhibition Differentially Modulate Cortical Interneuron Subclass Fate from Embryonic Stem Cells

    Directory of Open Access Journals (Sweden)

    David J. Tischfield

    2017-05-01

    Full Text Available Recent studies indicate that the location of neurogenesis within the medial ganglionic eminence (MGE critically influences the fate determination of cortical interneuron subgroups, with parvalbumin (Pv interneurons originating from subventricular zone divisions and somatostatin (Sst interneurons primarily arising from apical divisions. The aPKC-CBP and Notch signaling pathways regulate the transition from apical to basal progenitor and their differentiation into post-mitotic neurons. We find that aPKC inhibition enhances intermediate neurogenesis from stem cell-derived MGE progenitors, resulting in a markedly increased ratio of Pv- to Sst-expressing interneurons. Conversely, inhibition of Notch signaling enriches for Sst subtypes at the expense of Pv fates. These findings confirm that the mode of neurogenesis influences the fate of MGE-derived interneurons and provide a means of further enrichment for the generation of specific interneuron subgroups from pluripotent stem cells.

  19. Age-related neurochemical changes in the rhesus macaque cochlear nucleus.

    Science.gov (United States)

    Gray, Daniel T; Engle, James R; Recanzone, Gregg H

    2014-05-01

    Neurochemical changes in the expression of various proteins within the central auditory system have been associated with natural aging. These changes may compensate in part for the loss of auditory sensitivity arising from two phenomena of the aging auditory system: cochlear histopathologies and increased excitability of central auditory neurons. Recent studies in the macaque monkey have revealed age-related changes in the density of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase (NADPHd) and parvalbumin (PV)-positive cells within the inferior colliculus and superior olivary complex. The cochlear nucleus (CN), which is the first central auditory nucleus, remains unstudied. Since the CN participates in the generation of the auditory brainstem response (ABR) and receives direct innervation from the cochlea, it serves as an ideal nucleus to compare the relationship between these neurochemical changes and the physiological and peripheral changes of the aging auditory system. We used stereological sampling to calculate the densities of NADPHd and PV reactive neurons within the three subdivisions of the CN in middle-aged and aged rhesus macaques. Regression analyses of these values with ABR properties and cochlear histopathologies revealed relationships between these cell types and the changing characteristics of the aging auditory system. Our results indicate that NADPHd expression does change with age in a specific subdivision of the CN, but PV does not. Conversely, PV expression correlated with ABR amplitudes and outer hair cell loss in the cochlea, but NADPHd did not. These results indicate that NADPHd and PV may take part in distinct compensatory efforts of the aging auditory system. Copyright © 2013 Wiley Periodicals, Inc.

  20. A pharmacological study of the inhibition of ventral group Ia-excited spinal interneurones.

    Science.gov (United States)

    Lodge, D; Curtis, D R; Brand, S J

    1977-08-08

    In cats anaesthetized with pentobarbitone a pharmacological investigation was made of the inhibition by volleys in afferent fibres and ventral roots of physiologically identified Ia interneurones in the ventral horn. The recurrent inhibition of Ia interneurones by Renshaw cells, and the "mutual" inhibition between Ia interneurones, were suppressed by electrophoretic strychnine and are presumably mediated by glycine. Short latency and duration inhibitions by impulses in muscle and cutaneous afferents were also suppressed by strychnine. Electrophoretic GABA inhibited the firing of Ia interneurones and the effects of bicuculline methochloride suggested that this amino acid mediates longer latency and duration inhibition produced by afferent impulses of muscle and cutaneous origin.

  1. Prenatal restraint stress generates two distinct behavioral and neurochemical profiles in male and female rats.

    Science.gov (United States)

    Zuena, Anna Rita; Mairesse, Jerome; Casolini, Paola; Cinque, Carlo; Alemà, Giovanni Sebastiano; Morley-Fletcher, Sara; Chiodi, Valentina; Spagnoli, Luigi Giusto; Gradini, Roberto; Catalani, Assia; Nicoletti, Ferdinando; Maccari, Stefania

    2008-05-14

    Prenatal Restraint Stress (PRS) in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy) on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS ("PRS rats") showed increased anxiety-like behavior in the elevated plus maze (EPM), a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females.

  2. Prenatal restraint stress generates two distinct behavioral and neurochemical profiles in male and female rats.

    Directory of Open Access Journals (Sweden)

    Anna Rita Zuena

    Full Text Available Prenatal Restraint Stress (PRS in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS ("PRS rats" showed increased anxiety-like behavior in the elevated plus maze (EPM, a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females.

  3. Multi-dimensional classification of GABAergic interneurons with Bayesian network-modeled label uncertainty

    Science.gov (United States)

    Mihaljević, Bojan; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

    2014-01-01

    Interneuron classification is an important and long-debated topic in neuroscience. A recent study provided a data set of digitally reconstructed interneurons classified by 42 leading neuroscientists according to a pragmatic classification scheme composed of five categorical variables, namely, of the interneuron type and four features of axonal morphology. From this data set we now learned a model which can classify interneurons, on the basis of their axonal morphometric parameters, into these five descriptive variables simultaneously. Because of differences in opinion among the neuroscientists, especially regarding neuronal type, for many interneurons we lacked a unique, agreed-upon classification, which we could use to guide model learning. Instead, we guided model learning with a probability distribution over the neuronal type and the axonal features, obtained, for each interneuron, from the neuroscientists' classification choices. We conveniently encoded such probability distributions with Bayesian networks, calling them label Bayesian networks (LBNs), and developed a method to predict them. This method predicts an LBN by forming a probabilistic consensus among the LBNs of the interneurons most similar to the one being classified. We used 18 axonal morphometric parameters as predictor variables, 13 of which we introduce in this paper as quantitative counterparts to the categorical axonal features. We were able to accurately predict interneuronal LBNs. Furthermore, when extracting crisp (i.e., non-probabilistic) predictions from the predicted LBNs, our method outperformed related work on interneuron classification. Our results indicate that our method is adequate for multi-dimensional classification of interneurons with probabilistic labels. Moreover, the introduced morphometric parameters are good predictors of interneuron type and the four features of axonal morphology and thus may serve as objective counterparts to the subjective, categorical axonal features

  4. Expanding neurochemical investigations with multi-modal recording: simultaneous fast-scan cyclic voltammetry, iontophoresis, and patch clamp measurements

    Science.gov (United States)

    Kirkpatrick, D. C.; McKinney, C. J.; Manis, P. B.

    2016-01-01

    Multi-modal recording describes the simultaneous collection of information across distinct domains. Compared to isolated measurements, such studies can more easily determine relationships between varieties of phenomena. This is useful for neurochemical investigations which examine cellular activity in response to changes in the local chemical environment. In this study, we demonstrate a method to perform simultaneous patch clamp measurements with fast-scan cyclic voltammetry (FSCV) using optically isolated instrumentation. A model circuit simulating concurrent measurements was used to predict the electrical interference between instruments. No significant impact was anticipated between methods, and predictions were largely confirmed experimentally. One exception was due to capacitive coupling of the FSCV potential waveform into the patch clamp amplifier. However, capacitive transients measured in whole-cell current clamp recordings were well below the level of biological signals, which allowed the activity of cells to be easily determined. Next, the activity of medium spiny neurons (MSNs) was examined in the presence of an FSCV electrode to determine how the exogenous potential impacted nearby cells. The activities of both resting and active MSNs were unaffected by the FSCV waveform. Additionally, application of an iontophoretic current, used to locally deliver drugs and other neurochemicals, did not affect neighboring cells. Finally, MSN activity was monitored during iontophoretic delivery of glutamate, an excitatory neurotransmitter. Membrane depolarization and cell firing were observed concurrently with chemical changes around the cell resulting from delivery. In all, we show how combined electrophysiological and electrochemical measurements can relate information between domains and increase the power of neurochemical investigations. PMID:27314130

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Neuregulin 3 Mediates Cortical Plate Invasion and Laminar Allocation of GABAergic Interneurons

    Directory of Open Access Journals (Sweden)

    Giorgia Bartolini

    2017-01-01

    Full Text Available Neural circuits in the cerebral cortex consist of excitatory pyramidal cells and inhibitory interneurons. These two main classes of cortical neurons follow largely different genetic programs, yet they assemble into highly specialized circuits during development following a very precise choreography. Previous studies have shown that signals produced by pyramidal cells influence the migration of cortical interneurons, but the molecular nature of these factors has remained elusive. Here, we identified Neuregulin 3 (Nrg3 as a chemoattractive factor expressed by developing pyramidal cells that guides the allocation of cortical interneurons in the developing cortical plate. Gain- and loss-of-function approaches reveal that Nrg3 modulates the migration of interneurons into the cortical plate in a process that is dependent on the tyrosine kinase receptor ErbB4. Perturbation of Nrg3 signaling in conditional mutants leads to abnormal lamination of cortical interneurons. Nrg3 is therefore a critical mediator in the assembly of cortical inhibitory circuits.

  7. Serotonin inhibits low-threshold spike interneurons in the striatum

    Science.gov (United States)

    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

  8. Serotonin inhibits low-threshold spike interneurons in the striatum.

    Science.gov (United States)

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

    2012-05-15

    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-HT(2C) receptor agonists and reversed by 5-HT(2C) 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-HT(2C) receptors and increasing an M type current.

  9. Serotonin receptor 3A controls interneuron migration into the neocortex.

    Science.gov (United States)

    Murthy, Sahana; Niquille, Mathieu; Hurni, Nicolas; Limoni, Greta; Frazer, Sarah; Chameau, Pascal; van Hooft, Johannes A; Vitalis, Tania; Dayer, Alexandre

    2014-11-20

    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 serotonin receptor 3A (5-HT(3A)R) is specifically expressed in CGE-derived migrating interneurons and upregulated while they invade the developing cortex. Functional investigations using calcium imaging, electrophysiological recordings and migration assays indicate that CGE-derived INs increase their response to 5-HT(3A)R activation during the late phase of cortical plate invasion. Using genetic loss-of-function approaches and in vivo grafts, we further demonstrate that the 5-HT(3A)R is cell autonomously required for the migration and proper positioning of reelin-expressing CGE-derived INs in the neocortex. Our findings reveal a requirement for a serotonin receptor in controlling the migration and laminar positioning of a specific subtype of cortical IN.

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

    Science.gov (United States)

    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.

  11. Accumbens nNOS Interneurons Regulate Cocaine Relapse.

    Science.gov (United States)

    Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A; Gipson, Cassandra D; Neuhofer, Daniela; Roberts-Wolfe, Doug J; Spencer, Sade; Garcia-Keller, Constanza; Stankeviciute, Neringa M; Smith, Rachel J; Allen, Nicholas P; Lorang, Melissa R; Griffin, William C; Boger, Heather A; Kalivas, Peter W

    2017-01-25

    Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine seeking result from glutamate spillover, initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production. Pharmacological stimulation of mGluR5 in NAcore recapitulated cue-induced reinstatement in the absence of drug-associated cues. Using NO-sensitive electrodes, mGluR5 activation by glutamate was shown to stimulate NO production that depended on activation of neuronal nitric oxide synthase (nNOS). nNOS is expressed in ∼1% of NAcore neurons. Using a transgene strategy to express and stimulate designer receptors that mimicked mGluR5 signaling through Gq in nNOS interneurons, we recapitulated cue-induced reinstatement in the absence of cues. Conversely, using a transgenic caspase strategy, the intensity of cue-induced reinstatement was correlated with the extent of selective elimination of nNOS interneurons. The induction of t-SP during cued reinstatement depends on activating matrix metalloproteinases (MMPs) and selective chemogenetic stimulation of nNOS interneurons recapitulated MMP activation and t-SP induction (increase in AMPA currents in MSNs). These data demonstrate critical involvement of a sparse population of nNOS-expressing interneurons in cue-induced cocaine seeking, revealing a bottleneck in brain processing of drug-associated cues where therapeutic interventions could be effective in treating drug addiction. Relapse to cocaine use in a rat model is associated with transient increases in synaptic strength at prefrontal cortex synapses in the nucleus

  12. Parvalbumin fast-spiking interneurons are selectively altered by pediatric traumatic brain injury.

    Science.gov (United States)

    Nichols, Joshua; Bjorklund, George Reed; Newbern, Jason; Anderson, Trent

    2018-01-15

    Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Traditionally, ongoing neurodevelopment and neuroplasticity have thought to confer children with an advantage following TBI. However, recent findings indicate that the pediatric brain may be more sensitive to brain injury. Inhibitory interneurons are essential for proper cortical function and implicated in the pathophysiology of TBI, yet few studies have directly examined for TBI induced changes to interneurons themselves. To address this, we examine how inhibitory neurons are altered following controlled cortical impact (CCI) in juvenile mice with targeted Cre-dependent fluorescent labelling of interneurons (Vgat:Cre/Ai9 and PV:Cre/Ai6). While CCI failed to alter the number of excitatory neurons or somatostatin-expressing interneurons in the peri-injury zone it significantly decreased the density of parvalbumin (PV) immunoreactive cells by 71%. However, PV:Cre/Ai6 mice subjected to CCI showed a lesser extent of fluorescently labelled cell loss. PV interneurons are predominantly of a fast-spiking (FS) phenotype and when recorded electrophysiologically from the peri-injury zone exhibited similar intrinsic properties as control neurons. Synaptically, CCI induced a decrease in inhibitory drive onto FS interneurons combined with an increase in the strength of excitatory events. Our results indicate that CCI induced both a loss of PV interneurons and an even greater loss of PV expression. This suggests caution in interpreting changes in PV immunoreactivity alone as direct evidence of interneuronal loss. Further, in contrast with reports in adults TBI in the pediatric brain selectively alter PV-FS interneurons resulting in primarily a loss of interneuronal inhibition. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  13. Clozapine protection against gestational cocaine-induced neurochemical abnormalities.

    Science.gov (United States)

    Yablonsky-Alter, Elena; Gashi, Eleonora; Lidsky, Theodore I; Wang, Hoau-Yan; Banerjee, Shailesh P

    2005-01-01

    Clozapine was found to be effective in attenuating cocaine-induced neurochemical effects. We investigate whether clozapine influences in utero cocaine exposure-induced changes in striatal dopamine levels and cortical N-methyl-D-aspartate (NMDA) receptor density in mouse and rat brains. Pregnant mice or rats were injected with cocaine (5 or 10 mg/kg intraperitoneally) or saline every 24 h throughout gestation and continued for 6 weeks following the delivery. Striatal dopamine levels measured by high-pressure liquid chromatography were found to decrease 24 to 33% in gestational cocaine exposed between the ages of 3 to 15 days, but not in 42-day-old pups. The cortical NMDA receptor densities assessed either in the presence of 100 microM glutamate or 30 microM glycine were significantly increased in 15-day-old gestational cocaine-exposed rats. Simultaneous daily administration of 3 mg/kg clozapine with 5 mg/kg cocaine to pregnant mice protected against the decrease in striatal dopamine levels or an increase in the concentration of NMDA receptor measured in the presence of 100 microM glutamate in 15-day-old pups. Clozapine did not affect striatal dopamine levels by itself or when coadministered with cocaine in 42-day-old pups. The results show gestational cocaine may induce neurochemical abnormalities in brain exhibited as an increased glutamate NMDA receptor density together with a decreased striatal dopamine level. These effects of gestational cocaine exposure may be prevented by simultaneous administration of clozapine. Thus clozapine, which is a partial agonist at the NMDA receptor, may be of value in protecting against gestational cocaine-induced adverse effects in the brain.

  14. Neurochemical phenotype of cytoglobin‑expressing neurons in the rat hippocampus

    DEFF Research Database (Denmark)

    Hundahl, Christian Ansgar; Fahrenkrug, Jan; Hannibal, Jens

    2014-01-01

    of Cygb neurons remain uncharacterized by the neurochemical content. The aim of the present study was to provide an additional and more detailed neurochemical phenotype of Cygb-expressing neurons in the rat hippocampus. The rat hippocampus was chosen due to the abundance of Cygb, as well as this limbic...... of Cygb neurons co-expressing nNOS. Furthermore, it was shown that the majority of neurons expressing somastostatin and vasoactive intestinal peptide also co-express Cygb and nNOS. Detailed information regarding the neurochemical phenotype of Cygb neurons in the hippocampus can be a valuable tool...

  15. Adenosine-mediated modulation of ventral horn interneurons and spinal motoneurons in neonatal mice

    Science.gov (United States)

    Witts, Emily C.; Nascimento, Filipe

    2015-01-01

    Neuromodulation allows neural networks to adapt to varying environmental and biomechanical demands. Purinergic signaling is known to be an important modulatory system in many parts of the CNS, including motor control circuitry. We have recently shown that adenosine modulates the output of mammalian spinal locomotor control circuitry (Witts EC, Panetta KM, Miles GB. J Neurophysiol 107: 1925–1934, 2012). Here we investigated the cellular mechanisms underlying this adenosine-mediated modulation. Whole cell patch-clamp recordings were performed on ventral horn interneurons and motoneurons within in vitro mouse spinal cord slice preparations. We found that adenosine hyperpolarized interneurons and reduced the frequency and amplitude of synaptic inputs to interneurons. Both effects were blocked by the A1-type adenosine receptor antagonist DPCPX. Analysis of miniature postsynaptic currents recorded from interneurons revealed that adenosine reduced their frequency but not amplitude, suggesting that adenosine acts on presynaptic receptors to modulate synaptic transmission. In contrast to interneurons, recordings from motoneurons revealed an adenosine-mediated depolarization. The frequency and amplitude of synaptic inputs to motoneurons were again reduced by adenosine, but we saw no effect on miniature postsynaptic currents. Again these effects on motoneurons were blocked by DPCPX. Taken together, these results demonstrate differential effects of adenosine, acting via A1 receptors, in the mouse spinal cord. Adenosine has a general inhibitory action on ventral horn interneurons while potentially maintaining motoneuron excitability. This may allow for adaptation of the locomotor pattern generated by interneuronal networks while helping to ensure the maintenance of overall motor output. PMID:26311185

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

    Science.gov (United States)

    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.

  17. Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons

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    Avital eAdler

    2013-09-01

    Full Text Available The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs, and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs, which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs, presumably parvalbumin (PV expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation. TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit.

  18. Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition

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    Megan S. Wyeth

    2017-08-01

    Full Text Available Although Netos are considered auxiliary subunits critical for kainate receptor (KAR function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We demonstrate Neto1/2 expression in somatostatin (SOM-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1-, and parvalbumin (PV-containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.

  19. 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.

  20. The morphology and fine structure of the giant interneurons of the wood cricket Nemobius sylvestris.

    Science.gov (United States)

    Insausti, T C; Lazzari, C R; Casas, J

    2011-02-01

    The structural and ultrastructural characteristics of giant interneurons in the terminal abdominal ganglion of the cricket Nemobius sylvestris were investigated by means of cobalt and fluorescent dye backfilling and transmission electron microscopy. The projections of the 8 eight pairs of the biggest ascending interneurons (giant interneurons) are described in detail. The somata of all interneurons analyzed are located contralateral to their axons, which project to the posterior region of the terminal ganglion and arborise in the cercal glomerulus. Neuron 7-1a is an exception, because its arborisation is restricted to the anterior region of the ganglion. The fine structure of giant interneurons shows typical features of highly active cells. We observed striking indentations in the perineural layer, enabling the somata of the giant interneurons to be very close to the haemolymph. The cercal glomerulus exhibits a high diversity of synaptic contacts (i.e. axo-dendritic, axo-axonic, dendro-axonic, and dendro-dendritic), as well as areas of tight junctions. Electrical synapses seem to be present, as well as mixed synapses. The anatomical organization of the giant interneurons is finally discussed in terms of functional implications and on a comparative basis. Copyright © 2010 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Tris(2-chloroethyl)phosphate increases ambulatory activity in mice: pharmacological analyses of its neurochemical mechanism.

    Science.gov (United States)

    Umezu, T; Yonemoto, J; Soma, Y; Suzuki, T

    1998-01-01

    The present study was conducted to clarify the acute effect of tris(2-chloroethyl)phosphate (TRCP), an organophosphate flame-retardant, on spontaneous ambulatory activity (AA) in male ICR mice and to examine the neurochemical mechanism of this effect. Single dose administration of 200 mg/kg i.p. of TRCP increased AA in ICR mice. Neither the nicotinic cholinergic antagonist mecamylamine (MA) nor the muscarinic cholinergic antagonist scopolamine (SCP) affected the AA response to TRCP. On the other hand, the benzodiazepine agonist diazepam (DZ), the GABAA agonist muscimol (MUS) and the GABAB agonist baclofen (BAC) all attenuated the effect of TRCP. DZ and MUS blocked the increase of AA within the first 10 min after administration of TRCP. These drugs did not attenuate the AA-increasing effect of SCP, suggesting that the mechanism of TRCP action is distinct from that of SCP. MUS and BAC did, but DZ did not, inhibit the AA increasing effect of the dopaminergic agonist apomorphine (APO), suggesting that dopamine is involved in the control of AA, and that GABA can affect AA through interaction with dopaminergic neurons. These results suggest that TRCP acts as a GABA antagonist and not as a cholinergic agonist, and that TRCP increases AA in ICR mice through a GABAergic mechanism.

  3. Neurochemical imaging of Alzheimer`s disease and other degenerative dementias

    Energy Technology Data Exchange (ETDEWEB)

    Frey, K.A.; Minoshima, S.; Kuhl, D.E. [Ann Arbor, Univ. of Michigan, MI (United States). Dept. of Internal Medicine. Division of Nuclear Medicine

    1998-09-01

    A wide variety of neurochemical and functional imaging approaches have been applied to the study of progressive dementias, particularly Alzheimer`s disease (Ad) and related disorders. Despite considerable progress in the past decade, the cause(s) of most cases of Ad remain undetermined and preventive or protective therapies are lacking. Specifically-designed imaging procedures have permitted the testing of pathophysiological hypotheses of the etiology and progression of Ad, and have yielded important insights in several areas including the potential roles of cerebral cortical cholinergic lesions, cellular inflammation, and losses of cortical synapses. From the perspective of clinical diagnosis, PET glucose metabolism imaging with use of ({sup 18}F)2-fluorodeoxyglucose (FDG) is the most sensitive and specific imaging modality yet identified. The overall performance of PET FDG is favorable for routine clinical evaluation of suspected Ad, and will likely gain increasing utilization in the near future. Assessments of glucose metabolism and other, specific aspects of neurochemistry in Ad will provide direct measures of therapeutic drug actions and may permit distinction of symptomatic versus disease-modifying therapies as they are developed and introduced in clinical trials.

  4. Selective gene expression by postnatal electroporation during olfactory interneuron neurogenesis.

    Directory of Open Access Journals (Sweden)

    Alexander T Chesler

    Full Text Available Neurogenesis persists in the olfactory system throughout life. The mechanisms of how new neurons are generated, how they integrate into circuits, and their role in coding remain mysteries. Here we report a technique that will greatly facilitate research into these questions. We found that electroporation can be used to robustly and selectively label progenitors in the Subventicular Zone. The approach was performed postnatally, without surgery, and with near 100% success rates. Labeling was found in all classes of interneurons in the olfactory bulb, persisted to adulthood and had no adverse effects. The broad utility of electroporation was demonstrated by encoding a calcium sensor and markers of intracellular organelles. The approach was found to be effective in wildtype and transgenic mice as well as rats. Given its versatility, robustness, and both time and cost effectiveness, this method offers a powerful new way to use genetic manipulation to understand adult neurogenesis.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2016-02-01

    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. 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. 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. 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. © 2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of

  7. Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders.

    Science.gov (United States)

    Jacob, John

    2016-02-01

    Autism and epilepsy are two associated disorders that are highly prevalent, share common developmental origins, and demonstrate substantial heritability. In this review, cross-disciplinary data in a rapidly evolving field that bridges neurology and psychiatry are synthesized to identify shared biologic mechanisms. The relationship between these debilitating, lifelong conditions is examined at the clinical, genetic, and neurophysiologic levels in humans and in animal models. Scopus and PubMed searches were used to identify relevant literature. Clinical observations have prompted speculation about the interdependence of autism and epilepsy, but causal relationships have proved difficult to determine. Despite their heritability, the genetic basis of autism spectrum disorder (ASD) and epilepsy has remained largely elusive until the advent of next-generation sequencing. This approach has revealed that mutations that are either causal or confer an increased disease risk are found in numerous different genes, any one of which accounts for only a small percentage of cases. Conversely, even cases with identical clinical phenotypes can be genetically heterogeneous. Candidate gene identification has facilitated the development of mouse genetic models, which in parallel with human studies have implicated shared brain regions and circuits that mediate disease expression. Diverse genetic causes of ASD and epilepsy converge on cortical interneuron circuits as one important mediator of both disorders. Cortical interneurons are among the most diverse cell types in the brain and their unique chemical and electrical coupling exert a powerful inhibitory influence on excitatory neurons via the release of the neurotransmitter, γ-aminobutyric acid (GABA). These multifaceted approaches have validated theories derived from the field of developmental neurobiology, which propose that the neurologic and neuropsychiatric manifestations are caused by an altered ratio of excitation to

  8. Neurochemical features of endomorphin-2-containing neurons in the submucosal plexus of the rat colon.

    Science.gov (United States)

    Li, Jun-Ping; Zhang, Ting; Gao, Chang-Jun; Kou, Zhen-Zhen; Jiao, Xu-Wen; Zhang, Lian-Xiang; Wu, Zhen-Yu; He, Zhong-Yi; Li, Yun-Qing

    2015-09-14

    ChAT, SP, VIP or NOS were approximately 91% ± 2.6%, 36% ± 2.4%, 44% ± 2.5% and 44% ± 4.7%, respectively, but EM-2 did not co-localize with CGRP. EM-2-IR neurons are present in the submucosal plexus of the rat colon and express distinct neurochemical markers.

  9. Dendritic signaling in inhibitory interneurons: local tuning via group I metabotropic glutamate receptors

    Directory of Open Access Journals (Sweden)

    Olivier eCamiré

    2012-07-01

    Full Text Available Communication between neurons is achieved by rapid signal transduction via highly specialized structural elements known as synaptic contacts. In addition, numerous extrasynaptic mechanisms provide a flexible platform for the local regulation of synaptic signals. For example, peri- and extrasynaptic signaling through the group I metabotropic glutamate receptors (mGluRs can be involved in the highly compartmentalized regulation of dendritic ion conductances, the induction of input-specific synaptic plasticity, and the local release of retrograde messengers. Therefore, extrasynaptic mechanisms appear to play a key role in the local tuning of dendritic computations. Here, we review recent findings on the role of group I mGluRs in the dendritic signaling of inhibitory interneurons. We propose that group I mGluRs provide a dual-mode signaling device that integrates different patterns of neural activity. By implementing distinct forms of intrinsic and synaptic regulation, group I mGluRs may be responsible for the local fine-tuning of dendritic function.

  10. Audition in the praying mantis, Mantis religiosa L.: identification of an interneuron mediating ultrasonic hearing.

    Science.gov (United States)

    Yager, D D; Hoy, R R

    1989-08-01

    1. The praying mantis possesses a single ear located in the ventral midline of the metathorax. We have studied the mantis' auditory nervous system using both extracellular and intracellular techniques and have identified anatomically and physiologically a mirror-image pair of interneurons (MR-501-T3) in the metathoracic ganglion that mediates ultrasonic hearing. 2. MR-501-T3 is tuned broadly to ultrasound with best sensitivity (55-60 dB SPL) between 25 and 45 kHz. Its tuning matches closely that of the whole tympanal nerve. 3. The physiological responses of MR-501-T3 are characterized by: (1) a phasic-tonic firing pattern with a distinctive initial burst at 500-800 spikes/s; (2) minimum latencies of 8-12 ms; (3) no spontaneous activity; (4) sigmoid intensity response curves with a small (10 dB) dynamic range; (5) accurate coding of stimulus duration and of repetition rates up to 60 pps. 4. The ascending axon of MR-501-T3 conducts action potentials at 4 m/s, a rate comparable with some giant fiber systems. 5. MR-501-T3 shows no directional capability. Sound from right and left produce identical responses in both cells of the pair. Neither cutting one tympanal nerve nor removing one hemi-ear leads to different responses in the two cells indicating that they must receive a common input, either from the auditory afferents or from interneurons. We present evidence that the two cells are not directly connected. 6. MR-501-T3 is a large, symmetrical cell with its processes primarily in the intermediate neuropil (lateral ring tract). Its integration segment crosses the midline in the supramedian commissure, and the cell body lies dorsally near the entrance of the leg nerve. The axon travels in the dorsal lateral tract and is one of the largest (17 microns) in the connective. 7. Given the strong anatomical similarities between MR-501-T3 and the G and B cells of the locust, these cells may be homologous. 8. We present arguments based on our physiological results and existing

  11. Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics

    NARCIS (Netherlands)

    Lelental, N.; Brandner, S.; Kofanova, O.; Blennow, K.; Zetterberg, H.; Andreasson, U.; Engelborghs, S.; Mroczko, B.; Gabryelewicz, T.; Teunissen, C.; Mollenhauer, B.; Parnetti, L.; Chiasserini, D.; Molinuevo, J.L.; Perret-Liaudet, A.; Verbeek, M.M.; Andreasen, N.; Brosseron, F.; Bahl, J.M.; Herukka, S.K.; Hausner, L.; Frolich, L.; Labonte, A.; Poirier, J.; Miller, A.M.; Zilka, N.; Kovacech, B.; Urbani, A.; Suardi, S.; Oliveira, C. de; Baldeiras, I.; Dubois, B.; Rot, U.; Lehmann, S.; Skinningsrud, A.; Betsou, F.; Wiltfang, J.; Gkatzima, O.; Winblad, B.; Buchfelder, M.; Kornhuber, J.; Lewczuk, P.

    2016-01-01

    BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples.

  12. Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics

    NARCIS (Netherlands)

    Lelental, Natalia; Brandner, Sebastian; Kofanova, Olga; Blennow, Kaj; Zetterberg, Henrik; Andreasson, Ulf; Engelborghs, Sebastiaan; Mroczko, Barbara; Gabryelewicz, Tomasz; Teunissen, Charlotte; Mollenhauer, Brit; Parnetti, Lucilla; Chiasserini, Davide; Molinuevo, Jose Luis; Perret-Liaudet, Armand; Verbeek, Marcel M.; Andreasen, Niels; Brosseron, Frederic; Bahl, Justyna M. C.; Herukka, Sanna-Kaisa; Hausner, Lucrezia; Froelich, Lutz; Labonte, Anne; Poirier, Judes; Miller, Anne-Marie; Zilka, Norbert; Kovacech, Branislav; Urbani, Andrea; Suardi, Silvia; Oliveira, Catarina; Baldeiras, Ines; Dubois, Bruno; Rot, Uros; Lehmann, Sylvain; Skinningsrud, Anders; Betsou, Fay; Wiltfang, Jens; Gkatzima, Olymbia; Winblad, Bengt; Buchfelder, Michael; Kornhuber, Johannes; Lewczuk, Piotr

    2016-01-01

    Background: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples.

  13. Postsynaptic GABABRs Inhibit L-Type Calcium Channels and Abolish Long-Term Potentiation in Hippocampal Somatostatin Interneurons.

    Science.gov (United States)

    Booker, Sam A; Loreth, Desiree; Gee, Annabelle L; Watanabe, Masahiko; Kind, Peter C; Wyllie, David J A; Kulik, Ákos; Vida, Imre

    2018-01-02

    Inhibition provided by local GABAergic interneurons (INs) activates ionotropic GABAA and metabotropic GABAB receptors (GABABRs). Despite GABABRs representing a major source of inhibition, little is known of their function in distinct IN subtypes. Here, we show that, while the archetypal dendritic-inhibitory somatostatin-expressing INs (SOM-INs) possess high levels of GABABR on their somato-dendritic surface, they fail to produce significant postsynaptic inhibitory currents. Instead, GABABRs selectively inhibit dendritic CaV1.2 (L-type) Ca2+ channels on SOM-IN dendrites, leading to reduced calcium influx and loss of long-term potentiation at excitatory input synapses onto these INs. These data provide a mechanism by which GABABRs can contribute to disinhibition and control the efficacy of extrinsic inputs to hippocampal networks. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  14. Transient Suppression of Dbx1 PreBötzinger Interneurons Disrupts Breathing in Adult Mice.

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    Nikolas C Vann

    Full Text Available Interneurons derived from Dbx1-expressing precursors located in the brainstem preBötzinger complex (preBötC putatively form the core oscillator for inspiratory breathing movements. We tested this Dbx1 core hypothesis by expressing archaerhodopsin in Dbx1-derived interneurons and then transiently hyperpolarizing these neurons while measuring respiratory rhythm in vitro or breathing in vagus-intact adult mice. Transient illumination of the preBötC interrupted inspiratory rhythm in both slice preparations and sedated mice. In awake mice, light application reduced breathing frequency and prolonged the inspiratory duration. Support for the Dbx1 core hypothesis previously came from embryonic and perinatal mouse experiments, but these data suggest that Dbx1-derived preBötC interneurons are rhythmogenic in adult mice too. The neural origins of breathing behavior can be attributed to a localized and genetically well-defined interneuron population.

  15. Adult born olfactory bulb dopaminergic interneurons: molecular determinants and experience-dependent plasticity

    Directory of Open Access Journals (Sweden)

    Sara eBonzano

    2016-05-01

    Full Text Available The olfactory bulb (OB is a highly plastic brain region involved in the early processing of olfactory information. A remarkably feature of the OB circuits in rodents is the constitutive integration of new neurons that takes place during adulthood. Newborn cells in the adult OB are mostly inhibitory interneurons belonging to chemically, morphologically and functionally heterogeneous types. Although there is general agreement that adult neurogenesis in the OB plays a key role in sensory information processing and olfaction-related plasticity, the contribution of each interneuron subtype to such functions is far to be elucidated. Here, we focus on the dopaminergic (DA interneurons: we highlight recent findings about their morphological features and then describe the molecular factors required for the specification/differentiation and maintenance of the DA phenotype in adult born neurons. We also discuss dynamic changes of the DA interneuron population related to age, environmental stimuli and lesions, and their possible functional implications.

  16. A comparative perspective on minicolumns and inhibitory GABAergic interneurons in the neocortex

    Directory of Open Access Journals (Sweden)

    Mary Ann Raghanti

    2010-02-01

    Full Text Available Neocortical columns are functional and morphological units whose architecture may have been under selective evolutionary pressure in different mammalian lineages in response to encephalization and specializations of cognitive abilities. Inhibitory interneurons make a substantial contribution to the morphology and distribution of minicolumns within the cortex. In this context, we review differences in minicolumns and GABAergic interneurons among species and discuss possible implications for signaling among and within minicolumns. Furthermore, we discuss how abnormalities of both minicolumn disposition and inhibitory interneurons might be associated with neuropathological processes, such as Alzheimer’s disease, autism, and schizophrenia. Specifically, we will explore the possibility that phylogenetic variability in calcium-binding protein-expressing interneuron subtypes is directly related to differences in minicolumn morphology among species and might contribute to neuropathological susceptibility in humans.

  17. Neurochemical Effects of Chronic Administration of Calcitriol in Rats

    Directory of Open Access Journals (Sweden)

    Pei Jiang

    2014-12-01

    Full Text Available Despite accumulating data showing the various neurological actions of vitamin D (VD, its effects on brain neurochemistry are still far from fully understood. To further investigate the neurochemical influence of VD, we assessed neurotransmitter systems in the brain of rats following 6-week calcitriol (1,25-dihydroxyvitamin D administration (50 ng/kg/day or 100 ng/kg/day. Both the two doses of calcitriol enhanced VDR protein level without affecting serum calcium and phosphate status. Rats treated with calcitriol, especially with the higher dose, exhibited elevated γ-aminobutyric acid (GABA status. Correspondingly, the mRNA expression of glutamate decarboxylase (GAD 67 was increased. 100 ng/kg of calcitriol administration also increased glutamate and glutamine levels in the prefrontal cortex, but did not alter glutamine synthetase (GS expression. Additionally, calcitriol treatment promoted tyrosine hydroxylase (TH and tryptophan hydroxylase 2 (TPH2 expression without changing dopamine and serotonin status. However, the concentrations of the metabolites of dopamine and serotonin were increased and the drug use also resulted in a significant rise of monoamine oxidase A (MAOA expression, which might be responsible to maintain the homeostasis of dopaminergic and serotonergic neurotransmission. Collectively, the present study firstly showed the effects of calcitriol in the major neurotransmitter systems, providing new evidence for the role of VD in brain function.

  18. A neurochemical approach to valuation sensitivity over gains and losses.

    Science.gov (United States)

    Zhong, Songfa; Israel, Salomon; Xue, Hong; Sham, Pak C; Ebstein, Richard P; Chew, Soo Hong

    2009-12-07

    Prospect theory proposes the hypothesis that people have diminishing sensitivity in valuing increases in the size of monetary outcomes, for both gains and losses. For decision-making under risk, this implies a tendency to be risk-tolerant over losses while being generally risk averse over gains. We offer a neurochemistry-based model of the diminishing valuation sensitivity hypothesis. Specifically, we propose that dopamine tone modulates the sensitivity towards valuation of gains while serotonin tone modulates the sensitivity towards valuation of losses. Consequently, higher dopamine tone would yield a more concave valuation function over gains while higher serotonin tone would yield a more convex valuation function over losses. Using a neurogenetics strategy to test our neurochemical model, we find that subjects with the 9-repeat allele of DAT1 (lower DA tone) are more risk-tolerant over gains than subjects with the 10-repeat allele, and that subjects with the 10-repeat allele of STin2 (higher 5HT tone) are more risk-tolerant over losses than subjects with the 12-repeat allele. Overall, our results support the implications of our model and provide the first neurogenetics evidence that risk attitudes are partially hard-wired in differentiating between gain- and loss-oriented risks.

  19. Neurochemical Alterations in Sudden Unexplained Perinatal Deaths—A Review

    Directory of Open Access Journals (Sweden)

    Nazeer Muhammad

    2018-01-01

    Full Text Available Sudden unexpected perinatal collapse is a major trauma for the parents of victims. Sudden infant death syndrome (SIDS is unexpected and mysterious death of an apparently healthy neonate from birth till 1 year of age without any known causes, even after thorough postmortem investigations. However, the incidence of sudden intrauterine unexplained death syndrome (SIUDS is seven times higher as compared with SIDS. This observation is approximated 40–80%. Stillbirth is defined as death of a fetus after 20th week of gestation or just before delivery at full term without a known reason. Pakistan has the highest burden of stillbirth in the world. This basis of SIDS, SIUDS, and stillbirths eludes specialists. The purpose of this study is to investigate factors behind failure in control of these unexplained deaths and how research may go ahead with improved prospects. Animal models and physiological data demonstrate that sleep, arousal, and cardiorespiratory malfunctioning are abnormal mechanisms in SIUDS risk factors or in newborn children who subsequently die from SIDS. This review focuses on insights in neuropathology and mechanisms of SIDS and SIUDS in terms of different receptors involved in this major perinatal demise. Several studies conducted in the past decade have confirmed neuropathological and neurochemical anomalies related to serotonin transporter, substance P, acetylcholine α7 nicotine receptors, etc., in sudden unexplained fetal and infant deaths. There is need to focus more on research in this area to unveil the major curtain to neuroprotection by underlying mechanisms leading to such deaths.

  20. Dyslipidemia links obesity to early cerebral neurochemical alterations.

    Science.gov (United States)

    Haley, Andreana P; Gonzales, Mitzi M; Tarumi, Takashi; Tanaka, Hirofumi

    2013-10-01

    To examine the role of hypertension, hyperglycemia, and dyslipidemia in potentially accounting for obesity-related brain vulnerability in the form of altered cerebral neurochemistry. Sixty-four adults, ages 40-60 years, underwent a health screen and proton magnetic resonance spectroscopy ((1) H MRS) of occipitoparietal gray matter to measure N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI), and glutamate (Glu) relative to creatine (Cr). The causal steps approach and nonparametric bootstrapping were utilized to assess if fasting glucose, mean arterial pressure or peripheral lipid/lipoprotein levels mediate the relationship between body mass index (BMI) and cerebral neurochemistry. Higher BMI was significantly related to higher mI/Cr, independent of age and sex. BMI was also significantly related to two of the proposed mediators, triglyceride, and HDL-cholesterol, which were also independently related to increased mI/Cr. Finally, the relationship between BMI and mI/Cr was significantly attenuated after inclusion of triglyceride and HDL-cholesterol into the model, one at a time, indicating statistical mediation. Higher triglyceride and lower HDL levels statistically account for the association between BMI and myo-inositol, pointing toward a potentially critical role for dyslipidemia in the development of cerebral neurochemical alterations in obesity. Copyright © 2013 The Obesity Society.

  1. Neurochemical background and approaches in the understanding of motion sickness

    Science.gov (United States)

    Kohl, R. L.

    1982-01-01

    The problems and nature of space motion sickness were defined. The neurochemical and neurophysiological bases of vestibular system function and of the expression of motion sickness wre reviewed. Emphasis was given to the elucidation of the neuropharmacological mechanisms underlying the effects of scopolamine and amphetamine on motion sickness. Characterization of the ascending reticular activating system and the limbic system provided clues to the etiology of the side effects of scopolamine. The interrelationship between central cholinergic pathways and the peripheral (autonomic) expression of motion sickness was described. A correlation between the stress of excessive motion and a variety of hormonal responses to that stress was also detailed. The cholinergic system is involved in the efferent modulation of the vestibular hair cells, as an afferent modulator of the vestibular nuclei, in the activation of cortical and limbic structures, in the expression of motion sickness symptoms and most likely underscores a number of the hormonal changes that occur in stressful motion environments. The role of lecithin in the regulation of the levels of neurotransmitters was characterized as a possible means by which cholinergic neurochemistry can be modulated.

  2. Social Stress and Psychosis Risk: Common Neurochemical Substrates?

    Science.gov (United States)

    Mizrahi, Romina

    2016-02-01

    Environmental risk factors have been implicated in the etiology of psychotic disorders, with growing evidence showing the adverse effects of migration, social marginalization, urbanicity, childhood trauma, social defeat, and other adverse experiences on mental health in vulnerable populations. Collectively, social stress may be one mechanism that could link these environmental risk factors. The exact mechanism(s) by which social stress can affect brain function, and in particular the molecular targets involved in psychosis (such as the dopaminergic (DA) system), is (are) not fully understood. In this review, we will discuss the interplay between social environmental risk factors and molecular changes in the human brain; in particular, we will highlight the impact of social stress on three specific neurochemical systems: DA, neuroinflammation/immune, and endocannabinoid (eCB) signaling. We have chosen the latter two molecular pathways based on emerging evidence linking schizophrenia to altered neuroinflammatory processes and cannabis use. We further identify key developmental periods in which social stress interacts with these pathways, suggesting window(s) of opportunities for novel interventions. Taken together, we suggest that they may have a key role in the pathogenesis and disease progression, possibly provide novel treatment options for schizophrenia, and perhaps even prevent it.

  3. Expression and distribution of Kv4 potassium channel subunits and potassium channel interacting proteins in subpopulations of interneurons in the basolateral amygdala.

    Science.gov (United States)

    Dabrowska, J; Rainnie, D G

    2010-12-15

    The Kv4 potassium channel α subunits, Kv4.1, Kv4.2, and Kv4.3, determine some of the fundamental physiological properties of neurons in the CNS. Kv4 subunits are associated with auxiliary β-subunits, such as the potassium channel interacting proteins (KChIP1 - 4), which are thought to regulate the trafficking and gating of native Kv4 potassium channels. Intriguingly, KChIP1 is thought to show cell type-selective expression in GABA-ergic inhibitory interneurons, while other β-subunits (KChIP2-4) are associated with principal glutamatergic neurons. However, nothing is known about the expression of Kv4 family α- and β-subunits in specific interneurons populations in the BLA. Here, we have used immunofluorescence, co-immunoprecipitation, and Western Blotting to determine the relative expression of KChIP1 in the different interneuron subtypes within the BLA, and its co-localization with one or more of the Kv4 α subunits. We show that all three α-subunits of Kv4 potassium channel are found in rat BLA neurons, and that the immunoreactivity of KChIP1 closely resembles that of Kv4.3. Indeed, Kv4.3 showed almost complete co-localization with KChIP1 in the soma and dendrites of a distinct subpopulation of BLA neurons. Dual-immunofluorescence studies revealed this to be in BLA interneurons immunoreactive for parvalbumin, cholecystokin-8, and somatostatin. Finally, co-immunoprecipitation studies showed that KChIP1 was associated with all three Kv4 α subunits. Together our results suggest that KChIP1 is selectively expressed in BLA interneurons where it may function to regulate the activity of A-type potassium channels. Hence, KChIP1 might be considered as a cell type-specific regulator of GABAergic inhibitory circuits in the BLA. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Recursive Distinctioning

    CERN Document Server

    Isaacson, Joel

    2016-01-01

    Recursive distinctioning (RD) is a name coined by Joel Isaacson in his original patent document describing how fundamental patterns of process arise from the systematic application of operations of distinction and description upon themselves. Recursive distinctioning means just what it says. A pattern of distinctions is given in a space based on a graphical structure (such as a line of print or a planar lattice or given graph). Each node of the graph is occupied by a letter from some arbitrary alphabet. A specialized alphabet is given that can indicate distinctions about neighbors of a given node. The neighbors of a node are all nodes that are connected to the given node by edges in the graph. The letters in the specialized alphabet (call it SA) are used to describe the states of the letters in the given graph and at each stage in the recursion, letters in SA are written at all nodes in the graph, describing its previous state. The recursive structure that results from the iteration of descriptions is called ...

  5. Neurochemical consequence of steroid abuse: stanozolol-induced monoaminergic changes.

    Science.gov (United States)

    Tucci, Paolo; Morgese, Maria Grazia; Colaianna, Marilena; Zotti, Margherita; Schiavone, Stefania; Cuomo, Vincenzo; Trabace, Luigia

    2012-02-01

    An extensive literature has documented adverse effects on mental health in anabolic androgenic steroids (AAS) abusers. Depression seems a common adverse reaction in AAS abusers. Recently it has been reported that in a rat model of AAS abuse stanozolol induces behavioural and biochemical changes related to the pathophysiology of major depressive disorder. In the present study, we used the model of AAS abuse to examine possible changes in the monoaminergic system, a neurobiological substrate of depression, in different brain areas of stanozolol-treated animals. Wistar rats received repeated injections of stanozolol (5mg/kg, s.c.), or vehicle (propylene glycol, 1ml/kg) once daily for 4weeks. Twenty-four hours after last injection, changes of dopamine (DA) and relative metabolite levels, homovanilic acid (HVA) and 3,4-dihydroxy phenylacetic acid (DOPAC), serotonin (5-HT) and its metabolite levels, 5-hydroxy indolacetic acid (5-HIAA), and noradrenaline (NA) amount were investigated in prefrontal cortex (PFC), nucleus accumbens (NAC), striatum (STR) and hippocampus (HIPP). The analysis of data showed that after chronic stanozolol, DA levels were increased in the HIPP and decreased in the PFC. No significant changes were observed in the STR or in the NAC. 5-HT and 5-HIAA levels were decreased in all brain areas investigated after stanozolol exposure; however, the 5-HIAA/5-HT ratio was not altered. Taken together, our data indicate that chronic use of stanozolol significantly affects brain monoamines leading to neurochemical modifications possibly involved in depression and stress-related states. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Neurochemical organization of the nucleus paramedianus dorsalis in the human.

    Science.gov (United States)

    Baizer, Joan S; Baker, James F; Haas, Kristin; Lima, Raquel

    2007-10-24

    We have characterized the neurochemical organization of a small brainstem nucleus in the human brain, the nucleus paramedianus dorsalis (PMD). PMD is located adjacent and medial to the nucleus prepositus hypoglossi (PH) in the dorsal medulla and is distinguished by the pattern of immunoreactivity of cells and fibers to several markers including calcium-binding proteins, a synthetic enzyme for nitric oxide (neuronal nitric oxide synthase, nNOS) and a nonphosphorylated neurofilament protein (antibody SMI-32). In transverse sections, PMD is oval with its long axis aligned with the dorsal border of the brainstem. We identified PMD in eight human brainstems, but found some variability both in its cross-sectional area and in its A-P extent among cases. It includes calretinin immunoreactive large cells with oval or polygonal cell bodies. Cells in PMD are not immunoreactive for either calbindin or parvalbumin, but a few fibers immunoreactive to each protein are found within its central region. Cells in PMD are also immunoreactive to nNOS, and immunoreactivity to a neurofilament protein shows many labeled cells and fibers. No similar region is identified in atlases of the cat, mouse, rat or monkey brain, nor does immunoreactivity to any of the markers that delineate it in the human reveal a comparable region in those species. The territory that PMD occupies is included in PH in other species. Since anatomical and physiological data in animals suggest that PH may have multiple subregions, we suggest that the PMD in human may be a further differentiation of PH and may have functions related to the vestibular control of eye movements.

