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Sample records for extrabulbar gabaergic connections

  1. 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. 

  2. Extrabulbar olfactory system and nervus terminalis FMRFamide immunoreactive components in Xenopus laevis ontogenesis.

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    Pinelli, Claudia; D'Aniello, Biagio; Polese, Gianluca; Rastogi, Rakesh K

    2004-09-01

    The extrabulbar olfactory system (EBOS) is a collection of nerve fibers which originate from primary olfactory receptor-like neurons and penetrate into the brain bypassing the olfactory bulbs. Our description is based upon the application of two neuronal tracers (biocytin, carbocyanine DiI) in the olfactory sac, at the cut end of the olfactory nerve and in the telencephalon of the developing clawed frog. The extrabulbar olfactory system was observed already at stage 45, which is the first developmental stage compatible with our techniques; at this stage, the extrabulbar olfactory system fibers terminated diffusely in the preoptic area. A little later in development, i.e. at stage 50, the extrabulbar olfactory system was maximally developed, extending as far caudally as the rhombencephalon. In the metamorphosing specimens, the extrabulbar olfactory system appeared reduced in extension; caudally, the fiber terminals did not extend beyond the diencephalon. While a substantial overlapping of biocytin/FMRFamide immunoreactivity was observed along the olfactory pathways as well as in the telencephalon, FMRFamide immunoreactivity was never observed to be colocalized in the same cellular or fiber components visualized by tracer molecules. The question whether the extrabulbar olfactory system and the nervus terminalis (NT) are separate anatomical entities or represent an integrated system is discussed.

  3. Long-range GABAergic connections distributed throughout the neocortex and their possible function

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    Nobuaki eTamamaki

    2010-12-01

    Full Text Available Features and functions of long range GABAergic projection neurons in the developing cerebral cortex have been reported previously, although until now their significance in the adult cerebral cortex has remained uncertain. The septo-hippocampal circuit is one exception – in this system, long range mature GABAergic projection neurons have been well analyzed and their contribution to the generation of theta-oscillatory behavior in the hippocampus has been documented. To have a clue to the function of the GABAergic projection neurons in the neocortex, we view the long range GABAergic projections those participating in the cortico-cortical, cortico-fugal, and afferent projections in the cerebral cortex. Then, we consider the possibility that the GABAergic projection neurons are involved in the generation, modification, and/or synchronization of oscillations in mature neocortical neuron activity. When markers that identify the GABAergic projection neurons are examined in anatomical and developmental studies, it is clear that neuronal NO synthetase (nNOS-immunoreactivity can readily identify GABAergic projection fibers (i.e. those longer than 1.5 mm. To elucidate the role of the GABAergic projection neurons in the neocortex, it will be necessary to clarify the network constructed by nNOS-positive GABAergic projection neurons and their postsynaptic targets. Thus, our long-range goals will be to label and manipulate (including deleting the GABAergic projection neurons using genetic tools driven by a nNOS promoter. We recognize that this may be a complex endeavor, as most excitatory neurons in the murine neocortex express nNOS transiently. Nevertheless, additional studies characterizing long range GABAergic projection neurons will have great value to the overall understanding of mature cortical function.

  4. Distinct GABAergic targets of feedforward and feedback connections between lower and higher areas of rat visual cortex.

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    Gonchar, Yuri; Burkhalter, Andreas

    2003-11-26

    Processing of visual information is performed in different cortical areas that are interconnected by feedforward (FF) and feedback (FB) pathways. Although FF and FB inputs are excitatory, their influences on pyramidal neurons also depend on the outputs of GABAergic neurons, which receive FF and FB inputs. Rat visual cortex contains at least three different families of GABAergic neurons that express parvalbumin (PV), calretinin (CR), and somatostatin (SOM) (Gonchar and Burkhalter, 1997). To examine whether pathway-specific inhibition (Shao and Burkhalter, 1996) is attributable to distinct connections with GABAergic neurons, we traced FF and FB inputs to PV, CR, and SOM neurons in layers 1-2/3 of area 17 and the secondary lateromedial area in rat visual cortex. We found that in layer 2/3 maximally 2% of FF and FB inputs go to CR and SOM neurons. This contrasts with 12-13% of FF and FB inputs onto layer 2/3 PV neurons. Unlike inputs to layer 2/3, connections to layer 1, which contains CR but lacks SOM and PV somata, are pathway-specific: 21% of FB inputs go to CR neurons, whereas FF inputs to layer 1 and its CR neurons are absent. These findings suggest that FF and FB influences on layer 2/3 pyramidal neurons mainly involve disynaptic connections via PV neurons that control the spike outputs to axons and proximal dendrites. Unlike FF input, FB input in addition makes a disynaptic link via CR neurons, which may influence the excitability of distal pyramidal cell dendrites in layer 1.

  5. Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity.

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    Moeller, Scott J; London, Edythe D; Northoff, Georg

    2016-02-01

    Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Ventromedial hypothalamic expression of Bdnf is required to establish normal patterns of afferent GABAergic connectivity and responses to hypoglycemia

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    Anna Kamitakahara

    2016-02-01

    Full Text Available Objective: The ventromedial nucleus of the hypothalamus (VMH controls energy and glucose homeostasis through direct connections to a distributed network of nuclei in the hypothalamus, midbrain, and hindbrain. Structural changes in VMH circuit morphology have the potential to alter VMH function throughout life, however, molecular signals responsible for specifying its neural connections are not fully defined. The VMH contains a high density of neurons that express brain-derived neurotrophic factor (BDNF, a potent neurodevelopmental effector known to regulate neuronal survival, growth, differentiation, and connectivity in a number of neural systems. In the current study, we examined whether BDNF impacts the afferent and efferent connections of the VMH, as well as energy homeostatic function. Methods: To determine if BDNF is required for VMH circuit formation, a transgenic mouse model was used to conditionally delete Bdnf from steroidogenic factor 1 (SF1 expressing neurons of the VMH prior to the onset of establishing neural connections with other regions. Projections of SF1 expressing neurons were visualized with a genetically targeted fluorescent label and immunofluorescence was used to measure the density of afferents to SF1 neurons in the absence of BDNF. Physiological changes in body weight and circulating blood glucose were also evaluated in the mutant mice. Results: Our findings suggest that BDNF is required to establish normal densities of GABAergic afferents onto SF1 neurons located in the ventrolateral part of the VMH. Furthermore, loss of BDNF from VMH SF1 neurons results in impaired physiological responses to insulin-induced hypoglycemia. Conclusion: The results of this study indicate that BDNF is required for formation and/or maintenance of inhibitory inputs to SF1 neurons, with enduring effects on glycemic control. Author Video: Author Video Watch what authors say about their articles Keywords: Ventromedial nucleus of the hypothalamus

  7. Mechanisms of GABAergic Homeostatic Plasticity

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    Peter Wenner

    2011-01-01

    Full Text Available Homeostatic plasticity ensures that appropriate levels of activity are maintained through compensatory adjustments in synaptic strength and cellular excitability. For instance, excitatory glutamatergic synapses are strengthened following activity blockade and weakened following increases in spiking activity. This form of plasticity has been described in a wide array of networks at several different stages of development, but most work and reviews have focussed on the excitatory inputs of excitatory neurons. Here we review homeostatic plasticity of GABAergic neurons and their synaptic connections. We propose a simplistic model for homeostatic plasticity of GABAergic components of the circuitry (GABAergic synapses onto excitatory neurons, excitatory connections onto GABAergic neurons, cellular excitability of GABAergic neurons: following chronic activity blockade there is a weakening of GABAergic inhibition, and following chronic increases in network activity there is a strengthening of GABAergic inhibition. Previous work on GABAergic homeostatic plasticity supports certain aspects of the model, but it is clear that the model cannot fully account for some results which do not appear to fit any simplistic rule. We consider potential reasons for these discrepancies.

  8. GABAergic Mechanisms in Schizophrenia

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    de Jonge, Jeroen C; Vinkers, Christiaan H; Hulshoff Pol, Hilleke E

    2017-01-01

    Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from postmortem studies suggests that alterations in cortical γ-aminobutyric acid (GABAergic) neurons contribute to the clinical features...... of schizophrenia. In vivo measurement of brain GABA levels using magnetic resonance spectroscopy (MRS) offers the possibility to provide more insight into the relationship between problems in GABAergic neurotransmission and clinical symptoms of schizophrenia patients. This study reviews and links alterations...... in the GABA system in postmortem studies, animal models, and human studies in schizophrenia. Converging evidence implicates alterations in both presynaptic and postsynaptic components of GABAergic neurotransmission in schizophrenia, and GABA may thus play an important role in the pathophysiology...

  9. Retinal Astrocytes and GABAergic Wide-Field Amacrine Cells Express PDGFRα: Connection to Retinal Ganglion Cell Neuroprotection by PDGF-AA.

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    Takahama, Shokichi; Adetunji, Modupe O; Zhao, Tantai; Chen, Shan; Li, Wei; Tomarev, Stanislav I

    2017-09-01

    Our previous experiments demonstrated that intravitreal injection of platelet-derived growth factor-AA (PDGF-AA) provides retinal ganglion cell (RGC) neuroprotection in a rodent model of glaucoma. Here we used PDGFRα-enhanced green fluorescent protein (EGFP) mice to identify retinal cells that may be essential for RGC protection by PDGF-AA. PDGFRα-EGFP mice expressing nuclear-targeted EGFP under the control of the PDGFRα promoter were used. Localization of PDGFRα in the neural retina was investigated by confocal imaging of EGFP fluorescence and immunofluorescent labeling with a panel of antibodies recognizing different retinal cell types. Primary cultures of mouse RGCs were produced by immunopanning. Neurobiotin injection of amacrine cells in a flat-mounted retina was used for the identification of EGFP-positive amacrine cells in the inner nuclear layer. In the mouse neural retina, PDGFRα was preferentially localized in the ganglion cell and inner nuclear layers. Immunostaining of the retina demonstrated that astrocytes in the ganglion cell layer and a subpopulation of amacrine cells in the inner nuclear layer express PDGFRα, whereas RGCs (in vivo or in vitro) did not. PDGFRα-positive amacrine cells are likely to be Type 45 gamma-aminobutyric acidergic (GABAergic) wide-field amacrine cells. These data indicate that the neuroprotective effect of PDGF-AA in a rodent model of glaucoma could be mediated by astrocytes and/or a subpopulation of amacrine cells. We suggest that after intravitreal injection of PDGF-AA, these cells secrete factors protecting RGCs.

  10. Investigation of synapse formation and function in a glutamatergic-GABAergic two-neuron microcircuit.

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    Chang, Chia-Ling; Trimbuch, Thorsten; Chao, Hsiao-Tuan; Jordan, Julia-Christine; Herman, Melissa A; Rosenmund, Christian

    2014-01-15

    Neural circuits are composed of mainly glutamatergic and GABAergic neurons, which communicate through synaptic connections. Many factors instruct the formation and function of these synapses; however, it is difficult to dissect the contribution of intrinsic cell programs from that of extrinsic environmental effects in an intact network. Here, we perform paired recordings from two-neuron microculture preparations of mouse hippocampal glutamatergic and GABAergic neurons to investigate how synaptic input and output of these two principal cells develop. In our reduced preparation, we found that glutamatergic neurons showed no change in synaptic output or input regardless of partner neuron cell type or neuronal activity level. In contrast, we found that glutamatergic input caused the GABAergic neuron to modify its output by way of an increase in synapse formation and a decrease in synaptic release efficiency. These findings are consistent with aspects of GABAergic synapse maturation observed in many brain regions. In addition, changes in GABAergic output are cell wide and not target-cell specific. We also found that glutamatergic neuronal activity determined the AMPA receptor properties of synapses on the partner GABAergic neuron. All modifications of GABAergic input and output required activity of the glutamatergic neuron. Because our system has reduced extrinsic factors, the changes we saw in the GABAergic neuron due to glutamatergic input may reflect initiation of maturation programs that underlie the formation and function of in vivo neural circuits.

  11. Role of tonic GABAergic currents during pre- and early postnatal rodent development

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    Werner eKilb

    2013-09-01

    Full Text Available In the last three decades it became evident that the GABAergic system plays an essential role for the development of the central nervous system, by influencing the proliferation of neuronal precursors, neuronal migration and differentiation, as well as by controlling early activity patterns and thus formation of neuronal networks. GABA controls neuronal development via depolarizing membrane responses upon activation of ionotropic GABA receptors. However, many of these effects occur before the onset of synaptic GABAergic activity and thus require the presence of extrasynaptic tonic currents in neuronal precursors and immature neurons. This review summarizes our current knowledge about the role of tonic GABAergic currents during early brain development. In this review we compare the temporal sequence of the expression and functional relevance of different GABA receptor subunits, GABA synthesizing enzymes and GABA transporters. We also refer to other possible endogenous agonists of GABAA receptors. In addition, we describe functional consequences mediated by the GABAergic system during early developmental periods and discuss current models about the origin of extrasynaptic GABA and/or other endogenous GABAergic agonists during early developmental states. Finally, we present evidence that tonic GABAergic activity is also critically involved in the generation of physiological as well as pathophysiological activity patterns before and after the establishment of functional GABAergic synaptic connections.

  12. Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons.

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    Tepper, James M; Wilson, Charles J; Koós, Tibor

    2008-08-01

    There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of

  13. Innervation by a GABAergic neuron depresses spontaneous release in glutamatergic neurons and unveils the clamping phenotype of synaptotagmin-1

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    Wierda, Keimpe D B; Sørensen, Jakob Balslev

    2014-01-01

    The role of spontaneously occurring release events in glutamatergic and GABAergic neurons and their regulation is intensely debated. To study the interdependence of glutamatergic and GABAergic spontaneous release, we compared reciprocally connected "mixed" glutamatergic/GABAergic neuronal pairs...... from mice cultured on astrocyte islands with "homotypic" glutamatergic or GABAergic pairs and autaptic neurons. We measured mEPSC and mIPSC frequencies simultaneously from both neurons. Neuronal pairs formed both interneuronal synaptic and autaptic connections indiscriminately. We find that whereas m......EPSC and mIPSC frequencies did not deviate between autaptic and synaptic connections, the frequency of mEPSCs in mixed pairs was strongly depressed compared with either autaptic neurons or glutamatergic pairs. Simultaneous imaging of synapses, or comparison to evoked release amplitudes, showed...

  14. Discreet charm of the GABAergic bourgeoisie: superconnected cells conduct developmental symphonies.

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    Case, Marianne; Soltesz, Ivan

    2009-12-24

    In an exciting study in the December 4(th) issue of Science, Bonifazi and colleagues demonstrated the existence and importance of exceedingly rare but unusually richly connected cells in the developing hippocampus. Manipulating the activity of single GABAergic hub cells modulated network activity patterns, demonstrating their importance for coordinating synchronous activity. 2009 Elsevier Inc. All rights reserved.

  15. GABAergic circuit dysfunctions in neurodevelopmental disorders

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    Bidisha eChattopadhyaya

    2012-05-01

    Full Text Available GABAergic interneurons control neuronal excitability, integration, and plasticity. Further, they regulate the generation of temporal synchrony and oscillatory behavior among networks of pyramidal neurons. Such oscillations within and across neural systems are believed to serve various complex functions, such as perception, movement initiation, and memory. Alterations in the development of GABAergic circuits have been implicated in various brain diseases with neurodevelopmental origin. Here, we highlight recent studies suggesting a role for alterations of GABA transmission in the pathophysiology of two neurodevelopmental diseases, schizophrenia and autism. We further discuss how manipulations of GABA signaling may be used for novel therapeutic interventions.

  16. The Effects of GABAergic Polarity Changes on Episodic Neural Network Activity in Developing Neural Systems

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    Wilfredo Blanco

    2017-09-01

    Full Text Available Early in development, neural systems have primarily excitatory coupling, where even GABAergic synapses are excitatory. Many of these systems exhibit spontaneous episodes of activity that have been characterized through both experimental and computational studies. As development progress the neural system goes through many changes, including synaptic remodeling, intrinsic plasticity in the ion channel expression, and a transformation of GABAergic synapses from excitatory to inhibitory. What effect each of these, and other, changes have on the network behavior is hard to know from experimental studies since they all happen in parallel. One advantage of a computational approach is that one has the ability to study developmental changes in isolation. Here, we examine the effects of GABAergic synapse polarity change on the spontaneous activity of both a mean field and a neural network model that has both glutamatergic and GABAergic coupling, representative of a developing neural network. We find some intuitive behavioral changes as the GABAergic neurons go from excitatory to inhibitory, shared by both models, such as a decrease in the duration of episodes. We also find some paradoxical changes in the activity that are only present in the neural network model. In particular, we find that during early development the inter-episode durations become longer on average, while later in development they become shorter. In addressing this unexpected finding, we uncover a priming effect that is particularly important for a small subset of neurons, called the “intermediate neurons.” We characterize these neurons and demonstrate why they are crucial to episode initiation, and why the paradoxical behavioral change result from priming of these neurons. The study illustrates how even arguably the simplest of developmental changes that occurs in neural systems can present non-intuitive behaviors. It also makes predictions about neural network behavioral changes

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

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    Yuri Gonchar

    2008-03-01

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

  18. Subtypes of GABAergic neurons project axons in the neocortex

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    Shigeyoshi Higo

    2009-11-01

    Full Text Available γ-aminobutyric acid (GABAergic neurons in the neocortex have been regarded as interneurons and speculated to modulate the activity of neurons locally. Recently, however, several experiments revealed that neuronal nitric oxide synthase (nNOS-positive GABAergic neurons project cortico-cortically with long axons. In this study, we illustrate Golgi-like images of the nNOS-positive GABAergic neurons using a nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d reaction and follow the emanating axon branches in cat brain sections. These axon branches projected cortico-cortically with other non-labeled arcuate fibers, contra-laterally via the corpus callosum and anterior commissure. The labeled fibers were not limited to the neocortex but found also in the fimbria of the hippocampus. In order to have additional information on these GABAergic neuron projections, we investigated green fluorescent protein (GFP-labeled GABAergic neurons in GAD67-Cre knock-in / GFP Cre-reporter mice. GFP-labeled axons emanate densely, especially in the fimbria, a small number in the anterior commissure, and very sparsely in the corpus callosum. These two different approaches confirm that not only nNOS-positive GABAergic neurons but also other subtypes of GABAergic neurons project long axons in the cerebral cortex and are in a position to be involved in information processing.

  19. Hilar GABAergic Interneuron Activity Controls Spatial Learning and Memory Retrieval

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

    2012-01-01

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

  20. 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.

  1. GABAergic actions on cholinergic laterodorsal tegmental neurons

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    Kohlmeier, K A; Kristiansen, Uffe

    2010-01-01

    Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) play a critical role in regulation of behavioral state. Therefore, elucidation of mechanisms that control their activity is vital for understanding of how switching between wakefulness, sleep and anesthetic states is effectuated....... In vivo studies suggest that GABAergic mechanisms within the pons play a critical role in behavioral state switching. However, the postsynaptic, electrophysiological actions of GABA on LDT neurons, as well as the identity of GABA receptors present in the LDT mediating these actions is virtually unexplored...... neurons. Post-synaptic location of GABA(A) receptors was demonstrated by persistence of muscimol-induced inward currents in TTX and low Ca(2+) solutions. THIP, a selective GABA(A) receptor agonist with a preference for d-subunit containing GABA(A) receptors, induced inward currents, suggesting...

  2. Presynaptic miniature GABAergic currents in developing interneurons.

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

    2010-04-29

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

  3. GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies

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    de Jonge, Jeroen C.; Vinkers, Christiaan H.; Hulshoff Pol, Hilleke E.; Marsman, Anouk

    2017-01-01

    Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from postmortem studies suggests that alterations in cortical γ-aminobutyric acid (GABAergic) neurons contribute to the clinical features of schizophrenia. In vivo measurement of brain GABA levels using magnetic resonance spectroscopy (MRS) offers the possibility to provide more insight into the relationship between problems in GABAergic neurotransmission and clinical symptoms of schizophrenia patients. This study reviews and links alterations in the GABA system in postmortem studies, animal models, and human studies in schizophrenia. Converging evidence implicates alterations in both presynaptic and postsynaptic components of GABAergic neurotransmission in schizophrenia, and GABA may thus play an important role in the pathophysiology of schizophrenia. MRS studies can provide direct insight into the GABAergic mechanisms underlying the development of schizophrenia as well as changes during its course. PMID:28848455

  4. GABAergic Mechanisms in Schizophrenia : Linking Postmortem and In Vivo Studies

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    de Jonge, Jeroen C; Vinkers, Christiaan H; Hulshoff Pol, Hilleke E; Marsman, Anouk

    2017-01-01

    Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from postmortem studies suggests that alterations in cortical γ-aminobutyric acid (GABAergic) neurons contribute to the clinical features of

  5. GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies

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    Jeroen C. de Jonge

    2017-08-01

    Full Text Available Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from postmortem studies suggests that alterations in cortical γ-aminobutyric acid (GABAergic neurons contribute to the clinical features of schizophrenia. In vivo measurement of brain GABA levels using magnetic resonance spectroscopy (MRS offers the possibility to provide more insight into the relationship between problems in GABAergic neurotransmission and clinical symptoms of schizophrenia patients. This study reviews and links alterations in the GABA system in postmortem studies, animal models, and human studies in schizophrenia. Converging evidence implicates alterations in both presynaptic and postsynaptic components of GABAergic neurotransmission in schizophrenia, and GABA may thus play an important role in the pathophysiology of schizophrenia. MRS studies can provide direct insight into the GABAergic mechanisms underlying the development of schizophrenia as well as changes during its course.

  6. Role of astrocytic transport processes in glutamatergic and GABAergic neurotransmission

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    Schousboe, A; Sarup, A; Bak, L K

    2004-01-01

    The fine tuning of both glutamatergic and GABAergic neurotransmission is to a large extent dependent upon optimal function of astrocytic transport processes. Thus, glutamate transport in astrocytes is mandatory to maintain extrasynaptic glutamate levels sufficiently low to prevent excitotoxic...... neuronal damage. In GABA synapses hyperactivity of astroglial GABA uptake may lead to diminished GABAergic inhibitory activity resulting in seizures. As a consequence of this the expression and functional activity of astrocytic glutamate and GABA transport is regulated in a number of ways...

  7. Localization of the brainstem GABAergic neurons controlling paradoxical (REM sleep.

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    Emilie Sapin

    Full Text Available Paradoxical sleep (PS is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons are principally located in the ventrolateral periaqueductal gray (vlPAG and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe. Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles.

  8. Electrical and chemical transmission between striatal GABAergic output neurones in rat brain slices

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    Venance, Laurent; Glowinski, Jacques; Giaume, Christian

    2004-01-01

    Basal ganglia are interconnected subcortical nuclei, connected to the thalamus and all cortical areas involved in sensory motor control, limbic functions and cognition. The striatal output neurones (SONs), the major striatal population, are believed to act as detectors and integrators of distributed patterns of cerebral cortex inputs. Despite the key role of SONs in cortico-striatal information processing, little is known about their local interactions. Here, we report the existence and characterization of electrical and GABAergic transmission between SONs in rat brain slices. Tracer coupling (biocytin) incidence was high during the first two postnatal weeks and then decreased (postnatal days (P) 5–25, 60%; P25–30, 29%; n = 61). Electrical coupling was observed between 27% of SON pairs (coupling coefficient: 3.1 ± 0.3%, n = 89 at P15) and as shown by single-cell RT-PCR, several connexin (Cx) mRNAs were found to be expressed (Cx31.1, Cx32, Cx36 and Cx47). GABAergic synaptic transmission (abolished by bicuculline, a GABAA receptor antagonist) observed in 19% of SON pairs (n = 62) was reliable (mean failure rate of 6 ± 3%), precise (variation coefficient of latency, 0.06), strong (IPSC amplitudes of 38 ± 12 pA) and unidirectional. Interestingly, electrical and chemical transmission were mutually exclusive. These results suggest that preferential networks of electrically and chemically connected SONs, might be involved in the channelling of cortico-basal ganglia information processing. PMID:15235091

  9. Neuron-astrocyte interaction enhance GABAergic synaptic transmission in a manner dependent on key metabolic enzymes.

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    Przemysław eKaczor; Dariusz eRakus; Jerzy Władysław Mozrzymas; Jerzy Władysław Mozrzymas

    2015-01-01

    GABA is the major inhibitory neurotransmitter in the adult brain and mechanisms of GABAergic inhibition have been intensely investigated in the past decades. Recent studies provided evidence for an important role of astrocytes in shaping GABAergic currents. One of the most obvious, but yet poorly understood, mechanisms of the cross-talk between GABAergic currents and astrocytes is metabolism including neurotransmitter homeostasis. In particular, how modulation of GABAergic currents by astrocy...

  10. The space where aging acts: focus on the GABAergic synapse.

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    Rozycka, Aleksandra; Liguz-Lecznar, Monika

    2017-08-01

    As it was established that aging is not associated with massive neuronal loss, as was believed in the mid-20th Century, scientific interest has addressed the influence of aging on particular neuronal subpopulations and their synaptic contacts, which constitute the substrate for neural plasticity. Inhibitory neurons represent the most complex and diverse group of neurons, showing distinct molecular and physiological characteristics and possessing a compelling ability to control the physiology of neural circuits. This review focuses on the aging of GABAergic neurons and synapses. Understanding how aging affects synapses of particular neuronal subpopulations may help explain the heterogeneity of aging-related effects. We reviewed the literature concerning the effects of aging on the numbers of GABAergic neurons and synapses as well as aging-related alterations in their presynaptic and postsynaptic components. Finally, we discussed the influence of those changes on the plasticity of the GABAergic system, highlighting our results concerning aging in mouse somatosensory cortex and linking them to plasticity impairments and brain disorders. We posit that aging-induced impairments of the GABAergic system lead to an inhibitory/excitatory imbalance, thereby decreasing neuron's ability to respond with plastic changes to environmental and cellular challenges, leaving the brain more vulnerable to cognitive decline and damage by synaptopathic diseases. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  11. Fluoxetine disrupts motivation and GABAergic signaling in adolescent female hamsters.

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    Shannonhouse, John L; DuBois, Dustin W; Fincher, Annette S; Vela, Alejandra M; Henry, Morgan M; Wellman, Paul J; Frye, Gerald D; Morgan, Caurnel

    2016-08-01

    Initial antidepressant treatment can paradoxically worsen symptoms in depressed adolescents by undetermined mechanisms. Interestingly, antidepressants modulate GABAA receptors, which mediate paradoxical effects of other therapeutic drugs, particularly in females. Although the neuroanatomic site of action for this paradox is unknown, elevated GABAA receptor signaling in the nucleus accumbens can disrupt motivation. We assessed fluoxetine's effects on motivated behaviors in pubescent female hamsters - anhedonia in the reward investigational preference (RIP) test as well as anxiety in the anxiety-related feeding/exploration conflict (AFEC) test. We also assessed accumbal signaling by RT-PCR and electrophysiology. Fluoxetine initially worsened motivated behaviors at puberty, relative to adulthood. It also failed to improve these behaviors as pubescent hamsters transitioned into adulthood. Low accumbal mRNA levels of multiple GABAA receptor subunits and GABA-synthesizing enzyme, GAD67, assessed by RT-PCR, suggested low GABAergic tone at puberty. Nonetheless, rapid fluoxetine-induced reductions of α5GABAA receptor and BDNF mRNA levels at puberty were consistent with age-related differences in GABAergic responses to fluoxetine and disruption of the motivational state. Whole-cell patch clamping of accumbal slices also suggested low GABAergic tone by the low amplitude of miniature inhibitory postsynaptic currents (mIPSCs) at puberty. It also confirmed age-related differences in GABAergic responses to fluoxetine. Specifically, fluoxetine potentiated mIPSC amplitude and frequency at puberty, but attenuated the amplitude during adulthood. These results implicate GABAergic tone and GABAA receptor plasticity in adverse motivational responses and resistance to fluoxetine during adolescence. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Fluoxetine impairs GABAergic signaling in hippocampal slices from neonatal rats

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    Enrico eCherubini

    2013-05-01

    Full Text Available Fluoxetine (Prozac, an antidepressant known to selectively inhibit serotonin reuptake, is widely used to treat mood disorders in women suffering from depression during pregnancy and postpartum period. Several lines of evidence suggest that this drug, which crosses the human placenta and is secreted into milk during lactation, exerts its action not only by interfering with serotoninergic but also with GABAergic transmission. GABA is known to play a crucial role in the construction of neuronal circuits early in postnatal development. The immature hippocampus is characterized by an early type of network activity, the so-called Giant Depolarizing Potentials (GDPs, generated by the synergistic action of glutamate and GABA, both depolarizing and excitatory. Here we tested the hypothesis that fluoxetine may interfere with GABAergic signaling during the first postnatal week, thus producing harmful effects on brain development. At micromolar concentrations fluoxetine severely depressed GDPs frequency (IC50 22 M in a reversible manner and independently of its action on serotonin reuptake. This effect was dependent on a reduced GABAergic (but not glutamatergic drive to principal cells most probably from parvalbumin-positive fast spiking neurons. Cholecystokinin-positive GABAergic interneurons were not involved since the effects of the drug persisted when cannabinoid receptors were occluded with WIN55,212-2, a CB1/CB2 receptor agonist. Fluoxetine effects on GABAergic transmission were associated with a reduced firing rate of both principal cells and interneurons further suggesting that changes in network excitability account for GDPs disruption. This may have critical consequences on the functional organization and stabilization of neuronal circuits early in postnatal development.

  13. Deficient GABAergic gliotransmission may cause broader sensory tuning in schizophrenia.

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    Hoshino, Osamu

    2013-12-01

    We examined how the depression of intracortical inhibition due to a reduction in ambient GABA concentration impairs perceptual information processing in schizophrenia. A neural network model with a gliotransmission-mediated ambient GABA regulatory mechanism was simulated. In the network, interneuron-to-glial-cell and principal-cell-to-glial-cell synaptic contacts were made. The former hyperpolarized glial cells and let their transporters import (remove) GABA from the extracellular space, thereby lowering ambient GABA concentration, reducing extrasynaptic GABAa receptor-mediated tonic inhibitory current, and thus exciting principal cells. In contrast, the latter depolarized the glial cells and let the transporters export GABA into the extracellular space, thereby elevating the ambient GABA concentration and thus inhibiting the principal cells. A reduction in ambient GABA concentration was assumed for a schizophrenia network. Multiple dynamic cell assemblies were organized as sensory feature columns. Each cell assembly responded to one specific feature stimulus. The tuning performance of the network to an applied feature stimulus was evaluated in relation to the level of ambient GABA. Transporter-deficient glial cells caused a deficit in GABAergic gliotransmission and reduced ambient GABA concentration, which markedly deteriorated the tuning performance of the network, broadening the sensory tuning. Interestingly, the GABAergic gliotransmission mechanism could regulate local ambient GABA levels: it augmented ambient GABA around stimulus-irrelevant principal cells, while reducing ambient GABA around stimulus-relevant principal cells, thereby ensuring their selective responsiveness to the applied stimulus. We suggest that a deficit in GABAergic gliotransmission may cause a reduction in ambient GABA concentration, leading to a broadening of sensory tuning in schizophrenia. The GABAergic gliotransmission mechanism proposed here may have an important role in the

  14. Key Metabolic Enzymes Underlying Astrocytic Upregulation of GABAergic Plasticity

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    Przemysław T. Kaczor

    2017-05-01

    Full Text Available GABAergic plasticity is recognized as a key mechanism of shaping the activity of the neuronal networks. However, its description is challenging because of numerous neuron-specific mechanisms. In particular, while essential role of glial cells in the excitatory plasticity is well established, their involvement in GABAergic plasticity only starts to emerge. To address this problem, we used two models: neuronal cell culture (NC and astrocyte-neuronal co-culture (ANCC, where we chemically induced long-term potentiation at inhibitory synapses (iLTP. iLTP could be induced both in NC and ANCC but in ANCC its extent was larger. Importantly, this functional iLTP manifestation was accompanied by an increase in gephyrin puncta size. Furthermore, blocking astrocyte Krebs cycle with fluoroacetate (FA in ANCC prevented enhancement of both mIPSC amplitude and gephyrin puncta size but this effect was not observed in NC, indicating a key role in neuron-astrocyte cross-talk. Blockade of monocarboxylate transport with α-Cyano-4-hydroxycinnamic acid (4CIN abolished iLTP both in NC and ANCC and in the latter model prevented also enlargement of gephyrin puncta. Similarly, blockade of glycogen phosphorylase with BAYU6751 prevented enlargement of gephyrin puncta upon iLTP induction. Finally, block of glutamine synthetase with methionine sulfoxide (MSO nearly abolished mIPSC increase in both NMDA stimulated cell groups but did not prevent enlargement of gephyrin puncta. In conclusion, we provide further evidence that GABAergic plasticity is strongly regulated by astrocytes and the underlying mechanisms involve key metabolic enzymes. Considering the strategic role of GABAergic interneurons, the plasticity described here indicates possible mechanism whereby metabolism regulates the network activity.

  15. Impact of perinatal asphyxia on the GABAergic and locomotor system.

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    Van de Berg, W D J; Kwaijtaal, M; de Louw, A J A; Lissone, N P A; Schmitz, C; Faull, R L M; Blokland, A; Blanco, C E; Steinbusch, H W M

    2003-01-01

    Perinatal asphyxia can cause neuronal loss and depletion of neurotransmitters within the striatum. The striatum plays an important role in motor control, sensorimotor integration and learning. In the present study we investigated whether perinatal asphyxia leads to motor deficits related to striatal damage, and in particular to the loss of GABAergic neurons. Perinatal asphyxia was induced in time-pregnant Wistar rats on the day of delivery by placing the uterus horns, containing the pups, in a 37 degrees C water bath for 20 min. Three motor performance tasks (open field, grip test and walking pattern) were performed at 3 and 6 weeks of age. Antibodies against calbindin and parvalbumin were used to stain GABAergic striatal projection neurons and interneurons, respectively. The motor tests revealed subtle effects of perinatal asphyxia, i.e. small decrease in motor activity. Analysis of the walking pattern revealed an increase in stride width at 6 weeks of age after perinatal asphyxia. Furthermore, a substantial loss of calbindin-immunoreactive (-22%) and parvalbumin-immunoreactive (-43%) cells was found in the striatum following perinatal asphyxia at two months of age. GABA(A) receptor autoradiography revealed no changes in GABA binding activity within the striatum, globus pallidus or substantia nigra. We conclude that perinatal asphyxia resulted in a loss of GABAergic projection neurons and interneurons in the striatum without alteration of GABA(A) receptor affinity. Despite a considerable loss of striatal neurons, only minor deficits in motor performance were found after perinatal asphyxia.

  16. Cryopreservation of GABAergic Neuronal Precursors for Cell-Based Therapy.

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    Daniel Rodríguez-Martínez

    Full Text Available Cryopreservation protocols are essential for stem cells storage in order to apply them in the clinic. Here we describe a new standardized cryopreservation protocol for GABAergic neural precursors derived from the medial glanglionic eminence (MGE, a promising source of GABAergic neuronal progenitors for cell therapy against interneuron-related pathologies. We used 10% Me2SO as cryoprotectant and assessed the effects of cell culture amplification and cellular organization, as in toto explants, neurospheres, or individualized cells, on post-thaw cell viability and retrieval. We confirmed that in toto cryopreservation of MGE explants is an optimal preservation system to keep intact the interneuron precursor properties for cell transplantation, together with a high cell viability (>80% and yield (>70%. Post-thaw proliferation and self-renewal of the cryopreserved precursors were tested in vitro. In addition, their migration capacity, acquisition of mature neuronal morphology, and potency to differentiate into multiple interneuron subtypes were also confirmed in vivo after transplantation. The results show that the cryopreserved precursor features remained intact and were similar to those immediately transplanted after their dissection from the MGE. We hope this protocol will facilitate the generation of biobanks to obtain a permanent and reliable source of GABAergic precursors for clinical application in cell-based therapies against interneuronopathies.

  17. Shaping inhibition: activity dependent structural plasticity of GABAergic synapses

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    Carmen E Flores

    2014-10-01

    Full Text Available Inhibitory transmission through the neurotransmitter Ɣ-aminobutyric acid (GABA shapes network activity in the mammalian cerebral cortex by filtering synaptic incoming information and dictating the activity of principal cells. The incredibly diverse population of cortical neurons that use GABA as neurotransmitter shows an equally diverse range of mechanisms that regulate changes in the strength of GABAergic synaptic transmission and allow them to dynamically follow and command the activity of neuronal ensembles. Similarly to glutamatergic synaptic transmission, activity-dependent functional changes in inhibitory neurotransmission are accompanied by alterations in GABAergic synapse structure that range from morphological reorganization of postsynaptic density to de novo formation and elimination of inhibitory contacts. Here we review several aspects of structural plasticity of inhibitory synapses, including its induction by different forms of neuronal activity, behavioral and sensory experience and the molecular mechanisms and signaling pathways involved. We discuss the functional consequences of GABAergic synapse structural plasticity for information processing and memory formation in view of the heterogenous nature of the structural plasticity phenomena affecting inhibitory synapses impinging on somatic and dendritic compartments of cortical and hippocampal neurons.

  18. Two clusters of GABAergic ellipsoid body neurons modulate olfactory labile memory in Drosophila.

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    Zhang, Zhiping; Li, Xiaoting; Guo, Jing; Li, Yan; Guo, Aike

    2013-03-20

    In Drosophila, aversive olfactory memory is believed to be stored in a prominent brain structure, the mushroom body (MB), and two pairs of MB intrinsic neurons, the dorsal paired medial (DPM) and the anterior paired lateral (APL) neurons, are found to regulate the consolidation of middle-term memory (MTM). Here we report that another prominent brain structure, the ellipsoid body (EB), is also involved in the modulation of olfactory MTM. Activating EB R2/R4m neurons does not affect the learning index, but specifically eliminates anesthesia-sensitive memory (ASM), the labile component of olfactory MTM. We further demonstrate that approximately two-thirds of these EB neurons are GABAergic and are responsible for the suppression of ASM. Using GRASP (GFP reconstitution across synaptic partners), we reveal potential synaptic connections between the EB and MB in regions covering both the presynaptic and postsynaptic sites of EB neurons, suggesting the presence of bidirectional connections between these two important brain structures. These findings suggest the existence of direct connections between the MB and EB, and provide new insights into the neural circuit basis for olfactory labile memory in Drosophila.

  19. Live-Cell, Label-Free Identification of GABAergic and Non-GABAergic Neurons in Primary Cortical Cultures Using Micropatterned Surface

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    Kono, Sho; Kushida, Takatoshi; Hirano-Iwata, Ayumi; Niwano, Michio; Tanii, Takashi

    2016-01-01

    Excitatory and inhibitory neurons have distinct roles in cortical dynamics. Here we present a novel method for identifying inhibitory GABAergic neurons from non-GABAergic neurons, which are mostly excitatory glutamatergic neurons, in primary cortical cultures. This was achieved using an asymmetrically designed micropattern that directs an axonal process to the longest pathway. In the current work, we first modified the micropattern geometry to improve cell viability and then studied the axon length from 2 to 7 days in vitro (DIV). The cell types of neurons were evaluated retrospectively based on immunoreactivity against GAD67, a marker for inhibitory GABAergic neurons. We found that axons of non-GABAergic neurons grow significantly longer than those of GABAergic neurons in the early stages of development. The optimal threshold for identifying GABAergic and non-GABAergic neurons was evaluated to be 110 μm at 6 DIV. The method does not require any fluorescence labelling and can be carried out on live cells. The accuracy of identification was 98.2%. We confirmed that the high accuracy was due to the use of a micropattern, which standardized the development of cultured neurons. The method promises to be beneficial both for engineering neuronal networks in vitro and for basic cellular neuroscience research. PMID:27513933

  20. Taurine activates GABAergic networks in the neocortex of immature mice

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    Bogdan Aurel Sava

    2014-02-01

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

  1. Functional diversity of supragranular GABAergic neurons in the barrel cortex

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    Luc J Gentet

    2012-08-01

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

  2. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome.

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    Moore, Aleisha M; Prescott, Mel; Marshall, Christopher J; Yip, Siew Hoong; Campbell, Rebecca E

    2015-01-13

    Polycystic ovarian syndrome (PCOS), the leading cause of female infertility, is associated with an increase in luteinizing hormone (LH) pulse frequency, implicating abnormal steroid hormone feedback to gonadotropin-releasing hormone (GnRH) neurons. This study investigated whether modifications in the synaptically connected neuronal network of GnRH neurons could account for this pathology. The PCOS phenotype was induced in mice following prenatal androgen (PNA) exposure. Serial blood sampling confirmed that PNA elicits increased LH pulse frequency and impaired progesterone negative feedback in adult females, mimicking the neuroendocrine abnormalities of the clinical syndrome. Imaging of GnRH neurons revealed greater dendritic spine density that correlated with increased putative GABAergic but not glutamatergic inputs in PNA mice. Mapping of steroid hormone receptor expression revealed that PNA mice had 59% fewer progesterone receptor-expressing cells in the arcuate nucleus of the hypothalamus (ARN). To address whether increased GABA innervation to GnRH neurons originates in the ARN, a viral-mediated Cre-lox approach was taken to trace the projections of ARN GABA neurons in vivo. Remarkably, projections from ARN GABAergic neurons heavily contacted and even bundled with GnRH neuron dendrites, and the density of fibers apposing GnRH neurons was even greater in PNA mice (56%). Additionally, this ARN GABA population showed significantly less colocalization with progesterone receptor in PNA animals compared with controls. Together, these data describe a robust GABAergic circuit originating in the ARN that is enhanced in a model of PCOS and may underpin the neuroendocrine pathophysiology of the syndrome.

  3. Retinoic acid functions as a key GABAergic differentiation signal in the basal ganglia.

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    Christina Chatzi

    2011-04-01

    Full Text Available Although retinoic acid (RA has been implicated as an extrinsic signal regulating forebrain neurogenesis, the processes regulated by RA signaling remain unclear. Here, analysis of retinaldehyde dehydrogenase mutant mouse embryos lacking RA synthesis demonstrates that RA generated by Raldh3 in the subventricular zone of the basal ganglia is required for GABAergic differentiation, whereas RA generated by Raldh2 in the meninges is unnecessary for development of the adjacent cortex. Neurospheres generated from the lateral ganglionic eminence (LGE, where Raldh3 is highly expressed, produce endogenous RA, which is required for differentiation to GABAergic neurons. In Raldh3⁻/⁻ embryos, LGE progenitors fail to differentiate into either GABAergic striatal projection neurons or GABAergic interneurons migrating to the olfactory bulb and cortex. We describe conditions for RA treatment of human embryonic stem cells that result in efficient differentiation to a heterogeneous population of GABAergic interneurons without the appearance of GABAergic striatal projection neurons, thus providing an in vitro method for generation of GABAergic interneurons for further study. Our observation that endogenous RA is required for generation of LGE-derived GABAergic neurons in the basal ganglia establishes a key role for RA signaling in development of the forebrain.

  4. Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala

    DEFF Research Database (Denmark)

    Varodayan, Florence P.; Soni, Neeraj; Bajo, Michal

    2016-01-01

    release, and GABAergic dysregulation in the central nucleus of the amygdala (CeA) is critical in the transition to alcohol dependence. We investigated possible disruptions in CB1 signaling of rat CeA GABAergic transmission following intermittent ethanol exposure. In the CeA of alcohol-naive rats, CB1...

  5. Direction-selective circuitry in rat retina develops independently of GABAergic, cholinergic and action potential activity.

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    Le Sun

    Full Text Available The ON-OFF direction selective ganglion cells (DSGCs in the mammalian retina code image motion by responding much more strongly to movement in one direction. They do so by receiving inhibitory inputs selectively from a particular sector of processes of the overlapping starburst amacrine cells, a type of retinal interneuron. The mechanisms of establishment and regulation of this selective connection are unknown. Here, we report that in the rat retina, the morphology, physiology of the ON-OFF DSGCs and the circuitry for coding motion directions develop normally with pharmacological blockade of GABAergic, cholinergic activity and/or action potentials for over two weeks from birth. With recent results demonstrating light independent formation of the retinal DS circuitry, our results strongly suggest the formation of the circuitry, i.e., the connections between the second and third order neurons in the visual system, can be genetically programmed, although emergence of direction selectivity in the visual cortex appears to require visual experience.

  6. Cortical GABAergic excitation contributes to epileptic activities around human glioma

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    Pallud, Johan; Varlet, Pascale; Cresto, Noemie; Baulac, Michel; Duyckaerts, Charles; Kourdougli, Nazim; Chazal, Geneviève; Devaux, Bertrand; Rivera, Claudio; Miles, Richard; Capelle, Laurent; Huberfeld, Gilles

    2015-01-01

    Rationale Diffuse brain gliomas induce seizures in a majority of patients. As in most epileptic disorders, excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glial tumor cells. Thus the contribution of GABAergic mechanisms which depend on intracellular chloride and which are defective or pro-epileptic in other structural epilepsies merits closer study. Objective We studied in neocortical slices from the peritumoral security margin resected around human brain gliomas, the occurrence, networks, cells and signaling basis of epileptic activities. Results Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges. These events were synchronized, with a high frequency oscillation signature, in superficial layers of neocortex around glioma areas with tumor infiltration. Interictal-like events depended on both glutamatergic transmission and on depolarizing GABAergic signaling. About 65% of pyramidal cells were depolarized by GABA released by interneurons. This effect was related to perturbations in Chloride homeostasis, due to changes in expression of chloride co-transporters: KCC2 was reduced and expression of NKCC1 increased. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. Conclusions Epileptic activities are sustained by excitatory effects of GABA in the peritumoral human neocortex, as in temporal lobe epilepsies. Glutamate and GABA signaling are involved in oncogenesis and chloride homeostasis is perturbed. These same factors, induce an imbalance between synaptic excitatory and inhibition underly epileptic discharges in tumor patients. PMID:25009229

  7. GABAergic projections to the oculomotor nucleus in the goldfish (Carassius auratus

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    M. Angeles eLuque

    2011-02-01

    Full Text Available The mammalian oculomotor nucleus receives a strong -aminobutyric acid (GABAergic synaptic input, whereas such projections have rarely been reported in fish. In order to determine whether this synaptic organization is preserved across vertebrates, we investigated the GABAergic projections to the oculomotor nucleus in the goldfish by combining retrograde transport of biotin dextran amine, injected into the antidromically identified oculomotor nucleus, and GABA immunohistochemistry. The main source of GABAergic afferents to the oculomotor nucleus was the ipsilateral anterior octaval nucleus, with only a few, if any, GABAergic neurons being located in the contralateral tangential and descending nuclei of the octaval column. In mammals there is a nearly exclusive ipsilateral projection from vestibular neurons to the oculomotor nucleus via GABAergic inhibitory inputs; thus, the vestibulooculomotor GABAergic circuitry follows a plan that appears to be shared throughout the vertebrate phylogeny. The second major source of GABAergic projections was the rhombencephalic reticular formation, primarily from the medial area but, to a lesser extent, from the inferior area. A few GABAergic oculomotor projecting neurons were also observed in the ipsilateral nucleus of the medial longitudinal fasciculus. The GABAergic projections from neurons located in both the reticular formation surrounding the abducens nucleus and the nucleus of the medial reticular formation have primarily been related to the control of saccadic eye movements. Finally, all retrogradely labeled internuclear neurons of the abducens nucleus, and neurons in the cerebellum (close to the caudal lobe, were negative for GABA. These data suggest that the vestibuloocular and saccadic inhibitory GABAergic systems appear early in vertebrate phylogeny to modulate the firing properties of the oculomotor nucleus motoneurons.

  8. GABAergic Signaling within a Limbic-Hypothalamic Circuit Integrates Social and Anxiety-Like Behavior with Stress Reactivity.

    Science.gov (United States)

    Myers, Brent; Carvalho-Netto, Eduardo; Wick-Carlson, Dayna; Wu, Christine; Naser, Sam; Solomon, Matia B; Ulrich-Lai, Yvonne M; Herman, James P

    2016-05-01

    The posterior hypothalamic nucleus (PH) stimulates autonomic stress responses. However, the role of the PH in behavioral correlates of psychiatric illness, such as social and anxiety-like behavior, is largely unexplored, as is the neurochemistry of PH connectivity with limbic and neuroendocrine systems. Thus, the current study tested the hypothesis that GABAergic signaling within the PH is a critical link between forebrain behavior-regulatory nuclei and the neuroendocrine hypothalamus, integrating social and anxiety-related behaviors with physiological stress reactivity. To address this hypothesis, GABAA receptor pharmacology was used to locally inhibit or disinhibit the PH immediately before behavioral measures of social and anxiety-like behavior in rats. Limbic connectivity of the PH was then established by simultaneous co-injection of anterograde and retrograde tracers. Further, the role of PH GABAergic signaling in neuroendocrine stress responses was tested via inhibition/disinhibition of the PH. These studies determined a prominent role for the PH in the expression of anxiety-related behaviors and social withdrawal. Histological analyses revealed divergent stress-activated limbic input to the PH, emanating predominantly from the prefrontal cortex, lateral septum, and amygdala. PH projections also targeted both parvicellular and magnocellular peptidergic neurons in the paraventricular and supraoptic hypothalamus. Further, GABAA receptor pharmacology determined an excitatory effect of the PH on neuroendocrine responses to stress. These data indicate that the PH represents an important stress-integrative center, regulating behavioral processes and connecting the limbic forebrain with neuroendocrine systems. Moreover, the PH appears to be uniquely situated to have a role in stress-related pathologies associated with limbic-hypothalamic dysfunction.

  9. Synaptic and intrinsic activation of GABAergic neurons in the cardiorespiratory brainstem network.

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    Julie G Frank

    Full Text Available GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67 gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA. These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca(2+ currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a

  10. Synaptic and intrinsic activation of GABAergic neurons in the cardiorespiratory brainstem network.

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    Frank, Julie G; Mendelowitz, David

    2012-01-01

    GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca(2+) currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for

  11. Steroid influences on GABAergic neurotransmission: A behavioral and biochemical approach

    International Nuclear Information System (INIS)

    McCarthy, M.M.

    1989-01-01

    Steroid influences on GABAergic neurotransmission are varied and complex. However, there has been little investigation into the behavioral relevance of steroid effects on GABA. GABA had been implicated in the control of lordosis, a steroid dependent posture exhibited by sexually receptive female rats, but with conflicting results. This data demonstrated that GABA plays a dual role in the regulation of lordosis; stimulation of GABAergic transmission in the medial hypothalamus enhances lordosis whereas stimulation of GABA in the preoptic area inhibits lordosis. In separate experiments it was determined that progesterone enhances binding of the GABA A agonist, muscimol, in an in vitro exchange assay utilizing synaptic membranes prepared from the hypothalamus of ovariectomized rats. Scatchard analysis revealed a difference in affinity of the GABA A receptor between ovariectomized, receptive and post receptive females. In the preoptic area there was a significant decrease in the binding of 3 H-muscimol in receptive females versus post-receptive and ovariectomized rats. In other behavioral experiments, the influence of estrogen and progesterone on GABA-induced analgesia was assessed. Intrathecal infusion of a low dose of muscimol at the lumbar level of the spinal cord did not alter nociceptive thresholds in ovariectomized rats. However, when intact females were administered the same dose of muscimol, they exhibited differential responses over the estrous cycle. Females in estrus were analgesic after muscimol, whereas diestrus females did not differ from ovariectomized controls. Ovariectomized rats injected s.c. with progesterone (2mg) exhibited a pronounced analgesia after intrathecal muscimol beginning 15 minutes after steroid treatment, whereas similar treatment with estrogen (10ug) was without effect

  12. Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.

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    Cecilia Gonzalez Campo

    Full Text Available BACKGROUND: Reelin is a large secreted protein of the extracellular matrix that has been proposed to participate to the etiology of schizophrenia. During development, reelin is crucial for the correct cytoarchitecture of laminated brain structures and is produced by a subset of neurons named Cajal-Retzius. After birth, most of these cells degenerate and reelin expression persists in postnatal and adult brain. The phenotype of neurons that bind secreted reelin and whether the continuous secretion of reelin is required for physiological functions at postnatal stages remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Combining immunocytochemical and pharmacological approaches, we first report that two distinct patterns of reelin expression are present in cultured hippocampal neurons. We show that in hippocampal cultures, reelin is secreted by GABAergic neurons displaying an intense reelin immunoreactivity (IR. We demonstrate that secreted reelin binds to receptors of the lipoprotein family on neurons with a punctate reelin IR. Secondly, using calcium imaging techniques, we examined the physiological consequences of reelin secretion blockade. Blocking protein secretion rapidly and reversibly changes the subunit composition of N-methyl-D-aspartate glutamate receptors (NMDARs to a predominance of NR2B-containing NMDARs. Addition of recombinant or endogenously secreted reelin rescues the effects of protein secretion blockade and reverts the fraction of NR2B-containing NMDARs to control levels. Therefore, the continuous secretion of reelin is necessary to control the subunit composition of NMDARs in hippocampal neurons. CONCLUSIONS/SIGNIFICANCE: Our data show that the heterogeneity of reelin immunoreactivity correlates with distinct functional populations: neurons synthesizing and secreting reelin and/or neurons binding reelin. Furthermore, we show that continuous reelin secretion is a strict requirement to maintain the composition of NMDARs. We propose

  13. Expression of GABAergic receptors in mouse taste receptor cells.

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    Margaret R Starostik

    Full Text Available BACKGROUND: Multiple excitatory neurotransmitters have been identified in the mammalian taste transduction, with few studies focused on inhibitory neurotransmitters. Since the synthetic enzyme glutamate decarboxylase (GAD for gamma-aminobutyric acid (GABA is expressed in a subset of mouse taste cells, we hypothesized that other components of the GABA signaling pathway are likely expressed in this system. GABA signaling is initiated by the activation of either ionotropic receptors (GABA(A and GABA(C or metabotropic receptors (GABA(B while it is terminated by the re-uptake of GABA through transporters (GATs. METHODOLOGY/PRINCIPAL FINDINGS: Using reverse transcriptase-PCR (RT-PCR analysis, we investigated the expression of different GABA signaling molecules in the mouse taste system. Taste receptor cells (TRCs in the circumvallate papillae express multiple subunits of the GABA(A and GABA(B receptors as well as multiple GATs. Immunocytochemical analyses examined the distribution of the GABA machinery in the circumvallate papillae. Both GABA(A-and GABA(B- immunoreactivity were detected in the peripheral taste receptor cells. We also used transgenic mice that express green fluorescent protein (GFP in either the Type II taste cells, which can respond to bitter, sweet or umami taste stimuli, or in the Type III GAD67 expressing taste cells. Thus, we were able to identify that GABAergic receptors are expressed in some Type II and Type III taste cells. Mouse GAT4 labeling was concentrated in the cells surrounding the taste buds with a few positively labeled TRCs at the margins of the taste buds. CONCLUSIONS/SIGNIFICANCE: The presence of GABAergic receptors localized on Type II and Type III taste cells suggests that GABA is likely modulating evoked taste responses in the mouse taste bud.

  14. Abnormal GABAergic function and negative affect in schizophrenia.

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    Taylor, Stephan F; Demeter, Elise; Phan, K Luan; Tso, Ivy F; Welsh, Robert C

    2014-03-01

    Deficits in the γ-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level-dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1-3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated-directly or indirectly-with GABAergic function on a continuum with normal behavior.

  15. GABAergic modulation of visual gamma and alpha oscillations and its consequences for working memory performance

    NARCIS (Netherlands)

    Lozano Soldevilla, D.; Huurne, N.; Cools, R.; Jensen, O.

    2014-01-01

    BACKGROUND: Impressive in vitro research in rodents and computational modeling has uncovered the core mechanisms responsible for generating neuronal oscillations. In particular, GABAergic interneurons play a crucial role for synchronizing neural populations. Do these mechanistic principles apply to

  16. Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia

    NARCIS (Netherlands)

    Beverly, JL; De Vries, MG; Bouman, SD; Arseneau, LM

    Noradrenergic and GABAergic systems in the medial hypothalamus influence plasma glucose and may be activated during glucoprivation. Microdialysis probes were placed into the ventromedial nucleus (VMH), lateral hypothalamus (LHA), and paraventricular nucleus (PVH) of male Sprague-Dawley rats to

  17. Impaired GABAergic Inhibition in the Prefrontal Cortex of Early Postnatal Phencyclidine (PCP)-Treated Rats

    DEFF Research Database (Denmark)

    Kjaerby, Celia; Broberg, Brian V; Kristiansen, Uffe

    2014-01-01

    A compromised ¿-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-d-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmissio...... postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life....