  7. Neurochemical Evidence of Potential Neurotoxicity After Prophylactic Cranial Irradiation

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    Kalm, Marie, E-mail: marie.kalm@neuro.gu.se [Department of Clinical Neuroscience and Rehabilitation, Insitute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Abel, Edvard [Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Wasling, Pontus [Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Nyman, Jan [Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Hietala, Max Albert [Department of Neurology, Karolinska University Hospital, Stockholm (Sweden); Bremell, Daniel; Hagberg, Lars [Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Elam, Mikael [Department of Clinical Neuroscience and Rehabilitation, Insitute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Blennow, Kaj [Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal (Sweden); Björk-Eriksson, Thomas [Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Zetterberg, Henrik [Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal (Sweden); UCL Institute of Neurology, London (United Kingdom)

    2014-07-01

    Purpose: To examine whether cerebrospinal fluid biomarkers for neuroaxonal damage, neuroglial activation, and amyloid β–related processes could characterize the neurochemical response to cranial radiation. Methods and Materials: Before prophylactic cranial irradiation (PCI) of patients with small cell lung cancer, each patient underwent magnetic resonance imaging of the brain, lumbar puncture, and Mini-Mental State Examination of cognitive function. These examinations were repeated at approximately 3 and 12 months after radiation. Results: The major findings were as follows. (1) Cerebrospinal fluid markers for neuronal and neuroglial injury were elevated during the subacute phase after PCI. Neurofilament and T-tau increased 120% and 50%, respectively, after PCI (P<.05). The same was seen for the neuroglial markers YKL-40 and glial fibrillary acidic protein, which increased 144% and 106%, respectively, after PCI (P<.05). (2) The levels of secreted amyloid precursor protein-α and -β were reduced 44% and 46%, respectively, 3 months after PCI, and the levels continued to decrease as long as 1 year after treatment (P<.05). (3) Mini-Mental State Examination did not reveal any cognitive decline, indicating that a more sensitive test should be used in future studies. Conclusion: In conclusion, we were able to detect radiation therapy–induced changes in several markers reflecting neuronal injury, inflammatory/astroglial activation, and altered amyloid precursor protein/amyloid β metabolism, despite the low number of patients and quite moderate radiation doses (20-30 Gy). These changes are hypothesis generating and could potentially be used to assess the individual risk of developing long-term symptoms of chronic encephalopathy after PCI. This has to be evaluated in large studies with extended clinical follow-up and more detailed neurocognitive assessments.

  8. Caffeine triggers behavioral and neurochemical alterations in adolescent rats.

    Science.gov (United States)

    Ardais, A P; Borges, M F; Rocha, A S; Sallaberry, C; Cunha, R A; Porciúncula, L O

    2014-06-13

    Caffeine is the psychostimulant most consumed worldwide but concerns arise about the growing intake of caffeine-containing drinks by adolescents since the effects of caffeine on cognitive functions and neurochemical aspects of late brain maturation during adolescence are poorly known. We now studied the behavioral impact in adolescent male rats of regular caffeine intake at low (0.1mg/mL), moderate (0.3mg/mL) and moderate/high (1.0mg/mL) doses only during their active period (from 7:00 P.M. to 7:00 A.M.). All tested doses of caffeine were devoid of effects on locomotor activity, but triggered anxiogenic effects. Caffeine (0.3 and 1mg/mL) improved the performance in the object recognition task, but the higher dose of caffeine (1.0mg/mL) decreased the habituation to an open-field arena, suggesting impaired non-associative memory. All tested doses of caffeine decreased the density of glial fibrillary acidic protein and synaptosomal-associated protein-25, but failed to modify neuron-specific nuclear protein immunoreactivity in the hippocampus and cerebral cortex. Caffeine (0.3-1mg/mL) increased the density of brain-derived neurotrophic factor (BDNF) and proBDNF density as well as adenosine A1 receptor density in the hippocampus, whereas the higher dose of caffeine (1mg/mL) increased the density of proBDNF and BDNF and decreased A1 receptor density in the cerebral cortex. These findings document an impact of caffeine consumption in adolescent rats with a dual impact on anxiety and recognition memory, associated with changes in BDNF levels and decreases of astrocytic and nerve terminal markers without overt neuronal damage in hippocampal and cortical regions. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  9. Enrichment of MCI and early Alzheimer's disease treatment trials using neurochemical and imaging candidate biomarkers.

    LENUS (Irish Health Repository)

    Hampel, H

    2012-02-01

    In the earliest clinical stages of Alzheimer\\'s Disease (AD), when symptoms are mild, clinical diagnosis will still be difficult. AD related molecular mechanisms precede symptoms. Biological markers can serve as early diagnostic indicators, as markers of preclinical pathological change, e.g. underlying mechanisms of action (MoA). Hypothesis based candidates are derived from structural and functional neuroimaging as well as from cerebrospinal fluid (CSF) and plasma. Unbiased exploratory approaches e.g. proteome analysis or rater independent fully automated imaging post-processing methods yield novel candidates. Recent progress in the validation of core feasible imaging and neurochemical biomarkers for functions such as early detection, classification, progression and prediction of AD is summarized. Single core feasible biomarkers can already be used to enrich populations at risk for AD and may be further enhanced using distinct combinations. Some biomarkers are currently in the process of implementation as primary or secondary outcome variables into regulatory guideline documents, e.g. regarding phase II in drug development programs as outcome measures in proof of concept or dose finding studies. There are specific biomarkers available depending on the hypothesized mechanism of action of a medicinal product, e.g. impact on the amyloidogenic cascade or on tauhyperphosphorylation. Ongoing large-scale international controlled multi-center trials will provide further validation of selected core feasible imaging and CSF biomarker candidates as outcome measures in early AD for use in phase III clinical efficacy trials. There is a need of rigorous co-development of biological trait- and statemarker candidates facilitated through planned synergistic collaboration between academic, industrial and regulatory partners.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Franchi, Sira A.; Macco, Romina; Astro, Veronica; Tonoli, Diletta; Savino, Elisa; Valtorta, Flavia; Sala, Kristyna; Botta, Martina; de Curtis, Ivan

    2018-01-01

    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. PMID:29358905

  12. WINCS Harmoni: Closed-loop dynamic neurochemical control of therapeutic interventions

    Science.gov (United States)

    Lee, Kendall H.; Lujan, J. Luis; Trevathan, James K.; Ross, Erika K.; Bartoletta, John J.; Park, Hyung Ook; Paek, Seungleal Brian; Nicolai, Evan N.; Lee, Jannifer H.; Min, Hoon-Ki; Kimble, Christopher J.; Blaha, Charles D.; Bennet, Kevin E.

    2017-04-01

    There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni, which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy.

  13. A multi-compartment model for interneurons in the dorsal lateral geniculate nucleus.

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    Geir Halnes

    2011-09-01

    Full Text Available GABAergic interneurons (INs in the dorsal lateral geniculate nucleus (dLGN shape the information flow from retina to cortex, presumably by controlling the number of visually evoked spikes in geniculate thalamocortical (TC neurons, and refining their receptive field. The INs exhibit a rich variety of firing patterns: Depolarizing current injections to the soma may induce tonic firing, periodic bursting or an initial burst followed by tonic spiking, sometimes with prominent spike-time adaptation. When released from hyperpolarization, some INs elicit rebound bursts, while others return more passively to the resting potential. A full mechanistic understanding that explains the function of the dLGN on the basis of neuronal morphology, physiology and circuitry is currently lacking. One way to approach such an understanding is by developing a detailed mathematical model of the involved cells and their interactions. Limitations of the previous models for the INs of the dLGN region prevent an accurate representation of the conceptual framework needed to understand the computational properties of this region. We here present a detailed compartmental model of INs using, for the first time, a morphological reconstruction and a set of active dendritic conductances constrained by experimental somatic recordings from INs under several different current-clamp conditions. The model makes a number of experimentally testable predictions about the role of specific mechanisms for the firing properties observed in these neurons. In addition to accounting for the significant features of all experimental traces, it quantitatively reproduces the experimental recordings of the action-potential- firing frequency as a function of injected current. We show how and why relative differences in conductance values, rather than differences in ion channel composition, could account for the distinct differences between the responses observed in two different neurons, suggesting

  14. Mechanisms of firing patterns in fast-spiking cortical interneurons.

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    David Golomb

    2007-08-01

    Full Text Available Cortical fast-spiking (FS interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering. What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na(+, delayed-rectifier K(+, and slowly inactivating d-type K(+ conductances. The model is analyzed using nonlinear dynamical system theory. For small Na(+ window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, gd, and it is delayed for larger gd. As gd further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na(+ window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their gd and in the strength of their Na(+ window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction.

  15. Kainate receptor-mediated modulation of hippocampal fast spiking interneurons in a rat model of schizophrenia.

    Directory of Open Access Journals (Sweden)

    Barbara Gisabella

    Full Text Available Kainate receptor (KAR subunits are believed to be involved in abnormal GABAergic neurotransmission in the hippocampus (HIPP in schizophrenia (SZ and bipolar disorder. Postmortem studies have shown changes in the expression of the GluR5/6 subunits of KARs in the stratum oriens (SO of sectors CA2/3, where the basolateral amygdala (BLA sends a robust projection. Previous work using a rat model of SZ demonstrated that BLA activation leads to electrophysiological changes in fast-spiking interneurons in SO of CA2/3. The present study explores KAR modulation of interneurons in CA2/3 in response to BLA activation. Intrinsic firing properties of these interneurons through KAR-mediated activity were measured with patch-clamp recordings from rats that received 15 days of picrotoxin infusion into the BLA. Chronic BLA activation induced changes in the firing properties of CA2/3 interneurons associated with modifications in the function of KARs. Specifically, the responsiveness of these interneurons to activation of KARs was diminished in picrotoxin-treated rats, while the after-hyperpolarization (AHP amplitude was increased. In addition, we tested blockers of KAR subunits which have been shown to have altered gene expression in SO sector CA2/3 of SZ subjects. The GluR5 antagonist UBP296 further decreased AP frequency and increased AHP amplitude in picrotoxin-treated rats. Application of the GluR6/7 antagonist NS102 suggested that activation of GluR6/7 KARs may be required to maintain the high firing rates in SO interneurons in the presence of KA. Moreover, the GluR6/7 KAR-mediated signaling may be suppressed in PICRO-treated rats. Our findings indicate that glutamatergic activity from the BLA may modulate the firing properties of CA2/3 interneurons through GluR5 and GluR6/7 KARs. These receptors are expressed in GABAergic interneurons and play a key role in the synchronization of gamma oscillations. Modulation of interneuronal activity through KARs in

  16. Hilar somatostatin interneurons contribute to synchronized GABA activity in an in vitro epilepsy model.

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    Sabine Grosser

    Full Text Available Epilepsy is a disorder characterized by excessive synchronized neural activity. The hippocampus and surrounding temporal lobe structures appear particularly sensitive to epileptiform activity. Somatostatin (SST-positive interneurons within the hilar region have been suggested to gate hippocampal activity, and therefore may play a crucial role in the dysregulation of hippocampal activity. In this study, we examined SST interneuron activity in the in vitro 4-aminopyridine (4-AP model of epilepsy. We employed a multi-disciplinary approach, combining extracellular multi-electrode array (MEA recordings with patch-clamp recordings and optical imaging using a genetically encoded calcium sensor. We observed that hilar SST interneurons are strongly synchronized during 4-AP-induced local field potentials (LFPs, as assayed by Ca(2+ imaging as well as juxtacellular or intracellular recording. SST interneurons were particularly responsive to GABA-mediated LFPs that occurred in the absence of ionotropic glutamatergic transmission. Our results present evidence that the extensive synchronized activity of SST-expressing interneurons contribute to the generation of GABAergic LFPs in an in vitro model of temporal lobe seizures.

  17. Serotonin 3A receptor subtype as an early and protracted marker of cortical interneuron subpopulations.

    Science.gov (United States)

    Vucurovic, Ksenija; Gallopin, Thierry; Ferezou, Isabelle; Rancillac, Armelle; Chameau, Pascal; van Hooft, Johannes A; Geoffroy, Hélène; Monyer, Hannah; Rossier, Jean; Vitalis, Tania

    2010-10-01

    To identify neocortical neurons expressing the type 3 serotonergic receptor, here we used transgenic mice expressing the enhanced green fluorescent protein (GFP) under the control of the 5-HT(3A) promoter (5-HT(3A):GFP mice). By means of whole-cell patch-clamp recordings, biocytin labeling, and single-cell reversed-transcriptase polymerase chain reaction on acute brain slices of 5-HT(3A):GFP mice, we identified 2 populations of 5-HT(3A)-expressing interneurons within the somatosensory cortex. The first population was characterized by the frequent expression of the vasoactive intestinal peptide and a typical bipolar/bitufted morphology, whereas the second population expressed predominantly the neuropeptide Y and exhibited more complex dendritic arborizations. Most interneurons of this second group appeared very similar to neurogliaform cells according to their electrophysiological, molecular, and morphological properties. The combination of 5-bromo-2-deoxyuridine injections with 5-HT(3A) mRNA detection showed that cortical 5-HT(3A) interneurons are generated around embryonic day 14.5. Although at this stage the 5-HT(3A) receptor subunit is expressed in both the caudal ganglionic eminence and the entopeduncular area, homochronic in utero grafts experiments revealed that cortical 5-HT(3A) interneurons are mainly generated in the caudal ganglionic eminence. This protracted expression of the 5-HT(3A) subunit allowed us to study specific cortical interneuron populations from their birth to their final functional phenotype.

  18. A mutation in the pericentrin gene causes abnormal interneuron migration to the olfactory bulb in mice.

    Science.gov (United States)

    Endoh-Yamagami, Setsu; Karkar, Kameel M; May, Scott R; Cobos, Inma; Thwin, Myo T; Long, Jason E; Ashique, Amir M; Zarbalis, Konstantinos; Rubenstein, John L R; Peterson, Andrew S

    2010-04-01

    Precise control of neuronal migration is essential for proper function of the brain. Taking a forward genetic screen, we isolated a mutant mouse with defects in interneuron migration. By genetic mapping, we identified a frame shift mutation in the pericentrin (Pcnt) gene. The Pcnt gene encodes a large centrosomal coiled-coil protein that has been implicated in schizophrenia. Recently, frame shift and premature termination mutations in the pericentrin (PCNT) gene were identified in individuals with Seckel syndrome and microcephalic osteodysplastic primordial dwarfism (MOPD II), both of which are characterized by greatly reduced body and brain sizes. The mouse Pcnt mutant shares features with the human syndromes in its overall growth retardation and reduced brain size. We found that dorsal lateral ganglionic eminence (dLGE)-derived olfactory bulb interneurons are severely affected and distributed abnormally in the rostral forebrain in the mutant. Furthermore, mutant interneurons exhibit abnormal migration behavior and RNA interference knockdown of Pcnt impairs cell migration along the rostal migratory stream (RMS) into the olfactory bulb. These findings indicate that pericentrin is required for proper migration of olfactory bulb interneurons and provide a developmental basis for association of pericentrin function with interneuron defects in human schizophrenia. Copyright 2009 Elsevier Inc. All rights reserved.

  19. Extended Production of Cortical Interneurons into the Third Trimester of Human Gestation.

    Science.gov (United States)

    Arshad, Arslan; Vose, Linnea R; Vinukonda, Govindaiah; Hu, Furong; Yoshikawa, Kazuaki; Csiszar, Anna; Brumberg, Joshua C; Ballabh, Praveen

    2016-05-01

    In humans, the developmental origins of interneurons in the third trimester of pregnancy and the timing of completion of interneuron neurogenesis have remained unknown. Here, we show that the total and cycling Nkx2.1(+)and Dlx2(+)interneuron progenitors as well as Sox2(+)precursor cells were higher in density in the medial ganglionic eminence (MGE) compared with the lateral ganglionic eminence and cortical ventricular/subventricular zone (VZ/SVZ) of 16-35 gw subjects. The proliferation of these progenitors reduced as a function of gestational age, almost terminating by 35 gw. Proliferating Dlx2(+)cells were higher in density in the caudal ganglionic eminence (CGE) compared with the MGE, and persisted beyond 35 gw. Consistent with these findings, Sox2, Nkx2.1, Dlx2, and Mash1 protein levels were higher in the ganglionic eminences relative to the cortical VZ/SVZ. The density of gamma-aminobutyric acid-positive (GABA(+)) interneurons was higher in the cortical VZ/SVZ relative to MGE, but Nkx2.1 or Dlx2-expressing GABA(+)cells were more dense in the MGE compared with the cortical VZ/SVZ. The data suggest that the MGE and CGE are the primary source of cortical interneurons. Moreover, their generation continues nearly to the end of pregnancy, which may predispose premature infants to neurobehavioral disorders. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. Neurochemical dementia diagnostics for Alzheimer's disease and other dementias: an ISO 15189 perspective.

    Science.gov (United States)

    Waedt, Johanna; Kleinow, Martina; Kornhuber, Johannes; Lewczuk, Piotr

    2012-10-01

    Dementia is one of the most common causes of health problems in the elderly populations of Western industrialized countries. A combined analysis of cerebrospinal fluid-based neurochemical dementia diagnostics biomarkers (amyloid-β peptides, total tau and phosphorylated forms of tau) provides sensitivity and specificity in the range of 85% for the diagnosis of Alzheimer's disease, the most common cause of dementia. The alterations occur very early in the course of neurodegeneration, enabling medical follow-up of persons with increased risk of developing dementia. With a growing number of laboratories performing neurochemical dementia diagnostics routinely, it is important to standardize protocols and laboratory performance to enable comparisons of results and their interpretations. Together with the recently published expert guidelines for sample handling and preparation, as well as the interpretation (post-analytical) algorithms developed by experienced centers, ISO 15189 norm provides an extremely useful tool for standardization of neurochemical dementia diagnostics.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

    2017-01-01

    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. PMID:28871960

  3. Electrophysiological and morphological characterization of propriospinal interneurons in the thoracic spinal cord

    DEFF Research Database (Denmark)

    Saywell, S A; Ford, T W; Meehan, Claire Francesca

    2011-01-01

    Propriospinal interneurons in the thoracic spinal cord have vital roles not only in controlling respiratory and trunk muscles, but also in providing possible substrates for recovery from spinal cord injury. Intracellular recordings were made from such interneurons in anesthetized cats under...... neuromuscular blockade and with the respiratory drive stimulated by inhaled CO(2). The majority of the interneurons were shown by antidromic activation to have axons descending for at least two to four segments, mostly contralateral to the soma. In all, 81% of the neurons showed postsynaptic potentials (PSPs......) to stimulation of intercostal or dorsal ramus nerves of the same segment for low-threshold (= 5T) afferents. A monosynaptic component was present for the majority of the peripherally evoked excitatory PSPs. A central respiratory drive potential was present in most of the recordings, usually of small amplitude...

  4. New insights into the classification and nomenclature of cortical GABAergic interneurons

    Science.gov (United States)

    DeFelipe, Javier; López-Cruz, Pedro L.; Benavides-Piccione, Ruth; Bielza, Concha; Larrañaga, Pedro; Anderson, Stewart; Burkhalter, Andreas; Cauli, Bruno; Fairén, Alfonso; Feldmeyer, Dirk; Fishell, Gord; Fitzpatrick, David; Freund, Tamás F.; González-Burgos, Guillermo; Hestrin, Shaul; Hill, Sean; Hof, Patrick R.; Huang, Josh; Jones, Edward G.; Kawaguchi, Yasuo; Kisvárday, Zoltán; Kubota, Yoshiyuki; Lewis, David A.; Marín, Oscar; Markram, Henry; McBain, Chris J.; Meyer, Hanno S.; Monyer, Hannah; Nelson, Sacha B.; Rockland, Kathleen; Rossier, Jean; Rubenstein, John L. R.; Rudy, Bernardo; Scanziani, Massimo; Shepherd, Gordon M.; Sherwood, Chet C.; Staiger, Jochen F.; Tamás, Gábor; Thomson, Alex; Wang, Yun; Yuste, Rafael; Ascoli, Giorgio A.

    2013-01-01

    A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts’ assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus. PMID:23385869

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

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

    DEFF Research Database (Denmark)

    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......Decreased parvalbumin expression is a hallmark of the pathophysiology of schizophrenia and has been associated with abnormal cognitive processing and decreased network specificity. It is not known whether this decrease is due to reduced expression of the parvalbumin protein or degeneration...

  8. Distinctive Citizenship

    DEFF Research Database (Denmark)

    Kaur, Ravinder

    2009-01-01

    -colonial citizenship within the mass of refugees. The core principle of the official resettlement policy was self-rehabilitation, that is, the ability to become a productive citizen of the new nation state without state intervention. Thus, the onus of performing a successful transition - from refugee to citizen - lay......The refugee, in India's Partition history, appears as an enigmatic construct - part pitiful, part heroic, though mostly shorn of agency - representing the surface of the human tragedy of Partition. Yet this archetype masks the undercurrent of social distinctions that produced hierarchies of post...... on the resourcefulness of the refugees rather than the state. This article traces the differing historical trajectories followed by 'state-dependent' and 'self-reliant' refugees in the making of modern citizenry in post-colonial India...

  9. Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males.

    Science.gov (United States)

    Holland, Freedom H; Ganguly, Prabarna; Potter, David N; Chartoff, Elena H; Brenhouse, Heather C

    2014-04-30

    Early life stress exposure (ELS) yields risk for psychiatric disorders that might occur though a population-specific mechanism that impacts prefrontal cortical development. Sex differences in ELS effects are largely unknown and are also essential to understand social and cognitive development. ELS can cause dysfunction within parvalbumin (PVB)-containing inhibitory interneurons in the prefrontal cortex and in several prefrontal cortex-mediated behaviors including social interaction. Social behavior deficits are often the earliest observed changes in psychiatric disorders, therefore the time-course and causation of social interaction deficits after ELS are important to determine. PVB interneuron dysfunction can disrupt social behavior, and has been correlated in males with elevated markers of oxidative stress and inflammation, such as cyclooxygenase-2 after ELS. Here, we measured the effects of maternal separation ELS on social interaction behaviors in males and females. Prefrontal cortex PVB and cyclooxygenase-2 were also measured in juveniles and adolescents using Western blots. ELS led to social interaction alterations earlier in females than males. Sexually dimorphic behavioral changes were consistent with prefrontal cortex PVB loss after ELS. PVB levels were decreased in ELS-exposed juvenile females, while males exposed to ELS do not display parvalbumin decreases until adolescence. Early behavioral and PVB changes in females did not appear to be mediated through cyclooxygenase-2, since levels were not affected in ELS females. Therefore, these data suggest that ELS affects males and females differently and with distinct developmental profiles. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Development of intraoperative electrochemical detection: wireless instantaneous neurochemical concentration sensor for deep brain stimulation feedback.

    Science.gov (United States)

    Van Gompel, Jamie J; Chang, Su-Youne; Goerss, Stephan J; Kim, In Yong; Kimble, Christopher; Bennet, Kevin E; Lee, Kendall H

    2010-08-01

    Deep brain stimulation (DBS) is effective when there appears to be a distortion in the complex neurochemical circuitry of the brain. Currently, the mechanism of DBS is incompletely understood; however, it has been hypothesized that DBS evokes release of neurochemicals. Well-established chemical detection systems such as microdialysis and mass spectrometry are impractical if one is assessing changes that are happening on a second-to-second time scale or for chronically used implanted recordings, as would be required for DBS feedback. Electrochemical detection techniques such as fast-scan cyclic voltammetry (FSCV) and amperometry have until recently remained in the realm of basic science; however, it is enticing to apply these powerful recording technologies to clinical and translational applications. The Wireless Instantaneous Neurochemical Concentration Sensor (WINCS) currently is a research device designed for human use capable of in vivo FSCV and amperometry, sampling at subsecond time resolution. In this paper, the authors review recent advances in this electrochemical application to DBS technologies. The WINCS can detect dopamine, adenosine, and serotonin by FSCV. For example, FSCV is capable of detecting dopamine in the caudate evoked by stimulation of the subthalamic nucleus/substantia nigra in pig and rat models of DBS. It is further capable of detecting dopamine by amperometry and, when used with enzyme linked sensors, both glutamate and adenosine. In conclusion, WINCS is a highly versatile instrument that allows near real-time (millisecond) detection of neurochemicals important to DBS research. In the future, the neurochemical changes detected using WINCS may be important as surrogate markers for proper DBS placement as well as the sensor component for a "smart" DBS system with electrochemical feedback that allows automatic modulation of stimulation parameters. Current work is under way to establish WINCS use in humans.

  11. Functional organization of locomotor interneurons in the ventral lumbar spinal cord of the newborn rat.

    Directory of Open Access Journals (Sweden)

    Myriam Antri

    Full Text Available Although the mammalian locomotor CPG has been localized to the lumbar spinal cord, the functional-anatomical organization of flexor and extensor interneurons has not been characterized. Here, we tested the hypothesis that flexor and extensor interneuronal networks for walking are physically segregated in the lumbar spinal cord. For this purpose, we performed optical recordings and lesion experiments from a horizontally sectioned lumbar spinal cord isolated from neonate rats. This ventral hemi spinal cord preparation produces well-organized fictive locomotion when superfused with 5-HT/NMDA. The dorsal surface of the preparation was visualized using the Ca(2+ indicator fluo-4 AM, while simultaneously monitoring motor output at ventral roots L2 and L5. Using calcium imaging, we provided a general mapping view of the interneurons that maintained a stable phase relationship with motor output. We showed that the dorsal surface of L1 segment contains a higher density of locomotor rhythmic cells than the other segments. Moreover, L1 segment lesioning induced the most important changes in the locomotor activity in comparison with lesions at the T13 or L2 segments. However, no lesions led to selective disruption of either flexor or extensor output. In addition, this study found no evidence of functional parcellation of locomotor interneurons into flexor and extensor pools at the dorsal-ventral midline of the lumbar spinal cord of the rat.

  12. GABAERGIC MODULATION OF STRIATAL CHOLINERGIC INTERNEURONS - AN IN-VIVO MICRODIALYSIS STUDY

    NARCIS (Netherlands)

    DEBOER, P; WESTERINK, BHC

    Striatal cholinergic interneurons have been shown to receive input from striatal gamma-aminobutyric acid (GABA)-containing cell elements. GABA is known to act on two different types of receptors, the GABA(A) and the GABA(B) receptor. Using in vivo microdialysis, we have studied the effect of

  13. Parvalbumin-expressing interneurons coordinate hippocampal network dynamics required for memory consolidation

    Science.gov (United States)

    Ognjanovski, Nicolette; Schaeffer, Samantha; Wu, Jiaxing; Mofakham, Sima; Maruyama, Daniel; Zochowski, Michal; Aton, Sara J.

    2017-04-01

    Activity in hippocampal area CA1 is essential for consolidating episodic memories, but it is unclear how CA1 activity patterns drive memory formation. We find that in the hours following single-trial contextual fear conditioning (CFC), fast-spiking interneurons (which typically express parvalbumin (PV)) show greater firing coherence with CA1 network oscillations. Post-CFC inhibition of PV+ interneurons blocks fear memory consolidation. This effect is associated with loss of two network changes associated with normal consolidation: (1) augmented sleep-associated delta (0.5-4 Hz), theta (4-12 Hz) and ripple (150-250 Hz) oscillations; and (2) stabilization of CA1 neurons' functional connectivity patterns. Rhythmic activation of PV+ interneurons increases CA1 network coherence and leads to a sustained increase in the strength and stability of functional connections between neurons. Our results suggest that immediately following learning, PV+ interneurons drive CA1 oscillations and reactivation of CA1 ensembles, which directly promotes network plasticity and long-term memory formation.

  14. Slow excitatory synaptic potentials evoked by distension in myenteric descending interneurones of guinea-pig ileum

    Science.gov (United States)

    Thornton, P D J; Bornstein, J C

    2002-01-01

    The functional significance of the slow excitatory synaptic potentials (EPSPs) in myenteric neurones is unknown. We investigated this using intracellular recording from myenteric neurones in guinea-pig ileum, in vitro. In all, 121 neurones responded with fast EPSPs to distension of the intestine oral to the recording site. In 28 of these neurones, distension also evoked depolarizations similar to the slow EPSPs evoked by electrical stimulation in the same neurones. Intracellular injection of biocytin and immunohistochemistry revealed that neurones responding to distension with slow EPSPs were descending interneurones, which were immunoreactive for nitric oxide synthase (NOS). Other neurones, including inhibitory motor neurones and interneurones lacking NOS, did not respond to distension with slow EPSPs, but many had slow EPSPs evoked electrically. Slow EPSPs evoked electrically or by distension in NOS-immunoreactive descending interneurones were resistant to blockade of NK1 or NK3 tachykinin receptors (SR 140333, 100 nm; SR 142801, 100 nm, respectively) and group I metabotropic glutamate receptors (PHCCC, 10–30 μm), when the antagonists were applied in the recording chamber of a two-chambered organ bath. However, slow EPSPs evoked electrically in inhibitory motor neurones were substantially depressed by SR 140333 (100 nm). Blockade of synaptic transmission in the stimulation chamber of the organ bath abolished slow EPSPs evoked by distension, indicating that they arose from activity in interneurones, and not from anally directed, intrinsic sensory neurones. Thus, distension evokes slow EPSPs in a subset of myenteric neurones, which may be important for intestinal motility. PMID:11882690

  15. Evolution of a new sense for wind in flying phasmids? Afferents and interneurons

    Science.gov (United States)

    Hustert, Reinhold; Klug, Rebecca

    2009-12-01

    The evolution of winged stick insects (phasmids) from secondarily wingless ancestors was proposed in recent studies. We explored the cuticle of flying phasmids for wind sensors that could be involved in their flight control, comparable to those known for locusts. Surprisingly, wind-sensitive hairs (wsH) occur on the palps of mouthparts and on the antennae of the winged phasmid Sipyloidea sipylus which can fly in tethered position only when air currents blow over the mouthparts. The present study describes the morphology and major functional properties of these “new” wsH with soft and bulging hair bases which are different from the beaker-like hair bases of the wsH on the cerci of phasmids and the wsH described in other insects. The most sensitive wsH of antennae and palps respond with phasic-tonic afferents to air currents exceeding 0.2 ms-1. The fields of wsH on one side of the animal respond mainly to ventral, lateral, and frontal wind on the ipsilateral side of the head. Afferent inputs from the wsH converge but also diverge to a group of specific interneurons at their branches in the suboesophageal ganglion and can send their integrated input from wsH fields of the palps and antennae to the thoracic central nervous system. Response types of individual wsH-interneurons are either phasic or phasic-tonic to air puffs or constant air currents and also, the receptive fields of individual interneurons differ. We conclude that the “new” wsH system and its interneurons mainly serve to maintain flight activity in airborne phasmids and also, the “new” wsH must have emerged together with the integrating interneurons during the evolution from wingless to the recent winged forms of phasmids.

  16. GABA regulates the multidirectional tangential migration of GABAergic interneurons in living neonatal mice.

    Directory of Open Access Journals (Sweden)

    Hiroyuki Inada

    Full Text Available Cortical GABAergic interneurons originate from ganglionic eminences and tangentially migrate into the cortical plate at early developmental stages. To elucidate the characteristics of this migration of GABAergic interneurons in living animals, we established an experimental design specialized for in vivo time-lapse imaging of the neocortex of neonate mice with two-photon laser-scanning microscopy. In vesicular GABA/glycine transporter (VGAT-Venus transgenic mice from birth (P0 through P3, we observed multidirectional tangential migration of genetically-defined GABAergic interneurons in the neocortical marginal zone. The properties of this migration, such as the motility rate (distance/hr, the direction moved, and the proportion of migrating neurons to stationary neurons, did not change through P0 to P3, although the density of GABAergic neurons at the marginal zone decreased with age. Thus, the characteristics of the tangential motility of individual GABAergic neurons remained constant in development. Pharmacological block of GABA(A receptors and of the Na⁺-K⁺-Cl⁻ cotransporters, and chelating intracellular Ca²⁺, all significantly reduced the motility rate in vivo. The motility rate and GABA content within the cortex of neonatal VGAT-Venus transgenic mice were significantly greater than those of GAD67-GFP knock-in mice, suggesting that extracellular GABA concentration could facilitate the multidirectional tangential migration. Indeed, diazepam applied to GAD67-GFP mice increased the motility rate substantially. In an in vitro neocortical slice preparation, we confirmed that GABA induced a NKCC sensitive depolarization of GABAergic interneurons in VGAT-Venus mice at P0-P3. Thus, activation of GABA(AR by ambient GABA depolarizes GABAergic interneurons, leading to an acceleration of their multidirectional motility in vivo.

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

    Science.gov (United States)

    Hervig, Mona E; Thomsen, Morten S; Kalló, Imre; Mikkelsen, Jens D

    2016-10-15

    Dysfunction of N-Methyl-d-aspartate receptors (NMDARs) is believed to underlie some of the symptoms in schizophrenia, and non-competitive NMDAR antagonists (including phencyclidine (PCP)) are widely used as pharmacological schizophrenia models. Furthermore, mounting evidence suggests that impaired γ-aminobutyric acid (GABA) neurotransmission contributes to the cognitive deficits in schizophrenia. Thus alterations in GABAergic interneurons have been observed in schizophrenia patients and animal models. Acute systemic administration of PCP increases levels of c-Fos in several cortical 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 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 that a substantial part of this activation is present in GABAergic interneurons in certain regions. This suggests that the psychotomimetic effect of PCP may be mediated via GABAergic interneurons. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. The influence of contralateral primary afferents on Ia inhibitory interneurones in humans.

    Science.gov (United States)

    Delwaide, P J; Pepin, J L

    1991-01-01

    1. Contralateral influences on short latency reciprocal inhibition between wrist extensor and flexor muscles were investigated in twenty-two healthy volunteers. Reciprocal inhibition, probably mediated through the Ia inhibitory interneurone, was measured by conditioning the flexor carpi radialis (FCR) H reflex by weak stimulation of the ipsilateral radial nerve. Maximum reciprocal inhibition occurring at a precise delay between conditioning and conditioned stimulations was taken as the test level of inhibition. 2. Contralateral median or radial nerves were stimulated at short intervals before the onset of reciprocal inhibition. The latter was increased by 8.6% after median nerve stimulation and decreased by 16.5% after radial nerve stimulation. 3. The contribution of sensory fibres in the two nerves to contralateral effects was investigated by stimulating purely sensory branches of the nerves. No clear modification of the contralateral reciprocal inhibition was observed. The effects produced by mixed nerve stimulation are thus likely to have been mediated by Ia fibres. 4. In three hemiplegic patients where reciprocal inhibition was reduced unilaterally, stimulation on the spastic side produced contralateral effects similar to those observed in normal subjects. This result indicates that contralateral effects are not mediated through the Ia inhibitory interneurone ipsilateral to the conditioning stimulus. 5. Since contralateral effects occur after short delays (2 ms, median nerve; 3 ms, radial nerve), we suggest a functional scheme in which the excitability of Ia inhibitory interneurones is modified by contralateral primary afferents via the interneurones activated by group I fibres, probably Ia fibres. The short delays indicate that the interneurone transmitting primary afferent influences to the contralateral side is probably excitatory. PMID:1895236

  19. 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.

  20. 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.

  1. Acetylcholine release in mouse hippocampal CA1 preferentially activates inhibitory-selective interneurons via alpha4 beta2* nicotinic receptor activation

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    L. Andrew Bell

    2015-04-01

    Full Text Available Acetylcholine (ACh release onto nicotinic receptors directly activates subsets of inhibitory interneurons in hippocampal CA1. However, the specific interneurons activated and their effect on the hippocampal network is not completely understood. Therefore, we investigated subsets of hippocampal CA1 interneurons that respond to ACh release through the activation of nicotinic receptors and the potential downstream effects this may have on hippocampal CA1 network function. ACh was optogenetically released in mouse hippocampal slices by expressing the excitatory optogenetic protein oChIEF-tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated viral mediated transfection. The actions of optogenetically released ACh were assessed on both pyramidal neurons and different interneuron subtypes via whole cell patch clamp methods. Vasoactive intestinal peptide (VIP-expressing interneurons that selectively innervate other interneurons (VIP/IS were excited by ACh through the activation of nicotinic receptors containing alpah4 and beta2 subunits (alpha4 beta2*. ACh release onto VIP/IS was presynaptically inhibited by M2 muscarinic autoreceptors. ACh release produced spontaneous inhibitory postsynaptic current (sIPSC barrages blocked by dihydro-beta-erythroidine in interneurons but not pyramidal neurons. Optogenetic suppression of VIP interneurons did not inhibit these sIPSC barrages suggesting other interneuron-selective interneurons were also excited by 42* nicotinic receptor activation. In contrast, interneurons that innervate pyramidal neuron perisomatic regions were not activated by ACh release onto nicotinic receptors. Therefore, we propose ACh release in CA1 facilitates disinhibition through activation of 42* nicotinic receptors on interneuron-selective interneurons whereas interneurons that innervate pyramidal neurons are less affected by nicotinic receptor activation.

  2. 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

  3. Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy.

    Science.gov (United States)

    Duarte, João M N; Do, Kim Q; Gruetter, Rolf

    2014-07-01

    Alterations to brain homeostasis during development are reflected in the neurochemical profile determined noninvasively by (1)H magnetic resonance spectroscopy. We determined longitudinal biochemical modifications in the cortex, hippocampus, and striatum of C57BL/6 mice aged between 3 and 24 months . The regional neurochemical profile evolution indicated that aging induces general modifications of neurotransmission processes (reduced GABA and glutamate), primary energy metabolism (altered glucose, alanine, and lactate) and turnover of lipid membranes (modification of choline-containing compounds and phosphorylethanolamine), which are all probably involved in the frequently observed age-related cognitive decline. Interestingly, the neurochemical profile was different in male and female mice, particularly in the levels of taurine that may be under the control of estrogen receptors. These neurochemical profiles constitute the basal concentrations in cortex, hippocampus, and striatum of healthy aging male and female mice. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Integrative pathways linking close family ties to health: A neurochemical perspective.

    Science.gov (United States)

    Uchino, Bert N; Way, Baldwin M

    2017-09-01

    The quality of one's familial life, for better or worse, has been linked to physical health. Such associations are evident across a number of acute and chronic conditions and highlight the widespread impact that close relationships have on physical health. However, the field currently lacks a complete understanding of the integrative biological pathways underlying the association between close relationships and disease risk. This article reviews the main peripheral biological and central nervous system pathways linking positive and negative familial relationship processes to physical health outcomes. It emphasizes the role of neurochemical pathways in mediating the influence of social relationships on health-relevant peripheral physiological systems using the oxytocin system as a model. Such neurochemical approaches are an important step toward a more integrative understanding of complex biological pathways and has novel theoretical and intervention implications. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  5. 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.

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

    DEFF Research Database (Denmark)

    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...... understood. Here, we have used a simple model of afferent excitatory neurons and interneurons with lateral inhibition, reproducing a network topology found in many brain areas from the cerebellum to cortical columns. When endowed with spike-timing dependent plasticity (STDP) at the excitatory input synapses...... 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...

  7. In vivo effect of chronic hypoxia on the neurochemical profile of the developing rat hippocampus

    OpenAIRE

    Raman, Lakshmi; Tkac, Ivan; Ennis, Kathleen; Georgieff, Michael K.; Gruetter, Rolf; Rao, Raghavendra

    2005-01-01

    The cognitive deficits observed in children with cyanotic congenital heart disease suggest involvement of the developing hippocampus. Chronic postnatal hypoxia present during infancy in these children may play a role in these impairments. To understand the biochemical mechanisms of hippocampal injury in chronic hypoxia, a neurochemical profile consisting of 15 metabolite concentrations and 2 metabolite ratios in the hippocampus was evaluated in a rat model of chronic postnatal hypoxia using i...

  8. Neurochemical dynamics of acute orofacial pain in the human trigeminal brainstem nuclear complex.

    Science.gov (United States)

    de Matos, Nuno M P; Hock, Andreas; Wyss, Michael; Ettlin, Dominik A; Brügger, Mike

    2017-09-04

    The trigeminal brainstem sensory nuclear complex is the first central relay structure mediating orofacial somatosensory and nociceptive perception. Animal studies suggest a substantial involvement of neurochemical alterations at such basal CNS levels in acute and chronic pain processing. Translating this animal based knowledge to humans is challenging. Human related examining of brainstem functions are challenged by MR related peculiarities as well as applicability aspects of experimentally standardized paradigms. Based on our experience with an MR compatible human orofacial pain model, the aims of the present study were twofold: 1) from a technical perspective, the evaluation of proton magnetic resonance spectroscopy at 3 T regarding measurement accuracy of neurochemical profiles in this small brainstem nuclear complex and 2) the examination of possible neurochemical alterations induced by an experimental orofacial pain model. Data from 13 healthy volunteers aged 19-46 years were analyzed and revealed high quality spectra with significant reductions in total N-acetylaspartate (N-acetylaspartate + N-acetylaspartylglutamate) (-3.7%, p = 0.009) and GABA (-10.88%, p = 0.041) during the pain condition. These results might reflect contributions of N-acetylaspartate and N-acetylaspartylglutamate in neuronal activity-dependent physiologic processes and/or excitatory neurotransmission, whereas changes in GABA might indicate towards a reduction in tonic GABAergic functioning during nociceptive signaling. Summarized, the present study indicates the applicability of (1)H-MRS to obtain neurochemical dynamics within the human trigeminal brainstem sensory nuclear complex. Further developments are needed to pave the way towards bridging important animal based knowledge with human research to understand the neurochemistry of orofacial nociception and pain. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Induction of gram-negative bacterial growth by neurochemical containing banana (Musa x paradisiaca) extracts.

    Science.gov (United States)

    Lyte, M

    1997-09-15

    Bananas contain large quantities of neurochemicals. Extracts from the peel and pulp of bananas in increasing stages of ripening were prepared and evaluated for their ability to modulate the growth of non-pathogenic and pathogenic bacteria. Extracts from the peel, and to a much lesser degree the pulp, increased the growth of Gram-negative bacterial strains Escherichia coli O157:H7, Shigella flexneri, Enterobacter cloacae and Salmonella typhimurium, as well as two non-pathogenic E. coli strains, in direct relation to the content of norepinephrine and dopamine, but not serotonin. The growth of Gram-positive bacteria was not altered by any of the extracts. Supplementation of vehicle and pulp cultures with norepinephrine or dopamine yielded growth equivalent to peel cultures. Total organic analysis of extracts further demonstrated that the differential effects of peel and pulp on bacterial growth was not nutritionally based, but due to norepinephrine and dopamine. These results suggest that neurochemicals contained within foodstuffs may influence the growth of pathogenic and indigenous bacteria through direct neurochemical-bacterial interactions.

  10. Differential susceptibility of interneurons expressing neuropeptide Y or parvalbumin in the aged hippocampus to acute seizure activity.

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    Ramkumar Kuruba

    Full Text Available Acute seizure (AS activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE. Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY or the calcium binding protein parvalbumin (PV between young adult (5-months old and aged (22-months old F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.

  11. Neural and neurochemical basis of reinforcement-guided decision making.

    Science.gov (United States)

    Khani, Abbas; Rainer, Gregor

    2016-08-01

    Decision making is an adaptive behavior that takes into account several internal and external input variables and leads to the choice of a course of action over other available and often competing alternatives. While it has been studied in diverse fields ranging from mathematics, economics, ecology, and ethology to psychology and neuroscience, recent cross talk among perspectives from different fields has yielded novel descriptions of decision processes. Reinforcement-guided decision making models are based on economic and reinforcement learning theories, and their focus is on the maximization of acquired benefit over a defined period of time. Studies based on reinforcement-guided decision making have implicated a large network of neural circuits across the brain. This network includes a wide range of cortical (e.g., orbitofrontal cortex and anterior cingulate cortex) and subcortical (e.g., nucleus accumbens and subthalamic nucleus) brain areas and uses several neurotransmitter systems (e.g., dopaminergic and serotonergic systems) to communicate and process decision-related information. This review discusses distinct as well as overlapping contributions of these networks and neurotransmitter systems to the processing of decision making. We end the review by touching on neural circuitry and neuromodulatory regulation of exploratory decision making. Copyright © 2016 the American Physiological Society.

  12. Calcium-binding protein, secretagogin, characterizes novel groups of interneurons in the rat striatum.

    Science.gov (United States)

    Kosaka, Toshio; Yasuda, Seiko; Kosaka, Katsuko

    2017-06-01

    In the rat striatum numerous secretagogin (SCGN) positive neurons were scattered. They were heterogeneous in their morphological and chemical properties. We examined the colocalization of SCGN with known four interneuron markers, parvalbumin (PV), calretinin (CR), nitric oxide synthase (NOS) and choline acetyl transferase (ChAT). 60-70% of SCGN positive striatal neurons contained either PV or CR or ChAT, but none contained NOS. On the other hand the remaining 30-40% expressed none of these markers, most of which were GAD positive. The present study indicates that there are hitherto unknown groups of striatal interneurons in the rat striatum. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  13. 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.

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

    Science.gov (United States)

    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.

  15. Short-term synaptic plasticity at interneuronal synapses could sculpt rhythmic motor patterns

    Directory of Open Access Journals (Sweden)

    Yan eJia

    2016-02-01

    Full Text Available The output of a neuronal network depends on the organization and functional properties of its component cells and synapses. While the characterization of synaptic properties has lagged cellular analyses, a potentially important aspect in rhythmically active networks is how network synapses affect, and are in turn affected by, network activity. This could lead to a potential circular interaction where short-term activity-dependent synaptic plasticity is both influenced by and influences the network output. The analysis of synaptic plasticity in the lamprey locomotor network was extended here to characterize the short-term plasticity of connections between network interneurons and to try and address its potential network role. Paired recordings from identified interneurons in quiescent networks showed synapse-specific synaptic properties and plasticity that supported the presence of two hemisegmental groups that could influence bursting: depression in an excitatory interneuron group, and facilitation in an inhibitory feedback circuit. The influence of activity-dependent synaptic plasticity on network activity was investigated experimentally by changing Ringer Ca2+ levels, and in a simple computer model. A potential caveat of the experimental analyses was that changes in Ringer Ca2+ (and compensatory adjustments in Mg2+ in some cases could alter several other cellular and synaptic properties. Several of these properties were tested, and while there was some variability, these were not usually significantly affected by the Ringer changes. The experimental analyses suggested that depression of excitatory inputs had the strongest influence on the patterning of network activity. The simulation supported a role for this effect, and also suggested that the inhibitory facilitating group could modulate the influence of the excitatory synaptic depression. Short-term activity-dependent synaptic plasticity has not generally been considered in spinal cord

  16. In vivo calcium accumulation in presynaptic and postsynaptic dendrites of visual interneurons

    OpenAIRE

    Dürr, Volker; Egelhaaf, Martin

    1999-01-01

    In this comparative in vivo study of dendritic calcium accumulation, we describe the time course and spatial integration properties of two classes of visual interneurons in the lobula plate of the blowfly. Calcium accumulation was measured during visual motion stimulation, ensuring synaptic activation of the neurons within their natural spatial and temporal operating range. The compared cell classes, centrifugal horizontal (CH) and horizontal system (HS) cells, are known to receive retinotopi...

  17. 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 ...

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Short-Term Synaptic Plasticity at Interneuronal Synapses Could Sculpt Rhythmic Motor Patterns.

    Science.gov (United States)

    Jia, Yan; Parker, David

    2016-01-01

    The output of a neuronal network depends on the organization and functional properties of its component cells and synapses. While the characterization of synaptic properties has lagged cellular analyses, a potentially important aspect in rhythmically active networks is how network synapses affect, and are in turn affected by, network activity. This could lead to a potential circular interaction where short-term activity-dependent synaptic plasticity is both influenced by and influences the network output. The analysis of synaptic plasticity in the lamprey locomotor network was extended here to characterize the short-term plasticity of connections between network interneurons and to try and address its potential network role. Paired recordings from identified interneurons in quiescent networks showed synapse-specific synaptic properties and plasticity that supported the presence of two hemisegmental groups that could influence bursting: depression in an excitatory interneuron group, and facilitation in an inhibitory feedback circuit. The influence of activity-dependent synaptic plasticity on network activity was investigated experimentally by changing Ringer Ca(2+) levels, and in a simple computer model. A potential caveat of the experimental analyses was that changes in Ringer Ca(2+) (and compensatory adjustments in Mg(2+) in some cases) could alter several other cellular and synaptic properties. Several of these properties were tested, and while there was some variability, these were not usually significantly affected by the Ringer changes. The experimental analyses suggested that depression of excitatory inputs had the strongest influence on the patterning of network activity. The simulation supported a role for this effect, and also suggested that the inhibitory facilitating group could modulate the influence of the excitatory synaptic depression. Short-term activity-dependent synaptic plasticity has not generally been considered in spinal cord models. These

  20. Staining of cerebellar cortex granular layer interneurons with natural dye of Madder.

    Science.gov (United States)

    Gharravi, Anneh Mohammad

    2016-01-01

    The objective of the present study was an investigation of root Rubia Tinctorum (Madder) as a natural dye to identification of granular layer interneurons of the rat cerebellum. Seven to ten micrometre sections were collected from the cerebellum and stained only with Madder for 2, 24 and 48 h. Other sections were stained with Madder then with hematoxyllin, cresyl violet, eosin, light green. Microscopic identification of cells was performed based on cell morphology, reaction and binding of with the dye. All data were expressed as mean ± SD in and significance was set at p ≤0.05. Madder with alum as mordant resulted a deep red staining of interneurons. Unipolar brush cells (UBCs) were observed with a cell body diameter intermediate between granule and Golgi cells in the superficial layer of the granular layer. Golgi cells were identified almost as large as Purkinje cells with irregular rounded or polygonal morphology. Lugaro cells were observed as spindle-shaped cells adjacent to Purkinje layer. Results of the present study showed that mader could stain granular layer interneurons in cerebellum cortex of rat.

  1. Local Integration Accounts for Weak Selectivity of Mouse Neocortical Parvalbumin Interneurons.

    Science.gov (United States)

    Scholl, Benjamin; Pattadkal, Jagruti J; Dilly, Geoffrey A; Priebe, Nicholas J; Zemelman, Boris V

    2015-07-15

    Dissecting the functional roles of excitatory and inhibitory neurons in cortical circuits is a fundamental goal in neuroscience. Of particular interest are their roles in emergent cortical computations such as binocular integration in primary visual cortex (V1). We measured the binocular response selectivity of genetically defined subpopulations of excitatory and inhibitory neurons. Parvalbumin (PV+) interneurons received strong inputs from both eyes but lacked selectivity for binocular disparity. Because broad selectivity could result from heterogeneous synaptic input from neighboring neurons, we examined how individual PV+ interneuron selectivity compared to that of the local neuronal network, which is primarily composed of excitatory neurons. PV+ neurons showed functional similarity to neighboring neuronal populations over spatial distances resembling measurements of synaptic connectivity. On the other hand, excitatory neurons expressing CaMKIIα displayed no such functional similarity with the neighboring population. Our findings suggest that broad selectivity of PV+ interneurons results from nonspecific integration within local networks. VIDEO ABSTRACT. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Graphene Oxide Dysregulates Neuroligin/NLG-1-Mediated Molecular Signaling in Interneurons in Caenorhabditis elegans

    Science.gov (United States)

    Chen, He; Li, Huirong; Wang, Dayong

    2017-01-01

    Graphene oxide (GO) can be potentially used in many medical and industrial fields. Using assay system of Caenorhabditis elegans, we identified the NLG-1/Neuroligin-mediated neuronal signaling dysregulated by GO exposure. In nematodes, GO exposure significantly decreased the expression of NLG-1, a postsynaptic cell adhesion protein. Loss-of-function mutation of nlg-1 gene resulted in a susceptible property of nematodes to GO toxicity. Rescue experiments suggested that NLG-1 could act in AIY interneurons to regulate the response to GO exposure. In the AIY interneurons, PKC-1, a serine/threonine protein kinase C (PKC) protein, was identified as the downstream target for NLG-1 in the regulation of response to GO exposure. LIN-45, a Raf protein in ERK signaling pathway, was further identified as the downstream target for PKC-1 in the regulation of response to GO exposure. Therefore, GO may dysregulate NLG-1-mediated molecular signaling in the interneurons, and a neuronal signaling cascade of NLG-1-PKC-1-LIN-45 was raised to be required for the control of response to GO exposure. More importantly, intestinal RNAi knockdown of daf-16 gene encoding a FOXO transcriptional factor in insulin signaling pathway suppressed the resistant property of nematodes overexpressing NLG-1 to GO toxicity, suggesting the possible link between neuronal NLG-1 signaling and intestinal insulin signaling in the regulation of response to GO exposure.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

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    Losi, Gabriele; Mariotti, Letizia; Carmignoto, Giorgio

    2014-01-01

    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. PMID:25225102

  5. Cortical GABAergic Interneurons in Cross-Modal Plasticity following Early Blindness

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    Sébastien Desgent

    2012-01-01

    Full Text Available Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing γ-aminobutyric acid (GABA play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field.

  6. Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration.

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    Xiang, Yangfei; Tanaka, Yoshiaki; Patterson, Benjamin; Kang, Young-Jin; Govindaiah, Gubbi; Roselaar, Naomi; Cakir, Bilal; Kim, Kun-Yong; Lombroso, Adam P; Hwang, Sung-Min; Zhong, Mei; Stanley, Edouard G; Elefanty, Andrew G; Naegele, Janice R; Lee, Sang-Hun; Weissman, Sherman M; Park, In-Hyun

    2017-09-07

    Organoid techniques provide unique platforms to model brain development and neurological disorders. Whereas several methods for recapitulating corticogenesis have been described, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains, respectively. Population and single-cell RNA sequencing (RNA-seq) profiling combined with bulk assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses revealed transcriptional and chromatin accessibility dynamics and lineage relationships during MGE and cortical organoid development. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, fusing region-specific organoids followed by live imaging enabled analysis of human interneuron migration and integration. Together, our study provides a platform for generating domain-specific brain organoids and modeling human interneuron migration and offers deeper insight into molecular dynamics during human brain development. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. 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.

  8. 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.

  9. High Stimulus-Related Information in Barrel Cortex Inhibitory Interneurons.

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    Vicente Reyes-Puerta

    2015-06-01

    Full Text Available The manner in which populations of inhibitory (INH and excitatory (EXC neocortical neurons collectively encode stimulus-related information is a fundamental, yet still unresolved question. Here we address this question by simultaneously recording with large-scale multi-electrode arrays (of up to 128 channels the activity of cell ensembles (of up to 74 neurons distributed along all layers of 3-4 neighboring cortical columns in the anesthetized adult rat somatosensory barrel cortex in vivo. Using two different whisker stimulus modalities (location and frequency we show that individual INH neurons--classified as such according to their distinct extracellular spike waveforms--discriminate better between restricted sets of stimuli (≤6 stimulus classes than EXC neurons in granular and infra-granular layers. We also demonstrate that ensembles of INH cells jointly provide as much information about such stimuli as comparable ensembles containing the ~20% most informative EXC neurons, however presenting less information redundancy - a result which was consistent when applying both theoretical information measurements and linear discriminant analysis classifiers. These results suggest that a consortium of INH neurons dominates the information conveyed to the neocortical network, thereby efficiently processing incoming sensory activity. This conclusion extends our view on the role of the inhibitory system to orchestrate cortical activity.

  10. Vibratory interneurons in the non-hearing cave cricket indicate evolutionary origin of sound processing elements in Ensifera.

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    Stritih, Natasa; Stumpner, Andreas

    2009-01-01

    Tympanal hearing organs in the front tibiae of ensiferan insects supposedly evolved from vibration-sensitive tibial organs (TO), like those in the cave cricket Troglophilus neglectus (Rhaphidophoridae). If this is true, one expects to find interneurons in the cave cricket that are homologous to auditory neurons from hearing Ensifera. Therefore, we examined the central projections of the foreleg TO of the cave cricket, as well as morphology and response properties of interneurons responding to foreleg vibration. Sensory axons of the TO adjoined to the "tympanal nerve" terminate in the equivalent portion of the ring tract neuropile in the prothoracic ganglion as corresponding receptors of crickets and weta. We found nine putatively homologous elements to sound- and/or vibration-sensitive interneurons of Ensifera--one local neuron (unpaired median, DUM), three T-fibres (TN), three descending (DN) and two ascending neurons (AN). Presumable first-order interneurons arborising in the ring tract correspond to a local auditory DUM cell of bush crickets and to TN1, DN1 and AN2 of various Ensifera, respectively. Homologues of some prominent auditory cells, the "omega" neuron(s) and the ascending neuron 1 (AN1), however, were not found. We conclude that (a) T. neglectus interneurons are morphologically primitive with respect to those of hearing taxa, (b) significant changes in the dendritic structure/synaptic connectivity have taken place during the evolution of the most specialised first-order auditory interneurons of Ensifera, (c) the data do not contradict independent evolution of hearing in Grylloidea and Tettigonoidea. Other interneurons appear morpho-physiologically conserved across hearing and non-hearing species, possibly as a part of a multimodal "alert" system.

  11. NR2 subunits and NMDA receptors on lamina II inhibitory and excitatory interneurons of the mouse dorsal horn

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    MacDermott Amy B

    2010-05-01

    Full Text Available Abstract Background NMDA receptors expressed by spinal cord neurons in the superficial dorsal horn are involved in the development of chronic pain associated with inflammation and nerve injury. The superficial dorsal horn has a complex and still poorly understood circuitry that is mainly populated by inhibitory and excitatory interneurons. Little is known about how NMDA receptor subunit composition, and therefore pharmacology and voltage dependence, varies with neuronal cell type. NMDA receptors are typically composed of two NR1 subunits and two of four NR2 subunits, NR2A-2D. We took advantage of the differences in Mg2+ sensitivity of the NMDA receptor subtypes together with subtype preferring antagonists to identify the NR2 subunit composition of NMDA receptors expressed on lamina II inhibitory and excitatory interneurons. To distinguish between excitatory and inhibitory interneurons, we used transgenic mice expressing enhanced green fluorescent protein driven by the GAD67 promoter. Results Analysis of conductance ratio and selective antagonists showed that lamina II GABAergic interneurons express both the NR2A/B containing Mg2+ sensitive receptors and the NR2C/D containing NMDA receptors with less Mg2+ sensitivity. In contrast, excitatory lamina II interneurons express primarily NR2A/B containing receptors. Despite this clear difference in NMDA receptor subunit expression in the two neuronal populations, focally stimulated synaptic input is mediated exclusively by NR2A and 2B containing receptors in both neuronal populations. Conclusions Stronger expression of NMDA receptors with NR2C/D subunits by inhibitory interneurons compared to excitatory interneurons may provide a mechanism to selectively increase activity of inhibitory neurons during intense excitatory drive that can provide inhibitory feedback.

  12. The DYX2 locus and neurochemical signaling genes contribute to speech sound disorder and related neurocognitive domains.

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    Eicher, J D; Stein, C M; Deng, F; Ciesla, A A; Powers, N R; Boada, R; Smith, S D; Pennington, B F; Iyengar, S K; Lewis, B A; Gruen, J R

    2015-04-01

    A major milestone of child development is the acquisition and use of speech and language. Communication disorders, including speech sound disorder (SSD), can impair a child's academic, social and behavioral development. Speech sound disorder is a complex, polygenic trait with a substantial genetic component. However, specific genes that contribute to SSD remain largely unknown. To identify associated genes, we assessed the association of the DYX2 dyslexia risk locus and markers in neurochemical signaling genes (e.g., nicotinic and dopaminergic) with SSD and related endophenotypes. We first performed separate primary associations in two independent samples - Cleveland SSD (210 affected and 257 unaffected individuals in 127 families) and Denver SSD (113 affected individuals and 106 unaffected individuals in 85 families) - and then combined results by meta-analysis. DYX2 markers, specifically those in the 3' untranslated region of DCDC2 (P = 1.43 × 10(-4) ), showed the strongest associations with phonological awareness. We also observed suggestive associations of dopaminergic-related genes ANKK1 (P = 1.02 × 10(-2) ) and DRD2 (P = 9.22 × 10(-3) ) and nicotinic-related genes CHRNA3 (P = 2.51 × 10(-3) ) and BDNF (P = 8.14 × 10(-3) ) with case-control status and articulation. Our results further implicate variation in putative regulatory regions in the DYX2 locus, particularly in DCDC2, influencing language and cognitive traits. The results also support previous studies implicating variation in dopaminergic and nicotinic neural signaling influencing human communication and cognitive development. Our findings expand the literature showing genetic factors (e.g., DYX2) contributing to multiple related, yet distinct neurocognitive domains (e.g., dyslexia, language impairment, and SSD). How these factors interactively yield different neurocognitive and language-related outcomes remains to be elucidated. © 2015 The Authors. Genes, Brain and Behavior published by

  13. Mercury Vapour Long-Lasting Exposure: Lymphocyte Muscarinic Receptors as Neurochemical Markers of Accidental Intoxication

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    E. Roda

    2016-01-01

    Full Text Available Introduction. Chronic poisoning may result in home setting after mercury (Hg vapours inhalation from damaged devices. We report a chronic, nonoccupational Hg poisoning due to 10-year indoor exposure to mercury spillage. Case Report. A 72-year-old man with polyneuropathy of suspected toxic origin. At hospitalization, toxicological clinical evaluations confirmed the altered neurological picture documented across the last decade. Periodic blood and urine Hg levels (BHg, UHg monitoring were performed from admission (t0, until 1 year later (t2, paralleled by blood neurochemical markers assessment, that is, lymphocytes muscarinic receptors (l-MRs. At t0: BHg and UHg were 27 and 1.4 microg/L, respectively (normal values: BHg 1–4.5; UHg 0.1–4.5, associated with l-MRs increase, 185.82 femtomoL/million lymphocytes (normal range: 8.0–16.0. At t1 (two days after DMSA-mobilization test, BHg weak reduction, paralleled by UHg 3.7-fold increase, was measured together with further l-MRs enhancement (205.43 femtomoL/million lymphocytes. At t2 (eight months after two cycles of DMSA chelating therapy ending, gradual improving of clinical manifestations was accompanied by progressive decrease of BHg and UHg (4.0 and 2.8 microg/L, resp. and peripheral l-MRs neurochemical marker (24.89 femtomoL/million lymphocytes. Conclusion. l-MRs modulatory effect supports their use as peripheral neurochemical marker in Hg poisoning diagnosis and chelation therapy monitoring.

  14. Mercury Vapour Long-Lasting Exposure: Lymphocyte Muscarinic Receptors as Neurochemical Markers of Accidental Intoxication.

    Science.gov (United States)

    Roda, E; Giampreti, A; Vecchio, S; Apostoli, P; Coccini, T

    2016-01-01

    Introduction. Chronic poisoning may result in home setting after mercury (Hg) vapours inhalation from damaged devices. We report a chronic, nonoccupational Hg poisoning due to 10-year indoor exposure to mercury spillage. Case Report. A 72-year-old man with polyneuropathy of suspected toxic origin. At hospitalization, toxicological clinical evaluations confirmed the altered neurological picture documented across the last decade. Periodic blood and urine Hg levels (BHg, UHg) monitoring were performed from admission (t0), until 1 year later (t2), paralleled by blood neurochemical markers assessment, that is, lymphocytes muscarinic receptors (l-MRs). At t0: BHg and UHg were 27 and 1.4 microg/L, respectively (normal values: BHg 1-4.5; UHg 0.1-4.5), associated with l-MRs increase, 185.82 femtomoL/million lymphocytes (normal range: 8.0-16.0). At t1 (two days after DMSA-mobilization test), BHg weak reduction, paralleled by UHg 3.7-fold increase, was measured together with further l-MRs enhancement (205.43 femtomoL/million lymphocytes). At t2 (eight months after two cycles of DMSA chelating therapy ending), gradual improving of clinical manifestations was accompanied by progressive decrease of BHg and UHg (4.0 and 2.8 microg/L, resp.) and peripheral l-MRs neurochemical marker (24.89 femtomoL/million lymphocytes). Conclusion. l-MRs modulatory effect supports their use as peripheral neurochemical marker in Hg poisoning diagnosis and chelation therapy monitoring.

  15. Lentiviral expression of GAD67 and CCK promoter-driven opsins to target interneurons in vitro and in vivo.

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    Mantoan Ritter, Laura; Macdonald, Douglas C; Ritter, Georg; Escors, David; Chiara, Francesca; Cariboni, Anna; Schorge, Stephanie; Kullmann, Dimitri M; Collins, Mary

    2016-01-01

    The ability to manipulate the activity of interneurons with optogenetic tools offers the possibility of interfering with diseases caused by altered neuronal inhibition and synchrony, including epilepsy and schizophrenia. To develop vectors for therapeutic approaches, targeting optogenetic constructs to interneurons is therefore a key requirement. We investigated whether the interneuron-specific promoters glutamic acid decarboxylase (GAD)67 and cholecystokinin (CCK) allowed targeted lentiviral delivery of opsins to interneurons as a whole, or specifically CCK+ interneurons. We generated lentiviral (LV) plasmids encoding channelrhodopsin (ChR2) and halorhodopsin (NpHR) tagged with fluorophores and driven by GAD67 or CCK promoters. Adeno-associated virus (AAV) and LV vectors carrying opsins driven by pyramidal cell promoters were used as controls. We transduced neuronal cultures and rodent brain in vivo, immunostained specimens 6-8 weeks after in vivo injection and 7-14 days after in vitro transduction, and evaluated volume and specificity of expression by confocal microscopy. In vitro, 90% (19/21) of LV-CCK-NpHR2.0-EYFP expressing neurons were CCK+. In vivo, LV-GAD67-ChR2-mCherry was expressed in 2.6% (5/193), LV-GAD67-NpHR2.0-EYFP in approximately 15% (43/279) and LV-CCK-NpHR2.0-EYFP in 47% (9/19) of hippocampal GABA+ interneurons. GAD67 vectors expressed in larger volumes than CCK-driven constructs. AAV vector controls achieved the largest expression volumes. LV-CCK-NpHR2.0-EYFP may be useful for targeting CCK+ interneurons in culture. GAD67/CCK-driven lentiviral constructs are expressed in vivo, although expression is not specific for interneurons. Overall, expression levels are low compared to opsins driven by pyramidal cell promoters. A better understanding of GAD67 and CCK promoter structure or alternative techniques is required to reliably target opsins to interneurons using viral vectors. Copyright © 2016 John Wiley & Sons, Ltd.

  16. 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.

  17. Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism

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    Cecilia Tubert

    2016-09-01

    Full Text Available The mechanism underlying a hypercholinergic state in Parkinson’s disease (PD remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels.

  18. 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.

  19. Cannabinoids for the Treatment of Schizophrenia? A Balanced Neurochemical Framework for Both Adverse and Therapeutic Effects of Cannabis Use

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    Carissa M. Coulston

    2011-01-01

    Full Text Available Recent studies have found that cannabinoids may improve neuropsychological performance, ameliorate negative symptoms, and have antipsychotic properties for a subgroup of the schizophrenia population. These findings are in contrast to the longstanding history of adverse consequences of cannabis use, predominantly on the positive symptoms, and a balanced neurochemical basis for these opposing views is lacking. This paper details a review of the neurobiological substrates of schizophrenia and the neurochemical effects of cannabis use in the normal population, in both cortical (in particular prefrontal and subcortical brain regions. The aim of this paper is to provide a holistic neurochemical framework in which to understand how cannabinoids may impair, or indeed, serve to ameliorate the positive and negative symptoms as well as cognitive impairment. Directions in which future research can proceed to resolve the discrepancies are briefly discussed.

  20. Interneurons in the Honeybee Primary Auditory Center Responding to Waggle Dance-Like Vibration Pulses.

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    Ai, Hiroyuki; Kai, Kazuki; Kumaraswamy, Ajayrama; Ikeno, Hidetoshi; Wachtler, Thomas

    2017-11-01

    Female honeybees use the "waggle dance" to communicate the location of nectar sources to their hive mates. Distance information is encoded in the duration of the waggle phase (von Frisch, 1967). During the waggle phase, the dancer produces trains of vibration pulses, which are detected by the follower bees via Johnston's organ located on the antennae. To uncover the neural mechanisms underlying the encoding of distance information in the waggle dance follower, we investigated morphology, physiology, and immunohistochemistry of interneurons arborizing in the primary auditory center of the honeybee (Apis mellifera). We identified major interneuron types, named DL-Int-1, DL-Int-2, and bilateral DL-dSEG-LP, that responded with different spiking patterns to vibration pulses applied to the antennae. Experimental and computational analyses suggest that inhibitory connection plays a role in encoding and processing the duration of vibration pulse trains in the primary auditory center of the honeybee.SIGNIFICANCE STATEMENT The waggle dance represents a form of symbolic communication used by honeybees to convey the location of food sources via species-specific sound. The brain mechanisms used to decipher this symbolic information are unknown. We examined interneurons in the honeybee primary auditory center and identified different neuron types with specific properties. The results of our computational analyses suggest that inhibitory connection plays a role in encoding waggle dance signals. Our results are critical for understanding how the honeybee deciphers information from the sound produced by the waggle dance and provide new insights regarding how common neural mechanisms are used by different species to achieve communication. Copyright © 2017 the authors 0270-6474/17/3710624-12$15.00/0.

  1. 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

  2. HCN Channel Modulation of Synaptic Integration in GABAergic Interneurons in Malformed Rat Neocortex

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    John J. Hablitz

    2017-04-01

    Full Text Available Cortical malformations are often associated with pharmaco-resistant epilepsy. Alterations in hyperpolarization-activated, cyclic nucleotide-gated, non-specific cation (HCN channels have been shown to contribute to malformation associated hyperexcitability. We have recently demonstrated that expression of HCN channels and Ih current amplitudes are reduced in layer (L 5 pyramidal neurons of rats with freeze lesion induced malformations. These changes were associated with an increased EPSP temporal summation. Here, we examine the effects of HCN channel inhibition on synaptic responses in fast spiking, presumptive basket cells and accommodating, presumptive Martinotti, GABAergic interneurons in slices from freeze lesioned animals. In control animals, fast spiking cells showed small sag responses which were reduced by the HCN channel antagonist ZD7288. Fast spiking cells in lesioned animals showed absent or reduced sag responses. The amplitude of single evoked EPSPs in fast spiking cells in the control group was not affected by HCN channel inhibition with ZD7288. EPSP ratios during short stimulus trains at 25 Hz were not significantly different between control and lesion groups. ZD7288 produced an increase in EPSP ratios in the control but not lesion groups. Under voltage clamp conditions, ZD7288 did not affect EPSC ratios. In the control group, accommodating interneurons showed robust sag responses which were significantly reduced by ZD7288. HCN channel inhibition increased EPSP ratios and area in controls but not the lesioned group. The results indicate that HCN channels differentially modulate EPSPs in different classes of GABAergic interneurons and that this control is reduced in malformed rat neocortex.

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

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    Stracke, C.P.; Schoth, F.; Moeller-Hartmann, W.; Krings, T. [University Hospital of the University of Technology, Departments of Neuroradiology and Diagnostic Radiology, Aachen (Germany); Pettersson, L.G. [University of Goeteborg, Department of Physiology, Goeteborg (Sweden)

    2005-02-01

    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.)

  4. Bulbar microcircuit model predicts connectivity and roles of interneurons in odor coding.

    Directory of Open Access Journals (Sweden)

    Aditya Gilra

    Full Text Available Stimulus encoding by primary sensory brain areas provides a data-rich context for understanding their circuit mechanisms. The vertebrate olfactory bulb is an input area having unusual two-layer dendro-dendritic connections whose roles in odor coding are unclear. To clarify these roles, we built a detailed compartmental model of the rat olfactory bulb that synthesizes a much wider range of experimental observations on bulbar physiology and response dynamics than has hitherto been modeled. We predict that superficial-layer inhibitory interneurons (periglomerular cells linearize the input-output transformation of the principal neurons (mitral cells, unlike previous models of contrast enhancement. The linearization is required to replicate observed linear summation of mitral odor responses. Further, in our model, action-potentials back-propagate along lateral dendrites of mitral cells and activate deep-layer inhibitory interneurons (granule cells. Using this, we propose sparse, long-range inhibition between mitral cells, mediated by granule cells, to explain how the respiratory phases of odor responses of sister mitral cells can be sometimes decorrelated as observed, despite receiving similar receptor input. We also rule out some alternative mechanisms. In our mechanism, we predict that a few distant mitral cells receiving input from different receptors, inhibit sister mitral cells differentially, by activating disjoint subsets of granule cells. This differential inhibition is strong enough to decorrelate their firing rate phases, and not merely modulate their spike timing. Thus our well-constrained model suggests novel computational roles for the two most numerous classes of interneurons in the bulb.

  5. Selectivity of pyramidal cells and interneurons in the human medial temporal lobe

    Science.gov (United States)

    Mormann, Florian; Cerf, Moran; Koch, Christof; Fried, Itzhak; Quiroga, Rodrigo Quian

    2011-01-01

    Neurons in the medial temporal lobe (MTL) respond selectively to pictures of specific individuals, objects, and places. However, the underlying mechanisms leading to such degree of stimulus selectivity are largely unknown. A necessary step to move forward in this direction involves the identification and characterization of the different neuron types present in MTL circuitry. We show that putative principal cells recorded in vivo from the human MTL are more selective than putative interneurons. Furthermore, we report that putative hippocampal pyramidal cells exhibit the highest degree of selectivity within the MTL, reflecting the hierarchical processing of visual information. We interpret these differences in selectivity as a plausible mechanism for generating sparse responses. PMID:21715671

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

    DEFF Research Database (Denmark)

    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 an...... of aIINs versus dIINs, of aCINs versus dCINs, and of adIINs versus adCINs. The findings are compared to the organization of lumbar spinal INs in other vertebrate species....

  7. Microdialysis Coupled with LC-MS/MS for In Vivo Neurochemical Monitoring.

    Science.gov (United States)

    Zestos, Alexander G; Kennedy, Robert T

    2017-09-01

    Microdialysis is a powerful sampling technique used to monitor small molecules in vivo. Despite the many applications of microdialysis sampling, it is limited by the method of analyzing the resulting samples. An emerging technique for analysis of microdialysis samples is liquid chromatography-tandem mass spectrometry (LC-MS/MS). This technique is highly versatile, allowing multiplexed analysis of neurotransmitters, metabolites, and neuropeptides. Using LC-MS/MS for polar neurotransmitters is hampered by weak retention reverse phase LC columns. Several derivatization reagents have been utilized to enhance separation and resolution of neurochemicals in dialysate samples including benzoyl chloride (BzCl), dansyl chloride, formaldehyde, ethylchloroformate, and propionic anhydride. BzCl reacts with amine and phenol groups so that many neurotransmitters can be labeled. Besides improving separation on reverse phase columns, this reagent also increases sensitivity. It is available in a heavy form so that it can be used to make stable-isotope labeled internal standard for improved quantification. Using BzCl with LC-MS/MS has allowed for measuring as many as 70 neurochemicals in a single assay. With slightly different conditions, LC-MS/MS has also been used for monitoring endocannabinoids. LC-MS/MS is also useful for neuropeptide assay because it allows for highly sensitive, sequence specific measurement of most peptides. These advances have allowed for multiplexed neurotransmitter measurements in behavioral, circuit analysis, and drug effect studies.

  8. No neurochemical evidence of brain injury after blast overpressure by repeated explosions or firing heavy weapons.

    Science.gov (United States)

    Blennow, K; Jonsson, M; Andreasen, N; Rosengren, L; Wallin, A; Hellström, P A; Zetterberg, H

    2011-04-01

    Psychiatric and neurological symptoms are common among soldiers exposed to blast without suffering a direct head injury. It is not known whether such symptoms are direct consequences of blast overpressure. To examine if repeated detonating explosions or firing if of heavy weapons is associated with neurochemical evidence of brain damage. Three controlled experimental studies. In the first, army officers were exposed to repeated firing of a FH77B howitzer or a bazooka. Cerebrospinal fluid (CSF) was taken post-exposure to measure biomarkers for brain damage. In the second, officers were exposed for up to 150 blasts by firing a bazooka, and in the third to 100 charges of detonating explosives of 180 dB. Serial serum samples were taken after exposure. Results were compared with a control group consisting of 19 unexposed age-matched healthy volunteers. The CSF biomarkers for neuronal/axonal damage (tau and neurofilament protein), glial cell injury (GFAP and S-100b), blood-brain barrier damage (CSF/serum albumin ratio) and hemorrhages (hemoglobin and bilirubin) and the serum GFAP and S-100b showed normal and stable levels in all exposed officers. Repeated exposure to high-impact blast does not result in any neurochemical evidence of brain damage. These findings are of importance for soldiers regularly exposed to high-impact blast when firing artillery shells or other types of heavy weapons. © 2010 John Wiley & Sons A/S.

  9. Neurochemical effects of extended exposure to white spirit vapour at three concentration levels.

    Science.gov (United States)

    Savolainen, H; Pfäffli, P

    1982-03-01

    Male Wistar rats were exposed to 575 (100 ppm), 2875 (500 ppm) or 5750 mg/m3 (1000 ppm) white spirit vapour for 4-17 weeks 5 days a week, 6 h daily. Perirenal fat solvent concentration corresponded in composition and concentration to those of the vapour at all times. The neurochemical effects included a dose-dependent decrease in the cerebellar succinate dehydrogenase activity for 8 weeks while creatine kinase activity increased after 12 weeks. The specific creatine kinase activity in the glial cell fraction, a marker for astroglia, did not increase suggesting proliferation of astroglial cells in the homogenate. The serum creatine kinase activity originating mainly from striated muscle was below the control range at the two higher concentrations after 12 weeks. Simultaneous analyses for isolated muscle membrane sialic acid and uronic acid residues showed decreased concentrations in proportion to lipid phosphorus or total membrane protein. Thus, the white spirit mixture has neurochemical effects possibly caused by paraffins and the same components may have caused the muscle cell membrane effects. The lowest exposure concentration represents a virtual 'no effect' level for rats in the 17-week exposure.

  10. The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects.

    Science.gov (United States)

    Cotter, Rachel; Pei, Yue; Mus, Liudmila; Harmeier, Anja; Gainetdinov, Raul R; Hoener, Marius C; Canales, Juan J

    2015-01-01

    The newly discovered trace amine-associated receptor 1 (TAAR1) has the ability to regulate both dopamine function and psychostimulant action. Here, we tested in rats the ability of RO5203648, a selective TAAR1 partial agonist, to modulate the physiological and behavioral effects of methamphetamine (METH). In experiment 1, RO5203468 dose- and time-dependently altered METH-induced locomotor activity, manifested as an early attenuation followed by a late potentiation of METH's stimulating effects. In experiment 2, rats received a 14-day treatment regimen during which RO5203648 was co-administered with METH. RO5203648 dose-dependently attenuated METH-stimulated hyperactivity, with the effects becoming more apparent as the treatments progressed. After chronic exposure and 3-day withdrawal, rats were tested for locomotor sensitization. RO5203648 administration during the sensitizing phase prevented the development of METH sensitization. However, RO5203648, at the high dose, cross-sensitized with METH. In experiment 3, RO5203648 dose-dependently blocked METH self-administration without affecting operant responding maintained by sucrose, and exhibited lack of reinforcing efficacy when tested as a METH's substitute. Neurochemical data showed that RO5203648 did not affect METH-mediated DA efflux and uptake inhibition in striatal synaptosomes. In vivo, however, RO5203648 was able to transiently inhibit METH-induced accumulation of extracellular DA levels in the nucleus accumbens. Taken together, these data highlight the significant potential of TAAR1 to modulate METH's neurochemical and behavioral effects.

  11. Long-term potentiation in hippocampal oriens interneurons: postsynaptic induction, presynaptic expression and evaluation of candidate retrograde factors

    Science.gov (United States)

    Nicholson, Elizabeth; Kullmann, Dimitri M.

    2014-01-01

    Several types of hippocampal interneurons exhibit a form of long-term potentiation (LTP) that depends on Ca2+-permeable AMPA receptors and group I metabotropic glutamate receptors. Several sources of evidence point to a presynaptic locus of LTP maintenance. The retrograde factor that triggers the expression of LTP remains unidentified. Here, we show that trains of action potentials in putative oriens-lacunosum-moleculare interneurons of the mouse CA1 region can induce long-lasting potentiation of stimulus-evoked excitatory postsynaptic currents that mimics LTP elicited by high-frequency afferent stimulation. We further report that blockers of nitric oxide production or TRPV1 receptors failed to prevent LTP induction. The present results add to the evidence that retrograde signalling underlies N-methyl-d-aspartate (NMDA) receptor-independent LTP in oriens interneurons, mediated by an unidentified factor. PMID:24298136

  12. 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, stimulation......-induced calcium activity in neurons and astrocytes, and cerebral blood flow and oxygen responses in the somatosensory cortex of young adult and old adult mice in vivo using electrical whisker pad stimulation. Gamma activity was reduced in old adult mice, and associated with reduced calcium activity of PV......-dependent rise in O2 use, that is, the rise in the cerebral metabolic rate of oxygen (CMRO2) evoked by excitatory postsynaptic currents almost doubled in old adult mice. We conclude that PV interneuron function and gamma activity are particularly affected in old adult mice. Alterations in neurovascular coupling...

  13. Distinct behavioral consequences of short-term and prolonged GABAergic depletion in prefrontal cortex and dorsal hippocampus

    Directory of Open Access Journals (Sweden)

    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.

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

    DEFF Research Database (Denmark)

    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...

  15. Preferential expression of an AAV-2 construct in NOS-positive interneurons following intrastriatal injection.

    Science.gov (United States)

    Sin, Mihaela; Walker, Paul D; Bouhamdan, Mohamad; Quinn, John P; Bannon, Michael J

    2005-11-18

    Most CNS studies using recombinant adeno-associated virus type 2 (rAAV-2) vectors have focused on gene delivery for the purpose of gene therapy. In the present study, we examined the feasibility of using rAAV-2 vectors to study the regulation of preprotachykinin-A (PPT-A) promoter activity in striatal medium spiny projection neurons. An rAAV-2 vector incorporating a PPT promoter fragment (shown previously to confer some cell-specificity of expression in vitro) coupled to a green fluorescent protein (GFP) reporter gene was stereotaxically injected into the rat striatum. Since medium spiny projection neurons represent the predominant neuronal type (90-95%) in the striatum, we predicted that the vast majority of GFP-expressing cells would be of this phenotype. Surprisingly, the transgene was actually expressed in a similar number of medium spiny projection neurons and interneurons, while glial expression of GFP was not observed. A preponderance of GFP-expressing interneurons was immunoreactive for the marker neuronal nitric oxide synthase (nNOS). Our results suggest that viral vector-related events that occur during transduction are the determining factor in the pattern of transgene expression observed, while the influence of the transgene promoter appears to be secondary, at least under the conditions employed.

  16. Characterization of a novel subtype of hippocampal interneurons that express corticotropin-releasing hormone.

    Science.gov (United States)

    Hooper, Andrew; Maguire, Jamie

    2016-01-01

    A subset of corticotropin-releasing hormone (CRH) neurons was previously identified in the hippocampus with unknown function. Here we demonstrate that hippocampal CRH neurons represent a novel subtype of interneurons in the hippocampus, exhibiting unique morphology, electrophysiological properties, molecular markers, and connectivity. This subset of hippocampal CRH neurons in the mouse reside in the CA1 pyramidal cell layer and tract tracing studies using AAV-Flex-ChR2-tdTomato reveal dense back-projections of these neurons onto principal neurons in the CA3 region of the hippocampus. These hippocampal CRH neurons express both GABA and GAD67 and using in vitro optogenetic techniques, we demonstrate that these neurons make functional connections and release GABA onto CA3 principal neurons. The location, morphology, and importantly the functional connectivity of these neurons demonstrate that hippocampal CRH neurons represent a unique subtype of hippocampal interneurons. The connectivity of these neurons has significant implications for hippocampal function. © 2015 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    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.

  18. DCC mediated axon guidance of spinal interneurons is essential for normal locomotor central pattern generator function.

    Science.gov (United States)

    Rabe Bernhardt, Nadine; Memic, Fatima; Gezelius, Henrik; Thiebes, Anja-Lena; Vallstedt, Anna; Kullander, Klas

    2012-06-15

    Coordinated limb rhythmic movements take place through organized signaling in local spinal cord neuronal networks. The establishment of these circuitries during development is dependent on the correct guidance of axons to their targets. It has previously been shown that the well-known axon guidance molecule netrin-1 is required for configuring the circuitry that provides left-right alternating coordination in fictive locomotion. The attraction of commissural axons to the midline in response to netrin-1 has been shown to involve the netrin-1 receptor DCC (deleted in Colorectal Cancer). However, the role of DCC for the establishment of CPG coordination has not yet been resolved. We show that mice carrying a null mutation of DCC displayed an uncoordinated left-right activity during fictive locomotion accompanied by a loss of interneuronal subpopulations originating from commissural progenitors. Thus, DCC plays a crucial role in the formation of spinal neuronal circuitry coordinating left-right activities. Together with the previously published results from netrin-1 deficient mice, the data presented in this study suggest a role for the most ventral originating V3 interneurons in synchronous activities over the midline. Further, it provides evidence that axon crossing in the spinal cord is more intricately controlled than in previously suggested models of DCC-netrin-1 interaction. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Augmented inhibition from cannabinoid sensitive interneurons diminishes CA1 output after traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Brian Neal Johnson

    2014-12-01

    Full Text Available The neurological impairments associated with traumatic brain injury include learning and memory deficits and increased risk of seizures. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by traumatic brain injury. To examine network activity in the hippocampal CA1 region after lateral fluid percussion injury, we used a combination of voltage sensitive dye, field potential and patch clamp recording in mouse hippocampal brain slices. When the stratum radiatum was stimulated in slices from injured mice we found decreased depolarization in stratum radiatum and increased hyperpolarization in stratum oriens, together with a decrease in the percentage of pyramidal neurons firing stimulus-evoked action potentials. Increased hyperpolarization in stratum oriens persisted when glutamatergic transmission was blocked. However, we found no changes in stratum oriens responses when the alveus was stimulated to directly activate stratum oriens. These results suggest that the increased stratum oriens hyperpolarization evoked by stratum radiatum stimulation was mediated by interneurons that have cell bodies and/or axons in stratum radiatum, and form synapses in stratum pyramidale and stratum oriens. A low concentration (100 nM of the synthetic cannabinoid WIN55,212-2,restored CA1 output in slices from injured animals. These findings support the hypothesis that increased GABAergic signaling by cannabinoid sensitive interneurons contributes to the reduced CA1 output following traumatic brain injury.

  20. Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

    Science.gov (United States)

    Choi, Yun-Sik; Lin, Stanley L.; Lee, Boyoung; Kurup, Pradeep; Cho, Hee-Yeon; Naegele, Janice R.; Lombroso, Paul J.; Obrietan, Karl

    2009-01-01

    Excitotoxic cell death is one of the precipitating events in the development of temporal lobe epilepsy. Of particular prominence is the loss of GABAergic hilar neurons. Although the molecular mechanisms responsible for the selective vulnerability of these cells are not well understood, activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway has been implicated in neuroprotective responses to excitotoxicity in other neuronal populations. Here, we report that high levels of the striatal-enriched protein tyrosine phosphatase (STEP), a key regulator of ERK/MAPK signaling, are found in vulnerable somatostatin-immunoreactive hilar interneurons. Under both control conditions and after pilocarpine-induced status epilepticus (SE), ERK/MAPK activation was repressed in STEP-immunoreactive hilar neurons. This contrasts with robust SE-induced ERK/MAPK activation in the granule cell layer of the dentate gyrus, a cell region that does not express STEP. During pilocarpine-induced SE, in vivo disruption of STEP activity allowed activation of the MAPK pathway, leading to immediate-early gene expression and significant rescue from cell death. Thus, STEP increases the sensitivity of neurons to SE-induced excitotoxicity by specifically blocking a latent neuroprotective response initiated by the MAPK pathway. These findings identify a key set of signaling events that render somatostatinergic hilar interneurons vulnerable to SE-induced cell death. PMID:17360923

  1. Effects of Gladiolus dalenii on the Stress-Induced Behavioral, Neurochemical, and Reproductive Changes in Rats

    Directory of Open Access Journals (Sweden)

    David Fotsing

    2017-09-01

    Full Text Available Gladiolus dalenii is a plant commonly used in many regions of Cameroon as a cure for various diseases like headaches, epilepsy, schizophrenia, and mood disorders. Recent studies have revealed that the aqueous extract of G. dalenii (AEGD exhibited antidepressant-like properties in rats. Therefore, we hypothesized that the AEGD could protect from the stress-induced behavioral, neurochemical, and reproductive changes in rats. The objective of the present study was to elucidate the effect of the AEGD on behavioral, neurochemical, and reproductive characteristics, using female rats subjected to chronic immobilization stress. The chronic immobilization stress (3 h per day for 28 days was applied to induce female reproductive and behavioral impairments in rats. The immobilization stress was provoked in rats by putting them separately inside cylindrical restrainers with ventilated doors at ambient temperature. The plant extract was given to rats orally everyday during 28 days, 5 min before induction of stress. On a daily basis, a vaginal smear was made to assess the duration of the different phases of the estrous cycle and at the end of the 28 days of chronic immobilization stress, the rat’s behavior was assessed in the elevated plus maze. They were sacrificed by cervical disruption. The organs were weighed, the ovary histology done, and the biochemical parameters assessed. The findings of this research revealed that G. dalenii increased the entries and the time of open arm exploration in the elevated plus maze. Evaluation of the biochemical parameters levels indicated that there was a significant reduction in the corticosterone, progesterone, and prolactin levels in the G. dalenii aqueous extract treated rats compared to stressed rats whereas the levels of serotonin, triglycerides, adrenaline, cholesterol, glucose estradiol, follicle stimulating hormone and luteinizing hormone were significantly increased in the stressed rats treated with, G. dalenii

  2. Cerebellar neurochemical alterations in spinocerebellar ataxia type 14 appear to include glutathione deficiency.

    Science.gov (United States)

    Doss, Sarah; Rinnenthal, Jan Leo; Schmitz-Hübsch, Tanja; Brandt, Alexander U; Papazoglou, Sebastian; Lux, Silke; Maul, Stephan; Würfel, Jens; Endres, Matthias; Klockgether, Thomas; Minnerop, Martina; Paul, Friedemann

    2015-08-01

    Autosomal dominant ataxia type 14 (SCA14) is a rare usually adult-onset progressive disorder with cerebellar neurodegeneration caused by mutations in protein kinase C gamma. We set out to examine cerebellar and extracerebellar neurochemical changes in SCA14 by MR spectroscopy. In 13 SCA14 patients and 13 healthy sex- and age-matched controls, 3-T single-voxel brain proton MR spectroscopy was performed in a cerebellar voxel of interest (VOI) at TE = 30 ms to obtain a neurochemical profile of metabolites with short relaxation times. In the cerebellum and in additional VOIs in the prefrontal cortex, motor cortex, and somatosensory cortex, a second measurement was performed at TE = 144 ms to mainly extract the total N-acetyl-aspartate (tNAA) signal besides the signals for total creatine (tCr) and total choline (tCho). The cerebellar neurochemical profile revealed a decrease in glutathione (6.12E-06 ± 2.50E-06 versus 8.91E-06 ± 3.03E-06; p = 0028) and tNAA (3.78E-05 ± 5.67E-06 versus 4.25E-05 ± 5.15E-06; p = 0023) and a trend for reduced glutamate (2.63E-05 ± 6.48E-06 versus 3.15E-05 ± 7.61E-06; p = 0062) in SCA14 compared to controls. In the tNAA-focused measurement, cerebellar tNAA (296.6 ± 42.6 versus 351.7 ± 16.5; p = 0004) and tCr (272.1 ± 25.2 versus 303.2 ± 31.4; p = 0004) were reduced, while the prefrontal, somatosensory and motor cortex remained unaffected compared to controls. Neuronal pathology in SCA14 detected by MR spectroscopy was restricted to the cerebellum and did not comprise cortical regions. In the cerebellum, we found in addition to signs of neurodegeneration a glutathione reduction, which has been associated with cellular damage by oxidative stress in other neurodegenerative diseases such as Parkinson's disease and Friedreich's ataxia.

  3. Quantum Distinction: Quantum Distinctiones!

    OpenAIRE

    Zeps, Dainis

    2009-01-01

    10 pages; How many distinctions, in Latin, quantum distinctiones. We suggest approach of anthropic principle based on anthropic reference system which should be applied equally both in theoretical physics and in mathematics. We come to principle that within reference system of life subject of mathematics (that of thinking) should be equated with subject of physics (that of nature). For this reason we enter notions of series of distinctions, quantum distinction, and argue that quantum distinct...

  4. Neurochemical and electrical modulation of the Locus coeruleus: contribution to CO2 drive to breathe

    Directory of Open Access Journals (Sweden)

    Debora eDe Carvalho

    2014-08-01

    Full Text Available The Locus coeruleus (LC is a dorsal pontine region, situated bilaterally on the floor of the fourth ventricle. It is considered to be the major source of noradrenergic innervation in the brain. These neurons are highly sensitive to CO2 / pH, and chemical lesions of LC neurons largely attenuate the hypercapnic ventilatory response in unanesthetized adult rats. Developmental dysfunctions in these neurons are linked to pathological conditions such as Rett and sudden infant death syndromes, which can impair the control of the cardio-respiratory system. LC is densely innervated by fibers that contain glutamate, serotonin and ATP, and these neurotransmitters strongly affect LC activity, including central chemoreflexes. Aside from neurochemical modulation, LC neurons are also strongly electrically coupled, specifically through gap junctions, which play a role in the CO2 ventilatory response. This article reviews the available data on the role of chemical and electrical neuromodulation of the LC in the control of ventilation.

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

    DEFF Research Database (Denmark)

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

    2007-01-01

    , 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...

  6. Antipsychotics promote GABAergic interneuron genesis in the adult rat brain: Role of heat-shock protein production.

    Science.gov (United States)

    Kaneta, Hiroo; Ukai, Wataru; Tsujino, Hanako; Furuse, Kengo; Kigawa, Yoshiyasu; Tayama, Masaya; Ishii, Takao; Hashimoto, Eri; Kawanishi, Chiaki

    2017-09-01

    Current antipsychotics reduce positive symptoms and reverse negative symptoms in conjunction with cognitive behavioral issues with the goal of restoring impaired occupational and social functioning. However, limited information is available on their influence on gliogenesis or their neurogenic properties in adult schizophrenia brains, particularly on GABAergic interneuron production. In the present study, we used young adult subventricular zone (SVZ)-derived progenitor cells expressing proteoglycan NG2 cultures to examine the oligodendrocyte and GABAergic interneuron genesis effects of several kinds of antipsychotics on changes in differentiation function induced by exposure to the NMDA receptor antagonist MK-801. We herein demonstrated that antipsychotics promoted or restored changes in the oligodendrocyte/GABAergic interneuron differentiation functions of NG2(+) cells induced by the exposure to MK-801, which was considered to be one of the drug-induced schizophrenia model. We also demonstrated that antipsychotics restored heat-shock protein (HSP) production in NG2(+) cells with differentiation impairment. The antipsychotics olanzapine, aripiprazole, and blonanserin, but not haloperidol increased HSP90 levels, which were reduced by the exposure to MK-801. Our results showed that antipsychotics, particularly those recently synthesized, exerted similar GABAergic interneuron genesis effects on NG2(+) neuronal/glial progenitor cells in the adult rat brain by increasing cellular HSP production, and also suggest that HSP90 may play a crucial role in the pathophysiology of schizophrenia and is a key target for next drug development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Representation of behaviourally relevant information by blowfly motion-sensitive visual interneurons requires precise compensatory head movements

    NARCIS (Netherlands)

    Kern, R.; Hateren, J.H. van; Egelhaaf, M.

    2006-01-01

    Flying blowflies shift their gaze by saccadic turns of body and head, keeping their gaze basically fixed between saccades. For the head, this results in almost pure translational optic flow between saccades, enabling visual interneurons in the fly motion pathway to extract information about

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Ca2+ -Mediated Plateau Potentials in a Subpopulation of Interneurons in the Ventral Horn of the Turtle Spinal Cord

    DEFF Research Database (Denmark)

    Hounsgaard, J.; Kjaerulff, O.

    1992-01-01

    The response properties of interneurons in the ventral horn were studied in transverse slices of segments D8 to S2 from the turtle spinal cord, using the current clamp technique. In about half of the neurons the response properties were dominated by their ability to generate plateau potentials...

  10. Neurochemical changes in the hippocampus and prefrontal cortex associated with electroacupuncture for learning and memory impairment.

    Science.gov (United States)

    He, Jian; Zhao, Congkuai; Liu, Weilin; Huang, Jia; Liang, Shengxiang; Chen, Lidian; Tao, Jing

    2018-02-01

    Electroacupuncture (EA) has been widely used to treat cognitive impairment following cerebral ischemia. However, the functional mechanisms of EA have not been fully elucidated. The aim of the present study was to investigate whether EA at the GV 20 and DU 24 acupoints can improve the learning and memory ability via alteration of the neurochemical metabolism in the hippocampus (HPC) and prefrontal cortex (PFC) of rats with ischemia and reperfusion (I/R) injury. Sprague‑Dawley male rats were randomly divided into three groups, namely the sham group (n=12), the middle cerebral artery occlusion (MCAO) group (n=12) and the EA treatment (MCAO + EA) group (n=12). MCAO was performed to establish the left focal cerebral I/R injury model, and the GV 20 and DU 24 acupoints were then stimulated with EA for 30 min per time, once daily, for 7 consecutive days. The Morris water maze (MWM) test was used to assess learning and memory ability. T2‑weighted imaging was used to assess the cerebral infarct volume. Magnetic resonance spectroscopy was used to assess neurochemical metabolism of HPC and PFC. The neurological scores of the MCAO + EA group were significantly reduced compared with those of the MCAO group 7 days after EA treatment (Pplatform area was significantly higher in the MCAO + EA group compared with that in the MCAO group (P0.05). The ratios of NAA/Cr, Cho/Cr and Glu/Cr of left‑to‑right PFC were elevated (Plearning and memory ability, possibly through increasing the levels of NAA and Cho in the HPC and PFC of rats with I/R injury.

  11. Changes in neurochemicals within the ventrolateral medullary respiratory column in awake goats after carotid body denervation

    Science.gov (United States)

    Miller, Justin Robert; Neumueller, Suzanne; Muere, Clarissa; Olesiak, Samantha; Pan, Lawrence; Hodges, Matthew R.