  18. Loss of GABAergic inputs in APP/PS1 mouse model of Alzheimer's disease

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    Tutu Oyelami

    2014-04-01

    Full Text Available Alzheimer's disease (AD is characterized by symptoms which include seizures, sleep disruption, loss of memory as well as anxiety in patients. Of particular importance is the possibility of preventing the progressive loss of neuronal projections in the disease. Transgenic mice overexpressing EOFAD mutant PS1 (L166P and mutant APP (APP KM670/671NL Swedish (APP/PS1 develop a very early and robust Amyloid pathology and display synaptic plasticity impairments and cognitive dysfunction. Here we investigated GABAergic neurotransmission, using multi-electrode array (MEA technology and pharmacological manipulation to quantify the effect of GABA Blockers on field excitatory postsynaptic potentials (fEPSP, and immunostaining of GABAergic neurons. Using MEA technology we confirm impaired LTP induction by high frequency stimulation in APPPS1 hippocampal CA1 region that was associated with reduced alteration of the pair pulse ratio after LTP induction. Synaptic dysfunction was also observed under manipulation of external Calcium concentration and input-output curve. Electrophysiological recordings from brain slice of CA1 hippocampus area, in the presence of GABAergic receptors blockers cocktails further demonstrated significant reduction in the GABAergic inputs in APP/PS1 mice. Moreover, immunostaining of GAD65 a specific marker for GABAergic neurons revealed reduction of the GABAergic inputs in CA1 area of the hippocampus. These results might be linked to increased seizure sensitivity, premature death and cognitive dysfunction in this animal model of AD. Further in depth analysis of GABAergic dysfunction in APP/PS1 mice is required and may open new perspectives for AD therapy by restoring GABAergic function.

  19. Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation

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    Tanaka Shoji

    2008-04-01

    Full Text Available Abstract Background The GABAergic system in the brain seems to be dysfunctional in various psychiatric disorders. Many studies have suggested so far that, in schizophrenia patients, GABAergic inhibition is selectively but consistently reduced in the prefrontal cortex (PFC. Results This study used a computational model of the PFC to investigate the dynamics of the PFC circuit with and without chandelier cells and other GABAergic interneurons. The inhibition by GABAergic interneurons other than chandelier cells effectively regulated the PFC activity with rather low or modest levels of dopaminergic neurotransmission. This activity of the PFC is associated with normal cognitive functions and has an inverted-U shaped profile of dopaminergic modulation. In contrast, the chandelier cell-type inhibition affected only the PFC circuit dynamics in hyperdopaminergic conditions. Reduction of chandelier cell-type inhibition resulted in bistable dynamics of the PFC circuit, in which the upper stable state is associated with a hyperactive mode. When both types of inhibition were reduced, this hyperactive mode and the conventional inverted-U mode merged. Conclusion The results of our simulation suggest that, in schizophrenia, a reduction of GABAergic inhibition increases vulnerability to psychosis by (i producing the hyperactive mode of the PFC with hyperdopaminergic neurotransmission by dysfunctional chandelier cells and (ii increasing the probability of the transition to the hyperactive mode from the conventional inverted-U mode by dysfunctional GABAergic interneurons.

  20. Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus.

    Science.gov (United States)

    Chen, Z L; Huang, R Q

    2014-06-20

    Changes in extracellular pH have a modulatory effect on GABAA receptor function. It has been reported that pH sensitivity of the GABA receptor is dependent on subunit composition and GABA concentration. Most of previous investigations focused on GABA-evoked currents, which only reflect the postsynaptic receptors. The physiological relevance of pH modulation of GABAergic neurotransmission is not fully elucidated. In the present studies, we examined the influence of extracellular pH on the GABAA receptor-mediated inhibitory neurotransmission in rat hypothalamic neurons. The inhibitory postsynaptic currents (IPSCs), tonic currents, and the GABA-evoked currents were recorded with whole-cell patch techniques on the hypothalamic slices from Sprague-Dawley rats at 15-26 postnatal days. The amplitude and frequency of spontaneous GABA IPSCs were significantly increased while the external pH was changed from 7.3 to 8.4. In the acidic pH (6.4), the spontaneous GABA IPSCs were reduced in amplitude and frequency. The pH induced changes in miniature GABA IPSCs (mIPSCs) similar to that in spontaneous IPSCs. The pH effect on the postsynaptic GABA receptors was assessed with exogenously applied varying concentrations of GABA. The tonic currents and the currents evoked by sub-saturating concentration of GABA ([GABA]) (10 μM) were inhibited by acidic pH and potentiated by alkaline pH. In contrast, the currents evoked by saturating [GABA] (1mM) were not affected by pH changes. We also investigated the influence of pH buffers and buffering capacity on pH sensitivity of GABAA receptors on human recombinant α1β2γ2 GABAA receptors stably expressed in HEK 293 cells. The pH influence on GABAA receptors was similar in HEPES- and MES-buffered media, and not dependent on protonated buffers, suggesting that the observed pH effect on GABA response is a specific consequence of changes in extracellular protons. Our data suggest that the hydrogen ions suppress the GABAergic neurotransmission

  1. Subpopulations of somatostatin-immunoreactive nonpyramidal neurons in the amygdala and adjacent external capsule project to the basal forebrain: evidence for the existence of GABAergic projection neurons in the cortical nuclei and basolateral nuclear complex

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    Alexander J. McDonald

    2012-07-01

    Full Text Available The hippocampus and amygdala are key structures of the limbic system whose connections include reciprocal interactions with the basal forebrain (BF. The hippocampus receives both cholinergic and GABAergic afferents from the medial septal area of the BF. Hippocampal projections back to the medial septal area arise from nonpyramidal GABAergic neurons that express somatostatin (SOM, calbindin (CB, and neuropeptide Y (NPY. Recent experiments in our lab have demonstrated that the basolateral amygdala, like the hippocampus, receives both cholinergic and GABAergic afferents from the BF. These projections arise from neurons in the substantia innominata and ventral pallidum. It remained to be determined, however, whether the amygdala has projections back to the BF that arise from GABAergic nonpyramidal neurons. This question was investigated in the present study by combining Fluorogold (FG retrograde tract tracing with immunohistochemistry for GABAergic nonpyramidal cell markers, including SOM, CB, NPY, parvalbumin, calretinin, and glutamic acid decarboxylase (GAD. FG injections into the basal forebrain produced a diffuse array of retrogradely labeled neurons in many nuclei of the amygdala. The great majority of amygdalar FG+ neurons did not express nonpyramidal cell markers. However, a subpopulation of nonpyramidal SOM+ neurons, termed long range nonpyramidal neurons (LRNP neurons, in the external capsule, basolateral amygdala, and cortical and medial amygdalar nuclei were FG+. About one-third of the SOM+ LRNP neurons were CB+ or NPY+, and one-half were GAD+. It remains to be determined if these inhibitory amygdalar projections to the BF, like those from the hippocampus, are important for regulating synchronous oscillations in the amygdalar-BF network.

  2. Alterations of GABAergic Signaling in Autism Spectrum Disorders

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    Rocco Pizzarelli

    2011-01-01

    Full Text Available Autism spectrum disorders (ASDs comprise a heterogeneous group of pathological conditions, mainly of genetic origin, characterized by stereotyped behavior, marked impairment in verbal and nonverbal communication, social skills, and cognition. Interestingly, in a small number of cases, ASDs are associated with single mutations in genes encoding for neuroligin-neurexin families. These are adhesion molecules which, by regulating transsynaptic signaling, contribute to maintain a proper excitatory/inhibitory (E/I balance at the network level. Furthermore, GABA, the main inhibitory neurotransmitter in adult life, at late embryonic/early postnatal stages has been shown to depolarize and excite targeted cell through an outwardly directed flux of chloride. The depolarizing action of GABA and associated calcium influx regulate a variety of developmental processes from cell migration and differentiation to synapse formation. Here, we summarize recent data concerning the functional role of GABA in building up and refining neuronal circuits early in development and the molecular mechanisms regulating the E/I balance. A dysfunction of the GABAergic signaling early in development leads to a severe E/I unbalance in neuronal circuits, a condition that may account for some of the behavioral deficits observed in ASD patients.

  3. Short-term ionic plasticity at GABAergic synapses

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    Joseph Valentino Raimondo

    2012-10-01

    Full Text Available Fast synaptic inhibition in the brain is mediated by the pre-synaptic release of the neurotransmitter γ-Aminobutyric acid (GABA and the post-synaptic activation of GABA-sensitive ionotropic receptors. As with excitatory synapses, it is being increasinly appreciated that a variety of plastic processes occur at inhibitory synapses, which operate over a range of timescales. Here we examine a form of activity-dependent plasticity that is somewhat unique to GABAergic transmission. This involves short-lasting changes to the ionic driving force for the postsynaptic receptors, a process referred to as short-term ionic plasticity. These changes are directly related to the history of activity at inhibitory synapses and are influenced by a variety of factors including the location of the synapse and the post-synaptic cell’s ion regulation mechanisms. We explore the processes underlying this form of plasticity, when and where it can occur, and how it is likely to impact network activity.

  4. GABA, its receptors, and GABAergic inhibition in mouse taste buds.

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    Dvoryanchikov, Gennady; Huang, Yijen A; Barro-Soria, Rene; Chaudhari, Nirupa; Roper, Stephen D

    2011-04-13

    Taste buds consist of at least three principal cell types that have different functions in processing gustatory signals: glial-like (type I) cells, receptor (type II) cells, and presynaptic (type III) cells. Using a combination of Ca2+ imaging, single-cell reverse transcriptase-PCR and immunostaining, we show that GABA is an inhibitory transmitter in mouse taste buds, acting on GABA(A) and GABA(B) receptors to suppress transmitter (ATP) secretion from receptor cells during taste stimulation. Specifically, receptor cells express GABA(A) receptor subunits β2, δ, and π, as well as GABA(B) receptors. In contrast, presynaptic cells express the GABA(A) β3 subunit and only occasionally GABA(B) receptors. In keeping with the distinct expression pattern of GABA receptors in presynaptic cells, we detected no GABAergic suppression of transmitter release from presynaptic cells. We suggest that GABA may serve function(s) in taste buds in addition to synaptic inhibition. Finally, we also defined the source of GABA in taste buds: GABA is synthesized by GAD65 in type I taste cells as well as by GAD67 in presynaptic (type III) taste cells and is stored in both those two cell types. We conclude that GABA is an inhibitory transmitter released during taste stimulation and possibly also during growth and differentiation of taste buds.

  5. Developmental changes in GABAergic neurotransmission to presympathetic and cardiac parasympathetic neurons in the brainstem.

    Science.gov (United States)

    Dergacheva, Olga; Boychuk, Carie R; Mendelowitz, David

    2013-08-01

    Cardiovascular function is regulated by a dynamic balance composed of sympathetic and parasympathetic activity. Sympathoexcitatory presympathetic neurons (PSNs) in the rostral ventrolateral medulla project directly to cardiac and vasomotor sympathetic preganglionic neurons in the spinal cord. In proximity to the PSNs in the medulla, there are preganglionic cardiac vagal neurons (CVNs) within the nucleus ambiguus, which are critical for parasympathetic control of heart rate. Both CVNs and PSNs receive GABAergic synaptic inputs that change with challenges such as hypoxia and hypercapnia (H/H). Autonomic control of cardiovascular function undergoes significant changes during early postnatal development; however, little is known regarding postnatal maturation of GABAergic neurotransmission to these neurons. In this study, we compared changes in GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs and PSNs under control conditions and during H/H in postnatal day 2-5 (P5), 16-20 (P20), and 27-30 (P30) rats using an in vitro brainstem slice preparation. There was a significant enhancement in GABAergic neurotransmission to both CVNs and PSNs at age P20 compared with P5 and P30, with a more pronounced increase in PSNs. H/H did not significantly alter this enhanced GABAergic neurotransmission to PSNs in P20 animals. However, the frequency of GABAergic IPSCs in PSNs was reduced by H/H in P5 and P30 animals. In CVNs, H/H elicited an inhibition of GABAergic neurotransmission in all ages studied, with the most pronounced inhibition occurring at P20. In conclusion, there are critical development periods at which significant rearrangement occurs in the central regulation of cardiovascular function.

  6. Not a single but multiple populations of GABAergic neurons control sleep.

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    Luppi, Pierre-Hervé; Peyron, Christelle; Fort, Patrice

    2017-04-01

    The role of gamma-amino butyric acid (GABA) in sleep induction and maintenance is well accepted since most insomnia treatments target GABAa receptors. However, the population(s) of GABAergic neurons involved in the beneficial effect of GABA on sleep remains to be identified. This is not an easy task since GABAergic neurons are widely distributed in all brain structures. A recently growing number of populations of GABAergic neurons have been involved in sleep control. We first review here possible candidates for inducing non-rapid eye movement (NREM) sleep including the GABAergic neurons of the ventrolateral preoptic area, the parafacial zone in the brainstem, the nucleus accumbens and the cortex. We also discuss the role of several populations of GABAergic neurons in rapid eye movement (REM) sleep control. Indeed, it is well accepted that muscle atonia occurring during REM sleep is due to a GABA/glycinergic hyperpolarization of motoneurons. Recent evidence strongly suggests that these neurons are located in the ventral medullary reticular formation. It has also recently been shown that neurons containing the neuropeptide melanin concentrating hormone and GABA located in the lateral hypothalamic area control REM sleep expression. Finally, a population of REM-off GABAergic neurons located in the ventrolateral periaqueductal gray has been shown to gate REM sleep by inhibiting glutamatergic neurons located in the sublaterodorsal tegmental nucleus. In summary, recent data clearly indicate that multiple populations of GABAergic neurons located throughout the brain from the cortex to the medulla oblongata control NREM and REM sleep. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

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    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.

  8. GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.

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    Libor Velíšek

    Full Text Available Idiopathic generalized epilepsy (IGE syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/- mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/- males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/- female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/- vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/- mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR, yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/- mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i sex-specific increases in seizure susceptibility, ii the development of spontaneous seizures, and iii seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE.

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

    Science.gov (United States)

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

    2015-01-01

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

  10. Hypothalamic vasopressinergic projections innervate central amygdala GABAergic neurons: implications for anxiety and stress coping

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    Vito Salvador Hernandez

    2016-11-01

    Full Text Available The arginine-vasopressin (AVP-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs are known for their role in hydro-electrolytic balance control via their projections to neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula, and other brain regions, in which vasopressin infusion modulates contingent social and emotionally-affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA. The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS, consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN and supraoptic (SON nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptors mRNA were not detected, using the same method. Water-deprivation for 24 hrs, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze test, and this effect was mimicked by bilateral microinfusion of VP into the CeA. Anxious behavior induced by either water deprivation or VP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of central amygdala inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala.

  11. Long-term plasticity in identified hippocampal GABAergic interneurons in the CA1 area in vivo.

    Science.gov (United States)

    Lau, Petrina Yau-Pok; Katona, Linda; Saghy, Peter; Newton, Kathryn; Somogyi, Peter; Lamsa, Karri P

    2017-05-01

    Long-term plasticity is well documented in synapses between glutamatergic principal cells in the cortex both in vitro and in vivo. Long-term potentiation (LTP) and -depression (LTD) have also been reported in glutamatergic connections to hippocampal GABAergic interneurons expressing parvalbumin (PV+) or nitric oxide synthase (NOS+) in brain slices, but plasticity in these cells has not been tested in vivo. We investigated synaptically-evoked suprathreshold excitation of identified hippocampal neurons in the CA1 area of urethane-anaesthetized rats. Neurons were recorded extracellularly with glass microelectrodes, and labelled with neurobiotin for anatomical analyses. Single-shock electrical stimulation of afferents from the contralateral CA1 elicited postsynaptic action potentials with monosynaptic features showing short delay (9.95 ± 0.41 ms) and small jitter in 13 neurons through the commissural pathway. Theta-burst stimulation (TBS) generated LTP of the synaptically-evoked spike probability in pyramidal cells, and in a bistratified cell and two unidentified fast-spiking interneurons. On the contrary, PV+ basket cells and NOS+ ivy cells exhibited either LTD or LTP. An identified axo-axonic cell failed to show long-term change in its response to stimulation. Discharge of the cells did not explain whether LTP or LTD was generated. For the fast-spiking interneurons, as a group, no correlation was found between plasticity and local field potential oscillations (1-3 or 3-6 Hz components) recorded immediately prior to TBS. The results demonstrate activity-induced long-term plasticity in synaptic excitation of hippocampal PV+ and NOS+ interneurons in vivo. Physiological and pathological activity patterns in vivo may generate similar plasticity in these interneurons.

  12. Impaired GABAergic inhibition in the prefrontal cortex of early postnatal phencyclidine (PCP)-treated rats.

    Science.gov (United States)

    Kjaerby, Celia; Broberg, Brian V; Kristiansen, Uffe; Dalby, Nils Ole

    2014-09-01

    A compromised γ-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-D-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmission in adulthood. The present study examines prefrontal GABAergic transmission in adult rats administered with the NMDA receptor channel blocker, phencyclidine (PCP), for 3 days during the second postnatal week. Whole-cell patch-clamp recordings from pyramidal cells in PCP-treated rats showed a 22% reduction in the frequency of miniature inhibitory postsynaptic currents in layer II/III, but not in layer V pyramidal neurons of the prefrontal cortex. Furthermore, early postnatal PCP treatment caused insensitivity toward effects of the GABA transporter 1 (GAT-1) inhibitor, 1,2,5,6-tetrahydro-1-[2-[[(diphenyl-methylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid, and also diminished currents passed by δ-subunit-containing GABAA receptors in layer II/III pyramidal neurons. The observed impairments in GABAergic function are compatible with the alteration of GABAergic markers as well as cognitive dysfunction observed in early postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy.

    Science.gov (United States)

    Llansola, Marta; Montoliu, Carmina; Agusti, Ana; Hernandez-Rabaza, Vicente; Cabrera-Pastor, Andrea; Gomez-Gimenez, Belen; Malaguarnera, Michele; Dadsetan, Sherry; Belghiti, Majedeline; Garcia-Garcia, Raquel; Balzano, Tiziano; Taoro, Lucas; Felipo, Vicente

    2015-09-01

    The cognitive and motor alterations in hepatic encephalopathy (HE) are the final result of altered neurotransmission and communication between neurons in neuronal networks and circuits. Different neurotransmitter systems cooperate to modulate cognitive and motor function, with a main role for glutamatergic and GABAergic neurotransmission in different brain areas and neuronal circuits. There is an interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in HE. This interplay may occur: (a) in different brain areas involved in specific neuronal circuits; (b) in the same brain area through cross-modulation of glutamatergic and GABAergic neurotransmission. We will summarize some examples of the (1) interplay between glutamatergic and GABAergic neurotransmission alterations in different areas in the basal ganglia-thalamus-cortex circuit in the motor alterations in minimal hepatic encephalopathy (MHE); (2) interplay between glutamatergic and GABAergic neurotransmission alterations in cerebellum in the impairment of cognitive function in MHE through altered function of the glutamate-nitric oxide-cGMP pathway. We will also comment the therapeutic implications of the above studies and the utility of modulators of glutamate and GABA receptors to restore cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Organization of the torus longitudinalis in the rainbow trout (Oncorhynchus mykiss): an immunohistochemical study of the GABAergic system and a DiI tract-tracing study.

    Science.gov (United States)

    Folgueira, Mónica; Sueiro, Catalina; Rodríguez-Moldes, Isabel; Yáñez, Julián; Anadón, Ramón

    2007-07-10

    The torus longitudinalis (TL) is a tectum-associated structure of actinopterygian fishes. The organization of the TL of rainbow trout was studied with Nissl staining, Golgi methods, immunocytochemistry with antibodies to gamma-aminobutyric acid (GABA), glutamic acid decarboxylase (GAD), and the GABA(A) receptor subunits delta and beta2/beta 3, and with tract tracing methods. Two types of neuron were characterized: medium-sized GABAergic neurons and small GABA-negative granule cells. GABA(A) receptor subunit delta-like immunoreactivity delineated two different TL regions, ventrolateral and central. Small GABAergic cells were also observed in marginal and periventricular strata of the optic tectum. These results indicate the presence of local GABAergic inhibitory circuits in the TL system. For tract-tracing, a lipophilic dye (DiI) was applied to the TL and to presumed toropetal nuclei or toral targets. Toropetal neurons were observed in the optic tectum, in pretectal (central, intermediate, and paracommissural) nuclei, in the subvalvular nucleus, and associated with the pretectocerebellar tract. Torofugal fibers were numerous in the stratum marginale of the optic tectum. Toropetal pretectal nuclei also project to the cerebellum, and a few TL cells project to the cerebellar corpus. The pyramidal cells of the trout tectum were also studied by Golgi methods and local DiI labeling. The connections of trout TL revealed here were more similar to those recently reported in carp and holocentrids (Ito et al. [2003] J. Comp. Neurol. 457:202-211; Xue et al. [2003] J. Comp. Neurol. 462:194-212), than to those reported in earlier studies. However, important differences in organization of toropetal nuclei were noted between salmonids and these other teleosts. (c) 2007 Wiley-Liss, Inc.

  15. The Memory-Impairing Effects of Septal GABA Receptor Activation Involve GABAergic Septo-Hippocampal Projection Neurons

    Science.gov (United States)

    Krebs-Kraft, Desiree L.; Wheeler, Marina G.; Parent, Marise B.

    2007-01-01

    Septal infusions of the [gamma]-aminobutyric acid (GABA)[subscript A] agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA[subscript A] receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are…

  16. Functional hallmarks of GABAergic synapse maturation and the diverse roles of neurotrophins

    Directory of Open Access Journals (Sweden)

    Rosemarie eGrantyn

    2011-07-01

    Full Text Available Functional impairment of the adult brain can result from deficits in the ontogeny of GABAergic synaptic transmission. Gene defects underlying autism spectrum disorders, Rett’s syndrome or some forms of epilepsy, but also a diverse set of syndromes accompanying perinatal trauma, hormonal imbalances, intake of sleep-inducing or mood-improving drugs or, quite common, alcohol intake during pregnancy can alter GABA signaling early in life. The search for therapeutically relevant endogenous molecules or exogenous compounds able to alleviate the consequences of dysfunction of GABAergic transmission in the embryonic or postnatal brain requires a clear understanding of its site- and state-dependent development. At the level of single synapses, it is necessary to discriminate between presynaptic and postsynaptic alterations, and to define parameters that can be regarded as both suitable and accessible for the quantification of developmental changes. Here we focus on the performance of GABAergic synapses in two brain structures, the hippocampus and the superior colliculus, describe some novel aspects of neurotrophin effects during the development of GABAergic synaptic transmission and examine the applicability of the following rules: 1 Synaptic transmission starts with GABA, 2 Nascent/immature GABAergic synapses operate in a ballistic mode (multivesicular release, 3 Immature synaptic terminals release vesicles with higher probability than mature synapses, 4 Immature GABAergic synapses are prone to paired pulse and tetanic depression, 5 Synapse maturation is characterized by an increasing dominance of synchronous over asynchronous release, 6 In immature neurons GABA acts as a depolarizing transmitter, 7 Synapse maturation implies IPSC shortening due to an increase in alpha1 subunit expression, 8 Extrasynaptic (tonic conductances can inhibit the development of synaptic (phasic GABA actions.

  17. Neuron-astrocyte interaction enhance GABAergic synaptic transmission in a manner dependent on key metabolic enzymes.

    Directory of Open Access Journals (Sweden)

    Przemysław eKaczor

    2015-04-01

    Full Text Available GABA is the major inhibitory neurotransmitter in the adult brain and mechanisms of GABAergic inhibition have been intensely investigated in the past decades. Recent studies provided evidence for an important role of astrocytes in shaping GABAergic currents. One of the most obvious, but yet poorly understood, mechanisms of the cross-talk between GABAergic currents and astrocytes is metabolism including neurotransmitter homeostasis. In particular, how modulation of GABAergic currents by astrocytes depends on key enzymes involved in cellular metabolism remains largely unknown. To address this issue, we have considered two simple models of neuronal cultures: nominally astrocyte-free neuronal culture (NC and neuronal-astrocytic co-cultures (ANCC and miniature Inhibitory Postsynaptic Currents (mIPSCs were recorded in control conditions and in the presence of respective enzyme blockers. We report that enrichment of neuronal culture with astrocytes results in a marked increase in mIPSC frequency. This enhancement of GABAergic activity was accompanied by increased number of GAD65 and vGAT puncta, indicating that at least a part of the frequency enhancement was due to increased number of synaptic contacts. Inhibition of glutamine synthetase (with MSO strongly reduced mIPSC frequency in ANCC but had no effect in NC. Moreover, treatment of ANCC with inhibitor of glycogen phosphorylase (BAYU6751 or with selective inhibitor of astrocytic Krebs cycle,fluoroacetate, resulted in a marked reduction of mIPSC frequency in ANCC having no effect in NC. We conclude that GABAergic synaptic transmission strongly depends on neuron-astrocyte interaction in a manner dependent on key metabolic enzymes as well as on the Krebs cycle.

  18. Quantitative Study of NPY-Expressing GABAergic Neurons and Axons in Rat Spinal Dorsal Horn*

    OpenAIRE

    Polg?r, Erika; Sardella, Thomas CP; Watanabe, Masahiko; Todd, Andrew J

    2010-01-01

    Between 25?40% of neurons in laminae I?III are GABAergic, and some of these express neuropeptide Y (NPY). We previously reported that NPY-immunoreactive axons form numerous synapses on lamina III projection neurons that possess the neurokinin 1 receptor (NK1r). The aims of this study were to determine the proportion of neurons and GABAergic boutons in this region that contain NPY, and to look for evidence that they selectively innervate different neuronal populations. We found that 4?6% of ne...

  19. Expression of glutamic acid decarboxylase and identification of GABAergic cells in the ischemic rat dentate gyrus

    DEFF Research Database (Denmark)

    Müller, Georg Johannes; Dogonowski, Anne-Marie; Finsen, Bente

    2006-01-01

    We have investigated the glutamic acid dexcarboxylase (GAD) mRNA and protein isoforms as markers for ischemic loss of GABAergic neurons in the dentate hilus. Stereological counts of these neurons were performed in rats surviving 8 days after 10 min of transient forebrain ischemia, and in control...

  20. 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.

  1. Caffeine-Induced Suppression of GABAergic Inhibition and Calcium-Independent Metaplasticity

    Directory of Open Access Journals (Sweden)

    Masako Isokawa

    2016-01-01

    Full Text Available GABAergic inhibition plays a critical role in the regulation of neuron excitability; thus, it is subject to modulations by many factors. Recent evidence suggests the elevation of intracellular calcium ([Ca2+]i and calcium-dependent signaling molecules underlie the modulations. Caffeine induces a release of calcium from intracellular stores. We tested whether caffeine modulated GABAergic transmission by increasing [Ca2+]i. A brief local puff-application of caffeine to hippocampal CA1 pyramidal cells transiently suppressed GABAergic inhibitory postsynaptic currents (IPSCs by 73.2 ± 6.98%. Time course of suppression and the subsequent recovery of IPSCs resembled DSI (depolarization-induced suppression of inhibition, mediated by endogenous cannabinoids that require a [Ca2+]i rise. However, unlike DSI, caffeine-induced suppression of IPSCs (CSI persisted in the absence of a [Ca2+]i rise. Intracellular applications of BAPTA and ryanodine (which blocks caffeine-induced calcium release from intracellular stores failed to prevent the generation of CSI. Surprisingly, ruthenium red, an inhibitor of multiple calcium permeable/release channels including those of stores, induced metaplasticity by amplifying the magnitude of CSI independently of calcium. This metaplasticity was accompanied with the generation of a large inward current. Although ionic basis of this inward current is undetermined, the present result demonstrates that caffeine has a robust Ca2+-independent inhibitory action on GABAergic inhibition and causes metaplasticity by opening plasma membrane channels.

  2. Regulation of the Hippocampal Network by VGLUT3-Positive CCK- GABAergic Basket Cells

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    Caroline Fasano

    2017-05-01

    Full Text Available Hippocampal interneurons release the inhibitory transmitter GABA to regulate excitation, rhythm generation and synaptic plasticity. A subpopulation of GABAergic basket cells co-expresses the GABA/glycine vesicular transporters (VIAAT and the atypical type III vesicular glutamate transporter (VGLUT3; therefore, these cells have the ability to signal with both GABA and glutamate. GABAergic transmission by basket cells has been extensively characterized but nothing is known about the functional implications of VGLUT3-dependent glutamate released by these cells. Here, using VGLUT3-null mice we observed that the loss of VGLUT3 results in a metaplastic shift in synaptic plasticity at Shaeffer’s collaterals – CA1 synapses and an altered theta oscillation. These changes were paralleled by the loss of a VGLUT3-dependent inhibition of GABAergic current in CA1 pyramidal layer. Therefore presynaptic type III metabotropic could be activated by glutamate released from VGLUT3-positive interneurons. This putative presynaptic heterologous feedback mechanism inhibits local GABAergic tone and regulates the hippocampal neuronal network.

  3. GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction.

    Science.gov (United States)

    Saha, Rinki; Knapp, Stephanie; Chakraborty, Darpan; Horovitz, Omer; Albrecht, Anne; Kriebel, Martin; Kaphzan, Hanoch; Ehrlich, Ingrid; Volkmer, Hansjürgen; Richter-Levin, Gal

    2017-01-01

    Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum-BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum-BLA-LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

  4. Unique functional properties of somatostatin-expressing GABAergic neurons in mouse barrel cortex.

    NARCIS (Netherlands)

    Gentet, L.J.; Kremer, Y.; Taniguchi, H.; Huang, Z.J.; Staiger, J.F.; Petersen, C.C.H.

    2012-01-01

    Neocortical GABAergic neurons have diverse molecular, structural and electrophysiological features, but the functional correlates of this diversity are largely unknown. We found unique membrane potential dynamics of somatostatin-expressing (SOM) neurons in layer 2/3 of the primary somatosensory

  5. Mice deficient in transmembrane prostatic acid phosphatase display increased GABAergic transmission and neurological alterations.

    Directory of Open Access Journals (Sweden)

    Heidi O Nousiainen

    Full Text Available Prostatic acid phosphatase (PAP, the first diagnostic marker and present therapeutic target for prostate cancer, modulates nociception at the dorsal root ganglia (DRG, but its function in the central nervous system has remained unknown. We studied expression and function of TMPAP (the transmembrane isoform of PAP in the brain by utilizing mice deficient in TMPAP (PAP-/- mice. Here we report that TMPAP is expressed in a subpopulation of cerebral GABAergic neurons, and mice deficient in TMPAP show multiple behavioral and neurochemical features linked to hyperdopaminergic dysregulation and altered GABAergic transmission. In addition to increased anxiety, disturbed prepulse inhibition, increased synthesis of striatal dopamine, and augmented response to amphetamine, PAP-deficient mice have enlarged lateral ventricles, reduced diazepam-induced loss of righting reflex, and increased GABAergic tone in the hippocampus. TMPAP in the mouse brain is localized presynaptically, and colocalized with SNARE-associated protein snapin, a protein involved in synaptic vesicle docking and fusion, and PAP-deficient mice display altered subcellular distribution of snapin. We have previously shown TMPAP to reside in prostatic exosomes and we propose that TMPAP is involved in the control of GABAergic tone in the brain also through exocytosis, and that PAP deficiency produces a distinct neurological phenotype.

  6. Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia.

    Science.gov (United States)

    Balan, Shabeesh; Yamada, Kazuo; Iwayama, Yoshimi; Hashimoto, Takanori; Toyota, Tomoko; Shimamoto, Chie; Maekawa, Motoko; Takagai, Shu; Wakuda, Tomoyasu; Kameno, Yosuke; Kurita, Daisuke; Yamada, Kohei; Kikuchi, Mitsuru; Hashimoto, Tasuku; Kanahara, Nobuhisa; Yoshikawa, Takeo

    2017-07-01

    Involvement of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia pathogenesis through disrupted neurodevelopment has been highlighted in numerous studies. However, the function of common genetic variants of this system in determining schizophrenia risk is unknown. We therefore tested the association of 375 tagged SNPs in genes derived from the GABAergic system, such as GABA A receptor subunit genes, and GABA related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes involved in GABA receptor trafficking and scaffolding) in Japanese schizophrenia case-control samples (n=2926; 1415 cases and 1511 controls). We observed nominal association of SNPs in nine GABA A receptor subunit genes and the GPHN gene with schizophrenia, although none survived correction for study-wide multiple testing. Two SNPs located in the GABRA1 gene, rs4263535 (P allele =0.002; uncorrected) and rs1157122 (P allele =0.006; uncorrected) showed top hits, followed by rs723432 (P allele =0.007; uncorrected) in the GPHN gene. All three were significantly associated with schizophrenia and survived gene-wide multiple testing. Haplotypes containing associated variants in GABRA1 but not GPHN were significantly associated with schizophrenia. To conclude, we provided substantiating genetic evidence for the involvement of the GABAergic system in schizophrenia susceptibility. These results warrant further investigations to replicate the association of GABRA1 and GPHN with schizophrenia and to discern the precise mechanisms of disease pathophysiology. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Quasi-morphine abstinence behaviour GABA-ergic mechanisms and their localization

    NARCIS (Netherlands)

    J.W. van der Laan

    1981-01-01

    textabstractDi-n-propylacetate (DPA), generally known to be an anti-epileptic drug, induces a behavioural syndrome in rats resembling morphine abstinence behaviour, which is called, therefore, quasi-morphine abstinence beh~viour. An increase in GABA-ergic activity is probably responsible for this

  8. The role of spinal GABAergic circuits in the control of phrenic nerve motor output.

    Science.gov (United States)

    Marchenko, Vitaliy; Ghali, Michael G Z; Rogers, Robert F

    2015-06-01

    While supraspinal mechanisms underlying respiratory pattern formation are well characterized, the contribution of spinal circuitry to the same remains poorly understood. In this study, we tested the hypothesis that intraspinal GABAergic circuits are involved in shaping phrenic motor output. To this end, we performed bilateral phrenic nerve recordings in anesthetized adult rats and observed neurogram changes in response to knocking down expression of both isoforms (65 and 67 kDa) of glutamate decarboxylase (GAD65/67) using microinjections of anti-GAD65/67 short-interference RNA (siRNA) in the phrenic nucleus. The number of GAD65/67-positive cells was drastically reduced on the side of siRNA microinjections, especially in the lateral aspects of Rexed's laminae VII and IX in the ventral horn of cervical segment C4, but not contralateral to microinjections. We hypothesize that intraspinal GABAergic control of phrenic output is primarily phasic, but also plays an important role in tonic regulation of phrenic discharge. Also, we identified respiration-modulated GABAergic interneurons (both inspiratory and expiratory) located slightly dorsal to the phrenic nucleus. Our data provide the first direct evidence for the existence of intraspinal GABAergic circuits contributing to the formation of phrenic output. The physiological role of local intraspinal inhibition, independent of descending direct bulbospinal control, is discussed. Copyright © 2015 the American Physiological Society.

  9. Hypoxia preferentially destroys GABAergic neurons in developing rat neocortex explants in culture

    NARCIS (Netherlands)

    Romijn, H. J.; Ruijter, J. M.; Wolters, P. S.

    1988-01-01

    The hypothesis that hypoxic ischemia before or during the human birth process preferentially destroys GABAergic nerve cells, particularly in the neocortex, was tested in a tissue culture model system. To that end, rat neocortex explants dissected from 6-day-old rat pups and cultured to a

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

    Science.gov (United States)

    Losi, Gabriele; Mariotti, Letizia; Carmignoto, Giorgio

    2014-10-19

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

  11. Shared rhythmic subcortical GABAergic input to the entorhinal cortex and presubiculum.

    Science.gov (United States)

    Viney, Tim James; Salib, Minas; Joshi, Abhilasha; Unal, Gunes; Berry, Naomi; Somogyi, Peter

    2018-04-05

    Rhythmic theta frequency (~5-12 Hz) oscillations coordinate neuronal synchrony and higher frequency oscillations across the cortex. Spatial navigation and context-dependent episodic memories are represented in several interconnected regions including the hippocampal and entorhinal cortices, but the cellular mechanisms for their dynamic coupling remain to be defined. Using monosynaptically-restricted retrograde viral tracing in mice, we identified a subcortical GABAergic input from the medial septum that terminated in the entorhinal cortex, with collaterals innervating the dorsal presubiculum. Extracellularly recording and labeling GABAergic entorhinal-projecting neurons in awake behaving mice show that these subcortical neurons, named orchid cells, fire in long rhythmic bursts during immobility and locomotion. Orchid cells discharge near the peak of hippocampal and entorhinal theta oscillations, couple to entorhinal gamma oscillations, and target subpopulations of extra-hippocampal GABAergic interneurons. Thus, orchid cells are a specialized source of rhythmic subcortical GABAergic modulation of 'upstream' and 'downstream' cortico-cortical circuits involved in mnemonic functions. © 2018, Viney et al.

  12. Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model

    NARCIS (Netherlands)

    Heulens, Inge; D'Hulst, Charlotte; Van Dam, Debby; De Deyn, Peter P.; Kooy, R. Frank

    2012-01-01

    Molecular and electrophysiological studies have provided evidence for a general downregulation of the GABAergic system in the Fmr1 knockout mouse. GABA(A) receptors are the main inhibitory receptors in the brain and the GABA(A) receptor was proposed as a novel target for treatment of the fragile X

  13. Anatomical recovery of the GABAergic system after a complete spinal cord injury in lampreys.

    Science.gov (United States)

    Romaus-Sanjurjo, D; Valle-Maroto, S M; Barreiro-Iglesias, A; Fernández-López, B; Rodicio, M C

    2018-03-15

    Lampreys recover locomotion spontaneously several weeks after a complete spinal cord injury. Dysfunction of the GABAergic system following SCI has been reported in mammalian models. So, it is of great interest to understand how the GABAergic system of lampreys adapts to the post-injury situation and how this relates to spontaneous recovery. The spinal cord of lampreys contains 3 populations of GABAergic neurons and most of the GABAergic innervation of the spinal cord comes from these local cells. GABAB receptors are expressed in the spinal cord of lampreys and they play important roles in the control of locomotion. The aims of the present study were to quantify: 1) the changes in the number of GABAergic neurons and innervation of the spinal cord and 2) the changes in the expression of the gabab receptor subunits b1 and b2 in the spinal cord of the sea lamprey after SCI. We performed complete spinal cord transections at the level of the fifth gill of mature larval lampreys and GABA immunohistochemistry or gabab in situ hybridization experiments. Animals were analysed up to 10 weeks post-lesion (wpl), when behavioural analyses showed that they recovered normal appearing locomotion (stage 6 in the Ayer's scale of locomotor recovery). We observed a significant decrease in the number of GABA-ir cells and fibres 1 h after lesion both rostral and caudal to the lesion site. GABA-ir cell numbers and innervation were recovered to control levels 1 to 2 wpl. At 1, 4 and 10 wpl the expression of gabab1 and gabab2 transcripts was significantly decreased in the spinal cord compared to control un-lesioned animals. This is the first study reporting the quantitative long-term changes in the number of GABAergic cells and fibres and in the expression of gabab receptors in the spinal cord of any vertebrate following a traumatic SCI. Our results show that in lampreys there is a full recovery of the GABAergic neurons and a decrease in the expression of gabab receptors when functional

  14. Presynaptic inhibition of GABAergic synaptic transmission by adenosine in mouse hypothalamic hypocretin neurons.

    Science.gov (United States)

    Xia, J X; Xiong, J X; Wang, H K; Duan, S M; Ye, J N; Hu, Z A

    2012-01-10

    Hypocretin neurons in the lateral hypothalamus, a new wakefulness-promoting center, have been recently regarded as an important target involved in endogenous adenosine-regulating sleep homeostasis. The GABAergic synaptic transmissions are the main inhibitory afferents to hypocretin neurons, which play an important role in the regulation of excitability of these neurons. The inhibitory effect of adenosine, a homeostatic sleep-promoting factor, on the excitatory glutamatergic synaptic transmissions in hypocretin neurons has been well documented, whether adenosine also modulates these inhibitory GABAergic synaptic transmissions in these neurons has not been investigated. In this study, the effect of adenosine on inhibitory postsynaptic currents (IPSCs) in hypocretin neurons was examined by using perforated patch-clamp recordings in the acute hypothalamic slices. The findings demonstrated that adenosine suppressed the amplitude of evoked IPSCs in a dose-dependent manner, which was completely abolished by 8-cyclopentyltheophylline (CPT), a selective antagonist of adenosine A1 receptor but not adenosine A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl) xanthine. A presynaptic origin was suggested as following: adenosine increased paired-pulse ratio as well as reduced GABAergic miniature IPSC frequency without affecting the miniature IPSC amplitude. Further findings demonstrated that when the frequency of electrical stimulation was raised to 10 Hz, but not 1 Hz, a time-dependent depression of evoked IPSC amplitude was detected in hypocretin neurons, which could be partially blocked by CPT. However, under a higher frequency at 100 Hz stimulation, CPT had no action on the depressed GABAergic synaptic transmission induced by such tetanic stimulation in these hypocretin neurons. These results suggest that endogenous adenosine generated under certain stronger activities of synaptic transmissions exerts an inhibitory effect on GABAergic synaptic transmission in hypocretin

  15. Adenosine Inhibits the Excitatory Synaptic Inputs to Basal Forebrain Cholinergic, GABAergic and Parvalbumin Neurons in mice

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    Chun eYang

    2013-06-01

    Full Text Available Coffee and tea contain the stimulants caffeine and theophylline. These compounds act as antagonists of adenosine receptors. Adenosine promotes sleep and its extracellular concentration rises in association with prolonged wakefulness, particularly in the basal forebrain (BF region involved in activating the cerebral cortex. However, the effect of adenosine on identified BF neurons, especially non-cholinergic neurons, is incompletely understood. Here we used whole-cell patch-clamp recordings in mouse brain slices prepared from two validated transgenic mouse lines with fluorescent proteins expressed in GABAergic or parvalbumin (PV neurons to determine the effect of adenosine. Whole-cell recordings were made BF cholinergic neurons and from BF GABAergic & PV neurons with the size (>20 µm and intrinsic membrane properties (prominent H-currents corresponding to cortically projecting neurons. A brief (2 min bath application of adenosine (100 μM decreased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents in all groups of BF cholinergic, GABAergic and PV neurons we recorded. In addition, adenosine decreased the frequency of miniature EPSCs in BF cholinergic neurons. Adenosine had no effect on the frequency of spontaneous inhibitory postsynaptic currents in cholinergic neurons or GABAergic neurons with large H-currents but reduced them in a group of GABAergic neurons with smaller H-currents. All effects of adenosine were blocked by a selective, adenosine A1 receptor antagonist, cyclopentyltheophylline (CPT, 1 μM. Adenosine had no postsynaptic effects. Taken together, our work suggests that adenosine promotes sleep by an A1-receptor mediated inhibition of glutamatergic inputs to cortically-projecting cholinergic and GABA/PV neurons. Conversely, caffeine and theophylline promote attentive wakefulness by inhibiting these A1 receptors in BF thereby promoting the high-frequency oscillations in the cortex required for

  16. Developmental changes in GABAergic mechanisms in human visual cortex across the lifespan

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    Joshua G A Pinto

    2010-06-01

    Full Text Available Functional maturation of visual cortex is linked with dynamic changes in synaptic expression of GABAergic mechanisms. These include setting the excitation-inhibition balance required for experience-dependent plasticity, as well as, intracortical inhibition underlying development and aging of receptive field properties. Animal studies have shown developmental regulation of GABAergic mechanisms in visual cortex. In this study, we show for the first time how these mechanisms develop in the human visual cortex across the lifespan. We used Western blot analysis of postmortem tissue from human primary visual cortex (n=30, range: 20 days to 80 years to quantify expression of 8 pre- and post-synaptic GABAergic markers. We quantified the inhibitory modulating cannabinoid receptor (CB1, GABA vesicular transporter (VGAT, GABA synthesizing enzymes (GAD65/GAD67, GABAA receptor anchoring protein (Gephyrin, and GABAA receptor subunits (GABAA∝1, GABAA∝2, GABAA∝3. We found a complex pattern of changes, many of which were prolonged and continued well into into the teen, young adult, and even older adult years. These included a monotonic increase or decrease (GABAA∝1, GABAA∝2, a biphasic increase then decrease (GAD65, Gephyrin, or multiple increases and decreases (VGAT, CB1 across the lifespan. Comparing the balances between the pre- and post-synaptic markers we found 3 main transitions (early childhood, early teen years, aging when there were rapid switches in the composition of the GABAergic signaling system, indicating that functioning of the GABAergic system must change as the visual cortex develops and ages. Furthermore, these results provide key information for translating therapies developed in animal models into effective treatments for amblyopia in humans.

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

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    Judith M. Reichel

    2015-01-01

    Full Text Available GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epileptic seizures or schizophrenia. Schizophrenia itself is clinically defined by negative- (e.g. depression and positive- (e.g. hallucinations symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved.Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs in vitro and in vivo. Given their involvement in Schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC and dorsal hippocampus (dHPC in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days and short-term (< 14 days GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories.

  18. DEVELOPMENTAL HYPOTHYROIDISM REDUCES PARVALBUMIN EXPRESSION IN GABAERGIC NEURONS OF CORTEX AND HIPPOCAMPUS: IMMUNOHISTOCHEMICAL FINDINGS AND FUNCTIONAL CORRELATES.

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    GABAergic interneurons comprise the bulk of local inhibitory neuronal circuitry in cortex and hippocampus and a subpopulation of these interneurons contain the calcium binding protein, parvalbumin (PV). A previous report indicated that severe hypothyroidism reduced PV immunoreact...

  19. Accelerated Intoxication of GABAergic Synapses by Botulinum Neurotoxin A Disinhibits Stem Cell-Derived Neuron Networks Prior to Network Silencing

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    2015-04-23

    administered BoNT can lead to central nervous system intoxication is currently being debated. Recent findings in vitro and in vivo suggest that BoNT...Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Accelerated intoxication of GABAergic synapses by botulinum neurotoxin A disinhibits 5a...April 2015 Published: 23 April 2015 Citation: Beske PH, Scheeler SM, AdlerM and McNutt PM (2015) Accelerated intoxication of GABAergic synapses by

  20. Co-release of glutamate and GABA from single vesicles in GABAergic neurons exogenously expressing VGLUT3

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    Johannes eZimmermann

    2015-09-01

    Full Text Available The identity of the vesicle neurotransmitter transporter expressed by a neuron largely corresponds with the primary neurotransmitter that cell releases. However, the vesicular glutamate transporter subtype 3 (VGLUT3 is mainly expressed in non-glutamatergic neurons, including cholinergic, serotonergic, or GABAergic neurons. Though a functional role for glutamate release from these non-glutamatergic neurons has been demonstrated, the interplay between VGLUT3 and the neuron’s characteristic neurotransmitter transporter, particularly in the case of GABAergic neurons, at the synaptic and vesicular level is less clear. In this study, we explore how exogenous expression of VGLUT3 in striatal GABAergic neurons affects the packaging and release of glutamate and GABA in synaptic vesicles. We found that VGLUT3 expression in isolated, autaptic GABAergic neurons leads to action potential evoked release of glutamate. Under these conditions, glutamate and GABA could be packaged together in single vesicles release either spontaneously or asynchronously. However, the presence of glutamate in GABAergic vesicles did not affect uptake of GABA itself, suggesting a lack of synergy in vesicle filling for these transmitters. Finally, we found postsynaptic detection of glutamate released from GABAergic terminals difficult when bona fide glutamatergic synapses were present, suggesting that co-released glutamate cannot induce postsynaptic glutamate receptor clustering.

  1. Development of Cortical GABAergic Neurons: Interplay of progenitor diversity and environmental factors on fate specification

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    Juliana Alves Brandão

    2015-04-01

    Full Text Available Cortical GABAergic interneurons constitute an extremely diverse population of cells organized in a well-defined topology of precisely interconnected cells. They play a crucial role regulating inhibitory-excitatory balance in brain circuits, gating sensory perception and regulating spike timing to brain oscillations during distinct behaviors. Dysfunctions in the establishment of proper inhibitory circuits have been associated to several brain disorders such as autism, epilepsy and schizophrenia. In the rodent adult cortex, inhibitory neurons are generated during the second gestational week from distinct progenitor lineages located in restricted domains of the ventral telencephalon. However, only recently, studies have revealed some of the mechanisms generating the heterogeneity of neuronal subtypes and their modes of integration in brain networks. Here we will discuss some the events involved in the production of cortical GABAergic neuron diversity with focus on the interaction between intrinsically driven genetic programs and environmental signals during development.

  2. Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients

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    Michelle M. Solleveld

    2017-01-01

    First stimulant exposure at a young age is thus associated with lower baseline levels of GABA+ and increased responsivity in adulthood. This effect could not be found in patients that started treatment at an adult age. Hence, while adult stimulant treatment seems to exert no major effects on GABA+ levels in the mPFC, MPH may induce long-lasting alterations in the adult mPFC GABAergic system when treatment was started at a young age.

  3. Organization of GABAergic synaptic circuits in the rat ventral tegmental area.

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    Ciccarelli, Alessandro; Calza, Arianna; Panzanelli, Patrizia; Concas, Alessandra; Giustetto, Maurizio; Sassoè-Pognetto, Marco

    2012-01-01

    The ventral tegmental area (VTA) is widely implicated in drug addiction and other psychiatric disorders. This brain region is densely populated by dopaminergic (DA) neurons and also contains a sparse population of γ-aminobutyric acid (GABA)ergic cells that regulate the activity of the principal neurons. Therefore, an in-depth knowledge of the organization of VTA GABAergic circuits and of the plasticity induced by drug consumption is essential for understanding the mechanisms by which drugs induce stable changes in brain reward circuits. Using immunohistochemistry, we provide a detailed description of the localization of major GABA(A) and GABA(B) receptor subunits in the rat VTA. We show that DA and GABAergic cells express both GABA(A) and GABA(B) receptors. However VTA neurons differ considerably in the expression of GABA(A) receptor subunits, as the α1 subunit is associated predominantly with non-DA cells, whereas the α3 subunit is present at low levels in both types of VTA neurons. Using an unbiased stereological method, we then demonstrate that α1-positive elements represent only a fraction of non-DA neurons and that the ratio of DA and non-DA cells is quite variable throughout the rostro-caudal extent of the VTA. Interestingly, DA and non-DA cells receive a similar density of perisomatic synapses, whereas axo-dendritic synapses are significantly more abundant in non-DA cells, indicating that local interneurons receive prominent GABAergic inhibition. These findings reveal a differential expression of GABA receptor subtypes in the two major categories of VTA neurons and provide an anatomical basis for interpreting the plasticity of inhibitory circuits induced by drug exposure.

  4. Organization of GABAergic synaptic circuits in the rat ventral tegmental area.

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    Alessandro Ciccarelli

    Full Text Available The ventral tegmental area (VTA is widely implicated in drug addiction and other psychiatric disorders. This brain region is densely populated by dopaminergic (DA neurons and also contains a sparse population of γ-aminobutyric acid (GABAergic cells that regulate the activity of the principal neurons. Therefore, an in-depth knowledge of the organization of VTA GABAergic circuits and of the plasticity induced by drug consumption is essential for understanding the mechanisms by which drugs induce stable changes in brain reward circuits. Using immunohistochemistry, we provide a detailed description of the localization of major GABA(A and GABA(B receptor subunits in the rat VTA. We show that DA and GABAergic cells express both GABA(A and GABA(B receptors. However VTA neurons differ considerably in the expression of GABA(A receptor subunits, as the α1 subunit is associated predominantly with non-DA cells, whereas the α3 subunit is present at low levels in both types of VTA neurons. Using an unbiased stereological method, we then demonstrate that α1-positive elements represent only a fraction of non-DA neurons and that the ratio of DA and non-DA cells is quite variable throughout the rostro-caudal extent of the VTA. Interestingly, DA and non-DA cells receive a similar density of perisomatic synapses, whereas axo-dendritic synapses are significantly more abundant in non-DA cells, indicating that local interneurons receive prominent GABAergic inhibition. These findings reveal a differential expression of GABA receptor subtypes in the two major categories of VTA neurons and provide an anatomical basis for interpreting the plasticity of inhibitory circuits induced by drug exposure.

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

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    Sira A. Franchi

    2018-01-01

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

  6. Development of GPCR modulation of GABAergic transmission in chicken nucleus laminaris neurons.

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    Zheng-Quan Tang

    Full Text Available Neurons in the nucleus laminaris (NL of birds act as coincidence detectors and encode interaural time difference to localize the sound source in the azimuth plane. GABAergic transmission in a number of CNS nuclei including the NL is subject to a dual modulation by presynaptic GABA(B receptors (GABA(BRs and metabotropic glutamate receptors (mGluRs. Here, using in vitro whole-cell patch clamp recordings from acute brain slices of the chick, we characterized the following important but unknown properties pertaining to such a dual modulation: (1 emergence of functional GABA synapses in NL neurons; (2 the temporal onset of neuromodulation mediated by GABA(BRs and mGluRs; and (3 the physiological conditions under which GABA(BRs and mGluRs are activated by endogenous transmitters. We found that (1 GABA(AR-mediated synaptic responses were observed in about half of the neurons at embryonic day 11 (E11; (2 GABA(BR-mediated modulation of the GABAergic transmission was detectable at E11, whereas the modulation by mGluRs did not emerge until E15; and (3 endogenous activity of GABA(BRs was induced by both low- (5 or 10 Hz and high-frequency (200 Hz stimulation of the GABAergic pathway, whereas endogenous activity of mGluRs was induced by high- (200 Hz but not low-frequency (5 or 10 Hz stimulation of the glutamatergic pathway. Furthermore, the endogenous activity of mGluRs was mediated by group II but not group III members. Therefore, autoreceptor-mediated modulation of GABAergic transmission emerges at the same time when the GABA synapses become functional. Heteroreceptor-mediated modulation appears at a later time and is receptor type dependent in vitro.

  7. Spatio-temporal specialization of GABAergic septo-hippocampal neurons for rhythmic network activity.

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    Unal, Gunes; Crump, Michael G; Viney, Tim J; Éltes, Tímea; Katona, Linda; Klausberger, Thomas; Somogyi, Peter

    2018-03-03

    Medial septal GABAergic neurons of the basal forebrain innervate the hippocampus and related cortical areas, contributing to the coordination of network activity, such as theta oscillations and sharp wave-ripple events, via a preferential innervation of GABAergic interneurons. Individual medial septal neurons display diverse activity patterns, which may be related to their termination in different cortical areas and/or to the different types of innervated interneurons. To test these hypotheses, we extracellularly recorded and juxtacellularly labeled single medial septal neurons in anesthetized rats in vivo during hippocampal theta and ripple oscillations, traced their axons to distant cortical target areas, and analyzed their postsynaptic interneurons. Medial septal GABAergic neurons exhibiting different hippocampal theta phase preferences and/or sharp wave-ripple related activity terminated in restricted hippocampal regions, and selectively targeted a limited number of interneuron types, as established on the basis of molecular markers. We demonstrate the preferential innervation of bistratified cells in CA1 and of basket cells in CA3 by individual axons. One group of septal neurons was suppressed during sharp wave-ripples, maintained their firing rate across theta and non-theta network states and mainly fired along the descending phase of CA1 theta oscillations. In contrast, neurons that were active during sharp wave-ripples increased their firing significantly during "theta" compared to "non-theta" states, with most firing during the ascending phase of theta oscillations. These results demonstrate that specialized septal GABAergic neurons contribute to the coordination of network activity through parallel, target area- and cell type-selective projections to the hippocampus.

  8. A new role for GABAergic transmission in the control of male rat sexual behavior expression.

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    Rodríguez-Manzo, Gabriela; Canseco-Alba, Ana

    2017-03-01

    GABAergic transmission in the ventral tegmental area (VTA) exerts a tonic inhibitory influence on mesolimbic dopaminergic neurons' activity. Blockade of VTA GABA A receptors increases dopamine release in the nucleus accumbens (NAcc). Increases in NAcc dopamine levels typically accompany sexual behavior display. Copulation to satiety is characterized by the instatement of a long lasting (72h) sexual behavior inhibition and the mesolimbic system appears to be involved in this phenomenon. GABAergic transmission in the VTA might play a role in the maintenance of this long lasting sexual inhibitory state. To test this hypothesis, in the present work we investigated the effect of GABA A receptor blockade in sexually exhausted males 24h after copulation to satiety, once the sexual inhibitory state is established, and compared it with its effect in sexually experienced rats. Results showed that low doses of systemically administered bicuculline induced sexual behavior expression in sexually exhausted rats, but lacked an effect on copulation of sexually experienced animals. Intra-VTA bilateral infusion of bicuculline did not modify sexual behavior of sexually experienced rats, but induced sexual behavior expression in all the sexually exhausted males. Hence, GABA plays a role in the control of sexual behavior expression at the VTA. The role played by GABAergic transmission in male sexual behavior expression of animals with distinct sexual behavior conditions is discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Neurofeedback Control of the Human GABAergic System Using Non-invasive Brain Stimulation.