    2013-01-01

    A current and major unanswered question is why the highly sensitive central CO2/H+ chemoreceptors do not prevent hypoventilation-induced hypercapnia following carotid body denervation (CBD). Because perturbations involving the carotid bodies affect central neuromodulator and/or neurotransmitter levels within the respiratory network, we tested the hypothesis that after CBD there is an increase in inhibitory and/or a decrease in excitatory neurochemicals within the ventrolateral medullary column (VMC) in awake goats. Microtubules for chronic use were implanted bilaterally in the VMC within or near the pre-Bötzinger Complex (preBötC) through which mock cerebrospinal fluid (mCSF) was dialyzed. Effluent mCSF was collected and analyzed for neurochemical content. The goats hypoventilated (peak +22.3 ± 3.4 mmHg PaCO2) and exhibited a reduced CO2 chemoreflex (nadir, 34.8 ± 7.4% of control ΔV̇E/ΔPaCO2) after CBD with significant but limited recovery over 30 days post-CBD. After CBD, GABA and glycine were above pre-CBD levels (266 ± 29% and 189 ± 25% of pre-CBD; P 0.05) different from control after CBD. Analyses of brainstem tissues collected 30 days after CBD exhibited 1) a midline raphe-specific reduction (P < 0.05) in the percentage of tryptophan hydroxylase–expressing neurons, and 2) a reduction (P < 0.05) in serotonin transporter density in five medullary respiratory nuclei. We conclude that after CBD, an increase in inhibitory neurotransmitters and a decrease in excitatory neuromodulation within the VMC/preBötC likely contribute to the hypoventilation and attenuated ventilatory CO2 chemoreflex. PMID:23869058

  12. REM sleep deprivation reverses neurochemical and other depressive-like alterations induced by olfactory bulbectomy.

    Science.gov (United States)

    Maturana, Maira J; Pudell, Cláudia; Targa, Adriano D S; Rodrigues, Laís S; Noseda, Ana Carolina D; Fortes, Mariana H; Dos Santos, Patrícia; Da Cunha, Cláudio; Zanata, Sílvio M; Ferraz, Anete C; Lima, Marcelo M S

    2015-02-01

    There is compelling evidence that sleep deprivation (SD) is an effective strategy in promoting antidepressant effects in humans, whereas few studies were performed in relevant animal models of depression. Acute administration of antidepressants in humans and rats generates a quite similar effect, i.e., suppression of rapid eye movement (REM) sleep. Then, we decided to investigate the neurochemical alterations generated by a protocol of rapid eye movement sleep deprivation (REMSD) in the notably known animal model of depression induced by the bilateral olfactory bulbectomy (OBX). REMSD triggered antidepressant mechanisms such as the increment of brain-derived neurotrophic factor (BDNF) levels, within the substantia nigra pars compacta (SNpc), which were strongly correlated to the swimming time (r = 0.83; P < 0.0001) and hippocampal serotonin (5-HT) content (r = 0.66; P = 0.004). Moreover, there was a strong correlation between swimming time and hippocampal 5-HT levels (r = 0.70; P = 0.003), strengthen the notion of an antidepressant effect associated to REMSD in the OBX rats. In addition, REMSD robustly attenuated the hippocampal 5-HT deficiency produced by the OBX procedure. Regarding the rebound (REB) period, we observed the occurrence of a sustained antidepressant effect, indicated mainly by the swimming and climbing times which could be explained by the maintenance of the increased nigral BDNF expression. Hence, hippocampal 5-HT levels remained enhanced in the OBX group after this period. We suggested that the neurochemical complexity inflicted by the OBX model, counteracted by REMSD, is directly correlated to the nigral BDNF expression and hippocampal 5-HT levels. The present findings provide new information regarding the antidepressant mechanisms triggered by REMSD.

  13. Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress

    Science.gov (United States)

    Dolzani, Samuel D.; Tilden, Scott; Christianson, John P.; Kubala, Kenneth H.; Bartholomay, Kristi; Sperr, Katherine; Ciancio, Nicholas; Watkins, Linda R.; Maier, Steven F.

    2016-01-01

    Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochemical and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5-HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 week, or 2 weeks before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addition, ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacological inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection. SIGNIFICANCE STATEMENT The reported data show that systemic ketamine, given up to 2 weeks before a stressor, blunts behavioral and neurochemical effects of the stressor. The study also advances understanding of the mechanisms involved and suggests that ketamine acts at the prelimbic cortex to sensitize neurons that project to and inhibit the DRN. PMID:26740657

  14. Rapid sensing of l-leucine by human and murine hypothalamic neurons: Neurochemical and mechanistic insights.

    Science.gov (United States)

    Heeley, Nicholas; Kirwan, Peter; Darwish, Tamana; Arnaud, Marion; Evans, Mark L; Merkle, Florian T; Reimann, Frank; Gribble, Fiona M; Blouet, Clemence

    2018-02-07

    Dietary proteins are sensed by hypothalamic neurons and strongly influence multiple aspects of metabolic health, including appetite, weight gain, and adiposity. However, little is known about the mechanisms by which hypothalamic neural circuits controlling behavior and metabolism sense protein availability. The aim of this study is to characterize how neurons from the mediobasal hypothalamus respond to a signal of protein availability: the amino acid l-leucine. We used primary cultures of post-weaning murine mediobasal hypothalamic neurons, hypothalamic neurons derived from human induced pluripotent stem cells, and calcium imaging to characterize rapid neuronal responses to physiological changes in extracellular l-Leucine concentration. A neurochemically diverse subset of both mouse and human hypothalamic neurons responded rapidly to l-leucine. Consistent with l-leucine's anorexigenic role, we found that 25% of mouse MBH POMC neurons were activated by l-leucine. 10% of MBH NPY neurons were inhibited by l-leucine, and leucine rapidly reduced AGRP secretion, providing a mechanism for the rapid leucine-induced inhibition of foraging behavior in rodents. Surprisingly, none of the candidate mechanisms previously implicated in hypothalamic leucine sensing (K ATP channels, mTORC1 signaling, amino-acid decarboxylation) were involved in the acute activity changes produced by l-leucine. Instead, our data indicate that leucine-induced neuronal activation involves a plasma membrane Ca 2+ channel, whereas leucine-induced neuronal inhibition is mediated by inhibition of a store-operated Ca 2+ current. A subset of neurons in the mediobasal hypothalamus rapidly respond to physiological changes in extracellular leucine concentration. Leucine can produce both increases and decreases in neuronal Ca 2+ concentrations in a neurochemically-diverse group of neurons, including some POMC and NPY/AGRP neurons. Our data reveal that leucine can signal through novel mechanisms to rapidly

  15. Sensory receptors in the visceral pleura: neurochemical coding and live staining in whole mounts.

    Science.gov (United States)

    Pintelon, Isabel; Brouns, Inge; De Proost, Ian; Van Meir, Frans; Timmermans, Jean-Pierre; Adriaensen, Dirk

    2007-05-01

    Today, diagnosis and treatment of chest pain related to pathologic changes in the visceral pleura are often difficult. Data in the literature on the sensory innervation of the visceral pleura are sparse. The present study aimed at identifying sensory end-organs in the visceral pleura, and at obtaining more information about neurochemical coding. The immunocytochemcial data are mainly based on whole mounts of the visceral pleura of control and vagally denervated rats. It was shown that innervation of the rat visceral pleura is characterized by nerve bundles that enter in the hilus region and gradually split into slender bundles with a few nerve fibers. Separate nerve fibers regularly give rise to characteristic laminar terminals. Because of their unique association with the elastic fibers of the visceral pleura, we decided to refer to them as "visceral pleura receptors" (VPRs). Cryostat sections of rat lungs confirmed a predominant location on mediastinal and interlobar lung surfaces. VPRs can specifically be visualized by protein gene product 9.5 immunostaining, and were shown to express vesicular glutamate transporters, calbindin D28K, Na+/K+-ATPase, and P2X3 ATP-receptors. The sensory nerve fibers giving rise to VPRs appeared to be myelinated and to have a spinal origin. Because several of the investigated proteins have been reported as markers for sensory terminals in other organs, the present study revealed that VPRs display the neurochemical characteristics of mechanosensory and/or nociceptive terminals. The development of a live staining method, using AM1-43, showed that VPRs can be visualized in living tissue, offering an interesting model for future physiologic studies.

  16. Mercury exposure and neurochemical biomarkers in multiple brain regions of Wisconsin river otters (Lontra canadensis).

    Science.gov (United States)

    Dornbos, Peter; Strom, Sean; Basu, Niladri

    2013-04-01

    River otters are fish-eating wildlife that bioaccumulate high levels of mercury (Hg). Mercury is a proven neurotoxicant to mammalian wildlife, but little is known about the underlying, sub-clinical effects. Here, the overall goal was to increase understanding of Hg's neurological risk to otters. First, Hg values across several brain regions and tissues were characterized. Second, in three brain regions with known sensitivity to Hg (brainstem, cerebellum, and occipital cortex), potential associations among Hg levels and neurochemical biomarkers [N-methyl-D-aspartic acid (NMDA) and gamma-aminobutyric acid (GABAA) receptor] were explored. There were no significant differences in Hg levels across eight brain regions (rank order, highest to lowest: frontal cortex, cerebellum, temporal cortex, occipital cortex, parietal cortex, basal ganglia, brainstem, and thalamus), with mean values ranging from 0.7 to 1.3 ug/g dry weight. These brain levels were significantly lower than mean values in the muscle (2.1 ± 1.4 ug/g), liver (4.7 ± 4.3 ug/g), and fur (8.8 ± 4.8 ug/g). While a significant association was found between Hg and NMDA receptor levels in the brain stem (P = 0.028, rp = -0.293), no relationships were found in the cerebellum and occipital cortex. For the GABA receptor, no relationships were found. The lack of consistent Hg-associated neurochemical changes is likely due to low brain Hg levels in these river otters, which are amongst the lowest reported.

  17. The trace amine-associated receptor 1 modulates methamphetamine’s neurochemical and behavioural effects

    Directory of Open Access Journals (Sweden)

    Rachel eCotter

    2015-02-01

    Full Text Available The newly discovered trace amine-associated receptor 1 (TAAR1 has the ability to regulate both dopamine function and psychostimulant action. Here, we tested in rats the ability of RO5203648, a selective TAAR1 partial agonist, to modulate the physiological and behavioural effects of methamphetamine (METH. In experiment 1, RO5203468 dose- and time-dependently altered METH-induced locomotor activity, manifested as an early attenuation followed by a late potentiation of METH’s stimulating effects. In experiment 2, rats received a 14-day treatment regimen during which RO5203648 was co-administered with METH. RO5203648 dose-dependently attenuated METH-stimulated hyperactivity, with the effects becoming more apparent as the treatments progressed. After chronic exposure and 3-day withdrawal, rats were tested for locomotor sensitization. RO5203648 administration during the sensitizing phase prevented the development of METH sensitization. However, RO5203648, at the high dose, cross-sensitized with METH. In experiment 3, RO5203648 dose-dependently blocked METH self-administration without affecting operant responding maintained by sucrose, and exhibited lack of reinforcing efficacy when tested as a METH’s substitute. Neurochemical data showed that RO5203648 did not affect METH-mediated DA efflux and uptake inhibition in striatal synaptosomes. In vivo, however, RO5203648 was able to transiently inhibit METH-induced accumulation of extracellular DA levels in the nucleus accumbens. Taken together, these data highlight the significant potential of TAAR1 to modulate METH’s neurochemical and behavioural effects.

  18. White noise analysis of graded response in a wind-sensitive, nonspiking interneuron of the cockroach.

    Science.gov (United States)

    Kondoh, Y; Morishita, H; Arima, T; Okuma, J; Hasegawa, Y

    1991-04-01

    1. A novel approach using a Gaussian white noise as stimulus is described which allowed quantitative analysis of neuronal responses in the cercal system of the cockroach, Periplaneta americana. Cerci were stimulated by air displacement which was modulated by a sinusoidal and a white noise signal. During the stimulation, intracellular recordings were made from a uniquely identifiable, nonspiking, local interneuron which locates within the terminal abdominal ganglion. The white noise stimulation was cross-correlated with the evoked response to compute first- and second-order kernels that could define the cell's response dynamics. 2. The interneuron, cell 101, has an exceptionally large transverse neurite that connects two asymmetrical dendritic arborizations located on both sides of the ganglion. 3. The first-order Wiener kernels in cell 101 were biphasic (differentiating). The waveforms of the kernels produced by the ipsilateral and contralateral stimulations were roughly mirror images of each other: the kernels produced by wind stimuli on the side ipsilateral to the cell body of the interneuron are initially depolarized and then hyperpolarized, whereas those on the other side are initially hyperpolarized. The polarity reversal occurred along the midline of the animal's body, and no well-defined kernel was produced by a stimulus directed head on or from the tail. 4. Mean square error (MSE) between the actual response and the model prediction suggests that the linear component in cell 101 comprises half of the cell's total response (MSEs for the linear models were about 50% at preferred directions), whereas the second-order, non-linear component is insignificant. The linear component of the wind-evoked response was bandpass with the preferred frequency of 70-90 Hz. 5. Accounting for a noise, we reasonably assumed that at high frequencies the graded response in cell 101 is linearly related to a modulation of the air displacement and sensitive to the rate of change of

  19. Wireless Instantaneous Neurotransmitter Concentration System-based amperometric detection of dopamine, adenosine, and glutamate for intraoperative neurochemical monitoring.

    Science.gov (United States)

    Agnesi, Filippo; Tye, Susannah J; Bledsoe, Jonathan M; Griessenauer, Christoph J; Kimble, Christopher J; Sieck, Gary C; Bennet, Kevin E; Garris, Paul A; Blaha, Charles D; Lee, Kendall H

    2009-10-01

    In a companion study, the authors describe the development of a new instrument named the Wireless Instantaneous Neurotransmitter Concentration System (WINCS), which couples digital telemetry with fast-scan cyclic voltammetry (FSCV) to measure extracellular concentrations of dopamine. In the present study, the authors describe the extended capability of the WINCS to use fixed potential amperometry (FPA) to measure extracellular concentrations of dopamine, as well as glutamate and adenosine. Compared with other electrochemical techniques such as FSCV or high-speed chronoamperometry, FPA offers superior temporal resolution and, in combination with enzyme-linked biosensors, the potential to monitor nonelectroactive analytes in real time. The WINCS design incorporated a transimpedance amplifier with associated analog circuitry for FPA; a microprocessor; a Bluetooth transceiver; and a single, battery-powered, multilayer, printed circuit board. The WINCS was tested with 3 distinct recording electrodes: 1) a carbon-fiber microelectrode (CFM) to measure dopamine; 2) a glutamate oxidase enzyme-linked electrode to measure glutamate; and 3) a multiple enzyme-linked electrode (adenosine deaminase, nucleoside phosphorylase, and xanthine oxidase) to measure adenosine. Proof-of-principle analyses included noise assessments and in vitro and in vivo measurements that were compared with similar analyses by using a commercial hardwired electrochemical system (EA161 Picostat, eDAQ; Pty Ltd). In urethane-anesthetized rats, dopamine release was monitored in the striatum following deep brain stimulation (DBS) of ascending dopaminergic fibers in the medial forebrain bundle (MFB). In separate rat experiments, DBS-evoked adenosine release was monitored in the ventrolateral thalamus. To test the WINCS in an operating room setting resembling human neurosurgery, cortical glutamate release in response to motor cortex stimulation (MCS) was monitored using a large-mammal animal model, the pig. The

  20. 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.

  1. 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.

  2. 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.

  3. Serotonin immunoreactive interneurons in the brain of the Remipedia: new insights into the phylogenetic affinities of an enigmatic crustacean taxon.

    Science.gov (United States)

    Stemme, Torben; Iliffe, Thomas M; Bicker, Gerd; Harzsch, Steffen; Koenemann, Stefan

    2012-09-05

    Remipedia, a group of homonomously segmented, cave-dwelling, eyeless arthropods have been regarded as basal crustaceans in most early morphological and taxonomic studies. However, molecular sequence information together with the discovery of a highly differentiated brain led to a reconsideration of their phylogenetic position. Various conflicting hypotheses have been proposed including the claim for a basal position of Remipedia up to a close relationship with Malacostraca or Hexapoda. To provide new morphological characters that may allow phylogenetic insights, we have analyzed the architecture of the remipede brain in more detail using immunocytochemistry (serotonin, acetylated α-tubulin, synapsin) combined with confocal laser-scanning microscopy and image reconstruction techniques. This approach allows for a comprehensive neuroanatomical comparison with other crustacean and hexapod taxa. The dominant structures of the brain are the deutocerebral olfactory neuropils, which are linked by the olfactory globular tracts to the protocerebral hemiellipsoid bodies. The olfactory globular tracts form a characteristic chiasm in the center of the brain. In Speleonectes tulumensis, each brain hemisphere contains about 120 serotonin immunoreactive neurons, which are distributed in distinct cell groups supplying fine, profusely branching neurites to 16 neuropilar domains. The olfactory neuropil comprises more than 300 spherical olfactory glomeruli arranged in sublobes. Eight serotonin immunoreactive neurons homogeneously innervate the olfactory glomeruli. In the protocerebrum, serotonin immunoreactivity revealed several structures, which, based on their position and connectivity resemble a central complex comprising a central body, a protocerebral bridge, W-, X-, Y-, Z-tracts, and lateral accessory lobes. The brain of Remipedia shows several plesiomorphic features shared with other Mandibulata, such as deutocerebral olfactory neuropils with a glomerular organization

  4. Serotonin immunoreactive interneurons in the brain of the Remipedia: new insights into the phylogenetic affinities of an enigmatic crustacean taxon

    Directory of Open Access Journals (Sweden)

    Stemme Torben

    2012-09-01

    Full Text Available Abstract Background Remipedia, a group of homonomously segmented, cave-dwelling, eyeless arthropods have been regarded as basal crustaceans in most early morphological and taxonomic studies. However, molecular sequence information together with the discovery of a highly differentiated brain led to a reconsideration of their phylogenetic position. Various conflicting hypotheses have been proposed including the claim for a basal position of Remipedia up to a close relationship with Malacostraca or Hexapoda. To provide new morphological characters that may allow phylogenetic insights, we have analyzed the architecture of the remipede brain in more detail using immunocytochemistry (serotonin, acetylated α-tubulin, synapsin combined with confocal laser-scanning microscopy and image reconstruction techniques. This approach allows for a comprehensive neuroanatomical comparison with other crustacean and hexapod taxa. Results The dominant structures of the brain are the deutocerebral olfactory neuropils, which are linked by the olfactory globular tracts to the protocerebral hemiellipsoid bodies. The olfactory globular tracts form a characteristic chiasm in the center of the brain. In Speleonectes tulumensis, each brain hemisphere contains about 120 serotonin immunoreactive neurons, which are distributed in distinct cell groups supplying fine, profusely branching neurites to 16 neuropilar domains. The olfactory neuropil comprises more than 300 spherical olfactory glomeruli arranged in sublobes. Eight serotonin immunoreactive neurons homogeneously innervate the olfactory glomeruli. In the protocerebrum, serotonin immunoreactivity revealed several structures, which, based on their position and connectivity resemble a central complex comprising a central body, a protocerebral bridge, W-, X-, Y-, Z-tracts, and lateral accessory lobes. Conclusions The brain of Remipedia shows several plesiomorphic features shared with other Mandibulata, such as deutocerebral

  5. 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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  9. Spatiotemporal alterations of cortical network activity by selective loss of NOS-expressing interneurons .

    Directory of Open Access Journals (Sweden)

    Dan eShlosberg

    2012-02-01

    Full Text Available Deciphering the role of GABAergic neurons in large neuronal networks such as the neocortex forms a particularly complex task as they comprise a highly diverse population. The neuronal isoform of the enzyme nitric oxide synthase (nNOS is expressed in the neocortex by specific subsets of GABAergic neurons. These neurons can be identified in live brain slices by the nitric oxide (NO fluorescent indicator DAF-2DA. However, this indicator was found to be highly toxic to the stained neurons. We used this feature to induce acute phototoxic damage to NO-producing neurons in cortical slices, and measured subsequent alterations in parameters of cellular and network activity.Neocortical slices were briefly incubated in DAF-2DA and then illuminated through the 4X objective. Histochemistry for NADPH diaphorase, a marker for nNOS activity, revealed elimination of staining in the illuminated areas following treatment. Whole cell recordings from several neuronal types before, during and after illumination confirmed the selective damage to non fast-spiking interneurons. Treated slices displayed mild disinhibition. The reversal potential of compound synaptic events on pyramidal neurons became more positive, and their decay time constant was elongated, substantiating the removal of an inhibitory conductance. The horizontal decay of local field potentials (LFPs was significantly reduced at distances of 300-400 m from the stimulation, but not when inhibition was non-selectively weakened with the GABAA blocker picrotoxin. Finally, whereas the depression of LFPs along short trains of 40 Hz stimuli was linearly reduced with distance or initial amplitude in control slices, this ordered relationship was disrupted in DAF-treated slices. These results reveal that NO-producing interneurons in the neocortex convey lateral inhibition to neighboring columns, and shape the spatiotemporal dynamics of the network's activity.

  10. Pax3- and Pax7-mediated Dbx1 regulation orchestrates the patterning of intermediate spinal interneurons.

    Science.gov (United States)

    Gard, Chris; Gonzalez Curto, Gloria; Frarma, Youcef El-Mokhtar; Chollet, Elodie; Duval, Nathalie; Auzié, Valentine; Auradé, Frédéric; Vigier, Lisa; Relaix, Frédéric; Pierani, Alessandra; Causeret, Frédéric; Ribes, Vanessa

    2017-06-16

    Transcription factors are key orchestrators of the emergence of neuronal diversity within the developing spinal cord. As such, the two paralogous proteins Pax3 and Pax7 regulate the specification of progenitor cells within the intermediate neural tube, by defining a neat segregation between those fated to form motor circuits and those involved in the integration of sensory inputs. To attain insights into the molecular means by which they control this process, we have performed detailed phenotypic analyses of the intermediate spinal interneurons (IN), namely the dI6, V0D, V0VCG and V1 populations in compound null mutants for Pax3 and Pax7. This has revealed that the levels of Pax3/7 proteins determine both the dorso-ventral extent and the number of cells produced in each subpopulation; with increasing levels leading to the dorsalisation of their fate. Furthermore, thanks to the examination of mutants in which Pax3 transcriptional activity is skewed either towards repression or activation, we demonstrate that this cell diversification process is mainly dictated by Pax3/7 ability to repress gene expression. Consistently, we show that Pax3 and Pax7 inhibit the expression of Dbx1 and of its repressor Prdm12, fate determinants of the V0 and V1 interneurons, respectively. Notably, we provide evidence for the activity of several cis-regulatory modules of Dbx1 to be sensitive to Pax3 and Pax7 transcriptional activity levels. Altogether, our study provides insights into how the redundancy within a TF family, together with discrete dynamics of expression profiles of each member, are exploited to generate cellular diversity. Furthermore, our data supports the model whereby cell fate choices in the neural tube do not rely on binary decisions but rather on inhibition of multiple alternative fates. Copyright © 2017. Published by Elsevier Inc.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Chronic alcohol consumption leads to neurochemical changes in the nucleus accumbens that are not fully reversed by withdrawal.

    Science.gov (United States)

    Pereira, Pedro A; Neves, João; Vilela, Manuel; Sousa, Sérgio; Cruz, Catarina; Madeira, M Dulce

    2014-01-01

    Neuropeptide Y (NPY)- and acetylcholine-containing interneurons of the nucleus accumbens (NAc) seem to play a major role in the rewarding effects of alcohol. This study investigated the relationship between chronic alcohol consumption and subsequent withdrawal and the expression of NPY and acetylcholine in the NAc, and the possible involvement of nerve growth factor (NGF) in mediating the effects of ethanol. Rats ingesting an aqueous ethanol solution over 6months and rats subsequently deprived from ethanol during 2months were used to estimate the total number and the somatic volume of NPY and cholinergic interneurons, and the numerical density of cholinergic varicosities in the NAc. The tissue content of choline acetyltransferase (ChAT) and catecholamines were also determined. The number of NPY interneurons increased during alcohol ingestion and returned to control values after withdrawal. Conversely, the number and the size of cholinergic interneurons, and the amount of ChAT were unchanged in ethanol-treated and withdrawn rats, but the density of cholinergic varicosities was reduced by 50% during alcohol consumption and by 64% after withdrawal. The concentrations of dopamine and norepinephrine were unchanged both during alcohol consumption and after withdrawal. The administration of NGF to withdrawn rats significantly increased the number of NPY-immunoreactive neurons, the size of cholinergic neurons and the density of cholinergic varicosities. Present data show that chronic alcohol consumption leads to long-lasting neuroadaptive changes of the cholinergic innervation of the NAc and suggest that the cholinergic system is a potential target for the development of therapeutic strategies in alcoholism and abstinence. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Vanillin Attenuated Behavioural Impairments, Neurochemical Deficts, Oxidative Stress and Apoptosis Against Rotenone Induced Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Dhanalakshmi, Chinnasamy; Janakiraman, Udaiyappan; Manivasagam, Thamilarasan; Justin Thenmozhi, Arokiasamy; Essa, Musthafa Mohamed; Kalandar, Ameer; Khan, Mohammed Abdul Sattar; Guillemin, Gilles J

    2016-08-01

    Vanillin (4-hydroxy-3-methoxybenzaldehyde), a pleasant smelling organic aromatic compound, is widely used as a flavoring additive in food, beverage, cosmetic and drug industries. It is reported to cross the blood brain barrier and also displayed antioxidant and neuroprotective activities. We previously reported the neuroprotective effect of vanillin against rotenone induced in in vitro model of PD. The present experiment was aimed to analyze the neuroprotective effect of vanillin on the motor and non-motor deficits, neurochemical variables, oxidative, anti-oxidative indices and the expression of apoptotic markers against rotenone induced rat model of Parkinson's disease (PD). Rotenone treatment exhibited motor and non-motor impairments, neurochemical deficits, oxidative stress and apoptosis, whereas oral administration of vanillin attenuated the above-said indices. However further studies are needed to explore the mitochondrial protective and anti-inflammatory properties of vanillin, as these processes play a vital role in the cause and progression of PD.

  14. Do premotor interneurons act in parallel on spinal motoneurons and on dorsal horn spinocerebellar and spinocervical tract neurons in the cat?

    Science.gov (United States)

    Krutki, Piotr; Jelen, Sabina

    2011-01-01

    It has previously been established that ventral spinocerebellar tract (VSCT) neurons and dorsal spinocerebellar tract neurons located in Clarke's column (CC DSCT neurons) forward information on actions of premotor interneurons in reflex pathways from muscle afferents on α-motoneurons. Whether DSCT neurons located in the dorsal horn (dh DSCT neurons) and spinocervical tract (SCT) neurons are involved in forwarding similar feedback information has not yet been investigated. The aim of the present study was therefore to examine the input from premotor interneurons to these neurons. Electrical stimuli were applied within major hindlimb motor nuclei to activate axon-collaterals of interneurons projecting to these nuclei, and intracellular records were obtained from dh DSCT and SCT neurons. Direct actions of the stimulated interneurons were differentiated from indirect actions by latencies of postsynaptic potentials evoked by intraspinal stimuli and by the absence or presence of temporal facilitation. Direct actions of premotor interneurons were found in a smaller proportion of dh DSCT than of CC DSCT neurons. However, they were evoked by both excitatory and inhibitory interneurons, whereas only inhibitory premotor interneurons were previously found to affect CC DSCT neurons [as indicated by monosynaptic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) in dh DSCT and only IPSPs in CC DSCT neurons]. No effects of premotor interneurons were found in SCT neurons, since monosynaptic EPSPs or IPSPs were only evoked in them by stimuli applied outside motor nuclei. The study thus reveals a considerable differentiation of feedback information provided by different populations of ascending tract neurons. PMID:21273308

  15. From genes to behavior: investigations of neurochemical signaling come of age for the model crustacean Daphnia pulex.

    Science.gov (United States)

    Christie, Andrew E; McCoole, Matthew D

    2012-08-01

    The cladoceran crustacean Daphnia pulex has served as a standard organism for aquatic toxicity testing for decades. The model organism status of D. pulex rests largely on its remarkable ability to rapidly adapt morphologically, physiologically and behaviorally to a wide range of environmental challenges, as well as on its parthenogenetic reproduction and ease of laboratory culture. As in all multicellular organisms, neurochemical control systems are undoubtedly major contributors to the functional flexibility of Daphnia. Surprisingly, little work has focused on understanding its neurochemistry at any level. Recently, D. pulex has been the subject of extensive genome and transcriptome sequencing, and it is currently the only crustacean with a fully sequenced, publicly accessible genome. Although the molecular work was initiated for gene-based investigations of ecotoxicology and toxicogenomics, the data generated have allowed for investigations into numerous aspects of Daphnia biology, including its neurochemical signaling. This Commentary summarizes our knowledge of D. pulex neurochemistry obtained from recent genomic and transcriptomic studies, and places these data in context with other anatomical, biochemical and physiological experiments using D. pulex and its sister species Daphnia magna. Suggestions as to how the Daphnia molecular data may be useful for future investigations of crustacean neurochemical signaling are also provided.

  16. Piperine Augments the Protective Effect of Curcumin Against Lipopolysaccharide-Induced Neurobehavioral and Neurochemical Deficits in Mice.

    Science.gov (United States)

    Jangra, Ashok; Kwatra, Mohit; Singh, Tavleen; Pant, Rajat; Kushwah, Pawan; Sharma, Yogita; Saroha, Babita; Datusalia, Ashok Kumar; Bezbaruah, Babul Kumar

    2016-06-01

    The aim of the present study was to investigate the protective effects of curcumin alone and in combination with piperine against lipopolysaccharide (LPS)-induced neurobehavioral and neurochemical deficits in the mice hippocampus. Mice were treated with curcumin (100, 200, and 400 mg/kg, p.o.) and piperine (20 mg/kg, p.o.) for 7 days followed by LPS (0.83 mg/kg, i.p.) administration. Animals exhibited anxiety and depressive-like phenotype after 3 and 24 h of LPS exposure, respectively. LPS administration increased the oxido-nitrosative stress as evident by elevated levels of malondialdehyde, nitrite, and depletion of glutathione level in the hippocampus. Furthermore, we found raised level of pro-inflammatory cytokines (IL-1β and TNF-α) in the hippocampus of LPS-treated mice. Pretreatment with curcumin alleviated LPS-induced neurobehavioral and neurochemical deficits. Furthermore, co-administration of curcumin with piperine significantly potentiated the neuroprotective effect of curcumin. These results demonstrate that piperine enhanced the neuroprotective effect of curcumin against LPS-induced neurobehavioral and neurochemical deficits.

  17. Convergence of ipsi- and contralateral muscle afferents on common interneurons mediating reciprocal inhibition of ankle plantarflexors in humans

    DEFF Research Database (Denmark)

    Mrachacz-Kersting, Natalie; Geertsen, Svend S.; Stevenson, Andrew James Thomas

    2017-01-01

    Recent studies have shown that afferents arising from muscle receptors located on one side can affect the activity of muscles on the contralateral side. In animal preparations, evidence supports that afferent pathways originating from one limb converge onto interneurons mediating disynaptic...... reciprocal Ia inhibition of the opposite limb. This study was designed to investigate whether this pathway is similar in humans to that described in animals. Thirteen healthy volunteers participated in one of two experiments. In experiment 1, the effects of ipsilateral posterior tibial nerve (i...... induced a significantly greater inhibition compared to their separate effects. These data provide evidence of convergence on common inhibitory interneurons by muscle afferents activated by iPTN and cCPN stimulation during sitting. Since the inhibition elicited by cCPN stimulation is known to be mediated...

  18. 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.

  19. Effects of melatonin on aluminium-induced neurobehavioral and neurochemical changes in aging rats.

    Science.gov (United States)

    Allagui, M S; Feriani, A; Saoudi, M; Badraoui, R; Bouoni, Z; Nciri, R; Murat, J C; Elfeki, A

    2014-08-01

    This study aimed to investigate the potential protective effects of melatonin (Mel) against aluminium-induced neurodegenerative changes in aging Wistar rats (24-28months old). Herein, aluminium chloride (AlCl3) (50mg/kg BW/day) was administered by gavage, and melatonin (Mel) was co-administered to a group of Al-treated rats by an intra-peritoneal injection at a daily dose of 10mg/kg BW for four months. The findings revealed that aluminium administration induced a significant decrease in body weight associated with marked mortality for the old group of rats, which was more pronounced in old Al-treated rats. Behavioural alterations were assessed by 'open fields', 'elevated plus maze' and 'Radial 8-arms maze' tests. The results demonstrated that Mel co-administration alleviated neurobehavioral changes in both old and old Al-treated rats. Melatonin was noted to play a good neuroprotective role, reducing lipid peroxidation (TBARs), and enhancing enzymatic (SOD, CAT and GPx) activities in the brain organs of old control and old Al-treated rats. Mel treatment also reversed the decrease of AChE activity in the brain tissues, which was confirmed by histological sections. Overall, the results showed that Mel administration can induce beneficial effects for the treatment of Al-induced neurobehavioral and neurochemical changes in the central nervous system (CNS). Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioural, and neurotoxic effects of methamphetamine

    Science.gov (United States)

    Weinshenker, David; Ferrucci, Michela; Busceti, Carla L.; Biagioni, Francesca; Lazzeri, Gloria; Liles, L. Cameron; Lenzi, Paola; Murri, Luigi; Paparelli, Antonio; Fornai, Francesco

    2008-01-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus (LC), the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine β-hydroxylase; DBH). We found that genetic deletion of DBH (DBH −/− mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioural stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioural, and neurotoxic effects of METH. PMID:18042179

  1. Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine.

    Science.gov (United States)

    Weinshenker, David; Ferrucci, Michela; Busceti, Carla L; Biagioni, Francesca; Lazzeri, Gloria; Liles, L Cameron; Lenzi, Paola; Pasquali, Livia; Murri, Luigi; Paparelli, Antonio; Fornai, Francesco

    2008-04-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus, the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine beta-hydroxylase; DBH). We found that genetic deletion of DBH (DBH-/- mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioral stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioral, and neurotoxic effects of METH.

  2. ETIOLOGY, TRIGGERS AND NEUROCHEMICAL CIRCUITS ASSOCIATED WITH UNEXPECTED, EXPECTED, AND LABORATORY-INDUCED PANIC ATTACKS

    Science.gov (United States)

    Johnson, Philip L.; Federici, Lauren M.; Shekhar, Anantha

    2014-01-01

    Panic disorder (PD) is a severe anxiety disorder that is characterized by recurrent panic attacks (PA), which can be unexpected (uPA, i.e., no clear identifiable trigger) or expected (ePA). Panic typically involves an abrupt feeling of catastrophic fear or distress accompanied by physiological symptoms such as palpitations, racing heart, thermal sensations, and sweating. Recurrent uPA and ePA can also lead to agoraphobia, where subjects with PD avoid situations that were associated with PA. Here we will review recent developments in our understanding of PD, which includes discussions on: symptoms and signs associated with uPA and ePAs; Diagnosis of PD and the new DSM-V; biological etiology such as heritability and gene x environment and gene x hormonal development interactions; comparisons between laboratory and naturally occurring uPAs and ePAs; neurochemical systems that are associated with clinical PAs (e.g. gene associations; targets for triggering or treating PAs), adaptive fear and panic response concepts in the context of new NIH RDoc approach; and finally strengths and weaknesses of translational animal models of adaptive and pathological panic states. PMID:25130976

  3. Mercury exposure and neurochemical impacts in bald eagles across several Great Lakes states.

    Science.gov (United States)

    Rutkiewicz, Jennifer; Nam, Dong-Ha; Cooley, Thomas; Neumann, Kay; Padilla, Irene Bueno; Route, William; Strom, Sean; Basu, Niladri

    2011-10-01

    In this study, we assessed mercury (Hg) exposure in several tissues (brain, liver, and breast and primary feathers) in bald eagles (Haliaeetus leucocephalus) collected from across five Great Lakes states (Iowa, Michigan, Minnesota, Ohio, and Wisconsin) between 2002-2010, and assessed relationships between brain Hg and neurochemical receptors (NMDA and GABA(A)) and enzymes (glutamine synthetase (GS) and glutamic acid decarboxylase (GAD)). Brain total Hg (THg) levels (dry weight basis) averaged 2.80 μg/g (range: 0.2-34.01), and levels were highest in Michigan birds. THg levels in liver (r(p) = 0.805) and breast feathers (r(p) = 0.611) significantly correlated with those in brain. Brain Hg was not associated with binding to the GABA(A) receptor. Brain THg and inorganic Hg (IHg) were significantly positively correlated with GS activity (THg r(p) = 0.190; IHg r(p) = 0.188) and negatively correlated with NMDA receptor levels (THg r(p) = -0245; IHg r(p) = -0.282), and IHg was negatively correlated with GAD activity (r(s) = -0.196). We also report upon Hg demethylation and relationships between Hg and Se in brain and liver. These results suggest that bald eagles in the Great Lakes region are exposed to Hg at levels capable of causing subclinical neurological damage, and that when tissue burdens are related to proposed avian thresholds approximately 14-27% of eagles studied here may be at risk.

  4. Neurochemical factors underlying individual differences in locomotor activity and anxiety-like behavioral responses in zebrafish.

    Science.gov (United States)

    Tran, Steven; Nowicki, Magda; Muraleetharan, Arrujyan; Chatterjee, Diptendu; Gerlai, Robert

    2016-02-04

    Variation among individuals may arise for several reasons, and may have diverse underlying mechanisms. Individual differences have been studied in a variety of species, but recently a new model organism has emerged in this field that offers both sophistication in phenotypical characterization and powerful mechanistic analysis. Recently, zebrafish, one of the favorites of geneticists, have been shown to exhibit consistent individual differences in baseline locomotor activity. In the current study, we further explore this finding and examine whether individual differences in locomotor activity correlate with anxiety-like behavioral measures and with levels of dopamine, serotonin and the metabolites of these neurotransmitters. In addition, we examine whether individual differences in locomotor activity are also associated with reactivity to the locomotor stimulant effects of and neurochemical responses to acute ethanol exposure (30min long, 1% v/v ethanol bath application). Principal component analyses revealed a strong association among anxiety-like responses, locomotor activity, serotonin and dopamine levels. Furthermore, ethanol exposure was found to abolish the locomotion-dependent anxiety-like behavioral and serotonergic responses suggesting that this drug also engages a common underlying pathway. Overall, our results provide support for an important role of the serotonergic system in mediating individual differences in anxiety-like responses and locomotor activity in zebrafish and for a minor modulatory role of the dopaminergic system. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Curcumin ameliorates reserpine-induced pain-depression dyad: behavioural, biochemical, neurochemical and molecular evidences.

    Science.gov (United States)

    Arora, V; Kuhad, A; Tiwari, V; Chopra, K

    2011-11-01

    An apparent clinical relationship between pain and depression has long been recognized. Depression and pain are often diagnosed in the same patients. The emerging concept for pain-depression pathogenesis is the dysfunction of biogenic amine-mediated pain-depression control and the possible involvement of nitrodative stress-induced neurogenic inflammation. The present study was designed to investigate the effect of curcumin on reserpine-induced pain-depression dyad in rats. Administration of reserpine (1mg/kg subcutaneous daily for three consecutive days) led to a significant decrease in nociceptive threshold as evident from reduced paw withdrawal threshold in Randall Sellitto and von-Frey hair test as well as significant increase in immobility time in forced swim test. This behavioural deficit was integrated with decrease in the biogenic amine (dopamine, norepinephrine and serotonin) levels along with increased substance P concentration, nitrodative stress, inflammatory cytokines, NF-κβ and caspase-3 levels in different brain regions (cortex and hippocampus) of the reserpinised rats. Curcumin (100, 200, 300mg/kg; ip) dose dependently ameliorated the behavioural deficits associated with pain and depression by restoring behavioural, biochemical, neurochemical and molecular alterations against reserpine-induced pain-depression dyad in rats. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. Neurochemical and neuropharmacological aspects of circadian disruptions: an introduction to asynchronization.

    Science.gov (United States)

    Kohyama, Jun

    2011-06-01

    Circadian disruptions are common in modern society, and there is an urgent need for effective treatment strategies. According to standard diagnostic criteria, most adolescents showing both insomnia and daytime sleepiness are diagnosed as having behavioral-induced sleep efficiency syndrome resulting from insomnia due to inadequate sleep hygiene. However, a simple intervention of adequate sleep hygiene often fails to treat them. As a solution to this clinical problem, the present review first overviews the basic neurochemical and neuropharmachological aspects of sleep and circadian rhythm regulation, then explains several circadian disruptions from similar viewpoints, and finally introduces the clinical notion of asynchronization. Asynchronization is designated to explain the pathophysiology/pathogenesis of exhibition of both insomnia and hypersomnia in adolescents, which comprises disturbances in various aspects of biological rhythms. The major triggers for asynchronization are considered to be a combination of light exposure during the night, which disturbs the biological clock and decreases melatonin secretion, as well as a lack of light exposure in the morning, which prohibits normal synchronization of the biological clock to the 24-hour cycle of the earth and decreases the activity of serotonin. In the chronic phase of asynchronization, involvement of both wake- and sleep-promoting systems is suggested. Both conventional and alternative therapeutic approaches for potential treatment of asynchronization are suggested.

  7. Neurochemical changes in the pericalcarine cortex in congenital blindness attributable to bilateral anophthalmia.

    Science.gov (United States)

    Coullon, Gaelle S L; Emir, Uzay E; Fine, Ione; Watkins, Kate E; Bridge, Holly

    2015-09-01

    Congenital blindness leads to large-scale functional and structural reorganization in the occipital cortex, but relatively little is known about the neurochemical changes underlying this cross-modal plasticity. To investigate the effect of complete and early visual deafferentation on the concentration of metabolites in the pericalcarine cortex, (1)H magnetic resonance spectroscopy was performed in 14 sighted subjects and 5 subjects with bilateral anophthalmia, a condition in which both eyes fail to develop. In the pericalcarine cortex, where primary visual cortex is normally located, the proportion of gray matter was significantly greater, and levels of choline, glutamate, glutamine, myo-inositol, and total creatine were elevated in anophthalmic relative to sighted subjects. Anophthalmia had no effect on the structure or neurochemistry of a sensorimotor cortex control region. More gray matter, combined with high levels of choline and myo-inositol, resembles the profile of the cortex at birth and suggests that the lack of visual input from the eyes might have delayed or arrested the maturation of this cortical region. High levels of choline and glutamate/glutamine are consistent with enhanced excitatory circuits in the anophthalmic occipital cortex, which could reflect a shift toward enhanced plasticity or sensitivity that could in turn mediate or unmask cross-modal responses. Finally, it is possible that the change in function of the occipital cortex results in biochemical profiles that resemble those of auditory, language, or somatosensory cortex. Copyright © 2015 the American Physiological Society.

  8. Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice.

    Science.gov (United States)

    Drexel, Meinrad; Romanov, Roman A; Wood, James; Weger, Stefan; Heilbronn, Regine; Wulff, Peer; Tasan, Ramon O; Harkany, Tibor; Sperk, Günther

    2017-08-23

    Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present

  9. Calretinin periglomerular interneurons in mice olfactory bulb: cells of few words

    Directory of Open Access Journals (Sweden)

    Alex Fogli Iseppe

    2016-10-01

    Full Text Available Within the olfactory bulb (OB, periglomerular (PG cells consist of various types of interneurons, generally classified by their chemical properties such as neurotransmitter and calcium binding proteins.Calretinin (CR characterizes morphologically and functionally the more numerous and one of the less known subpopulation of PG cells in the OB. Using of transgenic mice expressing eGFP under the CR promoter, we have tried to obtain the first functional characterization of these cells. Electrophysiological recordings were made in these cells using the patch-clamp technique in thin slices. Using ion substitution methods and specific blockers, we dissected the main voltage-dependent conductances present, obtaining a complete kinetic description for each of them.The more peculiar property of these cells from the electrophysiological point of view is the presence only of a single K-current, the IA - there is no trace of delayed rectifier or of Ca-dependent K-current. Other currents identified, isolated and fully characterised are two inward currents, a fast sodium current and a small L-type calcium current, and an inward rectifier, h-type cationic current. As a consequence of the peculiar complement of voltage-dependent conductances present in these cells, and in particular the absence of delayed-rectifier potassium currents, under the functional point of view these cells present two interesting properties.First, in response to prolonged depolarisations, after the inactivation of the A-current, these cells behave as a purely ohmic elements, showing no outward rectification. Second, the CR cells studied can respond only with a single action potential to excitatory inputs; since they send inhibitory synapses to projection neurones, they seem to be designed to inhibit responses of the main neurones to isolated, random excitatory signals, losing their vetoing effect for more structured, repetitive excitatory signals, as result from odour detection

  10. Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves.

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    Funk, Chadd M; Peelman, Kayla; Bellesi, Michele; Marshall, William; Cirelli, Chiara; Tononi, Giulio

    2017-09-20

    During non-rapid eye-movement (NREM) sleep, cortical and thalamic neurons oscillate every second or so between ON periods, characterized by membrane depolarization and wake-like tonic firing, and OFF periods, characterized by membrane hyperpolarization and neuronal silence. Cortical slow waves, the hallmark of NREM sleep, reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because ∼70% of them are Martinotti cells that target diffusely layer I and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving male mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation during ON periods of NREM sleep triggers long OFF periods. Next, we show that chemogenetic activation of SOM+ cells increases slow-wave activity (SWA), slope of individual slow waves, and NREM sleep duration; whereas their chemogenetic inhibition decreases SWA and slow-wave incidence without changing time spent in NREM sleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing, triggers short OFF periods in NREM sleep, and increases NREM sleep duration. Thus SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated. SIGNIFICANCE STATEMENT Cortical slow waves are a defining feature of non-rapid eye-movement (NREM) sleep and are thought to be important for many of its restorative benefits. Yet, the mechanism by which cortical neurons abruptly and synchronously cease firing, the

  11. Soft-diet feeding impairs neural transmission between mitral cells and interneurons in the mouse olfactory bulb.

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    Noguchi, Tomohiro; Utsugi, Chizuru; Kashiwayanagi, Makoto

    2017-11-01

    (Objective) The subventricular zone in mice generates a lot of neuroblasts even during adulthood. These neuroblasts migrate to the olfactory bulb and differentiate into inhibitory interneurons such as granule cells and periglomerular cells. Olfactory sensory neurons receive information from various odorants and transmit it to the olfactory bulb. Our previous study showed that soft-diet feeding impairs neurogenesis in the subventricular zone, in turn leading to the reduction of odor-induced behaviors and Fos-immunoreactivities, the latter of which are markers of neural activity, at the olfactory bulb after exposure to odors. Release of GABA from inhibitory interneurons at the olfactory bulb induces inhibitory currents at the mitral cells, which are output neurons from the olfactory bulb. (Design) In the present study, we measured spontaneous inhibitory postsynaptic currents (sIPSCs) at the mitral cells of mice fed a soft diet in order to explore the effects of changes in texture of diets on neural function at the olfactory bulb. (Results) The soft-diet feeding extended the intervals between sIPSCs and reduced their peak amplitudes. (Conclusions) The present results suggest that soft-diet feeding in mice attenuates the neural functions of inhibitory interneurons at the olfactory bulb. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. V1 and V2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion

    Science.gov (United States)

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

    2014-01-01

    SUMMARY The 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. PMID:24698273

  13. Netrin-1-dependent spinal interneuron subtypes are required for the formation of left-right alternating locomotor circuitry.

    Science.gov (United States)

    Rabe, Nadine; Gezelius, Henrik; Vallstedt, Anna; Memic, Fatima; Kullander, Klas

    2009-12-16

    Neuronal circuits in the spinal cord that produce the rhythmic and coordinated activities necessary for limb movements are referred to as locomotor central pattern generators (CPGs). The identities and preceding development of neurons essential for coordination between left and right limbs are not yet known. We show that the ventral floor plate chemoattractant Netrin-1 preferentially guides dorsally originating subtypes of commissural interneurons, the majority of which are inhibitory. In contrast, the excitatory and ventralmost V3 subtype of interneurons have a normal number of commissural fibers in Netrin-1 mutant mice, thus being entirely independent of Netrin-1-mediated attraction. This selective loss of commissural fibers in Netrin-1 mutant mice resulted in an abnormal circuitry manifested by a complete switch from alternating to synchronous fictive locomotor activity suggesting that the most ventral-originating excitatory commissural interneurons are an important component of a left-right synchrony circuit in the locomotor CPG. Thus, during development, Netrin-1 plays a critical role for the establishment of a functional balanced CPG.

  14. Electrophysiological localization of distinct calcium potentials at selective somatodendritic sites in the substantia nigra

    DEFF Research Database (Denmark)

    Hounsgaard, J; Nedergaard, S; Greenfield, S A

    1992-01-01

    The dendrites of dopaminergic neurons in the substantia nigra play a pivotal role in the neurochemical homeostasis of the nucleus. It is conceivable therefore that the cell body and dendrites of these nigral neurons possess distinct and independent electro-responsive features. By means of differe......The dendrites of dopaminergic neurons in the substantia nigra play a pivotal role in the neurochemical homeostasis of the nucleus. It is conceivable therefore that the cell body and dendrites of these nigral neurons possess distinct and independent electro-responsive features. By means...... in the rostral substantia nigra, the dendrites are shown to be the origin of classic low-threshold and high-threshold type calcium potentials: indeed the high-threshold conductance appears to be exclusively dendritic. By contrast, in a second, more caudally located cell type, which discharges rhythmically......, a high-threshold calcium spike is located principally in the cell body. The differential localization of these calcium conductances in sub-populations of neurons is likely to determine the functions for the calcium responses in each type of neuron, and moreover highlight the dendrites as dynamic...

  15. Plastic changes in striatal fast-spiking interneurons following hemicerebellectomy and environmental enrichment.

    Science.gov (United States)

    De Bartolo, Paola; Gelfo, Francesca; Burello, Lorena; De Giorgio, Andrea; Petrosini, Laura; Granato, Alberto

    2011-09-01

    Recent findings suggest marked interconnections between the cerebellum and striatum, thus challenging the classical view of their segregated operation in motor control. Therefore, this study was aimed at further investigating this issue by analyzing the effects of hemicerebellectomy (HCb) on density and dendritic length of striatal fast-spiking interneurons (FSi). First, we analyzed the plastic rearrangements of striatal FSi morphology in hemicerebellectomized animals reared in standard conditions. Then, since environmental enrichment (EE) induces structural changes in experimental models of brain disease, we evaluated FSi morphology in lesioned animals exposed to an enriched environment after HCb. Although HCb did not affect FSi density, it progressively shrank dendritic branching of striatal FSi of both sides. These plastic changes, already evident 15 days after the cerebellar ablation, became very marked 30 days after the lesion. Such a relevant effect was completely abolished by postoperative enrichment. EE not only counteracted shrinkage of FSi dendritic arborization but also provoked a progressive increase in dendritic length which surpassed that of the controls as the enrichment period lengthened. These data confirm that the cerebellum and striatum are more interconnected than previously retained. Furthermore, cerebellar damage likely evokes a striatal response through cortical mediation. The EE probably modifies HCb-induced plastic changes in the striatum by increasing the efficiency of the cortical circuitry. This is the first study describing the morphological rearrangement of striatal FSi following a cerebellar lesion; it provides the basis for further studies aimed at investigating the mechanisms underlying cerebello-striatal "talking."

  16. Modeling of inter-neuronal coupling medium and its impact on neuronal synchronization.

    Science.gov (United States)

    Iqbal, Muhammad; Rehan, Muhammad; Hong, Keum-Shik

    2017-01-01

    In this paper, modeling of the coupling medium between two neurons, the effects of the model parameters on the synchronization of those neurons, and compensation of coupling strength deficiency in synchronization are studied. Our study exploits the inter-neuronal coupling medium and investigates its intrinsic properties in order to get insight into neuronal-information transmittance and, there from, brain-information processing. A novel electrical model of the coupling medium that represents a well-known RLC circuit attributable to the coupling medium's intrinsic resistive, inductive, and capacitive properties is derived. Surprisingly, the integration of such properties reveals the existence of a natural three-term control strategy, referred to in the literature as the proportional integral derivative (PID) controller, which can be responsible for synchronization between two neurons. Consequently, brain-information processing can rely on a large number of PID controllers based on the coupling medium properties responsible for the coherent behavior of neurons in a neural network. Herein, the effects of the coupling model (or natural PID controller) parameters are studied and, further, a supervisory mechanism is proposed that follows a learning and adaptation policy based on the particle swarm optimization algorithm for compensation of the coupling strength deficiency.

  17. Modeling of inter-neuronal coupling medium and its impact on neuronal synchronization

    Science.gov (United States)

    Iqbal, Muhammad; Hong, Keum-Shik

    2017-01-01

    In this paper, modeling of the coupling medium between two neurons, the effects of the model parameters on the synchronization of those neurons, and compensation of coupling strength deficiency in synchronization are studied. Our study exploits the inter-neuronal coupling medium and investigates its intrinsic properties in order to get insight into neuronal-information transmittance and, there from, brain-information processing. A novel electrical model of the coupling medium that represents a well-known RLC circuit attributable to the coupling medium’s intrinsic resistive, inductive, and capacitive properties is derived. Surprisingly, the integration of such properties reveals the existence of a natural three-term control strategy, referred to in the literature as the proportional integral derivative (PID) controller, which can be responsible for synchronization between two neurons. Consequently, brain-information processing can rely on a large number of PID controllers based on the coupling medium properties responsible for the coherent behavior of neurons in a neural network. Herein, the effects of the coupling model (or natural PID controller) parameters are studied and, further, a supervisory mechanism is proposed that follows a learning and adaptation policy based on the particle swarm optimization algorithm for compensation of the coupling strength deficiency. PMID:28486505

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Somatostatin receptor 1 and 5 double knockout mice mimic neurochemical changes of Huntington's disease transgenic mice.

    Directory of Open Access Journals (Sweden)

    Padmesh S Rajput

    Full Text Available Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD. However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5.To delineate subtype selective biological responses we have here investigated changes in SSTR1 and 5 double knockout mice brain and compared with HD transgenic mouse model (R6/2. Our study revealed significant loss of dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32 and comparable changes in SST, N-methyl-D-aspartic acid receptors subtypes, calbindin and brain nitric oxide synthase expression as well as in key signaling proteins including calpain, phospho-extracellular-signal-regulated kinases1/2, synapsin-IIa, protein kinase C-α and calcineurin in SSTR1/5(-/- and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice.This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntington's disease.

  2. Behavioural and neurochemical assessment of salvinorin A abuse potential in the rat.

    Science.gov (United States)

    Serra, Veronica; Fattore, Liana; Scherma, Maria; Collu, Roberto; Spano, Maria Sabrina; Fratta, Walter; Fadda, Paola

    2015-01-01

    Salvinorin A is a recreational drug derived from Salvia divinorum, a sage species long used as an entheogen. While salvinorin A has potent hallucinogenic properties, its abuse potential has not been assessed consistently in controlled behavioural and neurochemical studies in rodents. This study aimed to assess salvinorin A abuse potential by measuring its capacity to establish and maintain self-administration behaviour and to modify dopamine (DA) levels in the nucleus accumbens (NAcc) of rats. Male Lister Hooded (LH) and Sprague-Dawley (SD) rats were allowed to self-administer salvinorin A (0.5 or 1.0 μg/kg/infusion) intravenously 2 h/day for 20 days under a continuous schedule of reinforcement and lever pressing as operandum. LH rats discriminated between the active and inactive levers but did not reach the acquisition criterion for stable self-administration (≥12 active responses vs ≤5 inactive responses for at least 5 consecutive days). SD rats discriminated between the two levers at the lower dose only but, like LH rats, never acquired stable self-administration behaviour. Systemic salvinorin A increased extracellular DA in the NAcc shell of both LH (at ≥40 μg/kg) and SD rats (at ≥5 μg/kg), but injection into the ventral tegmental area (VTA) induced no significant change in NAcc DA concentration in LH rats and only brief elevations in SD rats. Salvinorin A differs from other commonly abused compounds since although it affects accumbal dopamine transmission, yet it is unable, at least at the tested doses, to sustain stable intravenous self-administration behaviour.

  3. Peptidergic nerve fibers in the urethra: Morphological and neurochemical characteristics in female mice of reproductive age.

    Science.gov (United States)

    Barry, Christine M; Ji, Esther; Sharma, Harman; Yap, Pauline; Spencer, Nicholas J; Matusica, Dusan; Haberberger, Rainer V

    2017-10-20

    Peptidergic nerve fibers provide important contributions to urethral function. Urethral innervation of female mice is not well documented. To determine the distribution and projection sites of nerve fibers immunoreactive for vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP), and neuropeptide Y (NPY) in the urethra of wild-type control mice and compare innervation characteristics between the proximal and distal urethra of young nullipara and older multipara mice. Furthermore, to identify the location and neurochemical coding of the spinal afferent nerve endings in the urethra, whose sensory neurons reside in lumbosacral dorsal root ganglia (DRG). Multiple labeling immunohistochemistry of urethral sections of nulliparous (6-8 weeks old), and multiparous (9-12 months old) mice, and anterograde axonal tracing from L5-S2 (DRG) in vivo. Abundant VIP-, CGRP-, SP-, and NPY-immunoreactive nerve fibers were identified in the adventitia, muscularis, and lamina propria of proximal and distal segments of the urethra. A proportion of fibers were closely associated with blood vessels, glands, and cells immunoreactive for PGP9.5. The epithelium contained abundant nerve fibers immunoreactive for CGRP and/or SP. Epithelial innervation was increased in the distal urethra of multipara mice. Abundant fibers were traced from L5-S2 DRG to all urethral regions. We present the first identification of spinal afferent endings in the urethra. Peptidergic nerve fibers, including multiple populations of spinal afferents, provide rich innervation of the female mouse urethra. The morphology of fibers in the epithelium and other regions suggests multiple nerve-cell interactions impacting on urethral function. © 2017 Wiley Periodicals, Inc.

  4. Morphological and neurochemical differences in peptidergic nerve fibers of the mouse vagina.

    Science.gov (United States)

    Barry, Christine M; Ji, Esther; Sharma, Harman; Beukes, Lara; Vilimas, Patricia I; DeGraaf, Yvette C; Matusica, Dusan; Haberberger, Rainer V

    2017-07-01

    The vagina is innervated by a complex arrangement of sensory, sympathetic, and parasympathetic nerve fibers that contain classical transmitters plus an array of neuropeptides and enzymes known to regulate diverse processes including blood flow and nociception. The neurochemical characteristics and distributions of peptide-containing nerves in the mouse vagina are unknown. This study used multiple labeling immunohistochemistry, confocal maging and analysis to investigate the presence and colocalization of the peptides vasoactive intestinal polypeptide (VIP), calcitonin-gene related peptide (CGRP), substance P (SP), neuropeptide tyrosine (NPY), and the nitric oxide synthesizing enzyme neuronal nitric oxide synthase (nNOS) in nerve fibers of the murine vaginal wall. We compared cervical and vulvar areas of the vagina in young nullipara and older multipara C57Bl/6 mice, and identified differences including that small ganglia were restricted to cervical segments, epithelial fibers were mainly present in vulvar segments and most nerve fibers were found in the lamina propria of the cervical region of the vagina, where a higher number of fibers containing immunoreactivity for VIP, CGRP, SP, or nNOS were found. Two populations of VIP-containing fibers were identified: fibers containing CGRP and fibers containing VIP but not CGRP. Differences between young and older mice were present in multiple layers of the vaginal wall, with older mice showing overall loss of innervation of epithelium of the proximal vagina and reduced proportions of VIP, CGRP, and SP containing nerve fibers in the distal epithelium. The distal vagina also showed increased vascularization and perivascular fibers containing NPY. Immunolabeling of ganglia associated with the vagina indicated the likely origin of some peptidergic fibers. Our results reveal regional differences and age- or parity-related changes in innervation of the mouse vagina, effecting the distribution of neuropeptides with diverse roles

  5. Neurochemically defined cell columns in the nucleus prepositus hypoglossi of the cat and monkey.

    Science.gov (United States)

    Baizer, Joan S; Baker, James F

    2006-06-13

    Many studies have shown that the nucleus prepositus hypoglossi (PH) participates with the vestibular nuclear complex, the cerebellum and the oculomotor nuclei in the control of eye movements. We have looked at the neurochemical organization of PH in the cat and monkey using a recently developed antibody, 8B3, that recognizes a chondroitin sulfate proteoglycan. In the cat, immunoreactivity to 8B3 labels a set of cells in PH. On frontal sections, these cells form a cluster that is seen over the entire anterior-posterior (A-P) extent of PH, but the number of cells in the cluster changes with A-P level. Earlier studies have identified an A-P cell column in PH of the cat whose neurons synthesize nitric oxide. We have used both single- and double-label protocols to investigate the relation between the two cell groups. Single-label studies show spatial overlap but that the cells immunoreactive to nitric oxide synthase (nNOS) are more numerous than cells immunoreactive to 8B3. Double-label studies show that all cells immunoreactive to 8B3 were also immunoreactive to nNOS, but, as suggested by the single-label data, there are many nNOS-immunoreactive cells not immunoreactive to 8B3. Populations of 8B3 and nNOS-immunoreactive cells are also found in PH of squirrel and macaque monkeys. The results suggest that nNOS-immunoreactive cells in PH may consist of two functionally different populations.

  6. Social vs. environmental stress models of depression from a behavioural and neurochemical approach.

    Science.gov (United States)

    Venzala, E; García-García, A L; Elizalde, N; Tordera, R M

    2013-07-01

    Major depression is a mental disorder often preceded by exposure to chronic stress or stressful life events. Recently, animal models based on social conflict such as chronic social defeat stress (CSDS) are proposed to be more relevant to stress-induced human psychopathology compared to environmental models like the chronic mild stress (CMS). However, while CMS reproduces specifically core depressive symptoms such as anhedonia and helplessness, CSDS studies rely on the analysis of stress-induced social avoidance, addressing different neuropsychiatric disorders. Here, we study comparatively the two models from a behavioural and neurochemical approach and their possible relevance to human depression. Mice (C57BL/6) were exposed to CMS or CSDS for six weeks and ten days. Anhedonia was periodically evaluated. A battery of test applied during the fourth week after the stress procedure included motor activity, memory, anxiety, social interaction and helplessness. Subsequently, we examined glutamate, GABA, 5-HT and dopamine levels in the prefrontal cortex, hippocampus and brainstem. CMS induced a clear depressive-like profile including anhedonia, helplessness and memory impairment. CSDS induced anhedonia, hyperactivity, anxiety and social avoidance, signs also common to anxiety and posttraumatic stress disorders. While both models disrupted the excitatory inhibitory balance in the prefrontal cortex, CMS altered importantly this balance in the brainstem. Moreover, CSDS decreased dopamine in the prefrontal cortex and brainstem. We suggests that while depressive-like behaviours might be associated to altered aminoacid neurotransmission in cortical and brain stem areas, CSDS induced anxiety behaviours might be linked to specific alteration of dopaminergic pathways involved in rewarding processes. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

  7. Multimodal neuroimaging based classification of autism spectrum disorder using anatomical, neurochemical, and white matter correlates.

    Science.gov (United States)

    Libero, Lauren E; DeRamus, Thomas P; Lahti, Adrienne C; Deshpande, Gopikrishna; Kana, Rajesh K

    2015-05-01

    Neuroimaging techniques, such as fMRI, structural MRI, diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (1H-MRS) have uncovered evidence for widespread functional and anatomical brain abnormalities in autism spectrum disorder (ASD) suggesting it to be a system-wide neural systems disorder. Nevertheless, most previous studies have focused on examining one index of neuropathology through a single neuroimaging modality, and seldom using multiple modalities to examine the same cohort of individuals. The current study aims to bring together multiple brain imaging modalities (structural MRI, DTI, and 1H-MRS) to investigate the neural architecture in the same set of individuals (19 high-functioning adults with ASD and 18 typically developing (TD) peers). Morphometry analysis revealed increased cortical thickness in ASD participants, relative to typical controls, across the left cingulate, left pars opercularis of the inferior frontal gyrus, left inferior temporal cortex, and right precuneus, and reduced cortical thickness in right cuneus and right precentral gyrus. ASD adults also had reduced fractional anisotropy (FA) and increased radial diffusivity (RD) for two clusters on the forceps minor of the corpus callosum, revealed by DTI analyses. 1H-MRS results showed a reduction in the N-acetylaspartate/Creatine ratio in dorsal anterior cingulate cortex (dACC) in ASD participants. A decision tree classification analysis across the three modalities resulted in classification accuracy of 91.9% with FA, RD, and cortical thickness as key predictors. Examining the same cohort of adults with ASD and their TD peers, this study found alterations in cortical thickness, white matter (WM) connectivity, and neurochemical concentration in ASD. These findings underscore the potential for multimodal imaging to better inform on the neural characteristics most relevant to the disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. NMR-Based Metabolic Profiling Reveals Neurochemical Alterations in the Brain of Rats Treated with Sorafenib.

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    Du, Changman; Shao, Xue; Zhu, Ruiming; Li, Yan; Zhao, Qian; Fu, Dengqi; Gu, Hui; Kong, Jueying; Luo, Li; Long, Hailei; Deng, Pengchi; Wang, Huijuan; Hu, Chunyan; Zhao, Yinglan; Cen, Xiaobo

    2015-11-01

    Sorafenib, an active multi-kinase inhibitor, has been widely used as a chemotherapy drug to treat advanced clear-cell renal cell carcinoma patients. In spite of the relative safety, sorafenib has been shown to exert a negative impact on cognitive functioning in cancer patients, specifically on learning and memory; however, the underlying mechanism remains unclear. In this study, an NMR-based metabolomics approach was applied to investigate the neurochemical effects of sorafenib in rats. Male rats were once daily administrated with 120 mg/kg sorafenib by gavage for 3, 7, and 28 days, respectively. NMR-based metabolomics coupled with histopathology examinations for hippocampus, prefrontal cortex (PFC), and striatum were performed. The (1)H NMR spectra data were analyzed by using multivariate pattern recognition techniques to show the time-dependent biochemical variations induced by sorafenib. Excellent separation was obtained and distinguishing metabolites were observed between sorafenib-treated and control rats. A total of 36 differential metabolites in hippocampus of rats treated with sorafenib were identified, some of which were significantly changed. Furthermore, these modified metabolites mainly reflected the disturbances in neurotransmitters, energy metabolism, membrane, and amino acids. However, only a few metabolites in PFC and striatum were altered by sorafenib. Additionally, no apparent histological changes in these three brain regions were observed in sorafenib-treated rats. Together, our findings demonstrate the disturbed metabonomics pathways, especially, in hippocampus, which may underlie the sorafenib-induced cognitive deficits in patients. This work also shows the advantage of NMR-based metabolomics over traditional approach on the study of biochemical effects of drugs.

  9. Neurochemical characterization of neurons expressing melanin-concentrating hormone receptor 1 in the mouse hypothalamus1

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    Chee, Melissa J. S.; Pissios, Pavlos; Maratos-Flier, Eleftheria

    2013-01-01

    Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that acts via MCH receptor 1 (MCHR1) in the mouse. It promotes positive energy balance thus mice lacking MCH or MCHR1 are lean, hyperactive, and resistant to diet-induced obesity. Identifying the cellular targets of MCH is an important step to understanding the mechanisms underlying MCH actions. We generated the Mchr1-cre mouse that expressed cre recombinase driven by the MCHR1 promoter and crossed it with a tdTomato reporter mouse. The resulting Mchr1-cre/tdTomato progeny expressed easily detectable tdTomato fluorescence in MCHR1 neurons, which were found throughout the olfactory system, striatum, and hypothalamus. To chemically identify MCH-targeted cell populations that play a role in energy balance, MCHR1 hypothalamic neurons were characterized by colabeling select hypothalamic neuropeptides with tdTomato fluorescence. TdTomato fluorescence colocalized with dynorphin, oxytocin, vasopressin, enkephalin, thyrothropin-releasing hormone, and corticotropin-releasing factor immunoreactive cells in the paraventricular nucleus. In the lateral hypothalamus, neurotensin but neither orexin nor MCH neurons expressed tdTomato. In the arcuate nucleus, both Neuropeptide Y and proopiomelanocortin cells expressed tdTomato. We further demonstrated that some of these arcuate neurons were also targets of leptin action. Interestingly, MCHR1 was expressed in the vast majority of leptin-sensitive proopiomelanocortin neurons, highlighting their importance for the orexigenic actions of MCH. Taken together, this study supports the use of the Mchr1-cre mouse for outlining the neuroanatomical distribution and neurochemical phenotype of MCHR1 neurons. PMID:23605441

  10. Neurochemical characterization of neurons expressing melanin-concentrating hormone receptor 1 in the mouse hypothalamus.

    Science.gov (United States)

    Chee, Melissa J S; Pissios, Pavlos; Maratos-Flier, Eleftheria

    2013-07-01

    Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that acts via MCH receptor 1 (MCHR1) in the mouse. It promotes positive energy balance; thus, mice lacking MCH or MCHR1 are lean, hyperactive, and resistant to diet-induced obesity. Identifying the cellular targets of MCH is an important step to understanding the mechanisms underlying MCH actions. We generated the Mchr1-cre mouse that expresses cre recombinase driven by the MCHR1 promoter and crossed it with a tdTomato reporter mouse. The resulting Mchr1-cre/tdTomato progeny expressed easily detectable tdTomato fluorescence in MCHR1 neurons, which were found throughout the olfactory system, striatum, and hypothalamus. To chemically identify MCH-targeted cell populations that play a role in energy balance, MCHR1 hypothalamic neurons were characterized by colabeling select hypothalamic neuropeptides with tdTomato fluorescence. TdTomato fluorescence colocalized with dynorphin, oxytocin, vasopressin, enkephalin, thyrothropin-releasing hormone, and corticotropin-releasing factor immunoreactive cells in the paraventricular nucleus. In the lateral hypothalamus, neurotensin, but neither orexin nor MCH neurons, expressed tdTomato. In the arcuate nucleus, both Neuropeptide Y and proopiomelanocortin cells expressed tdTomato. We further demonstrated that some of these arcuate neurons were also targets of leptin action. Interestingly, MCHR1 was expressed in the vast majority of leptin-sensitive proopiomelanocortin neurons, highlighting their importance for the orexigenic actions of MCH. Taken together, this study supports the use of the Mchr1-cre mouse for outlining the neuroanatomical distribution and neurochemical phenotype of MCHR1 neurons. Copyright © 2012 Wiley Periodicals, Inc.

  11. Disciplinary Distinction or Responsibility?

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    Rogers, Priscilla S.

    1996-01-01

    Argues that some of the disciplinary distinctions proposed in the lead articles of this special issue actually represent aspects of theory or practice that are fundamental to all four fields. Examines what is deemphasized to suggest where attention may be needed--in particular, disciplinary relationships with organizations and disciplinary…

  12. Effects of serotonin 2C receptor agonists on the behavioral and neurochemical effects of cocaine in squirrel monkeys.

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    Manvich, Daniel F; Kimmel, Heather L; Howell, Leonard L

    2012-05-01

    Accumulating evidence indicates that the serotonin system modulates the behavioral and neurochemical effects of cocaine, but the receptor subtypes mediating these effects remain unknown. Recent studies have demonstrated that pharmacological activation of the serotonin 2C receptor (5-HT(2C)R) attenuates the behavioral and neurochemical effects of cocaine in rodents, but such compounds have not been systematically evaluated in nonhuman primates. The present experiments sought to determine the impact of pretreatment with the preferential 5-HT(2C)R agonist m-chlorophenylpiperazine (mCPP) and the selective 5-HT(2C)R agonist Ro 60-0175 [(α-S)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate] on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press according to a 300-s fixed-interval schedule of stimulus termination, pretreatment with either 5-HT(2C)R agonist dose-dependently and insurmountably attenuated the behavioral stimulant effects of cocaine. In subjects trained to self-administer cocaine, both compounds dose-dependently and insurmountably attenuated cocaine-induced reinstatement of previously extinguished responding in an antagonist-reversible manner, and the selective agonist Ro 60-0175 also attenuated the reinforcing effects of cocaine during ongoing cocaine self-administration. It is noteworthy that the selective agonist Ro 60-0175 exhibited behavioral specificity because it did not significantly alter nondrug-maintained responding. Finally, in vivo microdialysis studies revealed that pretreatment with Ro 60-0175 caused a reduction of cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus. These results suggest that 5-HT(2C)R agonists functionally antagonize the behavioral effects of cocaine in nonhuman primates, possibly via a selective modulation of cocaine-induced dopamine increases within the mesolimbic dopamine system and may therefore represent a novel

  13. Dichotomous Effects of Mu Opioid Receptor Activation on Striatal Low-Threshold Spike Interneurons

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    Rasha Elghaba

    2017-12-01

    Full Text Available Striatal low-threshold spike interneurons (LTSIs are tonically active neurons that express GABA and nitric oxide synthase and are involved in information processing as well as neurovascular coupling. While mu opioid receptors (MORs and their ligand encephalin are prominent in the striatum, their action on LTSIs has not been investigated. We addressed this issue carrying out whole-cell recordings in transgenic mice in which the NPY-expressing neurons are marked with green fluorescent protein (GFP. The MOR agonist (D-Ala(2, N-MePhe(4, Gly-ol-enkephalin (DAMGO produced dual effects on subpopulations of LTSIs. DAMGO caused inhibitory effects, accompanied by decreases of spontaneous firing, in 62% of LTSIs, while depolarizing effects (accompanied by an increase in spontaneous firing were observed in 23% of LTSIs tested. The dual effects of DAMGO persisted in the presence of tetrodotoxin (TTX, a sodium channel blocker or in the presence of the nicotinic acetylcholine receptor antagonist mecamylamine. However, in the presence of either the GABAA receptor antagonist picrotoxin or the muscarinic cholinergic receptor antagonist atropine, DAMGO only elicited inhibitory effects on LTSIs. Furthermore, we found that DAMGO decreased the amplitude and frequency of spontaneous GABAergic events. Unexpectedly, these effects of DAMGO on spontaneous GABAergic events disappeared after blocking of the muscarinic and nicotinic cholinergic blockers, showing that GABA inputs to LTSIs are not directly modulated by presynaptic MORs. These finding suggest that activation of MORs affect LTSIs both directly and indirectly, through modulation of GABAergic and cholinergic tones. The complex balance between direct and indirect effects determines the net effect of DAMGO on LTSIs.

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

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    Ejaz, Naveed; Krapp, Holger G; Tanaka, Reiko J

    2013-01-01

    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 behavioral 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 behaviors 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 signaling 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 robots.

  15. Octopaminergic modulation of temporal frequency coding in an identified optic flow-processing interneuron

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    Kit D. Longden

    2010-11-01

    Full Text Available Flying generates predictably different patterns of optic flow compared with other locomotor states. A sensorimotor system tuned to rapid responses and a high bandwidth of optic flow would help the animal to avoid wasting energy through imprecise motor action. However, neural processing that covers a higher input bandwidth itself comes at higher energetic costs which would be a poor investment when the animal was not flying. How does the blowfly adjust the dynamic range of its optic flow-processing neurons to the locomotor state? Octopamine (OA is a biogenic amine central to the initiation and maintenance of flight in insects. We used an OA agonist chlordimeform (CDM to simulate the widespread OA release during flight and recorded the effects on the temporal frequency coding of the H2 cell. This cell is a visual interneuron known to be involved in flight stabilization reflexes. The application of CDM resulted in i an increase in the cell's spontaneous activity, expanding the inhibitory signalling range ii an initial response gain to moving gratings (20 – 60 ms post-stimulus that depended on the temporal frequency of the grating and iii a reduction in the rate and magnitude of motion adaptation that was also temporal frequency-dependent. To our knowledge, this is the first demonstration that the application of a neuromodulator can induce velocity-dependent alterations in the gain of a wide-field optic flow-processing neuron. The observed changes in the cell’s response properties resulted in a 33% increase of the cell’s information rate when encoding random changes in temporal frequency of the stimulus. The increased signalling range and more rapid, longer lasting responses employed more spikes to encode each bit, and so consumed a greater amount of energy. It appears that for the fly investing more energy in sensory processing during flight is more efficient than wasting energy on under-performing motor control.

  16. 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

  17. Persistent, generalized hypersensitivity of olfactory bulb interneurons after olfactory fear generalization.

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    Kass, Marley D; McGann, John P

    2017-11-08

    Generalization of fear from previously threatening stimuli to novel but related stimuli can be beneficial, but if fear overgeneralizes to inappropriate situations it can produce maladaptive behaviors and contribute to pathological anxiety. Appropriate fear learning can selectively facilitate early sensory processing of threat-predictive stimuli, but it is unknown if fear generalization has similarly generalized neurosensory consequences. We performed in vivo optical neurophysiology to visualize odor-evoked neural activity in populations of periglomerular interneurons in the olfactory bulb 1 day before, 1 day after, and 1 month after each mouse underwent an olfactory fear conditioning paradigm designed to promote generalized fear of odors. Behavioral and neurophysiological changes were assessed in response to a panel of odors that varied in similarity to the threat-predictive odor at each time point. After conditioning, all odors evoked similar levels of freezing behavior, regardless of similarity to the threat-predictive odor. Freezing significantly correlated with large changes in odor-evoked periglomerular cell activity, including a robust, generalized facilitation of the response to all odors, broadened odor tuning, and increased neural responses to lower odor concentrations. These generalized effects occurred within 24 h of a single conditioning session, persisted for at least 1 month, and were detectable even in the first moments of the brain's response to odors. The finding that generalized fear includes altered early sensory processing of not only the threat-predictive stimulus but also novel though categorically-similar stimuli may have important implications for the etiology and treatment of anxiety disorders with sensory sequelae. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. 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

  19. Gsg1, Trnp1, and Tmem215 Mark Subpopulations of Bipolar Interneurons in the Mouse Retina

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    Park, Ko Uoon; Randazzo, Grace; Jones, Kenneth L.; Brzezinski, Joseph A.

    2017-01-01

    Purpose How retinal bipolar cell interneurons are specified and assigned to specialized subtypes is only partially understood. In part, this is due to a lack of early pan- and subtype-specific bipolar cell markers. To discover these factors, we identified genes that were upregulated in Blimp1 (Prdm1) mutant retinas, which exhibit precocious bipolar cell development. Methods Postnatal day (P)2 retinas from Blimp1 conditional knock-out (CKO) mice and controls were processed for RNA sequencing. Genes that increased at least 45% and were statistically different between conditions were considered candidate bipolar-specific factors. Candidates were further evaluated by RT-PCR, in situ hybridization, and immunohistochemistry. Knock-in Tmem215-LacZ mice were used to better trace retinal expression. Results A comparison between Blimp1 CKO and control RNA-seq datasets revealed approximately 40 significantly upregulated genes. We characterized the expression of three genes that have no known function in the retina, Gsg1 (germ cell associated gene), Trnp1 (TMF-regulated nuclear protein), and Tmem215 (a predicted transmembrane protein). Germ cell associated gene appeared restricted to a small subset of cone bipolars while Trnp1 was seen in all ON type bipolar cells. Using Tmem215-LacZ heterozygous knock-in mice, we observed that β-galactosidase expression started early in bipolar cell development. In adults, Tmem215 was expressed by a subset of ON and OFF cone bipolar cells. Conclusions We have identified Gsg1, Tmem215, and Trnp1 as novel bipolar subtype-specific genes. The spatial and temporal pattern of their expression is consistent with a role in controlling bipolar subtype fate choice, differentiation, or physiology. PMID:28199486

  20. Elevated mercury exposure and neurochemical alterations in little brown bats (Myotis lucifugus) from a site with historical mercury contamination.

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    Nam, Dong-Ha; Yates, David; Ardapple, Pedro; Evers, David C; Schmerfeld, John; Basu, Niladri

    2012-05-01

    Despite evidence of persistent methylmercury (MeHg) contamination in the South River (Virginia, USA) ecosystem, there is little information concerning MeHg-associated neurological impacts in resident wildlife. Here we determined mercury (Hg) concentrations in tissues of insectivorous little brown bats (Myotis lucifugus) collected from a reference site and a MeHg-contaminated site in the South River ecosystem. We also explored whether neurochemical biomarkers (monoamine oxidase, MAO; acetylcholinesterase, ChE; muscarinic acetylcholine receptor, mAChR; N-methyl-D-aspartate receptor, NMDAR) previously shown to be altered by MeHg in other wildlife were associated with brain Hg levels in these bats. Concentrations of Hg (total and MeHg) in tissues were significantly higher (10-40 fold difference) in South River bats when compared to reference sites. Mean tissue mercury levels (71.9 ppm dw in liver, 7.14 ppm dw in brain, 132 ppm fw in fur) in the South River bats exceed (sub)-clinical thresholds in mammals. When compared to the South River bats, animals from the reference site showed a greater ability to demethylate MeHg in brain (33.1% of total Hg was MeHg vs. 65.5%) and liver (8.9% of total Hg was MeHg vs. 50.8%) thus suggesting differences in their ability to detoxify and eliminate Hg. In terms of Hg-associated neurochemical biomarker responses, interesting biphasic responses were observed with an inflection point between 1 and 5 ppm dw in the brain. In the reference bats Hg-associated decreases in MAO (r = -0.61; p exposures, differences in Hg metabolism, and the importance of the aforementioned neurochemicals in multiple facets of animal health, altered or perhaps even a lack of expected neurochemical responses in Hg-contaminated bats raise questions about the ecological and physiological impacts of Hg on the bat population as well as the broader ecosystem in the South River.

  1. Rapid recovery and altered neurochemical dependence of locomotor central pattern generation following lumbar neonatal spinal cord injury.

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    Züchner, Mark; Kondratskaya, Elena; Sylte, Camilla B; Glover, Joel C; Boulland, Jean-Luc

    2018-01-15

    Spinal compression injury targeted to the neonatal upper lumbar spinal cord, the region of highest hindlimb locomotor rhythmogenicity, leads to an initial paralysis of the hindlimbs. Behavioural recovery is evident within a few days and approaches normal function within about 3 weeks. Fictive locomotion in the isolated injured spinal cord cannot be elicited by a neurochemical cocktail containing NMDA, dopamine and serotonin 1 day post-injury, but can 3 days post-injury as readily as in the uninjured spinal cord. Low frequency coordinated rhythmic activity can be elicited in the isolated uninjured spinal cord by NMDA + dopamine (without serotonin), but not in the isolated injured spinal cord. In both the injured and uninjured spinal cord, eliciting bona fide fictive locomotion requires the additional presence of serotonin. Following incomplete compression injury in the thoracic spinal cord of neonatal mice 1 day after birth (P1), we previously reported that virtually normal hindlimb locomotor function is recovered within about 3 weeks despite substantial permanent thoracic tissue loss. Here, we asked whether similar recovery occurs following lumbar injury that impacts more directly on the locomotor central pattern generator (CPG). As in thoracic injuries, lumbar injuries caused about 90% neuronal loss at the injury site and increased serotonergic innervation below the injury. Motor recovery was slower after lumbar than thoracic injury, but virtually normal function was attained by P25 in both cases. Locomotor CPG status was tested by eliciting fictive locomotion in isolated spinal cords using a widely used neurochemical cocktail (NMDA, dopamine, serotonin). No fictive locomotion could be elicited 1 day post-injury, but could within 3 days post-injury as readily as in age-matched uninjured control spinal cords. Burst patterning and coordination were largely similar in injured and control spinal cords but there were differences. Notably, in both groups there

  2. 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

  3. [Structural and functional reorganization of the interneuronal contacts of the cerebral cortex after a single convulsive paroxysm].

    Science.gov (United States)

    Savchenko, Iu N; Ereniev, S I; Semchenko, V V; Stepanov, S S

    1987-01-01

    Using the technique of contrasting the cerebral tissue with phosphotungstic acid, the authors studied the structural and functional status of interneuronal contacts of the molecular layer of the sensomotor cortex in the brain of Krushinsky-Molodkina rats following convulsive sound stimulation and the subsequent audiogenic convulsive paroxysm. Marked reduction in the general number of synapses 4 h after the attack was attended by transformation of some flat functionally mature contacts into concave ones, which reflects the activation of the synaptic pool. The relative levels of concave and flat mature contacts returned to the initial level 8 to 24 h later.

  4. Temporal dynamics of distinct CA1 cell populations during unconscious state induced by ketamine.

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    Hui Kuang

    2010-12-01

    Full Text Available Ketamine is a widely used dissociative anesthetic which can induce some psychotic-like symptoms and memory deficits in some patients during the post-operative period. To understand its effects on neural population dynamics in the brain, we employed large-scale in vivo ensemble recording techniques to monitor the activity patterns of simultaneously recorded hippocampal CA1 pyramidal cells and various interneurons during several conscious and unconscious states such as awake rest, running, slow wave sleep, and ketamine-induced anesthesia. Our analyses reveal that ketamine induces distinct oscillatory dynamics not only in pyramidal cells but also in at least seven different types of CA1 interneurons including putative basket cells, chandelier cells, bistratified cells, and O-LM cells. These emergent unique oscillatory dynamics may very well reflect the intrinsic temporal relationships within the CA1 circuit. It is conceivable that systematic characterization of network dynamics may eventually lead to better understanding of how ketamine induces unconsciousness and consequently alters the conscious mind.

  5. Distinct kinetics of inhibitory currents in thalamocortical neurons that arise from dendritic or axonal origin.

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    Sunggu Yang

    Full Text Available Thalamocortical neurons in the dorsal lateral geniculate nucleus (dLGN transfer visual information from retina to primary visual cortex. This information is modulated by inhibitory input arising from local interneurons and thalamic reticular nucleus (TRN neurons, leading to alterations of receptive field properties of thalamocortical neurons. Local GABAergic interneurons provide two distinct synaptic outputs: axonal (F1 terminals and dendritic (F2 terminals onto dLGN thalamocortical neurons. By contrast, TRN neurons provide only axonal output (F1 terminals onto dLGN thalamocortical neurons. It is unclear if GABAA receptor-mediated currents originating from F1 and F2 terminals have different characteristics. In the present study, we examined multiple characteristics (rise time, slope, halfwidth and decay τ of GABAA receptor-mediated miniature inhibitory postsynaptic synaptic currents (mIPSCs originating from F1 and F2 terminals. The mIPSCs arising from F2 terminals showed slower kinetics relative to those from F1 terminals. Such differential kinetics of GABAAR-mediated responses could be an important role in temporal coding of visual signals.

  6. Voxel Scale Complex Networks of Functional Connectivity in the Rat Brain: Neurochemical State Dependence of Global and Local Topological Properties

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    Adam J. Schwarz

    2012-01-01

    Full Text Available Network analysis of functional imaging data reveals emergent features of the brain as a function of its topological properties. However, the brain is not a homogeneous network, and the dependence of functional connectivity parameters on neuroanatomical substrate and parcellation scale is a key issue. Moreover, the extent to which these topological properties depend on underlying neurochemical changes remains unclear. In the present study, we investigated both global statistical properties and the local, voxel-scale distribution of connectivity parameters of the rat brain. Different neurotransmitter systems were stimulated by pharmacological challenge (d-amphetamine, fluoxetine, and nicotine to discriminate between stimulus-specific functional connectivity and more general features of the rat brain architecture. Although global connectivity parameters were similar, mapping of local connectivity parameters at high spatial resolution revealed strong neuroanatomical dependence of functional connectivity in the rat brain, with clear differentiation between the neocortex and older brain regions. Localized foci of high functional connectivity independent of drug challenge were found in the sensorimotor cortices, consistent with the high neuronal connectivity in these regions. Conversely, the topological properties and node roles in subcortical regions varied with neurochemical state and were dependent on the specific dynamics of the different functional processes elicited.

  7. Cerebellar neurochemical and histopathological changes in rat model of Parkinson's disease induced by intrastriatal injection of rotenone.

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    Khadrawy, Yasser A; Mourad, Iman M; Mohammed, Haitham S; Noor, Neveen A; Aboul Ezz, Heba S

    2017-01-01

    The aim of the present work was to investigate the neurochemical changes induced in the cerebellum of rat model of Parkinson's disease (PD). Rats were divided into two groups; control and rat model of PD induced by the intrastriatal injection of rotenone. As compared to control, a significant increase in the excitatory amino acid neurotransmitters; glutamate and aspartate together with a significant decrease in the inhibitory amino acids, GABA, glycine and taurine were observed in the cerebellum of rat model of PD. This was associated with a significant increase in lipid peroxidation, nitric oxide and tumor necrosis factor-α and a significant decrease in reduced glutathione. A significant decrease in acetylcholinesterase and a significant increase in Na+,K+-ATPase were recorded in the cerebellum of rat model of PD. In addition the cerebellar sections from rat model of PD showed marked necrosis of Purkinje cells, irregular damaged cells, cytoplasmic shrinkage, necrosis and perineuronal vacuolation. The present results indicate that the disturbance in the balance between the excitatory and inhibitory amino acids may have a role in the pathogenesis of PD. According to the present neurochemical and histopathological changes, the cerebellum should be taken into consideration during the treatment of PD.

  8. Attenuation of neurobehavioral and neurochemical abnormalities in animal model of cognitive deficits of Alzheimer's disease by fermented soybean nanonutraceutical.

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    Bhatt, Prakash Chandra; Pathak, Shruti; Kumar, Vikas; Panda, Bibhu Prasad

    2018-02-01

    The present study was performed to evaluate the efficacy of nanonutraceuticals (NN) for attenuation of neurobehavioral and neurochemical abnormalities in Alzheimer's disease. Solid-state fermentation of soybean with Bacillus subtilis was performed to produce different metabolites (nattokinase, daidzin, genistin and glycitin and menaquinone-7). Intoxication of rats with colchicine caused impairment in learning and memory which was demonstrated in neurobehavioral paradigms (Morris water maze and passive avoidance) linked with decreased activity of acetylcholinesterase (AChE). NN treatment led to a significant increase in TLT in the retention trials as compared to acquisition trial TLT suggesting an improved learning and memory in rats. Further, treatment of NN caused an increase in the activity of AChE (42%), accompanied with a reduced activity of glutathione (42%), superoxide dismutase (43%) and catalase (41%). It also decreased the level of lipid peroxidation (28%) and protein carbonyl contents (30%) in hippocampus as compared to those treated with colchicine alone, suggesting a possible neuroprotective efficacy of NN. Interestingly, in silico studies also demonstrated an effective amyloid-β and BACE-1 inhibition activity. These findings clearly indicated that NN reversed colchicine-induced behavioral and neurochemical alterations through potent antioxidant activity and could possibly impart beneficial effects in cognitive defects associated with Alzheimer's disease.

  9. Neuroendocrine and neurochemical impact of aggressive social interactions in submissive and dominant mice: implications for stress-related disorders.

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    Audet, Marie-Claude; Anisman, Hymie

    2010-04-01

    Social conflicts may engender stress-related behavioural and physiological disturbances in the victims of aggression. In addition, stress-like neurochemical changes and ensuing depressive and anxiety symptoms might also be evident in the perpetrators of aggressive acts. The present investigation assessed basal levels of circulating corticosterone and of brain serotonin (5-HT) and norepinephrine (NE) in pre-identified submissive and dominant mice. In addition, brain neurochemical changes were determined following a single or three 15-min aggressive episodes both in submissive mice and in those that dominated the aggressive interplay. Three minutes after single and repeated confrontations, plasma corticosterone levels and 5-HT utilization within the prefrontal cortex (PFC) and hippocampus were increased to a comparable extent in submissive and dominant animals. Interestingly, however, NE utilization within the PFC and hippocampus was augmented to a greater level in submissive mice. These results suggest that 5-HT neuronal functioning was generally responsive to aggressive events, irrespective of social rank, whereas NE neuronal activity within the PFC and hippocampus was more sensitive to the submissive/dominance attributes of the social situation. It is possible that NE and 5-HT variations associated with an aggressive experience contribute to depressive- and anxiety-like manifestations typically observed after such psychosocial stressors, particularly in submissive mice. However, given that 5-HT changes occur irrespective of social rank, these data suggest that a toll is taken on both submissive and dominant mice, leaving them vulnerable to stress-related pathology.

  10. Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson's Disease.

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    He, Qing; Koprich, James B; Wang, Ying; Yu, Wen-bo; Xiao, Bao-guo; Brotchie, Jonathan M; Wang, Jian

    2016-05-01

    The accumulation of misfolded α-synuclein in dopamine (DA) neurons is believed to be of major importance in the pathogenesis of Parkinson's disease (PD). Animal models of PD, based on viral-vector-mediated over-expression of α-synuclein, have been developed and show evidence of dopaminergic toxicity, providing us a good tool to investigate potential therapies to interfere with α-synuclein-mediated pathology. An efficient disease-modifying therapeutic molecule should be able to interfere with the neurotoxicity of α-synuclein aggregation. Our study highlighted the ability of an autophagy enhancer, trehalose (at concentrations of 5 and 2% in drinking water), to protect against A53T α-synuclein-mediated DA degeneration in an adeno-associated virus serotype 1/2 (AAV1/2)-based rat model of PD. Behavioral tests and neurochemical analysis demonstrated a significant attenuation in α-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration including impaired DA neuronal survival and DA turnover, as well as α-synuclein accumulation and aggregation in the nigrostriatal system by commencing 5 and 2% trehalose at the same time as delivery of AAV. Trehalose (0.5%) was ineffective on the above behavioral and neurochemical deficits. Further investigation showed that trehalose enhanced autophagy in the striatum by increasing formation of LC3-II. This study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse α-synuclein aggregation for the treatment of PD.

  11. Using position emission tomography to investigate hormone-mediated neurochemical changes across the female lifespan: implications for depression.

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    Zsido, Rachel G; Villringer, Arno; Sacher, Julia

    2017-12-01

    Ovarian hormones, particularly oestrogen and progesterone, undergo major fluctuations across the female lifespan. These hormone transition periods, such as the transition from pregnancy to postpartum, as well as the transition into menopause (perimenopause), are also known to be times of elevated susceptibility to depression. This study reviews how these transition periods likely influence neurochemical changes in the brain that result in disease vulnerability. While there are known associations between oestrogen/progesterone and different monoaminergic systems, the interactions and their potential implications for mood disorders are relatively unknown. Positron Emission Tomography (PET) allows for the in-vivo quantification of such neurochemical changes, and, thus, can provide valuable insight into how both subtle and dramatic shifts in hormones contribute to the elevated rates of depression during pre-menstrual, post-partum, and perimenopausal periods in a woman's life. As one better understands how to address the challenges of PET studies involving highly vulnerable populations, such as women who have recently given birth, one will gain the insight necessary to design and individualize treatment and therapy. Understanding the precise time-line in younger women when dramatic fluctuations in the hormonal milieu may contribute to brain changes may present a powerful opportunity to intervene before a vulnerable state develops into a diseased state in later life.

  12. Cortical interneurons migrating on a pure substrate of N-cadherin exhibit fast synchronous centrosomal and nuclear movements and reduced ciliogenesis

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    Camilla eLuccardini

    2015-08-01

    Full Text Available The embryonic development of the cortex involves a phase of long distance migration of interneurons born in the basal telencephalon. Interneurons first migrate tangentially and then reorient their trajectories radially to enter the developing cortex. We have shown that migrating interneurons can assemble a primary cilium, which maintains the centrosome to the plasma membrane and processes signals to control interneuron trajectory (Baudoin et al., 2012. In the developing cortex, N-cadherin is expressed by migrating interneurons and by cells in their migratory pathway. N-cadherin promotes the motility and maintains the polarity of tangentially migrating interneurons (Luccardini et al., 2013. Because N-cadherin is an important factor that regulates the migration of MGE cells in vivo, we further characterized the motility and polarity of MGE cells on a substrate that only comprises this protein. MGE cells migrating on a N-cadherin substrate were seven times faster than on a laminin substrate and two times faster than on a substrate of cortical cells. A primary cilium was much less frequently observed on MGE cells migrating on N-cadherin than on laminin. Nevertheless, the mature centriole frequently docked to the plasma membrane in MGE cells migrating on N-cadherin, suggesting that plasma membrane docking is a basic feature of the centrosome in migrating MGE cells. On the N-cadherin substrate, centrosomal and nuclear movements were remarkably synchronous and the centrosome remained near the nucleus. Interestingly, MGE cells with cadherin invalidation presented centrosomal movements no longer coordinated with nuclear movements. In summary, MGE cells migrating on a pure substrate of N-cadherin show fast, coordinated nuclear and centrosomal movements, and rarely present a primary cilium.

  13. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.

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    Laura Leung

    Full Text Available 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.

  14. 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

    2017-02-03

    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.

  15. Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC.

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    Rao, S G; Williams, G V; Goldman-Rakic, P S

    1999-04-01

    Studies on the cellular mechanisms of working memory demonstrated that neurons in dorsolateral prefrontal cortex (dPFC) exhibit directionally tuned activity during an oculomotor delayed response. To determine the particular contributions of pyramidal cells and interneurons to spatial tuning in dPFC, we examined both individually and in pairs the tuning properties of regular-spiking (RS) and fast-spiking (FS) units that represent putative pyramidal cells and interneurons, respectively. Our main finding is that FS units possess spatially tuned sensory, motor, and delay activity (i. e., "memory fields") similar to those found in RS units. Furthermore, when recorded simultaneously at the same site, the majority of neighboring neurons, whether FS or RS, displayed isodirectional tuning, i.e., they shared very similar tuning angles for the sensory and delay phases of the task. As the trial entered the response phase of the task, many FS units shifted their direction of tuning and became cross-directional to adjacent RS units by the end of the trial. These results establish that a large part of inhibition in prefrontal cortex is spatially oriented rather than being untuned and simply regulating the threshold response of pyramidal cell output. Moreover, the isodirectional tuning between adjacent neurons supports a functional microcolumnar organization in dPFC for spatial memory fields similar to that found in other areas of cortex for sensory receptive fields.

  16. Hippocampal pathology in the human neuronal ceroid-lipofuscinoses: distinct patterns of storage deposition, neurodegeneration and glial activation.

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    Tyynelä, Jaana; Cooper, Jonathan D; Khan, M Nadeem; Shemilts, Stephen J A; Haltia, Matti

    2004-10-01

    The neuronal ceroid-lipofuscinoses (NCLs) are recessively inherited lysosomal storage diseases, currently classified into 8 forms (CLN1-CLN8). Collectively, the NCLs constitute the most common group of progressive encephalopathies of childhood, and present with visual impairment, psychomotor deterioration and severe seizures. Despite recent identification of the underlying disease genes, the mechanisms leading to neurodegeneration and epilepsy in the NCLs remain poorly understood. To investigate these events, we examined the patterns of storage deposition, neurodegeneration, and glial activation in the hippocampus of patients with CLN1, CLN2, CLN3, CLN5 and CLN8 using histochemistry and immunohistochemistry. These different forms of NCL shared distinct patterns of neuronal degeneration in the hippocampus, with heavy involvement of sectors CA2-CA4 but relative sparing of CA1. This selective pattern of degeneration was also observed in immunohistochemically identified interneurons, which exhibited a graded severity of loss according to phenotype, with calretinin-positive interneurons relatively spared. Furthermore, glial activation was also regionally specific, with microglial activation most pronounced in areas of greatest neuronal loss, and astrocyte activation prominent in areas where neuronal loss was less evident. In conclusion, the NCLs share a common pattern of selective hippocampal pathology, distinct from that seen in the majority of temporal lobe epilepsies.

  17. Behavioral and Neurochemical Studies in Stressed and Unstressed Rats Fed on Protein, Carbohydrate and Fat Rich Diet

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    Samia Moin§, Saida Haider*, Saima Khaliq1, Saiqa Tabassum and Darakhshan J. Haleem

    2012-05-01

    Full Text Available Stress produces behavioral and neurochemical deficits. To study the relationship between adaptation to stress and macronutrient intake, the present study was designed to monitor the effects of different diets on feed intake, growth rate and serotonin (5-Hydroxytryptamine, 5-HT metabolism following exposure to restraint stress in rats. Rats were divided into four groups (n=12 as control, sugar, protein and fat rich diet fed rats. After 5 weeks of treatment animals of each group were divided into unrestrained and restrained animals (n=6. Rats of restrained group were given immobilization stress for 2 hours/day for 5 days. Food intake and growth rates of unrestrained and restrained rats were monitored daily. Rats were decapitated on 6th day to collect brain samples for neurochemical estimation. Results show that sugar diet fed rats produced adaptation to stress early as compared to normal diet fed rats. Food intake and growth rates of unrestrained and restrained rats were comparable on 3rd day in sugar diet fed rats and on 4th day in normal diet fed rats. Stress decreased food intake and growth rates of protein and fat treated rats. Repeated stress did not alter brain 5-HT and 5-HIAA levels of normal diet fed rats and sugar diet fed rats. Protein diet fed restrained rats showed elevated brain 5-HT levels. Fat diet fed restrained rats significantly decreased brain TRP and 5-HIAA levels. Finding suggested that carbohydrate diet might protect against stressful conditions. Study also showed that nutritional status could alter different behaviors in response to a stressful environment.