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    Koganemaru, Satoko; Mikami, Yusuke; Maezawa, Hitoshi; Ikeda, Satoshi; Ikoma, Katsunori; Mima, Tatsuya

    2018-06-01

    Neurofeedback has been a powerful method for self-regulating brain activities to elicit potential ability of human mind. GABA is a major inhibitory neurotransmitter in the central nervous system. Transcranial magnetic stimulation (TMS) is a tool that can evaluate the GABAergic system within the primary motor cortex (M1) using paired-pulse stimuli, short intracortical inhibition (SICI). Herein we investigated whether neurofeedback learning using SICI enabled us to control the GABAergic system within the M1 area. Forty-five healthy subjects were randomly divided into two groups: those receiving SICI neurofeedback learning or those receiving no neurofeedback (control) learning. During both learning periods, subjects made attempts to change the size of a circle, which was altered according to the degree of SICI in the SICI neurofeedback learning group, and which was altered independent of the degree of SICI in the control learning group. Results demonstrated that the SICI neurofeedback learning group showed a significant enhancement in SICI. Moreover, this group showed a significant reduction in choice reaction time compared to the control group. Our findings indicate that humans can intrinsically control the intracortical GABAergic system within M1 and can thus improve motor behaviors by SICI neurofeedback learning. SICI neurofeedback learning is a novel and promising approach to control our neural system and potentially represents a new therapy for patients with abnormal motor symptoms caused by CNS disorders. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Medial septal GABAergic projection neurons promote object exploration behavior and type 2 theta rhythm

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    Gangadharan, Gireesh; Shin, Jonghan; Kim, Seong-Wook; Kim, Angela; Paydar, Afshin; Kim, Duk-Soo; Miyazaki, Taisuke; Watanabe, Masahiko; Yanagawa, Yuchio; Kim, Jinhyun; Kim, Yeon-Soo; Kim, Daesoo; Shin, Hee-Sup

    2016-01-01

    Exploratory drive is one of the most fundamental emotions, of all organisms, that are evoked by novelty stimulation. Exploratory behavior plays a fundamental role in motivation, learning, and well-being of organisms. Diverse exploratory behaviors have been described, although their heterogeneity is not certain because of the lack of solid experimental evidence for their distinction. Here we present results demonstrating that different neural mechanisms underlie different exploratory behaviors. Localized Cav3.1 knockdown in the medial septum (MS) selectively enhanced object exploration, whereas the null mutant (KO) mice showed enhanced-object exploration as well as open-field exploration. In MS knockdown mice, only type 2 hippocampal theta rhythm was enhanced, whereas both type 1 and type 2 theta rhythm were enhanced in KO mice. This selective effect was accompanied by markedly increased excitability of septo-hippocampal GABAergic projection neurons in the MS lacking T-type Ca2+ channels. Furthermore, optogenetic activation of the septo-hippocampal GABAergic pathway in WT mice also selectively enhanced object exploration behavior and type 2 theta rhythm, whereas inhibition of the same pathway decreased the behavior and the rhythm. These findings define object exploration distinguished from open-field exploration and reveal a critical role of T-type Ca2+ channels in the medial septal GABAergic projection neurons in this behavior. PMID:27208094

  11. Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade

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    Gregg W. Crabtree

    2016-10-01

    Full Text Available Proline dehydrogenase (PRODH, which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease.

  12. Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade.

    Science.gov (United States)

    Crabtree, Gregg W; Park, Alan J; Gordon, Joshua A; Gogos, Joseph A

    2016-10-04

    Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  13. Piriform cortical glutamatergic and GABAergic neurons express coordinated plasticity for whisker-induced odor recall.

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    Liu, Yahui; Gao, Zilong; Chen, Changfeng; Wen, Bo; Huang, Li; Ge, Rongjing; Zhao, Shidi; Fan, Ruichen; Feng, Jing; Lu, Wei; Wang, Liping; Wang, Jin-Hui

    2017-11-10

    Neural plasticity occurs in learning and memory. Coordinated plasticity at glutamatergic and GABAergic neurons during memory formation remains elusive, which we investigate in a mouse model of associative learning by cellular imaging and electrophysiology. Paired odor and whisker stimulations lead to whisker-induced olfaction response. In mice that express this cross-modal memory, the neurons in the piriform cortex are recruited to encode newly acquired whisker signal alongside innate odor signal, and their response patterns to these associated signals are different. There are emerged synaptic innervations from barrel cortical neurons to piriform cortical neurons from these mice. These results indicate the recruitment of associative memory cells in the piriform cortex after associative memory. In terms of the structural and functional plasticity at these associative memory cells in the piriform cortex, glutamatergic neurons and synapses are upregulated, GABAergic neurons and synapses are downregulated as well as their mutual innervations are refined in the coordinated manner. Therefore, the associated activations of sensory cortices triggered by their input signals induce the formation of their mutual synapse innervations, the recruitment of associative memory cells and the coordinated plasticity between the GABAergic and glutamatergic neurons, which work for associative memory cells to encode cross-modal associated signals in their integration, associative storage and distinguishable retrieval.

  14. Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses

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    Haowen Liu

    2018-02-01

    Full Text Available The locomotion of C. elegans is balanced by excitatory and inhibitory neurotransmitter release at neuromuscular junctions. However, the molecular mechanisms that maintain the balance of synaptic transmission remain enigmatic. Here, we investigated the function of voltage-gated Ca2+ channels in triggering spontaneous release at cholinergic and GABAergic synapses. Recordings of the miniature excitatory/inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively showed that UNC-2/CaV2 and EGL-19/CaV1 channels are the two major triggers for spontaneous release. Notably, however, Ca2+-independent spontaneous release was observed at GABAergic but not cholinergic synapses. Functional screening led to the identification of hypomorphic unc-64/Syntaxin-1A and snb-1/VAMP2 mutants in which mEPSCs are severely impaired, whereas mIPSCs remain unaltered, indicating differential regulation of these currents at cholinergic and GABAergic synapses. Moreover, Ca2+-independent spontaneous GABA release was nearly abolished in the hypomorphic unc-64 and snb-1 mutants, suggesting distinct mechanisms for Ca2+-dependent and Ca2+-independent spontaneous release.

  15. Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

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    Lee, Dong Kun; Jeong, Jae Hoon; Chun, Sung-Kun; Chua, Streamson; Jo, Young-Hwan

    2015-03-26

    Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

  16. Interplay between glucose and leptin signaling determines the strength of GABAergic synapses at POMC neurons

    Science.gov (United States)

    Lee, Dong Kun; Jeong, Jae Hoon; Chun, Sung-Kun; Chua, Streamson; Jo, Young-Hwan

    2015-01-01

    Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin’s action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signaling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signaling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons. PMID:25808323

  17. The neuronal identity bias behind neocortical GABAergic plasticity.

    Science.gov (United States)

    Allene, Camille; Lourenço, Joana; Bacci, Alberto

    2015-09-01

    In the neocortex, different types of excitatory and inhibitory neurons connect to one another following a detailed blueprint, defining functionally-distinct subnetworks, whose activity and modulation underlie complex cognitive functions. We review the cell-autonomous plasticity of perisomatic inhibition onto principal excitatory neurons. We propose that the tendency of different cortical layers to exhibit depression or potentiation of perisomatic inhibition is dictated by the specific identities of principal neurons (PNs). These are mainly defined by their projection targets and by their preference to be innervated by specific perisomatic-targeting basket cell types. Therefore, principal neurons responsible for relaying information to subcortical nuclei are differentially inhibited and show specific forms of plasticity compared to other PNs that are specialized in more associative functions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Glutamatergic and GABAergic neurotransmitter cycling and energy metabolism in rat cerebral cortex during postnatal development.

    Science.gov (United States)

    Chowdhury, Golam M I; Patel, Anant B; Mason, Graeme F; Rothman, Douglas L; Behar, Kevin L

    2007-12-01

    The contribution of glutamatergic and gamma-aminobutyric acid (GABA)ergic neurons to oxidative energy metabolism and neurotransmission in the developing brain is not known. Glutamatergic and GABAergic fluxes were assessed in neocortex of postnatal day 10 (P10) and 30 (P30) urethane-anesthetized rats infused intravenously with [1,6-(13)C(2)]glucose for different time intervals (time course) or with [2-(13)C]acetate for 2 to 3 h (steady state). Amino acid levels and (13)C enrichments were determined in tissue extracts ex vivo using (1)H-[(13)C]-NMR spectroscopy. Metabolic fluxes were estimated from the best fits of a three-compartment metabolic model (glutamatergic neurons, GABAergic neurons, and astroglia) to the (13)C-enrichment time courses of amino acids from [1,6-(13)C(2)]glucose, constrained by the ratios of neurotransmitter cycling (V(cyc))-to-tricarboxylic acid (TCA) cycle flux (V(TCAn)) calculated from the steady-state [2-(13)C]acetate enrichment data. From P10 to P30 increases in total neuronal (glutamate plus GABA) TCA cycle flux (3 x ; 0.24+/-0.05 versus 0.71+/-0.07 micromol per g per min, Pcycling flux (3.1 to 5 x ; 0.07 to 0.11 (+/-0.03) versus 0.34+/-0.03 micromol per g per min, Pcycling (DeltaV(cyc(tot))) and neuronal TCA cycle flux (DeltaV(TCAn(tot))) between P10 and P30 were 0.23 to 0.27 and 0.47 micromol per g per min, respectively, similar to the approximately 1:2 relationship previously reported for adult cortex. For the individual neurons, increases in V(TCAn) and V(cyc) were similar in magnitude (glutamatergic neurons, 2.7 x versus 2.8 to 4.6 x ; GABAergic neurons, approximately 5 x versus approximately 7 x), although GABAergic flux changes were larger. The findings show that glutamate and GABA neurons undergo large and approximately proportional increases in neurotransmitter cycling and oxidative energy metabolism during this major postnatal growth spurt.

  19. Acute orexigenic effect of agmatine involves interaction between central α2-adrenergic and GABAergic receptors.

    Science.gov (United States)

    Taksande, Brijesh Gulabrao; Sharma, Omi; Aglawe, Manish Manohar; Kale, Mayur Bhimrao; Gawande, Dinesh Yugraj; Umekar, Milind Janraoji; Kotagale, Nandkishor Ramdas

    2017-09-01

    Agmatine and GABA have been abundantly expressed in brain nuclei involved in regulation of energy homeostasis and promoting stimulation of food intake in rodents. However, their mutual interaction, if any, in the elicitation of feeding behavior is largely remains unclear. The current study provides experimental evidence for the possible interaction of agmatine, adrenergic and GABAergic systems in stimulation of feeding in satiated rats. Satiated rats fitted with intracerebroventricular (i.c.v.) cannulae and were administered agmatine, alone or jointly with (a) GABA A receptor agonist, muscimol, diazepam or antagonist bicuculline and flumazenil, GABA A positive modulator, allopregnanolone or negative modulator of GABA A receptor, dehydroepiandrosterone (b) In view of the high affinity of agmatine for α 2 -adrenoceptors and the close association between α 2 -adrenoceptors and GABAergic system, the effect of their modulators on feeding elicited by agmatine/GABAergic agonists were also examined. I.c.v. administration of agmatine (40-80μg/rat) induces the significant orexigenic effect in satiated rats. The orexigenic effect of agmatine was potentiated by muscimol (25ng/rat, i.c.v.); diazepam (0.5mg/kg, i.p.); allopregnanolone (0.5mg/kg, s.c.) and blocked by bicuculline (1mg/kg, i.p.) and dehydroepiandrosterone (4mg/kg,s.c.). However, it remained unaffected in presence of flumazenil (25ng/rat, i.c.v.). The orexigenic effect of agmatine and GABAergic agonists was potentiated by a α 2 -adrenoceptors agonist, clonidine (10ng/rat, i.c.v.) and blocked by its antagonist, yohimbine (5μg/rat, i.c.v.). Yohimbine also blocked the hyperphagic effect elicited by ineffective dose combination of agmatine (5μg/rat, i.c.v.) with muscimol (25ng/rat, i.c.v.) or diazepam (0.5mg/kg, i.p.) or allopregnanolone (0.5mg/kg,s.c.). The results of the present study suggest that agmatine induced α 2 -adrenoceptors activation might facilitate GABAergic activity to stimulate food intake in

  20. Optogenetic activation of leptin- and glucose-regulated GABAergic neurons in dorsomedial hypothalamus promotes food intake via inhibitory synaptic transmission to paraventricular nucleus of hypothalamus

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    Zesemdorj Otgon-Uul

    2016-08-01

    Full Text Available Objective: The dorsomedial hypothalamus (DMH has been considered an orexigenic nucleus, since the DMH lesion reduced food intake and body weight and induced resistance to diet-induced obesity. The DMH expresses feeding regulatory neuropeptides and receptors including neuropeptide Y (NPY, cocaine- and amphetamine-regulated transcript (CART, cholecystokinin (CCK, leptin receptor, and melanocortin 3/4 receptors. However, the principal neurons generating the orexigenic function in the DMH remain to be defined. This study aimed to clarify the role of the DMH GABAergic neurons in feeding regulation by using optogenetics and electrophysiological techniques. Methods: We generated the mice expressing ChRFR-C167A, a bistable chimeric channelrhodopsin, selectively in GABAergic neurons of DMH via locally injected adeno-associated virus 2. Food intake after optogenetic activation of DMH GABAergic neurons was measured. Electrophysiological properties of DMH GABAergic neurons were measured using slice patch clamp. Results: Optogenetic activation of DMH GABAergic neurons promoted food intake. Leptin hyperpolarized and lowering glucose depolarized half of DMH GABAergic neurons, suggesting their orexigenic property. Optical activation of axonal terminals of DMH GABAergic neurons at the paraventricular nucleus of hypothalamus (PVN, where anorexigenic neurons are localized, increased inhibitory postsynaptic currents on PVN neurons and promoted food intake. Conclusion: DMH GABAergic neurons are regulated by metabolic signals leptin and glucose and, once activated, promote food intake via inhibitory synaptic transmission to PVN. Keywords: Dorsomedial hypothalamus, GABAergic neuron, Feeding, Leptin, Glucose, Optogenetics

  1. Connecting Grammaticalisation

    DEFF Research Database (Denmark)

    Nørgård-Sørensen, Jens; Heltoft, Lars; Schøsler, Lene

    morphological, topological and constructional paradigms often connect to form complex paradigms. The book introduces the concept of connecting grammaticalisation to describe the formation, restructuring and dismantling of such complex paradigms. Drawing primarily on data from Germanic, Romance and Slavic...

  2. GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility.

    Science.gov (United States)

    Judson, Matthew C; Wallace, Michael L; Sidorov, Michael S; Burette, Alain C; Gu, Bin; van Woerden, Geeske M; King, Ian F; Han, Ji Eun; Zylka, Mark J; Elgersma, Ype; Weinberg, Richard J; Philpot, Benjamin D

    2016-04-06

    Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)-all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Distinct populations of GABAergic neurons in mouse rhombomere 1 express but do not require the homeodomain transcription factor PITX2.

    Science.gov (United States)

    Waite, Mindy R; Skaggs, Kaia; Kaviany, Parisa; Skidmore, Jennifer M; Causeret, Frédéric; Martin, James F; Martin, Donna M

    2012-01-01

    Hindbrain rhombomere 1 (r1) is located caudal to the isthmus, a critical organizer region, and rostral to rhombomere 2 in the developing mouse brain. Dorsal r1 gives rise to the cerebellum, locus coeruleus, and several brainstem nuclei, whereas cells from ventral r1 contribute to the trochlear and trigeminal nuclei as well as serotonergic and GABAergic neurons of the dorsal raphe. Recent studies have identified several molecular events controlling dorsal r1 development. In contrast, very little is known about ventral r1 gene expression and the genetic mechanisms regulating its formation. Neurons with distinct neurotransmitter phenotypes have been identified in ventral r1 including GABAergic, serotonergic, and cholinergic neurons. Here we show that PITX2 marks a distinct population of GABAergic neurons in mouse embryonic ventral r1. This population appears to retain its GABAergic identity even in the absence of PITX2. We provide a comprehensive map of markers that places these PITX2-positive GABAergic neurons in a region of r1 that intersects and is potentially in communication with the dorsal raphe. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Modulation of GABAergic Transmission in Development and Neurodevelopmental Disorders: Investigating Physiology and Pathology to Gain Therapeutic Perspectives

    Directory of Open Access Journals (Sweden)

    Gabriele eDeidda

    2014-05-01

    Full Text Available During mammalian ontogenesis, the neurotransmitter GABA is a fundamental regulator of neuronal networks. In neuronal development, GABAergic signaling regulates neural proliferation, migration, differentiation, and neuronal-network wiring. In the adult, GABA orchestrates the activity of different neuronal cell-types largely interconnected, by powerfully modulating synaptic activity. GABA exerts these functions by binding to chloride-permeable ionotropic GABAA receptors and metabotropic GABAB receptors. According to its functional importance during development, GABA is implicated in a number of neurodevelopmental disorders such as autism, Fragile X, Rett syndrome, Down syndrome, schizophrenia, Tourette's syndrome and neurofibromatosis.The strength and polarity of GABAergic transmission is continuously modulated during physiological, but also pathological conditions. For GABAergic transmission through GABAA receptors, strength regulation is achieved by different mechanisms such as modulation of GABAA receptors themselves, variation of intracellular chloride concentration, and alteration in GABA metabolism. In the never-ending effort to find possible treatments for GABA-related neurological diseases, of great importance would be modulating GABAergic transmission in a safe and possibly physiological way, without the dangers of either silencing network activity or causing epileptic seizures. In this review, we will discuss the different ways to modulate GABAergic transmission normally at work both during physiological and pathological conditions. Our aim is to highlight new research perspectives for therapeutic treatments that reinstate natural and physiological brain functions in neuro-pathological conditions.

  5. Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

    Science.gov (United States)

    Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

    2016-01-01

    Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets. PMID:27035941

  6. Glutamatergic and GABAergic TCA cycle and neurotransmitter cycling fluxes in different regions of mouse brain.

    Science.gov (United States)

    Tiwari, Vivek; Ambadipudi, Susmitha; Patel, Anant B

    2013-10-01

    The (13)C nuclear magnetic resonance (NMR) studies together with the infusion of (13)C-labeled substrates in rats and humans have provided important insight into brain energy metabolism. In the present study, we have extended a three-compartment metabolic model in mouse to investigate glutamatergic and GABAergic tricarboxylic acid (TCA) cycle and neurotransmitter cycle fluxes across different regions of the brain. The (13)C turnover of amino acids from [1,6-(13)C2]glucose was monitored ex vivo using (1)H-[(13)C]-NMR spectroscopy. The astroglial glutamate pool size, one of the important parameters of the model, was estimated by a short infusion of [2-(13)C]acetate. The ratio Vcyc/VTCA was calculated from the steady-state acetate experiment. The (13)C turnover curves of [4-(13)C]/[3-(13)C]glutamate, [4-(13)C]glutamine, [2-(13)C]/[3-(13)C]GABA, and [3-(13)C]aspartate from [1,6-(13)C2]glucose were analyzed using a three-compartment metabolic model to estimate the rates of the TCA cycle and neurotransmitter cycle associated with glutamatergic and GABAergic neurons. The glutamatergic TCA cycle rate was found to be highest in the cerebral cortex (0.91 ± 0.05 μmol/g per minute) and least in the hippocampal region (0.64 ± 0.07 μmol/g per minute) of the mouse brain. In contrast, the GABAergic TCA cycle flux was found to be highest in the thalamus-hypothalamus (0.28 ± 0.01 μmol/g per minute) and least in the cerebral cortex (0.24 ± 0.02 μmol/g per minute). These findings indicate that the energetics of excitatory and inhibitory function is distinct across the mouse brain.

  7. Neuroanatomic Relationships between the GABAergic and Serotonergic Systems in the Developing Human Medulla

    Science.gov (United States)

    Broadbelt, Kevin G.; Paterson, David S.; Rivera, Keith D.; Trachtenberg, Felicia L.; Kinney, Hannah C.

    2010-01-01

    γ-Amino butyric (GABA) critically influences serotonergic (5-HT) neurons in the raphé and extra-raphé of the medulla oblongata. In this study we hypothesize there are marked changes in the developmental profile of markers of the human medullary GABAergic system relative to the 5-HT system in early life. We used single- and double-label immunocytochemistry and tissue receptor autoradiography in 15 human medullae from fetal and infant cases ranging from 15 gestational weeks to 10 postnatal months, and compared our findings with an extensive 5-HT-related database in our laboratory. In the raphé obscurus, we identified two subsets of GABAergic neurons using glutamic acid decarboxylase (GAD65/67) immunostaining: one comprised of small, round neurons; the other, medium, spindle-shaped neurons. In three term medullae cases, positive immunoflorescent neurons for both tryptophan hydroxylase and GAD65/67 were counted within the raphé obscurus. This revealed approximately 6% of the total neurons counted in this nucleus expressed both GAD65/67 and TPOH suggesting co-production of GABA by a subset of 5-HT neurons. The distribution of GABAA binding was ubiquitous across medullary nuclei, with highest binding in the raphé obscurus. GABAA receptor subtypes α1 and α3 were expressed by 5-HT neurons, indicating the site of interaction of GABA with 5-HT neurons. These receptor subtypes and KCC2, a major chloride transporter, were differentially expressed across early development, from mid-gestation (20wks) and thereafter. The developmental profile of GABAergic markers changed dramatically relative to the 5-HT markers. These data provide baseline information for medullary studies of human pediatric disorders, such as sudden infant death syndrome. PMID:19926534

  8. The genesis of cerebellar GABAergic neurons: fate potential and specification mechanisms

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    Ketty eLeto

    2012-02-01

    Full Text Available The variety of neuronal phenotypes that populate the cerebellum derives from progenitors that proliferate in two germinal neuroepithelia: the ventricular zone generates GABAergic neurons, whereas the rhombic lip is the origin of glutamatergic types. Progenitors of the ventricular zone produce GABAergic projection neurons (Purkinje cells and nucleo-olivary neurons at the onset of cerebellar neurogenesis. Later on, however, these progenitors migrate into the prospective white matter, where they continue to divide up to postnatal development and generate different categories of inhibitory interneurons, according to precise spatio-temporal schedules. Projection neurons derive from discrete progenitor pools located in distinct microdomains of the ventricular zone, whereas interneurons originate from a single population of precursors, distinguished by the expression of the transcription factor Pax-2. Heterotopic/heterochronic transplantation experiments indicate that interneuron progenitors maintain full developmental potentialities up to the end of cerebellar development and acquire mature phenotypes under the influence of environmental cues present in the prospective white matter. Furthermore, the final fate choice occurs in postmitotic cells, rather than dividing progenitors. Extracerebellar cells grafted to the postnatal cerebellum are not responsive to local neurogenic cues and fail to adopt clear cerebellar identities. On the other hand, cerebellar cells grafted to extracerebellar regions retain typical phenotypes of cerebellar GABAergic interneurons, but acquire specific traits under the influence of local cues. These findings indicate that interneuron progenitors are multipotent and sensitive to spatio-temporally patterned environmental signals that regulate the genesis of different categories of interneurons, in precise quantities and at defined times and places.

  9. Activity strengths of cortical glutamatergic and GABAergic neurons are correlated with transgenerational inheritance of learning ability.

    Science.gov (United States)

    Liu, Yulong; Ge, Rongjing; Zhao, Xin; Guo, Rui; Huang, Li; Zhao, Shidi; Guan, Sudong; Lu, Wei; Cui, Shan; Wang, Shirlene; Wang, Jin-Hui

    2017-12-22

    The capabilities of learning and memory in parents are presumably transmitted to their offsprings, in which genetic codes and epigenetic regulations are thought as molecular bases. As neural plasticity occurs during memory formation as cellular mechanism, we aim to examine the correlation of activity strengths at cortical glutamatergic and GABAergic neurons to the transgenerational inheritance of learning ability. In a mouse model of associative learning, paired whisker and odor stimulations led to odorant-induced whisker motion, whose onset appeared fast (high learning efficiency, HLE) or slow (low learning efficiency, LLE). HLE male and female mice, HLE female and LLE male mice as well as HLE male and LLE female mice were cross-mated to have their first generation of offsprings, filials (F1). The onset of odorant-induced whisker motion appeared a sequence of high-to-low efficiency in three groups of F1 mice that were from HLE male and female mice, HLE female and LLE male mice as well as HLE male and LLE female mice. Activities related to glutamatergic neurons in barrel cortices appeared a sequence of high-to-low strength in these F1 mice from HLE male and female mice, HLE female and LLE male mice as well as HLE male and LLE female mice. Activities related to GABAergic neurons in barrel cortices appeared a sequence of low-to-high strength in these F1 mice from HLE male and female mice, HLE female and LLE male mice as well as HLE male and LLE female mice. Neuronal activity strength was linearly correlated to learning efficiency among three groups. Thus, the coordinated activities at glutamatergic and GABAergic neurons may constitute the cellular basis for the transgenerational inheritance of learning ability.

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

    Science.gov (United States)

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

    2018-04-15

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

  11. GABAergic modulation of visual gamma and alpha oscillations and its consequences for working memory performance.

    Science.gov (United States)

    Lozano-Soldevilla, Diego; ter Huurne, Niels; Cools, Roshan; Jensen, Ole

    2014-12-15

    Impressive in vitro research in rodents and computational modeling has uncovered the core mechanisms responsible for generating neuronal oscillations. In particular, GABAergic interneurons play a crucial role for synchronizing neural populations. Do these mechanistic principles apply to human oscillations associated with function? To address this, we recorded ongoing brain activity using magnetoencephalography (MEG) in healthy human subjects participating in a double-blind pharmacological study receiving placebo, 0.5 mg and 1.5 mg of lorazepam (LZP; a benzodiazepine upregulating GABAergic conductance). Participants performed a demanding visuospatial working memory (WM) task. We found that occipital gamma power associated with WM recognition increased with LZP dosage. Importantly, the frequency of the gamma activity decreased with dosage, as predicted by models derived from the rat hippocampus. A regionally specific gamma increase correlated with the drug-related performance decrease. Despite the system-wide pharmacological intervention, gamma power drug modulations were specific to visual cortex: sensorimotor gamma power and frequency during button presses remained unaffected. In contrast, occipital alpha power modulations during the delay interval decreased parametrically with drug dosage, predicting performance impairment. Consistent with alpha oscillations reflecting functional inhibition, LZP affected alpha power strongly in early visual regions not required for the task demonstrating a regional specific occipital impairment. GABAergic interneurons are strongly implicated in the generation of gamma and alpha oscillations in human occipital cortex where drug-induced power modulations predicted WM performance. Our findings bring us an important step closer to linking neuronal dynamics to behavior by embracing established animal models. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Genetic Deletion of the Clathrin Adaptor GGA3 Reduces Anxiety and Alters GABAergic Transmission.

    Directory of Open Access Journals (Sweden)

    Kendall R Walker

    Full Text Available Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3 is a monomeric clathrin adaptor that has been shown to regulate the trafficking of the Beta-site APP-cleaving enzyme (BACE1, which is required for production of the Alzheimer's disease (AD-associated amyloid βpeptide. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that depletion of GGA3 results in increased BACE1 levels and activity owing to impaired lysosomal trafficking and degradation. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We report here that GGA3 deletion results in novelty-induced hyperactivity and decreased anxiety-like behaviors. Given the pivotal role of GABAergic transmission in the regulation of anxiety-like behaviors, we performed electrophysiological recordings in hippocampal slices and found increased phasic and decreased tonic inhibition in the dentate gyrus granule cells (DGGC. Moreover, we found that the number of inhibitory synapses is increased in the dentate gyrus of GGA3 null mice in further support of the electrophysiological data. Thus, the increased GABAergic transmission is a leading candidate mechanism underlying the reduced anxiety-like behaviors observed in GGA3 null mice. All together these findings suggest that GGA3 plays a key role in GABAergic transmission. Since BACE1 levels are elevated in the brain of GGA3 null mice, it is possible that at least some of these phenotypes are a consequence of increased processing of BACE1 substrates.

  13. Genetic Deletion of the Clathrin Adaptor GGA3 Reduces Anxiety and Alters GABAergic Transmission.

    Science.gov (United States)

    Walker, Kendall R; Modgil, Amit; Albrecht, David; Lomoio, Selene; Haydon, Philip G; Moss, Stephen J; Tesco, Giuseppina

    2016-01-01

    Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) is a monomeric clathrin adaptor that has been shown to regulate the trafficking of the Beta-site APP-cleaving enzyme (BACE1), which is required for production of the Alzheimer's disease (AD)-associated amyloid βpeptide. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that depletion of GGA3 results in increased BACE1 levels and activity owing to impaired lysosomal trafficking and degradation. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We report here that GGA3 deletion results in novelty-induced hyperactivity and decreased anxiety-like behaviors. Given the pivotal role of GABAergic transmission in the regulation of anxiety-like behaviors, we performed electrophysiological recordings in hippocampal slices and found increased phasic and decreased tonic inhibition in the dentate gyrus granule cells (DGGC). Moreover, we found that the number of inhibitory synapses is increased in the dentate gyrus of GGA3 null mice in further support of the electrophysiological data. Thus, the increased GABAergic transmission is a leading candidate mechanism underlying the reduced anxiety-like behaviors observed in GGA3 null mice. All together these findings suggest that GGA3 plays a key role in GABAergic transmission. Since BACE1 levels are elevated in the brain of GGA3 null mice, it is possible that at least some of these phenotypes are a consequence of increased processing of BACE1 substrates.

  14. GABAergic systems in the vestibular nucleus and their contribution to vestibular compensation.

    Science.gov (United States)

    Gliddon, Catherine M; Darlington, Cynthia L; Smith, Paul F

    2005-01-01

    GABA and the GABAA and GABAB receptors play a pivotal role in the coordination of the central vestibular pathways. The commissural inhibition, which exists between the two vestibular nucleus complexes (VNCs) and which is responsible for enhancing the dynamic sensitivity of VNC neurons to head acceleration, is known to be substantially mediated by GABA acting on GABAA and GABAB receptors. After unilateral vestibular deafferentation (UVD), the large asymmetry in spontaneous resting activity between the two VNCs is reinforced and exacerbated by the GABAergic interaction between the ipsilateral and contralateral sides. Although it has been suggested that reduced GABAergic inhibition of the ipsilateral VNC may be partially responsible for the recovery of resting activity that underlies vestibular compensation of the static symptoms of UVD, at present there are few data available to test this hypothesis systematically. There is some evidence that GABA concentrations change in the ipsilateral VNC during the development of compensation; however, it is unclear whether these changes relate to GABA release or to metabolic pools of GABA. Most biochemical studies of GABA receptors have been conducted at the gene expression level. Therefore, it is unclear whether changes in the receptor protein also occur, although the most recent data suggest that changes in GABAA and GABAB receptor density in the VNC are unlikely. The few radioligand binding data relate to GABAA receptors with benzodiazepine binding sites only. A decrease in the sensitivity of ipsilateral VNC neurons from compensated animals to GABA receptor agonists has been reported; however, these studies have employed brainstem slices and therefore the functional identity of the neurons involved has been unclear. Although it seems likely that some changes in central GABAergic systems accompany the recovery of resting activity in the ipsilateral VNC during the development of vestibular compensation, at the present stage

  15. Abnormal GABAergic function and face processing in schizophrenia: A pharmacologic-fMRI study.

    Science.gov (United States)

    Tso, Ivy F; Fang, Yu; Phan, K Luan; Welsh, Robert C; Taylor, Stephan F

    2015-10-01

    The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli ("Do you like this face?"). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1-3weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii

    Science.gov (United States)

    Boychuk, Carie R.; Gyarmati, Peter; Xu, Hong

    2015-01-01

    Changes in blood glucose concentration alter autonomic function in a manner consistent with altered neural activity in brain regions controlling digestive processes, including neurons in the brain stem nucleus tractus solitarii (NTS), which process viscerosensory information. With whole cell or on-cell patch-clamp recordings, responses to elevating glucose concentration from 2.5 to 15 mM were assessed in identified GABAergic NTS neurons in slices from transgenic mice that express EGFP in a subset of GABA neurons. Single-cell real-time RT-PCR was also performed to detect glutamic acid decarboxylase (GAD67) in recorded neurons. In most identified GABA neurons (73%), elevating glucose concentration from 2.5 to 15 mM resulted in either increased (40%) or decreased (33%) neuronal excitability, reflected by altered membrane potential and/or action potential firing. Effects on membrane potential were maintained when action potentials or fast synaptic inputs were blocked, suggesting direct glucose sensing by GABA neurons. Glucose-inhibited GABA neurons were found predominantly in the lateral NTS, whereas glucose-excited cells were mainly in the medial NTS, suggesting regional segregation of responses. Responses were prevented in the presence of glucosamine, a glucokinase (GCK) inhibitor. Depolarizing responses were prevented when KATP channel activity was blocked with tolbutamide. Whereas effects on synaptic input to identified GABAergic neurons were variable in GABA neurons, elevating glucose increased glutamate release subsequent to stimulation of tractus solitarius in unlabeled, unidentified neurons. These results indicate that GABAergic NTS neurons act as GCK-dependent glucose sensors in the vagal complex, providing a means of modulating central autonomic signals when glucose is elevated. PMID:26084907

  17. Presynaptic CRF1 Receptors Mediate the Ethanol Enhancement of GABAergic Transmission in the Mouse Central Amygdala

    Directory of Open Access Journals (Sweden)

    Zhiguo Nie

    2009-01-01

    Full Text Available Corticotropin-releasing factor (CRF is a 41-amino-acid neuropeptide involved in stress responses initiated from several brain areas, including the amygdala formation. Research shows a strong relationship between stress, brain CRF, and excessive alcohol consumption. Behavioral studies suggest that the central amygdala (CeA is significantly involved in alcohol reward and dependence. We recently reported that the ethanol augmentation of GABAergic synaptic transmission in rat CeA involves CRF1 receptors, because both CRF and ethanol significantly enhanced the amplitude of evoked GABAergic inhibitory postsynaptic currents (IPSCs in CeA neurons from wild-type (WT and CRF2 knockout (KO mice, but not in neurons of CRF1 KO mice. The present study extends these findings using selective CRF receptor ligands, gene KO models, and miniature IPSC (mIPSC analysis to assess further a presynaptic role for the CRF receptors in mediating ethanol effects in the CeA. In whole-cell patch recordings of pharmacologically isolated GABAAergic IPSCs from slices of mouse CeA, both CRF and ethanol augmented evoked IPSCs in a concentration-dependent manner, with low EC50s. A CRF1 (but not CRF2 KO construct and the CRF1-selective nonpeptide antagonist NIH-3 (LWH-63 blocked the augmenting effect of both CRF and ethanol on evoked IPSCs. Furthermore, the new selective CRF1 agonist stressin1, but not the CRF2 agonist urocortin 3, also increased evoked IPSC amplitudes. Both CRF and ethanol decreased paired-pulse facilitation (PPF of evoked IPSCs and significantly enhanced the frequency, but not the amplitude, of spontaneous miniature GABAergic mIPSCs in CeA neurons of WT mice, suggesting a presynaptic site of action. The PPF effect of ethanol was abolished in CeA neurons of CRF1 KO mice. The CRF1 antagonist NIH-3 blocked the CRF- and ethanol-induced enhancement of mIPSC frequency in CeA neurons. These data indicate that presynaptic CRF1 receptors play a critical role in permitting

  18. Short-term mastication after weaning upregulates GABAergic signalling and reduces dendritic spine in thalamus.

    Science.gov (United States)

    Ogawa, Mana; Nagai, Toshitada; Saito, Yoshikazu; Miyaguchi, Hitonari; Kumakura, Kei; Abe, Keiko; Asakura, Tomiko

    2018-04-06

    Mastication enhances brain function and mental health, but little is known about the molecular mechanisms underlying the effects of mastication on neural development in early childhood. Therefore, we analysed the gene expression in juvenile neural circuits in rats fed with a soft or chow diet immediately after weaning. We observed that the gene expression patterns in the thalamus varied depending on the diet. Furthermore, gene ontology analysis revealed that two terms were significantly enhanced: chemical synaptic transmission and positive regulation of dendritic spine morphogenesis. With respect to chemical synaptic transmission, glutamate decarboxylase and GABA receptors were upregulated in the chow diet group. The related genes, including vesicular GABA transporter, were also upregulated, suggesting that mastication activates GABAergic signalling. With respect to dendritic spine morphogenesis, Ingenuity Pathway Analysis predicted fewer extension of neurites and neurons and fewer number of branches in the chow diet group. The numbers of spines in the ventral posterolateral and posteromedial regions were significantly decreased. These results suggest that mastication in the early developing period upregulates GABAergic signalling genes, with a decrease of spines in the thalamus. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging.

    Science.gov (United States)

    Albayram, Onder; Alferink, Judith; Pitsch, Julika; Piyanova, Anastasia; Neitzert, Kim; Poppensieker, Karola; Mauer, Daniela; Michel, Kerstin; Legler, Anne; Becker, Albert; Monory, Krisztina; Lutz, Beat; Zimmer, Andreas; Bilkei-Gorzo, Andras

    2011-07-05

    Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1(-/-)), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1(-/-) mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1(-/-) mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.

  20. Critical Roles of the Direct GABAergic Pallido-cortical Pathway in Controlling Absence Seizures

    Science.gov (United States)

    Li, Min; Ma, Tao; Wu, Shengdun; Ma, Jingling; Cui, Yan; Xia, Yang; Xu, Peng; Yao, Dezhong

    2015-01-01

    The basal ganglia (BG), serving as an intermediate bridge between the cerebral cortex and thalamus, are believed to play crucial roles in controlling absence seizure activities generated by the pathological corticothalamic system. Inspired by recent experiments, here we systematically investigate the contribution of a novel identified GABAergic pallido-cortical pathway, projecting from the globus pallidus externa (GPe) in the BG to the cerebral cortex, to the control of absence seizures. By computational modelling, we find that both increasing the activation of GPe neurons and enhancing the coupling strength of the inhibitory pallido-cortical pathway can suppress the bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) during absence seizures. Appropriate tuning of several GPe-related pathways may also trigger the SWD suppression, through modulating the activation level of GPe neurons. Furthermore, we show that the previously discovered bidirectional control of absence seizures due to the competition between other two BG output pathways also exists in our established model. Importantly, such bidirectional control is shaped by the coupling strength of this direct GABAergic pallido-cortical pathway. Our work suggests that the novel identified pallido-cortical pathway has a functional role in controlling absence seizures and the presented results might provide testable hypotheses for future experimental studies. PMID:26496656

  1. Enhancement of GABAergic transmission by zolpidem, an imidazopyridine with preferential affinity for type I benzodiazepine receptors.

    Science.gov (United States)

    Biggio, G; Concas, A; Corda, M G; Serra, M

    1989-02-28

    The effect of zolpidem, an imidazopyridine derivative with high affinity at the type I benzodiazepine recognition site, on the function of the GABAA/ionophore receptor complex was studied in vitro. Zolpidem, mimicking the action of diazepam, increased [3H]GABA binding, enhanced muscimol-stimulated 36Cl- uptake and reduced [35S]TBPS binding in rat cortical membrane preparations. Zolpidem was less effective than diazepam on the above parameters. Zolpidem induced a lower increase of [3H]GABA binding (23 vs. 35%) and muscimol-stimulated 36Cl- uptake (22 vs. 40%) and a smaller decrease of [35S]TBPS binding (47 vs. 77%) than diazepam. The finding that zolpidem enhanced the function of GABAergic synapses with an efficacy qualitatively and quantitatively different from that of diazepam suggests that this compound is a partial agonist at the benzodiazepine recognition site. Thus, our results are consistent with the view that the biochemical and pharmacological profile of a benzodiazepine recognition site ligand reflects its efficacy to enhance GABAergic transmission. Whether the preferential affinity of zolpidem at the type I site is involved in its atypical biochemical and pharmacological profile remains to be clarified.

  2. Learning-Dependent Plasticity of the Barrel Cortex Is Impaired by Restricting GABA-Ergic Transmission.

    Science.gov (United States)

    Posluszny, Anna; Liguz-Lecznar, Monika; Turzynska, Danuta; Zakrzewska, Renata; Bielecki, Maksymilian; Kossut, Malgorzata

    2015-01-01

    Experience-induced plastic changes in the cerebral cortex are accompanied by alterations in excitatory and inhibitory transmission. Increased excitatory drive, necessary for plasticity, precedes the occurrence of plastic change, while decreased inhibitory signaling often facilitates plasticity. However, an increase of inhibitory interactions was noted in some instances of experience-dependent changes. We previously reported an increase in the number of inhibitory markers in the barrel cortex of mice after fear conditioning engaging vibrissae, observed concurrently with enlargement of the cortical representational area of the row of vibrissae receiving conditioned stimulus (CS). We also observed that an increase of GABA level accompanied the conditioning. Here, to find whether unaltered GABAergic signaling is necessary for learning-dependent rewiring in the murine barrel cortex, we locally decreased GABA production in the barrel cortex or reduced transmission through GABAA receptors (GABAARs) at the time of the conditioning. Injections of 3-mercaptopropionic acid (3-MPA), an inhibitor of glutamic acid decarboxylase (GAD), into the barrel cortex prevented learning-induced enlargement of the conditioned vibrissae representation. A similar effect was observed after injection of gabazine, an antagonist of GABAARs. At the behavioral level, consistent conditioned response (cessation of head movements in response to CS) was impaired. These results show that appropriate functioning of the GABAergic system is required for both manifestation of functional cortical representation plasticity and for the development of a conditioned response.

  3. Traumatic Brain Injury Increases Cortical Glutamate Network Activity by Compromising GABAergic Control.

    Science.gov (United States)

    Cantu, David; Walker, Kendall; Andresen, Lauren; Taylor-Weiner, Amaro; Hampton, David; Tesco, Giuseppina; Dulla, Chris G

    2015-08-01

    Traumatic brain injury (TBI) is a major risk factor for developing pharmaco-resistant epilepsy. Although disruptions in brain circuitry are associated with TBI, the precise mechanisms by which brain injury leads to epileptiform network activity is unknown. Using controlled cortical impact (CCI) as a model of TBI, we examined how cortical excitability and glutamatergic signaling was altered following injury. We optically mapped cortical glutamate signaling using FRET-based glutamate biosensors, while simultaneously recording cortical field potentials in acute brain slices 2-4 weeks following CCI. Cortical electrical stimulation evoked polyphasic, epileptiform field potentials and disrupted the input-output relationship in deep layers of CCI-injured cortex. High-speed glutamate biosensor imaging showed that glutamate signaling was significantly increased in the injured cortex. Elevated glutamate responses correlated with epileptiform activity, were highest directly adjacent to the injury, and spread via deep cortical layers. Immunoreactivity for markers of GABAergic interneurons were significantly decreased throughout CCI cortex. Lastly, spontaneous inhibitory postsynaptic current frequency decreased and spontaneous excitatory postsynaptic current increased after CCI injury. Our results suggest that specific cortical neuronal microcircuits may initiate and facilitate the spread of epileptiform activity following TBI. Increased glutamatergic signaling due to loss of GABAergic control may provide a mechanism by which TBI can give rise to post-traumatic epilepsy. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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

    Science.gov (United States)

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

    2018-04-18

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

  5. Corticospinal tract insult alters GABAergic circuitry in the mammalian spinal cord

    Directory of Open Access Journals (Sweden)

    Jeffrey B. Russ

    2013-09-01

    Full Text Available During perinatal development, corticospinal tract (CST projections into the spinal cord help refine spinal circuitry. Although the normal developmental processes that are controlled by the arrival of corticospinal input are becoming clear, little is known about how perinatal cortical damage impacts specific aspects of spinal circuit development, particularly the inhibitory microcircuitry that regulates spinal reflex circuits. In this study, we sought to determine how ischemic cortical damage impacts the synaptic attributes of a well-characterized population of inhibitory, GABAergic interneurons, called GABApre neurons, which modulates the efficiency of proprioceptive sensory terminals in the sensorimotor reflex circuit. We found that putative GABApre interneurons receive CST input and, using an established mouse model of perinatal stroke, that cortical ischemic injury results in a reduction of CST density within the intermediate region of the spinal cord, where these interneurons reside. Importantly, CST alterations were restricted to the side contralateral to the injury. Within the synaptic terminals of the GABApre interneurons, we observed a dramatic upregulation of the 65-isoform of the GABA synthetic enzyme glutamic acid decarboxylase (GAD65. In accordance with the CST density reduction, GAD65 was elevated on the side of the spinal cord contralateral to cortical injury. This effect was not seen for other GABApre synaptic markers or in animals that received sham surgery. Our data reveal a novel effect of perinatal stroke that involves severe deficits in the architecture of descending spinal pathways, which in turn appear to promote molecular alterations in a specific spinal GABAergic circuit.

  6. Making Connections

    Science.gov (United States)

    Pien, Cheng Lu; Dongsheng, Zhao

    2011-01-01

    Effective teaching includes enabling learners to make connections within mathematics. It is easy to accord with this statement, but how often is it a reality in the mathematics classroom? This article describes an approach in "connecting equivalent" fractions and whole number operations. The authors illustrate how a teacher can combine a common…

  7. About Connections

    Directory of Open Access Journals (Sweden)

    Kathleen S Rockland

    2015-05-01

    Full Text Available Despite the attention attracted by connectomics, one can lose sight of the very real questions concerning What are connections? In the neuroimaging community, structural connectivity is ground truth and underlying constraint on functional or effective connectivity. It is referenced to underlying anatomy; but, as increasingly remarked, there is a large gap between the wealth of human brain mapping and the relatively scant data on actual anatomical connectivity. Moreover, connections have typically been discussed as pairwise, point x projecting to point y (or: to points y and z, or more recently, in graph theoretical terms, as nodes or regions and the interconnecting edges. This is a convenient shorthand, but tends not to capture the richness and nuance of basic anatomical properties as identified in the classic tradition of tracer studies. The present short review accordingly revisits connectional weights, heterogeneity, reciprocity, topography, and hierarchical organization, drawing on concrete examples. The emphasis is on presynaptic long-distance connections, motivated by the intention to probe current assumptions and promote discussions about further progress and synthesis.

  8. GDNF family ligands display distinct action profiles on cultured GABAergic and serotonergic neurons of rat ventral mesencephalon

    DEFF Research Database (Denmark)

    Ducray, Angélique; Krebs, Sandra H:; Schaller, Benoft

    2006-01-01

    Glial-cell-line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN), known as the GDNF family ligands (GFLs), influence the development, survival and differentiation of cultured dopaminergic neurons from ventral mesencephalon (VM). Detailed knowledge about...... factors for VM GABAergic and serotonergic neurons, demonstrating characteristic individual action profiles emphasizing their important and distinct roles during brain development....

  9. Midbrain and forebrain patterning delivers immunocytochemically and functionally similar populations of neuropeptide Y containing GABAergic neurons.

    Science.gov (United States)

    Khaira, S K; Nefzger, C M; Beh, S J; Pouton, C W; Haynes, J M

    2011-09-01

    Neurons differentiated in vitro from embryonic stem cells (ESCs) have the potential to serve both as models of disease states and in drug discovery programs. In this study, we use sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF-8) to enrich for forebrain and midbrain phenotypes from mouse ESCs. We then investigate, using Ca(2+) imaging and [(3)H]-GABA release studies, whether the GABAergic neurons produced exhibit distinct functional phenotypes. At day 24 of differentiation, reverse transcriptase-PCR showed the presence of both forebrain (Bf-1, Hesx1, Pgc-1α, Six3) and midbrain (GATA2, GATA3) selective mRNA markers in developing forebrain-enriched cultures. All markers were present in midbrain cultures except for Bf-1 and Pgc-1α. Irrespective of culture conditions all GABA immunoreactive neurons were also immunoreactive to neuropeptide Y (NPY) antibodies. Forebrain and midbrain GABAergic neurons responded to ATP (1 mM), L-glutamate (30 μM), noradrenaline (30 μM), acetylcholine (30 μM) and dopamine (30 μM), with similar elevations of intracellular Ca(2+)([Ca(2+)](i)). The presence of GABA(A) and GABA(B) antagonists, bicuculline (30 μM) and CGP55845 (1 μM), increased the elevation of [Ca(2+)](i) in response to dopamine (30 μM) in midbrain, but not forebrain GABAergic neurons. All agonists, except dopamine, elicited similar [(3)H]-GABA release from forebrain and midbrain cultures. Dopamine (30 μM) did not stimulate significant [(3)H]-GABA release in midbrain cultures, although it was effective in forebrain cultures. This study shows that differentiating neurons toward a midbrain fate restricts the expression of forebrain markers. Forebrain differentiation results in the expression of forebrain and midbrain markers. All GABA(+) neurons contain NPY, and show similar agonist-induced elevations of [Ca(2+)](i) and [(3)H]-GABA release. This study indicates that the pharmacological phenotype of these particular neurons may be independent of the addition of

  10. Internet Connectivity

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Internet Connectivity. BSNL, SIFY, HCL in Guwahati; only BSNL elsewhere in NE (local player in Shillong). Service poor; All vendors lease BW from BSNL.

  11. Mathematics Connection

    African Journals Online (AJOL)

    MATHEMATICS CONNECTION aims at providing a forum topromote the development of Mathematics Education in Ghana. Articles that seekto enhance the teaching and/or learning of mathematics at all levels of theeducational system are welcome.

  12. HR Connect

    Data.gov (United States)

    US Agency for International Development — HR Connect is the USAID HR personnel system which allows HR professionals to process HR actions related to employee's personal and position information. This system...

  13. The Frequency-Dependent Aerobic Exercise Effects of Hypothalamic GABAergic Expression and Cardiovascular Functions in Aged Rats

    Directory of Open Access Journals (Sweden)

    Yan Li

    2017-06-01

    Full Text Available A decline in cardiovascular modulation is a feature of the normal aging process and associated with cardiovascular diseases (CVDs such as hypertension and stroke. Exercise training is known to promote cardiovascular adaptation in young animals and positive effects on motor and cognitive capabilities, as well as on brain plasticity for all ages in mice. Here, we examine the question of whether aerobic exercise interventions may impact the GABAergic neurons of the paraventricular nucleus (PVN in aged rats which have been observed to have a decline in cardiovascular integration function. In the present study, young (2 months and old (24 months male Wistar rats were divided into young control (YC, old sedentary, old low frequency exercise (20 m/min, 60 min/day, 3 days/week, 12 weeks and old high frequency exercise (20 m/min, 60 min/day, 5 days/week, 12 weeks. Exercise training indexes were obtained, including resting heart rate (HR, blood pressure (BP, plasma norepinephrine (NE, and heart weight (HW-to-body weight (BW ratios. The brain was removed and processed according to the immunofluorescence staining and western blot used to analyze the GABAergic terminal density, the proteins of GAD67, GABAA receptor and gephyrin in the PVN. There were significant changes in aged rats compared with those in the YC. Twelve weeks aerobic exercise training has volume-dependent ameliorated effects on cardiovascular parameters, autonomic nervous activities and GABAergic system functions. These data suggest that the density of GABAergic declines in the PVN is associated with imbalance in autonomic nervous activities in normal aging. Additionally, aerobic exercise can rescue aging-related an overactivity of the sympathetic nervous system and induces modifications the resting BP and HR to lower values via improving the GABAergic system in the PVN.

  14. The Frequency-Dependent Aerobic Exercise Effects of Hypothalamic GABAergic Expression and Cardiovascular Functions in Aged Rats

    Science.gov (United States)

    Li, Yan; Zhao, Ziqi; Cai, Jiajia; Gu, Boya; Lv, Yuanyuan; Zhao, Li

    2017-01-01

    A decline in cardiovascular modulation is a feature of the normal aging process and associated with cardiovascular diseases (CVDs) such as hypertension and stroke. Exercise training is known to promote cardiovascular adaptation in young animals and positive effects on motor and cognitive capabilities, as well as on brain plasticity for all ages in mice. Here, we examine the question of whether aerobic exercise interventions may impact the GABAergic neurons of the paraventricular nucleus (PVN) in aged rats which have been observed to have a decline in cardiovascular integration function. In the present study, young (2 months) and old (24 months) male Wistar rats were divided into young control (YC), old sedentary, old low frequency exercise (20 m/min, 60 min/day, 3 days/week, 12 weeks) and old high frequency exercise (20 m/min, 60 min/day, 5 days/week, 12 weeks). Exercise training indexes were obtained, including resting heart rate (HR), blood pressure (BP), plasma norepinephrine (NE), and heart weight (HW)-to-body weight (BW) ratios. The brain was removed and processed according to the immunofluorescence staining and western blot used to analyze the GABAergic terminal density, the proteins of GAD67, GABAA receptor and gephyrin in the PVN. There were significant changes in aged rats compared with those in the YC. Twelve weeks aerobic exercise training has volume-dependent ameliorated effects on cardiovascular parameters, autonomic nervous activities and GABAergic system functions. These data suggest that the density of GABAergic declines in the PVN is associated with imbalance in autonomic nervous activities in normal aging. Additionally, aerobic exercise can rescue aging-related an overactivity of the sympathetic nervous system and induces modifications the resting BP and HR to lower values via improving the GABAergic system in the PVN. PMID:28713263

  15. Low-frequency electrical stimulation enhances the effectiveness of phenobarbital on GABAergic currents in hippocampal slices of kindled rats.

    Science.gov (United States)

    Asgari, Azam; Semnanian, Saeed; Atapour, Nafiseh; Shojaei, Amir; Moradi-Chameh, Homeira; Ghafouri, Samireh; Sheibani, Vahid; Mirnajafi-Zadeh, Javad

    2016-08-25

    Low frequency stimulation (LFS) has been proposed as a new approach in the treatment of epilepsy. The anticonvulsant mechanism of LFS may be through its effect on GABAA receptors, which are the main target of phenobarbital anticonvulsant action. We supposed that co-application of LFS and phenobarbital may increase the efficacy of phenobarbital. Therefore, the interaction of LFS and phenobarbital on GABAergic inhibitory post-synaptic currents (IPSCs) in kindled and control rats was investigated. Animals were kindled by electrical stimulation of basolateral amygdala in a semi rapid manner (12 stimulations/day). The effect of phenobarbital, LFS and phenobarbital+LFS was investigated on GABAA-mediated evoked and miniature IPSCs in the hippocampal brain slices in control and fully kindled animals. Phenobarbital and LFS had positive interaction on GABAergic currents. In vitro co-application of an ineffective pattern of LFS (100 pulses at afterdischarge threshold intensity) and a sub-threshold dose of phenobarbital (100μM) which had no significant effect on GABAergic currents alone, increased the amplitude and area under curve of GABAergic currents in CA1 pyramidal neurons of hippocampal slices significantly. Interestingly, the sub-threshold dose of phenobarbital potentiated the GABAergic currents when applied on the hippocampal slices of kindled animals which received LFS in vivo. Post-synaptic mechanisms may be involved in observed interactions. Obtained results implied a positive interaction between LFS and phenobarbital through GABAA currents. It may be suggested that a combined therapy of phenobarbital and LFS may be a useful manner for reinforcing the anticonvulsant action of phenobarbital. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. Effects of Repeated Stress on Age-Dependent GABAergic Regulation of the Lateral Nucleus of the Amygdala.

    Science.gov (United States)

    Zhang, Wei; Rosenkranz, J Amiel

    2016-08-01

    The adolescent age is associated with lability of mood and emotion. The onset of depression and anxiety disorders peaks during adolescence and there are differences in symptomology during adolescence. This points to differences in the adolescent neural circuitry that underlies mood and emotion, such as the amygdala. The human adolescent amygdala is more responsive to evocative stimuli, hinting to less local inhibitory regulation of the amygdala, but this has not been explored in adolescents. The amygdala, including the lateral nucleus (LAT) of the basolateral amygdala complex, is sensitive to stress. The amygdala undergoes maturational processes during adolescence, and therefore may be more vulnerable to harmful effects of stress during this time period. However, little is known about the effects of stress on the LAT during adolescence. GABAergic inhibition is a key regulator of LAT activity. Therefore, the purpose of this study was to test whether there are differences in the local GABAergic regulation of the rat adolescent LAT, and differences in its sensitivity to repeated stress. We found that LAT projection neurons are subjected to weaker GABAergic inhibition during adolescence. Repeated stress reduced in vivo endogenous and exogenous GABAergic inhibition of LAT projection neurons in adolescent rats. Furthermore, repeated stress decreased measures of presynaptic GABA function and interneuron activity in adolescent rats. In contrast, repeated stress enhanced glutamatergic drive of LAT projection neurons in adult rats. These results demonstrate age differences in GABAergic regulation of the LAT, and age differences in the mechanism for the effects of repeated stress on LAT neuron activity. These findings provide a substrate for increased mood lability in adolescents, and provide a substrate by which adolescent repeated stress can induce distinct behavioral outcomes and psychiatric symptoms.