  18. Protective effect of curcumin and its combination with piperine (bioavailability enhancer) against haloperidol-associated neurotoxicity: cellular and neurochemical evidence.

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    Bishnoi, Mahendra; Chopra, Kanwaljit; Rongzhu, Lu; Kulkarni, Shrinivas K

    2011-10-01

    Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects, particularly the irregular movements of chorionic type. This limitation presents a marked therapeutic challenge. The present study investigates the molecular etiology of haloperidol neurotoxicity and the role of curcumin, a well-known anti-oxidant, in ameliorating these adverse effects. The redox status of haloperidol-treated brains along with NO, TNF-α, NF-kappaB p65 subunit, caspase-3, and monoamine neurotransmitters were measured in the striatum of rat brain. Chronic treatment with haloperidol (5 mg/kg, i.p., 21 days) produced orofacial dyskinetic movements which were coupled with marked increase in oxidative stress parameters, TNF-α, caspase-3 activity in cytoplasmic lysate and active p65 sub unit of NF-kappaB in nuclear lysates of the striatum. Neurochemically, chronic administration of haloperidol resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin. The prototype atypical anti-psychotic, clozapine (10 mg/kg, i.p., 21 days) produced mild oxidative stress but did not alter any other parameters. Interestingly, co-administration of curcumin (25 and 50 mg/kg, i.p., 21 days) dose-dependently prevented all the behavioral, cellular, and neurochemical changes associated with the chronic administration of haloperidol. Curcumin per se (50 mg/kg) did not show any side effects. Co-administration of piperine significantly enhanced the effect of curcumin (25 mg/kg) but not of curcumin (50 mg/kg). Collectively, the data indicated the potential of curcumin as an adjunct to haloperidol treatment and provided initial clues to the underlying molecular mechanisms in haloperidol neurotoxicity. This study also provides a rationale for the combination of piperine and curcumin.

  19. Effects of electroconvulsive seizures on depression-related behavior, memory and neurochemical changes in Wistar and Wistar-Kyoto rats.

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    Kyeremanteng, C; MacKay, J C; James, J S; Kent, P; Cayer, C; Anisman, H; Merali, Z

    2014-10-03

    Investigations in healthy outbred rat strains have shown a potential role for brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis in the antidepressant and memory side effects of electroconvulsive therapy (ECT, or ECS in animals). The Wistar-Kyoto (WKY) rat strain is used as a genetic model of depression yet no studies to date have directly compared the impact of ECS on the WKY strain to its healthy outbred control (Wistar). The objective of this study is to examine behavioral (antidepressant and retrograde memory) and neurochemical (BDNF and HPA axis) changes immediately (1day) and at a longer delay (7days) after repeated ECS (5 daily administrations) in WKY and Wistar rats. Male Wistar and WKY rats received 5days of repeated ECS or sham treatment and were assessed 1 and 7days later for 1) depression-like behavior and mobility; 2) retrograde memory; and 3) brain BDNF protein, brain corticotropin-releasing factor (CRF) and plasma corticosterone levels. Both strains showed the expected antidepressant response and retrograde memory impairments at 1day following ECS, which were sustained at 7days. In addition, at 1day after ECS, Wistar and WKY rats showed similar elevations in brain BDNF and extra-hypothalamic CRF and no change in plasma corticosterone. At 7days after ECS, Wistar rats showed sustained elevations of brain BDNF and CRF, whereas WKY rats showed a normalization of brain BDNF, despite sustained elevations of brain CRF. The model of 5 daily ECS was effective at eliciting behavioral and neurochemical changes in both strains. A temporal association was observed between brain CRF levels, but not BDNF, and measures of antidepressant effectiveness of ECS and retrograde memory impairments suggesting that extra-hypothalamic CRF may be a potential important contributor to these behavioral effects after repeated ECS/ECT. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. Sparing of Descending Axons Rescues Interneuron Plasticity in the Lumbar Cord to Allow Adaptive Learning After Thoracic Spinal Cord Injury.

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    Hansen, Christopher N; Faw, Timothy D; White, Susan; Buford, John A; Grau, James W; Basso, D Michele

    2016-01-01

    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 (ILP). 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 7 days, 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 spared

  5. Functional Circuitry Effect of Ventral Tegmental Area Deep Brain Stimulation: Imaging and Neurochemical Evidence of Mesocortical and Mesolimbic Pathway Modulation.

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    Settell, Megan L; Testini, Paola; Cho, Shinho; Lee, Jannifer H; Blaha, Charles D; Jo, Hang J; Lee, Kendall H; Min, Hoon-Ki

    2017-01-01

    Background: The ventral tegmental area (VTA), containing mesolimbic and mesocortical dopaminergic neurons, is implicated in processes involving reward, addiction, reinforcement, and learning, which are associated with a variety of neuropsychiatric disorders. Electrical stimulation of the VTA or the medial forebrain bundle and its projection target the nucleus accumbens (NAc) is reported to improve depressive symptoms in patients affected by severe, treatment-resistant major depressive disorder (MDD) and depressive-like symptoms in animal models of depression. Here we sought to determine the neuromodulatory effects of VTA deep brain stimulation (DBS) in a normal large animal model (swine) by combining neurochemical measurements with functional magnetic resonance imaging (fMRI). Methods: Animals (n = 8 swine) were implanted with a unilateral DBS electrode targeting the VTA. During stimulation (130 Hz frequency, 0.25 ms pulse width, and 3 V amplitude), fMRI was performed. Following fMRI, fast-scan cyclic voltammetry in combination with carbon fiber microelectrodes was performed to quantify VTA-DBS-evoked dopamine release in the ipsilateral NAc. In a subset of swine, the blood oxygen level-dependent (BOLD) percent change evoked by stimulation was performed at increasing voltages (1, 2, and 3 V). Results: A significant increase in VTA-DBS-evoked BOLD signal was found in the following regions: the ipsilateral dorsolateral prefrontal cortex, anterior and posterior cingulate, insula, premotor cortex, primary somatosensory cortex, and striatum. A decrease in the BOLD signal was also observed in the contralateral parahippocampal cortex, dorsolateral and anterior prefrontal cortex, insula, inferior temporal gyrus, and primary somatosensory cortex (Bonferroni-corrected modulation of the neural circuitry associated with VTA-DBS was characterized in a large animal. Our findings suggest that VTA-DBS could affect the activity of neural systems and brain regions implicated in

  6. Transplacental exposure to AZT induces adverse neurochemical and behavioral effects in a mouse model: protection by L-acetylcarnitine.

    Directory of Open Access Journals (Sweden)

    Anna Rita Zuena

    Full Text Available Maternal-fetal HIV-1 transmission can be prevented by administration of AZT, alone or in combination with other antiretroviral drugs to pregnant HIV-1-infected women and their newborns. In spite of the benefits deriving from this life-saving prophylactic therapy, there is still considerable uncertainty on the potential long-term adverse effects of antiretroviral drugs on exposed children. Clinical and experimental studies have consistently shown the occurrence of mitochondrial dysfunction and increased oxidative stress following prenatal treatment with antiretroviral drugs, and clinical evidence suggests that the developing brain is one of the targets of the toxic action of these compounds possibly resulting in behavioral problems. We intended to verify the effects on brain and behavior of mice exposed during gestation to AZT, the backbone of antiretroviral therapy during human pregnancy. We hypothesized that glutamate, a neurotransmitter involved in excitotoxicity and behavioral plasticity, could be one of the major actors in AZT-induced neurochemical and behavioral alterations. We also assessed the antioxidant and neuroprotective effect of L-acetylcarnitine, a compound that improves mitochondrial function and is successfully used to treat antiretroviral-induced polyneuropathy in HIV-1 patients. We found that transplacental exposure to AZT given per os to pregnant mice from day 10 of pregnancy to delivery impaired in the adult offspring spatial learning and memory, enhanced corticosterone release in response to acute stress, increased brain oxidative stress also at birth and markedly reduced expression of mGluR1 and mGluR5 subtypes and GluR1 subunit of AMPA receptors in the hippocampus. Notably, administration during the entire pregnancy of L-acetylcarnitine was effective in preventing/ameliorating the neurochemical, neuroendocrine and behavioral adverse effects induced by AZT in the offspring. The present preclinical findings provide a

  7. Counselor Identity: Conformity or Distinction?

    Science.gov (United States)

    McLaughlin, Jerry E.; Boettcher, Kathryn

    2009-01-01

    The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

  8. Neurochemical phenotype and function of endomorphin 2-immunopositive neurons in the myenteric plexus of the rat colon

    Directory of Open Access Journals (Sweden)

    Yun-Qing eLi

    2014-12-01

    Full Text Available The distribution and activity of endomorphins (EMs, which are endogenous m-opioid receptor (MOR ligands in the gastrointestinal tract (GI, have yet to be elucidated. The current study aimed to shed light on this topic. EM2 was expressed in the enteric neurons in the myenteric plexus of the mid-colon. Of the EM2-immunoreactive (EM2-IR neurons, 53 ± 4.6%, 26 ± 4.5%, 26 ± 2.8% and 49 ± 4.2% displayed immunopositive staining for choline acetyl transferase (ChAT, substance P (SP, vasoactive intestinal peptide (VIP and nitric oxide synthetase (NOS, respectively. A bath application of EM2 (2 mM enhanced spontaneous contractile amplitude and tension, which were reversed by β-FNA (an antagonist of MOR but not NG-nitro-L-arginine methyl ether (L-NAME, a non-selective inhibitor of NOS or vasoactive intestinal peptide (VIP6-28 (an antagonist of the VIP receptor in the colonic strips. EM2 significantly suppressed inhibitory junction potentials (IJPs in 14 of the 17 examined circular muscle cells, and this effect was not antagonized by preincubation in L-NAME. EM2 was widely expressed in interneurons and motor neurons in the myenteric plexus and presynaptically inhibited fast IJPs, thereby enhancing spontaneous contraction and tension in the colonic smooth muscle.

  9. Interneurons and proprioneurons in the adult human spinal grey matter and in the general somatic and visceral afferent cranial nerve nuclei.

    OpenAIRE

    Abdel-Maguid, T E; Bowsher, D

    1984-01-01

    Using the classification of Abdel-Maguid & Bowsher (1984), interneurons of the dorsal horn of the grey matter of the human spinal cord and medulla oblongata were found to belong to only three 'families' of neurons, out of a possible thirteen. This is in itself one of the justifications for the method of classification. Functional identification of these human neurons has been made on the basis of topological, morphological and projectional comparison with known cells in other mammalian specie...

  10. Cell Type-Specific Expression of Corticotropin-Releasing Hormone-Binding Protein in GABAergic Interneurons in the Prefrontal Cortex

    Directory of Open Access Journals (Sweden)

    Kyle D. Ketchesin

    2017-10-01

    Full Text Available Corticotropin-releasing hormone-binding protein (CRH-BP is a secreted glycoprotein that binds CRH with very high affinity to modulate CRH receptor activity. CRH-BP is widely expressed throughout the brain, with particularly high expression in regions such as the amygdala, hippocampus, ventral tegmental area and prefrontal cortex (PFC. Recent studies suggest a role for CRH-BP in stress-related psychiatric disorders and addiction, with the PFC being a potential site of interest. However, the molecular phenotype of CRH-BP-expressing cells in this region has not been well-characterized. In the current study, we sought to determine the cell type-specific expression of CRH-BP in the PFC to begin to define the neural circuits in which this key regulator is acting. To characterize the expression of CRH-BP in excitatory and/or inhibitory neurons, we utilized dual in situ hybridization to examine the cellular colocalization of CRH-BP mRNA with vesicular glutamate transporter (VGLUT or glutamic acid decarboxylase (GAD mRNA in different subregions of the PFC. We show that CRH-BP is expressed predominantly in GABAergic interneurons of the PFC, as revealed by the high degree of colocalization (>85% between CRH-BP and GAD. To further characterize the expression of CRH-BP in this heterogenous group of inhibitory neurons, we examined the colocalization of CRH-BP with various molecular markers of GABAergic interneurons, including parvalbumin (PV, somatostatin (SST, vasoactive intestinal peptide (VIP and cholecystokinin (CCK. We demonstrate that CRH-BP is colocalized predominantly with SST in the PFC, with lower levels of colocalization in PV- and CCK-expressing neurons. Our results provide a more comprehensive characterization of the cell type-specific expression of CRH-BP and begin to define its potential role within circuits of the PFC. These results will serve as the basis for future in vivo studies to manipulate CRH-BP in a cell type-specific manner to better

  11. Chronic neurochemical and behavioral changes in MPTP-lesioned C57BL/6 mice: a model for Parkinson's disease.

    Science.gov (United States)

    Sundström, E; Fredriksson, A; Archer, T

    1990-10-01

    The long-term effect of the parkinsonism inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on pre- and postsynaptic structures of the nigrostriatal and mesolimbic dopamine (DA) system in adult C57BL/6 mice (2 x 40 mg/kg s.c.) was investigated using neurochemical and behavioral methods. It was found that MPTP induced a severe depletion of striatal DA levels (-80%) that persists for 4 weeks after treatment, with less severe effects in nucleus accumbens (-36%) and the olfactory tubercle (-52%). These depletions are associated with decreased tyrosine hydroxylase (TH) activity as determined in vivo and increased turnover of DA. MPTP treatment did not induce any change in the DA2-receptor as determined by [3H]spiperone binding or by two different behavioral tests, i.e. apomorphine-induced climbing and apomorphine-induced stereotypies. No significant weight loss during 4 weeks after MPTP was found. The spontaneous motor activity in these mice was profoundly and persistently depressed (-66%) as a result of the MPTP-induced DA denervation and the motor deficit was completely reversed by L-DOPA treatment. We suggest that MPTP-treated C57BL/6 mice may serve as a suitable model for Parkinson's disease.

  12. Theophylline, adenosine receptor antagonist prevents behavioral, biochemical and neurochemical changes associated with an animal model of tardive dyskinesia.

    Science.gov (United States)

    Bishnoi, Mahendra; Chopra, Kanwaljit; Kulkarni, Shrinivas K

    2007-01-01

    Tardive dyskinesia is considered to be the late onset adverse effect of prolonged administration of typical neuroleptic drugs. Adenosine is now widely accepted as the major inhibitory neuromodulators in the central nervous system besides GABA. Antagonists of A2A receptors are known to confer protection against neuronal damage caused by toxins and reactive oxygen species. The present study investigated the effect of adenosine receptor antagonist, theophylline (25 and 50 mg/kg, ip) in an animal model of tardive dyskinesia by using different behavioral (orofacial dyskinetic movements, stereotypy, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase)) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg ip for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by theophylline. Chronic administration of haloperidol also resulted in the increased dopamine receptor sensitivity as evidenced by increased locomotor activity and stereotypic rearing. Further, it also decreased % retention time in elevated plus maze paradigm. Pretreatment with theophylline reversed these behavioral changes. Chronic administration of haloperidol also induced oxidative damage in all the brain regions which was prevented by theophylline, especially in the striatum. Chronic administration of haloperidol resulted in a decrease in dopamine levels which was reversed by treatment with theophylline (at higher doses). The findings of the present study suggested the involvement of adenosinergic receptor system in the development of tardive dyskinesia and possible therapeutic potential of theophylline in this disorder.

  13. In vivo magnetic resonance studies reveal neuroanatomical and neurochemical abnormalities in the serine racemase knockout mouse model of schizophrenia.

    Science.gov (United States)

    Puhl, Matthew D; Mintzopoulos, Dionyssios; Jensen, J Eric; Gillis, Timothy E; Konopaske, Glenn T; Kaufman, Marc J; Coyle, Joseph T

    2015-01-01

    Decreased availability of the N-methyl-D-aspartate receptor (NMDAR) co-agonist D-serine is thought to promote NMDAR hypofunction and contribute to the pathophysiology of schizophrenia, including neuroanatomical abnormalities, such as cortical atrophy and ventricular enlargement, and neurochemical abnormalities, such as aberrant glutamate and γ-aminobutyric acid (GABA) signaling. It is thought that these abnormalities directly relate to the negative symptoms and cognitive impairments that are hallmarks of the disorder. Because of the genetic complexity of schizophrenia, animal models of the disorder are extremely valuable for the study of genetically predisposing factors. Our laboratory developed a transgenic mouse model lacking serine racemase (SR), the synthetic enzyme of d-serine, polymorphisms of which are associated with schizophrenia. Null mutants (SR-/-) exhibit NMDAR hypofunction and cognitive impairments. We used 9.4 T magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to compare in vivo brain structure and neurochemistry in wildtype (WT) and SR-/- mice. Mice were anesthetized with isoflurane for MRI and MRS scans. Compared to WT controls, SR-/- mice exhibited 23% larger ventricular volumes (pcomparable to those previously reported in humans with schizophrenia. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Functional and neurochemical interactions within the amygdala-medial prefrontal cortex circuit and their relevance to emotional processing.

    Science.gov (United States)

    Delli Pizzi, Stefano; Chiacchiaretta, Piero; Mantini, Dante; Bubbico, Giovanna; Ferretti, Antonio; Edden, Richard A; Di Giulio, Camillo; Onofrj, Marco; Bonanni, Laura

    2017-04-01

    The amygdala-medial prefrontal cortex (mPFC) circuit plays a key role in emotional processing. GABA-ergic inhibition within the mPFC has been suggested to play a role in the shaping of amygdala activity. However, the functional and neurochemical interactions within the amygdala-mPFC circuits and their relevance to emotional processing remain unclear. To investigate this circuit, we obtained resting-state functional magnetic resonance imaging (rs-fMRI) and proton MR spectroscopy in 21 healthy subjects to assess the potential relationship between GABA levels within mPFC and the amygdala-mPFC functional connectivity. Trait anxiety was assessed using the State-Trait Anxiety Inventory (STAI-Y2). Partial correlations were used to measure the relationships among the functional connectivity outcomes, mPFC GABA levels and STAI-Y2 scores. Age, educational level and amount of the gray and white matters within 1 H-MRS volume of interest were included as nuisance variables. The rs-fMRI signals of the amygdala and the vmPFC were significantly anti-correlated. This negative functional coupling between the two regions was inversely correlated with the GABA+/tCr level within the mPFC and the STAI-Y2 scores. We suggest a close relationship between mPFC GABA levels and functional interactions within the amygdala-vmPFC circuit, providing new insights in the physiology of emotion.

  15. Magnesium Sulfate Prevents Neurochemical and Long-Term Behavioral Consequences of Neonatal Excitotoxic Lesions: Comparison Between Male and Female Mice.

    Science.gov (United States)

    Daher, Ismaël; Le Dieu-Lugon, Bérénice; Dourmap, Nathalie; Lecuyer, Matthieu; Ramet, Lauriane; Gomila, Cathy; Ausseil, Jérôme; Marret, Stéphane; Leroux, Philippe; Roy, Vincent; El Mestikawy, Salah; Daumas, Stéphanie; Gonzalez, Bruno; Leroux-Nicollet, Isabelle; Cleren, Carine

    2017-10-01

    Magnesium sulfate (MgSO4) administration to mothers at risk of preterm delivery is proposed as a neuroprotective strategy against neurological alterations such as cerebral palsy in newborns. However, long-term beneficial or adverse effects of MgSO4 and sex-specific sensitivity remain to be investigated. We conducted behavioral and neurochemical studies of MgSO4 effects in males and females, from the perinatal period to adolescence in a mouse model of cerebral neonatal lesion. The lesion was produced in 5-day-old (P5) pups by ibotenate intracortical injection. MgSO4 (600 mg/kg, i.p.) prior to ibotenate prevented lesion-induced sensorimotor alterations in both sexes at P6 and P7. The lesion increased glutamate level at P10 in the prefrontal cortex, which was prevented by MgSO4 in males. In neonatally lesioned adolescent mice, males exhibited more sequelae than females in motor and cognitive functions. In the perirhinal cortex of adolescent mice, the neonatal lesion induced an increase in vesicular glutamate transporter 1 density in males only, which was negatively correlated with cognitive scores. Long-term sequelae were prevented by neonatal MgSO4 administration. MgSO4 never induced short- or long-term deleterious effect on its own. These results also strongly suggest that sex-specific neuroprotection should be foreseen in preterm infants. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  16. Ketamine alters cortical integration of GABAergic interneurons and induces long-term sex-dependent impairments in transgenic Gad67-GFP mice

    Science.gov (United States)

    Aligny, C; Roux, C; Dourmap, N; Ramdani, Y; Do-Rego, J-C; Jégou, S; Leroux, P; Leroux-Nicollet, I; Marret, S; Gonzalez, B J

    2014-01-01

    Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, widely used as an anesthetic in neonatal pediatrics, is also an illicit drug named Super K or KitKat consumed by teens and young adults. In the immature brain, despite several studies indicating that NMDA antagonists are neuroprotective against excitotoxic injuries, there is more and more evidence indicating that these molecules exert a deleterious effect by suppressing a trophic function of glutamate. In the present study, we show using Gad67-GFP mice that prenatal exposure to ketamine during a time-window in which GABAergic precursors are migrating results in (i) strong apoptotic death in the ganglionic eminences and along the migratory routes of GABAergic interneurons; (ii) long-term deficits in interneuron density, dendrite numbers and spine morphology; (iii) a sex-dependent deregulation of γ-aminobutyric acid (GABA) levels and GABA transporter expression; (iv) sex-dependent changes in the response to glutamate-induced calcium mobilization; and (v) the long-term sex-dependent behavioral impairment of locomotor activity. In conclusion, using a preclinical approach, the present study shows that ketamine exposure during cortical maturation durably affects the integration of GABAergic interneurons by reducing their survival and differentiation. The resulting molecular, morphological and functional modifications are associated with sex-specific behavioral deficits in adults. In light of the present data, it appears that in humans, ketamine could be deleterious for the development of the brain of preterm neonates and fetuses of addicted pregnant women. PMID:24991763

  17. Interneurons and proprioneurons in the adult human spinal grey matter and in the general somatic and visceral afferent cranial nerve nuclei.

    Science.gov (United States)

    Abdel-Maguid, T E; Bowsher, D

    1984-08-01

    Using the classification of Abdel-Maguid & Bowsher (1984), interneurons of the dorsal horn of the grey matter of the human spinal cord and medulla oblongata were found to belong to only three 'families' of neurons, out of a possible thirteen. This is in itself one of the justifications for the method of classification. Functional identification of these human neurons has been made on the basis of topological, morphological and projectional comparison with known cells in other mammalian species. Among the cells identified are gelatinosal interneurons and Renshaw cells of laminae VII and VIII. Neurons belonging to the same 'family' as Waldeyer cells of lamina I continue around the outer edge of the grey matter, their dendrites forming a part of the boundary between grey and white matter. Interneurons with small and very small dendrite fields lie on interlaminar boundaries and have mediolaterally oriented dendrites, in contrast to the craniocaudally oriented dendritic field of most dorsal horn neurons. If such dendrites lying along interlaminar boundaries are also found to exist in other species, it may explain the abrupt change in physiological characteristics which is found on passing an electrode from one lamina to another.

  18. Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum.

    Science.gov (United States)

    Hiroi, N; Graybiel, A M

    1996-10-07

    Atypical and typical neuroleptics, when administered chronically, can bring about profound but contrasting changes in schizophrenic symptoms and motor activation and dramatically modulate brain neurochemistry. To explore the transcriptional events that might be involved in this neurochemical regulation, we used immunohistochemistry and immunoblotting to examine the expression patterns of two bZip transcription factors, c-Fos and FosB, in the striatum of rats treated acutely and chronically with neuroleptic drugs of different classes. Typical and atypical neuroleptic drugs produced contrasting regulatory effects on a FosB-like protein of ca. 36-39 kDa, the molecular weight of truncated FosB (delta FosB). Chronic treatments with two typical neuroleptics, haloperidol and metoclopramide, but not with the atypical neuroleptic clozapine, led to markedly enhanced FosB-like immunoreactivity in the caudoputamen. Further, c-Fos-like protein in the striatum, considered a marker for the induction of antipsychotic actions by neuroleptic treatments, was downregulated by chronic treatment with the two potent antipsychotic drugs tested, but not by chronic treatment with metoclopramide, which has low antipsychotic efficacy but induces extrapyramidal side effects. These results suggest that chronic treatments with neuroleptics having different effects on cognitive and motor behavior induce different long-term changes in transcription factor expression in the striatum. Nevertheless, we found that neuroleptics of both classes regulated transcription factor expression in overlapping populations of striatal neurons expressing enkephalin or DARPP-32. Contrasting patterns of transcriptional regulation in these neurons may thus contribute to the distinct neurochemical and behavioral effects that characterize neuroleptics of different classes.

  19. Blood-based neurochemical diagnosis of vascular dementia: a pilot study.

    Science.gov (United States)

    Bibl, Mirko; Esselmann, Hermann; Mollenhauer, Brit; Weniger, Godehard; Welge, Volker; Liess, Michael; Lewczuk, Piotr; Otto, Markus; Schulz, Jörg B; Trenkwalder, Claudia; Kornhuber, Johannes; Wiltfang, Jens

    2007-10-01

    Blood-based tests for the differential diagnosis of Alzheimer's disease (AD) are under intensive investigation and have shown promising results with regard to Abeta40 and Abeta42 peptide species in incipient AD. Moreover, plasma Abeta40 was suggested as an independent cerebrovascular risk factor candidate. These considerations prompted us to analyse a total of 72 plasma samples in vascular dementias (VAD, n = 15), AD with cerebrovascular disease (AD with CVD, n = 7), AD (n = 15), Parkinson's disease and Parkinson's disease dementia (PD/PDD, n = 20) and 15 patients with depression that served as controls (DC) for distinct plasma amyloid-beta (Abeta) peptide patterns. For the analysis of plasma we used immunoprecipitation followed by the quantitative Abeta-SDS-PAGE/immunoblot. For comparison, CSF tau and Abeta1-42 analyses were performed. The major outcome was an increase in Abeta1-40 in plasma of VAD paralleled by a decrease in the ratio of Abeta1-38/Abeta1-40. The ratio Abeta1-38/Abeta1-40 in plasma enabled contrasts of beyond 85% and 80% for discriminating VAD from DC and all other patients, respectively. In CSF, we confirmed the typical CSF biomarker constellation of increased tau and diminished Abeta1-42 levels for AD. The diagnostic accuracy of plasma Abeta1-38/Abeta1-40 for VAD resembled the accuracy of CSF biomarkers for AD. From the presented results, we consider the ratio of plasma Abeta1-38/Abeta1-40 peptides to be a blood-based biomarker candidate for VAD.

  20. Npas4 regulates Mdm2 and thus Dcx in experience-dependent dendritic spine development of newborn olfactory bulb interneurons.

    Science.gov (United States)

    Yoshihara, Sei-Ichi; Takahashi, Hiroo; Nishimura, Nobushiro; Kinoshita, Masahito; Asahina, Ryo; Kitsuki, Michiko; Tatsumi, Kana; Furukawa-Hibi, Yoko; Hirai, Hirokazu; Nagai, Taku; Yamada, Kiyofumi; Tsuboi, Akio

    2014-08-07

    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. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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.

  2. Prolonged response to calling songs by the L3 auditory interneuron in female crickets (Acheta domesticus): intracellular evaluation.

    Science.gov (United States)

    Navia, Benjamin; Stout, John; Atkins, Gordon

    2003-03-01

    The L3 auditory interneuron in female Acheta domesticus, produces two different responses to the male calling song: an immediate response and a prolonged response. The prolonged response exhibited spiking activity and a correlated prolonged depolarization, both of which are clearly seen in intracellular recordings. The morphology revealed by intracellular staining was clearly the L3 neuron. The amplitude of the prolonged depolarization associated with the prolonged response increased with increases in sound intensity, resulting in increased spiking rates. Both depolarization and sound presentation increased the spiking rate and the slope of pre-potentials (thus leading to spiking threshold more quickly). Injecting hyperpolarizing current had the expected opposite effect. The effects of positive current injection and sound presentation were additive, resulting in spiking rates that were approximately double the rates in response to sound alone. Short postsynaptic potentials (PSPs), whose duration ranged from 15-60 ms, which may lead to action potentials were also observed in all recordings and summated with the prolonged depolarization, increasing the probability of spiking. Copyright 2003 Wiley-Liss, Inc.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Repeated Blockade of NMDA Receptors during Adolescence Impairs Reversal Learning and Disrupts GABAergic Interneurons in Rat Medial Prefrontal Cortex

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

  7. Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat.

    Science.gov (United States)

    Eskow Jaunarajs, Karen L; Dupre, Kristin B; Ostock, Corinne Y; Button, Thomas; Deak, Terrence; Bishop, Christopher

    2010-10-01

    Depression and anxiety are the prevalent nonmotor symptoms that worsen quality of life for Parkinson's disease (PD) patients. Although dopamine (DA) cell loss is a commonly proposed mechanism, the reported efficacy of DA replacement therapy with L-DOPA on affective symptoms is inconsistent. To delineate the effects of DA denervation and chronic L-DOPA treatment on affective behaviors, male Sprague-Dawley rats received unilateral 6-hydroxydopamine or sham lesions and were treated daily with L-DOPA (12 mg/kg+benserazide, 15 mg/kg, subcutaneously) or vehicle (0.9% NaCl, 0.1% ascorbic acid) for 28 days before commencing investigations into anxiety (locomotor chambers, social interaction) and depression-like behaviors (forced swim test) during the OFF phase of L-DOPA. One hour after the final treatments, rats were killed and striatum, prefrontal cortex, hippocampus, and amygdala were analyzed through high-performance liquid chromatography for monoamine levels. In locomotor chambers and social interaction, DA lesions exerted mild anxiogenic effects. Surprisingly, chronic L-DOPA treatment did not improve these effects. Although DA lesion reduced climbing behaviors on day 2 of exposure to the forced swim test, chronic L-DOPA treatment did not reverse these effects. Neurochemically, L-DOPA treatment in hemiparkinsonian rats reduced norepinephrine levels in the prefrontal cortex, striatum, and hippocampus. Collectively, these data suggest that chronic L-DOPA therapy in severely DA-lesioned rats does not improve nonmotor symptoms and may impair nondopaminergic processes, indicating that long-term L-DOPA therapy does not exert necessary neuroplastic changes for improving affect.

  8. Microfluidic Platform with In-Chip Electrophoresis Coupled to Mass Spectrometry for Monitoring Neurochemical Release from Nerve Cells.

    Science.gov (United States)

    Li, Xiangtang; Hu, Hankun; Zhao, Shulin; Liu, Yi-Ming

    2016-05-17

    Chemical stimulus-induced neurotransmitter release from neuronal cells is well-documented. However, the dynamic changes in neurochemical release remain to be fully explored. In this work, a three-layered microfluidic chip was fabricated and evaluated for studying the dynamics of neurotransmitter release from PC-12 cells. The chip features integration of a nanoliter sized chamber for cell perfusion, pneumatic pressure valves for fluidic control, a microfluidic channel for electrophoretic separation, and a nanoelectrospray emitter for ionization in MS detection. Deploying this platform, a microchip electrophoresis-mass spectrometric method (MCE-MS) was developed to simultaneously quantify important neurotransmitters, including dopamine (DA), serotonin (5-HT), aspartic acid (Asp), and glutamic acid (Glu) without need for labeling or enrichment. Monitoring neurotransmitter release from PC-12 cells exposed to KCl (or alcohol) revealed that all four neurotransmitters investigated were released. Two release patterns were observed, one for the two monoamine neurotransmitters (i.e., DA and 5-HT) and another for the two amino acid neurotransmitters. Release dynamics for the two monoamine neurotransmitters was significantly different. The cells released DA most quickly and heavily in response to the stimulation. After exposure to the chemical stimulus for 4 min, the DA level in the perfusate from the cells was 86% lower than that at the beginning. Very interestingly, the cells started to release 5-HT in large quantities when they stopped releasing DA. These results suggest that DA and 5-HT are packaged into different vesicle pools and they are mobilized differently in response to chemical stimuli. The microfluidic platform proposed is proven useful for monitoring cellular release in biological studies.

  9. Effects of polychlorinated biphenyl (PCB) on regulation of thyroid-, growth-, and neurochemically related developmental processes in young rats

    Energy Technology Data Exchange (ETDEWEB)

    Juarez de Ku, L.M.

    1992-01-01

    Neonatal exposure to the toxic chemical polychlorinated biphenyl (PCB) induces hypothyroidism and retarded growth. Neonatal rats made hypothyroid by chemical or surgical means experience retarded growth and subnormal activity of choline acetyltransferase (ChAT) This study compared thyroid-, growth-, and neurochemically-related processes altered by hypothyroidism induced by other means, with PCB-induced hypothyroidism: (1) titers of thyroid stimulating hormone (TSH); (2) titers of hormones that regulate growth [growth hormone (GH), insulin-growth like factor-I (IGF-1), growth hormone releasing hormone (GHRH) and somatostatin (SS)]; or (3) brain ChAT activity. Whether PCB-induced growth retardation and other alterations are secondary to accompanying hypothyroidism rather than or in addition to a direct effect of PCB was also examined. Pregnant rats were fed chow containing 0 (controls), 62.5, 125, or 250 ppm PCB (entering offspring through placenta and milk) throughout pregnancy and lactation. Neonates exposed to PCB displayed many alterations similar to those made hypothyroid by other means: depression of overall and skeletal growth, circulating by other means: depression of overall and skeletal growth, circulating T[sub 4] levels and ChAT activity, and no change in hypothalamic GHRH and SS concentrations. Differences included a paradoxical increase in circulating GH levels, and no significant alteration of circulation IGF-1 and TSH levels and pituitary GH and TSH levels (although trends were in the expected direction). Thus, PCB-induced hypothyroidism may partially cause altered skeletal growth, circulating GH and TSH concentrations, and ChAT activity. Both T[sub 4] and T[sub 3] injections returned circulating TSH and GH levels and pituitary TSH content toward control levels; T[sub 3] restored skeletal, but not overall growth; and T[sub 4] elevated ChAT activity.

  10. An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

    Science.gov (United States)

    Dencker, Ditte; Weikop, Pia; Sørensen, Gunnar; Woldbye, David P. D.; Wörtwein, Gitta; Wess, Jürgen; Fink-Jensen, Anders

    2014-01-01

    Rationale The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M4 acetylcholine receptor subtype is centrally involved in regulation of dopamine release in striatal areas. Consequently, striatal M4 receptors could be a novel target for modulating psychostimulant effects of cocaine. Objectives For the first time, we here addressed this issue by investigating the effects of a novel selective positive allosteric modulator of M4 receptors, VU0152100, on cocaine-induced behavioral and neurochemical effects in mice. Methods To investigate the effect of VU0152100 on the acute reinforcing effects of cocaine, we use an acute-cocaine self-administration model. We used in vivo microdialysis to investigate whether the effects of VU0152100 in the behavioral studies were mediated via effects on dopaminergic neurotransmission. In addition the effect of VU0152100 on cocaine-induced hyperactivity and rotarod performance was evaluated. Results We found that VU0152100 caused a prominent reduction in cocaine self-administration, cocaine-induced hyperlocomotion, and cocaine-induced striatal dopamine increase, without affecting motor performance. Consistent with these effects of VU0152100 being mediated via M4 receptors, its inhibitory effects on cocaine-induced increases in striatal dopamine were abolished in M4 receptor knockout mice. Furthermore, selective deletion of the M4 receptor gene in dopamine D1 receptor-expressing neurons resulted in a partial reduction of the VU0152100 effect, indicating that VU0152100 partly regulates dopaminergic neurotransmission via M4 receptors co-localized with D1 receptors. Conclusions These results show that positive allosteric modulators of the M4 receptor deserve attention as agents in the future treatment of cocaine abuse. PMID:22648127

  11. Neurochemical and Neuroanatomical Plasticity Following Memory Training and Yoga Interventions in Older Adults with Mild Cognitive Impairment

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    Hongyu Yang

    2016-11-01

    Full Text Available Behavioral interventions are becoming increasingly popular approaches to ameliorate age-related cognitive decline, but their underlying neurobiological mechanisms and clinical efficiency have not been fully elucidated. The present study explored brain plasticity associated with two behavioral interventions, memory enhancement training (MET and a mind-body practice (yogic meditation, in healthy seniors with mild cognitive impairment (MCI using structural magnetic resonance imaging (MRI and proton magnetic resonance spectroscopy (1H-MRS. Senior participants (age ≥ 55 years with MCI were randomized to the MET or yogic meditation interventions. For both interventions, participants completed either MET training or Kundalini yoga for 60-min sessions over 12 weeks, with 12-min daily homework assignments. Gray matter volume and metabolite concentrations in the dorsal anterior cingulate cortex (dACC and bilateral hippocampus were measured by structural MRI and 1H-MRS at baseline and after 12 weeks of training. Metabolites measured included glutamate-glutamine (Glx, choline-containing compounds (Cho, including glycerophosphocholine and phosphocholine, gamma-aminobutyric acid (GABA, and N-acetyl aspartate and N-acetylaspartyl-glutamate (NAA-NAAG. In total, 11 participants completed MET and 14 completed yogic meditation for this study. Structural MRI analysis showed an interaction between time and group in dACC, indicating a trend towards increased gray matter volume after the MET intervention. 1H-MRS analysis showed an interaction between time and group in choline-containing compounds in bilateral hippocampus, induced by significant decreases after the MET intervention. Though preliminary, our results suggest that memory training induces structural and neurochemical plasticity in seniors with mild cognitive impairment. Further research is needed to determine whether mind-body interventions like yoga yield similar neuroplastic changes.

  12. Separating common from distinctive variation.

    Science.gov (United States)

    van der Kloet, Frans M; Sebastián-León, Patricia; Conesa, Ana; Smilde, Age K; Westerhuis, Johan A

    2016-06-06

    Joint and individual variation explained (JIVE), distinct and common simultaneous component analysis (DISCO) and O2-PLS, a two-block (X-Y) latent variable regression method with an integral OSC filter can all be used for the integrated analysis of multiple data sets and decompose them in three terms: a low(er)-rank approximation capturing common variation across data sets, low(er)-rank approximations for structured variation distinctive for each data set, and residual noise. In this paper these three methods are compared with respect to their mathematical properties and their respective ways of defining common and distinctive variation. The methods are all applied on simulated data and mRNA and miRNA data-sets from GlioBlastoma Multiform (GBM) brain tumors to examine their overlap and differences. When the common variation is abundant, all methods are able to find the correct solution. With real data however, complexities in the data are treated differently by the three methods. All three methods have their own approach to estimate common and distinctive variation with their specific strength and weaknesses. Due to their orthogonality properties and their used algorithms their view on the data is slightly different. By assuming orthogonality between common and distinctive, true natural or biological phenomena that may not be orthogonal at all might be misinterpreted.

  13. Serotonergic Modulation Differentially Targets Distinct Network Elements within the Antennal Lobe of Drosophila melanogaster.

    Science.gov (United States)

    Sizemore, Tyler R; Dacks, Andrew M

    2016-11-15

    Neuromodulation confers flexibility to anatomically-restricted neural networks so that animals are able to properly respond to complex internal and external demands. However, determining the mechanisms underlying neuromodulation is challenging without knowledge of the functional class and spatial organization of neurons that express individual neuromodulatory receptors. Here, we describe the number and functional identities of neurons in the antennal lobe of Drosophila melanogaster that express each of the receptors for one such neuromodulator, serotonin (5-HT). Although 5-HT enhances odor-evoked responses of antennal lobe projection neurons (PNs) and local interneurons (LNs), the receptor basis for this enhancement is unknown. We used endogenous reporters of transcription and translation for each of the five 5-HT receptors (5-HTRs) to identify neurons, based on cell class and transmitter content, that express each receptor. We find that specific receptor types are expressed by distinct combinations of functional neuronal classes. For instance, the excitatory PNs express the excitatory 5-HTRs, while distinct classes of LNs each express different 5-HTRs. This study therefore provides a detailed atlas of 5-HT receptor expression within a well-characterized neural network, and enables future dissection of the role of serotonergic modulation of olfactory processing.

  14. Inhibitory Interneurons That Express GFP in the PrP-GFP Mouse Spinal Cord Are Morphologically Heterogeneous, Innervated by Several Classes of Primary Afferent and Include Lamina I Projection Neurons among Their Postsynaptic Targets

    Science.gov (United States)

    Ganley, Robert P.; Iwagaki, Noboru; del Rio, Patricia; Baseer, Najma; Dickie, Allen C.; Boyle, Kieran A.; Polgár, Erika; Watanabe, Masahiko; Abraira, Victoria E; Zimmerman, Amanda

    2015-01-01

    The superficial dorsal horn of the spinal cord contains numerous inhibitory interneurons, which regulate the transmission of information perceived as touch, pain, or itch. Despite the importance of these cells, our understanding of their roles in the neuronal circuitry is limited by the difficulty in identifying functional populations. One group that has been identified and characterized consists of cells in the mouse that express green fluorescent protein (GFP) under control of the prion protein (PrP) promoter. Previous reports suggested that PrP-GFP cells belonged to a single morphological class (central cells), received inputs exclusively from unmyelinated primary afferents, and had axons that remained in lamina II. However, we recently reported that the PrP-GFP cells expressed neuronal nitric oxide synthase (nNOS) and/or galanin, and it has been shown that nNOS-expressing cells are more diverse in their morphology and synaptic connections. We therefore used a combined electrophysiological, pharmacological, and anatomical approach to reexamine the PrP-GFP cells. We provide evidence that they are morphologically diverse (corresponding to “unclassified” cells) and receive synaptic input from a variety of primary afferents, with convergence onto individual cells. We also show that their axons project into adjacent laminae and that they target putative projection neurons in lamina I. This indicates that the neuronal circuitry involving PrP-GFP cells is more complex than previously recognized, and suggests that they are likely to have several distinct roles in regulating the flow of somatosensory information through the dorsal horn. PMID:25972186

  15. Defining poverty as distinctively human

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    H.P.P. Lötter

    2007-05-01

    Full Text Available While it is relatively easy for most people to identify human beings suffering from poverty, it is rather more difficult to come to a proper understanding of poverty. In this article the author wants to deepen our understanding of poverty by interpreting the conventional definitions of poverty in a new light. The article starts with a defence of a claim that poverty is a concept uniquely applicable to humans. It then present a critical discussion of the distinction between absolute and relative poverty and it is then argued that a revision of this distinction can provide general standards applicable to humans everywhere.

  16. 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.

  17. Interaction between Purkinje cells and inhibitory interneurons may create adjustable output waveforms to generate timed cerebellar output.

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    Simon Hong

    Full Text Available We develop a new model that explains how the cerebellum may generate the timing in classical delay eyeblink conditioning. Recent studies show that both Purkinje cells (PCs and inhibitory interneurons (INs have parallel signal processing streams with two time scales: an AMPA receptor-mediated fast process and a metabotropic glutamate receptor (mGluR-mediated slow process. Moreover, one consistent finding is an increased excitability of PC dendrites (in Larsell's lobule HVI in animals when they acquire the classical delay eyeblink conditioning naturally, in contrast to in vitro studies, where learning involves long-term depression (LTD. Our model proposes that the delayed response comes from the slow dynamics of mGluR-mediated IP3 activation, and the ensuing calcium concentration change, and not from LTP/LTD. The conditioned stimulus (tone, arriving on the parallel fibers, triggers this slow activation in INs and PC spines. These excitatory (from PC spines and inhibitory (from INs signals then interact at the PC dendrites to generate variable waveforms of PC activation. When the unconditioned stimulus (puff, arriving on the climbing fibers, is coupled frequently with this slow activation the waveform is amplified (due to an increased excitability and leads to a timed pause in the PC population. The disinhibition of deep cerebellar nuclei by this timed pause causes the delayed conditioned response. This suggested PC-IN interaction emphasizes a richer role of the INs in learning and also conforms to the recent evidence that mGluR in the cerebellar cortex may participate in slow motor execution. We show that the suggested mechanism can endow the cerebellar cortex with the versatility to learn almost any temporal pattern, in addition to those that arise in classical conditioning.

  18. 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

  19. Segmental organization of vestibulospinal inputs to spinal interneurons mediating crossed activation of thoracolumbar motoneurons in the neonatal mouse.

    Science.gov (United States)

    Kasumacic, Nedim; Lambert, François M; Coulon, Patrice; Bras, Helene; Vinay, Laurent; Perreault, Marie-Claude; Glover, Joel C

    2015-05-27

    Vestibulospinal pathways activate contralateral motoneurons (MNs) in the thoracolumbar spinal cord of the neonatal mouse exclusively via axons descending ipsilaterally from the vestibular nuclei via the lateral vestibulospinal tract (LVST; Kasumacic et al., 2010). Here we investigate how transmission from the LVST to contralateral MNs is mediated by descending commissural interneurons (dCINs) in different spinal segments. We test the polysynaptic nature of this crossed projection by assessing LVST-mediated ventral root (VR) response latencies, manipulating synaptic responses pharmacologically, and tracing the pathway transynaptically from hindlimb extensor muscles using rabies virus (RV). Longer response latencies in contralateral than ipsilateral VRs, near-complete abolition of LVST-mediated calcium responses in contralateral MNs by mephenesin, and the absence of transsynaptic RV labeling of contralateral LVST neurons within a monosynaptic time window all indicate an overwhelmingly polysynaptic pathway from the LVST to contralateral MNs. Optical recording of synaptically mediated calcium responses identifies LVST-responsive ipsilateral dCINs that exhibit segmental differences in proportion and dorsoventral distribution. In contrast to thoracic and lower lumbar segments, in which most dCINs are LVST responsive, upper lumbar segments stand out because they contain a much smaller and more ventrally restricted subpopulation of LVST-responsive dCINs. A large proportion of these upper lumbar LVST-responsive dCINs project to contralateral L5, which contains many of the hindlimb extensor MNs activated by the LVST. A selective channeling of LVST inputs through segmentally and dorsoventrally restricted subsets of dCINs provides a mechanism for targeting vestibulospinal signals differentially to contralateral trunk and hindlimb MNs in the mammalian spinal cord. Copyright © 2015 the authors 0270-6474/15/358158-12$15.00/0.

  20. The subcellular distribution of T-type Ca2+ channels in interneurons of the lateral geniculate nucleus.

    Science.gov (United States)

    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.

  1. Comprehensive characterization of neurochemicals in three zebrafish chemical models of human acute organophosphorus poisoning using liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Gómez-Canela, Cristian; Tornero-Cañadas, Daniel; Prats, Eva; Piña, Benjamí; Tauler, Romà; Raldúa, Demetrio

    2018-02-01

    There is a growing interest in biological models to investigate the effect of neurotransmitter dysregulation on the structure and function of the central nervous system (CNS) at different stages of development. Zebrafish, a vertebrate model increasingly used in neurobiology and neurotoxicology, shares the common neurotransmitter systems with mammals, including glutamate, GABA, glycine, dopamine, norepinephrine, epinephrine, serotonin, acetylcholine, and histamine. In this study, we have evaluated the performance of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the multiresidue determination of neurotransmitters and related metabolites. In a first step, ionization conditions were tested in positive electrospray mode and optimum fragmentation patterns were determined to optimize two selected reaction monitoring (SRM) transitions. Chromatographic conditions were optimized considering the chemical structure and chromatographic behavior of the analyzed compounds. The best performance was obtained with a Synergy Polar-RP column, which allowed the separation of the 38 compounds in 30 min. In addition, the performance of LC-MS/MS was studied in terms of linearity, sensitivity, intra- and inter-day precision, and overall robustness. The developed analytical method was able to quantify 27 of these neurochemicals in zebrafish chemical models for mild (P1), moderate (P2), and severe (P3) acute organophosphorus poisoning (OPP). The results show a general depression of synaptic-related neurochemicals, including the excitatory and inhibitory amino acids, as well as altered phospholipid metabolism, with specific neurochemical profiles associated to the different grades of severity. These results confirmed that the developed analytical method is a new tool for neurotoxicology research using the zebrafish model.

  2. Neurochemical differences in learning and memory paradigms among rats supplemented with anthocyanin-rich blueberry diets and exposed to acute doses of 56Fe particles

    Science.gov (United States)

    Poulose, Shibu M.; Rabin, Bernard M.; Bielinski, Donna F.; Kelly, Megan E.; Miller, Marshall G.; Thanthaeng, Nopporn; Shukitt-Hale, Barbara

    2017-02-01

    The protective effects of anthocyanin-rich blueberries (BB) on brain health are well documented and are particularly important under conditions of high oxidative stress, which can lead to "accelerated aging." One such scenario is exposure to space radiation, consisting of high-energy and -charge particles (HZE), which are known to cause cognitive dysfunction and deleterious neurochemical alterations. We recently tested the behavioral and neurochemical effects of acute exposure to HZE particles such as 56Fe, within 24-48 h after exposure, and found that radiation primarily affects memory and not learning. Importantly, we observed that specific brain regions failed to upregulate antioxidant and anti-inflammatory mechanisms in response to this insult. To further examine these endogenous response mechanisms, we have supplemented young rats with diets rich in BB, which are known to contain high amounts of antioxidant-phytochemicals, prior to irradiation. Exposure to 56Fe caused significant neurochemical changes in hippocampus and frontal cortex, the two critical regions of the brain involved in cognitive function. BB supplementation significantly attenuated protein carbonylation, which was significantly increased by exposure to 56Fe in the hippocampus and frontal cortex. Moreover, BB supplementation significantly reduced radiation-induced elevations in NADPH-oxidoreductase-2 (NOX2) and cyclooxygenase-2 (COX-2), and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) in the hippocampus and frontal cortex. Overall results indicate that 56Fe particles may induce their toxic effects on hippocampus and frontal cortex by reactive oxygen species (ROS) overload, which can cause alterations in the neuronal environment, eventually leading to hippocampal neuronal death and subsequent impairment of cognitive function. Blueberry supplementation provides an effective preventative measure to reduce the ROS load on the CNS in an event of acute HZE exposure.

  3. Educational Psychology: The Distinctive Contribution

    Science.gov (United States)

    Cameron, R. J.

    2006-01-01

    This paper, written in the twenty-first anniversary year of the journal "Educational Psychology in Practice", attempts to uncover those distinctive aspects of the discipline and the practice of applied psychology in general and educational psychology in particular. After considering some of the reasons for attempting this task at this point in…

  4. Separating common from distinctive variation

    NARCIS (Netherlands)

    van der Kloet, F.M.; Sebastián-León, P.; Conesa, A.; Smilde, A.K.; Westerhuis, J.A.

    2016-01-01

    BACKGROUND: Joint and individual variation explained (JIVE), distinct and common simultaneous component analysis (DISCO) and O2-PLS, a two-block (X-Y) latent variable regression method with an integral OSC filter can all be used for the integrated analysis of multiple data sets and decompose them in

  5. Altered posterior cingulate cortical cyctoarchitecture, but normal density of neurons and interneurons in the posterior cingulate cortex and fusiform gyrus in autism.

    Science.gov (United States)

    Oblak, Adrian L; Rosene, Douglas L; Kemper, Thomas L; Bauman, Margaret L; Blatt, Gene J

    2011-06-01

    Autism is a developmental disorder with prenatal origins, currently estimated to affect 1 in 91 children in the United States. Social-emotional deficits are a hallmark of autism and early neuropathology studies have indicated involvement of the limbic system. Imaging studies demonstrate abnormal activation of the posterior cingulate cortex (PCC), a component of the limbic system. Abnormal activation has also been noted in the fusiform gyrus (FFG), a region important for facial recognition and a key element in social interaction. A potential imbalance between excitatory and inhibitory interneurons in the cortex may contribute to altered information processing in autism. Furthermore, reduced numbers of GABA receptors have previously been reported in the autistic brain. Thionin-stained sections were used to qualitatively assess cytoarchitectonic patterning and quantitatively determine the density of neurons and immunohistochemistry was used to determine the densities of a subset of GABAergic interneurons utilizing parvalbumin-and calbindin-immunoreactivity. In autism, the PCC displayed altered cytoarchitecture with irregularly distributed neurons, poorly demarcated layers IV and V, and increased presence of white matter neurons. In contrast, no neuropathology was observed in the FFG. There was no significant difference in the density of thionin, parvalbumin, or calbindin interneurons in either region and there was a trend towards a reduced density of calbindin neurons in the PCC. This study highlights the presence of abnormal findings in the PCC, which appear to be developmental in nature and could affect the local processing of social-emotional behaviors as well as functioning of interrelated areas. Copyright © 2011, International Society for Autism Research, Wiley Periodicals, Inc.

  6. Innervation of burst firing spiny interneurons by pyramidal cells in deep layers of rat somatomotor cortex: paired intracellular recordings with biocytin filling.

    Science.gov (United States)

    Deuchars, J; Thomson, A M

    1995-12-01

    Intracellular recordings were obtained from a class of neuron defined electrophysiologically as burst firing interneurons in layers V and VI in slices of adult rat somatomotor cortex. Four of these cells were recovered histologically. These four cells had resting membrane potentials between -68 and -80 mV, a mean input resistance of 77 +/- 16.2 M omega (measured from the voltage deflection produced by a 100 ms, 0.5 nA hyperpolarizing pulse delivered from a membrane potential of -80 mV) and responded to injections of depolarizing current from membrane potentials negative of -70 to -75 mV with an initial burst of action potentials followed by a complex afterhyperpolarization. In response to injection of larger (0.5-1.5 nA) hyperpolarizing current pulses from membrane potentials between -60 and -70 mV, 15 of 20 burst firing cells (three of four recovered histologically) that were tested displayed delayed inward rectification, and in all 20 cells of this type, responses to large negative current pulses were followed by a rebound depolarization that could initiate action potentials. Filling of four of these cells with biocytin and subsequent histological processing revealed that they were bitufted with sparsely to medium spiny dendrites and extensive local axon ramifications. These neurons are similar to low threshold spiking cells [Kawaguchi (1993) J. Neurophysiol. 69, 416-431]. Ultrastructural examination of the axons of three cells revealed that of 53 labelled terminals studied, the majority formed synaptic contacts with dendritic shafts. Filling neurons with biocytin during paired intracellular recordings resulted in three well labelled interneurons, each of which was postsynaptic to a simultaneously recorded pyramidal neuron. In these pairs both cells were identified, but the presynaptic axon was poorly labelled in one. In one of the two pairs in which the pre- and postsynaptic neurons were fully recovered, light microscopic assessment indicated that the axon of

  7. Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

    Directory of Open Access Journals (Sweden)

    Cecilia Csölle

    Full Text Available Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7 results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/- displayed decreased immobility in the tail suspension test (TST and an attenuated anhedonia response in the sucrose preference test (SPT following bacterial endotoxin (LPS challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [(3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5. An increased 5-bromo-2-deoxyuridine (BrdU incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [(3H]5-HT and an elevated number of [(3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus.

  8. Jugular venous overflow of noradrenaline from the brain: a neurochemical indicator of cerebrovascular sympathetic nerve activity in humans

    Science.gov (United States)

    Mitchell, David A; Lambert, Gavin; Secher, Niels H; Raven, Peter B; van Lieshout, Johannes; Esler, Murray D

    2009-01-01

    A novel neurochemical method was applied for studying the activity of sympathetic nerves in the human cerebral vascular system. The aim was to investigate whether noradrenaline plasma kinetic measurements made with internal jugular venous sampling reflect cerebrovascular sympathetic activity. A database was assembled of fifty-six healthy subjects in whom total body noradrenaline spillover (indicative of whole body sympathetic nervous activity), brain noradrenaline spillover and brain lipophlic noradrenaline metabolite (3,4-dihydroxyphenolglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG)) overflow rates were measured. These measurements were also made following ganglion blockade (trimethaphan, n= 6), central sympathetic inhibition (clonidine, n= 4) and neuronal noradrenaline uptake blockade (desipramine, n= 13) and in a group of patients (n= 9) with pure autonomic failure (PAF). The mean brain noradrenline spillover and brain noradrenaline metabolite overflow in healthy subjects were 12.5 ± 1.8, and 186.4 ± 25 ng min−1, respectively, with unilateral jugular venous sampling for both. Total body noradrenaline spillover was 605.8 ng min−1± 34.4 ng min−1. As expected, trimethaphan infusion lowered brain noradrenaline spillover (P= 0.03), but perhaps surprisingly increased jugular overflow of brain metabolites (P= 0.01). Suppression of sympathetic nervous outflow with clonidine lowered brain noradrenaline spillover (P= 0.004), without changing brain metabolite overflow (P= 0.3). Neuronal noradrenaline uptake block with desipramine lowered the transcranial plasma extraction of tritiated noradrenaline (P= 0.001). The PAF patients had 77% lower brain noradrenaline spillover than healthy recruits (P= 0.06), indicating that in them sympathetic nerve degeneration extended to the cerebral circulation, but metabolites overflow was similar to healthy subjects (P= 0.3). The invariable discordance between noradrenline spillover and noradrenaline metabolite overflow

  9. Species, sex and individual differences in the vasotocin/vasopressin system: relationship to neurochemical signaling in the social behavior neural network.

    Science.gov (United States)

    Albers, H Elliott

    2015-01-01

    Arginine-vasotocin (AVT)/arginine vasopressin (AVP) are members of the AVP/oxytocin (OT) superfamily of peptides that are involved in the regulation of social behavior, social cognition and emotion. Comparative studies have revealed that AVT/AVP and their receptors are found throughout the "social behavior neural network (SBNN)" and display the properties expected from a signaling system that controls social behavior (i.e., species, sex and individual differences and modulation by gonadal hormones and social factors). Neurochemical signaling within the SBNN likely involves a complex combination of synaptic mechanisms that co-release multiple chemical signals (e.g., classical neurotransmitters and AVT/AVP as well as other peptides) and non-synaptic mechanisms (i.e., volume transmission). Crosstalk between AVP/OT peptides and receptors within the SBNN is likely. A better understanding of the functional properties of neurochemical signaling in the SBNN will allow for a more refined examination of the relationships between this peptide system and species, sex and individual differences in sociality. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. [Correlation of neurochemical metabolism with memory function in young adult patients with first-episode depression studied with proton magnetic resonance spectroscopy].

    Science.gov (United States)

    Liu, Weibo; Yu, Hualiang; Jiang, Biao; Zheng, Leilei; Yu, Shaohua; Pan, Bing; Yu, Risheng

    2013-07-01

    To investigate the correlation of neurochemical metabolism in hippocampus with memory function in young adult patients with first-episode depression. Twenty patients with first-episode depression (patient group) and fifteen health subjects (control group) were enrolled in the study. The neurochemical metabolism, including the levels of N-acetylaspartate (NAA), Choline (Cho), Creatine (Cr), Myoinositol (mI) were measured by proton magnetic resonance spectroscope (1H-MRS) in bilateral hippocampus. Wechsler Memory Scale (WMS) were used to examine the memory function in both groups. The memory quotient (89.15 ±6.62) of patient group was significantly lower than that of controls (P memory,short-term memory and immediate memory in patients were also lower than those of controls (Pmemory deficit and abnormal metabolism function of neuron cell in hippocampus coexist in young adult patients with first-episode depression, and the lower NAA/Cr and higher mI/Cr ratio in the left hippocampus may result in the memory deficit.

  11. Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes.

    Science.gov (United States)

    Bhutani, Mohit Kumar; Bishnoi, Mahendra; Kulkarni, Shrinivas K

    2009-03-01

    Curcumin, a yellow pigment extracted from rhizomes of the plant Curcuma longa (turmeric), has been widely used as food additive and also as a herbal medicine throughout Asia. The present study was designed to study the pharmacological, biochemical and neurochemical effects of daily administration of curcumin to rats subjected to chronic unpredictable stress. Curcumin treatment (20 and 40 mg/kg, i.p., 21 days) significantly reversed the chronic unpredictable stress-induced behavioral (increase immobility period), biochemical (increase monoamine oxidase activity) and neurochemical (depletion of brain monoamine levels) alterations. The combination of piperine (2.5 mg/kg, i.p., 21 days), a bioavailability enhancer, with curcumin (20 and 40 mg/kg, i.p., 21 days) showed significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory (MAO-A) effects as compared to curcumin effect per se. This study provided a scientific rationale for the use of curcumin and its co-administration with piperine in the treatment of depressive disorders.

  12. Dysregulation of brain reward systems in eating disorders: neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa.

    Science.gov (United States)

    Avena, Nicole M; Bocarsly, Miriam E

    2012-07-01

    Food intake is mediated, in part, through brain pathways for motivation and reinforcement. Dysregulation of these pathways may underlay some of the behaviors exhibited by patients with eating disorders. Research using animal models of eating disorders has greatly contributed to the detailed study of potential brain mechanisms that many underlie the causes or consequences of aberrant eating behaviors. This review focuses on neurochemical evidence of reward-related brain dysfunctions obtained through animal models of binge eating, bulimia nervosa, or anorexia nervosa. The findings suggest that alterations in dopamine (DA), acetylcholine (ACh) and opioid systems in reward-related brain areas occur in response to binge eating of palatable foods. Moreover, animal models of bulimia nervosa suggest that while bingeing on palatable food releases DA, purging attenuates the release of ACh that might otherwise signal satiety. Animal models of anorexia nervosa suggest that restricted access to food enhances the reinforcing effects of DA when the animal does eat. The activity-based anorexia model suggests alterations in mesolimbic DA and serotonin occur as a result of restricted eating coupled with excessive wheel running. These findings with animal models complement data obtained through neuroimaging and pharmacotherapy studies of clinical populations. Information on the neurochemical consequences of the behaviors associated with these eating disorders will be useful in understanding these complex disorders and may inform future therapeutic approaches, as discussed here. This article is part of a Special Issue entitled 'Central Control of Food Intake'. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Grima: A Distinct Emotion Concept?

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    Schweiger Gallo, Inge; Fernández-Dols, José-Miguel; Gollwitzer, Peter M.; Keil, Andreas

    2017-01-01

    People experience an unpleasant sensation when hearing a scratch on a board or plate. The present research focuses on this aversive experience known in Spanish as ‘grima’ with no equivalent term in English and German. We hypothesized that this aversive experience constitutes a distinctive, separate emotional concept. In Study 1, we found that the affective meaning of ‘grima’ was closer to disgust than to other emotion concepts. Thus, in Study 2 we explored the features of grima and compared them with disgust. As grima was reported to be predominantly elicited by certain auditory stimuli and associated with a distinctive physiological pattern, Study 3 used direct measures of physiological arousal to test the assumption of a distinctive pattern of physiological responses elicited by auditory stimuli of grima and disgust, and found different effects on heart rate but not on skin conductance. In Study 4, we hypothesized that only participants with an implementation intention geared toward down-regulating grima would be able to successfully weaken the grima- but not disgust- experience. Importantly, this effect was specific as it held true for the grima-eliciting sounds only, but did not affect disgust-related sounds. Finally, Study 5 found that English and German speakers lack a single accessible linguistic label for the pattern of aversive reactions termed by Spanish speaking individuals as ‘grima’, whereas the elicitors of other emotions were accessible and accurately identified by German, English, as well as Spanish speakers. PMID:28217102

  14. 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 BACKGROUND: 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. METHODS AND MAIN RESULTS: 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. CONCLUSIONS: 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

  15. Characterisation of type I and type II nNOS-expressing interneurons in the barrel cortex of mouse

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    Quentin ePerrenoud

    2012-06-01

    Full Text Available In the neocortex, neuronal Nitric Oxide-Synthase (nNOS is essentially expressed in two sets of GABAergic neurons: type I neurons displaying a high expression and type II neurons displaying a weaker expression. Using immunocytochemistry on mice expressing GFP under the control of the glutamic acid decarboxylase 67k (GAD67 promoter we studied the distribution of type I and type II neurons in the barrel cortex and their expression of parvalbumin (PV, somatostatin (SOM and vasoactive intestinal peptide (VIP. We found that type I neurons accumulated in deeper layers and expressed SOM (91.5% while type II neurons concentrated in layer II/III and VI and expressed PV (17.7%, SOM (18.7% and VIP (10.2%. We then characterised 42 nNOS transcribing neurons ex vivo, using whole-cell recordings coupled to singe-cell RT-PCR and biocytin labelling. Unsupervised cluster analysis of this sample disclosed four classes. One cluster (n=7 corresponded to large, deep layer neurons, displaying a high expression of SOM (85.7% and were thus very likely to correspond to type I neurons. The three other clusters were neurogliaform-like interneurons (n=19, deep layer neurons transcribing PV or SOM (n=9 and neurons transcribing VIP (n=7, matching the features of type II cells. Finally, we performed nNOS immunohistochemistry on two mouse lines in which GFP/YFP labelling revealed the expression of two specific developmental genes (Lhx6 and 5-HT3A. We found that type I neurons expressed Lhx6 but never 5-HT3A, indicating that they originate in the medial ganglionic eminence (MGE. Type II neurons expressed Lhx6 (63% and 5-HT3A (34.4% supporting that they derive either from the MGE or from the caudal ganglionic eminence (CGE and the entopeduncular preoptic area (AEP/PO. Together, our results support the view that type I neurons form a particular class of SOM-expressing neurons while type II neurons are heterogeneous and comprise at least three classes.

  16. Neuregulin repellent signaling via ErbB4 restricts GABAergic interneurons to migratory paths from ganglionic eminence to cortical destinations

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    Li Hao

    2012-02-01

    Full Text Available Abstract Background Cortical GABAergic interneurons (INs are generated in the medial ganglionic eminence (MGE and migrate tangentially into cortex. Because most, if not all, migrating MGE-derived INs express the neuregulin (NRG receptor, ErbB4, we investigated influences of Nrg1 isoforms and Nrg3 on IN migration through ventral telencephalon (vTel and within cortex. Results During IN migration, NRG expression domains and distributions of ErbB4-expressing, MGE-derived INs are complementary with minimal overlap, both in vTel and cortex. In wild-type mice, within fields of NRG expression, these INs are focused at positions of low or absent NRG expression. However, in ErbB4-/- HER4heart mutant mice in which INs lack ErbB4, these complementary patterns are degraded with considerable overlap evident between IN distribution and NRG expression domains. These findings suggest that NRGs are repellents for migrating ErbB4-expressing INs, a function supported by in vitro and in vivo experiments. First, in collagen co-cultures, MGE-derived cells preferentially migrate away from a source of secreted NRGs. Second, cells migrating from wild-type MGE explants on living forebrain slices from wild-type embryonic mice tend to avoid endogenous NRG expression domains, whereas this avoidance behavior is not exhibited by ErbB4-deficient cells migrating from MGE explants and instead they have a radial pattern with a more uniform distribution. Third, ectopic NRG expression in the IN migration pathway produced by in utero electroporation blocks IN migration and results in cortex distal to the blockade being largely devoid of INs. Finally, fewer INs reach cortex in ErbB4 mutants, indicating that NRG-ErbB4 signaling is required for directing IN migration from the MGE to cortex. Conclusions Our results show that NRGs act as repellents for migrating ErbB4-expressing, MGE-derived GABAergic INs and that the patterned expression of NRGs funnels INs as they migrate from the MGE

  17. Roles of Molecular Layer Interneurons in Sensory Information Processing in Mouse Cerebellar Cortex Crus II In Vivo

    Science.gov (United States)

    Chu, Chun-Ping; Bing, Yan-Hua; Liu, Heng; Qiu, De-Lai

    2012-01-01

    Background 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. Methods and Main Results 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 GABAA 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. Conclusions 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

  18. NOX2 Mediated-Parvalbumin Interneuron Loss Might Contribute to Anxiety-Like and Enhanced Fear Learning Behavior in a Rat Model of Post-Traumatic Stress Disorder.

    Science.gov (United States)

    Liu, Fang-Fang; Yang, Lin-Dong; Sun, Xiao-Ru; Zhang, Hui; Pan, Wei; Wang, Xing-Ming; Yang, Jian-Jun; Ji, Mu-Huo; Yuan, Hong-Mei

    2016-12-01

    Post-traumatic stress disorder (PTSD) is a common psychiatric disease following exposure to a severe traumatic event or physiological stress, yet the precise mechanisms underlying PTSD remains largely to be determined. Using an animal model of PTSD induced by a single prolonged stress (SPS), we assessed the role of hippocampal nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and parvalbumin (PV) interneurons in the development of PTSD symptoms. In the present study, behavioral tests were performed by the open field (day 13 after SPS) and fear conditioning tests (days 13 and 14 after SPS). For the interventional study, rats were chronically treated with a NADPH oxidase inhibitor apocynin either by early or delayed administration. The levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-10, malondialdehyde, superoxide dismutase, NOX2, 4-hydroxynonenal, and PV in the hippocampus were measured at the indicated time points. In the present study, we showed that SPS rats displayed anxiety-like and enhanced fear learning behavior, which was accompanied by the increased expressions of malondialdehyde, IL-6, NOX2, 4-hydroxynonenal, and decreased PV expression. Notably, early but not delayed treatment with apocynin reversed all these abnormalities after SPS. In conclusion, our results provided evidence that NOX2 activation in the hippocampus, at least in part, contributes to oxidative stress and neuroinflammation, which further results in PV interneuron loss and consequent PTSD symptoms in a rat model of PTSD induced by SPS.

  19. Acetylcholine-Based Entropy in Response Selection: A Model of How Striatal Interneurons Modulate Exploration, Exploitation, and Response Variability in Decision Making

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    Andrea eStocco

    2012-02-01

    Full Text Available The basal ganglia play a fundamental role in decision making. Their contribution is typically modeled within a reinforcement learning framework, with the basal ganglia learning to select the options associated with highest value and their dopamine inputs conveying performance feedback. This basic framework, however, does not account for the role of cholinergic interneurons in the striatum, and does not easily explain certain dynamic aspects of decision-making and skill acquisition like the generation of exploratory actions. This paper describes BABE (Basal ganglia Acetylcholine-Based Entropy, a model of the acetylcholine system in the striatum that provides a unified explanation for these phenomena. According to this model, cholinergic interneurons in the striatum control the level of variability in behavior by modulating the number of possible responses that are considered by the basal ganglia, as well as the level of competition between them. This mechanism provides a natural way to account for the role of basal ganglia in generating behavioral variability during the acquisition of certain cognitive skills, as well as for modulating exploration and exploitation in decision making. Compared to a typical reinforcement learning model, BABE showed a greater modulation of response variability in the face of changes in the reward contingencies, allowing for faster learning (and re-learning of option values. Finally, the paper discusses the possible applications of the model to other domains.

  20. Prolonged response to calling songs by the L3 auditory interneuron in female crickets (Acheta domesticus): possible roles in regulating phonotactic threshold and selectiveness for call carrier frequency.

    Science.gov (United States)

    Bronsert, Michael; Bingol, Hilary; Atkins, Gordon; Stout, John

    2003-03-01

    L3, an auditory interneuron in the prothoracic ganglion of female crickets (Acheta domesticus) exhibited two kinds of responses to models of the male's calling song (CS): a previously described, phasically encoded immediate response; a more tonically encoded prolonged response. The onset of the prolonged response required 3-8 sec of stimulation to reach its maximum spiking rate and 6-20 sec to decay once the calling song ceased. It did not encode the syllables of the chirp. The prolonged response was sharply selective for the 4-5 kHz carrier frequency of the male's calling songs and its threshold tuning matched the threshold tuning of phonotaxis, while the immediate response of the same neuron was broadly tuned to a wide range of carrier frequencies. The thresholds for the prolonged response covaried with the changing phonotactic thresholds of 2- and 5-day-old females. Treatment of females with juvenile hormone reduced the thresholds for both phonotaxis and the prolonged response by equivalent amounts. Of the 3 types of responses to CSs provided by the ascending L1 and L3 auditory interneurons, the threshold for L3's prolonged response, on average, best matched the same females phonotactic threshold. The prolonged response was stimulated by inputs from both ears while L3's immediate response was driven only from its axon-ipsilateral ear. The prolonged response was not selective for either the CS's syllable period or chirp rate. Copyright 2003 Wiley-Liss, Inc.

  1. In vivo neurochemical evidence that newly synthesised GABA activates GABA(B), but not GABA(A), receptors on dopaminergic nerve endings in the nucleus accumbens of freely moving rats

    NARCIS (Netherlands)

    Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

    2012-01-01

    GABA released from accumbal GABAergic interneurons plays an inhibitory role in the regulation of dopamine efflux through GABA(B) and GABA(A) receptors located on accumbal dopaminergic nerve endings. The cytosolic newly synthesised GABA alters vesicular GABA levels and, accordingly, the amount of

  2. Distinctive Modulation of Dopamine Release in the Nucleus Accumbens Shell Mediated by Dopamine and Acetylcholine Receptors.

    Science.gov (United States)

    Shin, Jung Hoon; Adrover, Martin F; Alvarez, Veronica A

    2017-11-15

    Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals in vivo and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to drugs of abuse. A disynaptic mechanism for DA release was reported and shown to require synchronized firing of cholinergic interneurons (CINs) and activation of nicotinic acetylcholine (ACh) receptors (nAChRs) in DA neuron (DAN) axons. The properties of this disynaptic mechanism of DA transmission are not well understood in the NAc shell. In this study, in vitro fast-scan cyclic voltammetry was used to examine the modulation of DA transmission evoked by CINs firing in the shell of mice and compared with other striatal regions. We found that DA signals in the shell displayed significant degree of summation in response to train stimulation of CINs, contrary to core and dorsal striatum. The summation was amplified by a D2-like receptor antagonist and experiments with mice with targeted deletion of D2 receptors to DANs or CINs revealed that D2 receptors in CINs mediate a fast inhibition observed within 100 ms of the first pulse, whereas D2 autoreceptors in DAN terminals are engaged in a slower inhibition that peaks at ∼500 ms. ACh also contributes to the use-dependent inhibition of DA release through muscarinic receptors only in the shell, where higher activity of acetylcholinesterase minimizes nAChR desensitization and promotes summation. These findings show that DA signals are modulated differentially by endogenous DA and ACh in the shell, which may underlie the unique features of shell DA signals in vivoSIGNIFICANCE STATEMENT The present study reports that dopamine (DA) release evoked by activation of cholinergic interneurons displays a high degree of summation in the shell and shows unique modulation by endogenous DA and acetylcholine. Desensitization of nicotinic receptors, which is a prevailing mechanism for use-dependent inhibition in the nucleus accumbens core and dorsal striatum, is

  3. Lineage Reprogramming of Astroglial Cells from Different Origins into Distinct Neuronal Subtypes

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    Malek Chouchane

    2017-07-01

    Full Text Available Astroglial cells isolated from the rodent postnatal cerebral cortex are particularly susceptible to lineage reprogramming into neurons. However, it remains unknown whether other astroglial populations retain the same potential. Likewise, little is known about the fate of induced neurons (iNs in vivo. In this study we addressed these questions using two different astroglial populations isolated from the postnatal brain reprogrammed either with Neurogenin-2 (Neurog2 or Achaete scute homolog-1 (Ascl1. We show that cerebellum (CerebAstro and cerebral cortex astroglia (CtxAstro generates iNs with distinctive neurochemical and morphological properties. Both astroglial populations contribute iNs to the olfactory bulb following transplantation in the postnatal and adult mouse subventricular zone. However, only CtxAstro transfected with Neurog2 differentiate into pyramidal-like iNs after transplantation in the postnatal cerebral cortex. Altogether, our data indicate that the origin of the astroglial population and transcription factors used for reprogramming, as well as the region of integration, affect the fate of iNs.

  4. Anatomically distinct dopamine release during anticipation and experience of peak emotion to music.

    Science.gov (United States)

    Salimpoor, Valorie N; Benovoy, Mitchel; Larcher, Kevin; Dagher, Alain; Zatorre, Robert J

    2011-02-01

    Music, an abstract stimulus, can arouse feelings of euphoria and craving, similar to tangible rewards that involve the striatal dopaminergic system. Using the neurochemical specificity of [(11)C]raclopride positron emission tomography scanning, combined with psychophysiological measures of autonomic nervous system activity, we found endogenous dopamine release in the striatum at peak emotional arousal during music listening. To examine the time course of dopamine release, we used functional magnetic resonance imaging with the same stimuli and listeners, and found a functional dissociation: the caudate was more involved during the anticipation and the nucleus accumbens was more involved during the experience of peak emotional responses to music. These results indicate that intense pleasure in response to music can lead to dopamine release in the striatal system. Notably, the anticipation of an abstract reward can result in dopamine release in an anatomical pathway distinct from that associated with the peak pleasure itself. Our results help to explain why music is of such high value across all human societies.

  5. Sex differences in the adolescent developmental trajectory of parvalbumin interneurons in the hippocampus: a role for estradiol.

    Science.gov (United States)

    Wu, YeeWen Candace; Du, Xin; van den Buuse, Maarten; Hill, Rachel A

    2014-07-01

    Gender differences in the neurodevelopmental disorder, schizophrenia, have been described for nearly all features of the illness. Reduced hippocampal expression of the GABAergic interneuron marker, parvalbumin (PV), and GABA synthesizing enzyme, GAD67, are consistently reported in schizophrenia. However, little is known of the expression patterns of hippocampal PV and GAD67 during adolescence and their interaction with sex steroid hormones during adolescent development. This study examined the effects of altered sex steroid hormone levels during adolescence on protein levels of PV, GAD67 and estrogen receptors (ERα/β) in the hippocampus of mice. Protein expression of PV and GAD67 was measured in the dorsal (DHP) and ventral (VHP) hippocampus of female and male C57Bl/6 mice by Western blot in a week by week analysis from pre-pubescence to adulthood (week 3-12). Fluorescent immunohistochemistry (IHC) was used to investigate the relationship between ERs and PV(+) cells in the hippocampus of female mice at young adulthood (week 10-11). To further examine the role of sex steroid hormones on PV and GAD67 expression, gonadectomy and hormone replacement was done at 5 weeks of age. Female mice showed a significant gradual increase in PV expression from 3 to 12 weeks of age in the DHP and VHP which correlated with serum 17β-estradiol levels. Fluorescent IHC showed approximately 30-50% co-localization of ER-α in PV(+) cells in the female DHP and VHP (dentate gryus/hilus and CA1-CA3). Adolescent ovariectomy significantly reduced PV expression in the DHP but not VHP of female mice, while 17β-estradiol replacement prevented this deficit in DHP PV levels. ER-α expression, but not ER-β, was also reduced in the DHP following ovariectomy with no significant effect of 17β-estradiol replacement. In contrast to female mice, male mice did not show any significant changes in hippocampal PV/GAD67 expression throughout adolescent development. Furthermore, adolescent castration and

  6. Brain region-specific perfluoroalkylated sulfonate (PFSA) and carboxylic acid (PFCA) accumulation and neurochemical biomarker responses in east Greenland polar bears (Ursus maritimus).

    Science.gov (United States)

    Eggers Pedersen, Kathrine; Basu, Niladri; Letcher, Robert; Greaves, Alana K; Sonne, Christian; Dietz, Rune; Styrishave, Bjarne

    2015-04-01

    Perfluoroalkyl substances (PFASs) is a growing class of contaminants in the Arctic environment, and include the established perfluorinated sulfonates (PFSAs; especially perfluorooctane sulfonate (PFOS)) and carboxylic acids (PFCAs). PFSAs and PFCAs of varying chain length have been reported to bioaccumulate in lipid rich tissues of the brain among other tissues such as liver, and can reach high concentrations in top predators including the polar bear. PFCA and PFSA bioaccummulation in the brain has the potential to pose neurotoxic effects and therefore we conducted a study to investigate if variations in neurochemical transmitter systems i.e. the cholinergic, glutaminergic, dopaminergic and GABAergic, could be related to brain-specific bioaccumulation of PFASs in East Greenland polar bears. Nine brain regions from nine polar bears were analyzed for enzyme activity (monoamine oxidase (MAO), acetylcholinesterase (AChE) and glutamine synthetase (GS)) and receptor density (dopamine-2 (D2), muscarinic cholinergic (mAChR) and gamma-butyric acid type A (GABA-A)) along with PFSA and PFCA concentrations. Average brain ∑PFSA concentration was 25ng/g ww where PFOS accounted for 91%. Average ∑PFCA concentration was 88ng/g ww where PFUnDA, PFDoDA and PFTrDA combined accounted for 79%. The highest concentrations of PFASs were measured in brain stem, cerebellum and hippocampus. Correlative analyses were performed both across and within brain regions. Significant positive correlations were found between PFASs and MAO activity in occipital lobe (e.g. ∑PFCA; rp=0.83, p=0.041, n=6) and across brain regions (e.g. ∑PFCA; rp=0.47, p=0.001, ∑PFSA; rp=0.44, p>0.001; n=50). GABA-A receptor density was positively correlated with two PFASs across brain regions (PFOS; rp=0.33, p=0.02 and PFDoDA; rp=0.34, p=0.014; n=52). Significant negative correlations were found between mAChR density and PFASs in cerebellum (e.g. ∑PFCA; rp=-0.95, p=0.013, n=5) and across brain regions (e.g.

  7. Applying Time-sharing technique in a multimodal compact low-power CMOS neurochip for simultaneous neurochemical and action potential recording.

    Science.gov (United States)

    Poustinchi, Mohammad; Stacey, R Greg; Musallam, Sam

    2014-01-01

    Brain is an electrochemical system and recent studies suggest simultaneous measurement of interrelated brain's electrical and neurochemical activity may lead to better understanding of brain function in addition to developing optimal neural prosthetics. By exploiting opamp Time-sharing technique to minimized power dissipation and silicon area, we have fabricated a power efficient implantable CMOS microsystem for simultaneous measurement of Action Potential (AP) and neurotransmitter concentration. Both AP-recording and neurotransmitter sensing subsystems share a single 653 nW amplifier which senses picoscale to microscale current that corresponds to micromolar neurotransmitter concentration and microscale AP voltage. This microsystem is fabricated in CMOS 0.18 μm technology and tested using recorded signals from dorsal premotor cortex (PMd) area of a macaque monkey in our lab.

  8. Behavioral, neurochemical and pharmaco-EEG profiles of the psychedelic drug 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in rats.

    Science.gov (United States)

    Páleníček, Tomáš; Fujáková, Michaela; Brunovský, Martin; Horáček, Jiří; Gorman, Ingmar; Balíková, Marie; Rambousek, Lukáš; Syslová, Kamila; Kačer, Petr; Zach, Petr; Bubeníková-Valešová, Věra; Tylš, Filip; Kubešová, Anna; Puskarčíková, Jana; Höschl, Cyril

    2013-01-01

    Behavioral, neurochemical and pharmaco-EEG profiles of a new synthetic drug 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in rats were examined. Locomotor effects, prepulse inhibition (PPI) of acoustic startle reaction (ASR), dopamine and its metabolite levels in nucleus accumbens (NAc), EEG power spectra and coherence in freely moving rats were analysed. Amphetamine was used as a reference compound. 2C-B had a biphasic effect on locomotion with initial inhibitory followed by excitatory effect; amphetamine induced only hyperlocomotion. Both drugs induced deficits in the PPI; however they had opposite effects on ASR. 2C-B increased dopamine but decreased 3,4-dihydroxyphenylacetic acid (DOPAC) in the NAc. Low doses of 2C-B induced a decrease in EEG power spectra and coherence. On the contrary, high dose of 2C-B 50 mg/kg had a temporally biphasic effect with an initial decrease followed by an increase in EEG power; decrease as well as increase in EEG coherence was observed. Amphetamine mainly induced an increase in EEG power and coherence in theta and alpha bands. Increases in the theta and alpha power and coherence in 2C-B and amphetamine were temporally linked to an increase in locomotor activity and DA levels in NAc. 2C-B is a centrally active compound similar to other hallucinogens, entactogens and stimulants. Increased dopamine and decreased DOPAC in the NAc may reflect its psychotomimetic and addictive potential and monoaminoxidase inhibition. Alterations in brain functional connectivity reflected the behavioral and neurochemical changes produced by the drug; a correlation between EEG changes and locomotor behavior was observed.

  9. Modulatory effect of cilostazol on tramadol-induced behavioral and neurochemical alterations in rats challenged across the forced swim despair test

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    Noha M. Gamil

    2016-06-01

    Full Text Available Pain-associated depression is encountered clinically in some cases such as cancer, chronic neuropathy, and after operations. Tramadol is an opioid analgesic drug that may modulate monoaminergic neurotransmission by inhibition of noradrenaline and serotonin reuptake that may contribute to its antidepressant-like effects. Clinically, tramadol is used either alone or in combination with other NSAIDs in the treatment of cases associated with pain and depression, e.g. low back pain, spinal cord injury, and post-operative pain management. However, tramadol monotherapy as an antidepressant is impeded by severe adverse effects including seizures and serotonin syndrome. Interestingly, phosphodiesterase-III inhibitors demonstrated novel promising antidepressant effects. Among which, cilostazol was reported to attenuate depression in post-stroke cases, geriatrics and patients undergoing carotid artery stenting. Therefore, this study was carried out to investigate the possible antidepressant-like effects of tramadol and/or cilostazol on the behavioral level in experimental animals, and to examine the neurochemical and biochemical effects of tramadol, cilostazol and their combination in rats, in order to explore the probable mechanisms of action underlying their effects. To achieve our target, male albino mice and rats were randomly allocated into five groups and administered either vehicle for control, fluoxetine (20 mg/kg, p.o., tramadol HCl (20 mg/kg, p.o., cilostazol (100 mg/kg, p.o., or combination of both tramadol and cilostazol. At day 14, mice and rats were challenged in the tail suspension test and forced swim test, respectively. Rats were sacrificed and brains were isolated for determination of brain monoamines, MDA, NO, SOD, and TNF-α. The current results showed that concurrent administration of cilostazol to tramadol-treated animals modulated depression on the behavioral level, and showed ameliorative neurochemical and biochemical effects

  10. Unique Behavioral and Neurochemical Effects Induced by Repeated Adolescent Consumption of Caffeine-Mixed Alcohol in C57BL/6 Mice.

    Science.gov (United States)

    Robins, Meridith T; Lu, Julie; van Rijn, Richard M

    2016-01-01

    The number of highly caffeinated products has increased dramatically in the past few years. Among these products, highly caffeinated energy drinks are the most heavily advertised and purchased, which has resulted in increased incidences of co-consumption of energy drinks with alcohol. Despite the growing number of adolescents and young adults reporting caffeine-mixed alcohol use, knowledge of the potential consequences associated with co-consumption has been limited to survey-based results and in-laboratory human behavioral testing. Here, we investigate the effect of repeated adolescent (post-natal days P35-61) exposure to caffeine-mixed alcohol in C57BL/6 mice on common drug-related behaviors such as locomotor sensitivity, drug reward and cross-sensitivity, and natural reward. To determine changes in neurological activity resulting from adolescent exposure, we monitored changes in expression of the transcription factor ΔFosB in the dopaminergic reward pathway as a sign of long-term increases in neuronal activity. Repeated adolescent exposure to caffeine-mixed alcohol exposure induced significant locomotor sensitization, desensitized cocaine conditioned place preference, decreased cocaine locomotor cross-sensitivity, and increased natural reward consumption. We also observed increased accumulation of ΔFosB in the nucleus accumbens following repeated adolescent caffeine-mixed alcohol exposure compared to alcohol or caffeine alone. Using our exposure model, we found that repeated exposure to caffeine-mixed alcohol during adolescence causes unique behavioral and neurochemical effects not observed in mice exposed to caffeine or alcohol alone. Based on similar findings for different substances of abuse, it is possible that repeated exposure to caffeine-mixed alcohol during adolescence could potentially alter or escalate future substance abuse as means to compensate for these behavioral and neurochemical alterations.

  11. Unique Behavioral and Neurochemical Effects Induced by Repeated Adolescent Consumption of Caffeine-Mixed Alcohol in C57BL/6 Mice.

    Directory of Open Access Journals (Sweden)

    Meridith T Robins

    Full Text Available The number of highly caffeinated products has increased dramatically in the past few years. Among these products, highly caffeinated energy drinks are the most heavily advertised and purchased, which has resulted in increased incidences of co-consumption of energy drinks with alcohol. Despite the growing number of adolescents and young adults reporting caffeine-mixed alcohol use, knowledge of the potential consequences associated with co-consumption has been limited to survey-based results and in-laboratory human behavioral testing. Here, we investigate the effect of repeated adolescent (post-natal days P35-61 exposure to caffeine-mixed alcohol in C57BL/6 mice on common drug-related behaviors such as locomotor sensitivity, drug reward and cross-sensitivity, and natural reward. To determine changes in neurological activity resulting from adolescent exposure, we monitored changes in expression of the transcription factor ΔFosB in the dopaminergic reward pathway as a sign of long-term increases in neuronal activity. Repeated adolescent exposure to caffeine-mixed alcohol exposure induced significant locomotor sensitization, desensitized cocaine conditioned place preference, decreased cocaine locomotor cross-sensitivity, and increased natural reward consumption. We also observed increased accumulation of ΔFosB in the nucleus accumbens following repeated adolescent caffeine-mixed alcohol exposure compared to alcohol or caffeine alone. Using our exposure model, we found that repeated exposure to caffeine-mixed alcohol during adolescence causes unique behavioral and neurochemical effects not observed in mice exposed to caffeine or alcohol alone. Based on similar findings for different substances of abuse, it is possible that repeated exposure to caffeine-mixed alcohol during adolescence could potentially alter or escalate future substance abuse as means to compensate for these behavioral and neurochemical alterations.

  12. Biologically distinct subsets of nevi

    Science.gov (United States)

    ROGERS, Tova; MARINO, Maria L.; RACITI, Patricia; JAIN, Manu; BUSAM, Klaus J.; MARCHETTI, Michael A.; MARGHOOB, Ashfaq A.

    2017-01-01

    Melanocytic nevi (MN) encompass a range of benign tumors with varying microscopic and macroscopic features. Their development is a multifactorial process under genetic and environmental influences. The clinical importance of MN lies in distinguishing them from melanoma and in recognizing their associations with melanoma risk and cancer syndromes. Historically, the distinction between the different types of MN, as well as between MN and melanoma, was based on clinical history, gross morphology, and histopathological features. While histopathology with clinical correlation remains the gold standard for differentiating and diagnosing melanocytic lesions, in some cases, this may not be possible. The use of dermoscopy has allowed for the assessment of subsurface skin structures and has contributed to the clinical evaluation and classification of MN. Genetic profiling, while still in its early stages, has the greatest potential to refine the classification of MN by clarifying their developmental processes, biological behaviors, and relationships to melanoma. Here we review the most salient clinical, dermoscopic, histopathological, and genetic features of different MN subgroups. PMID:27119653

  13. Penoscrotal porokeratosis: A distinct entity

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    Rajiv Joshi

    2015-01-01

    Full Text Available A 26-year-old man presented with five months history of redness associated with itching and burning over the scrotum and shaft of the penis with a persistent rash on those sites. There had been no response to topical steroid and antifungal creams. Clinical examination revealed a large well-circumscribed erythematous plaque with a thready raised border with a tiny groove at its summit that involved almost two-thirds of the ventral part of the shaft of the penis. Ill-defined erythema with a granular surface was seen over the anterior scrotal skin. A 4 mm punch biopsy of the plaque on the penile shaft revealed multiple cornoid lamellae located adjacent to one another. The patient was treated with topical emollients. Follow up after four months revealed almost complete resolution of the plaque on the penile shaft. Penoscrotal porokeratosis appears to be a distinct entity in the family of porokeratotic diseases, described only in young males in their twenties with involvement of the penile shaft and anterior scrotum with severe burning and itching and histologically associated with multiple cornoid lamellae. It may represent an unusual epidermal porokeratotic reaction pattern and may be a self-resolving condition.

  14. Experimentally constrained CA1 fast-firing parvalbumin-positive interneuron network models exhibit sharp transitions into coherent high frequency rhythms.

    Science.gov (United States)

    Ferguson, Katie A; Huh, Carey Y L; Amilhon, Bénédicte; Williams, Sylvain; Skinner, Frances K

    2013-01-01

    The coupling of high frequency oscillations (HFOs; >100 Hz) and theta oscillations (3-12 Hz) in the CA1 region of rats increases during REM sleep, indicating that it may play a role in memory processing. However, it is unclear whether the CA1 region itself is capable of providing major contributions to the generation of HFOs, or if they are strictly driven through input projections. Parvalbumin-positive (PV+) interneurons may play an essential role in these oscillations due to their extensive connections with neighboring pyramidal cells, and their characteristic fast-spiking. Thus, we created mathematical network models to investigate the conditions under which networks of CA1 fast-spiking PV+ interneurons are capable of producing high frequency population rhythms. We used whole-cell patch clamp recordings of fast-spiking, PV+ cells in the CA1 region of an intact hippocampal preparation in vitro to derive cellular properties, from which we constrained an Izhikevich-type model. Novel, biologically constrained network models were constructed with these individual cell models, and we investigated networks across a range of experimentally determined excitatory inputs and inhibitory synaptic strengths. For each network, we determined network frequency and coherence. Network simulations produce coherent firing at high frequencies (>90 Hz) for parameter ranges in which PV-PV inhibitory synaptic conductances are necessarily small and external excitatory inputs are relatively large. Interestingly, our networks produce sharp transitions between random and coherent firing, and this sharpness is lost when connectivity is increased beyond biological estimates. Our work suggests that CA1 networks may be designed with mechanisms for quickly gating in and out of high frequency coherent population rhythms, which may be essential in the generation of nested theta/high frequency rhythms.

  15. Experimentally constrained CA1 fast-firing parvalbumin-positive interneuron network models exhibit sharp transitions into coherent high frequency rhythms

    Directory of Open Access Journals (Sweden)

    Katie A Ferguson

    2013-10-01

    Full Text Available The coupling of high frequency oscillations (HFOs; >100 Hz and theta oscillations (3-12 Hz in the CA1 region of rats increases during REM sleep, indicating that it may play a role in memory processing. However, it is unclear whether the CA1 region itself is capable of providing major contributions to the generation of HFOs, or if they are strictly driven through input projections. Parvalbumin-positive (PV+ interneurons may play an essential role in these oscillations due to their extensive connections with neighbouring pyramidal cells, and their characteristic fast-spiking. Thus, we created mathematical network models to investigate the conditions under which networks of CA1 fast-spiking PV+ interneurons are capable of producing high frequency population rhythms.We used whole-cell patch clamp recordings of fast-spiking, PV+ cells in the CA1 region of an intact hippocampal preparation in vitro to derive cellular properties, from which we constrained an Izhikevich-type model. Novel, biologically constrained network models were constructed with these individual cell models, and we investigated networks across a range of experimentally determined excitatory inputs and inhibitory synaptic strengths. For each network, we determined network frequency and coherence.Network simulations produce coherent firing at high frequencies (> 90 Hz for parameter ranges in which PV-PV inhibitory synaptic conductances are necessarily small and external excitatory inputs are relatively large. Interestingly, our networks produce sharp transitions between random and coherent firing, and this sharpness is lost when connectivity is increased beyond biological estimates. Our work suggests that CA1 networks may be designed with mechanisms for quickly gating in and out of high frequency coherent population rhythms, which may be essential in the generation of nested theta/high frequency rhythms.

  16. The effects of anodal transcranial direct current stimulation and patterned electrical stimulation on spinal inhibitory interneurons and motor function in patients with spinal cord injury.

    Science.gov (United States)

    Yamaguchi, Tomofumi; Fujiwara, Toshiyuki; Tsai, Yun-An; Tang, Shuen-Chang; Kawakami, Michiyuki; Mizuno, Katsuhiro; Kodama, Mitsuhiko; Masakado, Yoshihisa; Liu, Meigen

    2016-06-01

    Supraspinal excitability and sensory input may play an important role for the modulation of spinal inhibitory interneurons and functional recovery among patients with incomplete spinal cord injury (SCI). Here, we investigated the effects of anodal transcranial direct current stimulation (tDCS) combined with patterned electrical stimulation (PES) on spinal inhibitory interneurons in patients with chronic incomplete SCI and in healthy individuals. Eleven patients with incomplete SCI and ten healthy adults participated in a single-masked, sham-controlled crossover study. PES involved stimulating the common peroneal nerve with a train of ten 100 Hz pulses every 2 s for 20 min. Anodal tDCS (1 mA) was simultaneously applied to the primary motor cortex that controls the tibialis anterior muscle. We measured reciprocal inhibition and presynaptic inhibition of a soleus H-reflex by stimulating the common peroneal nerve prior to tibial nerve stimulation, which elicits the H-reflex. The inhibition was assessed before, immediately after, 10 min after and 20 min after the stimulation. Compared with baseline, simultaneous application of anodal tDCS with PES significantly increased changes in disynaptic reciprocal inhibition and long-latency presynaptic inhibition in both healthy and SCI groups for at least 20 min after the stimulation (all, p stimulation (p = 0.004). In conclusion, anodal tDCS combined with PES could induce spinal plasticity and improve ankle movement in patients with incomplete SCI.

  17. Using a Semi-Automated Strategy to Develop Multi-Compartment Models That Predict Biophysical Properties of Interneuron-Specific 3 (IS3) Cells in Hippocampus.

    Science.gov (United States)

    Guet-McCreight, Alexandre; Camiré, Olivier; Topolnik, Lisa; Skinner, Frances K

    2016-01-01

    Determining how intrinsic cellular properties govern and modulate neuronal input-output processing is a critical endeavor for understanding microcircuit functions in the brain. However, lack of cellular specifics and nonlinear interactions prevent experiments alone from achieving this. Building and using cellular models is essential in these efforts. We focus on uncovering the intrinsic properties of mus musculus hippocampal type 3 interneuron-specific (IS3) cells, a cell type that makes GABAergic synapses onto specific interneuron types, but not pyramidal cells. While IS3 cell morphology and synaptic output have been examined, their voltage-gated ion channel profile and distribution remain unknown. We combined whole-cell patch-clamp recordings and two-photon dendritic calcium imaging to examine IS3 cell membrane and dendritic properties. Using these data as a target reference, we developed a semi-automated strategy to obtain multi-compartment models for a cell type with unknown intrinsic properties. Our approach is based on generating populations of models to capture determined features of the experimental data, each of which possesses unique combinations of channel types and conductance values. From these populations, we chose models that most closely resembled the experimental data. We used these models to examine the impact of specific ion channel combinations on spike generation. Our models predict that fast delayed rectifier currents should be present in soma and proximal dendrites, and this is confirmed using immunohistochemistry. Further, without A-type potassium currents in the dendrites, spike generation is facilitated at more distal synaptic input locations. Our models will help to determine the functional role of IS3 cells in hippocampal microcircuits.

  18. The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT3 receptor expressing interneurons: An in vitro study in rat hippocampus slices.