  17. Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder

    DEFF Research Database (Denmark)

    Naaijen, Jill; Bralten, Janita; Poelmans, Geert

    2017-01-01

    Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance...... within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms...... is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants...

  18. 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.

  19. [Local GABA-ergic modulation of serotonergic neuron activity in the nucleus raphe magnus].

    Science.gov (United States)

    Iniushkin, A N; Merkulova, N A; Orlova, A O; Iniushkina, E M

    2009-07-01

    In voltage-clamp experimental on slices of the rat brainstem the effects of 5-HT and GABA on serotonergic neurons of nucleus raphe magnus were investigated. Local applications of 5-HT induced an increase in IPCSs frequency and amplitude in 45% of serotonergic cells. The effect suppressed by the blocker of fast sodium channels tetradotoxin. Antagonist of GABA receptor gabazine blocked IPSCs in neurons both sensitive and non-sensitive to 5-HT action. Applications of GABA induced a membrane current (I(GABA)), which was completely blocked by gabazine. The data suggest self-control of the activity of serotonergic neurons in nucleus raphe magnus by negative feedback loop via local GABAergic interneurons.

  20. Pharmacological evidence for GABAergic and glutamatergic involvement in the convulsant and behavioral effects of glutaric acid.

    Science.gov (United States)

    Lima, T T; Begnini, J; de Bastiani, J; Fialho, D B; Jurach, A; Ribeiro, M C; Wajner, M; de Mello, C F

    1998-08-17

    The effect of intrastriatal administration of glutaric acid (GTR), a metabolite that accumulates in glutaric acidemia type I (GA-I), on the behavior of adult male rats was investigated. After cannula placing, rats received unilateral intrastriatal injections of GTR buffered to pH 7.4 with NaOH or NaCl. GTR induced rotational behavior toward the contralateral side of injection and clonic convulsions in a dose-dependent manner. Rotational behavior was prevented by intrastriatal preadministration of DNQX and muscimol, but not by the preadministration of MK-801. Convulsions were prevented by intrastriatal preinjection of muscimol. This study provides evidence for a participation of glutamatergic non-NMDA and GABAergic mechanisms in the GTR-induced behavioral alterations. These findings may be of value in understanding the physiopathology of the neurological dysfunction in glutaric acidemia.

  1. Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain.

    Science.gov (United States)

    Tiwari, Vivek; Veeraiah, Pandichelvam; Subramaniam, Vaidyanathan; Patel, Anant Bahadur

    2014-03-01

    This study investigates the effects of ethanol on neuronal and astroglial metabolism using (1)H-[(13)C]-NMR spectroscopy in conjunction with infusion of [1,6-(13)C2]/[1-(13)C]glucose or [2-(13)C]acetate, respectively. A three-compartment metabolic model was fitted to the (13)C turnover of GluC3 , GluC4, GABAC 2, GABAC 3, AspC3 , and GlnC4 from [1,6-(13)C2 ]glucose to determine the rates of tricarboxylic acid (TCA) and neurotransmitter cycle associated with glutamatergic and GABAergic neurons. The ratio of neurotransmitter cycle to TCA cycle fluxes for glutamatergic and GABAegic neurons was obtained from the steady-state [2-(13)C]acetate experiment and used as constraints during the metabolic model fitting. (1)H MRS measurement suggests that depletion of ethanol from cerebral cortex follows zero order kinetics with rate 0.18 ± 0.04 μmol/g/min. Acute exposure of ethanol reduces the level of glutamate and aspartate in cortical region. GlnC4 labeling was found to be unchanged from a 15 min infusion of [2-(13)C]acetate suggesting that acute ethanol exposure does not affect astroglial metabolism in naive mice. Rates of TCA and neurotransmitter cycle associated with glutamatergic and GABAergic neurons were found to be significantly reduced in cortical and subcortical regions. Acute exposure of ethanol perturbs the level of neurometabolites and decreases the excitatory and inhibitory activity differentially across the regions of brain. Depletion of ethanol and its effect on brain functions were measured using (1)H and (1)H-[(13)C]-NMR spectroscopy in conjunction with infusion of (13)C-labeled substrates. Ethanol depletion from brain follows zero order kinetics. Ethanol perturbs level of glutamate, and the excitatory and inhibitory activity in mice brain. © 2013 International Society for Neurochemistry.

  2. Lamina-specific contribution of glutamatergic and GABAergic potentials to hippocampal sharp wave-ripple complexes.

    Science.gov (United States)

    Schönberger, Jan; Draguhn, Andreas; Both, Martin

    2014-01-01

    The mammalian hippocampus expresses highly organized patterns of neuronal activity which form a neuronal correlate of spatial memories. These memory-encoding neuronal ensembles form on top of different network oscillations which entrain neurons in a state- and experience-dependent manner. The mechanisms underlying activation, timing and selection of participating neurons are incompletely understood. Here we studied the synaptic mechanisms underlying one prominent network pattern called sharp wave-ripple complexes (SPW-R) which are involved in memory consolidation during sleep. We recorded SPW-R with extracellular electrodes along the different layers of area CA1 in mouse hippocampal slices. Contribution of glutamatergic excitation and GABAergic inhibition, respectively, was probed by local application of receptor antagonists into s. radiatum, pyramidale and oriens. Laminar profiles of field potentials show that GABAergic potentials contribute substantially to sharp waves and superimposed ripple oscillations in s. pyramidale. Inhibitory inputs to s. pyramidale and s. oriens are crucial for action potential timing by ripple oscillations, as revealed by multiunit-recordings in the pyramidal cell layer. Glutamatergic afferents, on the other hand, contribute to sharp waves in s. radiatum where they also evoke a fast oscillation at ~200 Hz. Surprisingly, field ripples in s. radiatum are slightly slower than ripples in s. pyramidale, resulting in a systematic shift between dendritic and somatic oscillations. This complex interplay between dendritic excitation and perisomatic inhibition may be responsible for the precise timing of discharge probability during the time course of SPW-R. Together, our data illustrate a complementary role of spatially confined excitatory and inhibitory transmission during highly ordered network patterns in the hippocampus.

  3. Establishing Connectivity

    DEFF Research Database (Denmark)

    Kjær, Poul F.

    Global law settings are characterised by a structural pre-eminence of connectivity norms, a type of norm which differs from coherency or possibility norms. The centrality of connectivity norms emerges from the function of global law, which is to increase the probability of transfers of condensed ...... and human rights can be understood as serving a constitutionalising function aimed at stabilising and facilitating connectivity. This allows for an understanding of colonialism and contemporary global governance as functional, but not as normative, equivalents.......Global law settings are characterised by a structural pre-eminence of connectivity norms, a type of norm which differs from coherency or possibility norms. The centrality of connectivity norms emerges from the function of global law, which is to increase the probability of transfers of condensed...... social components, such as economic capital and products, religious doctrines and scientific knowledge, from one legally structured context to another within world society. This was the case from colonialism and colonial law to contemporary global supply chains and human rights. Both colonial law...

  4. Connected Traveler

    Energy Technology Data Exchange (ETDEWEB)

    2016-06-01

    The Connected Traveler framework seeks to boost the energy efficiency of personal travel and the overall transportation system by maximizing the accuracy of predicted traveler behavior in response to real-time feedback and incentives. It is anticipated that this approach will establish a feedback loop that 'learns' traveler preferences and customizes incentives to meet or exceed energy efficiency targets by empowering individual travelers with information needed to make energy-efficient choices and reducing the complexity required to validate transportation system energy savings. This handout provides an overview of NREL's Connected Traveler project, including graphics, milestones, and contact information.

  5. [Effect of stimulation of GABA-ergic structures of the substantia nigra and caudate nucleus on food-getting behavior in the cat].

    Science.gov (United States)

    Shugalev, N P

    1983-01-01

    A study was made of the functional significance of GABA-ergic structures of the substantia nigra (SN) and the caudate nucleus (CN) and their role in food-procuring behaviour of cats. Analysis was made of behavioral and EEG-effects of local GABA and the GABA antagonist, picrotoxin, microinjections into the studied brain structures. Stimulation of the GABA-ergic structures of the SN produced a sedative effect and depression of the cat food-procuring behaviour. Effects of stimulation of the CN GABA-ergic structures were to a great degree reverse. The conclusion has been made that GABA-ergic structures of the SN and the CN play different roles in controlling the CN inhibitory influence upon food-procuring behaviour.

  6. Making connections

    NARCIS (Netherlands)

    Marion Duimel

    2007-01-01

    Original title: Verbinding maken; senioren en internet. More and more older people are finding their way to the Internet. Many people aged over 50 who have only recently gone online say that a new world has opened up for them. By connecting to the Internet they have the feeling that they

  7. CMS Connect

    Science.gov (United States)

    Balcas, J.; Bockelman, B.; Gardner, R., Jr.; Hurtado Anampa, K.; Jayatilaka, B.; Aftab Khan, F.; Lannon, K.; Larson, K.; Letts, J.; Marra Da Silva, J.; Mascheroni, M.; Mason, D.; Perez-Calero Yzquierdo, A.; Tiradani, A.

    2017-10-01

    The CMS experiment collects and analyzes large amounts of data coming from high energy particle collisions produced by the Large Hadron Collider (LHC) at CERN. This involves a huge amount of real and simulated data processing that needs to be handled in batch-oriented platforms. The CMS Global Pool of computing resources provide +100K dedicated CPU cores and another 50K to 100K CPU cores from opportunistic resources for these kind of tasks and even though production and event processing analysis workflows are already managed by existing tools, there is still a lack of support to submit final stage condor-like analysis jobs familiar to Tier-3 or local Computing Facilities users into these distributed resources in an integrated (with other CMS services) and friendly way. CMS Connect is a set of computing tools and services designed to augment existing services in the CMS Physics community focusing on these kind of condor analysis jobs. It is based on the CI-Connect platform developed by the Open Science Grid and uses the CMS GlideInWMS infrastructure to transparently plug CMS global grid resources into a virtual pool accessed via a single submission machine. This paper describes the specific developments and deployment of CMS Connect beyond the CI-Connect platform in order to integrate the service with CMS specific needs, including specific Site submission, accounting of jobs and automated reporting to standard CMS monitoring resources in an effortless way to their users.

  8. Accumulation of GABAergic neurons, causing a focal ambient GABA gradient, and downregulation of KCC2 are induced during microgyrus formation in a mouse model of polymicrogyria.

    Science.gov (United States)

    Wang, Tianying; Kumada, Tatsuro; Morishima, Toshitaka; Iwata, Satomi; Kaneko, Takeshi; Yanagawa, Yuchio; Yoshida, Sachiko; Fukuda, Atsuo

    2014-04-01

    Although focal cortical malformations are considered neuronal migration disorders, their formation mechanisms remain unknown. We addressed how the γ-aminobutyric acid (GABA)ergic system affects the GABAergic and glutamatergic neuronal migration underlying such malformations. A focal freeze-lesion (FFL) of the postnatal day zero (P0) glutamic acid decarboxylase-green fluorescent protein knock-in mouse neocortex produced a 3- or 4-layered microgyrus at P7. GABAergic interneurons accumulated around the necrosis including the superficial region during microgyrus formation at P4, whereas E17.5-born, Cux1-positive pyramidal neurons outlined the GABAergic neurons and were absent from the superficial layer, forming cell-dense areas in layer 2 of the P7 microgyrus. GABA imaging showed that an extracellular GABA level temporally increased in the GABAergic neuron-positive area, including the necrotic center, at P4. The expression of the Cl(-) transporter KCC2 was downregulated in the microgyrus-forming GABAergic and E17.5-born glutamatergic neurons at P4; these cells may need a high intracellular Cl(-) concentration to induce depolarizing GABA effects. Bicuculline decreased the frequency of spontaneous Ca(2+) oscillations in these microgyrus-forming cells. Thus, neonatal FFL causes specific neuronal accumulation, preceded by an increase in ambient GABA during microgyrus formation. This GABA increase induces GABAA receptor-mediated Ca(2+) oscillation in KCC2-downregulated microgyrus-forming cells, as seen in migrating cells during early neocortical development.

  9. Gendered Connections

    DEFF Research Database (Denmark)

    Jensen, Steffen Bo

    2009-01-01

    This article explores the gendered nature of urban politics in Cape Town by focusing on a group of female, township politicians. Employing the Deleuzian concept of `wild connectivity', it argues that these politically entrepreneurial women were able to negotiate a highly volatile urban landscape...... by drawing on and operationalizing violent, male networks — from struggle activists' networks, to vigilante groups and gangs, to the police. The fact that they were women helped them to tap into and exploit these networks. At the same time, they were restricted by their sex, as their ability to navigate...... space also drew on quite traditional notions of female respectability. Furthermore, the article argues, the form of wild connectivity to an extent was a function of the political transition, which destabilized formal structures of gendered authority. It remains a question whether this form...

  10. Inhibition of GABAergic Neurotransmission by HIV-1 Tat and Opioid Treatment in the Striatum Involves μ-opioid Receptors

    Directory of Open Access Journals (Sweden)

    Changqing Xu

    2016-11-01

    Full Text Available Due to combined antiretroviral therapy (cART, human immunodeficiency virus type 1 (HIV-1 is considered a chronic disease with high prevalence of mild forms of neurocognitive impairments, also referred to as HIV-associated neurocognitive disorders (HAND. Although opiate drug use can exacerbate HIV-1 Tat-induced neuronal damage, it remains unknown how and to what extent opioids interact with Tat on the GABAergic system. We conducted whole-cell recordings in mouse striatal slices and examined the effects of HIV-1 Tat in the presence and absence of morphine (1 μM and damgo (1 μM on GABAergic neurotransmission. Results indicated a decrease in the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs and miniature IPSCs (mIPSCs by Tat (5 – 50 nM in a concentration-dependent manner. The significant Tat-induced decrease in IPSCs was abolished when removing extracellular and/or intracellular calcium. Treatment with morphine or damgo alone significantly decreased the frequency, but not amplitude of IPSCs. Interestingly, morphine but not damgo indicated an additional downregulation of the mean frequency of mIPSCs in combination with Tat. Pretreatment with naloxone (1 μM and CTAP (1 μM prevented the Tat-induced decrease in sIPSCs frequency but only naloxone prevented the combined Tat and morphine effect on mIPSCs frequency. Results indicate a Tat- or opioid-induced decrease in GABAergic neurotransmission via µ-opioid receptors with combined Tat and morphine effects involving additional opioid receptor-related mechanisms. Exploring the interactions between Tat and opioids on the GABAergic system may help to guide future research on HAND in the context of opiate drug use.

  11. Inhibition of GABAergic Neurotransmission by HIV-1 Tat and Opioid Treatment in the Striatum Involves ?-Opioid Receptors

    OpenAIRE

    Xu, Changqing; Fitting, Sylvia

    2016-01-01

    Due to combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease with high prevalence of mild forms of neurocognitive impairments, also referred to as HIV-associated neurocognitive disorders (HAND). Although opiate drug use can exacerbate HIV-1 Tat-induced neuronal damage, it remains unknown how and to what extent opioids interact with Tat on the GABAergic system. We conducted whole-cell recordings in mouse striatal slices and examined...

  12. GABAergic Control of Nigrostriatal and Mesolimbic Dopamine in the Rat Brain

    Directory of Open Access Journals (Sweden)

    Susanne Nikolaus

    2018-03-01

    Full Text Available Purpose: The present study assessed the effects of the GABAA receptor (R agonist muscimol (MUS, and the GABAAR antagonist bicuculline (BIC on neocortical and subcortical radioligand binding to dopamine D2/3Rs in relation to motor and exploratory behaviors in the rat.Methods: D2/3R binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [123I]IBZM as radioligand. Motor/exploratory behaviors were assessed for 30 min in an open field prior to radioligand administration. Anatomical information was gained with a dedicated small animal MRI tomograph. Based on the Paxinos rat brain atlas, regions of interest were defined on SPECT-MRI overlays. Estimations of the binding potentials in baseline and after challenges were obtained by computing ratios of the specifically bound compartments to the cerebellar reference region.Results: After MUS, D2/3R binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ≤ p ≤ 0.012. In all these areas, except for the thalamus, D2/3R binding was negatively correlated with grooming in the first half and positively correlated with various motor/exploratory behaviors in the second half of the testing session. After BIC, D2/3R binding was significantly elevated in caudateputamen (p = 0.022 and thalamus (p = 0.047 relative to baseline. D2/3R binding in caudateputamen and thalamus was correlated negatively with sitting duration and sitting frequency and positively with motor/exploratory behaviors in the first half of the testing time.Conclusions: Findings indicate direct GABAergic control over nigrostriatal and mesolimbic dopamine levels in relation to behavioral action. This may be of relevance for neuropsychiatric conditions such as anxiety disorder and schizophrenia, which are characterized by both dopaminergic and GABAergic dysfunction.

  13. The interaction of central nitrergic and GABAergic systems on food intake in neonatal layer-type chicks.

    Science.gov (United States)

    Mokhtarpouriani, Kasra; Zendehdel, Morteza; Jonaidi, Hossein; Babapour, Vahab; Shayan, Parviz

    2016-05-01

    Most physiological behaviors such as food intake are controlled by the hypothalamus and its nuclei. It has been demonstrated that injection of the paraventricular nucleus of the hypothalamus with nitric oxide (NO) donors elicited changes in the concentration of some amino acids, including GABA. Also, central nitrergic and GABAergic systems are known to provide inputs to the paraventricular nucleus and are involved in food intake control. Therefore, the present study examines the probable interaction of central nitrergic and GABAergic systems on food intake in neonatal layer-type chicks. The results of this study showed that intracerebroventricular (ICV) injection of L-arginine (400 and 800 nmol), as a NO donor, significantly decreased food intake (P 0.05). Also, the hypophagic effect of L-arginine (800 nmol) was significantly amplified in ICV co-injection of picrotoxin (0.5 µg), a GABAA antagonist, or CGP54626 (21 ng), a GABAB antagonist, with L-arginine (800 nmol) (P < 0.001). These results probably suggest an interaction of central nitrergic and GABAergic systems on food intake in neonatal layer-type chicks and GABAA receptors play a major role in this interaction.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Modulation of Network Oscillatory Activity and GABAergic Synaptic Transmission by CB1 Cannabinoid Receptors in the Rat Medial Entorhinal Cortex

    Directory of Open Access Journals (Sweden)

    Nicola H. Morgan

    2008-01-01

    Full Text Available Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide (ACPA; 10 M, an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500 nM, increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.

  16. Chronic restraint stress impairs endocannabinoid mediated suppression of GABAergic signaling in the hippocampus of adult male rats.

    Science.gov (United States)

    Hu, Wen; Zhang, Mingyue; Czéh, Boldizsár; Zhang, Weiqi; Flügge, Gabriele

    2011-07-15

    Chronic stress, a risk factor for the development of psychiatric disorders, is known to induce alterations in neuronal networks in many brain areas. Previous studies have shown that chronic stress changes the expression of the cannabinoid receptor 1 (CB1) in the brains of adult rats, but neurophysiological consequences of these changes remained unclear. Here we demonstrate that chronic restraint stress causes a dysfunction in CB1 mediated modulation of GABAergic transmission in the hippocampus. Using an established protocol, adult male Sprague Dawley rats were daily restrained for 21 days and whole-cell voltage clamp was performed at CA1 pyramidal neurons. When recording carbachol-evoked inhibitory postsynaptic currents (IPSCs) which presumably originate from CB1 expressing cholecystokinin (CCK) interneurons, we found that depolarization-induced suppression of inhibition (DSI) was impaired by the stress. DSI is a form of short-term plasticity at GABAergic synapses that is known to be CB1 mediated and has been suggested to be involved in hippocampal information encoding. Chronic stress attenuated the depolarization-induced suppression of the frequency of carbachol-evoked IPSCs. Incubation with a CB1 receptor antagonist prevented this DSI effect in control but not in chronically stressed animals. The stress-induced impairment of CB1-mediated short-term plasticity at GABAergic synapses may underlie cognitive deficits which are commonly observed in animal models of stress as well as in patients with stress-related psychiatric disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Behavior-Dependent Activity and Synaptic Organization of Septo-hippocampal GABAergic Neurons Selectively Targeting the Hippocampal CA3 Area.

    Science.gov (United States)

    Joshi, Abhilasha; Salib, Minas; Viney, Tim James; Dupret, David; Somogyi, Peter

    2017-12-20

    Rhythmic medial septal (MS) GABAergic input coordinates cortical theta oscillations. However, the rules of innervation of cortical cells and regions by diverse septal neurons are unknown. We report a specialized population of septal GABAergic neurons, the Teevra cells, selectively innervating the hippocampal CA3 area bypassing CA1, CA2, and the dentate gyrus. Parvalbumin-immunopositive Teevra cells show the highest rhythmicity among MS neurons and fire with short burst duration (median, 38 ms) preferentially at the trough of both CA1 theta and slow irregular oscillations, coincident with highest hippocampal excitability. Teevra cells synaptically target GABAergic axo-axonic and some CCK interneurons in restricted septo-temporal CA3 segments. The rhythmicity of their firing decreases from septal to temporal termination of individual axons. We hypothesize that Teevra neurons coordinate oscillatory activity across the septo-temporal axis, phasing the firing of specific CA3 interneurons, thereby contributing to the selection of pyramidal cell assemblies at the theta trough via disinhibition. VIDEO ABSTRACT. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture

    International Nuclear Information System (INIS)

    Vutskits, Laszlo; Gascon, Eduardo; Potter, Gael; Tassonyi, Edomer; Kiss, Jozsef Z.

    2007-01-01

    Administration of subanesthetic concentrations of ketamine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors, is a widely accepted therapeutic modality in perioperative and chronic pain management. Although extensive clinical use has demonstrated its safety, recent human histopathological observations as well as laboratory data suggest that ketamine can exert adverse effects on central nervous system neurons. To further investigate this issue, the present study was designed to evaluate the effects of ketamine on the survival and dendritic arbor architecture of differentiated γ-aminobutyric acidergic (GABAergic) interneurons in vitro. We show that short-term exposure of cultures to ketamine at concentrations of ≥20 μg/ml leads to a significant cell loss of differentiated cells and that non-cell death-inducing concentrations of ketamine (10 μg/ml) can still initiate long-term alterations of dendritic arbor in differentiated neurons, including dendritic retraction and branching point elimination. Most importantly, we also demonstrate that chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal morphology and thus might lead to dysfunctions of neural networks

  19. GABAergic circuits control input-spike coupling in the piriform cortex.

    Science.gov (United States)

    Luna, Victor M; Schoppa, Nathan E

    2008-08-27

    Odor coding in mammals is widely believed to involve synchronized gamma frequency (30-70 Hz) oscillations in the first processing structure, the olfactory bulb. How such inputs are read in downstream cortical structures however is not known. Here we used patch-clamp recordings in rat piriform cortex slices to examine cellular mechanisms that shape how the cortex integrates inputs from bulb mitral cells. Electrical stimulation of mitral cell axons in the lateral olfactory tract (LOT) resulted in excitation of pyramidal cells (PCs), which was followed approximately 10 ms later by inhibition that was highly reproducible between trials in its onset time. This inhibition was somatic in origin and appeared to be driven through a feedforward mechanism, wherein GABAergic interneurons were directly excited by mitral cell axons. The precise inhibition affected action potential firing in PCs in two distinct ways. First, by abruptly terminating PC excitation, it limited the PC response to each EPSP to exactly one, precisely timed action potential. In addition, inhibition limited the summation of EPSPs across time, such that PCs fired action potentials in strong preference for synchronized inputs arriving in a time window of inputs arriving as a synchronized gamma frequency pattern.

  20. Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks.

    Science.gov (United States)

    Perea, Gertrudis; Gómez, Ricardo; Mederos, Sara; Covelo, Ana; Ballesteros, Jesús J; Schlosser, Laura; Hernández-Vivanco, Alicia; Martín-Fernández, Mario; Quintana, Ruth; Rayan, Abdelrahman; Díez, Adolfo; Fuenzalida, Marco; Agarwal, Amit; Bergles, Dwight E; Bettler, Bernhard; Manahan-Vaughan, Denise; Martín, Eduardo D; Kirchhoff, Frank; Araque, Alfonso

    2016-12-24

    Interneurons are critical for proper neural network function and can activate Ca 2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABA A receptors, potentiation involved astrocyte GABA B receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABA B receptor ( Gabbr1 ) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.

  1. The central GABAergic system and control of food intake under different experimental conditions.

    Science.gov (United States)

    Olgiati, V R; Netti, C; Guidobono, F; Pecile, A

    1980-01-01

    Intracerebroventricular injections of gamma-aminobutyric acid (GABA) and of the GABA-transaminase inhibitor, ethanolamine-O-sulphate (EOS), decreased the food intake of freely-fed (GABA and EOS) and food-deprived rats (EOS). The effect, still evident 24 h after treatment, was not decreased by the GABA receptor-blocker bicuculline. In contrast, intracerebroventricular injections of the GABA receptor-agonist, muscimol, caused an increase in food intake of freely-fed rats that was antagonized by bicuculline. The eating of animals receiving only bicuculline was stimulated in free-feeding and depressed in food-deprived conditions. These opposite results suggest that muscimol binds preferentially to some GABA receptors, probably those within the satiety-controlling areas (i.e. ventromedial hypothalamus), and that bicuculline influences mainly those postsynaptic neurons where GABAergic inputs prevail. These observations and the data from EOS- and GABA-treated rats provide evidence for involvement of GABA neurons in the regulation of feeding behaviour. The balance of the different effects produced in each of these areas by this modulation appears to be a decrease in feeding behaviour.

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

    Directory of Open Access Journals (Sweden)

    Alfred Xuyang Sun

    2016-08-01

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

  3. GABAergic modulation of DC stimulation-induced motor cortex excitability shifts in humans.

    Science.gov (United States)

    Nitsche, Michael A; Liebetanz, David; Schlitterlau, Anett; Henschke, Undine; Fricke, Kristina; Frommann, Kai; Lang, Nicolas; Henning, Stefan; Paulus, Walter; Tergau, Frithjof

    2004-05-01

    Weak transcranial DC stimulation (tDCS) of the human motor cortex results in excitability shifts during and after the end of stimulation, which are most probably localized intracortically. Anodal stimulation enhances excitability, whereas cathodal stimulation reduces it. Although the after-effects of tDCS are NMDA receptor-dependent, nothing is known about the involvement of additional receptors. Here we show that pharmacological strengthening of GABAergic inhibition modulates selectively the after-effects elicited by anodal tDCS. Administration of the GABA(A) receptor agonist lorazepam resulted in a delayed, but then enhanced and prolonged anodal tDCS-induced excitability elevation. The initial absence of an excitability enhancement under lorazepam is most probably caused by a loss of the anodal tDCS-generated intracortical diminution of inhibition and enhancement of facilitation, which occurs without pharmacological intervention. The reasons for the late-occurring excitability enhancement remain unclear. Because intracortical inhibition and facilitation are not changed in this phase compared with pre-tDCS values, excitability changes originating from remote cortical or subcortical areas could be involved.

  4. Novel codrugs with GABAergic activity for dopamine delivery in the brain.

    Science.gov (United States)

    Denora, Nunzio; Cassano, Tommaso; Laquintana, Valentino; Lopalco, Antonio; Trapani, Adriana; Cimmino, Concetta Stefania; Laconca, Leonardo; Giuffrida, Andrea; Trapani, Giuseppe

    2012-11-01

    This study investigates the use of codrugs of the GABAergic agent 2-phenyl-imidazo[1,2-a]pyridinacetamide and dopamine (DA) or ethyl ester L-Dopa (LD) as a strategy to deliver DA and simultaneously activate GABA-receptors in the brain. For this purpose, both DA and LD ethyl ester were linked by carbamate bond to imidazo[1,2-a]pyridine acetamide moieties to yield two DA- and two LD-imidazopyridine derivatives. These compounds were evaluated in vitro to assess their stability, binding affinities and cell membrane transport, and in vivo to assess their bio-availability via microdialysis studies. The two DA derivatives were adequately stable in buffered solution, but underwent cleavage in diluted human serum. By contrast, the LD derivatives were unstable in buffered solution. Receptor binding studies showed that the DA-imidazopyridine carbamates had binding affinity for benzodiazepine receptors in the nanomolar range. Brain microdialysis experiments indicated that intraperitoneal administration of the DA derivatives sustained DA levels in rat striatum over a 4-h period. These results suggest that DA-imidazopyridine carbamates are new DA codrugs with potential application for DA replacement therapy. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Maturation of GABAergic inhibition promotes strengthening of temporally coherent inputs among convergent pathways.

    Directory of Open Access Journals (Sweden)

    Sandra J Kuhlman

    2010-06-01

    Full Text Available Spike-timing-dependent plasticity (STDP, a form of Hebbian plasticity, is inherently stabilizing. Whether and how GABAergic inhibition influences STDP is not well understood. Using a model neuron driven by converging inputs modifiable by STDP, we determined that a sufficient level of inhibition was critical to ensure that temporal coherence (correlation among presynaptic spike times of synaptic inputs, rather than initial strength or number of inputs within a pathway, controlled postsynaptic spike timing. Inhibition exerted this effect by preferentially reducing synaptic efficacy, the ability of inputs to evoke postsynaptic action potentials, of the less coherent inputs. In visual cortical slices, inhibition potently reduced synaptic efficacy at ages during but not before the critical period of ocular dominance (OD plasticity. Whole-cell recordings revealed that the amplitude of unitary IPSCs from parvalbumin positive (Pv+ interneurons to pyramidal neurons increased during the critical period, while the synaptic decay time-constant decreased. In addition, intrinsic properties of Pv+ interneurons matured, resulting in an increase in instantaneous firing rate. Our results suggest that maturation of inhibition in visual cortex ensures that the temporally coherent inputs (e.g. those from the open eye during monocular deprivation control postsynaptic spike times of binocular neurons, a prerequisite for Hebbian mechanisms to induce OD plasticity.

  6. 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.

  7. Dynamics of action potential initiation in the GABAergic thalamic reticular nucleus in vivo.

    Science.gov (United States)

    Muñoz, Fabián; Fuentealba, Pablo

    2012-01-01

    Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold.

  8. Acute morphine alters GABAergic transmission in the central amygdala during naloxone-precipitated morphine withdrawal: role of cyclic AMP

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    Michal eBajo

    2014-06-01

    Full Text Available The central amygdala (CeA plays an important role in opioid addiction. Therefore, we examined the effects of naloxone-precipitated morphine withdrawal (WD on GABAergic transmission in rat CeA neurons using whole-cell recordings with naloxone in the bath. The basal frequency of miniature inhibitory postsynaptic currents (mIPSCs increased in CeA neurons from WD compared to placebo rats. Acute morphine (10 M had mixed effects (> 20% change from baseline on mIPSCs in placebo and WD rats. In most CeA neurons (64% from placebo rats, morphine significantly decreased mIPSC frequency and amplitude. In 32% of placebo neurons, morphine significantly increased mIPSC amplitudes but had no effect on mIPSC frequency. In WD rats, acute morphine significantly increased mIPSC frequency but had no effect on mIPSC amplitude in 41% of CeA neurons. In 45% of cells, acute morphine significantly decreased mIPSC frequency and amplitude. Pre-treatment with the cyclic AMP inhibitor (R-adenosine, cyclic 3’,5’-(hydrogenphosphorothioate triethylammonium (RP, prevented acute morphine-induced potentiation of mIPSCs. Pre-treatment of slices with the Gi/o G-protein subunit inhibitor pertussis toxin (PTX did not prevent the acute morphine-induced enhancement or inhibition of mIPSCs. PTX and RP decreased basal mIPSC frequencies and amplitudes only in WD rats. The results suggest that inhibition of GABAergic transmission in the CeA by acute morphine is mediated by PTX-insensitive mechanisms, although PTX-sensitive mechanisms cannot be ruled out for non-morphine responsive cells; by contrast, potentiation of GABAergic transmission is mediated by activated cAMP signaling that also mediates the increased basal GABAergic transmission in WD rats. Our data indicate that during the acute phase of WD, the CeA opioid and GABAergic systems undergo neuroadaptative changes conditioned by a previous chronic morphine exposure and dependence.

  9. Cosmic Connections

    CERN Document Server

    Ellis, Jonathan Richard

    2003-01-01

    A National Research Council study on connecting quarks with the cosmos has recently posed a number of the more important open questions at the interface between particle physics and cosmology. These questions include the nature of dark matter and dark energy, how the Universe began, modifications to gravity, the effects of neutrinos on the Universe, how cosmic accelerators work, and whether there are new states of matter at high density and pressure. These questions are discussed in the context of the talks presented at this Summer Institute.

  10. Places Connected:

    DEFF Research Database (Denmark)

    Hansen, Annette Skovsted

    This paper argues that development assistance contributed to the globalization of the 20th century by financing truly global networks of people. By focusing on the networks financed by development assistance bound by the national histories of Denmark and Japan, I illustrate how the people who...... experiences of place, however, when it is often the same people who experience many different places? Along with many other so-called donors in the 1950s, Denmark and Japan chose to invest in the education of own and other nationals involved in development and thereby financed personal connections between...... individuals throughout the world. Development assistance , where there are two or three links only between a Bangladeshi farmer, a street child in Sao Paolo and the President of the United States, the Queen of Denmark, or a suburban house wife in Japan, who has never left the Osaka area, but mothered a United...

  11. The GAD-given Right of Dentate Gyrus Granule Cells to Become GABAergic

    Science.gov (United States)

    Mody, Istvan

    2002-01-01

    Janus, the ancient Roman God of Gates and Doors had two faces: one looked into the past, and the other, into the future. Do neurons possess a Janus face when it comes to neurotransmitters, or a given neuron is to be forever solely γ-aminobutyric acid (GABA) ergic, glutamatergic, dopaminergic, peptidergic, or YOURPREFERREDTRANSMITTERergic? The answer is that the terminals of many neurons are homes to even more than two neurotransmitters. All this in spite of the “one neuron–one transmitter” usual misinterpretation of Sir Henry Hallett Dale's postulate, originally meant to indicate that a metabolic process taking place in the cell body can influence all processes of the same neuron. A large variety of neurons in the CNS, many of them GABAergic, produce and release chemicals that satisfy some of the criteria used to define neurotransmitters. The usual scenario for a dual-transmitter terminal is that the fast-acting transmitter such as GABA or glutamate is stored in regular synaptic vesicles, whereas a neuropeptide is stored in dense core vesicles 1. The vesicular zinc found in many glutamatergic terminals also may be considered to be a second neurotransmitter, based on its vesicular packaging with the aid of a specific vesicular transporter, and its postsynaptic actions through high-affinity binding sites and permeation through certain channels 2. Whenever a “fast” and a “slow” neurotransmitter are present in the same presynaptic terminal, it is customary to assume that their release can be differentially regulated 1. There is little convincing experimental support for this phenomenon in the mammalian CNS. The coexistence of two “fast” neurotransmitters in the same terminal is less frequent, but not unheard of. In neonatal sympathetic neurons cocultured with cardiac myocytes, norepinephrine and acetylcholine coexist and have opposite actions on the cardiac muscle cells 3. Very recently we learned that brain-derived neurotrophic factor acting at the

  12. Estrogen administration modulates hippocampal GABAergic subpopulations in the hippocampus of trimethyltin-treated rats

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    Valentina eCorvino

    2015-11-01

    Full Text Available Given the well-documented involvement of estrogens in the modulation of hippocampal functions in both physiological and pathological conditions, the present study investigates the effects of 17-beta estradiol (E2 administration in the rat model of hippocampal neurodegeneration induced by trimethyltin (TMT administration (8mg/kg, characterized by loss of pyramidal neurons in CA1, CA3/hilus hippocampal subfields associated with astroglial and microglial activation, seizures and cognitive impairment. After TMT/saline treatment, ovariectomized animals received two doses of E2 (0.2 mg/kg i.p. or vehicle, and were sacrificed 48h or 7 days after TMT-treatment. Our results indicate that in TMT-treated animals E2 administration induces the early (48h upregulation of genes involved in neuroprotection and synaptogenesis, namely Bcl2, trkB, Cadherin and cyclin-dependent-kinase-5. Increased expression levels of glutamic acid decarboxylase (gad 67, neuropeptide Y (Npy, parvalbumin , Pgc-1α and Sirtuin 1genes, the latter involved in parvalbumin (PV synthesis, were also evident. Unbiased stereology performed on rats sacrificed 7 days after TMT treatment showed that although E2 does not significantly influence the extent of TMT-induced neuronal death, significantly enhances the TMT-induced modulation of GABAergic interneuron population size in selected hippocampal subfields. In particular, E2 administration causes, in TMT treated rats, a significant increase in the number of GAD67-expressing interneurons in CA1 stratum oriens, CA3 pyramidal layer, hilus and dentate gyrus, accompanied by a parallel increase in NPY-expressing cells, essentially in the same regions, and of PV-positive cells in CA1 pyramidal layer. The present results add information concerning the role of in vivo E2 administration on mechanisms involved in cellular plasticity in the adult brain.

  13. Distribution of glutamatergic, GABAergic, and glycinergic neurons in the auditory pathways of macaque monkeys.

    Science.gov (United States)

    Ito, T; Inoue, K; Takada, M

    2015-12-03

    Macaque monkeys use complex communication calls and are regarded as a model for studying the coding and decoding of complex sound in the auditory system. However, little is known about the distribution of excitatory and inhibitory neurons in the auditory system of macaque monkeys. In this study, we examined the overall distribution of cell bodies that expressed mRNAs for VGLUT1, and VGLUT2 (markers for glutamatergic neurons), GAD67 (a marker for GABAergic neurons), and GLYT2 (a marker for glycinergic neurons) in the auditory system of the Japanese macaque. In addition, we performed immunohistochemistry for VGLUT1, VGLUT2, and GAD67 in order to compare the distribution of proteins and mRNAs. We found that most of the excitatory neurons in the auditory brainstem expressed VGLUT2. In contrast, the expression of VGLUT1 mRNA was restricted to the auditory cortex (AC), periolivary nuclei, and cochlear nuclei (CN). The co-expression of GAD67 and GLYT2 mRNAs was common in the ventral nucleus of the lateral lemniscus (VNLL), CN, and superior olivary complex except for the medial nucleus of the trapezoid body, which expressed GLYT2 alone. In contrast, the dorsal nucleus of the lateral lemniscus, inferior colliculus, thalamus, and AC expressed GAD67 alone. The absence of co-expression of VGLUT1 and VGLUT2 in the medial geniculate, medial superior olive, and VNLL suggests that synaptic responses in the target neurons of these nuclei may be different between rodents and macaque monkeys. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. GABAergic synapse properties may explain genetic variation in hippocampal network oscillations in mice

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    Tim S Heistek

    2010-06-01

    Full Text Available Cognitive ability and the properties of brain oscillation are highly heritable in humans. Genetic variation underlying oscillatory activity might give rise to differences in cognition and behavior. How genetic diversity translates into altered properties of oscillations and synchronization of neuronal activity is unknown. To address this issue, we investigated cellular and synaptic mechanisms of hippocampal fast network oscillations in eight genetically distinct inbred mouse strains. The frequency of carbachol-induced oscillations differed substantially between mouse strains. Since GABAergic inhibition sets oscillation frequency, we studied the properties of inhibitory synaptic inputs (IPSCs received by CA3 and CA1 pyramidal cells of three mouse strains that showed the highest, lowest and intermediate frequencies of oscillations. In CA3 pyramidal cells, the frequency of rhythmic IPSC input showed the same strain differences as the frequency of field oscillations. Furthermore, IPSC decay times in both CA1 and CA3 pyramidal cells were faster in mouse strains with higher oscillation frequencies than in mouse strains with lower oscillation frequency, suggesting that differences in GABAA-receptor subunit composition exist between these strains. Indeed, gene expression of GABAA-receptor β2 (Gabrb2 and β3 (Gabrb2 subunits was higher in mouse strains with faster decay kinetics compared with mouse strains with slower decay kinetics. Hippocampal pyramidal neurons in mouse strains with higher oscillation frequencies and faster decay kinetics fired action potential at higher frequencies. These data indicate that differences in genetic background may result in different GABAA-receptor subunit expression, which affects the rhythm of pyramidal neuron firing and fast network activity through GABA synapse kinetics.

  15. Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse Nucleus Accumbens

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    Giuseppe eGangarossa

    2013-02-01

    Full Text Available The nucleus accumbens (NAc is a critical brain region involved in many reward-related behaviors. The NAc comprises major compartments the core and the shell, which encompass several subterritories. GABAergic medium-sized spiny neurons (MSNs constitute the output neurons of the NAc core and shell. While the functional organization of the NAc core outputs resembles the one described for the dorsal striatum, a simple classification of the NAc shell neurons has been difficult to define due to the complexity of the compartmental segregation of cells. We used a variety of BAC transgenic mice expressing enhanced green fluorescence (EGFP or the Cre-recombinase (Cre under the control of the promoter of dopamine D1, D2, and D3 receptors and of adenosine A2a receptor to dissect the microanatomy of the NAc. Moreover, using various immunological markers we characterized in detail the distribution of MSNs in the mouse NAc. In addition, cell-type specific ERK phosphorylation in the NAc subterritories was analyzed following acute administration of SKF81297 (a D1R-like agonist, quinpirole (a D2R-like agonist, apomorphine (a non-selective DA receptor agonist, raclopride (a D2R-like antagonist, and psychostimulant drugs, including cocaine and d-amphetamine. Each drug generated a unique topography and cell-type specific activation of ERK in the NAc. Our results show the existence of marked differences in the receptor expression pattern and functional activation of MSNs within the shell subterritories. This study emphasizes the anatomical and functional heterogeneity of the NAc, which will have to be considered in its further study.

  16. GABAergic inhibition through synergistic astrocytic neuronal interaction transiently decreases vasopressin neuronal activity during hypoosmotic challenge.

    Science.gov (United States)

    Wang, Yu-Feng; Sun, Min-Yu; Hou, Qiuling; Hamilton, Kathryn A

    2013-04-01

    The neuropeptide vasopressin is crucial to mammalian osmotic regulation. Local hypoosmotic challenge transiently decreases and then increases vasopressin secretion. To investigate mechanisms underlying this transient response, we examined the effects of hypoosmotic challenge on the electrical activity of rat hypothalamic supraoptic nucleus (SON) vasopressin neurons using patch-clamp recordings. We found that 5 min exposure of hypothalamic slices to hypoosmotic solution transiently increased inhibitory postsynaptic current (IPSC) frequency and reduced the firing rate of vasopressin neurons. Recovery occurred by 10 min of exposure, even though the osmolality remained low. The γ-aminobutyric acid (GABA)A receptor blocker, gabazine, blocked the IPSCs and the hypoosmotic suppression of firing. The gliotoxin l-aminoadipic acid blocked the increase in IPSC frequency at 5 min and the recovery of firing at 10 min, indicating astrocytic involvement in hypoosmotic modulation of vasopressin neuronal activity. Moreover, β-alanine, an osmolyte of astrocytes and GABA transporter (GAT) inhibitor, blocked the increase in IPSC frequency at 5 min of hypoosmotic challenge. Confocal microscopy of immunostained SON sections revealed that astrocytes and magnocellular neurons both showed positive staining of vesicular GATs (VGAT). Hypoosmotic stimulation in vivo reduced the number of VGAT-expressing neurons, and increased co-localisation and molecular association of VGAT with glial fibrillary acidic protein that increased significantly by 10 min. By 30 min, neuronal VGAT labelling was partially restored, and astrocytic VGAT was relocated to the ventral portion while it decreased in the somatic zone of the SON. Thus, synergistic astrocytic and neuronal GABAergic inhibition could ensure that vasopressin neuron firing is only transiently suppressed under hypoosmotic conditions. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  17. GABAergic inhibition of leg motoneurons is required for normal walking behavior in freely moving Drosophila.

    Science.gov (United States)

    Gowda, Swetha B M; Paranjpe, Pushkar D; Reddy, O Venkateswara; Thiagarajan, Devasena; Palliyil, Sudhir; Reichert, Heinrich; VijayRaghavan, K

    2018-02-27

    Walking is a complex rhythmic locomotor behavior generated by sequential and periodical contraction of muscles essential for coordinated control of movements of legs and leg joints. Studies of walking in vertebrates and invertebrates have revealed that premotor neural circuitry generates a basic rhythmic pattern that is sculpted by sensory feedback and ultimately controls the amplitude and phase of the motor output to leg muscles. However, the identity and functional roles of the premotor interneurons that directly control leg motoneuron activity are poorly understood. Here we take advantage of the powerful genetic methodology available in Drosophila to investigate the role of premotor inhibition in walking by genetically suppressing inhibitory input to leg motoneurons. For this, we have developed an algorithm for automated analysis of leg motion to characterize the walking parameters of wild-type flies from high-speed video recordings. Further, we use genetic reagents for targeted RNAi knockdown of inhibitory neurotransmitter receptors in leg motoneurons together with quantitative analysis of resulting changes in leg movement parameters in freely walking Drosophila Our findings indicate that targeted down-regulation of the GABA A receptor Rdl (Resistance to Dieldrin) in leg motoneurons results in a dramatic reduction of walking speed and step length without the loss of general leg coordination during locomotion. Genetically restricting the knockdown to the adult stage and subsets of motoneurons yields qualitatively identical results. Taken together, these findings identify GABAergic premotor inhibition of motoneurons as an important determinant of correctly coordinated leg movements and speed of walking in freely behaving Drosophila . Copyright © 2018 the Author(s). Published by PNAS.

  18. Medullary GABAergic mechanisms contribute to electroacupuncture modulation of cardiovascular depressor responses during gastric distention in rats

    Science.gov (United States)

    Guo, Zhi-Ling; Li, Min; Longhurst, John C.

    2013-01-01

    Electroacupuncture (EA) at P5–P6 acupoints overlying the median nerves typically reduces sympathoexcitatory blood pressure (BP) reflex responses in eucapnic rats. Gastric distention in hypercapnic acidotic rats, by activating both vagal and sympathetic afferents, decreases heart rate (HR) and BP through actions in the rostral ventrolateral medulla (rVLM) and nucleus ambiguus (NAmb), leading to sympathetic withdrawal and parasympathetic activation, respectively. A GABAA mechanism in the rVLM mediates the decreased sympathetic outflow. The present study investigated the hypothesis that EA modulates gastric distention-induced hemodynamic depressor and bradycardia responses through nuclei that process parasympathetic and sympathetic outflow. Anesthetized hypercapnic acidotic rats manifested repeatable decreases in BP and HR with gastric distention every 10 min. Bilateral EA at P5–P6 for 30 min reversed the hypotensive response from −26 ± 3 to −6 ± 1 mmHg and the bradycardia from −35 ± 11 to −10 ± 3 beats/min for a period that lasted more than 70 min. Immunohistochemistry and in situ hybridization to detect c-Fos protein and GAD 67 mRNA expression showed that GABAergic caudal ventral lateral medulla (cVLM) neurons were activated by EA. Glutamatergic antagonism of cVLM neurons with kynurenic acid reversed the actions of EA. Gabazine used to block GABAA receptors microinjected into the rVLM or cVLM reversed EA's action on both the reflex depressor and bradycardia responses. EA modulation of the decreased HR was inhibited by microinjection of gabazine into the NAmb. Thus, EA through GABAA receptor mechanisms in the rVLM, cVLM, and NAmb modulates gastric distention-induced reflex sympathoinhibition and vagal excitation. PMID:23302958

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

    Science.gov (United States)

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

    2016-12-01

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

  20. Substance P as a putative efferent transmitter mediates GABAergic inhibition in mouse taste buds.

    Science.gov (United States)

    Huang, Anthony Y; Wu, Sandy Y

    2018-04-01

    Capsaicin-mediated modulation of taste nerve responses is thought to be produced indirectly by the actions of neuropeptides, for example, CGRP and substance P (SP), on taste cells implying they play a role in taste sensitivity. During the processing of gustatory information in taste buds, CGRP shapes peripheral taste signals via serotonergic signalling. The underlying assumption has been that SP exerts its effects on taste transmitter secretion in taste buds of mice. To test this assumption, we investigated the net effect of SP on taste-evoked ATP secretion from mouse taste buds, using functional calcium imaging with CHO cells expressing high-affinity transmitter receptors as cellular biosensors. Our results showed that SP elicited PLC activation-dependent intracellular Ca 2+ transients in taste cells via neurokinin 1 receptors, most likely on glutamate-aspartate transporter-expressing Type I cells. Furthermore, SP caused Type I cells to secrete GABA. Combined with the recent findings that GABA depresses taste-evoked ATP secretion, the current results indicate that SP elicited secretion of GABA, which provided negative feedback onto Type II (receptor) cells to reduce taste-evoked ATP secretion. These findings are consistent with a role for SP as an inhibitory transmitter that shapes the peripheral taste signals, via GABAergic signalling, during the processing of gustatory information in taste buds. Notably, the results suggest that SP is intimately associated with GABA in mammalian taste signal processing and demonstrate an unanticipated route for sensory information flow within the taste bud. © 2018 The British Pharmacological Society.

  1. Clonidine, an alpha2-receptor agonist, diminishes GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus.

    Science.gov (United States)

    Philbin, Kerry E; Bateman, Ryan J; Mendelowitz, David

    2010-08-06

    In hypertension, there is an autonomic imbalance in which sympathetic activity dominates over parasympathetic control. Parasympathetic activity to the heart originates from cardiac vagal neurons located in the nucleus ambiguus. Presympathetic neurons that project to sympathetic neurons in the spinal cord are located in the ventral brainstem in close proximity to cardiac vagal neurons, and many of these presympathetic neurons are catecholaminergic. In addition to their projection to the spinal cord, many of these presympathetic neurons have axon collaterals that arborize into neighboring cardiorespiratory locations and likely release norepinephrine onto nearby neurons. Activation of alpha(2)-adrenergic receptors in the central nervous system evokes a diverse range of physiological effects, including reducing blood pressure. This study tests whether clonidine, an alpha(2)-adrenergic receptor agonist, alters excitatory glutamatergic, and/or inhibitory GABAergic or glycinergic synaptic neurotransmission to cardiac vagal neurons in the nucleus ambiguus. Cardiac vagal neurons were identified in an in vitro brainstem slice preparation, and synaptic events were recording using whole cell voltage clamp methodologies. Clonidine significantly inhibited GABAergic neurotransmission but had no effect on glycinergic or glutamatergic pathways to cardiac vagal neurons. This diminished inhibitory GABAergic neurotransmission to cardiac vagal neurons would increase parasympathetic activity to the heart, decreasing heart rate and blood pressure. The results presented here provide a cellular substrate for the clinical use of clonidine as a treatment for hypertension as well as a role in alleviating posttraumatic stress disorder by evoking an increase in parasympathetic cardiac vagal activity, and a decrease in heart rate and blood pressure. Copyright 2010 Elsevier B.V. All rights reserved.

  2. Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy

    Science.gov (United States)

    Buckmaster, Paul S.; Abrams, Emily; Wen, Xiling

    2018-01-01

    Epilepsy occurs in one of 26 people. Temporal lobe epilepsy is common and can be difficult to treat effectively. It can develop after brain injuries that damage the hippocampus. Multiple pathophysiological mechanisms involving the hippocampal dentate gyrus have been proposed. This study evaluated a mouse model of temporal lobe epilepsy to test which pathological changes in the dentate gyrus correlate with seizure frequency and help prioritize potential mechanisms for further study. FVB mice (n = 127) that had experienced status epilepticus after systemic treatment with pilocarpine 31–61 days earlier were video-monitored for spontaneous, convulsive seizures 9 hr/day every day for 24–36 days. Over 4,060 seizures were observed. Seizure frequency ranged from an average of one every 3.6 days to one every 2.1 hr. Hippocampal sections were processed for Nissl stain, Prox1-immunocytochemistry, GluR2-immunocytochemistry, Timm stain, glial fibrillary acidic protein-immunocytochemistry, glutamic acid decarboxylase in situ hybridization, and parvalbumin-immunocytochemistry. Stereological methods were used to measure hilar ectopic granule cells, mossy cells, mossy fiber sprouting, astrogliosis, and GABAergic interneurons. Seizure frequency was not significantly correlated with the generation of hilar ectopic granule cells, the number of mossy cells, the extent of mossy fiber sprouting, the extent of astrogliosis, or the number of GABAergic interneurons in the molecular layer or hilus. Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons. These findings prioritize the loss of granule cell layer interneurons for further testing as a potential cause of temporal lobe epilepsy. PMID:28425097

  3. GABAergic activities control spike timing- and frequency-dependent long-term depression at hippocampal excitatory synapses

    Directory of Open Access Journals (Sweden)

    Makoto Nishiyama

    2010-06-01

    Full Text Available GABAergic interneuronal network activities in the hippocampus control a variety of neural functions, including learning and memory, by regulating θ and γ oscillations. How these GABAergic activities at pre- and post-synaptic sites of hippocampal CA1 pyramidal cells differentially contribute to synaptic function and plasticity during their repetitive pre- and post-synaptic spiking at θ and γ oscillations is largely unknown. We show here that activities mediated by postsynaptic GABAARs and presynaptic GABABRs determine, respectively, the spike timing- and frequency-dependence of activity-induced synaptic modifications at Schaffer collateral-CA1 excitatory synapses. We demonstrate that both feedforward and feedback GABAAR-mediated inhibition in the postsynaptic cell controls the spike timing-dependent long-term depression of excitatory inputs (“e-LTD” at the θ frequency. We also show that feedback postsynaptic inhibition specifically causes e-LTD of inputs that induce small postsynaptic currents (<70 pA with LTP timing, thus enforcing the requirement of cooperativity for induction of long-term potentiation at excitatory inputs (“e-LTP”. Furthermore, under spike-timing protocols that induce e-LTP and e-LTD at excitatory synapses, we observed parallel induction of LTP and LTD at inhibitory inputs (“i-LTP” and “i-LTD” to the same postsynaptic cells. Finally, we show that presynaptic GABABR-mediated inhibition plays a major role in the induction of frequency-dependent e-LTD at α and β frequencies. These observations demonstrate the critical influence of GABAergic interneuronal network activities in regulating the spike timing and frequency dependences of long-term synaptic modifications in the hippocampus.

  4. A very large number of GABAergic neurons are activated in the tuberal hypothalamus during paradoxical (REM sleep hypersomnia.

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    Emilie Sapin

    Full Text Available We recently discovered, using Fos immunostaining, that the tuberal and mammillary hypothalamus contain a massive population of neurons specifically activated during paradoxical sleep (PS hypersomnia. We further showed that some of the activated neurons of the tuberal hypothalamus express the melanin concentrating hormone (MCH neuropeptide and that icv injection of MCH induces a strong increase in PS quantity. However, the chemical nature of the majority of the neurons activated during PS had not been characterized. To determine whether these neurons are GABAergic, we combined in situ hybridization of GAD(67 mRNA with immunohistochemical detection of Fos in control, PS deprived and PS hypersomniac rats. We found that 74% of the very large population of Fos-labeled neurons located in the tuberal hypothalamus after PS hypersomnia were GAD-positive. We further demonstrated combining MCH immunohistochemistry and GAD(67in situ hybridization that 85% of the MCH neurons were also GAD-positive. Finally, based on the number of Fos-ir/GAD(+, Fos-ir/MCH(+, and GAD(+/MCH(+ double-labeled neurons counted from three sets of double-staining, we uncovered that around 80% of the large number of the Fos-ir/GAD(+ neurons located in the tuberal hypothalamus after PS hypersomnia do not contain MCH. Based on these and previous results, we propose that the non-MCH Fos/GABAergic neuronal population could be involved in PS induction and maintenance while the Fos/MCH/GABAergic neurons could be involved in the homeostatic regulation of PS. Further investigations will be needed to corroborate this original hypothesis.