    Science.gov (United States)

    Dale, Elena; Grunnet, Morten; Pehrson, Alan L; Frederiksen, Kristen; Larsen, Peter H; Nielsen, Jacob; Stensbøl, Tine B; Ebert, Bjarke; Yin, Haolan; Lu, Dunguo; Liu, Huiquing; Jensen, Thomas N; Yang, Charles R; Sanchez, Connie

    2017-12-21

    The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, 5-HT1D, 5-HT3, 5-HT7 receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine's functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT3A receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT3A receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage-clamping methods. The patched neurons were subsequently filled with biocytin for confirmation of 5-HT3 receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT3 receptor antagonist ondansetron potently antagonized 5-HT-induced currents in the cellular assays, vortioxetine had a slower off-rate than ondansetron in oocytes expressing 5-HT3A receptors. Furthermore, vortioxetine's but not ondansetron's 5-HT3 receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT3A receptors. Finally, in 5-HT3 receptor-expressing GABAergic interneurons from the CA1 stratum radiatum, vortioxetine and ondansetron blocked depolarizations induced by superfusion of either 5-HT or the 5-HT3 receptor agonist mCPBG. Taken together, these data add to a growing literature supporting the idea that vortioxetine may inhibit GABAergic neurotransmission in some brain regions via a 5-HT3 receptor antagonism-dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling. Copyright © 2017. Published by Elsevier B.V.

  19. [Dendritic arborization patterns of interneurons labeled with a lectin, Vicia villosa, in rat cerebral cortex: studies by intracellular injection of lucifer yellow using aldehyde-fixed slices].

    Science.gov (United States)

    Ojima, H

    1993-04-01

    In order to characterize the dendritic field of a number of interneurons in the cerebral cortex, the labeling of extracellular sugar chains which define a subset of interneurons was combined with the subsequent intracellular filling of dyes in aldehyde-fixed tissue. Neurons whose cell body had been outlined by a lectin, Vicia villosa (VVA), which recognizes terminal N-acetylgalactosamine, were intracellularly injected with a fluorescent tracer, Lucifer yellow (LY), in the rat parietal cortex under direct visualization. After immunohistochemical detection of LY, somal morphology and the dendritic fields of injected neurons were reconstructed from serial sections and characterized in each of the layers II/III, IV, V and VI. Multipolar, flask-shaped and bitufted somata were VVA-positive. Multipolar neurons with round soma and spherical dendritic field were found in layers II/III, IV and V, while those with vertically elongated dendritic fields were found in layer VI. Cell bodies were located roughly in the center of the spherical or cylindrical dendritic fields. Neurons with apparently multipolar but flask- or pear-shaped soma were found frequently in layer IV, and much less frequently in layer II/III and VI. The majority of the dendrites originated from the neck portion of flask and formed a roughly spherical dendritic field with the cell body located more or less eccentrically. Some neurons in layer IV had an oval, somewhat vertically elongated soma and displayed a typical bitufted dendritic arborization pattern with vertically elongated dendritic fields. The overall dendritic field sizes of the cells gradually increased at deeper layers of the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Distinctiveness of Ugandapithecus from Proconsul

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    Gommery, D.

    2009-12-01

    Full Text Available The decision to create the genus Ugandapithecus by Senut et al., 2000 has been criticised, either directly and in detail by MacLatchy & Rossie (2005b who argued that it is a junior synonym of Proconsul, or indirectly without providing reasons, firstly by Harrison (2001 who wrote that he did not retain it as a genus distinct from Proconsul, and then by Suwa et al., (2007 who employed the name “Ugandapithecus” with inverted commas, implying some degree of doubt about its validity as a genus, but without providing details. More recently Harrison & Andrews (2009 have recognised the Meswa sample as a separate species but they argue that it should be maintained within Proconsul, despite the morphological differences that it has from other species of the genus. We here re-examine the question by comparing, on the one hand, the holotype maxilla of Proconsul africanus, the type species of the genus, with the upper dentition of Ugandapithecus major, and, on the other hand, the holotype mandible of Ugandapithecus major with the lower dentition and mandibles previously attributed to Proconsul africanus. We conclude that the differences between the known upper and lower dentitions of P. africanus and U. major are of such a degree that the two taxa warrant generic separation, and that the differences are not related to sexual dimorphism. Where Proconsul africanus differs from Ugandapithecus major, it approaches Proconsul nyanzae and Proconsul heseloni from Rusinga.Furthermore, the range of morphometric variation within the fossil samples previously attributed to Ugandapithecus major is so great that it far surpasses variation in any other hominoid, fossil or extant. Previously this great amount of variation was interpreted to mean that U. major was extremely dimorphic, with huge males and small females, but if this is true, then U. major would be unique among hominoids in having females in which the cheek teeth fall completely outside the range of

  1. Morphological and electrophysiological features of motor neurons and putative interneurons in the dorsal vagal complex of rats and mice

    Science.gov (United States)

    Gao, Hong; Glatzer, Nicholas R.; Williams, Kevin W.; Derbenev, Andrei V.; Liu, Dan; Smith, Bret N.

    2009-01-01

    The dorsal motor nucleus of the vagus (DMV) contains preganglionic motor neurons that control viscera along the subdiaphragmatic digestive tract, but may also contain neurons that do not project to the viscera. Neurons that expressed EGFP 60-72 h subsequent to PRV-152 inoculation of vagal terminals in the stomach wall were targeted for whole-cell patch-clamp recording and biocytin filling in transverse brainstem slices from rats and their quantitative morphological and electrophysiological characteristics were compared with uninfected cells. Over 90% of PRV-152 labeled neurons were also labeled subsequent to intraperitoneal injection of FluoroGold, indicating most were preganglionic motor neurons. In reconstructed neurons with an identifiable axon trajectory, two cellular subtypes were distinguished. The axon projected ventrolaterally from the DMV in 44 of 49 cells and these were likely to be vagal motor neurons. Axons of other neurons ramified within the nucleus tractus solitarius (NTS) or DMV. These cells were smaller and otherwise morphologically distinct from putative motor neurons. Transgenic mice with GFP-expressing inhibitory neurons (i.e., GIN mice) were used to identify a GABAergic subset vagal neurons. These neurons had locally-ramifying axons and formed a morphologically distinct subset of DMV cells, which were similar in size and axon trajectory to GABAergic neurons in the NTS. Most neurons in the DMV therefore possess morphological features of motor neurons, but locally projecting cells and inhibitory neurons with distinct morphological features are also found within the DMV. These cells likely contribute to regulation of vagal function. PMID:19619517

  2. The Gastric Ganglion of Octopus vulgaris: Preliminary Characterization of Gene- and Putative Neurochemical-Complexity, and the Effect of Aggregata octopiana Digestive Tract Infection on Gene Expression

    Science.gov (United States)

    Baldascino, Elena; Di Cristina, Giulia; Tedesco, Perla; Hobbs, Carl; Shaw, Tanya J.; Ponte, Giovanna; Andrews, Paul L. R.

    2017-01-01

    The gastric ganglion is the largest visceral ganglion in cephalopods. It is connected to the brain and is implicated in regulation of digestive tract functions. Here we have investigated the neurochemical complexity (through in silico gene expression analysis and immunohistochemistry) of the gastric ganglion in Octopus vulgaris and tested whether the expression of a selected number of genes was influenced by the magnitude of digestive tract parasitic infection by Aggregata octopiana. Novel evidence was obtained for putative peptide and non-peptide neurotransmitters in the gastric ganglion: cephalotocin, corticotrophin releasing factor, FMRFamide, gamma amino butyric acid, 5-hydroxytryptamine, molluscan insulin-related peptide 3, peptide PRQFV-amide, and tachykinin–related peptide. Receptors for cholecystokininA and cholecystokininB, and orexin2 were also identified in this context for the first time. We report evidence for acetylcholine, dopamine, noradrenaline, octopamine, small cardioactive peptide related peptide, and receptors for cephalotocin and octopressin, confirming previous publications. The effects of Aggregata observed here extend those previously described by showing effects on the gastric ganglion; in animals with a higher level of infection, genes implicated in inflammation (NFκB, fascin, serpinB10 and the toll-like 3 receptor) increased their relative expression, but TNF-α gene expression was lower as was expression of other genes implicated in oxidative stress (i.e., superoxide dismutase, peroxiredoxin 6, and glutathione peroxidase). Elevated Aggregata levels in the octopuses corresponded to an increase in the expression of the cholecystokininA receptor and the small cardioactive peptide-related peptide. In contrast, we observed decreased relative expression of cephalotocin, dopamine β-hydroxylase, peptide PRQFV-amide, and tachykinin-related peptide genes. A discussion is provided on (i) potential roles of the various molecules in food intake

  3. The Gastric Ganglion of Octopus vulgaris: Preliminary Characterization of Gene- and Putative Neurochemical-Complexity, and the Effect of Aggregata octopiana Digestive Tract Infection on Gene Expression

    Directory of Open Access Journals (Sweden)

    Elena Baldascino

    2017-12-01

    Full Text Available The gastric ganglion is the largest visceral ganglion in cephalopods. It is connected to the brain and is implicated in regulation of digestive tract functions. Here we have investigated the neurochemical complexity (through in silico gene expression analysis and immunohistochemistry of the gastric ganglion in Octopus vulgaris and tested whether the expression of a selected number of genes was influenced by the magnitude of digestive tract parasitic infection by Aggregata octopiana. Novel evidence was obtained for putative peptide and non-peptide neurotransmitters in the gastric ganglion: cephalotocin, corticotrophin releasing factor, FMRFamide, gamma amino butyric acid, 5-hydroxytryptamine, molluscan insulin-related peptide 3, peptide PRQFV-amide, and tachykinin–related peptide. Receptors for cholecystokininA and cholecystokininB, and orexin2 were also identified in this context for the first time. We report evidence for acetylcholine, dopamine, noradrenaline, octopamine, small cardioactive peptide related peptide, and receptors for cephalotocin and octopressin, confirming previous publications. The effects of Aggregata observed here extend those previously described by showing effects on the gastric ganglion; in animals with a higher level of infection, genes implicated in inflammation (NFκB, fascin, serpinB10 and the toll-like 3 receptor increased their relative expression, but TNF-α gene expression was lower as was expression of other genes implicated in oxidative stress (i.e., superoxide dismutase, peroxiredoxin 6, and glutathione peroxidase. Elevated Aggregata levels in the octopuses corresponded to an increase in the expression of the cholecystokininA receptor and the small cardioactive peptide-related peptide. In contrast, we observed decreased relative expression of cephalotocin, dopamine β-hydroxylase, peptide PRQFV-amide, and tachykinin-related peptide genes. A discussion is provided on (i potential roles of the various molecules

  4. SU-F-I-68: Longitudinal Neurochemical Changes On Rat Prefrontal Cortex of Single Prolonged Stress Model by Using Proton Magnetic Resonance Spectroscopy at 9.4T

    Energy Technology Data Exchange (ETDEWEB)

    Lim, S-I; Yoo, C-H [Department of Biomedical Engineering, and Research Institute of Biomedical Engineering, The Catholic University of Korea College of Medicine, Seoul, Seoul (Korea, Republic of); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Seoul (Korea, Republic of); Song, K-H; Choe, B-Y [Department of Biomedical Engineering, and Research Institute of Biomedical Engineering, The Catholic University of Korea College of Medicine, Seoul, Seoul (Korea, Republic of); Woo, D-C [Asan Institute for Life Sciences, Asan Medical Center, Seoul, Seoul (Korea, Republic of)

    2016-06-15

    Purpose: Single prolonged stress (SPS) is an animal model of posttraumatic stress disorder (PTSD). However, it has not been known how PTSD develops from the first exposure to traumatic events and neurochemical differences between acute/single stress and PTSD-triggering stress. Therefore, the object of this study is to determine time-dependent neurochemical changes in prefrontal cortex (PFC) of rats using in vivo proton magnetic resonance spectroscopy (1H-MRS). Methods: Male Sprague-Dawley rats (n=14; body weight=200–220g) were used. The SPS protocol was used in this study. Rats were restrained for 2h and then immediately forced to swim for 20min in water (20–24 Celsius). After a 15-min recuperation period, rats were exposed to ether (using a desiccator) until general anesthesia occurred (<5min). In vivo proton MRS was performed 30min before the SPS (Base), approximately 10min after the SPS (D+0), 3 (D+3) and 7 (D+7) days after SPS to investigate time-dependent changes on metabolites levels in the PFC. Acquisition of in vivo MRS spectra and MRI was conducted at the four time points using 9.4 T Agilent Scanner. Concentration of metabolites was quantified by LCModel. Results: Statistical significance was analyzed using one-way ANOVA with post hoc Tukey HSD tests to assess the metabolite changes in the PFC. The SPS resulted in significant stress-induced differences for 7 days in glutamine (F(3,52)=6.750, P=0.001), choline-containing compounds (F(3,52)=16.442, P=0.000), glutamine/glutamate concentrations (F(3,52)=7.352, P=0.000). Conclusion: PTSD in human is associated with decreased neuronal activity in the PFC. In this study, SPS altered total choline, glutamine levels but not NAA levels in the PFC of the rats. Therefore, for the three stressors and quiescent period of seven days, SPS attenuated excitatory tone and membrane turnover but did not affect neural integrity in the PFC.

  5. Anormalidades neuropatológicas e neuroquímicas no transtorno afetivo bipolar Neuropathological and neurochemical abnormalities in bipolar disorder

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    Benício Noronha Frey

    2004-09-01

    Full Text Available OBJETIVOS: Estudos pós-mortem, farmacológicos, de neuroimagem e em modelos animais têm demonstrado uma possível associação de mecanismos de sinalização intracelular na fisiopatologia do transtorno afetivo bipolar (TAB. Esse trabalho tem como objetivo revisar os achados em neuropatologia e bioquímica celular. MÉTODOS: Foi realizada uma pesquisa ao MEDLINE, entre 1980 e 2003, tendo sido utilizados os unitermos: bipolar disorder, signaling, second messengers e postmortem, além de referências cruzadas dos artigos selecionados. RESULTADOS: uropatológicos demonstraram uma diminuição do número de células neuronais e gliais, principalmente no córtex pré-frontal de pacientes bipolares. Estudos neuroquímicos demonstraram alterações nas vias do AMPc, fosfatidilinositol, Wnt/GSK-3beta e Ca++ intracelular nesses pacientes. CONCLUSÃO: Os achados de alterações neuropatológicas e neuroquímicas no TAB podem estar relacionados com a fisiopatologia deste transtorno e com os efeitos dos estabilizadores de humor. No entanto, mais estudos são necessários para esclarecer o papel das cascatas de sinalização intracelular na patogênese deste transtorno.OBJECTIVES: Postmortem, pharmacological, neuroimaging, and animal model studies have demonstrated a possible association of intracellular signaling mechanisms in the pathophysiology of bipolar disorder. The objective of this paper is to review the findings in neuropathology and cellular biochemistry. METHODS: We performed a MEDLINE research, between 1980-2003, using bipolar disorder, signaling, second messengers, and postmortem as keywords, and cross-references. RESULTS: Neuropathological studies reported a decrease in neuronal and glial cells, mainly in the prefrontal cortex of bipolar patients. Neurochemical studies reported dysfunction in cAMP, phosphoinositide, Wnt/GSK-3b, and intracellular Ca++ pathways in these patients. CONCLUSION: The neuropathological and neurochemical abnormalities

  6. Similar distribution changes of GABAergic interneuron subpopulations in contrast to the different impact on neurogenesis between developmental and adult-stage hypothyroidism in the hippocampal dentate gyrus in rats.

    Science.gov (United States)

    Shiraki, Ayako; Akane, Hirotoshi; Ohishi, Takumi; Wang, Liyun; Morita, Reiko; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-10-01

    Hypothyroidism affects neurogenesis. The present study was performed to clarify the sensitivity of neurogenesis-related cellular responses in the hippocampal dentate gyrus between developmental and adult-stage hypothyroidism. An exposure study of methimazole (MMI) as an anti-thyroid agent at 0, 50, 200 ppm in the drinking water was performed using pregnant rats from gestation day 10 to postnatal day (PND) 21 (developmental hypothyroidism) and adult male rats by setting an identical exposure period from PND 46 through to PND 77 (adult-stage hypothyroidism). Offspring with developmental hypothyroidism were killed at PND 21 or PND 77, and animals with adult-stage hypothyroidism were killed at PND 77. Proliferation and apoptosis were unchanged in the dentate subgranular zone by either developmental or adult-stage hypothyroidism. With regard to precursor granule cells, a sustained reduction of paired box 6-positive stem or early progenitor cells and a transient reduction of doublecortin-positive late-stage progenitor cells were observed after developmental hypothyroidism with MMI at 50 and 200 ppm. These cells were unchanged by adult-stage hypothyroidism. With regard to γ-aminobutyric acid (GABA) ergic interneuron subpopulations in the dentate hilus, the number of parvalbumin-positive cells was decreased and the number of calretinin-positive cells was increased after both developmental and adult-stage hypothyroidism with MMI at 50 and 200 ppm. Fluctuations in GABAergic interneuron numbers with developmental hypothyroidism continued through to PND 77 with 200 ppm MMI. Considering the roles of GABAergic interneuron subpopulations in neurogenesis and neuronal differentiation, subpopulation changes in GABAergic interneurons by hypothyroidism may be the signature of aberrant neurogenesis even at the adult stage.

  7. Behavioral and neurochemical effects of alpha lipoic acid associated with omega-3 in tardive dyskinesia induced by chronic haloperidol in rats.

    Science.gov (United States)

    de Araújo, Dayane Pessoa; Camboim, Thaisa Gracielle Martins; Silva, Ana Patrícia Magalhães; Silva, Caio da Fonseca; de Sousa, Rebeca Canuto; Barbosa, Mabson Delâno Alves; Oliveira, Lucidio Clebeson; Cavalcanti, José Rodolfo Lopes de Paiva; Lucena, Eudes Euler de Souza; Guzen, Fausto Pierdoná

    2017-07-01

    Tardive dyskinesia (TD) is characterized by involuntary movements of the lower portion of the face being related to typical antipsychotic therapy. TD is associated with the oxidative imbalance in the basal ganglia. Lipoic acid (LA) and omega-3 (ω-3) are antioxidants acting as enzyme cofactors, regenerating antioxidant enzymes. This study aimed to investigate behavioral and neurochemical effects of supplementation with LA (100 mg/kg) and ω-3 (1 g/kg) in the treatment of TD induced by chronic use of haloperidol (HAL) (1 mg/kg) in rats. Wistar male rats were used, weighing between 180-200 g. The animals were treated chronically (31 days) with LA alone or associated with HAL or ω-3. Motor behavior was assessed by open-field test, the catalepsy test, and evaluation of orofacial dyskinesia. Oxidative stress was accessed by determination of lipid peroxidation and concentration of nitrite. LA and ω-3 alone or associated caused an improvement in motor performance by increasing locomotor activity in the open-field test and decreased the permanence time on the bar in the catalepsy test and decreased the orofacial dyskinesia. LA and ω-3 showed antioxidant effects, decreasing lipid peroxidation and nitrite levels. Thus, the use of LA associated with ω-3 reduced the extrapyramidal effects produced by chronic use of HAL.

  8. Towards a neurochemical profile of the amygdala using short-TE1H magnetic resonance spectroscopy at 3 T.

    Science.gov (United States)

    Schubert, Florian; Kühn, Simone; Gallinat, Jürgen; Mekle, Ralf; Ittermann, Bernd

    2017-05-01

    The amygdala plays a key role in emotional learning and in the processing of emotions. As disturbed amygdala function has been linked to several psychiatric conditions, a knowledge of its biochemistry, especially neurotransmitter levels, is highly desirable. The spin echo full intensity acquired localized (SPECIAL) sequence, together with a transmit/receive coil, was used to perform very short-TE magnetic resonance spectroscopy at 3 T to determine the neurochemical profile in a spectroscopic voxel containing the amygdala in 21 healthy adult subjects. For spectral analysis, advanced data processing was applied in combination with a macromolecule baseline measured in the anterior cingulate for spectral fitting. The concentrations of total N-acetylaspartate, total creatine, total choline, myo-inositol and, for the first time, glutamate were quantified with high reliability (uncertainties far below 10%). For these metabolites, the inter-individual variability, reflected by the relative standard deviations for the cohort studied, varied between 12% (glutamate) and 22% (myo-inositol). Glutamine and glutathione could also be determined, albeit with lower precision. Retest on four subjects showed good reproducibility. The devised method allows the determination of metabolite concentrations in the amygdala voxel, including glutamate, provides an estimation of glutamine and glutathione, and may help in the study of disturbed amygdala metabolism in pathologies such as anxiety disorder, autism and major depression. Copyright © 2017 John Wiley & Sons, Ltd.

  9. Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson’s Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat

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    Dayane Pessoa de Araújo

    2013-01-01

    Full Text Available This study aimed to investigate behavioral and neurochemical effects of α-lipoic acid (100 mg/kg or 200 mg/kg alone or associated with L-DOPA using an animal model of Parkinson’s disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. α-Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA at cylinder test. α-lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, α-lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that α-lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment.

  10. Toward an in Vivo Neurochemical Profile: Quantification of 18 Metabolites in Short-Echo-Time 1H NMR Spectra of the Rat Brain

    Science.gov (United States)

    Pfeuffer, Josef; Tkáč , Ivan; Provencher, Stephen W.; Gruetter, Rolf

    1999-11-01

    Localized in vivo1H NMR spectroscopy was performed with 2-ms echo time in the rat brain at 9.4 T. Frequency domain analysis with LCModel showed that the in vivo spectra can be explained by 18 metabolite model solution spectra and a highly structured background, which was attributed to resonances with fivefold shorter in vivo T1 than metabolites. The high spectral resolution (full width at half maximum approximately 0.025 ppm) and sensitivity (signal-to-noise ratio approximately 45 from a 63-μL volume, 512 scans) was used for the simultaneous measurement of the concentrations of metabolites previously difficult to quantify in 1H spectra. The strongly represented signals of N-acetylaspartate, glutamate, taurine, myo-inositol, creatine, phosphocreatine, glutamine, and lactate were quantified with Cramér-Rao lower bounds below 4%. Choline groups, phosphorylethanolamine, glucose, glutathione, γ-aminobutyric acid, N-acetylaspartylglutamate, and alanine were below 13%, whereas aspartate and scyllo-inositol were below 22%. Intra-assay variation was assessed from a time series of 3-min spectra, and the coefficient of variation was similar to the calculated Cramér-Rao lower bounds. Interassay variation was determined from 31 pooled spectra, and the coefficient of variation for total creatine was 7%. Tissue concentrations were found to be in very good agreement with neurochemical data from the literature.

  11. Social conformity despite individual preferences for distinctiveness.

    Science.gov (United States)

    Smaldino, Paul E; Epstein, Joshua M

    2015-03-01

    We demonstrate that individual behaviours directed at the attainment of distinctiveness can in fact produce complete social conformity. We thus offer an unexpected generative mechanism for this central social phenomenon. Specifically, we establish that agents who have fixed needs to be distinct and adapt their positions to achieve distinctiveness goals, can nevertheless self-organize to a limiting state of absolute conformity. This seemingly paradoxical result is deduced formally from a small number of natural assumptions and is then explored at length computationally. Interesting departures from this conformity equilibrium are also possible, including divergence in positions. The effect of extremist minorities on these dynamics is discussed. A simple extension is then introduced, which allows the model to generate and maintain social diversity, including multimodal distinctiveness distributions. The paper contributes formal definitions, analytical deductions and counterintuitive findings to the literature on individual distinctiveness and social conformity.

  12. Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns.

    Science.gov (United States)

    Bergman, Peter; Adori, Csaba; Vas, Szilvia; Kai-Larsen, Ylva; Sarkanen, Tomi; Cederlund, Andreas; Agerberth, Birgitta; Julkunen, Ilkka; Horvath, Beata; Kostyalik, Diana; Kalmár, Lajos; Bagdy, Gyorgy; Huutoniemi, Anne; Partinen, Markku; Hökfelt, Tomas

    2014-09-02

    Narcolepsy is a chronic sleep disorder, likely with an autoimmune component. During 2009 and 2010, a link between A(H1N1)pdm09 Pandemrix vaccination and onset of narcolepsy was suggested in Scandinavia. In this study, we searched for autoantibodies related to narcolepsy using a neuroanatomical array: rat brain sections were processed for immunohistochemistry/double labeling using patient sera/cerebrospinal fluid as primary antibodies. Sera from 89 narcoleptic patients, 52 patients with other sleep-related disorders (OSRDs), and 137 healthy controls were examined. Three distinct patterns of immunoreactivity were of particular interest: pattern A, hypothalamic melanin-concentrating hormone and proopiomelanocortin but not hypocretin/orexin neurons; pattern B, GABAergic cortical interneurons; and pattern C, mainly globus pallidus neurons. Altogether, 24 of 89 (27%) narcoleptics exhibited pattern A or B or C. None of the patterns were exclusive for narcolepsy but were also detected in the OSRD group at significantly lower numbers. Also, some healthy controls exhibited these patterns. The antigen of pattern A autoantibodies was identified as the common C-terminal epitope of neuropeptide glutamic acid-isoleucine/α-melanocyte-stimulating hormone (NEI/αMSH) peptides. Passive transfer experiments on rat showed significant effects of pattern A human IgGs on rapid eye movement and slow-wave sleep time parameters in the inactive phase and EEG θ-power in the active phase. We suggest that NEI/αMSH autoantibodies may interfere with the fine regulation of sleep, contributing to the complex pathogenesis of narcolepsy and OSRDs. Also, patterns B and C are potentially interesting, because recent data suggest a relevance of those brain regions/neuron populations in the regulation of sleep/arousal.

  13. Interneurons and beta-amyloid in the olfactory bulb, anterior olfactory nucleus and olfactory tubercle in APPxPS1 transgenic mice model of Alzheimer's disease.

    Science.gov (United States)

    Saiz-Sanchez, Daniel; De La Rosa-Prieto, Carlos; Ubeda-Bañon, Isabel; Martinez-Marcos, Alino

    2013-09-01

    Impaired olfaction has been described as an early symptom in Alzheimer's disease (AD). Neuroanatomical changes underlying this deficit in the olfactory system are largely unknown. Given that interneuron populations are crucial in olfactory information processing, we have quantitatively analyzed somatostatin- (SOM), parvalbumin- (PV), and calretinin-expressing (CR) cells in the olfactory bulb, anterior olfactory nucleus, and olfactory tubercle in PS1 x APP double transgenic mice model of AD. The experiments were performed in wild type and double transgenic homozygous animal groups of 2, 4, 6, and 8 months of age to analyze early stages of the pathology. In addition, beta-amyloid (Aβ) expression and its correlation with SOM cells have been quantified under confocal microscopy. The results indicate increasing expressions of Aβ with aging as well as an early fall of SOM and CR expression, whereas PV was decreased later in the disease progression. These observations evidence an early, preferential vulnerability of SOM and CR cells in rostral olfactory structures during AD that may be useful to unravel neural basis of olfactory deficits associated to this neurodegenerative disorder. Copyright © 2013 Wiley Periodicals, Inc.

  14. Distinctiveness and the Attentional Boost Effect.

    Science.gov (United States)

    Smith, S Adam; Mulligan, Neil W

    2018-02-01

    The typical pattern of results in divided attention experiments is that subjects in a full attention (FA) condition perform markedly better on tests of memory than subjects in a divided attention (DA) condition which forces subjects to split their attention between studying to-be-remembered stimuli and completing some peripheral task. Nevertheless, recent research has revealed an exception wherein stimuli presented concurrently with targets in a detection task are better remembered than stimuli which co-occur with distractors. Research on this phenomenon-the Attentional Boost Effect (ABE)-has demonstrated that the ABE is reduced or eliminated for words made distinct by their word frequency or orthographic properties-forms of secondary distinctiveness. However, it is unclear how primary distinctiveness effects may interact with the ABE. The current study observed how perceptual and semantic manipulations of primary distinctiveness via the isolation paradigm interact with the ABE, and revealed these interactions to be fundamentally different than those of secondary distinctiveness. Specifically, whereas the effects of secondary distinctiveness in earlier studies were found to be redundant with the ABE, the current study demonstrated that items characterized by primary distinctiveness enhanced memory performance independently of the ABE. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  15. 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.

  16. Distinctiveness of Saudi Arabian EFL Learners

    OpenAIRE

    Manssour Habbash; Srinivasa Rao Idapalapati

    2016-01-01

    In view of the increasing concern among English language teachers dealing with students from Saudi Arabia, as it manifests in TESOL community discussions, about the uniqueness of Saudi Arabian EFL learners, this paper attempts to document the outcome of a study of their distinctiveness from the perspective of expatriate teachers working for PYPs (Preparatory Year Programs) in Saudi Arabia. This study examines the distinctiveness with regard to the learning attitudes of Saudi students that are...

  17. Neurochemical evidence supporting dopamine D1-D2 receptor heteromers in the striatum of the long-tailed macaque: changes following dopaminergic manipulation.

    Science.gov (United States)

    Rico, Alberto J; Dopeso-Reyes, Iria G; Martínez-Pinilla, Eva; Sucunza, Diego; Pignataro, Diego; Roda, Elvira; Marín-Ramos, David; Labandeira-García, José L; George, Susan R; Franco, Rafael; Lanciego, José L

    2017-05-01

    Although it has long been widely accepted that dopamine receptor types D1 and D2 form GPCR heteromers in the striatum, the presence of D1-D2 receptor heteromers has been recently challenged. In an attempt to properly characterize D1-D2 receptor heteromers, here we have used the in situ proximity ligation assay (PLA) in striatal sections comprising the caudate nucleus, the putamen and the core and shell territories of the nucleus accumbens. Experiments were carried out in control macaques as well as in MPTP-treated animals (with and without dyskinesia). Obtained data support the presence of D1-D2 receptor heteromers within all the striatal subdivisions, with the highest abundance in the accumbens shell. Dopamine depletion by MPTP resulted in an increase of D1-D2 density in caudate and putamen which was normalized by levodopa treatment. Two different sizes of heteromers were consistently found, thus suggesting that besides individual heteromers, D1-D2 receptor heteromers are sometimes organized in macromolecular complexes made of a number of D1-D2 heteromers. Furthermore, the PLA technique was combined with different neuronal markers to properly characterize the identities of striatal neurons expressing D1-D2 heteromers. We have found that striatal projection neurons giving rise to either the direct or the indirect basal ganglia pathways expressed D1-D2 heteromers. Interestingly, macromolecular complexes of D1-D2 heteromers were only found within cholinergic interneurons. In summary, here we provide overwhelming proof that D1 and D2 receptors form heteromeric complexes in the macaque striatum, thus representing a very appealing target for a number of brain diseases involving dopamine dysfunction.

  18. Interferon-gamma deficiency modifies the motor and co-morbid behavioral pathology and neurochemical changes provoked by the pesticide paraquat.

    Science.gov (United States)

    Litteljohn, D; Mangano, E; Shukla, N; Hayley, S

    2009-12-29

    In addition to nigrostriatal pathology and corresponding motor disturbances, Parkinson's disease (PD) is often characterized by co-morbid neuropsychiatric symptoms, most notably anxiety and depression. Separate lines of evidence indicate that inflammatory processes associated with microglial activation and cytokine release may be fundamental to the progression of both PD and its co-morbid psychiatric pathology. Accordingly, we assessed the contribution of the pro-inflammatory cytokine, interferon-gamma (IFN-gamma), to a range of PD-like pathology provoked by the ecologically relevant herbicide and dopamine (DA) toxin, paraquat. To this end, paraquat provoked overt motor impairment (reduced home-cage activity and impaired vertical climbing) and signs of anxiety-like behavior (reduced open field exploration) in wild-type but not IFN-gamma-deficient mice. Correspondingly, paraquat promoted somewhat divergent variations in neurochemical activity among wild-type and IFN-gamma null mice at brain sites important for both motor (striatum) and co-morbid affective pathologies (dorsal hippocampus, medial prefrontal cortex, and locus coeruleus). Specifically, the herbicide provoked a dosing regimen-dependent reduction in striatal DA levels that was prevented by IFN-gamma deficiency. In addition, the herbicide influenced serotonergic and noradrenergic activity within the dorsal hippocampus and medial prefrontal cortex; and elevated noradrenergic activity within the locus coeruleus. Although genetic ablation of IFN-gamma had relatively few effects on monoamine variations within the locus coeruleus and prefrontal cortex, loss of the pro-inflammatory cytokine did normalize the paraquat-induced noradrenergic alterations within the hippocampus. These findings further elucidate the functional implications of paraquat intoxication and suggest an important role for IFN-gamma in the striatal and motor pathology, as well as the co-morbid behavioral and hippocampal changes induced by

  19. The expression of Toll-like receptor 4, 7 and co-receptors in neurochemical sub-populations of rat trigeminal ganglion sensory neurons.

    Science.gov (United States)

    Helley, M P; Abate, W; Jackson, S K; Bennett, J H; Thompson, S W N

    2015-12-03

    The recent discovery that mammalian nociceptors express Toll-like receptors (TLRs) has raised the possibility that these cells directly detect and respond to pathogens with implications for either direct nociceptor activation or sensitization. A range of neuronal TLRs have been identified, however a detailed description regarding the distribution of expression of these receptors within sub-populations of sensory neurons is lacking. There is also some debate as to the composition of the TLR4 receptor complex on sensory neurons. Here we use a range of techniques to quantify the expression of TLR4, TLR7 and some associated molecules within neurochemically-identified sub-populations of trigeminal (TG) and dorsal root (DRG) ganglion sensory neurons. We also detail the pattern of expression and co-expression of two isoforms of lysophosphatidylcholine acyltransferase (LPCAT), a phospholipid remodeling enzyme previously shown to be involved in the lipopolysaccharide-dependent TLR4 response in monocytes, within sensory ganglia. Immunohistochemistry shows that both TLR4 and TLR7 preferentially co-localize with transient receptor potential vallinoid 1 (TRPV1) and purinergic receptor P2X ligand-gated ion channel 3 (P2X3), markers of nociceptor populations, within both TG and DRG. A gene expression profile shows that TG sensory neurons express a range of TLR-associated molecules. LPCAT1 is expressed by a proportion of both nociceptors and non-nociceptive neurons. LPCAT2 immunostaining is absent from neuronal profiles within both TG and DRG and is confined to non-neuronal cell types under naïve conditions. Together, our results show that nociceptors express the molecular machinery required to directly respond to pathogenic challenge independently from the innate immune system. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Influences of Chronic Mild Stress Exposure on Motor, Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice.

    Science.gov (United States)

    Janakiraman, Udaiyappan; Manivasagam, Thamilarasan; Thenmozhi, Arokiasamy Justin; Essa, Musthafa Mohamed; Barathidasan, Rajamani; SaravanaBabu, Chidambaram; Guillemin, Gilles J; Khan, Mohammed A S

    2016-01-01

    Parkinson's disease (PD) is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic) neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS) such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS), a paradigm developed as an animal model of depression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg. body wt.) with probenecid (250 mg/kg, s.c.) (MPTP/p) induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks) of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor) impairments, levels and expressions of dopamine (DA), serotonin (5-HT), DAergic markers such as tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporters-2 (VMAT 2) and α-synuclein in nigrostriatal (striatum (ST) and substantia nigra (SN)) and extra-nigrostriatal (hippocampus, cortex and cerebellum) tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and α-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD.

  1. Influences of Chronic Mild Stress Exposure on Motor, Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice.

    Directory of Open Access Journals (Sweden)

    Udaiyappan Janakiraman

    Full Text Available Parkinson's disease (PD is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS, a paradigm developed as an animal model of depression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg. body wt. with probenecid (250 mg/kg, s.c. (MPTP/p induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor impairments, levels and expressions of dopamine (DA, serotonin (5-HT, DAergic markers such as tyrosine hydroxylase (TH, dopamine transporter (DAT, vesicular monoamine transporters-2 (VMAT 2 and α-synuclein in nigrostriatal (striatum (ST and substantia nigra (SN and extra-nigrostriatal (hippocampus, cortex and cerebellum tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and α-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD.

  2. Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats

    Science.gov (United States)

    Schindler, Charles W.; Thorndike, Eric B.; Goldberg, Steven R.; Lehner, Kurt R.; Cozzi, Nicholas V.; Brandt, Simon D.; Baumann, Michael H.

    2015-01-01

    Rationale 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called “bath salts” products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine and serotonin (5-HT). Objectives We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. Methods To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. Results MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly, and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. By contrast, methylone self-administration (0.3 & 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. Conclusions Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats suggesting these drugs possess significant abuse liability in humans. PMID:26319160

  3. Reinforcing and neurochemical effects of the "bath salts" constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats.

    Science.gov (United States)

    Schindler, Charles W; Thorndike, Eric B; Goldberg, Steven R; Lehner, Kurt R; Cozzi, Nicholas V; Brandt, Simon D; Baumann, Michael H

    2016-05-01

    3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called "bath salts" products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT). We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. In contrast, methylone self-administration (0.3 and 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats, suggesting these drugs possess significant abuse liability in humans.

  4. Distinctiveness of Saudi Arabian EFL Learners

    Directory of Open Access Journals (Sweden)

    Manssour Habbash

    2016-04-01

    Full Text Available In view of the increasing concern among English language teachers dealing with students from Saudi Arabia, as it manifests in TESOL community discussions, about the uniqueness of Saudi Arabian EFL learners, this paper attempts to document the outcome of a study of their distinctiveness from the perspective of expatriate teachers working for PYPs (Preparatory Year Programs in Saudi Arabia. This study examines the distinctiveness with regard to the learning attitudes of Saudi students that are often cultivated by the culture and academic environment in their homeland. Employing an emic approach for collecting the required data an analysis was carried out in light of the other studies on ‘education’ in Saudi Arabia that have particular reference to the factors that can positively influence student motivation, student success and the academic environment. The findings were used in constructing the rationale behind such distinctiveness. Assuming that the outcome of the discussion on the findings of this exploration can be helpful for teachers in adapting their teaching methodology and improving their teacher efficacy in dealing with students both from the kingdom and in the kingdom, some recommendations are made. Keywords: China Distinctiveness, Saudi Arabian University context, Expatriate teachers’ perspective, Distinctiveness Theory

  5. Regulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene Dysbindin-1.

    Science.gov (United States)

    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.

  6. NPR-9, a Galanin-Like G-Protein Coupled Receptor, and GLR-1 Regulate Interneuronal Circuitry Underlying Multisensory Integration of Environmental Cues in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    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

  7. 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.

    Science.gov (United States)

    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.

  8. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

    Science.gov (United States)

    Ladrón de Guevara-Miranda, David; Millón, Carmelo; Rosell-Valle, Cristina; Pérez-Fernández, Mercedes; Missiroli, Michele; Serrano, Antonia; Pavón, Francisco J.; Rodríguez de Fonseca, Fernando; Martínez-Losa, Magdalena; Álvarez-Dolado, Manuel; Santín, Luis J.

    2017-01-01

    ABSTRACT 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. PMID:28138095

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  11. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

    Directory of Open Access Journals (Sweden)

    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.

  12. Low and high gamma oscillations in rat ventral striatum have distinct relationships to behavior, reward, and spiking activity on a learned spatial decision task

    Directory of Open Access Journals (Sweden)

    Matthijs A A Van Der Meer

    2009-06-01

    Full Text Available Local field potential (LFP oscillations in the brain reflect organization thought to be important for perception, attention, movement, and memory. In the basal ganglia, including dorsal striatum, dysfunctional LFP states are associated with Parkinson’s disease, while in healthy subjects, dorsal striatal LFPs have been linked to decision-making processes. However, LFPs in ventral striatum have been less studied. We report that in rats running a spatial decision task, prominent gamma-50 (45-55 Hz and gamma-80 (70-85 Hz oscillations in ventral striatum had distinct relationships to behavior, task events, and spiking activity. Gamma-50 power increased sharply following reward delivery and before movement initiation, while in contrast, gamma-80 power ramped up gradually to reward locations. Gamma-50 power was low and contained little structure during early learning, but rapidly developed a stable pattern, while gamma-80 power was initially high before returning to a stable level within a similar timeframe. Putative fast-spiking interneurons (FSIs showed phase, firing rate, and coherence relationships with gamma-50 and gamma-80, indicating that the observed LFP patterns are locally relevant. Furthermore, in a number of FSIs such relationships were specific to gamma-50 or gamma-80, suggesting that partially distinct FSI populations mediate the effects of gamma-50 and gamma-80.

  13. Antidepressant-like activity of the endogenous amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline in the behavioral despair test in the rat, and its neurochemical correlates: a comparison with the classical antidepressant, imipramine.

    Science.gov (United States)

    Wąsik, Agnieszka; Możdżeń, Edyta; Romańska, Irena; Michaluk, Jerzy; Antkiewicz-Michaluk, Lucyna

    2013-01-30

    Disturbances in noradrenergic and serotonergic transmissions have been postulated to form neurochemical background of depression. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous substance which exhibits neuroprotective, antiaddictive and monoamine oxidase (MAO)-inhibiting properties. In the present study, we tested antidepressant-like effects of 1MeTIQ in comparison with the tricyclic antidepressant, imipramine in the forced swimming test in the rat. Additionally, in neurochemical studies, we estimated the rate of monoamine (dopamine, noradrenaline and serotonin) metabolism in the rat brain structures. The findings have shown that 1MeTIQ similarly to imipramine produced a dose-dependent antidepressant-like effect in the forced swimming test. The neurochemical data showed that 1MeTIQ produced a significant elevation of serotonin concentration in the brain structures with simultaneous reduction of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Moreover, 1MeTIQ slightly increased noradrenaline level but induced a significant elevation of its metabolite, 3-metoxy-4-hydroxyphenylglycol (MHPG). Furthermore, 1MeTIQ affected also dopamine metabolism, and decreased the level of 3,4-dihydroxyphenylacetic acid (DOPAC) with a simultaneous significant increase in the concentration of 3-methoxytyramine (3-MT) in all investigated structures. Such mechanism of action leads to a decrease in the production of free radicals during MAO-dependent dopamine oxidation in the brain. In conclusion, we suggest that antidepressant-like activity of 1MeTIQ is based on the unique and complex mechanism of action in which the activation of monoaminergic systems and scavenging of free radicals plays a crucial role. 1MeTIQ as an endogenous compound may be beneficial from the clinical point of view as a new safer and more efficient antidepressant. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. On Hobbes’s distinction of accidents

    Directory of Open Access Journals (Sweden)

    Lupoli Agostino

    2012-06-01

    Full Text Available An interpolation introduced by K. Schuhmann in his critical edition of "De corpore" (chap. VI, § 13 diametrically overturns the meaning of Hobbes’s doctrine of distinction of accidents in comparison with all previous editions. The article focuses on the complexity of this crucial juncture in "De corpore" argument on which depends the interpretation of Hobbes’s whole conception of science. It discusses the reasons pro and contra Schuhmann’s interpolation and concludes against it, because it is not compatible with the rationale underlying the complex architecture of "De corpore", which involves a symmetry between the ‘logical’ distinction of accidents and the ‘metaphysical’ distinction of phantasms.

  15. Distinctive Dynamic Capabilities for New Business Creation

    DEFF Research Database (Denmark)

    Rosenø, Axel; Enkel, Ellen; Mezger, Florian

    2013-01-01

    and fast-paced industries, and that similarities exist across industries. Hence, the study contributes to dynamic capabilities literature by: 1) identifying the distinctive dynamic capabilities for new business creation; 2) shifting focus away from dynamic capabilities in environments characterised by high......This study examines the distinctive dynamic capabilities for new business creation in established companies. We argue that these are very different from those for managing incremental innovation within a company's core business. We also propose that such capabilities are needed in both slow...... clock-speed and uncertainty towards considering dynamic capabilities for the purpose of developing new businesses, which also implies a high degree of uncertainty. Based on interviews with 33 companies, we identify distinctive dynamic capabilities for new business creation, find that dynamic...

  16. Common and distinct components in data fusion

    DEFF Research Database (Denmark)

    Smilde, Age Klaas; Mage, Ingrid; Næs, Tormod

    2016-01-01

    measurements are obtained. Data fusion is concerned with analyzing such sets of data simultaneously to arrive at a global view of the system under study. One of the upcoming areas of data fusion is exploring whether the data sets have something in common or not. This gives insight into common and distinct...... and understanding their relative merits. This paper provides a unifying framework for this subfield of data fusion by using rigorous arguments from linear algebra. The most frequently used methods for distinguishing common and distinct components are explained in this framework and some practical examples are given...

  17. Achieving global distinction | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2010-11-03

    Nov 3, 2010 ... For 40 years, IDRC has worked with some of the brightest minds in the world, supporting their ideas and promoting innovation. Many researchers we supported early in their careers later achieved global distinction for their scientific work. Among them:

  18. Hydraulic fracturing with distinct element method

    NARCIS (Netherlands)

    Pruiksma, J.P.; Bezuijen, A.

    2002-01-01

    In this report, hydraulic fracturing is investigated using the distinct element code PFC2D from Itasca. Special routines were written to be able to model hydraulic fracturing. These include adding fluid flow to PFC2D and updating the fluid flow domains when fractures appear. A brief description of

  19. Smallest graphs with distinct singleton centers

    OpenAIRE

    Brandes, Ulrik; Hildenbrand, Jan

    2014-01-01

    An incredible number of centrality indices has been proposed to date (Todeschini & Consonni, 2009). Four of them, however, can be considered prototypical because they operationalize distinct concepts of centrality and together cover the bulk of analyses and empirical uses: degree, closeness, betweenness, and eigenvector centrality.

  20. Repeated, Intermittent Social Defeat across the Entire Juvenile Period Resulted in Behavioral, Physiological, Hormonal, Immunological, and Neurochemical Alterations in Young Adult Male Golden Hamsters

    Science.gov (United States)

    Yu, Wei-Chun; Liu, Ching-Yi; Lai, Wen-Sung

    2016-01-01

    The developing brain is vulnerable to social defeat during the juvenile period. As complements of human studies, animal models of social defeat provide a straightforward approach to investigating the functional and neurobiological consequences of social defeats. Taking advantage of agonist behavior and social defeat in male golden hamster, a set of 6 experiments was conducted to investigate the consequences at multiple levels in young adulthood resulting from repeated, intermittent social defeats or “social threats” across the entire juvenile period. Male hamsters at postnatal day 28 (P28) were randomly assigned to either the social defeat, “social threat”, or arena control group, and they correspondingly received a series of nine social interaction trials (i.e., either social defeat, “social threat”, or arena control conditions) from P33 to P66. At the behavioral level (Experiment 1), we found that repeated social defeats (but not “social threats”) significantly impacted locomotor activity in the familiar context and social interaction in the familiar/unfamiliar social contexts. At the physiological and hormonal levels (Experiments 2 and 3), repeated social defeat significantly enhanced the cortisol and norepinephrine concentrations in blood. Enlargement of the spleen was also found in the social defeat and “social threat” groups. At the immunological level (Experiment 4), the social defeat group showed lower levels of pro-inflammatory cytokines in the hypothalamus and hippocampus but higher concentration of IL-6 in the striatum compared to the other two groups. At the neurochemical level (Experiment 5), the socially defeated hamsters mainly displayed reductions of dopamine, dopamine metabolites, and 5-HT levels in the striatum and decreased level of 5-HT in the hippocampus. In Experiment 6, an increase in the spine density of hippocampal CA1 pyramidal neurons was specifically observed in the “social threat” group. Collectively, our

  1. Identification and distribution of neuronal nitric oxide synthase and neurochemical markers in the neuroepithelial cells of the gill and the skin in the giant mudskipper, Periophthalmodon schlosseri.

    Science.gov (United States)

    Zaccone, Giacomo; Lauriano, Eugenia Rita; Kuciel, Michał; Capillo, Gioele; Pergolizzi, Simona; Alesci, Alessio; Ishimatsu, Atsushi; Ip, Yuen Kwong; Icardo, Jose M

    2017-08-05

    Mudskippers are amphibious fishes living in mudflats and mangroves. These fishes hold air in their large buccopharyngeal-opercular cavities where respiratory gas exchange takes place via the gills and higher vascularized epithelium lining the cavities and also the skin epidermis. Although aerial ventilation response to changes in ambient gas concentration has been studied in mudskippers, the localization and distribution of respiratory chemoreceptors, their neurochemical coding and function as well as physiological evidence for the gill or skin as site for O2 and CO2 sensing are currently not known. In the present study we assessed the distribution of serotonin, acetylcholine, catecholamines and nitric oxide in the neuroepithelial cells (NECs) of the mudskipper gill and skin epithelium using immunohistochemistry and confocal microscopy. Colocalization studies showed that 5-HT is coexpressed with nNOS, Na+/K+-ATPase, TH and VAChT; nNOS is coexpressed with Na+/K+-ATPase and TH in the skin. In the gill 5-HT is coexpressed with nNOS and VAhHT and nNOS is coexpressed with Na+/K+-ATPase and TH. Acetylcholine is also expressed in chain and proximal neurons projecting to the efferent filament artery and branchial smooth muscle. The serotonergic cells c labeled with VAChT, nNOS and TH, thus indicating the presence of NEC populations and the possibility that these neurotransmitters (other than serotonin) may act as primary transmitters in the hypoxic reflex in fish gills. Immunolabeling with TH antibodies revealed that NECs in the gill and the skin are innervated by catecholaminergic nerves, thus suggesting that these cells are involved in a central control of branchial functions through their relationships with the sympathetic branchial nervous system. The Na+/K+-ATPase in mitochondria-rich cells (MRCs), which are most concentrated in the gill lamellar epithelium, is colabeled with nNOS and associated with TH nerve terminals. TH-immunopositive fine varicosities were also

  2. Neurochemical Profile of Dementia Pugilistica

    OpenAIRE

    Kokjohn, Tyler A.; Maarouf, Chera L.; Daugs, Ian D.; Hunter, Jesse M.; Charisse M Whiteside; Malek-Ahmadi, Michael; Rodriguez, Emma; Kalback, Walter; Jacobson, Sandra A.; Sabbagh, Marwan N; Beach, Thomas G; Roher, Alex E.

    2013-01-01

    Dementia pugilistica (DP), a suite of neuropathological and cognitive function declines after chronic traumatic brain injury (TBI), is present in approximately 20% of retired boxers. Epidemiological studies indicate TBI is a risk factor for neurodegenerative di