  5. GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid schizophrenia: A post-mortem study.

    Science.gov (United States)

    Steiner, Johann; Brisch, Ralf; Schiltz, Kolja; Dobrowolny, Henrik; Mawrin, Christian; Krzyżanowska, Marta; Bernstein, Hans-Gert; Jankowski, Zbigniew; Braun, Katharina; Schmitt, Andrea; Bogerts, Bernhard; Gos, Tomasz

    2016-11-01

    Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and residual schizophrenia. GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem schizophrenia patient samples (10 paranoid and 6 residual schizophrenia cases) were compared with those from 16 matched controls. Overall, schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P=0.033). However, the diagnostic subgroups differed significantly (Pparanoid versus residual patients (P=0.036) and controls (Pparanoid versus residual schizophrenia cases (P=0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r=0.850, P=0.004; left: r=0.800, P=0.010). Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy.

    Science.gov (United States)

    Buckmaster, Paul S; Abrams, Emily; Wen, Xiling

    2017-08-01

    Epilepsy occurs in one of 26 people. Temporal lobe epilepsy is common and can be difficult to treat effectively. It can develop after brain injuries that damage the hippocampus. Multiple pathophysiological mechanisms involving the hippocampal dentate gyrus have been proposed. This study evaluated a mouse model of temporal lobe epilepsy to test which pathological changes in the dentate gyrus correlate with seizure frequency and help prioritize potential mechanisms for further study. FVB mice (n = 127) that had experienced status epilepticus after systemic treatment with pilocarpine 31-61 days earlier were video-monitored for spontaneous, convulsive seizures 9 hr/day every day for 24-36 days. Over 4,060 seizures were observed. Seizure frequency ranged from an average of one every 3.6 days to one every 2.1 hr. Hippocampal sections were processed for Nissl stain, Prox1-immunocytochemistry, GluR2-immunocytochemistry, Timm stain, glial fibrillary acidic protein-immunocytochemistry, glutamic acid decarboxylase in situ hybridization, and parvalbumin-immunocytochemistry. Stereological methods were used to measure hilar ectopic granule cells, mossy cells, mossy fiber sprouting, astrogliosis, and GABAergic interneurons. Seizure frequency was not significantly correlated with the generation of hilar ectopic granule cells, the number of mossy cells, the extent of mossy fiber sprouting, the extent of astrogliosis, or the number of GABAergic interneurons in the molecular layer or hilus. Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons. These findings prioritize the loss of granule cell layer interneurons for further testing as a potential cause of temporal lobe epilepsy. © 2017 Wiley Periodicals, Inc.

  7. Passiflora incarnata attenuation of neuropathic allodynia and vulvodynia apropos GABA-ergic and opioidergic antinociceptive and behavioural mechanisms.

    Science.gov (United States)

    Aman, Urooj; Subhan, Fazal; Shahid, Muhammad; Akbar, Shehla; Ahmad, Nisar; Ali, Gowhar; Fawad, Khwaja; Sewell, Robert D E

    2016-02-24

    Passiflora incarnata is widely used as an anxiolytic and sedative due to its putative GABAergic properties. Passiflora incarnata L. methanolic extract (PI-ME) was evaluated in an animal model of streptozotocin-induced diabetic neuropathic allodynia and vulvodynia in rats along with antinociceptive, anxiolytic and sedative activities in mice in order to examine possible underlying mechanisms. PI-ME was tested preliminary for qualitative phytochemical analysis and then quantitatively by proximate and GC-MS analysis. The antinociceptive property was evaluated using the abdominal constriction assay and hot plate test. The anxiolytic activity was performed in a stair case model and sedative activity in an open field test. The antagonistic activities were evaluated using naloxone and/or pentylenetetrazole (PTZ). PI-ME was evaluated for prospective anti-allodynic and anti-vulvodynic properties in a rat model of streptozotocin induced neuropathic pain using the static and dynamic testing paradigms of mechanical allodynia and vulvodynia. GC-MS analysis revealed that PI-ME contained predominant quantities of oleamide (9-octadecenamide), palmitic acid (hexadecanoic acid) and 3-hydroxy-dodecanoic acid, among other active constituents. In the abdominal constriction assay and hot plate test, PI-ME produced dose dependant, naloxone and pentylenetetrazole reversible antinociception suggesting an involvement of opioidergic and GABAergic mechanisms. In the stair case test, PI-ME at 200 mg/kg increased the number of steps climbed while at 600 mg/kg a significant decrease was observed. The rearing incidence was diminished by PI-ME at all tested doses and in the open field test, PI-ME decreased locomotor activity to an extent that was analagous to diazepam. The effects of PI-ME were antagonized by PTZ in both the staircase and open field tests implicating GABAergic mechanisms in its anxiolytic and sedative activities. In the streptozotocin-induced neuropathic nociceptive model, PI

  8. Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala

    DEFF Research Database (Denmark)

    Varodayan, Florence P.; Bajo, Michal; Soni, Neeraj

    2017-01-01

    in BLA pyramidal neurons of rats exposed to 2–3 weeks intermittent ethanol. In the naïve rat BLA, the CB1 agonist WIN 55,212-2 (WIN) decreased GABA release, and this effect was prevented by the CB1 antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent......1 influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and, thus, may contribute to the alcohol-dependent state....

  9. Topographic and functional neuroanatomical study of GABAergic disinhibitory striatum-nigral inputs and inhibitory nigrocollicular pathways: neural hodology recruiting the substantia nigra, pars reticulata, for the modulation of the neural activity in the inferior colliculus involved with panic-like emotions.

    Science.gov (United States)

    Castellan-Baldan, Lissandra; da Costa Kawasaki, Mateus; Ribeiro, Sandro José; Calvo, Fabrício; Corrêa, Vani Maria Alves; Coimbra, Norberto Cysne

    2006-08-01

    Considering the influence of the substantia nigra on mesencephalic neurons involved with fear-induced reactions organized in rostral aspects of the dorsal midbrain, the present work investigated the topographical and functional neuroanatomy of similar influence on caudal division of the corpora quadrigemina, addressing: (a) the neural hodology connecting the neostriatum, the substantia nigra, periaqueductal gray matter and inferior colliculus (IC) neural networks; (b) the influence of the inhibitory neostriatonigral-nigrocollicular GABAergic links on the control of the defensive behavior organized in the IC. The effects of the increase or decrease of activity of nigrocollicular inputs on defensive responses elicited by either electrical or chemical stimulation of the IC were also determined. Electrolytic or chemical lesions of the substantia nigra, pars reticulata (SNpr), decreased the freezing and escape behaviors thresholds elicited by electrical stimulation of the IC, and increased the behavioral responses evoked by the GABAA blockade in the same sites of the mesencephalic tectum (MT) electrically stimulated. These findings were corroborated by similar effects caused by microinjections of the GABAA-receptor agonist muscimol in the SNpr, followed by electrical and chemical stimulations of the IC. The GABAA blockade in the SNpr caused a significant increase in the defensive behavior thresholds elicited by electrical stimulation of the IC and a decrease in the mean incidence of panic-like responses induced by microinjections of bicuculline in the mesencephalic tectum (inferior colliculus). These findings suggest that the substantia nigra receives GABAergic inputs that modulate local and also inhibitory GABAergic outputs toward the IC. In fact, neurotracing experiments with fast blue and iontophoretic microinjections of biotinylated dextran amine either into the inferior colliculus or in the reticular division of the substantia nigra demonstrated a neural link

  10. Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons.

    Science.gov (United States)

    Yamada, Mayumi; Seto, Yusuke; Taya, Shinichiro; Owa, Tomoo; Inoue, Yukiko U; Inoue, Takayoshi; Kawaguchi, Yoshiya; Nabeshima, Yo-Ichi; Hoshino, Mikio

    2014-04-02

    In the cerebellum, the bHLH transcription factors Ptf1a and Atoh1 are expressed in distinct neuroepithelial regions, the ventricular zone (VZ) and the rhombic lip (RL), and are required for producing GABAergic and glutamatergic neurons, respectively. However, it is unclear whether Ptf1a or Atoh1 is sufficient for specifying GABAergic or glutamatergic neuronal fates. To test this, we generated two novel knock-in mouse lines, Ptf1a(Atoh1) and Atoh1(Ptf1a), that are designed to express Atoh1 and Ptf1a ectopically in the VZ and RL, respectively. In Ptf1a(Atoh1) embryos, ectopically Atoh1-expressing VZ cells produced glutamatergic neurons, including granule cells and deep cerebellar nuclei neurons. Correspondingly, in Atoh1(Ptf1a) animals, ectopically Ptf1a-expressing RL cells produced GABAergic populations, such as Purkinje cells and GABAergic interneurons. Consistent results were also obtained from in utero electroporation of Ptf1a or Atoh1 into embryonic cerebella, suggesting that Ptf1a and Atoh1 are essential and sufficient for GABAergic versus glutamatergic specification in the neuroepithelium. Furthermore, birthdating analyses with BrdU in the knock-in mice or with electroporation studies showed that ectopically produced fate-changed neuronal types were generated at temporal schedules closely simulating those of the wild-type RL and VZ, suggesting that the VZ and RL share common temporal information. Observations of knock-in brains as well as electroporated brains revealed that Ptf1a and Atoh1 mutually negatively regulate their expression, probably contributing to formation of non-overlapping neuroepithelial domains. These findings suggest that Ptf1a and Atoh1 specify spatial identities of cerebellar neuron progenitors in the neuroepithelium, leading to appropriate production of GABAergic and glutamatergic neurons, respectively.

  11. Specific rescue by ortho-hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB.

    Science.gov (United States)

    Guirao, Verónica; Martí-Sistac, Octavi; DeGregorio-Rocasolano, Núria; Ponce, Jovita; Dávalos, Antoni; Gasull, Teresa

    2017-11-01

    The statin atorvastatin (ATV) given as a post-treatment has been reported beneficial in stroke, although the mechanisms involved are not well understood so far. Here, we investigated in vitro the effect of post-treatment with ATV and its main bioactive metabolite ortho-hydroxy ATV (o-ATV) on neuroprotection after oxygen and glucose deprivation (OGD), and the role of the pro-survival cAMP response element-binding protein (CREB). Post-OGD treatment of primary cultures of rat cortical neurons with o-ATV, but not ATV, provided neuroprotection to a specific subset of cortical neurons that were large and positive for glutamic acid decarboxylase (large-GAD (+) neurons, GABAergic). Significantly, only these GABAergic neurons showed an increase in phosphorylated CREB (pCREB) early after neuronal cultures were treated post-OGD with o-ATV. We found that o-ATV, but not ATV, increased the neuronal uptake of glutamate from the medium; this provides a rationale for the specific effect of o-ATV on pCREB in large-GABAergic neurons, which have a higher ratio of synaptic (pCREB-promoting) vs extrasynaptic (pCREB-reducing) N-methyl-D-aspartate (NMDA) receptors (NMDAR) than that of small-non-GABAergic neurons. When we pharmacologically increased pCREB levels post-OGD in non-GABAergic neurons, through the selective activation of synaptic NMDAR, we observed as well long-lasting neuronal survival. We propose that the statin metabolite o-ATV given post-OGD boosts the intrinsic pro-survival factor pCREB in large-GABAergic cortical neurons in vitro, this contributing to protect them from OGD. © 2017 International Society for Neurochemistry.

  12. [Effect of activation and blockade of the GABA-ergic system of the substantia nigra in the midbrain on the realization of conditioned food reflexes in dogs].

    Science.gov (United States)

    Iakimovskiĭ, A F

    1988-01-01

    Bilateral injection of 45 mcg of GABA into substantia nigra pars compacta produced in dogs a manifested improvement of parameters of the conditioned differentiation inhibition but failed to influence the positive Pavlovian alimentary conditioned reflex. Injection of GABA synaptic antagonist--picrotoxin impaired conditioned alimentary behaviour. Numerous injections of the GABAergic pharmacological agents resulted in motor disturbance--rotatory movements--and skin trophic deviations. The data obtained and literature references give ground for discussion of the role of striato-nigral and internal GABAergic substantia nigra systems in the positive modulation of adaptive alimentary behaviour and conditioned stimuli differentiation.

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

    Directory of Open Access Journals (Sweden)

    Fatemah Alherz

    2017-06-01

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

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

    Science.gov (United States)

    Doron, Guy; Rosenblum, Kobi

    2010-07-01

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

  15. Hippocampal dendritic spines remodeling and fear memory are modulated by GABAergic signaling within the basolateral amygdala complex.

    Science.gov (United States)

    Giachero, Marcelo; Calfa, Gaston D; Molina, Victor A

    2015-05-01

    GABAergic signaling in the basolateral amygdala complex (BLA) plays a crucial role on the modulation of the stress influence on fear memory. Moreover, accumulating evidence suggests that the dorsal hippocampus (DH) is a downstream target of BLA neurons in contextual fear. Given that hippocampal structural plasticity is proposed to provide a substrate for the storage of long-term memories, the main aim of this study is to evaluate the modulation of GABA neurotransmission in the BLA on spine density in the DH following stress on contextual fear learning. The present findings show that prior stressful experience promoted contextual fear memory and enhanced spine density in the DH. Intra-BLA infusion of midazolam, a positive modulator of GABAa sites, prevented the facilitating influence of stress on both fear retention and hippocampal dendritic spine remodeling. Similarly to the stress-induced effects, the blockade of GABAa sites within the BLA ameliorated fear memory emergence and induced structural remodeling in the DH. These findings suggest that GABAergic transmission in BLA modulates the structural changes in DH associated to the influence of stress on fear memory. © 2015 Wiley Periodicals, Inc.

  16. Clarified Açaí (Euterpe oleracea Juice as an Anticonvulsant Agent: In Vitro Mechanistic Study of GABAergic Targets

    Directory of Open Access Journals (Sweden)

    Gabriela P. F. Arrifano

    2018-01-01

    Full Text Available Seizures affect about 50 million people around the world. Approximately 30% of seizures are refractory to the current pharmacological arsenal, so, the pursuit of new therapeutic alternatives is essential. Clarified Euterpe oleracea (EO juice showed anticonvulsant properties similar to diazepam in an in vivo model with pentylenetetrazol, a GABAA receptor blocker. This study investigated the effects of EO on the main GABAergic targets for anticonvulsant drugs, analyzing the effect on the GABA receptor’s benzodiazepine and picrotoxinin binding sites and the GABA uptake. Primary cultures of cortical neurons and astrocytes were treated with EO (0–25% for up to 90 min. [3H]Flunitrazepam and [3H]TBOB binding, [3H]GABA uptake, cell viability, and morphology were assayed. Nonlethal concentrations of EO increased agonist binding and decreased antagonist binding in cortical neurons. Low concentrations significantly inhibited GABA uptake, especially in astrocytes, suggesting an accumulation of endogenous GABA in the synaptic cleft. The results demonstrate, for the first time, that EO can improve GABAergic neurotransmission via interactions with GABAA receptor and modulation of GABA uptake. Understanding these molecular mechanisms will help in the treatment of seizures and epilepsy, especially in developing countries where geographic isolation and low purchasing power are the main barriers to access to adequate treatment.

  17. GABAergic mechanisms are involved in the antihyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory hyperalgesia.

    Science.gov (United States)

    Stepanović-Petrović, Radica M; Tomić, Maja A; Vucković, Sonja M; Kocev, Nikola; Ugresić, Nenad D; Prostran, Milica S; Bosković, Bogdan

    2008-01-01

    The purpose of this study was to investigate the involvement of GABAergic mechanisms in the antihyperalgesic effect of carbamazepine and oxcarbazepine by examining the effect of bicuculline (GABA(A) receptor antagonist) on these effects of antiepileptic drugs. Rats were intraplantarly (i.pl.) injected with the proinflammatory compound concanavalin A (Con A). A paw-pressure test was used to determine: (1) the development of hyperalgesia induced by Con A; (2) the effects of carbamazepine/oxcarbazepine on Con A-induced hyperalgesia, and (3) the effects of bicuculline on the carbamazepine/oxcarbazepine antihyperalgesia. Intraperitoneally injected bicuculline (0.5-1 mg/kg, i.p.) exhibited significant suppression of the systemic antihyperalgesic effects of carbamazepine (27 mg/kg, i.p.) and oxcarbazepine (80 mg/kg, i.p.). When applied intraplantarly, bicuculline (0.14 mg/paw, i.pl.) did not produce any change in the peripheral antihyperalgesic effects of carbamazepine (0.14 mg/paw, i.pl.) and oxcarbazepine (0.5 mg/paw, i.pl.). Bicuculline alone did not produce an intrinsic effect in the paw-pressure test. These results indicate that the antihyperalgesic effects of carbamazepine and oxcarbazepine against inflammatory hyperalgesia involve in part the GABAergic inhibitory modulation of pain transmission at central, but not at peripheral sites, which is mediated via GABA(A) receptor activation. Copyright 2008 S. Karger AG, Basel.

  18. Activation of GABAergic pathway by hypocretin in the median raphe nucleus (MRN) mediates stress-induced theta rhythm in rats.

    Science.gov (United States)

    Hsiao, Yi-Tse; Jou, Shuo-Bin; Yi, Pei-Lu; Chang, Fang-Chia

    2012-07-15

    The frequency of electroencephalograms (EEGs) is predominant in theta rhythm during stress (e.g., footshock) in rats. Median raphe nucleus (MRN) desynchronizes hippocampal theta waves via activation of GABAergic neurons in the medial septum-diagonal band of Broca (MS-DBB), a theta rhythm pacemaker. Increased hypocretin mediates stress responses in addition to the maintenance of wakefulness. Hypocretin receptors are abundant in the MRN, suggesting a possible role of hypocretin in modulating stress-induced theta rhythm. Our results indicated that the intensity of theta waves was enhanced by footshock and that a hypocretin receptor antagonist (TCS1102) suppressed the footshock-induced theta waves. Administration of hypocretin-1 (1 and 10 μg) and hypocretin-2 (10 μg) directly into the MRN simulated the effect of footshock and significantly increased theta waves. Co-administration of GABA(A) receptor antagonist, bicuculline, into the MRN blocked the increase of theta waves induced by hypocretins or footshock. These results suggested that stress enhances the release of hypocretins, activates GABAergic neurons in the MRN, blocks the ability of MRN to desynchronize theta waves, and subsequently increases the intensity of theta rhythm. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. In vivo temporal property of GABAergic neural transmission in collateral feed-forward inhibition system of hippocampal-prefrontal pathway.

    Science.gov (United States)

    Takita, Masatoshi; Kuramochi, Masahito; Izaki, Yoshinori; Ohtomi, Michiko

    2007-05-30

    Anatomical evidence suggests that rat CA1 hippocampal afferents collaterally innervate excitatory projecting pyramidal neurons and inhibitory interneurons, creating a disynaptic, feed-forward inhibition microcircuit in the medial prefrontal cortex (mPFC). We investigated the temporal relationship between the frequency of paired synaptic transmission and gamma-aminobutyric acid (GABA)ergic receptor-mediated modulation of the microcircuit in vivo under urethane anesthesia. Local perfusions of a GABAa antagonist (-)-bicuculline into the mPFC via microdialysis resulted in a statistically significant disinhibitory effect on intrinsic GABA action, increasing the first and second mPFC responses following hippocampal paired stimulation at interstimulus intervals of 100-200 ms, but not those at 25-50 ms. This (-)-bicuculline-induced disinhibition was compensated by the GABAa agonist muscimol, which itself did not attenuate the intrinsic oscillation of the local field potentials. The perfusion of a sub-minimal concentration of GABAb agonist (R)-baclofen slightly enhanced the synaptic transmission, regardless of the interstimulus interval. In addition to the tonic control by spontaneous fast-spiking GABAergic neurons, it is clear the sequential transmission of the hippocampal-mPFC pathway can phasically drive the collateral feed-forward inhibition system through activation of a GABAa receptor, bringing an active signal filter to the various types of impulse trains that enter the mPFC from the hippocampus in vivo.

  20. Essential Oils and Their Constituents Targeting the GABAergic System and Sodium Channels as Treatment of Neurological Diseases

    Directory of Open Access Journals (Sweden)

    Ze-Jun Wang

    2018-05-01

    Full Text Available Essential oils and the constituents in them exhibit different pharmacological activities, such as antinociceptive, anxiolytic-like, and anticonvulsant effects. They are widely applied as a complementary therapy for people with anxiety, insomnia, convulsion, pain, and cognitive deficit symptoms through inhalation, oral administration, and aromatherapy. Recent studies show that essential oils are emerging as a promising source for modulation of the GABAergic system and sodium ion channels. This review summarizes the recent findings regarding the pharmacological properties of essential oils and compounds from the oils and the mechanisms underlying their effects. Specifically, the review focuses on the essential oils and their constituents targeting the GABAergic system and sodium channels, and their antinociceptive, anxiolytic, and anticonvulsant properties. Some constituents target transient receptor potential (TRP channels to exert analgesic effects. Some components could interact with multiple therapeutic target proteins, for example, inhibit the function of sodium channels and, at the same time, activate GABAA receptors. The review concentrates on perspective compounds that could be better candidates for new drug development in the control of pain and anxiety syndromes.

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

    Science.gov (United States)

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

    2016-08-25

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

  2. Functional and ultrastructural neuroanatomy of interactive intratectal/tectonigral mesencephalic opioid inhibitory links and nigrotectal GABAergic pathways: involvement of GABAA and mu1-opioid receptors in the modulation of panic-like reactions elicited by electrical stimulation of the dorsal midbrain.

    Science.gov (United States)

    Ribeiro, S J; Ciscato, J G; de Oliveira, R; de Oliveira, R C; D'Angelo-Dias, R; Carvalho, A D; Felippotti, T T; Rebouças, E C C; Castellan-Baldan, L; Hoffmann, A; Corrêa, S A L; Moreira, J E; Coimbra, N C

    2005-12-01

    In the present study, the functional neuroanatomy of nigrotectal-tectonigral pathways as well as the effects of central administration of opioid antagonists on aversive stimuli-induced responses elicited by electrical stimulation of the midbrain tectum were determined. Central microinjections of naloxonazine, a selective mu(1)-opiod receptor antagonist, in the mesencephalic tectum (MT) caused a significant increase in the escape thresholds elicited by local electrical stimulation. Furthermore, either naltrexone or naloxonazine microinjected in the substantia nigra, pars reticulata (SNpr), caused a significant increase in the defensive thresholds elicited by electrical stimulation of the continuum comprised by dorsolateral aspects of the periaqueductal gray matter (dlPAG) and deep layers of the superior colliculus (dlSC), as compared with controls. These findings suggest an opioid modulation of GABAergic inhibitory inputs controlling the defensive behavior elicited by MT stimulation, in cranial aspects. In fact, iontophoretic microinjections of the neurotracer biodextran into the SNpr, a mesencephalic structure rich in GABA-containing neurons, show outputs to neural substrate of the dlSC/dlPAG involved with the generation and organization of fear- and panic-like reactions. Neurochemical lesion of the nigrotectal pathways increased the sensitivity of the MT to electrical (at alertness, freezing and escape thresholds) and chemical (blockade of GABA(A) receptors) stimulation, suggesting a tonic modulatory effect of the nigrotectal GABAergic outputs on the neural networks of the MT involved with the organization of the defensive behavior and panic-like reactions. Labeled neurons of the midbrain tectum send inputs with varicosities to ipsi and contralateral dlSC/dlPAG and ipsilateral substantia nigra, pars reticulata and compacta, in which the anterograde and retrograde tracing from a single injection indicates that the substantia nigra has reciprocal connections with

  3. Minimum cost connection networks

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Tvede, Mich

    In the present paper we consider the allocation of cost in connection networks. Agents have connection demands in form of pairs of locations they want to be connected. Connections between locations are costly to build. The problem is to allocate costs of networks satisfying all connection demands...

  4. Non-Invasive Evaluation of the GABAergic/Glutamatergic System in Autistic Patients Observed by MEGA-Editing Proton MR Spectroscopy Using a Clinical 3 Tesla Instrument

    Science.gov (United States)

    Harada, Masafumi; Taki, Masako M.; Nose, Ayumi; Kubo, Hitoshi; Mori, Kenji; Nishitani, Hiromu; Matsuda, Tsuyoshi

    2011-01-01

    Amino acids related to neurotransmitters and the GABAergic/glutamatergic system were measured using a 3 T-MRI instrument in 12 patients with autism and 10 normal controls. All measurements were performed in the frontal lobe (FL) and lenticular nuclei (LN) using a conventional sequence for n-acetyl aspartate (NAA) and glutamate (Glu), and the…

  5. Synthesis of neurotransmitter GABA via the neuronal tricarboxylic acid cycle is elevated in rats with liver cirrhosis consistent with a high GABAergic tone in chronic hepatic encephalopathy

    DEFF Research Database (Denmark)

    Leke, Renata; Bak, Lasse Kristoffer; Iversen, Peter

    2011-01-01

    J. Neurochem. (2011) 117, 824-832. ABSTRACT: Hepatic encephalopathy (HE) is a neuropsychiatric complication to liver disease. It is known that ammonia plays a role in the pathogenesis of HE and disturbances in the GABAergic system have been related to HE. Synthesis of GABA occurs by decarboxylation...

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

    Science.gov (United States)

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

    2012-01-01

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

  7. Altered expression of genes involved in GABAergic transmission and neuromodulation of granule cell activity in the cerebellum of schizophrenia patients.

    Science.gov (United States)

    Bullock, W Michael; Cardon, Karen; Bustillo, Juan; Roberts, Rosalinda C; Perrone-Bizzozero, Nora I

    2008-12-01

    Deficits in gamma-aminobutyric acid (GABA) signaling have been described in the prefrontal cortex, limbic system, and cerebellum in individuals with schizophrenia. The purpose of the present study was to further investigate cerebellar gene expression alterations as they relate to decreases in GABAergic transmission by examining the expression of GABAergic markers, N-methyl-d-aspartic-acid (NMDA) receptor subunits, and cerebellum neuromodulators in individuals with schizophrenia. Subjects were postmortem men with a diagnosis of schizophrenia (N=13) and a postmortem interval-matched non-psychiatric male comparison group (N=13). The authors utilized real-time-quantitative polymerase chain reaction (PCR) to measure mRNA levels of the following GABAergic markers: glutamic acid decarboxylase (GAD) 65 and 67; GABA plasma membrane transporter-1 (GAT-1); GABA type A (GABA(A)) receptor subunits alpha(6), beta(3), and delta; and parvalbumin. In addition, real-time-quantitative PCR was utilized to assess mRNA levels of the NMDA receptor (NR) subunits NR1, NR2-A, NR2-B, NR2-C, and NR2-D as well as the cerebellar neuromodulators glutamate receptor (GluR)-6, kainate-preferring glutamate receptor subunit-2 (KA2), metabotropic glutamate receptor (mGluR)-2 and mGluR3, and neuronal nitric oxide synthase. Measurements for mRNA levels were determined using lateral cerebellar hemisphere tissue from both schizophrenia and comparison subjects. Schizophrenia subjects showed significant decreases in mRNA levels of GAD(67), GAD(65), GAT-1, mGluR2, and neuronal nitric oxide synthase. Increases in GABA(A)-alpha(6 )and GABA(A)-delta as well as GluR6 and KA2 were also observed. Medication effects on the expression of the same genes were examined in rats treated with either haloperidol (Sprague-Dawley rats [N=16]) or clozapine (Long-Evans rats [N=20]). Both haloperidol and clozapine increased the levels of GAD(67) in the cerebellum and altered the expression of other cerebellar mRNAs. These

  8. DISSECTING HABITAT CONNECTIVITY

    Science.gov (United States)

    abstractConnectivity is increasingly recognized as an important element of a successful reserve design. Connectivity matters in reserve design to the extent that it promotes or hinders the viability of target populations. While conceptually straightforward, connectivity i...

  9. Mixed Connective Tissue Disease

    Science.gov (United States)

    Mixed connective tissue disease Overview Mixed connective tissue disease has signs and symptoms of a combination of disorders — primarily lupus, scleroderma and polymyositis. For this reason, mixed connective tissue disease ...

  10. Undifferentiated Connective Tissue Disease

    Science.gov (United States)

    ... Home Conditions Undifferentiated Connective Tissue Disease (UCTD) Undifferentiated Connective Tissue Disease (UCTD) Make an Appointment Find a Doctor ... by Barbara Goldstein, MD (February 01, 2016) Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune disease. This ...

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

    Science.gov (United States)

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

    2018-05-01

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

  12. Regulation of Substantia Nigra Pars Reticulata GABAergic Neuron Activity by H2O2 via Flufenamic Acid-Sensitive Channels and KATP Channels

    Science.gov (United States)

    Lee, Christian R.; Witkovsky, Paul; Rice, Margaret E.

    2011-01-01

    Substantia nigra pars reticulata (SNr) GABAergic neurons are key output neurons of the basal ganglia. Given the role of these neurons in motor control, it is important to understand factors that regulate their firing rate and pattern. One potential regulator is hydrogen peroxide (H2O2), a reactive oxygen species that is increasingly recognized as a neuromodulator. We used whole-cell current clamp recordings of SNr GABAergic neurons in guinea-pig midbrain slices to determine how H2O2 affects the activity of these neurons and to explore the classes of ion channels underlying those effects. Elevation of H2O2 levels caused an increase in the spontaneous firing rate of SNr GABAergic neurons, whether by application of exogenous H2O2 or amplification of endogenous H2O2 through inhibition of glutathione peroxidase with mercaptosuccinate. This effect was reversed by flufenamic acid (FFA), implicating transient receptor potential (TRP) channels. Conversely, depletion of endogenous H2O2 by catalase, a peroxidase enzyme, decreased spontaneous firing rate and firing precision of SNr neurons, demonstrating tonic control of firing rate by H2O2. Elevation of H2O2 in the presence of FFA revealed an inhibition of tonic firing that was prevented by blockade of ATP-sensitive K+ (KATP) channels with glibenclamide. In contrast to guinea-pig SNr neurons, the dominant effect of H2O2 elevation in mouse SNr GABAergic neurons was hyperpolarization, indicating a species difference in H2O2-dependent regulation. Thus, H2O2 is an endogenous modulator of SNr GABAergic neurons, acting primarily through presumed TRP channels in guinea-pig SNr, with additional modulation via KATP channels to regulate SNr output. PMID:21503158

  13. Intermodal Passenger Connectivity Database -

    Data.gov (United States)

    Department of Transportation — The Intermodal Passenger Connectivity Database (IPCD) is a nationwide data table of passenger transportation terminals, with data on the availability of connections...

  14. Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

    Science.gov (United States)

    Villette, Vincent; Poindessous-Jazat, Frédérique; Simon, Axelle; Léna, Clément; Roullot, Elodie; Bellessort, Brice; Epelbaum, Jacques; Dutar, Patrick; Stéphan, Aline

    2010-08-18

    The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

  15. Effects of met-enkephalin on GABAergic spontaneous miniature IPSPs in organotypic slice cultures of the rat hippocampus

    DEFF Research Database (Denmark)

    Rekling, J C

    1993-01-01

    The action of met-enkephalin on GABAergic spontaneous miniature IPSPs (smIPSPs) was investigated in CA1 neurons from hippocampal slice cultures. In the presence of excitatory amino acid blockers (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline, DL-2-amino-5-phosphonovaleric acid) and TTX...... the amplitude distribution of the smIPSPs. The proportion of "large" smIPSPs was reduced, but a loss of "small" smIPSPs also contributed to the reduction in smIPSP frequency. The selective mu-receptor agonist DAGO mimicked the effect of met-enkephalin and naloxone blocked the effect of DAGO. Hyperpolarization......IPSP frequency, nor did it block the effect of DAGO. These results suggest that CA1 pyramidal cells of hippocampal organotypic cultures are tonically inhibited by spontaneous release of GABA, through a release mechanism that is independent of propagated sodium action potentials. Met-enkephalin and DAGO reduce...

  16. Improving treatment of patients with schizophrenia - glutamatergic and GABAergic disturbances as possible markers of choice-of-treatment

    DEFF Research Database (Denmark)

    Bojesen, Kirsten Borup; Jessen, Kasper; Rostrup, Egill

    the progressive loss of brain tissue and functions seen in many patients. The neurotransmitter gamma-amino-butyric-acid, (GABA), regulates levels of glutamate, and hypofunctional GABAergic interneurons may cause the high levels of glutamate in patients with schizophrenia. Objectives: To test the hypothesis...... of glutamate and GABA and psychopathology as well as level of function. Methods: The study is a prospective follow-up study of 60 antipsychotic naïve patients with schizophrenia and 60 matched healthy controls. Levels of glutamate and GABA are measured with proton magnetic resonance imaging (1H-MRS) before......Background: Insufficient treatment response to dopaminergic antipsychotics constitutes a major challenge in the treatment of patients with schizophrenia and seems to be related to persistently high levels of the neurotransmitter glutamate. Excess glutamate is neurotoxic and highly likely causes...

  17. Prior stress promotes the generalization of contextual fear memories: Involvement of the gabaergic signaling within the basolateral amygdala complex.

    Science.gov (United States)

    Bender, C L; Otamendi, A; Calfa, G D; Molina, V A

    2018-04-20

    Fear generalization occurs when a response, previously acquired with a threatening stimulus, is transferred to a similar one. However, it could be maladaptive when stimuli that do not represent a real threat are appraised as dangerous, which is a hallmark of several anxiety disorders. Stress exposure is a major risk factor for the occurrence of anxiety disorders and it is well established that it influences different phases of fear memory; nevertheless, its impact on the generalization of contextual fear memories has been less studied. In the present work, we have characterized the impact of acute restraint stress prior to contextual fear conditioning on the generalization of this fear memory, and the role of the GABAergic signaling within the basolateral amygdala complex (BLA) on the stress modulatory effects. We have found that a single stress exposure promoted the generalization of this memory trace to a different context that was well discriminated in unstressed conditioned animals. Moreover, this effect was dependent on the formation of a contextual associative memory and on the testing order (i.e., conditioning context first vs generalization context first). Furthermore, we observed that increasing GABA-A signaling by intra-BLA midazolam administration prior to the stressful session exposure prevented the generalization of fear memory, whereas intra-BLA administration of the GABA-A antagonist (Bicuculline), prior to fear conditioning, induced the generalization of fear memory in unstressed rats. We concluded that stress exposure, prior to contextual fear conditioning, promotes the generalization of fear memory and that the GABAergic transmission within the BLA has a critical role in this phenomenon. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Chaoborus and gasterosteus anti-predator responses in Daphnia pulex are mediated by independent cholinergic and gabaergic neuronal signals.

    Directory of Open Access Journals (Sweden)

    Linda C Weiss

    Full Text Available Many prey species evolved inducible defense strategies that protect effectively against predation threats. Especially the crustacean Daphnia emerged as a model system for studying the ecology and evolution of inducible defenses. Daphnia pulex e.g. shows different phenotypic adaptations against vertebrate and invertebrate predators. In response to the invertebrate phantom midge larvae Chaoborus (Diptera D. pulex develops defensive morphological defenses (neckteeth. Cues originating from predatory fish result in life history changes in which resources are allocated from somatic growth to reproduction. While there are hints that responses against Chaoborus cues are transmitted involving cholinergic neuronal pathways, nothing is known about the neurophysiology underlying the transmission of fish related cues. We investigated the neurophysiological basis underlying the activation of inducible defenses in D. pulex using induction assays with the invertebrate predator Chaoborus and the three-spined stickleback Gasterosteus aculeatus. Predator-specific cues were combined with neuro-effective substances that stimulated or inhibited the cholinergic and gabaergic nervous system. We show that cholinergic-dependent pathways are involved in the perception and transmission of Chaoborus cues, while GABA was not involved. Thus, the cholinergic nervous system independently mediates the development of morphological defenses in response to Chaoborus cues. In contrast, only the inhibitory effect of GABA significantly influence fish-induced life history changes, while the application of cholinergic stimulants had no effect in combination with fish related cues. Our results show that cholinergic stimulation mediates signal transmission of Chaoborus cues leading to morphological defenses. Fish cues, which are responsible for predator-specific life history adaptations involve gabaergic control. Our study shows that both pathways are independent and thus potentially

  19. Participation of the GABAergic system in the anesthetic effect of Lippia alba (Mill.) N.E. Brown essential oil

    Energy Technology Data Exchange (ETDEWEB)

    Heldwein, C.G.; Silva, L.L. [Departamento de Farmácia Industrial, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil); Reckziegel, P. [Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil); Barros, F.M.C. [Departamento de Farmácia Industrial, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil); Bürger, M.E.; Baldisserotto, B. [Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil); Mallmann, C.A. [Departamento de Medicina Veterinária Preventiva, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil); Schmidt, D.; Caron, B.O. [Departamento de Ciências Agronômicas e Ambientais, Universidade Federal de Santa Maria, Campus de Frederico Westphalen, Frederico Westphalen, RS (Brazil); Heinzmann, B.M. [Departamento de Farmácia Industrial, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil)

    2012-04-05

    The objective of this study was to identify the possible involvement of the GABAergic system in the anesthetic effect of Lippia alba essential oil (EO). We propose a new animal model using silver catfish (Rhamdia quelen) exposed to an anesthetic bath to study the mechanism of action of EO. To observe the induction and potentiation of the anesthetic effect of EO, juvenile silver catfish (9.30 ± 1.85 g; 10.15 ± 0.95 cm; N = 6) were exposed to various concentrations of L. alba EO in the presence or absence of diazepam [an agonist of high-affinity binding sites for benzodiazepinic (BDZ) sites coupled to the GABA{sub A} receptor complex]. In another experiment, fish (N = 6) were initially anesthetized with the EO and then transferred to an anesthetic-free aquarium containing flumazenil (a selective antagonist of binding sites for BDZ coupled to the GABA{sub A} receptor complex) or water to assess recovery time from the anesthesia. In this case, flumazenil was used to observe the involvement of the GABA-BDZ receptor in the EO mechanism of action. The results showed that diazepam potentiates the anesthetic effect of EO at all concentrations tested. Fish exposed to diazepam and EO showed faster recovery from anesthesia when flumazenil was added to the recovery bath (12.0 ± 0.3 and 7.2 ± 0.7, respectively) than those exposed to water (9.2 ± 0.2 and 3.5 ± 0.3, respectively). In conclusion, the results demonstrated the involvement of the GABAergic system in the anesthetic effect of L. alba EO on silver catfish.

  20. GABAergic Neurons in the Rat Medial Septal Complex Express Relaxin-3 Receptor (RXFP3 mRNA

    Directory of Open Access Journals (Sweden)

    Hector Albert-Gascó

    2018-01-01

    Full Text Available The medial septum (MS complex modulates hippocampal function and related behaviors. Septohippocampal projections promote and control different forms of hippocampal synchronization. Specifically, GABAergic and cholinergic projections targeting the hippocampal formation from the MS provide bursting discharges to promote theta rhythm, or tonic activity to promote gamma oscillations. In turn, the MS is targeted by ascending projections from the hypothalamus and brainstem. One of these projections arises from the nucleus incertus in the pontine tegmentum, which contains GABA neurons that co-express the neuropeptide relaxin-3 (Rln3. Both stimulation of the nucleus incertus and septal infusion of Rln3 receptor agonist peptides promotes hippocampal theta rhythm. The Gi/o-protein-coupled receptor, relaxin-family peptide receptor 3 (RXFP3, is the cognate receptor for Rln3 and identification of the transmitter phenotype of neurons expressing RXFP3 in the septohippocampal system can provide further insights into the role of Rln3 transmission in the promotion of septohippocampal theta rhythm. Therefore, we used RNAscope multiplex in situ hybridization to characterize the septal neurons expressing Rxfp3 mRNA in the rat. Our results demonstrate that Rxfp3 mRNA is abundantly expressed in vesicular GABA transporter (vGAT mRNA- and parvalbumin (PV mRNA-positive GABA neurons in MS, whereas ChAT mRNA-positive acetylcholine neurons lack Rxfp3 mRNA. Approximately 75% of Rxfp3 mRNA-positive neurons expressed vGAT mRNA (and 22% were PV mRNA-positive, while the remaining 25% expressed Rxfp3 mRNA only, consistent with a potential glutamatergic phenotype. Similar proportions were observed in the posterior septum. The occurrence of RXFP3 in PV-positive GABAergic neurons gives support to a role for the Rln3-RXFP3 system in septohippocampal theta rhythm.

  1. Participation of the GABAergic system in the anesthetic effect of Lippia alba (Mill.) N.E. Brown essential oil

    International Nuclear Information System (INIS)

    Heldwein, C.G.; Silva, L.L.; Reckziegel, P.; Barros, F.M.C.; Bürger, M.E.; Baldisserotto, B.; Mallmann, C.A.; Schmidt, D.; Caron, B.O.; Heinzmann, B.M.

    2012-01-01

    The objective of this study was to identify the possible involvement of the GABAergic system in the anesthetic effect of Lippia alba essential oil (EO). We propose a new animal model using silver catfish (Rhamdia quelen) exposed to an anesthetic bath to study the mechanism of action of EO. To observe the induction and potentiation of the anesthetic effect of EO, juvenile silver catfish (9.30 ± 1.85 g; 10.15 ± 0.95 cm; N = 6) were exposed to various concentrations of L. alba EO in the presence or absence of diazepam [an agonist of high-affinity binding sites for benzodiazepinic (BDZ) sites coupled to the GABA A receptor complex]. In another experiment, fish (N = 6) were initially anesthetized with the EO and then transferred to an anesthetic-free aquarium containing flumazenil (a selective antagonist of binding sites for BDZ coupled to the GABA A receptor complex) or water to assess recovery time from the anesthesia. In this case, flumazenil was used to observe the involvement of the GABA-BDZ receptor in the EO mechanism of action. The results showed that diazepam potentiates the anesthetic effect of EO at all concentrations tested. Fish exposed to diazepam and EO showed faster recovery from anesthesia when flumazenil was added to the recovery bath (12.0 ± 0.3 and 7.2 ± 0.7, respectively) than those exposed to water (9.2 ± 0.2 and 3.5 ± 0.3, respectively). In conclusion, the results demonstrated the involvement of the GABAergic system in the anesthetic effect of L. alba EO on silver catfish

  2. Minimum cost connection networks

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Tvede, Mich

    2015-01-01

    In the present paper we consider the allocation of costs in connection networks. Agents have connection demands in form of pairs of locations they want to have connected. Connections between locations are costly to build. The problem is to allocate costs of networks satisfying all connection...... demands. We use a few axioms to characterize allocation rules that truthfully implement cost minimizing networks satisfying all connection demands in a game where: (1) a central planner announces an allocation rule and a cost estimation rule; (2) every agent reports her own connection demand as well...... as all connection costs; (3) the central planner selects a cost minimizing network satisfying reported connection demands based on the estimated costs; and, (4) the planner allocates the true costs of the selected network. It turns out that an allocation rule satisfies the axioms if and only if relative...

  3. Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat.

    Science.gov (United States)

    Zhang, Min; Balmadrid, Christian; Kelley, Ann E

    2003-04-01

    The current studies were designed to evaluate whether incentive motivation for palatable food is altered after manipulations of opioid, GABAergic, and dopaminergic transmission within the nucleus accumbens. A progressive ratio schedule was used to measure lever-pressing for sugar pellets after microinfusion of drugs into the nucleus accumbens in non-food-deprived rats. The mu opioid agonist D-Ala2, NMe-Phe4, Glyo15-enkephalin and the indirect dopamine agonist amphetamine induced a marked increase in break point and correct lever-presses; the GABA(A) agonist muscimol did not affect breakpoint or lever-presses. The data suggest that opioid, dopaminergic, and GABAergic systems within the accumbens differentially modulate food-seeking behavior through mechanisms related to hedonic evaluation of food, incentive salience, and control of motor feeding circuits, respectively.

  4. A possible role of the non-GAT1 GABA transporters in transfer of GABA from GABAergic to glutamatergic neurons in mouse cerebellar neuronal cultures

    DEFF Research Database (Denmark)

    Suñol, C; Babot, Z; Cristòfol, R

    2010-01-01

    Cultures of dissociated cerebellum from 7-day-old mice were used to investigate the mechanism involved in synthesis and cellular redistribution of GABA in these cultures consisting primarily of glutamatergic granule neurons and a smaller population of GABAergic Golgi and stellate neurons......3 transporters. Only a small population of cells were immuno-stained for GAD while many cells exhibited VGlut-1 like immuno-reactivity which, however, never co-localized with GAD positive neurons. This likely reflects the small number of GABAergic neurons compared to the glutamatergic granule......M concentrations (95%). Essentially all neurons showed GABA like immunostaining albeit with differences in intensity. The results indicate that GABA which is synthesized in a small population of GAD-positive neurons is redistributed to essentially all neurons including the glutamatergic granule cells. GAT1...

  5. Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: effects on proactive interference.

    Science.gov (United States)

    Pang, Kevin C H; Jiao, Xilu; Sinha, Swamini; Beck, Kevin D; Servatius, Richard J

    2011-08-01

    The medial septum and diagonal band (MSDB) are important in spatial learning and memory. On the basis of the excitotoxic damage of GABAergic MSDB neurons, we have recently suggested a role for these neurons in controlling proactive interference. Our study sought to test this hypothesis in different behavioral procedures using a new GABAergic immunotoxin. GABA-transporter-saporin (GAT1-SAP) was administered into the MSDB of male Sprague-Dawley rats. Following surgery, rats were trained in a reference memory water maze procedure for 5 days, followed by a working memory (delayed match to position) water maze procedure. Other rats were trained in a lever-press avoidance procedure after intraseptal GAT1-SAP or sham surgery. Intraseptal GAT1-SAP extensively damaged GABAergic neurons while sparing most cholinergic MSDB neurons. Rats treated with GAT1-SAP were not impaired in acquiring a spatial reference memory, learning the location of the escape platform as rapidly as sham rats. In contrast, GAT1-SAP rats were slower than sham rats to learn the platform location in a delayed match to position procedure, in which the platform location was changed every day. Moreover, GAT1-SAP rats returned to previous platform locations more often than sham rats. In the active avoidance procedure, intraseptal GAT1-SAP impaired extinction but not acquisition of the avoidance response. Using a different neurotoxin and behavioral procedures than previous studies, the results of this study paint a similar picture that GABAergic MSDB neurons are important for controlling proactive interference. Copyright © 2010 Wiley-Liss, Inc.

  6. Ergosteryl 2-naphthoate, An Ergosterol Derivative, Exhibits Antidepressant Effects Mediated by the Modification of GABAergic and Glutamatergic Systems

    Directory of Open Access Journals (Sweden)

    Mingzhu Lin

    2017-03-01

    Full Text Available Phytosterols are a kind of natural component including sitosterol, campesterol, avenasterol, ergosterol (Er and others. Their main natural sources are vegetable oils and their processed products, followed by grains, by-products of cereals and nuts, and small amounts of fruits, vegetables and mushrooms. In this study, three new Er monoester derivatives were obtained from the reflux reaction with Er: organic acids (furoic acid, salicylic acid and 2-naphthoic acid, 1-Ethylethyl-3-(3-dimethyllaminopropyl carbodiimide hydrochloride (EDCI and 4-dimethylaminopyridine (DMAP in dichloromethane. Their chemical structures were defined by IR and NMR. The present study was also undertaken to investigate the antidepressant-like effects of Er and its derivatives in male adult mice models of depression, and their probable involvement of GABAergic and glutamatergic systems by the forced swim test (FST. The results indicated that Er and its derivatives display antidepressant effects. Moreover, one derivative of Er, ergosteryl 2-naphthoate (ErN, exhibited stronger antidepressant activity in vivo compared to Er. Acute administration of ErN (5 mg/kg, i.p. and a combination of ErN (0.5 mg/kg, i.p., reboxetine (2.5 mg/kg, i.p., and tianeptine (15 mg/kg, i.p. reduced the immobility time in the FST. Pretreatment with bicuculline (a competitive γ-aminobutyric acid (GABA antagonist, 4 mg/kg, i.p. and N-methyl-d-aspartic acid (NMDA, an agonist at the glutamate site, 75 mg/kg, i.p. effectively reversed the antidepressant-like effect of ErN (5 mg/kg, i.p.. However, prazosin (a α1-adrenoceptor antagonist, 1 mg/kg, i.p. and haloperidol (a non-selective D2 receptor antagonist, 0.2 mg/kg, i.p. did not eliminate the reduced immobility time. Altogether, these results indicated that ErN produced antidepressant-like activity, which might be mediated by GABAergic and glutamatergic systems.

  7. GABAergic and cortical and subcortical glutamatergic axon terminals contain CB1 cannabinoid receptors in the ventromedial nucleus of the hypothalamus.

    Directory of Open Access Journals (Sweden)

    Leire Reguero

    Full Text Available BACKGROUND: Type-1 cannabinoid receptors (CB(1R are enriched in the hypothalamus, particularly in the ventromedial hypothalamic nucleus (VMH that participates in homeostatic and behavioral functions including food intake. Although CB(1R activation modulates excitatory and inhibitory synaptic transmission in the brain, CB(1R contribution to the molecular architecture of the excitatory and inhibitory synaptic terminals in the VMH is not known. Therefore, the aim of this study was to investigate the precise subcellular distribution of CB(1R in the VMH to better understand the modulation exerted by the endocannabinoid system on the complex brain circuitries converging into this nucleus. METHODOLOGY/PRINCIPAL FINDINGS: Light and electron microscopy techniques were used to analyze CB(1R distribution in the VMH of CB(1R-WT, CB(1R-KO and conditional mutant mice bearing a selective deletion of CB(1R in cortical glutamatergic (Glu-CB(1R-KO or GABAergic neurons (GABA-CB(1R-KO. At light microscopy, CB(1R immunolabeling was observed in the VMH of CB(1R-WT and Glu-CB(1R-KO animals, being remarkably reduced in GABA-CB(1R-KO mice. In the electron microscope, CB(1R appeared in membranes of both glutamatergic and GABAergic terminals/preterminals. There was no significant difference in the percentage of CB(1R immunopositive profiles and CB(1R density in terminals making asymmetric or symmetric synapses in CB(1R-WT mice. Furthermore, the proportion of CB(1R immunopositive terminals/preterminals in CB(1R-WT and Glu-CB(1R-KO mice was reduced in GABA-CB(1R-KO mutants. CB(1R density was similar in all animal conditions. Finally, the percentage of CB(1R labeled boutons making asymmetric synapses slightly decreased in Glu-CB(1R-KO mutants relative to CB(1R-WT mice, indicating that CB(1R was distributed in cortical and subcortical excitatory synaptic terminals. CONCLUSIONS/SIGNIFICANCE: Our anatomical results support the idea that the VMH is a relevant hub candidate in

  8. Connected vehicle standards.

    Science.gov (United States)

    2016-01-01

    Connected vehicles have the potential to transform the way Americans travel by : allowing cars, buses, trucks, trains, traffic signals, smart phones, and other devices to : communicate through a safe, interoperable wireless network. A connected vehic...

  9. Inward rectifier K+ channel and T-type Ca2+ channel contribute to enhancement of GABAergic transmission induced by β1-adrenoceptor in the prefrontal cortex.

    Science.gov (United States)

    Luo, Fei; Zheng, Jian; Sun, Xuan; Tang, Hua

    2017-02-01

    The functions of prefrontal cortex (PFC) are sensitive to norepinephrine (NE). Endogenously released NE influences synaptic transmission through activation of different subtypes of adrenergic receptors in PFC including α 1 , α 2 , β 1 or β 2 -adrenoceptor. Our recent study has revealed that β 1 -adrenoceptor (β 1 -AR) activation modulates glutamatergic transmission in the PFC, whereas the roles of β 1 -AR in GABAergic transmission are elusive. In the current study, we probed the effects of the β 1 -AR agonist dobutamine (Dobu) on GABAergic transmission onto pyramidal neurons in the PFC of juvenile rats. Dobu increased both the frequency and amplitude of miniature IPSCs (mIPSCs). Ca 2+ influx through T-type voltage-gated Ca 2+ channel was required for Dobu-enhanced mIPSC frequency. We also found that Dobu facilitated GABA release probability and the number of releasable vesicles through regulating T-type Ca 2+ channel. Dobu depolarized GABAergic fast-spiking (FS) interneurons with no effects on the firing rate of action potentials (APs) of interneurons. Dobu-induced depolarization of FS interneurons required inward rectifier K + channel (Kir). Our results suggest that Dobu increase GABA release via inhibition of Kir, which further depolarizes FS interneurons resulting in Ca 2+ influx via T-type Ca 2+ channel. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Connecting to Everyday Practices

    DEFF Research Database (Denmark)

    Iversen, Ole Sejer; Smith, Rachel Charlotte

    2012-01-01

    construction and reproduction of cultural heritage creating novel connections between self and others and between past, present and future. We present experiences from a current research project, the Digital Natives exhibition, in which social media was designed as an integral part of the exhibition to connect...... focusing on the connections between audiences practices and the museum exhibition....

  11. Possible GABAergic modulation in the protective effect of zolpidem in acute hypoxic stress-induced behavior alterations and oxidative damage.

    Science.gov (United States)

    Kumar, Anil; Goyal, Richa

    2008-03-01

    Hypoxia is an environmental stressor that is known to elicit alterations in both the autonomic nervous system and endocrine functions. The free radical or oxidative stress theory holds that oxidative reactions are mainly underlying neurodegenerative disorders. In fact among complex metabolic reactions occurring during hypoxia, many could be related to the formation of oxygen derived free radicals, causing a wide spectrum of cell damage. In present study, we investigated possible involvement of GABAergic mechanism in the protective effect of zolpidem against acute hypoxia-induced behavioral modification and biochemical alterations in mice. Mice were subjected to acute hypoxic stress for a period of 2 h. Acute hypoxic stress for 2 h caused significant impairment in locomotor activity, anxiety-like behavior, and antinocioceptive effect in mice. Biochemical analysis revealed a significant increased malondialdehyde, nitrite concentrations and depleted reduced glutathione and catalase levels. Pretreatment with zolpidem (5 and 10 mg/kg, i.p.) significantly improved locomotor activity, anti-anxiety effect, reduced tail flick latency and attenuated oxidative damage (reduced malondialdehyde, nitrite concentration, and restoration of reduced glutathione and catalase levels) as compared to stressed control (hypoxia) (P zolpidem (5 mg/kg) was blocked significantly by picrotoxin (1.0 mg/kg) or flumazenil (2 mg/kg) and potentiated by muscimol (0.05 mg/kg) in hypoxic animals (P zolpidem (5 mg/kg) per se (P zolpidem against hypoxic stress.

  12. Effects of Fluoxetine and Visual Experience on Glutamatergic and GABAergic Synaptic Proteins in Adult Rat Visual Cortex123

    Science.gov (United States)

    Beshara, Simon; Beston, Brett R.; Pinto, Joshua G. A.

    2015-01-01

    Abstract Fluoxetine has emerged as a novel treatment for persistent amblyopia because in adult animals it reinstates critical period-like ocular dominance plasticity and promotes recovery of visual acuity. Translation of these results from animal models to the clinic, however, has been challenging because of the lack of understanding of how this selective serotonin reuptake inhibitor affects glutamatergic and GABAergic synaptic mechanisms that are essential for experience-dependent plasticity. An appealing hypothesis is that fluoxetine recreates a critical period (CP)-like state by shifting synaptic mechanisms to be more juvenile. To test this we studied the effect of fluoxetine treatment in adult rats, alone or in combination with visual deprivation [monocular deprivation (MD)], on a set of highly conserved presynaptic and postsynaptic proteins (synapsin, synaptophysin, VGLUT1, VGAT, PSD-95, gephyrin, GluN1, GluA2, GluN2B, GluN2A, GABAAα1, GABAAα3). We did not find evidence that fluoxetine shifted the protein amounts or balances to a CP-like state. Instead, it drove the balances in favor of the more mature subunits (GluN2A, GABAAα1). In addition, when fluoxetine was paired with MD it created a neuroprotective-like environment by normalizing the glutamatergic gain found in adult MDs. Together, our results suggest that fluoxetine treatment creates a novel synaptic environment dominated by GluN2A- and GABAAα1-dependent plasticity. PMID:26730408

  13. Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism.

    Science.gov (United States)

    Naaijen, J; Bralten, J; Poelmans, G; Glennon, J C; Franke, B; Buitelaar, J K

    2017-01-10

    Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.

  14. Involvement of GABAergic pathway in the sedative activity of apigenin, the main flavonoid from Passiflora quadrangularis pericarp

    Directory of Open Access Journals (Sweden)

    Andressa C. Gazola

    Full Text Available Abstract In the current study we showed that oral administration of an aqueous extract of Passiflora quadrangularis L., Passifloraceae, pericarp results in a significant prolongation of the sleep duration in mice evaluated in the ethyl ether-induced hypnosis test which indicates sedative effects. Apigenin, the main flavonoid of the extract, induced a similar sedative response when applied alone, at a dose equivalent to that found in the extract, suggesting that apigenin is mediating the sedative effects of P. quadrangularis extract. In addition, the sedative effect of apigenin was blocked by pretreatment with the benzodiazepine antagonist flumazenil (1 mg/kg, suggesting an interaction of apigenin with gamma-aminobutyric acid type A (GABAA receptors. However, apigenin at concentrations 0.1–50 µM failed to enhance GABA-induced currents through GABAA receptors (α1β2γ2S expressed in Xenopus oocytes. Nevertheless, based on our results, we suggest that the in vivo sedative effect of the P. quadrangularis extract and its main flavonoid apigenin maybe be due to an enhancement of the GABAergic system.

  15. 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.

  16. Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex.

    Science.gov (United States)

    Jeong, Da Un; Oh, Jin Hwan; Lee, Ji Eun; Lee, Jihyeon; Cho, Zang Hee; Chang, Jin Woo; Chang, Won Seok

    2016-01-01

    Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by ¹⁸F-2-fluoro-2-deoxyglucose positron emission tomography. During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.

  17. Positive effects of β-amyrin on pentobarbital-induced sleep in mice via GABAergic neurotransmitter system.

    Science.gov (United States)

    Jeon, Se Jin; Park, Ho Jae; Gao, Qingtao; Lee, Hyung Eun; Park, Se Jin; Hong, Eunyoung; Jang, Dae Sik; Shin, Chan Young; Cheong, Jae Hoon; Ryu, Jong Hoon

    2015-09-15

    Sleep loss, insomnia, is considered a sign of imbalance of physiological rhythm, which can be used as pre-clinic diagnosis of various neuropsychiatric disorders. The aim of the present study is to understand the pharmacological actions of α- or β-amyrin, natural triterpene compound, on the sleep in mice. To analyze the sleeping behavior, we used the well-known pentobarbital-induced sleeping model after single administration of either α- or β-amyrin. The sleeping onset time was remarkably decreased and duration was prolonged by β-amyrin (1, 3, or 10mg/kg) but not by α-amyrin (1, 3, or 10mg/kg). These effects were significantly blocked by GABAA receptor antagonist, bicuculline. Moreover, β-amyrin increased brain GABA level compared to the vehicle administration. Overall, the present study suggests that β-amyrin would enhance the total sleeping behavior in pentobarbital-induced sleeping model via the activation of GABAergic neurotransmitter system through GABA content in the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Chronically reinforced, operant olfactory conditioning increases the number of newborn GABAergic olfactory periglomerular neurons in the adult rat.

    Science.gov (United States)

    Tapia-Rodríguez, Miguel; Esquivelzeta-Rabell, José F; Gutiérrez-Ospina, Gabriel

    2012-12-01

    The mammalian brain preserves the ability to replace olfactory periglomerular cells (PGC) throughout life. Even though we have detailed a great deal the mechanisms underlying stem and amplifying cells maintenance and proliferation, as well as those modulating migration and differentiation, our knowledge on PGC phenotypic plasticity is at best fragmented and controversial. Here we explored whether chronically reinforced olfactory conditioning influences the phenotype of newborn PGC. Accordingly, olfactory conditioned rats showed increased numbers of GAD 65/67 positive PGC. Because such phenotypic change was not accompanied neither by increments in the total number of PGC, or periglomerular cell nuclei labeled with bromodeoxyuridine, nor by reductions in the number of tyrosine hydroxylase (TH), calbindin (CB) or calretinin (CR) immunoreactive PGC, we speculate that increments in the number of GABAergic PGC occur at the expense of other PGC phenotypes. In any event, these results support that adult newborn PGC phenotype may be subjected to phenotypic plasticity influenced by sensory stimulation. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Network connectivity value.

    Science.gov (United States)

    Dragicevic, Arnaud; Boulanger, Vincent; Bruciamacchie, Max; Chauchard, Sandrine; Dupouey, Jean-Luc; Stenger, Anne

    2017-04-21

    In order to unveil the value of network connectivity, we formalize the construction of ecological networks in forest environments as an optimal control dynamic graph-theoretic problem. The network is based on a set of bioreserves and patches linked by ecological corridors. The node dynamics, built upon the consensus protocol, form a time evolutive Mahalanobis distance weighted by the opportunity costs of timber production. We consider a case of complete graph, where the ecological network is fully connected, and a case of incomplete graph, where the ecological network is partially connected. The results show that the network equilibrium depends on the size of the reception zone, while the network connectivity depends on the environmental compatibility between the ecological areas. Through shadow prices, we find that securing connectivity in partially connected networks is more expensive than in fully connected networks, but should be undertaken when the opportunity costs are significant. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Cell-Type-Specific Circuit Connectivity of Hippocampal CA1 Revealed through Cre-Dependent Rabies Tracing

    Directory of Open Access Journals (Sweden)

    Yanjun Sun

    2014-04-01

    Full Text Available We developed and applied a Cre-dependent, genetically modified rabies-based tracing system to map direct synaptic connections to specific CA1 neuron types in the mouse hippocampus. We found common inputs to excitatory and inhibitory CA1 neurons from CA3, CA2, the entorhinal cortex (EC, the medial septum (MS, and, unexpectedly, the subiculum. Excitatory CA1 neurons receive inputs from both cholinergic and GABAergic MS neurons, whereas inhibitory neurons receive a great majority of inputs from GABAergic MS neurons. Both cell types also receive weaker input from glutamatergic MS neurons. Comparisons of inputs to CA1 PV+ interneurons versus SOM+ interneurons showed similar strengths of input from the subiculum, but PV+ interneurons received much stronger input than SOM+ neurons from CA3, the EC, and the MS. Thus, rabies tracing identifies hippocampal circuit connections and maps how the different input sources to CA1 are distributed with different strengths on each of its constituent cell types.

  1. Localization, distribution, and connectivity of neuropeptide Y in the human and porcine retinas-A comparative study.

    Science.gov (United States)

    Christiansen, Anders Tolstrup; Kiilgaard, Jens Folke; Klemp, Kristian; Woldbye, David Paul Drucker; Hannibal, Jens

    2018-04-17

    Neuropeptide Y (NPY) is a peptide neurotransmitter abundantly expressed in the mammalian retina. Since its discovery, NPY has been studied in retinas of several species, but detailed characterization of morphology, cell-type, and connectivity has never been conducted in larger mammals including humans and pigs. As the pig due to size and cellular composition is a well-suited animal for retinal research, we chose to compare the endogenous NPY system of the human retina to that of pigs to support future research in this field. In the present study, using immunohistochemistry, confocal microscopy and 3D reconstructions, we found NPY to be expressed in GABAergic and calretinin-immunoreactive (-ir) amacrine cells of both species as well as parvalbumin-ir amacrine cells of humans. Furthermore, we identified at least two different types of medium- to wide-field NPY-ir amacrine cells. Finally, we detected likely synaptic appositions between the NPY-ir amacrine cells and melanopsin- and nonmelanopsin-ir ganglion cells, GABAergic and dopaminergic amacrine cells, rod bipolar cells, and horizontal cells, suggesting that NPY-ir cells play diverse roles in modulation of both image and non-image forming retinal signaling. These findings extend existing knowledge on NPY and NPY-expressing cells in the human and porcine retina showing a high degree of comparability. The extensive distribution and connectivity of NPY-ir cells described in the present study further highlights the potential importance of NPY signaling in retinal function. © 2018 Wiley Periodicals, Inc.

  2. Effects of GABAergic modulators on food and cocaine self-administration in baboons.

    Science.gov (United States)

    Weerts, Elise M; Froestl, Wolfgang; Griffiths, Roland R

    2005-12-12

    Drugs that indirectly alter dopaminergic systems may alter the reinforcing effects of cocaine. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has extensive neural connections in mesolimbic regions that appear to modulate dopamine. The current study evaluated the effects of GABA(B) receptor agonists baclofen and CGP44532, the benzodiazepine agonist alprazolam, and the GABA reuptake inhibitor tiagabine on lever responding maintained by low dose cocaine injections (0.032 mg/kg) or by food pellet (1 g) delivery in baboons. The benzodiazepine antagonist flumazenil was tested as a negative control. Cocaine or food was available under a fixed ratio (FR 10) schedule of reinforcement during daily 2-h sessions. During baseline conditions, cocaine and pellets maintained similar numbers of reinforcers per session. Baclofen, CGP44532 and tiagabine dose-dependently reduced the number of cocaine injections, where as the benzodiazepine antagonist flumazenil did not. Baclofen, CGP44532 and tiagabine also produced dose-related decreases in food-maintained behavior. In contrast, the benzodiazepine agonist alprazolam, which positively modulates GABA(A) receptors via the benzodiazepine site, produced decreases in cocaine self-injection, but not food-maintained behavior. Thus, the effects of alprazolam were specific for cocaine-maintained behavior, where as the effects of baclofen and CGP44532 were not.

  3. Layer 5 Callosal Parvalbumin-Expressing Neurons: A Distinct Functional Group of GABAergic Neurons.

    Science.gov (United States)

    Zurita, Hector; Feyen, Paul L C; Apicella, Alfonso Junior

    2018-01-01

    Previous studies have shown that parvalbumin-expressing neurons (CC-Parv neurons) connect the two hemispheres of motor and sensory areas via the corpus callosum, and are a functional part of the cortical circuit. Here we test the hypothesis that layer 5 CC-Parv neurons possess anatomical and molecular mechanisms which dampen excitability and modulate the gating of interhemispheric inhibition. In order to investigate this hypothesis we use viral tracing to determine the anatomical and electrophysiological properties of layer 5 CC-Parv and parvalbumin-expressing (Parv) neurons of the mouse auditory cortex (AC). Here we show that layer 5 CC-Parv neurons had larger dendritic fields characterized by longer dendrites that branched farther from the soma, whereas layer 5 Parv neurons had smaller dendritic fields characterized by shorter dendrites that branched nearer to the soma. The layer 5 CC-Parv neurons are characterized by delayed action potential (AP) responses to threshold currents, lower firing rates, and lower instantaneous frequencies compared to the layer 5 Parv neurons. Kv1.1 containing K + channels are the main source of the AP repolarization of the layer 5 CC-Parv and have a major role in determining both the spike delayed response, firing rate and instantaneous frequency of these neurons.

  4. Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

    Science.gov (United States)

    Abekawa, Tomohiro; Ito, Koki; Nakagawa, Shin; Koyama, Tsukasa

    2007-06-01

    Neurodevelopmental deficits of parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.

  5. Handbook of networking & connectivity

    CERN Document Server

    McClain, Gary R

    1994-01-01

    Handbook of Networking & Connectivity focuses on connectivity standards in use, including hardware and software options. The book serves as a guide for solving specific problems that arise in designing and maintaining organizational networks.The selection first tackles open systems interconnection, guide to digital communications, and implementing TCP/IP in an SNA environment. Discussions focus on elimination of the SNA backbone, routing SNA over internets, connectionless versus connection-oriented networks, internet concepts, application program interfaces, basic principles of layering, proto

  6. 78 FR 55684 - ConnectED Workshop

    Science.gov (United States)

    2013-09-11

    ... tools move everything from homework assignments to testing into the cloud. The workshop will explore possible strategies to connect virtually all of our students to next-generation broadband in a timely, cost-effective way. It will also share promising practices, from NTIA's Broadband Technology Opportunities...

  7. The Connected Traveler

    Energy Technology Data Exchange (ETDEWEB)

    Young, Stanley

    2017-04-24

    The Connected Traveler project is a multi-disciplinary undertaking that seeks to validate potential for transformative transportation system energy savings by incentivizing energy efficient travel behavior.

  8. Connections: All Issues

    Science.gov (United States)

    Goals Recycling Green Purchasing Pollution Prevention Reusing Water Resources Environmental Management Plateau, and more... Connections Newsletter December 2016 December 2016 Science-themed gifts available at

  9. GABAergic contributions to gating, timing, and phase precession of hippocampal neuronal activity during theta oscillations.

    Science.gov (United States)

    Cutsuridis, Vassilis; Hasselmo, Michael

    2012-07-01

    Successful spatial exploration requires gating, storage, and retrieval of spatial memories in the correct order. The hippocampus is known to play an important role in the temporal organization of spatial information. Temporally ordered spatial memories are encoded and retrieved by the firing rate and phase of hippocampal pyramidal cells and inhibitory interneurons with respect to ongoing network theta oscillations paced by intra- and extrahippocampal areas. Much is known about the anatomical, physiological, and molecular characteristics as well as the connectivity and synaptic properties of various cell types in the hippocampal microcircuits, but how these detailed properties of individual neurons give rise to temporal organization of spatial memories remains unclear. We present a model of the hippocampal CA1 microcircuit based on observed biophysical properties of pyramidal cells and six types of inhibitory interneurons: axo-axonic, basket, bistratistified, neurogliaform, ivy, and oriens lacunosum-moleculare cells. The model simulates a virtual rat running on a linear track. Excitatory transient inputs come from the entorhinal cortex (EC) and the CA3 Schaffer collaterals and impinge on both the pyramidal cells and inhibitory interneurons, whereas inhibitory inputs from the medial septum impinge only on the inhibitory interneurons. Dopamine operates as a gate-keeper modulating the spatial memory flow to the PC distal dendrites in a frequency-dependent manner. A mechanism for spike-timing-dependent plasticity in distal and proximal PC dendrites consisting of three calcium detectors, which responds to the instantaneous calcium level and its time course in the dendrite, is used to model the plasticity effects. The model simulates the timing of firing of different hippocampal cell types relative to theta oscillations, and proposes functional roles for the different classes of the hippocampal and septal inhibitory interneurons in the correct ordering of spatial memories

  10. The anxiolytic-like effect of 6-styryl-2-pyrone in mice involves GABAergic mechanism of action.

    Science.gov (United States)

    Chaves, Edna Maria Camelo; Honório-Júnior, Jose Eduardo Ribeiro; Sousa, Caren Nádia Soares; Monteiro, Valdécio Silveira; Nonato, Dayanne Terra Tenório; Dantas, Leonardo Pimentel; Lúcio, Ana Silvia Suassuna Carneiro; Barbosa-Filho, José Maria; Patrocínio, Manoel Cláudio Azevedo; Viana, Glauce Socorro Barros; Vasconcelos, Silvânia Maria Mendes

    2018-02-01

    The present work aims to investigate the anxiolytic activity of 6-styryl-2-pyrone (STY), obtained from Aniba panurensis, in behavioral tests and amino acids dosage on male Swiss mice. The animals were treated with STY (1, 10 or 20 mg), diazepam (DZP 1 or 2 mg/kg) or imipramine (IMI 30 mg/kg). Some groups were administered with flumazenil, 30 min before administration of the STYor DZP. The behavioral tests performed were open field, rota rod, elevated plus maze (EPM), hole-board (HB) and tail suspension test (TST). After behavioral tests, these animals were sacrificed and had their prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) dissected for assaying amino acids (aspartate- ASP, glutamate- GLU, glycine- GLY, taurine- TAU and Gamma-aminobutyric acid- GABA). In EPM test, STY or DZP increased the number of entries and the time of permanence in the open arms, but these effects were reverted by flumazenil. In the HB test, STY increased the number of head dips however this effect was blocked by flumazenil. The effects of the STY on amino acid concentration in PFC showed increased GLU, GABA and TAU concentrations. In hippocampus, STY increased the concentrations of all amino acids studied. In striatum, STY administration at lowest dose reduced GLU concentrations, while the highest dosage caused the opposite effect. GLI, TAU and GABA concentrations increased with STY administration at highest doses. In conclusion, this study showed that STY presents an anxiolytic-like effect in behavioral tests that probably is related to GABAergic mechanism of action.

  11. GABAergic transmission and chloride equilibrium potential are not modulated by pyruvate in the developing optic tectum of Xenopus laevis tadpoles.

    Directory of Open Access Journals (Sweden)

    Arseny S Khakhalin

    Full Text Available In the developing mammalian brain, gamma-aminobutyric acid (GABA is thought to play an excitatory rather than an inhibitory role due to high levels of intracellular Cl(- in immature neurons. This idea, however, has been questioned by recent studies which suggest that glucose-based artificial cerebrospinal fluid (ACSF may be inadequate for experiments on immature and developing brains. These studies suggest that immature neurons may require alternative energy sources, such as lactate or pyruvate. Lack of these other energy sources is thought to result in artificially high intracellular Cl(- concentrations, and therefore a more depolarized GABA receptor (GABAR reversal potential. Since glucose metabolism can vary widely among different species, it is important to test the effects of these alternative energy sources on different experimental preparations. We tested whether pyruvate affects GABAergic transmission in isolated brains of developing wild type Xenopus tadpoles in vitro by recording the responsiveness of tectal neurons to optic nerve stimulation, and by measuring currents evoked by local GABA application in a gramicidin perforated patch configuration. We found that, in contrast with previously reported results, the reversal potential for GABAR-mediated currents does not change significantly between developmental stages 45 and 49. Partial substitution of glucose by pyruvate had only minor effects on both the GABA reversal potential, and the responsiveness of tectal neurons at stages 45 and 49. Total depletion of energy sources from the ACSF did not affect neural responsiveness. We also report a strong spatial gradient in GABA reversal potential, with immature cells adjacent to the lateral and caudal proliferative zones having more positive reversal potentials. We conclude that in this experimental preparation standard glucose-based ACSF is an appropriate extracellular media for in vitro experiments.

  12. The role of GABAergic system on the inhibitory effect of ghrelin on food intake in neonatal chicks.

    Science.gov (United States)

    Jonaidi, H; Abbassi, L; Yaghoobi, M M; Kaiya, H; Denbow, D M; Kamali, Y; Shojaei, B

    2012-06-27

    Ghrelin is a gut-brain peptide that has a stimulatory effect on food intake in mammals. In contrast, this peptide decreases food intake in neonatal chicks when injected intracerebroventricularly (ICV). In mammals, neuropeptide Y (NPY) mediates the orexigenic effect of ghrelin whereas in chicks it appears that corticotrophin releasing factor (CRF) is partially involved in the inhibitory effect of ghrelin on food intake. Gamma aminobutyric acid (GABA) has a stimulatory effect on food intake in mammals and birds. In this study we investigated whether the anorectic effect of ghrelin is mediated by the GABAergic system. In Experiment 1, 3h-fasted chicks were given an ICV injection of chicken ghrelin and picrotoxin, a GABA(A) receptors antagonist. Picrotoxin decreased food intake compared to the control chicks indicating a stimulatory effect of GABA(A) receptors on food intake. However, picrotoxin did not alter the inhibitory effect of ghrelin on food intake. In Experiment 2, THIP hydrochloride, a GABA(A) receptor agonist, was used in place of picrotoxin. THIP hydrochloride appeared to partially attenuate the decrease in food intake induced by ghrelin at 30 min postinjection. In Experiment 3, the effect of ICV injection of chicken ghrelin on gene expression of glutamate decarboxylase (GAD)(1) and GAD(2), GABA synthesis enzymes in the brain stem including hypothalamus, was investigated. The ICV injection of chicken ghrelin significantly reduced GAD(2) gene expression. These findings suggest that ghrelin may decrease food intake in neonatal chicks by reducing GABA synthesis and thereby GABA release within brain feeding centers. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  13. A single GABAergic neuron mediates feedback of odor-evoked signals in the mushroom body of larval Drosophila

    Directory of Open Access Journals (Sweden)

    Liria Monica Masuda-Nakagawa

    2014-04-01

    Full Text Available Inhibition has a central role in defining the selectivity of the responses of higher order neurons to sensory stimuli. However, the circuit mechanisms of regulation of these responses by inhibitory neurons are still unclear. In Drosophila, the mushroom bodies (MBs are necessary for olfactory memory, and by implication for the selectivity of learned responses to specific odors. To understand the circuitry of inhibition in the calyx (the input dendritic region of the MBs, and its relationship with MB excitatory activity, we used the simple anatomy of the Drosophila larval olfactory system to identify any inhibitory inputs that could contribute to the selectivity of MB odor responses. We found that a single neuron accounts for all detectable GABA innervation in the calyx of the MBs, and that this neuron has presynaptic terminals in the calyx and postsynaptic branches in the MB lobes (output axonal area. We call this neuron the larval anterior paired lateral (APL neuron, because of its similarity to the previously described adult APL neuron. Reconstitution of GFP partners (GRASP suggests that the larval APL makes extensive contacts with the MB intrinsic neurons, Kenyon Cells (KCs, but few contacts with incoming projection neurons. Using calcium imaging of neuronal activity in live larvae, we show that the larval APL responds to odors, in a mannner that requires output from KCs. Our data suggest that the larval APL is the sole GABAergic neuron that innervates the MB input region and carries inhibitory feedback from the MB output region, consistent with a role in modulating the olfactory selectivity of MB neurons.

  14. Reciprocal cholinergic and GABAergic modulation of the small ventrolateral pacemaker neurons of Drosophila's circadian clock neuron network.

    Science.gov (United States)

    Lelito, Katherine R; Shafer, Orie T

    2012-04-01

    The relatively simple clock neuron network of Drosophila is a valuable model system for the neuronal basis of circadian timekeeping. Unfortunately, many key neuronal classes of this network are inaccessible to electrophysiological analysis. We have therefore adopted the use of genetically encoded sensors to address the physiology of the fly's circadian clock network. Using genetically encoded Ca(2+) and cAMP sensors, we have investigated the physiological responses of two specific classes of clock neuron, the large and small ventrolateral neurons (l- and s-LN(v)s), to two neurotransmitters implicated in their modulation: acetylcholine (ACh) and γ-aminobutyric acid (GABA). Live imaging of l-LN(v) cAMP and Ca(2+) dynamics in response to cholinergic agonist and GABA application were well aligned with published electrophysiological data, indicating that our sensors were capable of faithfully reporting acute physiological responses to these transmitters within single adult clock neuron soma. We extended these live imaging methods to s-LN(v)s, critical neuronal pacemakers whose physiological properties in the adult brain are largely unknown. Our s-LN(v) experiments revealed the predicted excitatory responses to bath-applied cholinergic agonists and the predicted inhibitory effects of GABA and established that the antagonism of ACh and GABA extends to their effects on cAMP signaling. These data support recently published but physiologically untested models of s-LN(v) modulation and lead to the prediction that cholinergic and GABAergic inputs to s-LN(v)s will have opposing effects on the phase and/or period of the molecular clock within these critical pacemaker neurons.

  15. Acute anal stretch inhibits NMDA-dependent pelvic-urethra reflex potentiation via spinal GABAergic inhibition in anesthetized rats.

    Science.gov (United States)

    Chen, Sung-Lang; Huang, Yu-Hui; Kao, Yu-Lin; Chen, Gin-Den; Cheng, Chen-Li; Peng, Hsien-Yu; Liao, Jiuan-Miaw; Huang, Pei-Chen; Tsai, Shih-Jei; Lin, Tzer-Bin

    2008-10-01

    The impact of acute anal stretch on the pelvic-urethra reflex potentiation was examined in urethane-anesthetized rats by recording the external urethra sphincter electromyogram activity evoked by the pelvic afferent stimulation. Test stimulation (1 stimulation/30 s) evoked a baseline reflex activity with a single action potential that was abolished by gallamine (5 mg/kg iv). On the other hand, the repetitive stimulation (1 stimulation/1 s) induced spinal reflex potentiation (SRP) that was attenuated by intrathecal 6-cyano-7-nitroquinoxaline-2,4-dione (a glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionat receptor antagonist, 100 microM, 10 microl) and d-2-amino-5-phosphonovalerate [a glutamatergic N-methyl-D-aspartate (NMDA) antagonist, 100 microM, 10 microl]. Acute anal stretch using a mosquito clamp with a distance of 4 mm exhibited no effect, whereas distances of 8 mm attenuated and 12 mm abolished the repetitive stimulation-induced SRP. Intrathecal NMDA (100 microM, 10 microl) reversed the abolition on SRP caused by anal stretch. On the other hand, pretreated bicuculline [gamma-aminobutyric acid (GABA) A receptor antagonist, 100 microM, 10 microl] but not hydroxysaclofen (GABAB receptor antagonist) counteracted the abolition on the repetitive stimulation-induced SRP caused by the anal stretch. All of the results suggested that anal stretch may be used as an adjunct to assist voiding dysfunction in patients with overactive urethra sphincter and that GABAergic neurotransmission is important in the neural mechanisms underlying external urethra sphincter activity inhibited by anal stretch.

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

    Science.gov (United States)

    Bezaire, Marianne J; Soltesz, Ivan

    2013-09-01

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

  17. Archives: Mathematics Connection

    African Journals Online (AJOL)

    Items 1 - 9 of 9 ... Archives: Mathematics Connection. Journal Home > Archives: Mathematics Connection. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register · Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives. 1 - 9 of 9 Items. 2011 ...

  18. Connective Tissue Disorders

    Science.gov (United States)

    ... of connective tissue. Over 200 disorders that impact connective tissue. There are different types: Genetic disorders, such as Ehlers-Danlos syndrome, Marfan syndrome, and osteogenesis imperfecta Autoimmune disorders, such as lupus and scleroderma Cancers, like some types of soft tissue sarcoma Each ...

  19. Generalized connectivity of graphs

    CERN Document Server

    Li, Xueliang

    2016-01-01

    Noteworthy results, proof techniques, open problems and conjectures in generalized (edge-) connectivity are discussed in this book. Both theoretical and practical analyses for generalized (edge-) connectivity of graphs are provided. Topics covered in this book include: generalized (edge-) connectivity of graph classes, algorithms, computational complexity, sharp bounds, Nordhaus-Gaddum-type results, maximum generalized local connectivity, extremal problems, random graphs, multigraphs, relations with the Steiner tree packing problem and generalizations of connectivity. This book enables graduate students to understand and master a segment of graph theory and combinatorial optimization. Researchers in graph theory, combinatorics, combinatorial optimization, probability, computer science, discrete algorithms, complexity analysis, network design, and the information transferring models will find this book useful in their studies.

  20. Handbook of Brain Connectivity

    CERN Document Server

    Jirsa, Viktor K

    2007-01-01

    Our contemporary understanding of brain function is deeply rooted in the ideas of the nonlinear dynamics of distributed networks. Cognition and motor coordination seem to arise from the interactions of local neuronal networks, which themselves are connected in large scales across the entire brain. The spatial architectures between various scales inevitably influence the dynamics of the brain and thereby its function. But how can we integrate brain connectivity amongst these structural and functional domains? Our Handbook provides an account of the current knowledge on the measurement, analysis and theory of the anatomical and functional connectivity of the brain. All contributors are leading experts in various fields concerning structural and functional brain connectivity. In the first part of the Handbook, the chapters focus on an introduction and discussion of the principles underlying connected neural systems. The second part introduces the currently available non-invasive technologies for measuring struct...

  1. Modeling Structural Brain Connectivity

    DEFF Research Database (Denmark)

    Ambrosen, Karen Marie Sandø

    The human brain consists of a gigantic complex network of interconnected neurons. Together all these connections determine who we are, how we react and how we interpret the world. Knowledge about how the brain is connected can further our understanding of the brain’s structural organization, help...... improve diagnosis, and potentially allow better treatment of a wide range of neurological disorders. Tractography based on diffusion magnetic resonance imaging is a unique tool to estimate this “structural connectivity” of the brain non-invasively and in vivo. During the last decade, brain connectivity...... has increasingly been analyzed using graph theoretic measures adopted from network science and this characterization of the brain’s structural connectivity has been shown to be useful for the classification of populations, such as healthy and diseased subjects. The structural connectivity of the brain...

  2. ‘Amygdala activation and GABAergic gene expression in hippocampal sub-regions at the interplay of stress and spatial learning

    Directory of Open Access Journals (Sweden)

    Osnat eHadad-Ophir

    2014-01-01

    Full Text Available Molecular processes in GABAergic local circuit neurons critically contribute to information processing in the hippocampus and to stress-induced activation of the amygdala. In the current study, we determined expression changes in GABA-related factors induced in subregions of the dorsal hippocampus as well as in the BLA of rats 5h after spatial learning in a Morris Water maze, using laser microdissection and quantitative real-time PCR. Spatial learning resulted in highly selective pattern of changes in hippocampal subregions: gene expression levels of neuropeptide Y were reduced in the hilus of the dentate gyrus, whereas somatostatin was increased in the stratum oriens of CA3. The GABA-synthesizing enzymes GAD65 and GAD67 as well as the neuropeptide cholecystokinin were reduced in stratum oriens of CA1. In the BLA, expression of GAD65 and GAD67 were reduced compared to a handled Control group. These expression patterns were further compared to alterations in a group of rats that have been exposed to the water maze but were not provided with an invisible escape platform. In this Water Exposure group, no expression changes were observed in any of the hippocampal subregions, but a differential regulation of all selected target genes was evident in the BLA. These findings suggest that expression changes of GABAergic factors in the hippocampus are associated with spatial learning, while additional stress effects modulate expression alterations in the BLA. Indeed, while in both experimental groups plasma corticosterone levels were enhanced, only Water Exposure stress activated the basolateral amygdala, as indicated by increased levels of phosphorylated ERK1/2. Altered GABAergic function in the BLA may thus contribute to memory consolidation in the hippocampus, in relation to levels of stress and emotionality associated with the experience.

  3. Sensitivity of the prefrontal GABAergic system to chronic stress in male and female mice: Relevance for sex differences in stress-related disorders.

    Science.gov (United States)

    Shepard, Ryan; Page, Chloe E; Coutellier, Laurence

    2016-09-22

    Stress-induced modifications of the prefrontal cortex (PFC) are believed to contribute to the onset of mood disorders, such as depression and anxiety, which are more prevalent in women. In depression, the PFC is hypoactive; however the origin of this hypoactivity remains unclear. Possibly, stress could impact the prefrontal GABAergic inhibitory system that, as a result, impairs the functioning of downstream limbic structures controlling emotions. Preclinical evidence indicates that the female PFC is more sensitive to the effects of stress. These findings suggest that exposure to stress could lead to sex-specific alterations in prefrontal GABAergic signaling, which contribute to sex-specific abnormal functioning of limbic regions. These limbic changes could promote the onset of depressive and anxiety behaviors in a sex-specific manner, providing a possible mechanism mediating sex differences in the clinical presentation of stress-related mood disorders. We addressed this hypothesis using a mouse model of stress-induced depressive-like behaviors: the unpredictable chronic mild stress (UCMS) paradigm. We observed changes in prefrontal GABAergic signaling after exposure to UCMS most predominantly in females. Increased parvalbumin (PV) expression and decreased prefrontal neuronal activity were correlated in females with severe emotionality deficit following UCMS, and with altered activity of the amygdala. In males, small changes in emotionality following UCMS were associated with minor changes in prefrontal PV expression, and with hypoactivity of the nucleus accumbens. Our data suggest that prefrontal hypoactivity observed in stress-related mood disorders could result from stress-induced increases in PV expression, particularly in females. This increased vulnerability of the female prefrontal PV system to stress could underlie sex differences in the prevalence and symptomatology of stress-related mood disorders. Copyright © 2016 IBRO. Published by Elsevier Ltd. All

  4. Histamine facilitates GABAergic transmission in the rat entorhinal cortex: Roles of H1 and H2 receptors, Na+ -permeable cation channels, and inward rectifier K+ channels.

    Science.gov (United States)

    Cilz, Nicholas I; Lei, Saobo

    2017-05-01

    In the brain, histamine (HA) serves as a neuromodulator and a neurotransmitter released from the tuberomammillary nucleus (TMN). HA is involved in wakefulness, thermoregulation, energy homeostasis, nociception, and learning and memory. The medial entorhinal cortex (MEC) receives inputs from the TMN and expresses HA receptors (H 1 , H 2 , and H 3 ). We investigated the effects of HA on GABAergic transmission in the MEC and found that HA significantly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) with an EC 50 of 1.3 µM, but failed to significantly alter sIPSC amplitude. HA-induced increases in sIPSC frequency were sensitive to tetrodotoxin (TTX), required extracellular Ca 2+ , and persisted when GDP-β-S, a G-protein inactivator, was applied postsynaptically via the recording pipettes, indicating that HA increased GABA release by facilitating the excitability of GABAergic interneurons in the MEC. Recordings from local MEC interneurons revealed that HA significantly increased their excitability as determined by membrane depolarization, generation of an inward current at -65 mV, and augmentation of action potential firing frequency. Both H 1 and H 2 receptors were involved in HA-induced increases in sIPSCs and interneuron excitability. Immunohistochemical staining showed that both H 1 and H 2 receptors are expressed on GABAergic interneurons in the MEC. HA-induced depolarization of interneurons involved a mixed ionic mechanism including activation of a Na + -permeable cation channel and inhibition of a cesium-sensitive inward rectifier K + channel, although HA also inhibited the delayed rectifier K + channels. Our results may provide a cellular mechanism, at least partially, to explain the roles of HA in the brain. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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

    Science.gov (United States)

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

    2012-01-04

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

  6. Bidirectional Signaling of Neuregulin-2 Mediates Formation of GABAergic Synapses and Maturation of Glutamatergic Synapses in Newborn Granule Cells of Postnatal Hippocampus.

    Science.gov (United States)

    Lee, Kyu-Hee; Lee, Hyunsu; Yang, Che Ho; Ko, Jeong-Soon; Park, Chang-Hwan; Woo, Ran-Sook; Kim, Joo Yeon; Sun, Woong; Kim, Joung-Hun; Ho, Won-Kyung; Lee, Suk-Ho

    2015-12-16

    Expression of neuregulin-2 (NRG2) is intense in a few regions of the adult brain where neurogenesis persists; however, little is understood about its role in developments of newborn neurons. To study the role of NRG2 in synaptogenesis at different developmental stages, newborn granule cells in rat hippocampal slice cultures were labeled with retrovirus encoding tetracycline-inducible microRNA targeting NRG2 and treated with doxycycline (Dox) at the fourth or seventh postinfection day (dpi). The developmental increase of GABAergic postsynaptic currents (GPSCs) was suppressed by the early Dox treatment (4 dpi), but not by late treatment (7 dpi). The late Dox treatment was used to study the effect of NRG2 depletion specific to excitatory synaptogenesis. The Dox effect on EPSCs emerged 4 d after the impairment in dendritic outgrowth became evident (10 dpi). Notably, Dox treatment abolished the developmental increases of AMPA-receptor mediated EPSCs and the AMPA/NMDA ratio, indicating impaired maturation of glutamatergic synapses. In contrast to GPSCs, Dox effects on EPSCs and dendritic growth were independent of ErbB4 and rescued by concurrent overexpression of NRG2 intracellular domain. These results suggest that forward signaling of NRG2 mediates GABAergic synaptogenesis and its reverse signaling contributes to dendritic outgrowth and maturation of glutamatergic synapses. The hippocampal dentate gyrus is one of special brain regions where neurogenesis persists throughout adulthood. Synaptogenesis is a critical step for newborn neurons to be integrated into preexisting neural network. Because neuregulin-2 (NRG2), a growth factor, is intensely expressed in these regions, we investigated whether it plays a role in synaptogenesis and dendritic growth. We found that NRG2 has dual roles in the development of newborn neurons. For GABAergic synaptogenesis, the extracellular domain of NRG2 acts as a ligand for a receptor on GABAergic neurons. In contrast, its intracellular

  7. Variant BDNF-Val66Met Polymorphism is Associated with Layer-Specific Alterations in GABAergic Innervation of Pyramidal Neurons, Elevated Anxiety and Reduced Vulnerability of Adolescent Male Mice to Activity-Based Anorexia.

    Science.gov (United States)

    Chen, Yi-Wen; Surgent, Olivia; Rana, Barkha S; Lee, Francis; Aoki, Chiye

    2017-08-01

    Previously, we determined that rodents' vulnerability to food restriction (FR)-evoked wheel running during adolescence (activity-based anorexia, ABA) is associated with failures to increase GABAergic innervation of hippocampal and medial prefrontal pyramidal neurons. Since brain-derived neurotrophic factor (BDNF) promotes GABAergic synaptogenesis, we hypothesized that individual differences in this vulnerability may arise from differences in the link between BDNF bioavailability and FR-evoked wheel running. We tested this hypothesis in male BDNF-Val66Met knock-in mice (BDNFMet/Met), known for reduction in the activity-dependent BDNF secretion and elevated anxiety-like behaviors. We found that 1) in the absence of FR or a wheel (i.e., control), BDNFMet/Met mice are more anxious than wild-type (WT) littermates, 2) electron microscopically verified GABAergic innervations of pyramidal neurons of BDNFMet/Met mice are reduced at distal dendrites in hippocampal CA1 and medial prefrontal cortex, 3) following ABA, WT mice exhibit anxiety equal to those of the BDNFMet/Met mice and have lost GABAergic innervation along distal dendrites, 4) BDNFMet/Met mice show blunted ABA vulnerability, and 5) unexpectedly, GABAergic innervation is higher at somata of BDNFMet/Met mice than of WT. We conclude that lamina-specific GABAergic inhibition is important for regulating anxiety, whether arising from environmental stress, such as food deprivation, or genetically, such as BDNFMet/Met single nucleotide polymorphism. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Connected motorcycle system performance.

    Science.gov (United States)

    2016-01-15

    This project characterized the performance of Connected Vehicle Systems (CVS) on motorcycles based on two key components: global positioning and wireless communication systems. Considering that Global Positioning System (GPS) and 5.9 GHz Dedicated Sh...

  9. Connected vehicle applications : environment.

    Science.gov (United States)

    2016-01-01

    The U.S. Department of Transportation has developed a number of connected vehicle environmental applications, including the Applications for the Environment Real-Time Information Synthesis (AERIS) research program applications and road weather applic...

  10. Connected vehicle applications : safety.

    Science.gov (United States)

    2016-01-01

    Connected vehicle safety applications are designed to increase situational awareness : and reduce or eliminate crashes through vehicle-to-infrastructure, vehicle-to-vehicle, : and vehicle-to-pedestrian data transmissions. Applications support advisor...

  11. IDRC Connect User Guide

    International Development Research Centre (IDRC) Digital Library (Canada)

    Kristina Kamichaitis

    Once an account has been created by IDRC staff, you will receive .... content label in the table to access additional information. Table 3: ... One of the primary functions of IDRC Connect is to enable efficient and automated submission of final.

  12. Connected vehicles and cybersecurity.

    Science.gov (United States)

    2016-01-01

    Connected vehicles are a next-generation technology in vehicles and in infrastructure that will make travel safer, cleaner, and more efficient. The advanced wireless technology enables vehicles to share and communicate information with each other and...

  13. Hydrologically Connected Road Segments

    Data.gov (United States)

    Vermont Center for Geographic Information — Link it ArcGIS Item is HERE.The connectivity layer was created to assist municipalities in preparing for the forthcoming DEC Municipal Roads General Permit in 2018....

  14. IDRC Connect User Guide

    International Development Research Centre (IDRC) Digital Library (Canada)

    Kristina Kamichaitis

    IDRC Extranet home page, which is an umbrella for a number of applications available to IDRC external users. ... IDRC Connect is not formatted for mobile users. ..... Thesis. • Training Material. • Website. • Working Paper. • Workshop Report.

  15. Anticonvulsant mechanism of saponins fraction from adventitious roots of Ficus religiosa: possible modulation of GABAergic, calcium and sodium channel functions

    Directory of Open Access Journals (Sweden)

    Damanpreet Singh

    Full Text Available ABSTRACT In our previous studies, quantified saponins-rich fraction from adventitious root extract of Ficus religiosa L., Moraceae, showed anticonvulsant effect in acute, as well as chronic mice models of epilepsy. The present study was designed to reveal putative anticonvulsant mechanism of quantified saponins-rich fraction using target specific animal models. The anticonvulsant effect of quantified saponins-rich fraction was initially studied in maximal electroshock and pentylenetetrazol test at 1, 2 and 4 mg/kg; i.p. doses. Based on the results of initial anticonvulsant testing, different groups of mice were injected with vehicle or quantified saponins-rich fraction (4 mg/kg; i.p., 30 min prior to an injection of N-methyl-D-aspartic acid (100 mg/kg; s.c., bicuculline (5 mg/kg; i.p., strychnine hydrochloride (2 mg/kg; i.p., BAY k-8644 (37.5 µg; i.c.v., veratridine (500 µg/kg; i.p. and the convulsive episodes were studied. Treatment with the extract (1, 2 and 4 mg/kg showed significant protection in maximal electroshock and pentylenetetrazol-induced convulsion tests, in a dose-dependent manner. Moreover, quantified saponins-rich fraction at 4 mg/kg dose showed significant increase in latency to clonic convulsions, decrease in seizure severity and increase in average wave amplitude in bicuculline, BAY k-8644 and veratridine tests, respectively, as compared to vehicle control. However, SRF treatment failed to abolish N-methyl-D-aspartic acid and strychnine-induced convulsions, indicated by insignificant change in the appearance of turning behavior and onset of tonic extension, respectively, as compared to vehicle control. From the results of present study, it is concluded that quantified saponins-rich fraction suppress maximal electroshock, pentylenetetrazol, bicuculline, BAY k-8644 and veratridine-induced convulsions, indicating its GABAergic, Na+ and Ca2+ channel modulatory effects. Further it can be correlated that quantified saponins

  16. Short-term repeated corticosterone administration enhances glutamatergic but not GABAergic transmission in the rat motor cortex.

    Science.gov (United States)

    Kula, Joanna; Blasiak, Anna; Czerw, Anna; Tylko, Grzegorz; Sowa, Joanna; Hess, Grzegorz

    2016-04-01

    It has been demonstrated that stress impairs performance of skilled reaching and walking tasks in rats due to the action of glucocorticoids involved in the stress response. Skilled reaching and walking are controlled by the primary motor cortex (M1); however, it is not known whether stress-related impairments in skilled motor tasks are related to functional and/or structural alterations within the M1. We studied the effects of single and repeated injections of corticosterone (twice daily for 7 days) on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) recorded from layer II/III pyramidal neurons in ex vivo slices of the M1, prepared 2 days after the last administration of the hormone. We also measured the density of dendritic spines on pyramidal cells and the protein levels of selected subunits of AMPA, NMDA, and GABAA receptors after repeated corticosterone administration. Repeatedly administered corticosterone induced an increase in the frequency but not in the amplitude of sEPSCs, while a single administration had no effect on the recorded excitatory currents. The frequency and amplitude of sIPSCs as well as the excitability of pyramidal cells were changed neither after single nor after repeated corticosterone administration. Treatment with corticosterone for 7 days did not modify the density of dendritic spines on pyramidal neurons. Corticosterone influenced neither the protein levels of GluA1, GluA2, GluN1, GluN2A, and GluN2B subunits of glutamate receptors nor those of α1, β2, and γ2 subunits of the GABAA receptor. The increase in sEPSCs frequency induced by repeated corticosterone administration faded out within 7 days. These data indicate that prolonged administration of exogenous corticosterone selectively and reversibly enhances glutamatergic, but not GABAergic transmission in the rat motor cortex. Our results suggest that corticosterone treatment results in an enhancement of spontaneous glutamate release from presynaptic

  17. [Connective tissue and inflammation].

    Science.gov (United States)

    Jakab, Lajos

    2014-03-23

    The author summarizes the structure of the connective tissues, the increasing motion of the constituents, which determine the role in establishing the structure and function of that. The structure and function of the connective tissue are related to each other in the resting as well as inflammatory states. It is emphasized that cellular events in the connective tissue are part of the defence of the organism, the localisation of the damage and, if possible, the maintenance of restitutio ad integrum. The organism responds to damage with inflammation, the non specific immune response, as well as specific, adaptive immunity. These processes are located in the connective tissue. Sterile and pathogenic inflammation are relatively similar processes, but inevitable differences are present, too. Sialic acids and glycoproteins containing sialic acids have important roles, and the role of Siglecs is also highlighted. Also, similarities and differences in damages caused by pathogens and sterile agents are briefly summarized. In addition, the roles of adhesion molecules linked to each other, and the whole event of inflammatory processes are presented. When considering practical consequences it is stressed that the structure (building up) of the organism and the defending function of inflammation both have fundamental importance. Inflammation has a crucial role in maintaining the integrity and the unimpaired somato-psychological state of the organism. Thus, inflammation serves as a tool of organism identical with the natural immune response, inseparably connected with the specific, adaptive immune response. The main events of the inflammatory processes take place in the connective tissue.

  18. Quick connect fastener

    Science.gov (United States)

    Weddendorf, Bruce

    1994-01-01

    A quick connect fastener and method of use is presented wherein the quick connect fastener is suitable for replacing available bolts and screws, the quick connect fastener being capable of installation by simply pushing a threaded portion of the connector into a member receptacle hole, the inventive apparatus being comprised of an externally threaded fastener having a threaded portion slidably mounted upon a stud or bolt shaft, wherein the externally threaded fastener portion is expandable by a preloaded spring member. The fastener, upon contact with the member receptacle hole, has the capacity of presenting cylindrical threads of a reduced diameter for insertion purposes and once inserted into the receiving threads of the receptacle member hole, are expandable for engagement of the receptacle hole threads forming a quick connect of the fastener and the member to be fastened, the quick connect fastener can be further secured by rotation after insertion, even to the point of locking engagement, the quick connect fastener being disengagable only by reverse rotation of the mated thread engagement.

  19. Connectivity in river deltas

    Science.gov (United States)

    Passalacqua, P.; Hiatt, M. R.; Sendrowski, A.

    2016-12-01

    Deltas host approximately half a billion people and are rich in ecosystem diversity and economic resources. However, human-induced activities and climatic shifts are significantly impacting deltas around the world; anthropogenic disturbance, natural subsidence, and eustatic sea-level rise are major causes of threat to deltas and in many cases have compromised their safety and sustainability, putting at risk the people that live on them. In this presentation, I will introduce a framework called Delta Connectome for studying connectivity in river deltas based on different representations of a delta as a network. Here connectivity indicates both physical connectivity (how different portions of the system interact with each other) as well as conceptual (pathways of process coupling). I will explore several network representations and show how quantifying connectivity can advance our understanding of system functioning and can be used to inform coastal management and restoration. From connectivity considerations, the delta emerges as a leaky network that evolves over time and is characterized by continuous exchanges of fluxes of matter, energy, and information. I will discuss the implications of connectivity on delta functioning, land growth, and potential for nutrient removal.

  20. Preceding weak noise sharpens the frequency tuning and elevates the response threshold of the mouse inferior collicular neurons through GABAergic inhibition.

    Science.gov (United States)

    Wang, Xin; Jen, Philip H-S; Wu, Fei-Jian; Chen, Qi-Cai

    2007-09-05

    In acoustic communication, animals must extract biologically relevant signals that are embedded in noisy environment. The present study examines how weak noise may affect the auditory sensitivity of neurons in the central nucleus of the mouse inferior colliculus (IC) which receives convergent excitatory and inhibitory inputs from both lower and higher auditory centers. Specifically, we studied the frequency sensitivity and minimum threshold of IC neurons using a pure tone probe and a weak white noise masker under forward masking paradigm. For most IC neurons, probe-elicited response was decreased by a weak white noise that was presented at a specific gap (i.e. time window). When presented within this time window, weak noise masking sharpened the frequency tuning curve and increased the minimum threshold of IC neurons. The degree of weak noise masking of these two measurements increased with noise duration. Sharpening of the frequency tuning curve and increasing of the minimum threshold of IC neurons during weak noise masking were mostly mediated through GABAergic inhibition. In addition, sharpening of frequency tuning curve by the weak noise masker was more effective at the high than at low frequency limb. These data indicate that in the real world the ambient noise may improve frequency sensitivity of IC neurons through GABAergic inhibition while inevitably decrease the frequency response range and sensitivity of IC neurons.

  1. Connectable solar air collectors

    Energy Technology Data Exchange (ETDEWEB)

    Oestergaard Jensen, S.; Bosanac, M.

    2002-02-01

    The project has proved that it is possible to manufacture solar air collector panels, which in an easy way can be connected into large collector arrays with integrated ducting without loss of efficiency. The developed connectable solar air collectors are based on the use of matrix absorbers in the form of perforated metal sheets. Three interconnected solar air collectors of the above type - each with an transparent area of approx. 3 m{sup 2} - was tested and compared with parallel tests on two single solar air collectors also with a transparent area of approx. 3 m{sup 2} One of the single solar air collectors has an identical absorber as the connectable solar air collectors while the absorber of the other single solar air collector was a fibre cloth. The efficiency of the three solar air collectors proved to be almost identical in the investigated range of mass flow rates and temperature differences. The solar air collectors further proved to be very efficient - as efficient as the second most efficient solar air collectors tested in the IEA task 19 project Solar Air Systems. Some problems remain although to be solved: the pressure drop across especially the connectable solar air collectors is too high - mainly across the inlets of the solar air collectors. It should, however, be possible to considerably reduce the pressure losses with a more aerodynamic design of the inlet and outlet of the solar air collectors; The connectable solar air collectors are easy connectable but the air tightness of the connections in the present form is not good enough. As leakage leads to lower efficiencies focus should be put on making the connections more air tight without loosing the easiness in connecting the solar air collectors. As a spin off of the project a simple and easy way to determine the efficiency of solar, air collectors for pre-heating of fresh air has been validated. The simple method of determining the efficiency has with success been compared with an advance method

  2. Connections of the superior paraolivary nucleus of the rat: II. Reciprocal connections with the tectal longitudinal column

    Directory of Open Access Journals (Sweden)

    Antonio eViñuela

    2011-02-01

    Full Text Available The superior paraolivary nucleus (SPON, a prominent GABAergic center of the mammalian auditory brainstem, projects to the ipsilateral inferior colliculus (IC and sends axons through the commissure of the IC (CoIC. Herein we demonstrate that the SPON is reciprocally connected with the recently discovered tectal longitudinal column (TLC. The TLC is a long and narrow structure that spans nearly the entire midbrain tectum longitudinally, immediately above the periaqueductal gray matter (PAG and very close to the midline.Unilateral injections of biotinylated dextran into the SPON of the rat label abundant terminal fibers in the TLC of both sides, with an ipsilateral predominance. The SPON provides a dense innervation of the entire rostrocaudal extent of the ipsilateral TLC, and a relatively sparser innervation of the caudal and rostral portions of the contralateral TLC. SPON fibers reach the TLC by two routes: as collaterals of axons of the CoIC, and as axons that circumvent the ipsilateral IC before traveling in the deep layers of the superior colliculus.The density of these projections identifies SPON as a significant source of input to the TLC. Other targets of the SPON discovered in this study include the deep layers of the superior colliculus and the PAG. The same experiments reveal numerous labeled cell bodies in the TLC, interspersed among the labeled SPON fibers. This observation suggests that the SPON is a significant target of TLC projections.The discovery of novel reciprocal connections between the SPON and the TLC opens unexpected avenues for investigation of sound processing in mammalian brainstem circuits.

  3. Connectivity and superconductivity

    CERN Document Server

    Rubinstein, Jacob

    2000-01-01

    The motto of connectivity and superconductivity is that the solutions of the Ginzburg--Landau equations are qualitatively influenced by the topology of the boundaries, as in multiply-connected samples. Special attention is paid to the "zero set", the set of the positions (also known as "quantum vortices") where the order parameter vanishes. The effects considered here usually become important in the regime where the coherence length is of the order of the dimensions of the sample. It takes the intuition of physicists and the awareness of mathematicians to find these new effects. In connectivity and superconductivity, theoretical and experimental physicists are brought together with pure and applied mathematicians to review these surprising results. This volume is intended to serve as a reference book for graduate students and researchers in physics or mathematics interested in superconductivity, or in the Schrödinger equation as a limiting case of the Ginzburg--Landau equations.

  4. A super soliton connection

    International Nuclear Information System (INIS)

    Gurses, M.; Oguz, O.

    1985-07-01

    Integrable super non-linear classical partial differential equations are considered. A super s1(2,R) algebra valued connection 1-form is constructed. It is shown that curvature 2-form of this super connection vanishes by virtue of the integrable super equations of motion. A super extension of the AKNS scheme is presented and a class of super extension of the Lax hierarchy and super non-linear Schroedinger equation are found. O(N) extension and the Baecklund transformations of the above super equations are also considered. (author)

  5. Connecting textual segments

    DEFF Research Database (Denmark)

    Brügger, Niels

    2017-01-01

    history than just the years of the emergence of the web, the chapter traces the history of how segments of text have deliberately been connected to each other by the use of specific textual and media features, from clay tablets, manuscripts on parchment, and print, among others, to hyperlinks on stand......In “Connecting textual segments: A brief history of the web hyperlink” Niels Brügger investigates the history of one of the most fundamental features of the web: the hyperlink. Based on the argument that the web hyperlink is best understood if it is seen as another step in a much longer and broader...

  6. Best connected rectangular arrangements

    Directory of Open Access Journals (Sweden)

    Krishnendra Shekhawat

    2016-03-01

    Full Text Available It can be found quite often in the literature that many well-known architects have employed either the golden rectangle or the Fibonacci rectangle in their works. On contrary, it is rare to find any specific reason for using them so often. Recently, Shekhawat (2015 proved that the golden rectangle and the Fibonacci rectangle are one of the best connected rectangular arrangements and this may be one of the reasons for their high presence in architectural designs. In this work we present an algorithm that generates n-4 best connected rectangular arrangements so that the proposed solutions can be further used by architects for their designs.

  7. Connections among quantum logics

    International Nuclear Information System (INIS)

    Lock, P.F.; Hardegree, G.M.

    1985-01-01

    This paper gives a brief introduction to the major areas of work in quantum event logics: manuals (Foulis and Randall) and semi-Boolean algebras (Abbott). The two theories are compared, and the connection between quantum event logics and quantum propositional logics is made explicit. In addition, the work on manuals provides us with many examples of results stated in Part I. (author)

  8. Connectivity measures: a review

    Czech Academy of Sciences Publication Activity Database

    Kindlmann, Pavel; Burel, F.

    2008-01-01

    Roč. 23, č. 1 (2008), s. 879-890 ISSN 0921-2973 R&D Projects: GA MŠk LC06073; GA AV ČR(CZ) IAA6087301 Institutional research plan: CEZ:AV0Z60870520 Keywords : Conservation biology * Habitat fragmentation * Landscape connectivity * Measures * Species extinction Subject RIV: EH - Ecology, Behaviour Impact factor: 2.453, year: 2008

  9. Clip, connect, clone

    DEFF Research Database (Denmark)

    Fujima, Jun; Lunzer, Aran; Hornbæk, Kasper

    2010-01-01

    using three mechanisms: clipping of input and result elements from existing applications to form cells on a spreadsheet; connecting these cells using formulas, thus enabling result transfer between applications; and cloning cells so that multiple requests can be handled side by side. We demonstrate...

  10. A Connective Pedagogy.

    Science.gov (United States)

    Goral, Mary

    2000-01-01

    Our increasingly hurried lifestyle, changes in family structure, and intense economic pressures place stress on children and families. Waldorf education provides an educational environment that alleviates this stress through a connective pedagogy that encompasses continuity of people, curriculum, and instruction; a reverence and respect for the…

  11. Connected vehicle application : safety.

    Science.gov (United States)

    2015-01-01

    Connected vehicle safety applications are designed to increase situational awareness : and reduce or eliminate crashes through vehicle-to-infrastructure (V2I), vehicle-to-vehicle (V2V), and vehicle-to-pedestrian (V2P) data transmissions. Applications...

  12. Mathematics Connection: Editorial Policies

    African Journals Online (AJOL)

    Focus and Scope. MATHEMATICS CONNECTION aims at providing a forum to promote the development of Mathematics Education in Ghana. Articles that seek to enhance the teaching and/or learning of mathematics at all levels of the educational system are welcome ...

  13. Making the Connection

    Science.gov (United States)

    Perna, Mark C.

    2006-01-01

    Enrollment marketing is not just about enrollment; it is about creating relationships and serving one's community or target audience for many years. In this article, the author states that the first step in building such relationships is making a connection, and that is what effective marketing is all about. Administrators, teachers and critical…

  14. Connecting numeric models

    International Nuclear Information System (INIS)

    Caremoli, C.; Erhard, P.

    1996-01-01

    Computerized simulation uses calculation codes whose validation is reliable. Reactor simulators should take greater advantage of latest computer technology impact, in particular in the field of parallel processing. Instead of creating more global simulation codes whose validation might be a problem, connecting several existing codes should be a promising solution. (D.L.). 3 figs

  15. From connection to customer

    International Nuclear Information System (INIS)

    Milatz, H.; Soeters, R.

    2001-01-01

    Energy companies can no longer be certain that a customer today will remain a customer tomorrow. They have to work hard to achieve that. They are going from thinking in terms of connections to pampering their customers. Good Customer Relationship Management is a way to achieve a competitive advantage. The whole organisation has to adapt, particularly the customer orientation of employees

  16. Mapping functional connectivity

    Science.gov (United States)

    Peter Vogt; Joseph R. Ferrari; Todd R. Lookingbill; Robert H. Gardner; Kurt H. Riitters; Katarzyna Ostapowicz

    2009-01-01

    An objective and reliable assessment of wildlife movement is important in theoretical and applied ecology. The identification and mapping of landscape elements that may enhance functional connectivity is usually a subjective process based on visual interpretations of species movement patterns. New methods based on mathematical morphology provide a generic, flexible,...

  17. IDRC Connect User Guide

    International Development Research Centre (IDRC) Digital Library (Canada)

    Kristina Kamichaitis

    2 Jul 2015 ... IDRC Connect contribuye a la aplicación de la Política de Acceso abierto de IDRC facilitando ..... Tesis. • Material de capacitación. • Sitio web. • Documento de trabajo ..... incluir planes de estudios, metodologías y manuales.

  18. Na+/K+-ATPase inhibition partially mimics the ethanol-induced increase of the Golgi cell-dependent component of the tonic GABAergic current in rat cerebellar granule cells.

    Directory of Open Access Journals (Sweden)

    Marvin R Diaz

    Full Text Available Cerebellar granule cells (CGNs are one of many neurons that express phasic and tonic GABAergic conductances. Although it is well established that Golgi cells (GoCs mediate phasic GABAergic currents in CGNs, their role in mediating tonic currents in CGNs (CGN-I(tonic is controversial. Earlier studies suggested that GoCs mediate a component of CGN-I(tonic that is present only in preparations from immature rodents. However, more recent studies have detected a GoC-dependent component of CGN-I(tonic in preparations of mature rodents. In addition, acute exposure to ethanol was shown to potentiate the GoC component of CGN-I(tonic and to induce a parallel increase in spontaneous inhibitory postsynaptic current frequency at CGNs. Here, we tested the hypothesis that these effects of ethanol on GABAergic transmission in CGNs are mediated by inhibition of the Na(+/K(+-ATPase. We used whole-cell patch-clamp electrophysiology techniques in cerebellar slices of male rats (postnatal day 23-30. Under these conditions, we reliably detected a GoC-dependent component of CGN-I(tonic that could be blocked with tetrodotoxin. Further analysis revealed a positive correlation between basal sIPSC frequency and the magnitude of the GoC-dependent component of CGN-I(tonic. Inhibition of the Na(+/K(+-ATPase with a submaximal concentration of ouabain partially mimicked the ethanol-induced potentiation of both phasic and tonic GABAergic currents in CGNs. Modeling studies suggest that selective inhibition of the Na(+/K(+-ATPase in GoCs can, in part, explain these effects of ethanol. These findings establish a novel mechanism of action of ethanol on GABAergic transmission in the central nervous system.

  19. Detoxification of ammonia in mouse cortical GABAergic cell cultures increases neuronal oxidative metabolism and reveals an emerging role for release of glucose-derived alanine

    DEFF Research Database (Denmark)

    Leke, Renata; Bak, Lasse Kristoffer; Anker, Malene

    2011-01-01

    Cerebral hyperammonemia is believed to play a pivotal role in the development of hepatic encephalopathy (HE), a debilitating condition arising due to acute or chronic liver disease. In the brain, ammonia is thought to be detoxified via the activity of glutamine synthetase, an astrocytic enzyme....... Moreover, it has been suggested that cerebral tricarboxylic acid (TCA) cycle metabolism is inhibited and glycolysis enhanced during hyperammonemia. The aim of this study was to characterize the ammonia-detoxifying mechanisms as well as the effects of ammonia on energy-generating metabolic pathways...... in a mouse neuronal-astrocytic co-culture model of the GABAergic system. We found that 5 mM ammonium chloride affected energy metabolism by increasing the neuronal TCA cycle activity and switching the astrocytic TCA cycle toward synthesis of substrate for glutamine synthesis. Furthermore, ammonia exposure...

  20. Creatine Enhances Transdifferentiation of Bone Marrow Stromal Cell-Derived Neural Stem Cell Into GABAergic Neuron-Like Cells Characterized With Differential Gene Expression.

    Science.gov (United States)

    Darabi, Shahram; Tiraihi, Taki; Delshad, AliReza; Sadeghizadeh, Majid; Taheri, Taher; Hassoun, Hayder K

    2017-04-01

    Creatine was reported to induce bone marrow stromal cells (BMSC) into GABAergic neuron-like cells (GNLC). In a previous study, creatine was used as a single inducer for BMSC into GNLC with low yield. In this study, BMSC-derived neurospheres (NS) have been used in generating GABAergic phenotype. The BMSC were isolated from adult rats and used in generating neurospheres and used for producing neural stem cells (NSC). A combination of all-trans-retinoic acid (RA), the ciliary neurotrophic factor (CNTF), and creatine was used in order to improve the yield of GNLC. We also used other protocols for the transdifferentiation including RA alone; RA and creatine; RA and CNTF; and RA, CNTF, and creatine. The BMSC, NSC, and GNLC were characterized by specific markers. The activity of the GNLC was evaluated using FM1-43. The isolated BMSC expressed Oct4, fibronectin, and CD44. The NS were immunoreactive to nestin and SOX2, the NSC were immunoreactive to nestin, NF68 and NF160, while the GNLC were immunoreactive to GAD1/2, VGAT, GABA, and synaptophysin. Oct4 and c-MYC, pluripotency genes, were expressed in the BMSC, while SOX2 and c-MYC were expressed in the NSC. The activity of GNLC indicates that the synaptic vesicles were released upon stimulation. The conclusion is that the combination of RA, CNTF, and creatine induced differentiation of neurosphere-derived NSC into GNLC within 1 week. This protocol gives higher yield than the other protocols used in this study. The mechanism of induction was clearly associated with several differential pluripotent genes.

  1. GABAergic mechanism mediated via D receptors in the rat periaqueductal gray participates in the micturition reflex: an in vivo microdialysis study.

    Science.gov (United States)

    Kitta, Takeya; Matsumoto, Machiko; Tanaka, Hiroshi; Mitsui, Takahiko; Yoshioka, Mitsuhiro; Nonomura, Katsuya

    2008-06-01

    The periaqueductal gray (PAG) is critically involved in the micturition reflex, but little is known about the neuronal mechanisms involved. The present study elucidated dynamic changes in dopamine (DA), glutamate and gamma-aminobutyric acid (GABA) in the rat PAG during the micturition reflex, with a focus on dopaminergic modulation using in vivo microdialysis combined with cystometrography. Extracellular levels of DA and glutamate increased, whereas levels of GABA decreased, in parallel with the micturition reflex. Application of a D(1) receptor antagonist into the PAG produced increases in maximal voiding pressure (MVP) and decreases in intercontraction interval (ICI), suggesting that the micturition reflex was facilitated by D(1) receptor blockade. The D(1) receptor antagonist prevented micturition-induced decreases in GABA efflux but had no effect on DA or glutamate. Neither a D(2) receptor antagonist nor a D(1)/D(2) receptor agonist affected these neurochemical and physiological parameters. Micturition-induced inhibition of GABA was not observed in 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of Parkinson's disease. 6-OHDA-lesioned rats exhibited bladder hyperactivity evaluated by increases in MVP and decreases in ICI, mimicking facilitation of the micturition reflex induced by D(1) receptor blockade. These findings suggest that the micturition reflex is under tonic dopaminergic regulation through D(1) receptors, in which a GABAergic mechanism is involved. Bladder hyperactivity observed in 6-OHDA-lesioned rats may be caused by dysfunction of GABAergic regulation underlying the micturition reflex. The present findings contribute to our understanding not only of the neurophysiology of the micturition reflex but also of the pathophysiology of lower urinary tract dysfunction in patients with Parkinson's disease.

  2. Betaine attenuates memory impairment after water-immersion restraint stress and is regulated by the GABAergic neuronal system in the hippocampus.

    Science.gov (United States)

    Kunisawa, Kazuo; Kido, Kiwamu; Nakashima, Natsuki; Matsukura, Takuya; Nabeshima, Toshitaka; Hiramatsu, Masayuki

    2017-02-05

    GABA mediated neuronal system regulates hippocampus-dependent memory and stress responses by controlling plasticity and neuronal excitability. Here, we demonstrate that betaine ameliorates water-immersion restraint stress (WIRS)-induced memory impairments. This improvement was inhibited by a betaine/GABA transporter-1 (GABA transporter-2: GAT2) inhibitor, NNC 05-2090. In this study, we investigated whether memory amelioration by betaine was mediated by the GABAergic neuronal system. Adult male mice were co-administered betaine and GABA receptor antagonists after WIRS. We also examined whether memory impairment after WIRS was attenuated by GABA receptor agonists. The memory functions were evaluated using a novel object recognition test 3-6 days after WIRS and/or the step-down type passive avoidance test at 7-8 days. The co-administration of the GABA A receptor antagonist bicuculline (1mg/kg) or the GABA B receptor antagonist phaclofen (10mg/kg) 1h after WIRS suppressed the memory-improving effects induced by betaine. Additionally, the administration of the GABA A receptor agonist muscimol (1mg/kg) or the GABA B receptor agonist baclofen (10mg/kg) 1h after WIRS attenuated memory impairments. These results were similar to the data observed with betaine. The treatment with betaine after WIRS significantly decreased the expression of GABA transaminase, and this effect was partially blocked by NNC 05-2090 in the hippocampus. WIRS caused a transient increase in hippocampal GABA levels and the changes after WIRS were not affected by betaine treatment in an in vivo microdialysis study. These results suggest that the beneficial effects of betaine may be mediated in part by changing the GABAergic neuronal system. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Connecting the Production Multiple

    DEFF Research Database (Denmark)

    Lichen, Alex Yu; Mouritsen, Jan

    &OP process itself is a fluid object, but there is still possibility to organise the messy Production. There are connections between the Production multiple and the managerial technology fluid. The fluid enacted the multiplicity of Production thus making it more difficult to be organised because there were...... in opposite directions. They are all part of the fluid object. There is no single chain of circulating references that makes the object a matter of fact. Accounting fluidity means that references drift back and forth and enact new realities also connected to the chain. In this setting future research may......This paper is about objects. It follows post ANT trajectories and finds that objects are multiple and fluid. Extant classic ANT inspired accounting research largely sees accounting inscriptions as immutable mobiles. Although multiplicity of objects upon which accounting acts has been explored...

  4. Evaluation of 604 Connect

    OpenAIRE

    Ladner, S.; Ihnat, M.

    2000-01-01

    The Vancouver Community Network (VCN) is a not-for-profit Internet Service Provider (ISP), based on the “freenet” model of public Internet access. As a VolNet delivery agency, VCN committed to providing participating organizations with the following: (1) A communications protocol, (2) Internet Access, (3) Computer Equipment, (4) Training, and (5) Technical Support. In April 1999, VCN began receiving applications from non-profit organizations for its 604 Connect program, so named for the 604 t...

  5. Energy storage connection system

    Science.gov (United States)

    Benedict, Eric L.; Borland, Nicholas P.; Dale, Magdelena; Freeman, Belvin; Kite, Kim A.; Petter, Jeffrey K.; Taylor, Brendan F.

    2012-07-03

    A power system for connecting a variable voltage power source, such as a power controller, with a plurality of energy storage devices, at least two of which have a different initial voltage than the output voltage of the variable voltage power source. The power system includes a controller that increases the output voltage of the variable voltage power source. When such output voltage is substantially equal to the initial voltage of a first one of the energy storage devices, the controller sends a signal that causes a switch to connect the variable voltage power source with the first one of the energy storage devices. The controller then causes the output voltage of the variable voltage power source to continue increasing. When the output voltage is substantially equal to the initial voltage of a second one of the energy storage devices, the controller sends a signal that causes a switch to connect the variable voltage power source with the second one of the energy storage devices.

  6. Cutter Connectivity Bandwidth Study

    Science.gov (United States)

    2002-10-01

    The goal of this study was to determine how much bandwidth is required for cutters to meet emerging data transfer requirements. The Cutter Connectivity Business Solutions Team with guidance front the Commandant's 5 Innovation Council sponsored this study. Today, many Coast Guard administrative and business functions are being conducted via electronic means. Although our larger cutters can establish part-time connectivity using commercial satellite communications (SATCOM) while underway, there are numerous complaints regarding poor application performance. Additionally, smaller cutters do not have any standard means of underway connectivity. The R&D study shows the most important factor affecting web performance and enterprise applications onboard cutters was latency. Latency describes the time it takes the signal to reach the satellite and come back down through space. The latency due to use of higher orbit satellites is causing poor application performance and inefficient use of expensive SATCOM links. To improve performance, the CC must, (1) reduce latency by using alternate communications links such as low-earth orbit satellites, (2) tailor applications to the SATCOM link and/or (3) optimize protocols used for data communication to minimize time required by present applications to establish communications between the user and the host systems.

  7. Finding significantly connected voxels based on histograms of connection strengths

    DEFF Research Database (Denmark)

    Kasenburg, Niklas; Pedersen, Morten Vester; Darkner, Sune

    2016-01-01

    We explore a new approach for structural connectivity based segmentations of subcortical brain regions. Connectivity based segmentations are usually based on fibre connections from a seed region to predefined target regions. We present a method for finding significantly connected voxels based...... on the distribution of connection strengths. Paths from seed voxels to all voxels in a target region are obtained from a shortest-path tractography. For each seed voxel we approximate the distribution with a histogram of path scores. We hypothesise that the majority of estimated connections are false-positives...... and that their connection strength is distributed differently from true-positive connections. Therefore, an empirical null-distribution is defined for each target region as the average normalized histogram over all voxels in the seed region. Single histograms are then tested against the corresponding null...

  8. Strong, reliable and precise synaptic connections between thalamic relay cells and neurones of the nucleus reticularis in juvenile rats

    Science.gov (United States)

    Gentet, Luc J; Ulrich, Daniel

    2003-01-01

    The thalamic reticular nucleus (nRT) is composed entirely of GABAergic inhibitory neurones that receive input from pyramidal cortical neurones and excitatory relay cells of the ventrobasal complex of the thalamus (VB). It plays a major role in the synchrony of thalamic networks, yet the synaptic connections it receives from VB cells have never been fully physiologically characterised. Here, whole-cell current-clamp recordings were obtained from 22 synaptically connected VB-nRT cell pairs in slices of juvenile (P14–20) rats. At 34–36 °C, single presynaptic APs evoked unitary EPSPs in nRT cells with a peak amplitude of 7.4 ± 1.5 mV (mean ± s.e.m.) and a decay time constant of 15.1 ± 0.9 ms. Only four out of 22 pairs showed transmission failures at a mean rate of 6.8 ± 1.1 %. An NMDA receptor (NMDAR)-mediated component was significant at rest and subsequent EPSPs in a train were depressed. Only one out of 14 pairs tested was reciprocally connected; the observed IPSPs in the VB cell had a peak amplitude of 0.8 mV and were completely abolished in the presence of 10 μm bicuculline. Thus, synaptic connections from VB cells to nRT neurones are mainly ‘drivers’, while a small subset of cells form closed disynaptic loops. PMID:12563005

  9. The Berry's connection

    International Nuclear Information System (INIS)

    Le Tourneux, J.

    1989-01-01

    A course on the Berry's connection is presented. The main steps leading to the Berry's discovery are reviewed and the obtained equations are examined. Some applications of Berry's formulation are presented. They include diatomic molecules, dipole-quadrupole interaction in spherical mucleus and diabolic pair transfer. The experimental results presented are the spectrum of the Na 3 molecule, the propagation of photons in an helical optical fiber and the neutron spin rotation. Non-abelian problems and the Aharonow-Anandan phase are discussed [fr

  10. The CONNECT project

    DEFF Research Database (Denmark)

    Assaf, Yaniv; Alexander, Daniel C; Jones, Derek K

    2013-01-01

    Of Neuroimagers for the Non-invasive Exploration of brain Connectivity and Tracts) project aimed to combine tractography and micro-structural measures of the living human brain in order to obtain a better estimate of the connectome, while also striving to extend validation of these measurements. This paper...... summarizes the project and describes the perspective of using micro-structural measures to study the connectome.......In recent years, diffusion MRI has become an extremely important tool for studying the morphology of living brain tissue, as it provides unique insights into both its macrostructure and microstructure. Recent applications of diffusion MRI aimed to characterize the structural connectome using...

  11. Skeletal muscle connective tissue

    DEFF Research Database (Denmark)

    Brüggemann, Dagmar Adeline

    in the structure of fibrous collagen and myofibers at high-resolution. The results demonstrate that the collagen composition in the extra cellular matrix of Gadus morhua fish muscle is much more complex than previously anticipated, as it contains type III, IV, V  and VI collagen in addition to type I. The vascular....... Consequently, functional structures, ensuring "tissue maintenance" must form a major role of connective tissue, in addition that is to the force transmitting structures one typically finds in muscle. Vascular structures have also been shown to change their mechanical properties with age and it has been shown...

  12. Conformally connected universes

    International Nuclear Information System (INIS)

    Cantor, M.; Piran, T.

    1983-01-01

    A well-known difficulty associated with the conformal method for the solution of the general relativistic Hamiltonian constraint is the appearance of an aphysical ''bag of gold'' singularity at the nodal surface of the conformal factor. This happens whenever the background Ricci scalar is too large. Using a simple model, it is demonstrated that some of these singular solutions do have a physical meaning, and that these can be considered as initial data for Universe containing black holes, which are connected, in a conformally nonsingular way with each other. The relation between the ADM mass and the horizon area in this solution supports the cosmic censorship conjecture. (author)

  13. Heritable Disorders of Connective Tissue

    Science.gov (United States)

    ... Home Health Topics English Español Heritable Disorders of Connective Tissue Basics In-Depth Download Download EPUB Download PDF ... they? Points To Remember About Heritable Disorders of Connective Tissue There are more than 200 heritable disorders that ...

  14. LHCb connects its pipes

    CERN Multimedia

    2006-01-01

    Two weeks ago the first beryllium section of the LHCb beam vacuum chamber was installed. This three-day operation, after requiring lengthy preparation work, demanded patience and precision as the first of four sections of the beampipe was connected to the vertex locator (VeLo) vacuum vessel. The AT-VAC Group with the collaboration of PH/LBD, including Gloria Corti, Tatsuya Nakada, Patrice Mermet, Delios Ramos, Frans Mul, Bruno Versollato, Bernard Corajod, and Raymond Veness. (Not pictured: Adriana Rossi and Laurent Bouvet) This first installed section is composed of a nearly two-metre long conical tube of one-millimetre thick beryllium and of a thin spherical-shaped window, 800 millimeter diameter, made of an aluminum alloy, and has the appearance of a mushroom lying on its side. The window is connected to the conical part of the beampipe through an aluminum alloy bellow, which is needed to allow for mechanical alignment once the assembly is installed. Beryllium was chosen as the material for 12 m of the 19...

  15. Connective tissue activation. XVII

    International Nuclear Information System (INIS)

    Weiss, J.J.; Donakowski, C.; Anderson, B.; Meyers, S.; Castor, C.W.

    1980-01-01

    The platelet-derived connective tissue activating peptide (CTAP-III) has been shown to be an important factor stimulating the metabolism and proliferation of human connective tissue cell strains, including synovial tissue cells. The quantities of CTAP-III affecting the cellular changes and the amounts in various biologic fluids and tissues are small. The objectives of this study were to develop a radioimmunoassay (RIA) for CTAP-III and to ascertain the specificities of the anti-CTAP-III sera reagents. The antisera were shown not to cross-react with a number of polypeptide hormones. However, two other platelet proteins β-thromboglobulin and low affinity platelet factor-4, competed equally as well as CTAP-III for anti-CTAP-III antibodies in the RIA system. Thus, the three platelet proteins are similar or identical with respect to those portions of the molecules constituting the reactive antigenic determinants. The levels of material in normal human platelet-free plasma that inhibited anti-CTAP-III- 125 I-CTAP-III complex formation were determined to be 34+-13 (S.D.) ng/ml. (Auth.)

  16. Connectivity-oriented urban projects

    NARCIS (Netherlands)

    Philibert Petit, E.

    2006-01-01

    This thesis is about connections in the built environment, networked connections for the mobility of people at the smallest scale of the urban realm: the pedestrian scale. It deals with applications of the new science of networks as a tool for observation and assessment of connectivity in the urban

  17. Airport industry connectivity report: 2015

    NARCIS (Netherlands)

    Boonekamp, T.; Lieshout, R.; Burghouwt, G.

    2015-01-01

    This report is an update of the 'Airport Industry Connectivity Report 2004-2014'. It's focused on more recent developments and charting how Europe’s connectivity has evolved over the past 12 months. Airport connectivity is an increasingly discussed topic in European policy circles. With good reason.

  18. Connecting Architecture and Implementation

    Science.gov (United States)

    Buchgeher, Georg; Weinreich, Rainer

    Software architectures are still typically defined and described independently from implementation. To avoid architectural erosion and drift, architectural representation needs to be continuously updated and synchronized with system implementation. Existing approaches for architecture representation like informal architecture documentation, UML diagrams, and Architecture Description Languages (ADLs) provide only limited support for connecting architecture descriptions and implementations. Architecture management tools like Lattix, SonarJ, and Sotoarc and UML-tools tackle this problem by extracting architecture information directly from code. This approach works for low-level architectural abstractions like classes and interfaces in object-oriented systems but fails to support architectural abstractions not found in programming languages. In this paper we present an approach for linking and continuously synchronizing a formalized architecture representation to an implementation. The approach is a synthesis of functionality provided by code-centric architecture management and UML tools and higher-level architecture analysis approaches like ADLs.

  19. More features, greater connectivity.

    Science.gov (United States)

    Hunt, Sarah

    2015-09-01

    Changes in our political infrastructure, the continuing frailties of our economy, and a stark growth in population, have greatly impacted upon the perceived stability of the NHS. Healthcare teams have had to adapt to these changes, and so too have the technologies upon which they rely to deliver first-class patient care. Here Sarah Hunt, marketing co-ordinator at Aid Call, assesses how the changing healthcare environment has affected one of its fundamental technologies - the nurse call system, argues the case for wireless such systems in terms of what the company claims is greater adaptability to changing needs, and considers the ever-wider range of features and functions available from today's nurse call equipment, particularly via connectivity with both mobile devices, and ancillaries ranging from enuresis sensors to staff attack alert 'badges'.

  20. Practicing (Dis)connections

    DEFF Research Database (Denmark)

    The paper addresses the reciprocal notions of mobility and mobilisation in medical imaging practice, in view of the contingent and multiple character of the knowledge-practices involving such images – and their interpretation – within and across situated settings. Based on an ethnographically......’s development of in-house examination protocols as a consequence of its having replaced an older, pre-existing MRI scanner with a new model. This re-domestication of MRI as occasioned by the replacement scanner offers a range of sociomaterial and sociotechnical contingencies in the practice to come to light...... of the epistemic underpinnings which render, and condition, how connections are mediated across extended settings of practice (in the MRI unit, at interdisciplinary case conferences, and at other hospitals, etc.). This relational view allows for the heterogeneity entailed in the domestication of the MRI scanner...

  1. Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behaviour modification and oxidative damage in mice.

    Science.gov (United States)

    Kumar, Anil; Singh, Anant

    2009-08-01

    Sleep is an important physiological process responsible for the maintenance of physical, mental and emotional health of a living being. Sleep deprivation is considered risky for several pathological diseases such as anxiety and motor and cognitive dysfunctions. Sleep deprivation has recently been reported to cause oxidative damage. This study has been designed to explore the possible involvement of the GABAergic mechanism in protective effects of melatonin against 72-h sleep deprivation-induced behaviour modification and oxidative damage in mice. Mice were sleep-deprived for a period of 72 h using the grid over water suspended method. Animals were divided into groups of 6-8 animals each. Melatonin (5 and 10 mg/kg), flumazenil (0.5 mg/kg), picrotoxin (0.5 mg/kg) and muscimol (0.05 mg/kg) were administered for 5 days starting 2 days before 72-h sleep deprivation. Various behavioural tests (plus maze, zero maze, mirror chamber, actophotometer) and body weight assessment followed by oxidative stress parameters (malondialdehyde level, glutathione, catalase, nitrite and protein) were carried out. The 72-h sleep deprivation caused significant anxiety-like behaviour, weight loss, impaired locomotor activity and oxidative damage as compared with naïve (without sleep deprivation). Treatment with melatonin (5 mg/kg and 10 mg/kg, ip) significantly improved locomotor activity, weight loss and antianxiety effect as compared with control (sleep-deprived). Biochemically, melatonin treatment significantly restored reduced glutathione, catalase activity, attenuated lipid peroxidation and nitrite level as compared with control animals (72-h sleep-deprived). Flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) pretreatments with a lower dose of melatonin (5 mg/kg) significantly antagonized the protective effect of melatonin. However, muscimol (0.05 mg/kg) pretreatment with melatonin (5 mg/kg, ip) potentiated the protective effect of melatonin which was significant as compared with their

  2. Hypocretin-1 (orexin A) prevents the effects of hypoxia/hypercapnia and enhances the GABAergic pathway from the lateral paragigantocellular nucleus to cardiac vagal neurons in the nucleus ambiguus.

    Science.gov (United States)

    Dergacheva, O; Philbin, K; Bateman, R; Mendelowitz, D

    2011-02-23

    Hypocretins (orexins) are hypothalamic neuropeptides that play a crucial role in regulating sleep/wake states and autonomic functions including parasympathetic cardiac activity. We have recently demonstrated stimulation of the lateral paragigantocellular nucleus (LPGi), the nucleus which is thought to play a role in rapid eye movement (REM) sleep control, activates an inhibitory pathway to preganglionic cardiac vagal neurons in the nucleus ambiguus (NA). In this study we test the hypothesis that hypocretin-1 modulates the inhibitory neurotransmission to cardiac vagal neurons evoked by stimulation of the LPGi using whole-cell patch-clamp recordings in an in vitro brain slice preparation from rats. Activation of hypocretin-1 receptors produced a dose-dependent and long-term facilitation of GABAergic postsynaptic currents evoked by electrical stimulation of the LPGi. Hypoxia/hypercapnia diminished LPGi-evoked GABAergic current in cardiac vagal neurons and this inhibition by hypoxia/hypercapnia was prevented by pre-application of hypocretin-1. The action of hypocretin-1 was blocked by the hypocretin-1 receptor antagonist SB-334867. Facilitation of LPGi-evoked GABAergic current in cardiac vagal neurons under both normal condition and during hypoxia/hypercapnia could be the mechanism by which hypocretin-1 affects parasympathetic cardiac function and heart rate during REM sleep. Furthermore, our findings indicate a new potential mechanism that might be involved in the cardiac arrhythmias, bradycardia, and sudden cardiac death that can occur during sleep. Copyright © 2011. Published by Elsevier Ltd.

  3. Mesoscale Connections Summer 2017

    Energy Technology Data Exchange (ETDEWEB)

    Kippen, Karen Elizabeth [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Bourke, Mark Andrew M. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-06-21

    Our challenge derives from the fact that in metals or explosives grains, interfaces and defects control engineering performance in ways that are neither amenable to continuum codes (which fail to rigorously describe the heterogeneities derived from microstructure) nor computationally tractable to first principles atomistic calculations. This is a region called the mesoscale, which stands at the frontier of our desire to translate fundamental science insights into confidence in aging system performance over the range of extreme conditions relevant in a nuclear weapon. For dynamic problems, the phenomena of interest can require extremely good temporal resolutions. A shock wave traveling at 1000 m/s (or 1 mm/μs) passes through a grain with a diameter of 1 micron in a nanosecond (10-9 sec). Thus, to observe the mesoscale phenomena—such as dislocations or phase transformations—as the shock passes, temporal resolution better than picoseconds (10-12 sec) may be needed. As we anticipate the science challenges over the next decade, experimental insights on material performance at the micron spatial scale with picosecond temporal resolution—at the mesoscale— are a clear challenge. This is a challenge fit for Los Alamos in partnership with our sister labs and academia. Mesoscale Connections will draw attention to our progress as we tackle the mesoscale challenge. We hope you like it and encourage suggestions of content you are interested in.

  4. Detoxification of ammonia in mouse cortical GABAergic cell cultures increases neuronal oxidative metabolism and reveals an emerging role for release of glucose-derived alanine.

    Science.gov (United States)

    Leke, Renata; Bak, Lasse K; Anker, Malene; Melø, Torun M; Sørensen, Michael; Keiding, Susanne; Vilstrup, Hendrik; Ott, Peter; Portela, Luis V; Sonnewald, Ursula; Schousboe, Arne; Waagepetersen, Helle S

    2011-04-01

    Cerebral hyperammonemia is believed to play a pivotal role in the development of hepatic encephalopathy (HE), a debilitating condition arising due to acute or chronic liver disease. In the brain, ammonia is thought to be detoxified via the activity of glutamine synthetase, an astrocytic enzyme. Moreover, it has been suggested that cerebral tricarboxylic acid (TCA) cycle metabolism is inhibited and glycolysis enhanced during hyperammonemia. The aim of this study was to characterize the ammonia-detoxifying mechanisms as well as the effects of ammonia on energy-generating metabolic pathways in a mouse neuronal-astrocytic co-culture model of the GABAergic system. We found that 5 mM ammonium chloride affected energy metabolism by increasing the neuronal TCA cycle activity and switching the astrocytic TCA cycle toward synthesis of substrate for glutamine synthesis. Furthermore, ammonia exposure enhanced the synthesis and release of alanine. Collectively, our results demonstrate that (1) formation of glutamine is seminal for detoxification of ammonia; (2) neuronal oxidative metabolism is increased in the presence of ammonia; and (3) synthesis and release of alanine is likely to be important for ammonia detoxification as a supplement to formation of glutamine.

  5. Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson's Disease? The Potential Role of Zolpidem in the Treatment of Parkinson's Disease

    Science.gov (United States)

    Daniele, Antonio; Panza, Francesco; Greco, Antonio; Logroscino, Giancarlo; Seripa, Davide

    2016-01-01

    At present, patients with advanced Parkinson's disease (PD) are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only for GABAA receptors containing the α-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation of GABAA receptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce through GABAA receptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD. PMID:27293955

  6. Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify GABAergic inhibition

    Directory of Open Access Journals (Sweden)

    Schlichter Rémy

    2008-05-01

    Full Text Available Abstract Background Recent evidence suggests that oxytocin (OT, secreted in the superficial spinal cord dorsal horn by descending axons of paraventricular hypothalamic nucleus (PVN neurons, produces antinociception and analgesia. The spinal mechanism of OT is, however, still unclear and requires further investigation. We have used patch clamp recording of lamina II neurons in spinal cord slices and immunocytochemistry in order to identify PVN-activated neurons in the superficial layers of the spinal cord and attempted to determine how this neuronal population may lead to OT-mediated antinociception. Results We show that OT released during PVN stimulation specifically activates a subpopulation of lamina II glutamatergic interneurons which are localized in the most superficial layers of the dorsal horn of the spinal cord (lamina I-II. This OT-specific stimulation of glutamatergic neurons allows the recruitment of all GABAergic interneurons in lamina II which produces a generalized elevation of local inhibition, a phenomenon which might explain the reduction of incoming Aδ and C primary afferent-mediated sensory messages. Conclusion Our results obtained in lamina II of the spinal cord provide the first clear evidence of a specific local neuronal network that is activated by OT release to induce antinociception. This OT-specific pathway might represent a novel and interesting therapeutic target for the management of neuropathic and inflammatory pain.

  7. Central analgesic activity of the aqueous and ethanolic extracts of the leaves of Albizia lebbeck: role of the GABAergic and serotonergic pathways.

    Science.gov (United States)

    Meshram, Girish G; Kumar, Anil; Rizvi, Waseem; Tripathi, C D; Khan, R A

    2015-01-01

    Albizia lebbeck Benth. is extensively used in Indian traditional medicine for treating several painful and inflammatory disorders. The possible central analgesic activity and the underlying mechanism of action of the aqueous (AE) and ethanolic extracts (EE) of the leaves of A. lebbeck were investigated in Wistar rats using Eddy's hot plate and the tail flick tests. In order to investigate the underlying mechanism of action, rats were pretreated with naloxone, bicuculline or methysergide and then were administered a per os (p.o.) dose of AE or EE. AE and EE caused a significant (p<0.05) elevation in the mean basal reaction time in the hot plate method and an increase in the latency time in the tail flick method. In rats pretreated with bicuculline and methysergide, a significant (p<0.05) reduction in the analgesic activity was observed in comparison to AE and EE. Thus, AE and EE exhibited significant central analgesic activity and act possibly via the GABAergic and serotonergic pathways. The flavonoids and saponins found in the leaves could be responsible for the observed effect.

  8. Transnational Connections and Multiple Belongings

    DEFF Research Database (Denmark)

    Galal, Lise Paulsen; Sparre, Sara Cathrine Lei

    With the purpose of presenting DIMECCE key findings, we in this paper present different aspects, potentials and challenges related to the Middle Eastern Christians transnational connections and multiple belonging. We distinguish between individual transnational connections and practices, such as ......, such as family relations, churches as transnational – or global – institutions, and other organisations and associations established to support politically, socially or culturally connections and development in the country or region of origin....

  9. Anonymous Connections and Onion Routing

    National Research Council Canada - National Science Library

    Syverson, Paul F; Goldschlag, David M; Reed, Michael G

    1997-01-01

    .... Unmodified Internet applications can use these anonymous connections by means of proxies. The proxies may also make communication anonymous by removing identifying information from the data stream...

  10. Interstate Connections - CEHC [ds619

    Data.gov (United States)

    California Natural Resource Agency — The California Department of Transportation (Caltrans) and California Department of Fish and Game (CDFG) commissioned the California Essential Habitat Connectivity...

  11. Family Connections: Building Connections among Home, School, and Community

    Science.gov (United States)

    Dikkers, Amy Garrett

    2013-01-01

    Recent research on parental involvement has explored connections between parental involvement in school and children's academic achievement. While many schools have active parent organizations and a base of parents who offer additional support, others struggle to make connections with their parents or community members. Even in places with active…

  12. Carl Sagan's Cosmic Connection

    Science.gov (United States)

    Sagan, Carl; Agel, Jerome

    2000-08-01

    Foreword Freeman Dyson; Personal reflections Ann Druyan; Preface; Part I. Cosmic Perspective: 1. A transitional animal; 2. The Unicorn of Cetus; 3. A message from earth; 4. A message to earth; 5. Experiments in utopias; 6. Chauvinism; 7. Space exploration as a human enterprise I. The scientific interest; 8. Space exploration as a human enterprise II. The public interest; 9. Space exploration as a human enterprise III. The historical interest; Part II. The Solar System: 10. On teaching the first grade; 11. 'The ancient and legendary Gods of old'; 12. The Venus detective story; 13. Venus is hell; 14. Science and 'intelligence'; 15. The moons of Barsoom; 16. The mountains of Mars I. Observations from earth; 17. The mountains of Mars II. Observations from space; 18. The canals of Mars; 19. The lost pictures of Mars; 20. The Ice Age and the cauldron; 21. Beginnings and ends of the Earth; 22. Terraforming the plants; 23. The exploration and utlization of the solar system; Part III. Beyond the Solar System: 24. Some of my best friends are dolphins; 25. 'Hello, central casting? Send me twenty extraterrestrials'; 26. The cosmic connection; 27. Extraterrestrial life: an idea whose time has come; 28. Has the Earth been visited?; 29. A search strategy for detecting extraterrestrial intelligence; 30. If we succeed 31. Cables, drums, and seashells; 32. The night freight to the stars; 33. Astroengineering; 34. Twenty questions: a classification of cosmic civilisations; 35. Galactic cultural exchanges; 36. A passage to elsewhere; 37. Starfolk I. A Fable; 38. Starfolk II. A future; 39. Starfolk III. The cosmic Cheshire cats; Epilog David Morrison; Index.

  13. Juno, The Cultural Connection

    Science.gov (United States)

    Clarke, Theodore

    2017-04-01

    After a 5 year journey and a billion miles cartwheeling through the vastness of space, the Juno spacecraft is in orbit about the planet Jupiter. With its suite of scientific instruments Juno scientists will catch a glimpse of the dawn of creation of our own solar system. Juno will address origins, asking for us all, Who am I? Where do I come from? But Juno is more than a space laboratory to study the planet Jupiter. Juno embodies the history of humankind's perception of the universe from Aristotle, Copernicus and Galileo, to the Juno spacecraft peering beneath the clouds of Jupiter. Juno embodies the literature of classical mythology and the timeless masterpieces of the Renaissance and Baroque periods in its very name. Juno carries to Jupiter small statuettes of the gods Jupiter and Juno and the scientist Galileo. Juno embodies cosmic visualization experiences through first ever movies of the moon occulting Earth (>2 million hits on YouTube) and the Galilean satellites orbiting about Jupiter (>1.8 million hits on You Tube). Juno embodies the stirring music of modern Greek composer Vangelis, the Orpheus of Juno, who provided the score for the movies of the moon occulting Earth and of the Galilean satellites orbiting Jupiter. Juno embodies down to Earth visualization experiences through trajectory models created of Juno's passage through the Earth-moon system and Juno's entire orbital mission at Jupiter. Juno is the embodiment of public engagement in its science in a fishbowl program. Indeed, because Juno is the embodiment of this remarkable union of science and technology, history and literature, music and art, and visualization and public engagement, Juno is truly an ambassador to the universe of a New Renaissance. In my paper, "Juno, the Cultural Connection," I will unveil a dimension of the Juno mission to the planet Jupiter that will appeal to a broad sector of the global public.

  14. Sub-unit Specific Regulation of Type-A GABAergic Receptors during Post-Natal Development of the Auditory Cortex

    Directory of Open Access Journals (Sweden)

    Liisa A. Tremere

    2011-01-01

    Full Text Available The GABA-A receptor has been strongly implicated in the organization and function of cortical sensory circuits in the adult mammal. In the present work, changes in the expression patterns of select GABA-A subunits were examined as a function of development. The RNA expression profiles for three subunit types were studied, α1, β2/3 and δ at four developmental time points, (p0, p15, p30 and p90. The o1, β2/3 subunits were present at birth and following a modest increase early in life; mRNA expression for these subunits were found at stable levels throughout life. The expression pattern for the δ subunit showed the most dramatic changes in the number of positive cells as a function of age. In early life, p0 through p15 expression of mRNA for the δ subunit was quite low but increased in later life, p30 and p90. Together these data suggest that much of the potential for inhibitory connectivity is laid down in the pre and early post-natal periods.

  15. The Always-Connected Generation

    Science.gov (United States)

    Bull, Glen

    2010-01-01

    The Pew Internet and American Life project characterizes the millennials--the first generation to come of age in the new millennium--as the first "always-connected" generation. Significant aspects of culture are changing as a result. A changing world where all students are connected all the time has substantial educational implications. Despite…

  16. Partitioning graphs into connected parts

    NARCIS (Netherlands)

    Hof, van 't P.; Paulusma, D.; Woeginger, G.J.; Frid, A.; Morozov, A.S.; Rybalchenko, A.; Wagner, K.W.

    2009-01-01

    The 2-DISJOINT CONNECTED SUBGRAPHS problem asks if a given graph has two vertex-disjoint connected subgraphs containing pre-specified sets of vertices. We show that this problem is NP-complete even if one of the sets has cardinality 2. The LONGEST PATH CONTRACTIBILITY problem asks for the largest

  17. Connections for Small Vertex Models

    Indian Academy of Sciences (India)

    This paper is a first attempt at calssifying connections on small vertex models i.e., commuting squares of the form displayed in (1.2) below. ... obtain necessary conditions for two such `model connections' in (2, ) to be ... Current Issue : Vol.

  18. Privacy and the Connected Society

    DEFF Research Database (Denmark)

    Sørensen, Lene Tolstrup; Khajuria, Samant; Skouby, Knud Erik

    The Vision of the 5G enabled connected society is highly based on the evolution and implementation of Internet of Things. This involves, amongst others, a significant raise in devices, sensors and communication in pervasive interconnections as well as cooperation amongst devices and entities across...... the society. Enabling the vision of the connected society, researchers point in the direction of security and privacy as areas to challenge the vision. By use of the Internet of Things reference model as well as the vision of the connected society, this paper identifies privacy of the individual with respect...... to three selected areas: Shopping, connected cars and online gaming. The paper concludes that privacy is a complexity within the connected society vision and that thee is a need for more privacy use cases to shed light on the challenge....

  19. Functional interaction and cross-tolerance between ethanol and Δ9-THC: possible modulation by mouse cerebellar adenosinergic A1/GABAergic-A receptors.

    Science.gov (United States)

    Dar, M Saeed

    2014-08-15

    We have previously shown a functional motor interaction between ethanol and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) that involved cerebellar adenosinergic A1 and GABAergic A receptor modulation. We now report the development of cross-tolerance between intracerebellar Δ(9)-THC and intraperitoneal ethanol using ataxia as the test response in male CD-1 mice. The drugs [Δ(9)-THC (20 μg), N(6)-cyclohexyladenosine, CHA (12 ng), muscimol (20 ng)] used in the study were directly microinfused stereotaxically via guide cannulas into the cerebellum except ethanol. Δ(9)-THC, infused once daily for 5 days followed 16 h after the last infusion by acute ethanol (2g/kg) and Rotorod evaluation, virtually abolished ethanol ataxia indicating development of cross-tolerance. The cross-tolerance was also observed when the order of ethanol and Δ(9)-THC treatment was reversed, i.e., ethanol injected once daily for 5 days followed 16 h after the last ethanol injection by Δ(9)-THC infusion. The cross-tolerance appeared within 24-48 h, lasted over 72 h and was maximal in 5-day ethanol/Δ(9)-THC-treated animals. Finally, tolerance in chronic ethanol/Δ(9)-THC/-treated animals developed not only to ethanol/Δ(9)-THC-induced ataxia, respectively, but also to the ataxia potentiating effect of CHA and muscimol, indicating modulation by cerebellar adenosinergic A1 and GABAA receptors. A practical implication of these results could be that marijuana smokers may experience little or no negative effects such as ataxia following alcohol consumption. Clinically, such antagonism of ethanol-induced ataxia can be observed in marijuana users thereby encouraging more alcohol consumption and thus may represent a risk factor for the development of alcoholism in this segment of population. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. β-Hydroxybutyrate is the preferred substrate for GABA and glutamate synthesis while glucose is indispensable during depolarization in cultured GABAergic neurons.

    Science.gov (United States)

    Lund, Trine M; Obel, Linea F; Risa, Øystein; Sonnewald, Ursula

    2011-08-01

    The ketogenic diet has multiple beneficial effects not only in treatment of epilepsy, but also in that of glucose transporter 1 deficiency, cancer, Parkinson's disease, obesity and pain. Thus, there is an increasing interest in understanding the mechanism behind this metabolic therapy. Patients on a ketogenic diet reach high plasma levels of ketone bodies, which are used by the brain as energy substrates. The interaction between glucose and ketone bodies is complex and there is still controversy as to what extent it affects the homeostasis of the neurotransmitters glutamate, aspartate and GABA. The present study was conducted to study this metabolic interaction in cultured GABAergic neurons exposed to different combinations of (13)C-labeled and unlabeled glucose and β-hydroxybutyrate. Depolarization was induced and the incorporation of (13)C into glutamate, GABA and aspartate was analyzed. The presence of β-hydroxybutyrate together with glucose did not affect the total GABA content but did, however, decrease the aspartate content to a lower value than when either glucose or β-hydroxybutyrate was employed alone. When combinations of the two substrates were used (13)C-atoms from β-hydroxybutyrate were found in all three amino acids to a greater extent than (13)C-atoms from glucose, but only the (13)C contribution from [1,6-(13)C]glucose increased upon depolarization. In conclusion, β-hydroxybutyrate was preferred over glucose as substrate for amino acid synthesis but the total content of aspartate decreased when both substrates were present. Furthermore only the use of glucose increased upon depolarization. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome may be mediated by misregulation of the GABAergic system via the diazepam binding inhibitor

    Directory of Open Access Journals (Sweden)

    Breitling Rainer

    2004-03-01

    Full Text Available Abstract Background Zellweger syndrome (ZS is a fatal inherited disease caused by peroxisome biogenesis deficiency. Patients are characterized by multiple disturbances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct craniofacial malformations. Median live expectancy of ZS patients is less than one year. While the molecular basis of peroxisome biogenesis and metabolism is known in considerable detail, it is unclear how peroxisome deficiency leads to the most severe neurological symptoms. Recent analysis of ZS mouse models has all but invalidated previous hypotheses. Hypothesis We suggest that a regulatory rather than a metabolic defect is responsible for the drastic impairment of brain function in ZS patients. Testing the hypothesis Using microarray analysis we identify diazepam binding inhibitor/acyl-CoA binding protein (DBI as a candidate protein that might be involved in the pathogenic mechanism of ZS. DBI has a dual role as a neuropeptide antagonist of GABA(A receptor signaling in the brain and as a regulator of lipid metabolism. Repression of DBI in ZS patients could result in an overactivation of GABAergic signaling, thus eventually leading to the characteristic hypotonia and seizures. The most important argument for a misregulation of GABA(A in ZS is, however, provided by the striking similarity between ZS and "benzodiazepine embryofetopathy", a malformation syndrome observed after the abuse of GABA(A agonists during pregnancy. Implications of the hypothesis We present a tentative mechanistic model of the effect of DBI misregulation on neuronal function that could explain some of the aspects of the pathology of Zellweger syndrome.

  2. Increases in food intake or food-seeking behavior induced by GABAergic, opioid, or dopaminergic stimulation of the nucleus accumbens: is it hunger?

    Science.gov (United States)

    Hanlon, Erin C; Baldo, Brian A; Sadeghian, Ken; Kelley, Ann E

    2004-03-01

    Previous work has shown that stimulation of GABAergic, opioid, or dopaminergic systems within the nucleus accumbens modulates food intake and food-seeking behavior. However, it is not known whether such stimulation mimics a motivational state of food deprivation that commonly enables animals to learn a new operant response to obtain food. In order to address this question, acquisition of lever pressing for food in hungry animals was compared with acquisition in non-food-deprived rats subjected to various nucleus accumbens drug treatments. All animals were given the opportunity to learn an instrumental response (a lever press) to obtain a food pellet. Prior to training, ad lib-fed rats were infused with the gamma-aminobutyric acid (GABA)A agonist muscimol (100 ng/0.5 microl per side) or the mu-opioid receptor agonist D-Ala2, N-me-Phe4, Gly-ol5-enkephalin (DAMGO, 0.25 microg/0.5 microl per side), or saline into the nucleus accumbens shell (AcbSh). The indirect dopamine agonist amphetamine (10 microg/0.5 microl per side) was infused into the AcbSh or nucleus accumbens core (AcbC) of ad lib-fed rats. An additional group was food deprived and infused with saline in the AcbSh. Chow and sugar pellet intake responses after drug treatments were also evaluated in free-feeding tests. Muscimol, DAMGO, or amphetamine did not facilitate acquisition of lever pressing for food, despite clearly increasing food intake in free-feeding tests. In contrast, food-deprived animals rapidly learned the task. These findings suggest that pharmacological stimulation of any of these neurochemical systems in isolation is insufficient to enable acquisition of a food-reinforced operant task. Thus, these selective processes, while likely involved in control of food intake and food-seeking behavior, appear unable to recapitulate the conditions necessary to mimic the state of negative energy balance.

  3. Substance P Activates Ca2+-Permeable Nonselective Cation Channels through a Phosphatidylcholine-Specific Phospholipase C Signaling Pathway in nNOS-Expressing GABAergic Neurons in Visual Cortex.

    Science.gov (United States)

    Endo, Toshiaki; Yanagawa, Yuchio; Komatsu, Yukio

    2016-02-01

    To understand the functions of the neocortex, it is essential to characterize the properties of neurons constituting cortical circuits. Here, we focused on a distinct group of GABAergic neurons that are defined by a specific colocalization of intense labeling for both neuronal nitric oxide synthase (nNOS) and substance P (SP) receptor [neurokinin 1 (NK1) receptors]. We investigated the mechanisms of the SP actions on these neurons in visual cortical slices obtained from young glutamate decarboxylase 67-green fluorescent protein knock-in mice. Bath application of SP induced a nonselective cation current leading to depolarization that was inhibited by the NK1 antagonists in nNOS-immunopositive neurons. Ruthenium red and La(3+), transient receptor potential (TRP) channel blockers, suppressed the SP-induced current. The SP-induced current was mediated by G proteins and suppressed by D609, an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), but not by inhibitors of phosphatidylinositol-specific PLC, adenylate cyclase or Src tyrosine kinases. Ca(2+) imaging experiments under voltage clamp showed that SP induced a rise in intracellular Ca(2+) that was abolished by removal of extracellular Ca(2+) but not by depletion of intracellular Ca(2+) stores. These results suggest that SP regulates nNOS neurons by activating TRP-like Ca(2+)-permeable nonselective cation channels through a PC-PLC-dependent signaling pathway. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. Anxiolytic-Like Effects and Increase in Locomotor Activity Induced by Infusions of NMDA into the Ventral Hippocampus in Rat: Interaction with GABAergic System.

    Science.gov (United States)

    Bina, Payvand; Rezvanfard, Mehrnaz; Ahmadi, Shamseddin; Zarrindast, Mohammad Reza

    2014-10-01

    In this study, we investigated the role of N-Methyl-D-Aspartate (NMDA) receptors in the ventral hippocampus (VH) and their possible interactions with GABAA system on anxiety-like behaviors. We used an elevated-plus maze test (EPM) to assess anxiety-like behaviors and locomotor activity in male Wistar rats. The results showed that intra-VH infusions of different doses of NMDA (0.25 and 0.5 μg/rat) increased locomotor activity, and also induced anxiolytic-like behaviors, as revealed by a tendency to increase percentage of open arm time (%OAT), and a significant increase in percentage of open arm entries (%OAE). The results also showed that intra-VH infusions of muscimol (0.5 and 1 μg/rat) or bicuculline (0.5 and 1 μg/rat) did not significantly affect anxiety-like behaviors, but bicuculline at dose of 1 μg/rat increased locomotor activity. Intra-VH co-infusions of muscimol (0.5 μg/rat) along with low doses of NMDA (0.0625 and 0.125 μg/rat) showed a tendency to increase %OAT, %OAE and locomotor activity; however, no interaction was observed between the drugs. Interestingly, intra-VH co-infusions of bicuculline (0.5 μg/rat) along with effective doses of NMDA (0.25 and 0.5 μg/rat) decreased %OAT, %OAE and locomotor activity, and a significant interaction between two drugs was observed. It can be concluded that GABAergic system may mediate the anxiolytic-like effects and increase in locomotor activity induced by NMDA in the VH.

  5. Study of GABAergic extra-synaptic tonic inhibition in single neurons and neural populations by traversing neural scales: application to propofol-induced anaesthesia.

    Science.gov (United States)

    Hutt, Axel; Buhry, Laure

    2014-12-01

    Anaesthetic agents are known to affect extra-synaptic GABAergic receptors, which induce tonic inhibitory currents. Since these receptors are very sensitive to small concentrations of agents, they are supposed to play an important role in the underlying neural mechanism of general anaesthesia. Moreover anaesthetic agents modulate the encephalographic activity (EEG) of subjects and hence show an effect on neural populations. To understand better the tonic inhibition effect in single neurons on neural populations and hence how it affects the EEG, the work considers single neurons and neural populations in a steady-state and studies numerically and analytically the modulation of their firing rate and nonlinear gain with respect to different levels of tonic inhibition. We consider populations of both type-I (Leaky Integrate-and-Fire model) and type-II (Morris-Lecar model) neurons. To bridge the single neuron description to the population description analytically, a recently proposed statistical approach is employed which allows to derive new analytical expressions for the population firing rate for type-I neurons. In addition, the work shows the derivation of a novel transfer function for type-I neurons as considered in neural mass models and studies briefly the interaction of synaptic and extra-synaptic inhibition. We reveal a strong subtractive and divisive effect of tonic inhibition in type-I neurons, i.e. a shift of the firing rate to higher excitation levels accompanied by a change of the nonlinear gain. Tonic inhibition shortens the excitation window of type-II neurons and their populations while maintaining the nonlinear gain. The gained results are interpreted in the context of recent experimental findings under propofol-induced anaesthesia.

  6. miRNAs may regulate GABAergic transmission associated genes in aged rats with anesthetics-induced recognition and working memory dysfunction.

    Science.gov (United States)

    Shan, Ligang; Ma, Duo; Zhang, Chengshen; Xiong, Wei; Zhang, Yi

    2017-09-01

    Isoflurane and sevoflurane are widely used anesthetics in surgery and administration of these anesthetics could lead to postoperative cognitive dysfunction (POCD). However, the mechanisms remain unclear. Aged Wistar rats were exposed to isoflurane and sevoflurane for 2 or 4h. Recognition memory and spatial working memory were measured using Novel object recognition (NOR) and Y-maze test, respectively. Apoptotic cells were detected by TUNEL staining. miRNA expression was measured by Real-time PCR while protein expression was measured by Western blot. Dual-Luciferase reporter assay was used to establish the direct relationship between miRNAs and Gabra5 and gephyrin gene expression. Exposure to isoflurane and sevoflurane for 2 or 4h significantly decreased the NOR index in the NOR test and spontaneous alternations in arm entries in the Y-maze test in aged rats. TUNEL staining showed that isoflurane and sevoflurane administration significantly induced apoptosis in the mPFC and hippocampus. The protein level of α5 GABA A receptor (α5GABA A R), gephyrin, and dystrophin were significantly increased, whereas the expression of miR-30a, miR-31, miR-190a, and miR-190b was significantly decreased in the hippocampus and mPFC in aged rats exposed to isoflurane and sevoflurane compared to control rats. The protein levels of α5GABA A R, gephyrin, and dystrophin protein in the hippocampus and the mPFC significantly correlated with NOR index and spontaneous alternations. Dual-Luciferase reporter assay showed that miR-30a and miR-190a/b mimics significantly inhibited Gabra5 and gephyrin gene expression, respectively. There might be a miRNAs-GABAergic transmission pathway which may be involved in the pathophysiological alteration in anesthetics-induced POCD. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. GABAERGIC ALTERATIONS IN NEOCORTEX OF PATIENTS WITH PHARMACORESISTANT TEMPORAL LOBE EPILEPSY CAN EXPLAIN THE COMORBIDITY OF ANXIETY AND DEPRESSION: THE POTENTIAL IMPACT OF CLINICAL FACTORS

    Directory of Open Access Journals (Sweden)

    Luisa Lilia Rocha

    2015-01-01

    Full Text Available Temporal lobe epilepsy (TLE is a chronic neurodegenerative disease with a high prevalence of psychiatric disorders. Temporal neocortex contributes to either seizure propagation or generation in TLE, a situation that has been associated with alterations of the γ-aminobutyric acid (GABA system. On the other hand, an impaired neurotransmission mediated by GABA in temporal neocortex has also been involved with the pathophysiology of psychiatric disorders. In spite of these situations, the role of the necortical GABA system in the comorbidity of TLE and mood disorders has not been investigated. The present study was designed to identify alterations in the GABA system such as: binding to GABAA and GABAB receptors and benzodiazepine site, the tissue content of GABA and the expression of the mRNA encoding the α1-6, β1-3 and γ GABAA subunits, in the temporal neocortex of surgically treated patients with TLE with and without anxiety and/or depression. Neocortex of patients with TLE and comorbid anxiety and/or depression showed increased expression of the mRNA encoding the γ2-subunit, reduced GABAB-induced G protein activation in spite of elevated GABAB binding, and lower tissue content of GABA when compared to autopsy controls. Some of these changes significantly correlated with seizure frequency and duration of epilepsy. The results obtained suggest a dysfunction of the GABAergic neurotransmission in temporal neocortex of patients with TLE and comorbid anxiety and/or depression that could be also influenced by clinical factors such as seizure frequency and duration of illness.

  8. Properly colored connectivity of graphs

    CERN Document Server

    Li, Xueliang; Qin, Zhongmei

    2018-01-01

    A comprehensive survey of proper connection of graphs is discussed in this book with real world applications in computer science and network security. Beginning with a brief introduction, comprising relevant definitions and preliminary results, this book moves on to consider a variety of properties of graphs that imply bounds on the proper connection number. Detailed proofs of significant advancements toward open problems and conjectures are presented with complete references. Researchers and graduate students with an interest in graph connectivity and colorings will find this book useful as it builds upon fundamental definitions towards modern innovations, strategies, and techniques. The detailed presentation lends to use as an introduction to proper connection of graphs for new and advanced researchers, a solid book for a graduate level topics course, or as a reference for those interested in expanding and further developing research in the area.

  9. Connected vehicle pilot deployment program.

    Science.gov (United States)

    2014-01-01

    The U.S. Department of Transportations (USDOTs) connected vehicle research : program is a multimodal initiative to enable safe, interoperable, networked wireless : communications among vehicles, infrastructure, and personal communications : dev...

  10. Cybersecurity for Connected Diabetes Devices.

    Science.gov (United States)

    Klonoff, David C

    2015-04-16

    Diabetes devices are increasingly connected wirelessly to each other and to data-displaying reader devices. Threats to the accurate flow of information and commands may compromise the function of these devices and put their users at risk of health complications. Sound cybersecurity of connected diabetes devices is necessary to maintain confidentiality, integrity, and availability of the data and commands. Diabetes devices can be hacked by unauthorized agents and also by patients themselves to extract data that are not automatically provided by product software. Unauthorized access to connected diabetes devices has been simulated and could happen in reality. A cybersecurity standard designed specifically for connected diabetes devices will improve the safety of these products and increase confidence of users that the products will be secure. © 2015 Diabetes Technology Society.

  11. Functional Connectivity of Human Chewing

    Science.gov (United States)

    Quintero, A.; Ichesco, E.; Schutt, R.; Myers, C.; Peltier, S.; Gerstner, G.E.

    2013-01-01

    Mastication is one of the most important orofacial functions. The neurobiological mechanisms of masticatory control have been investigated in animal models, but less so in humans. This project used functional connectivity magnetic resonance imaging (fcMRI) to assess the positive temporal correlations among activated brain areas during a gum-chewing task. Twenty-nine healthy young-adults underwent an fcMRI scanning protocol while they chewed gum. Seed-based fcMRI analyses were performed with the motor cortex and cerebellum as regions of interest. Both left and right motor cortices were reciprocally functionally connected and functionally connected with the post-central gyrus, cerebellum, cingulate cortex, and precuneus. The cerebellar seeds showed functional connections with the contralateral cerebellar hemispheres, bilateral sensorimotor cortices, left superior temporal gyrus, and left cingulate cortex. These results are the first to identify functional central networks engaged during mastication. PMID:23355525

  12. Connecting and Networking for Schools

    Science.gov (United States)

    Resources for connecting and networking for schools through e-newsletters, finding school IAQ Champions and other EPA school programs such as Asthma, Energy Star, Clean School Bus USA, School Flag, etc.

  13. The Prdm13 histone methyltransferase encoding gene is a Ptf1a-Rbpj downstream target that suppresses glutamatergic and promotes GABAergic neuronal fate in the dorsal neural tube

    DEFF Research Database (Denmark)

    Hanotel, Julie; Bessodes, Nathalie; Thélie, Aurore

    2014-01-01

    The basic helix-loop-helix (bHLH) transcriptional activator Ptf1a determines inhibitory GABAergic over excitatory glutamatergic neuronal cell fate in progenitors of the vertebrate dorsal spinal cord, cerebellum and retina. In an in situ hybridization expression survey of PR domain containing genes...... encoding putative chromatin-remodeling zinc finger transcription factors in Xenopus embryos, we identified Prdm13 as a histone methyltransferase belonging to the Ptf1a synexpression group. Gain and loss of Ptf1a function analyses in both frog and mice indicates that Prdm13 is positively regulated by Ptf1a...

  14. Visualizing neuronal network connectivity with connectivity pattern tables

    Directory of Open Access Journals (Sweden)

    Eilen Nordlie

    2010-01-01

    Full Text Available Complex ideas are best conveyed through well-designed illustrations. Up to now, computational neuroscientists have mostly relied on box-and-arrow diagrams of even complex neuronal networks, often using ad hoc notations with conflicting use of symbols from paper to paper. This significantly impedes the communication of ideas in neuronal network modeling. We present here Connectivity Pattern Tables (CPTs as a clutter-free visualization of connectivity in large neuronal networks containing two-dimensional populations of neurons. CPTs can be generated automatically from the same script code used to create the actual network in the NEST simulator. Through aggregation, CPTs can be viewed at different levels, providing either full detail or summary information. We also provide the open source ConnPlotter tool as a means to create connectivity pattern tables.

  15. MedlinePlus Connect: How it Works

    Science.gov (United States)

    ... Connect → How it Works URL of this page: https://medlineplus.gov/connect/howitworks.html MedlinePlus Connect: How ... will change.) Old URLs New URLs Web Application https://apps.nlm.nih.gov/medlineplus/services/mpconnect.cfm? ...

  16. MedlinePlus Connect in Use

    Science.gov (United States)

    ... MedlinePlus Connect in Use URL of this page: https://medlineplus.gov/connect/users.html MedlinePlus Connect in ... will change.) Old URLs New URLs Web Application https://apps.nlm.nih.gov/medlineplus/services/mpconnect.cfm? ...

  17. Brain Connectivity and Visual Attention

    Science.gov (United States)

    Parks, Emily L.

    2013-01-01

    Abstract Emerging hypotheses suggest that efficient cognitive functioning requires the integration of separate, but interconnected cortical networks in the brain. Although task-related measures of brain activity suggest that a frontoparietal network is associated with the control of attention, little is known regarding how components within this distributed network act together or with other networks to achieve various attentional functions. This review considers both functional and structural studies of brain connectivity, as complemented by behavioral and task-related neuroimaging data. These studies show converging results: The frontal and parietal cortical regions are active together, over time, and identifiable frontoparietal networks are active in relation to specific task demands. However, the spontaneous, low-frequency fluctuations of brain activity that occur in the resting state, without specific task demands, also exhibit patterns of connectivity that closely resemble the task-related, frontoparietal attention networks. Both task-related and resting-state networks exhibit consistent relations to behavioral measures of attention. Further, anatomical structure, particularly white matter pathways as defined by diffusion tensor imaging, places constraints on intrinsic functional connectivity. Lastly, connectivity analyses applied to investigate cognitive differences across individuals in both healthy and diseased states suggest that disconnection of attentional networks is linked to deficits in cognitive functioning, and in extreme cases, to disorders of attention. Thus, comprehensive theories of visual attention and their clinical translation depend on the continued integration of behavioral, task-related neuroimaging, and brain connectivity measures. PMID:23597177

  18. Random Interchange of Magnetic Connectivity

    Science.gov (United States)

    Matthaeus, W. H.; Ruffolo, D. J.; Servidio, S.; Wan, M.; Rappazzo, A. F.

    2015-12-01

    Magnetic connectivity, the connection between two points along a magnetic field line, has a stochastic character associated with field lines random walking in space due to magnetic fluctuations, but connectivity can also change in time due to dynamical activity [1]. For fluctuations transverse to a strong mean field, this connectivity change be caused by stochastic interchange due to component reconnection. The process may be understood approximately by formulating a diffusion-like Fokker-Planck coefficient [2] that is asymptotically related to standard field line random walk. Quantitative estimates are provided, for transverse magnetic field models and anisotropic models such as reduced magnetohydrodynamics. In heliospheric applications, these estimates may be useful for understanding mixing between open and close field line regions near coronal hole boundaries, and large latitude excursions of connectivity associated with turbulence. [1] A. F. Rappazzo, W. H. Matthaeus, D. Ruffolo, S. Servidio & M. Velli, ApJL, 758, L14 (2012) [2] D. Ruffolo & W. Matthaeus, ApJ, 806, 233 (2015)

  19. Continuously Connected With Mobile IP

    Science.gov (United States)

    2002-01-01

    Cisco Systems developed Cisco Mobile Networks, making IP devices mobile. With this innovation, a Cisco router and its connected IP devices can roam across network boundaries and connection types. Because a mobile user is able to keep the same IP address while roaming, a live IP connection can be maintained without interruption. Glenn Research Center jointly tested the technology with Cisco, and is working to use it on low-earth-orbiting research craft. With Cisco's Mobile Networks functionality now available in Cisco IOS Software release 12.2(4)T, the commercial advantages and benefits are numerous. The technology can be applied to public safety, military/homeland security, emergency management services, railroad and shipping systems, and the automotive industry. It will allow ambulances, police, firemen, and the U.S. Coast Guard to stay connected to their networks while on the move. In the wireless battlefield, the technology will provide rapid infrastructure deployment for U.S. national defense. Airline, train, and cruise passengers utilizing Cisco Mobile Networks can fly all around the world with a continuous Internet connection. Cisco IOS(R) Software is a registered trademark of Cisco Systems.

  20. In vivo and in vitro evaluation of [18F]FETO with respect to the adrenocortical and GABAergic system in rats

    International Nuclear Information System (INIS)

    Mitterhauser, Markus; Wadsak, Wolfgang; Wabnegger, Leila; Sieghart, Werner; Viernstein, Helmut; Kletter, Kurt; Dudczak, Robert

    2003-01-01

    11β-Hydroxylase (CYP11B1, P450 11β ) plays an important role in the biosynthesis of cortisol and aldosterone and has been shown to be a good target for the in vivo imaging of adrenocortical incidentalomas in nuclear medicine. [ 11 C]Metomidate (MTO), a potent inhibitor of this enzyme, is used for positron emission tomography (PET) imaging of adrenocortical pathology. The synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[ 18 F]fluoroethylester (FETO), a close analogue to MTO and etomidate (ETO), has been presented recently, and the present investigation aimed to characterise the in vivo distribution of FETO. Since ETO is a well-known anaesthetic drug acting via the GABAergic system, the interaction of FETO with GABA A receptors was also evaluated. Eighteen male Sprague-Dawley rats were injected with 1.73-3.06 MBq of FETO into a tail vein after venodilatation in a 40 C water bath. Rats were sacrificed by exsanguination from the abdominal aorta under deep ether anaesthesia after 10 (n=6), 30 (n=6) or 60 min (n=6); organs were removed, weighed and counted. For binding experiments, rat cerebellar membranes were incubated for 90 min at 4 C in TC-50 buffer, 150 mM NaCl and 2 nM of [ 3 H]flunitrazepam in the absence or presence of 10 μM diazepam or various concentrations of ETO, MTO and FETO. In vivo evaluation evinced very high uptake in the adrenal glands (7.52%±1.19% ID/g at 30 min), followed by lung (1.18%±0.19% ID/g, 10 min), liver (0.59%±0.13% ID/g, 10 min) and duodenum (0.7%±0.29% ID/g, 60 min). No defluorination nor fluoroethyl-ester cleavage was observed. When brain regions were compared with the thalamus (the reference region), highest relative uptake was seen in the cortex (2.34), followed by ''rest brain'' (2.13) and cerebellum (1.96). FETO and ETO were able to increase the binding of [ 3 H]flunitrazepam with similar potencies and to a comparable extent. It is concluded that FETO shows characteristics suitable for the imaging of

  1. In vivo and in vitro evaluation of [{sup 18}F]FETO with respect to the adrenocortical and GABAergic system in rats

    Energy Technology Data Exchange (ETDEWEB)

    Mitterhauser, Markus [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Department of Pharmaceutic Technology and Biopharmaceutics, University of Vienna (Austria); Hospital Pharmacy of the General Hospital of Vienna (Austria); Wadsak, Wolfgang [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Department of Inorganic Chemistry, University of Vienna (Austria); Ludwig-Boltzmann-Institute for Nuclear Medicine, Vienna (Austria); Wabnegger, Leila; Sieghart, Werner [Institute for Brain Research, University of Vienna (Austria); Viernstein, Helmut [Department of Pharmaceutic Technology and Biopharmaceutics, University of Vienna (Austria); Kletter, Kurt [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Dudczak, Robert [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria)

    2003-10-01

    11{beta}-Hydroxylase (CYP11B1, P450{sub 11{beta}}) plays an important role in the biosynthesis of cortisol and aldosterone and has been shown to be a good target for the in vivo imaging of adrenocortical incidentalomas in nuclear medicine. [{sup 11}C]Metomidate (MTO), a potent inhibitor of this enzyme, is used for positron emission tomography (PET) imaging of adrenocortical pathology. The synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[{sup 18}F]fluoroethylester (FETO), a close analogue to MTO and etomidate (ETO), has been presented recently, and the present investigation aimed to characterise the in vivo distribution of FETO. Since ETO is a well-known anaesthetic drug acting via the GABAergic system, the interaction of FETO with GABA{sub A} receptors was also evaluated. Eighteen male Sprague-Dawley rats were injected with 1.73-3.06 MBq of FETO into a tail vein after venodilatation in a 40 C water bath. Rats were sacrificed by exsanguination from the abdominal aorta under deep ether anaesthesia after 10 (n=6), 30 (n=6) or 60 min (n=6); organs were removed, weighed and counted. For binding experiments, rat cerebellar membranes were incubated for 90 min at 4 C in TC-50 buffer, 150 mM NaCl and 2 nM of [{sup 3}H]flunitrazepam in the absence or presence of 10 {mu}M diazepam or various concentrations of ETO, MTO and FETO. In vivo evaluation evinced very high uptake in the adrenal glands (7.52%{+-}1.19% ID/g at 30 min), followed by lung (1.18%{+-}0.19% ID/g, 10 min), liver (0.59%{+-}0.13% ID/g, 10 min) and duodenum (0.7%{+-}0.29% ID/g, 60 min). No defluorination nor fluoroethyl-ester cleavage was observed. When brain regions were compared with the thalamus (the reference region), highest relative uptake was seen in the cortex (2.34), followed by ''rest brain'' (2.13) and cerebellum (1.96). FETO and ETO were able to increase the binding of [{sup 3}H]flunitrazepam with similar potencies and to a comparable extent. It is concluded

  2. Hitchin's connection in metaplectic quantization

    DEFF Research Database (Denmark)

    Andersen, Jørgen Ellegaard; Gammelgaard, Niels Leth; Lauridsen, Magnus Roed

    2012-01-01

    We give a differential geometric construction of a connection, which we call the Hitchin connection, in the bundle of quantum Hilbert spaces arising from metaplectically corrected geometric quantization of a prequantizable, symplectic manifold, endowed with a rigid family of Kähler structures, all...... manifold in question. Furthermore, when we are in a setting similar to the moduli space, we give an explicit formula and show that this connection agrees with previous constructions....... of which give vanishing first Dolbeault cohomology groups. This generalizes work of both Hitchin, Scheinost and Schottenloher, and Andersen, since our construction does not need that the first Chern class is proportional to the class of the symplectic form, nor do we need compactness of the symplectic...

  3. Review on Cold-Formed Steel Connections

    Science.gov (United States)

    Tan, Cher Siang; Mohammad, Shahrin; Md Tahir, Mahmood; Shek, Poi Ngian

    2014-01-01

    The concept of cold-formed light steel framing construction has been widespread after understanding its structural characteristics with massive research works over the years. Connection serves as one of the important elements for light steel framing in order to achieve its structural stability. Compared to hot-rolled steel sections, cold-formed steel connections perform dissimilarity due to the thin-walled behaviour. This paper aims to review current researches on cold-formed steel connections, particularly for screw connections, storage rack connections, welded connections, and bolted connections. The performance of these connections in the design of cold-formed steel structures is discussed. PMID:24688448

  4. Semantic connections: exploring and manipulating connections in smart spaces

    NARCIS (Netherlands)

    Vlist, van der B.J.J.; Niezen, G.; Hu, J.; Feijs, L.M.G.

    2010-01-01

    In envisioned smart environments, enabled by ubiquitous computing technologies, electronic objects will be able to interconnect and interoperate. How will users of such smart environments make sense of the connections that are made and the information that is exchanged? This Internet of Things could

  5. Whole-brain functional connectivity predicted by indirect structural connections

    DEFF Research Database (Denmark)

    Røge, Rasmus; Ambrosen, Karen Marie Sandø; Albers, Kristoffer Jon

    2017-01-01

    Modern functional and diffusion magnetic resonance imaging (fMRI and dMRI) provide data from which macro-scale networks of functional and structural whole brain connectivity can be estimated. Although networks derived from these two modalities describe different properties of the human brain, the...

  6. Formal connections in deformation quantization

    DEFF Research Database (Denmark)

    Masulli, Paolo

    The field of this thesis is deformation quantization, and we consider mainly symplectic manifolds equipped with a star product. After reviewing basics in complex geometry, we introduce quantization, focusing on geometric quantization and deformation quantization. The latter is defined as a star...... characteristic class, and that formal connections form an affine space over the derivations of the star products. Moreover, if the parameter space for the family of star products is contractible, we obtain that any two flat formal connections are gauge equivalent via a self-equivalence of the family of star...

  7. Developing a Connective Feminine Discourse

    DEFF Research Database (Denmark)

    Rahbek, Ulla

    2015-01-01

    This paper discusses the work of the Australian writer and historian Drusilla Modjeska through a focus on the intersections between women‟s lives, love and art, which constitute the central triptych of Modjeska‟s writing. It argues that Modjeska's oeuvre unfolds a connective feminine discourse...... through a development of what the paper calls hinging tropes, discursive connectors that join life, love and art, such as weaving, folding and talking. That connective feminine discourse is indeed central to Modjeska‟s personal and sometimes idiosyncratic feminism...

  8. C-connected frame congruences

    Directory of Open Access Journals (Sweden)

    Dharmanand Baboolal

    2017-01-01

    Full Text Available We discuss the congruences $theta$ that are connected as  elements of the (totally disconnected congruence frame $CF L$,  and show that they are in a one-to-one correspondence with the completely prime elements of $L$, giving an explicit formula. Then we investigate those frames $L$ with enough connected congruences to cover the whole of $CF L$. They are, among others, shown to be $T_D$-spatial;  characteristics for some special cases (Boolean, linear, scattered and Noetherian are presented.

  9. Ekspert i undervisning - IRIS Connect

    DEFF Research Database (Denmark)

    Wullum, Annemette Heine; Eriksen, Frits Hedegaard

    Ekspert i undervisning – IRIS Connect Credoet bag de seneste års mange læreruddannelsesreformer har været, at flere og dybere kundskaber vil styrke de studerendes forudsætninger for at løse opgaverne i pædagogisk praksis. Et forhold, som bliver overset i forbindelse med uddannelsesreformerne, er...... praksis, og hvad ”effektiv” undervisning er. Hovedantagelserne bag projektet er, at de studerendes personbundne kundskaber kan synliggøres, at deres lægmandsopfattelser af, hvad ”effektiv” undervisning er, kan udfordres gennem analyser og drøftelser, og at brugen af IRIS Connects dataindsamlings- og...

  10. Finite connectivity attractor neural networks

    International Nuclear Information System (INIS)

    Wemmenhove, B; Coolen, A C C

    2003-01-01

    We study a family of diluted attractor neural networks with a finite average number of (symmetric) connections per neuron. As in finite connectivity spin glasses, their equilibrium properties are described by order parameter functions, for which we derive an integral equation in replica symmetric approximation. A bifurcation analysis of this equation reveals the locations of the paramagnetic to recall and paramagnetic to spin-glass transition lines in the phase diagram. The line separating the retrieval phase from the spin-glass phase is calculated at zero temperature. All phase transitions are found to be continuous

  11. Art and the Cosmic Connection

    Science.gov (United States)

    Cobb, Whitney H.; Aiello, Monica Petty; Macdonald, Reeves; Asplund, Shari

    2014-01-01

    The interdisciplinary unit described in this article utilizes "Art and the Cosmic Connection," a free program conceived of by artists Monica and Tyler Aiello and developed by the artists, scientists, and educators through NASA's Discovery and New Frontiers Programs, to inspire learners to explore mysterious worlds in our solar…

  12. Reduced prefrontal connectivity in psychopathy.

    Science.gov (United States)

    Motzkin, Julian C; Newman, Joseph P; Kiehl, Kent A; Koenigs, Michael

    2011-11-30

    Linking psychopathy to a specific brain abnormality could have significant clinical, legal, and scientific implications. Theories on the neurobiological basis of the disorder typically propose dysfunction in a circuit involving ventromedial prefrontal cortex (vmPFC). However, to date there is limited brain imaging data to directly test whether psychopathy may indeed be associated with any structural or functional abnormality within this brain area. In this study, we employ two complementary imaging techniques to assess the structural and functional connectivity of vmPFC in psychopathic and non-psychopathic criminals. Using diffusion tensor imaging, we show that psychopathy is associated with reduced structural integrity in the right uncinate fasciculus, the primary white matter connection between vmPFC and anterior temporal lobe. Using functional magnetic resonance imaging, we show that psychopathy is associated with reduced functional connectivity between vmPFC and amygdala as well as between vmPFC and medial parietal cortex. Together, these data converge to implicate diminished vmPFC connectivity as a characteristic neurobiological feature of psychopathy.

  13. Connections in wood and foliage

    Science.gov (United States)

    Kevin T. Smith

    2009-01-01

    Trees are networked systems that capture energy, move massive amounts of water and material, and provide the setting for human society and for the lives of many associated organisms. Tree survival depends on making and breaking the right connections within these networks.

  14. The Hanze-India Connection

    NARCIS (Netherlands)

    Velthuijsen, Hugo

    2010-01-01

    Hanze India connection. Presentatie gehouden op 09-06-2010. Bestaat uit foto's. Op uitnodiging van KPN, sponsor van het lectoraat New Business & ICT, bezocht Hugo Velthuijsen een aantal steden in India. Het doel was om ter plekke een beeld te krijgen van de mogelijkheden van IT en Business

  15. Grouted Connections with Shear Keys

    DEFF Research Database (Denmark)

    Pedersen, Ronnie; Jørgensen, M. B.; Damkilde, Lars

    2012-01-01

    This paper presents a finite element model in the software package ABAQUS in which a reliable analysis of grouted pile-to-sleeve connections with shear keys is the particular purpose. The model is calibrated to experimental results and a consistent set of input parameters is estimated so that dif...... that different structural problems can be reproduced successfully....

  16. Tilting-connected symmetric algebras

    OpenAIRE

    Aihara, Takuma

    2010-01-01

    The notion of silting mutation was introduced by Iyama and the author. In this paper we mainly study silting mutation for self-injective algebras and prove that any representation-finite symmetric algebra is tilting-connected. Moreover we give some sufficient conditions for a Bongartz-type Lemma to hold for silting objects.

  17. The Histogram-Area Connection

    Science.gov (United States)

    Gratzer, William; Carpenter, James E.

    2008-01-01

    This article demonstrates an alternative approach to the construction of histograms--one based on the notion of using area to represent relative density in intervals of unequal length. The resulting histograms illustrate the connection between the area of the rectangles associated with particular outcomes and the relative frequency (probability)…

  18. Connecting Slope, Steepness, and Angles

    Science.gov (United States)

    Nagle, Courtney R.; Moore-Russo, Deborah

    2013-01-01

    All teachers, especially high school teachers, face the challenge of ensuring that students have opportunities to relate and connect the various representations and notions of mathematics concepts developed over the course of the pre-K-12 mathematics curriculum. NCTM's (2000) Representation Standard emphasizes the importance of students being…

  19. Isolating highly connected induced subgraphs

    DEFF Research Database (Denmark)

    Penev, Irena; Thomasse, Stephan; Trotignon, Nicolas

    2016-01-01

    We prove that any graph G of minimum degree greater than 2k(2) - 1 has a (k + 1)-connected induced subgraph H such that the number of vertices of H that have neighbors outside of H is at most 2k(2) - 1. This generalizes a classical result of Mader, which states that a high minimum degree implies ...

  20. Elementary Algebra Connections to Precalculus

    Science.gov (United States)

    Lopez-Boada, Roberto; Daire, Sandra Arguelles

    2013-01-01

    This article examines the attitudes of some precalculus students to solve trigonometric and logarithmic equations and systems using the concepts of elementary algebra. With the goal of enticing the students to search for and use connections among mathematical topics, they are asked to solve equations or systems specifically designed to allow…

  1. Connected Firms and Investor Myopia

    NARCIS (Netherlands)

    Ginglinger, Edith; Hébert, Camille; Renneboog, Luc

    2017-01-01

    Conglomerates, multinational corporations and business groups are non-exclusive forms of complex firms. Often organized as corporate networks, complex firms control a myriad of firms connected through ownership links. We investigate whether parent-subsidiary links within corporate networks enhance

  2. Indicators of Malicious SSL Connections

    NARCIS (Netherlands)

    Bortolameotti, Riccardo; Peter, Andreas; Everts, Maarten Hinderik; Bolzoni, D.

    2015-01-01

    Internet applications use SSL to provide data confidential- ity to communicating entities. The use of encryption in SSL makes it impossible to distinguish between benign and malicious connections as the content cannot be inspected. Therefore, we propose and evaluate a set of indicators for malicious

  3. Indicators of malicious SSL connections

    NARCIS (Netherlands)

    Bortolameotti, R.; Peter, A.; Everts, M.H.; Bolzoni, D.

    2015-01-01

    Internet applications use SSL to provide data confidentiality to communicating entities. The use of encryption in SSL makes it impossible to distinguish between benign and malicious connections as the content cannot be inspected. Therefore, we propose and evaluate a set of indicators for malicious

  4. Connecting Leadership and Learning: Do Versatile Learners make Connective Leaders?

    OpenAIRE

    Jill L. Robinson

    2016-01-01

    Recent failures in leadership, suggest that creating better-quality leadership development programs is critical. In moving from theory to practice, this paper examined the relationship between learning style and leadership style which may enable us to move away from one-size-fits-all leadership development programs. Utilizing Kolb’s Experiential Learning Model and Connective Leadership theory, approximately 3600 college students were analyzed to discover whether versatility in learning styles...

  5. Connecting leadership and learning: Do versatile learners make connective leaders?

    OpenAIRE

    Robinson, Jill L.

    2016-01-01

    Recent failures in leadership, suggest that creating better-quality leadership development programs is critical. In moving from theory to practice, this paper examined the relationship between learning style and leadership style which may enable us to move away from one-size-fits-all leadership development programs. Utilizing Kolb’s Experiential Learning Model and Connective Leadership theory, approximately 3600 college students were analyzed to discover whether versatility in learning styles...

  6. Connecting Leadership and Learning: Do Versatile Learners make Connective Leaders?

    OpenAIRE

    Jill L. Robinson

    2016-01-01

    Abstract Recent failures in leadership, suggest that creating better-quality leadership development programs is critical. In moving from theory to practice, this paper examined the relationship between learning style and leadership style which may enable us to move away from one-size-fits-all leadership development programs. Utilizing Kolb’s Experiential Learning Model and Connective Leadership theory, approximately 3600 college students were analyzed to discover whether versatility in le...

  7. Nonrandom network connectivity comes in pairs

    Directory of Open Access Journals (Sweden)

    Felix Z. Hoffmann

    2017-02-01

    Full Text Available Overrepresentation of bidirectional connections in local cortical networks has been repeatedly reported and is a focus of the ongoing discussion of nonrandom connectivity. Here we show in a brief mathematical analysis that in a network in which connection probabilities are symmetric in pairs, Pij = Pji, the occurrences of bidirectional connections and nonrandom structures are inherently linked; an overabundance of reciprocally connected pairs emerges necessarily when some pairs of neurons are more likely to be connected than others. Our numerical results imply that such overrepresentation can also be sustained when connection probabilities are only approximately symmetric.

  8. Content, Context & Connectivity Persuasive Interplay

    DEFF Research Database (Denmark)

    Sørensen, Christian Grund

    2013-01-01

    -supported research project under EACEA). In the development of this project several categories of content have been implemented in technology enhanced learning tools. These have been designed to support learning in different contexts and eventually the role of the connectivity of these learning objects and tools......The aim of this paper is to discuss the relationship between content, context and connectivity and suggesting a model of Dynamic Interplay. This is done in relation to a specific learning environment concerning cultural mediation, in casu the Kaj Munk Case of the EuroPLOT-project (an EU...... is discussed. Focus is here on The Kaj Munk Study Edition, The Conceptual Pond, Immersive Layers Design, and Generative Learning Objects (GLOs) which are applications affiliated with the Munk case. This paper explores the persuasive potential of the interplay between the different applications for the benefit...

  9. A Building Connecting Separated Communities

    DEFF Research Database (Denmark)

    Axel, Erik

    Producing something for general use involves the designers' anticipation of the use of the object. Personal as well as professional experience is involved in the design anticipations of the process. Using an object means exploring it as a concrete arrangement for our everyday conduct of life....... in no systematic sequence. This, among other things, separates design and use, which is worth investigating in order to understand the problems involved in connecting the design of a house and analyzing the experience of a user. We undertook a preliminary investigation of how a dormitory for visiting students from...... with students from other dormitories, and connect with the Danes from other sections of the building isolating themselves. The janitor was surprised at the supposed function of the washing machines. Since other dormitories at the campus did not provide washing machines, the ones at the house investigated were...

  10. UNBIASED ESTIMATORS OF SPECIFIC CONNECTIVITY

    Directory of Open Access Journals (Sweden)

    Jean-Paul Jernot

    2011-05-01

    Full Text Available This paper deals with the estimation of the specific connectivity of a stationary random set in IRd. It turns out that the "natural" estimator is only asymptotically unbiased. The example of a boolean model of hypercubes illustrates the amplitude of the bias produced when the measurement field is relatively small with respect to the range of the random set. For that reason unbiased estimators are desired. Such an estimator can be found in the literature in the case where the measurement field is a right parallelotope. In this paper, this estimator is extended to apply to measurement fields of various shapes, and to possess a smaller variance. Finally an example from quantitative metallography (specific connectivity of a population of sintered bronze particles is given.

  11. The business case for connectivity

    Science.gov (United States)

    Adams, Dennis; Hirschheim, Rudy

    1991-01-01

    Information systems that provide competitive advantages to organizations can be broadly classified into those that improve the effectiveness of a business function and those that improve the reach of information in the organization. The latter, organizational connectivity systems, can be categorized as intraorganizational and interorganizational systems. Intraorganization systems provide connectivity to function areas within the business, while interorganizational systems support the exchange of business data between independent business units. These system are not confined to a single entity but span organizational boundaries which can be national or international in scope. A series of case studies was undertaken in an effort to better understand the issues and problems associated with providing an increased flow of information within and outside of an organization. Ten issues emerged from this study. In summary, it is necessary for firms to first consider how effective their internal communications systems are before launching projects that tie the organization to external systems.

  12. Ongoing Space Physics - Astrophysics Connections

    OpenAIRE

    Eichler, David

    2005-01-01

    I review several ongoing connections between space physics and astrophysics: a) Measurements of energetic particle spectra have confirmed theoretical prediction of the highest energy to which shocks can accelerate particles, and this has direct bearing on the origin of the highest energy cosmic rays. b) Mass ejection in solar flares may help us understand photon ejection in the giant flares of magnetar outbursts. c) Measurements of electron heat fluxes in the solar wind can help us understand...

  13. Connecting Remote Clusters with ATM

    Energy Technology Data Exchange (ETDEWEB)

    Hu, T.C.; Wyckoff, P.S.

    1998-10-01

    Sandia's entry into utilizing clusters of networked workstations is called Computational Plant or CPlant for short. The design of CPlant uses Ethernet to boot the individual nodes, Myrinet to communicate within a node cluster, and ATM to connect between remote clusters. This SAND document covers the work done to enable the use of ATM on the CPlant nodes in the Fall of 1997.

  14. Regional connectivity in continental ASEAN

    OpenAIRE

    Taguchi, Hiroyuki; Nozaki, Kenji

    2014-01-01

    This chapter examines the issue on Mekong region’s connectivity on quantitative base through the analysis of the gravity trade model and its modified fragmentation model. The main findings are as follows: First, the evolution of international production networks (IPNs) between Thailand and Vietnam as well as the other advanced ASEAN could be identified in terms of their two-way trade integration of machinery parts and components beyond the gravity trade standard. Second, the trade intensity o...

  15. Collective action, clientelism and connectivity

    DEFF Research Database (Denmark)

    Shami, Mahvish

    that the unequal relationship between landlords and peasants does not, in and by itself, block peasant collective action. Rather, it is the interaction between clientelism and isolation that allow patrons to block community based projects. Despite still relying on powerful landlords, peasants in connected villages...... face no such constraints. On the contrary, their patrons assisted them in their collective endeavours, making the hierarchical network an added resource for peasants to rely upon....

  16. Altered Insula Connectivity under MDMA.

    Science.gov (United States)

    Walpola, Ishan C; Nest, Timothy; Roseman, Leor; Erritzoe, David; Feilding, Amanda; Nutt, David J; Carhart-Harris, Robin L

    2017-10-01

    Recent work with noninvasive human brain imaging has started to investigate the effects of 3,4-methylenedioxymethamphetamine (MDMA) on large-scale patterns of brain activity. MDMA, a potent monoamine-releaser with particularly pronounced serotonin- releasing properties, has unique subjective effects that include: marked positive mood, pleasant/unusual bodily sensations and pro-social, empathic feelings. However, the neurobiological basis for these effects is not properly understood, and the present analysis sought to address this knowledge gap. To do this, we administered MDMA-HCl (100 mg p.o.) and, separately, placebo (ascorbic acid) in a randomized, double-blind, repeated-measures design with twenty-five healthy volunteers undergoing fMRI scanning. We then employed a measure of global resting-state functional brain connectivity and follow-up seed-to-voxel analysis to the fMRI data we acquired. Results revealed decreased right insula/salience network functional connectivity under MDMA. Furthermore, these decreases in right insula/salience network connectivity correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA. The present findings highlight insular disintegration (ie, compromised salience network membership) as a neurobiological signature of the MDMA experience, and relate this brain effect to trait anxiety and acutely altered bodily sensations-both of which are known to be associated with insular functioning.

  17. Evaluation of GABAergic neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-20-one as a neurobiological substrate for the anti-anxiety effect of ethanol in rats.

    Science.gov (United States)

    Hirani, Khemraj; Sharma, Ajay N; Jain, Nishant S; Ugale, Rajesh R; Chopde, Chandrabhan T

    2005-07-01

    Acute systemic ethanol administration is known to elevate plasma and cerebral levels of neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha, 5alpha-THP; allopregnanolone) to a concentration sufficient to potentiate GABA(A) receptors. We have earlier demonstrated that 3alpha, 5alpha-THP mediates the antidepressant-like effect of ethanol in Porsolt forced swim test. The aim of the present study is to explain the relationship between endogenous GABAergic neurosteroids and anxiolytic effect of ethanol in Sprague-Dawley rats. The mediation of 3alpha, 5alpha-THP in the anti-anxiety effect of ethanol was assessed by pharmacological interactions of ethanol with various endogenous neurosteroidal modulators and using simulated physiological conditions of altered neurosteroid content in elevated plus maze (EPM) test. Pretreatment of 3alpha, 5alpha-THP (0.5-2.5 mug/rat, i.c.v.) or neurosteroidogenic agents such as 3alpha, 5alpha-THP precursor progesterone (5 or 10 mg/kg, i.p.), 11-beta hydroxylase inhibitor metyrapone (50 or 100 mg/kg, i.p.) or the GABA(A) receptor agonist muscimol (25 ng/rat, i.c.v.) significantly potentiated the anti-anxiety effect of ethanol (1 g/kg, i.p.). On the other hand, the GABAergic antagonistic neurosteroid dehydroepiandrosterone sulphate (DHEAS) (1 mg/kg, i.p.), the GABA(A) receptor blocker bicuculline (1 mg/kg, i.p.), the 5alpha-reductase inhibitor finasteride (50 x 2 mg/kg, s.c.) or the mitochondrial diazepam binding inhibitory receptor antagonist PK11195 (1 mg/kg, i.p.) reduced ethanol-induced preference of time spent and number of entries into open arms. Anti-anxiety effect of ethanol was abolished in adrenalectomized (ADX) rats as compared to sham-operated control. This ADX-induced blockade was restored by prior systemic injection of progesterone, signifying the contribution of peripheral steroidogenesis in ethanol anxiolysis. Socially isolated animals known to exhibit decreased brain 3alpha, 5alpha-THP and GABA(A) receptor

  18. Interlaminar and lateral excitatory amino acid connections in the striate cortex of monkey

    International Nuclear Information System (INIS)

    Kisvarday, Z.F.; Cowey, A.; Smith, A.D.; Somogyi, P.

    1989-01-01

    The intrinsic excitatory amino acid pathways within the striate cortex of monkeys were studied by autoradiographic detection of retrogradely labeled somata following microinjections of D-3H-aspartate (D-3H-Asp) into different layers. The labeled amino acid was selectively accumulated by subpopulations of neurons and, to a small extent, by glial cells, the latter mainly in the supragranular layers. Immunocytochemical detection of neurons containing GABA showed that, apart from a few cells exclusively in layer I, GABAergic neurons do not accumulate D-3H-Asp. Several lines of evidence suggest that D-3H-Asp uptake occurred only at nerve terminals; thus, the pattern of perikaryal labeling allowed the delineation of interlaminar and lateral projections. Neurons in layer I probably project laterally, and layer I receives wide-ranging projections from layer IVB and layer V from cells up to 1300 microns laterally. Some neurons in layer II send a focused projection to lower layer VI. Some neurons in layers II/III project up to 1 mm laterally within their own layer, but relatively few neurons can be labeled in these projections. Similarly, in layers II/III few neurons can be retrogradely labeled from layers V and upper VI, and this projection is organized such that cells closer to the pia project deeper in layer V/VI. The connections of layer IVA could not be revealed separately because of the difficulty of confining injections to this thin sublamina. Neurons in layer IVB project up to 1300 microns within IVB itself. A small number of cells from IVB also project to layers III, IVC-alpha, V, and VI with much more restricted lateral spread. Neurons in upper IVC-alpha send axons to layer IVB with at least 600-800 microns lateral spread. Neurons in lower IVC-alpha/upper IVC-beta project to layer III with at least 300-500 microns lateral spread

  19. Interlaminar and lateral excitatory amino acid connections in the striate cortex of monkey

    Energy Technology Data Exchange (ETDEWEB)

    Kisvarday, Z.F.; Cowey, A.; Smith, A.D.; Somogyi, P.

    1989-02-01

    The intrinsic excitatory amino acid pathways within the striate cortex of monkeys were studied by autoradiographic detection of retrogradely labeled somata following microinjections of D-3H-aspartate (D-3H-Asp) into different layers. The labeled amino acid was selectively accumulated by subpopulations of neurons and, to a small extent, by glial cells, the latter mainly in the supragranular layers. Immunocytochemical detection of neurons containing GABA showed that, apart from a few cells exclusively in layer I, GABAergic neurons do not accumulate D-3H-Asp. Several lines of evidence suggest that D-3H-Asp uptake occurred only at nerve terminals; thus, the pattern of perikaryal labeling allowed the delineation of interlaminar and lateral projections. Neurons in layer I probably project laterally, and layer I receives wide-ranging projections from layer IVB and layer V from cells up to 1300 microns laterally. Some neurons in layer II send a focused projection to lower layer VI. Some neurons in layers II/III project up to 1 mm laterally within their own layer, but relatively few neurons can be labeled in these projections. Similarly, in layers II/III few neurons can be retrogradely labeled from layers V and upper VI, and this projection is organized such that cells closer to the pia project deeper in layer V/VI. The connections of layer IVA could not be revealed separately because of the difficulty of confining injections to this thin sublamina. Neurons in layer IVB project up to 1300 microns within IVB itself. A small number of cells from IVB also project to layers III, IVC-alpha, V, and VI with much more restricted lateral spread. Neurons in upper IVC-alpha send axons to layer IVB with at least 600-800 microns lateral spread. Neurons in lower IVC-alpha/upper IVC-beta project to layer III with at least 300-500 microns lateral spread.

  20. Interlaminar and lateral excitatory amino acid connections in the striate cortex of monkey.

    Science.gov (United States)

    Kisvarday, Z F; Cowey, A; Smith, A D; Somogyi, P

    1989-02-01

    The intrinsic excitatory amino acid pathways within the striate cortex of monkeys were studied by autoradiographic detection of retrogradely labeled somata following microinjections of D-3H-aspartate (D-3H-Asp) into different layers. The labeled amino acid was selectively accumulated by subpopulations of neurons and, to a small extent, by glial cells, the latter mainly in the supragranular layers. Immunocytochemical detection of neurons containing GABA showed that, apart from a few cells exclusively in layer I, GABAergic neurons do not accumulate D-3H-Asp. Several lines of evidence suggest that D-3H-Asp uptake occurred only at nerve terminals; thus, the pattern of perikaryal labeling allowed the delineation of interlaminar and lateral projections. Neurons in layer I probably project laterally, and layer I receives wide-ranging projections from layer IVB and layer V from cells up to 1300 microns laterally. Some neurons in layer II send a focused projection to lower layer VI. Some neurons in layers II/III project up to 1 mm laterally within their own layer, but relatively few neurons can be labeled in these projections. Similarly, in layers II/III few neurons can be retrogradely labeled from layers V and upper VI, and this projection is organized such that cells closer to the pia project deeper in layer V/VI. The connections of layer IVA could not be revealed separately because of the difficulty of confining injections to this thin sublamina. Neurons in layer IVB project up to 1300 microns within IVB itself. A small number of cells from IVB also project to layers III, IVC-alpha, V, and VI with much more restricted lateral spread. Neurons in upper IVC-alpha send axons to layer IVB with at least 600-800 microns lateral spread. Neurons in lower IVC-alpha/upper IVC-beta project to layer III with at least 300-500 microns lateral spread. The bottom 50-80 microns of layer IVC-beta contains neurons with a very focused projection, apparently exclusively to the layer III

  1. The smart/connected city and its implications for connected transportation.

    Science.gov (United States)

    2014-10-14

    This white paper outlines the potential for the emerging connected transportation system to interface with smart/connected cities. Its aim is to lay the foundation for defining steps that the U.S. Department of Transportation (USDOT) Connected Vehicl...

  2. The selective alpha7 nicotinic acetylcholine receptor agonist PNU-282987 [N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride] enhances GABAergic synaptic activity in brain slices and restores auditory gating deficits in anesthetized rats.

    Science.gov (United States)

    Hajós, M; Hurst, R S; Hoffmann, W E; Krause, M; Wall, T M; Higdon, N R; Groppi, V E

    2005-03-01

    Schizophrenic patients are thought to have an impaired ability to process sensory information. This deficit leads to disrupted auditory gating measured electrophysiologically as a reduced suppression of the second of paired auditoryevoked responses (P50) and is proposed to be associated with decreased function and/or expression of the homomeric alpha7 nicotinic acetylcholine receptor (nAChR). Here, we provide evidence that N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-282987), a novel selective agonist of the alpha7 nAChR, evoked whole-cell currents from cultured rat hippocampal neurons that were sensitive to the selective alpha7 nAChR antagonist methyllycaconitine (MLA) and enhanced GABAergic synaptic activity when applied to hippocampal slices. Amphetamine-induced sensory gating deficit, determined by auditory-evoked potentials in hippocampal CA3 region, was restored by systemic administration of PNU-282987 in chloral hydrate-anesthetized rats. Auditory gating of rat reticular thalamic neurons was also disrupted by amphetamine; however, PNU-282987 normalized gating deficit only in a subset of tested neurons (6 of 11). Furthermore, PNU-282987 improved the inherent hippocampal gating deficit occurring in a subpopulation of anesthetized rats, and enhanced amphetamine-induced hippocampal oscillation. We propose that the alpha7 nAChR agonist PNU-282987, via modulating/enhancing hippocampal GABAergic neurotransmission, improves auditory gating and enhances hippocampal oscillatory activity. These results provide further support for the concept that drugs that selectively activate alpha7 nAChRs may offer a novel, potential pharmacotherapy in treatment of schizophrenia.

  3. Systematic study of association of four GABAergic genes: glutamic acid decarboxylase 1 gene, glutamic acid decarboxylase 2 gene, GABA(B) receptor 1 gene and GABA(A) receptor subunit beta2 gene, with schizophrenia using a universal DNA microarray.

    Science.gov (United States)

    Zhao, Xu; Qin, Shengying; Shi, Yongyong; Zhang, Aiping; Zhang, Jing; Bian, Li; Wan, Chunling; Feng, Guoyin; Gu, Niufan; Zhang, Guangqi; He, Guang; He, Lin

    2007-07-01

    Several studies have suggested the dysfunction of the GABAergic system as a risk factor in the pathogenesis of schizophrenia. In the present study, case-control association analysis was conducted in four GABAergic genes: two glutamic acid decarboxylase genes (GAD1 and GAD2), a GABA(A) receptor subunit beta2 gene (GABRB2) and a GABA(B) receptor 1 gene (GABBR1). Using a universal DNA microarray procedure we genotyped a total of 20 SNPs on the above four genes in a study involving 292 patients and 286 controls of Chinese descent. Statistically significant differences were observed in the allelic frequencies of the rs187269C/T polymorphism in the GABRB2 gene (P=0.0450, chi(2)=12.40, OR=1.65) and the -292A/C polymorphism in the GAD1 gene (P=0.0450, chi(2)=14.64 OR=1.77). In addition, using an electrophoretic mobility shift assay (EMSA), we discovered differences in the U251 nuclear protein binding to oligonucleotides representing the -292 SNP on the GAD1 gene, which suggests that the -292C allele has reduced transcription factor binding efficiency compared with the 292A allele. Using the multifactor-dimensionality reduction method (MDR), we found that the interactions among the rs187269C/T polymorphism in the GABRB2 gene, the -243A/G polymorphism in the GAD2 gene and the 27379C/T and 661C/T polymorphisms in the GAD1 gene revealed a significant association with schizophrenia (Pschizophrenia in the Chinese population.

  4. Study of rectenna array connection

    Energy Technology Data Exchange (ETDEWEB)

    Miura, T.; Shinohara, N.; Matsumoto, H. [Kyoto Univ., Uji (Japan). Engineering Research Inst.

    1997-11-01

    A study was conducted in which a new rectenna working at 2.45 GHz microwave was developed for ground-to-ground microwave power transmission. The new rectenna consists of an antenna section and a rectifying section. The new design is simple and therefore more accurate than a micro-strip type patch antenna. The efficiency of conversion of microwave power to direct current depends on the mutual dependence of antenna elements and circuit conditions of rectifying sections. A series of experiments were conducted to analyze the rectenna characteristics and a method for efficiently connecting rectenna arrays was proposed. 3 refs., 2 tabs., 15 figs.

  5. CODAC systems arrangement and connectivity

    Energy Technology Data Exchange (ETDEWEB)

    Gulati, Hitesh Kumar, E-mail: hkgulati@gmail.com; Beltran, David; Kuehn, Ingo; Kotamaki, Miikka; Makijarvi, Petri; Wallander, Anders

    2013-10-15

    Highlights: •The CODAC system is a distributed system and scattered in many buildings connected with cables. Building construction for ITER project is just started so volume reservation for different CODAC component is done based on the content of this paper. •The 2-D and 3-D diagrams have been prepared which are showing the location of different CODAC equipment and their connectivity. •The different requirements regarding raised access (false) floor, power requirements, heat load, installation, maintenance, redundancy, and segregation etc. have been considered. -- Abstract: The CODAC system is responsible for integrating all ITER plant system Instrumentation and Control systems and enabling operation of ITER machine as a single integrated facility. The different ITER plant systems and their Instrumentation and Control systems are distributed in several ITER buildings on the ITER platform. The CODAC systems have to interface with all these distributed plant system I and C systems. CODAC systems will be composed of several physical systems or components like networks, servers, workstations (terminals), large displays, PSH, storage systems etc. Several rooms in different buildings have been defined to house all above equipment. The site-wide CODAC network infrastructure will be based on a dual (redundant) star topology. The two redundant star points will house the core networking switches. These redundant core switches will be installed in different buildings. Cubicles used for network infrastructure are distributed among “hutches,” where a CODAC hutch is a room or area equipped with appropriate heating, ventilation, air conditioning and uninterruptible power which will be directly connected through two star points. The responsibility of CODAC infrastructure ends up to the plant system I and C cubicles so several passive CODAC network panels have identified in all I and C rooms of different plant buildings. This CODAC Network Panel will be the physical

  6. Recreating Intimacy With Connected Consumers

    Directory of Open Access Journals (Sweden)

    Stephen Andrew

    2017-11-01

    Full Text Available In the good old times shop manager knew their customers personally and were able to tailor offerings to their needs and desires. But how can we create meaningful moments for connected consumers in global markets? Yasmeen Ahmad explains how in digital times data fill in. Smart algorithms help generate insights and enable real time action to provide the right product and service to the right customer at the right time. Companies that don’t want to be left behind a digital elite need to remain close to their customers across multiple digital touchpoints. Being capable of reading, interpreting and acting upon consumers` traces is a prerequisite.

  7. Battery impedance spectroscopy using bidirectional grid connected

    Indian Academy of Sciences (India)

    Keywords. Impedance spectroscopy; grid connection; battery converter; state of charge; health monitoring ... The converter is grid connected and controlled to operate at unity power factor. Additional ... Sadhana. Current Issue : Vol. 43, Issue 6.

  8. Connecting Related Rates and Differential Equations

    Science.gov (United States)

    Brandt, Keith

    2012-01-01

    This article points out a simple connection between related rates and differential equations. The connection can be used for in-class examples or homework exercises, and it is accessible to students who are familiar with separation of variables.

  9. National connected vehicle field infrastructure footprint analysis.

    Science.gov (United States)

    2014-06-01

    The fundamental premise of the connected vehicle initiative is that enabling wireless connectivity among vehicles, the infrastructure, and mobile devices will bring about transformative changes in safety, mobility, and the environmental impacts in th...

  10. Connected and autonomous vehicles 2040 vision.

    Science.gov (United States)

    2014-07-01

    The Pennsylvania Department of Transportation (PennDOT) commissioned a one-year project, Connected and Autonomous : Vehicles 2040 Vision, with researchers at Carnegie Mellon University (CMU) to assess the implications of connected and : autonomous ve...

  11. Microglomerular Synaptic Complexes in the Sky-Compass Network of the Honeybee Connect Parallel Pathways from the Anterior Optic Tubercle to the Central Complex.

    Science.gov (United States)

    Held, Martina; Berz, Annuska; Hensgen, Ronja; Muenz, Thomas S; Scholl, Christina; Rössler, Wolfgang; Homberg, Uwe; Pfeiffer, Keram

    2016-01-01

    While the ability of honeybees to navigate relying on sky-compass information has been investigated in a large number of behavioral studies, the underlying neuronal system has so far received less attention. The sky-compass pathway has recently been described from its input region, the dorsal rim area (DRA) of the compound eye, to the anterior optic tubercle (AOTU). The aim of this study is to reveal the connection from the AOTU to the central complex (CX). For this purpose, we investigated the anatomy of large microglomerular synaptic complexes in the medial and lateral bulbs (MBUs/LBUs) of the lateral complex (LX). The synaptic complexes are formed by tubercle-lateral accessory lobe neuron 1 (TuLAL1) neurons of the AOTU and GABAergic tangential neurons of the central body's (CB) lower division (TL neurons). Both TuLAL1 and TL neurons strongly resemble neurons forming these complexes in other insect species. We further investigated the ultrastructure of these synaptic complexes using transmission electron microscopy. We found that single large presynaptic terminals of TuLAL1 neurons enclose many small profiles (SPs) of TL neurons. The synaptic connections between these neurons are established by two types of synapses: divergent dyads and divergent tetrads. Our data support the assumption that these complexes are a highly conserved feature in the insect brain and play an important role in reliable signal transmission within the sky-compass pathway.

  12. Connectivity editing for quadrilateral meshes

    KAUST Repository

    Peng, Chihan; Zhang, Eugene; Kobayashi, Yoshihiro; Wonka, Peter

    2011-01-01

    We propose new connectivity editing operations for quadrilateral meshes with the unique ability to explicitly control the location, orientation, type, and number of the irregular vertices (valence not equal to four) in the mesh while preserving sharp edges. We provide theoretical analysis on what editing operations are possible and impossible and introduce three fundamental operations to move and re-orient a pair of irregular vertices. We argue that our editing operations are fundamental, because they only change the quad mesh in the smallest possible region and involve the fewest irregular vertices (i.e., two). The irregular vertex movement operations are supplemented by operations for the splitting, merging, canceling, and aligning of irregular vertices. We explain how the proposed highlevel operations are realized through graph-level editing operations such as quad collapses, edge flips, and edge splits. The utility of these mesh editing operations are demonstrated by improving the connectivity of quad meshes generated from state-of-art quadrangulation techniques. © 2011 ACM.

  13. Connectivity editing for quadrilateral meshes

    KAUST Repository

    Peng, Chihan

    2011-12-12

    We propose new connectivity editing operations for quadrilateral meshes with the unique ability to explicitly control the location, orientation, type, and number of the irregular vertices (valence not equal to four) in the mesh while preserving sharp edges. We provide theoretical analysis on what editing operations are possible and impossible and introduce three fundamental operations to move and re-orient a pair of irregular vertices. We argue that our editing operations are fundamental, because they only change the quad mesh in the smallest possible region and involve the fewest irregular vertices (i.e., two). The irregular vertex movement operations are supplemented by operations for the splitting, merging, canceling, and aligning of irregular vertices. We explain how the proposed highlevel operations are realized through graph-level editing operations such as quad collapses, edge flips, and edge splits. The utility of these mesh editing operations are demonstrated by improving the connectivity of quad meshes generated from state-of-art quadrangulation techniques. © 2011 ACM.

  14. Astrophysicists' conversational connections on Twitter.

    Directory of Open Access Journals (Sweden)

    Kim Holmberg

    Full Text Available Because Twitter and other social media are increasingly used for analyses based on altmetrics, this research sought to understand what contexts, affordance use, and social activities influence the tweeting behavior of astrophysicists. Thus, the presented study has been guided by three research questions that consider the influence of astrophysicists' activities (i.e., publishing and tweeting frequency and of their tweet construction and affordance use (i.e. use of hashtags, language, and emotions on the conversational connections they have on Twitter. We found that astrophysicists communicate with a variety of user types (e.g. colleagues, science communicators, other researchers, and educators and that in the ego networks of the astrophysicists clear groups consisting of users with different professional roles can be distinguished. Interestingly, the analysis of noun phrases and hashtags showed that when the astrophysicists address the different groups of very different professional composition they use very similar terminology, but that they do not talk to each other (i.e. mentioning other user names in tweets. The results also showed that in those areas of the ego networks that tweeted more the sentiment of the tweets tended to be closer to neutral, connecting frequent tweeting with information sharing activities rather than conversations or expressing opinions.

  15. Embedded adhesive connection for laminated glass plates

    DEFF Research Database (Denmark)

    Hansen, Jens Zangenberg; Poulsen, S.H.; Bagger, A.

    2012-01-01

    The structural behavior of a new connection design, the embedded adhesive connection, used for laminated glass plates is investigated. The connection consists of an aluminum plate encapsulated in-between two adjacent triple layered laminated glass plates. Fastening between glass and aluminum...... usage in a design situation. The embedded connection shows promising potential as a future fastening system for load-carrying laminated glass plates....

  16. Intermodal connectivity in Europe, an empirical exploration

    NARCIS (Netherlands)

    de Langen, P.W.; Lases Figueroa, D.M.; van Donselaar, K.H.; Bozuwa, J.

    2017-01-01

    In this paper we analyse the intermodal connectivity in Europe. The empirical analysis is to our knowledge the first empirical analysis of intermodal connections, and is based on a comprehensive database of intermodal connections in Europe. The paper focuses on rail and barge services, as they are

  17. Airport industry connectivity report: 2004-2014

    NARCIS (Netherlands)

    Burghouwt, G.; Lieshout, R.

    2014-01-01

    Airport connectivity is an increasingly discussed topic in European policy circles. With good reason. Connectivity is closely connected with productivity, economic growth and international trade. And with the centre of global economic activity shifting eastward, it is essential that Europe remains

  18. MedlinePlus Connect: Web Service

    Science.gov (United States)

    ... MedlinePlus Connect → Web Service URL of this page: https://medlineplus.gov/connect/service.html MedlinePlus Connect: Web ... will change.) Old URLs New URLs Web Application https://apps.nlm.nih.gov/medlineplus/services/mpconnect.cfm? ...

  19. MedlinePlus Connect: Web Application

    Science.gov (United States)

    ... MedlinePlus Connect → Web Application URL of this page: https://medlineplus.gov/connect/application.html MedlinePlus Connect: Web ... will change.) Old URLs New URLs Web Application https://apps.nlm.nih.gov/medlineplus/services/mpconnect.cfm? ...

  20. MedlinePlus Connect: Technical Information

    Science.gov (United States)

    ... MedlinePlus Connect → Technical Information URL of this page: https://medlineplus.gov/connect/technical.html MedlinePlus Connect: Technical ... will change.) Old URLs New URLs Web Application https://apps.nlm.nih.gov/medlineplus/services/mpconnect.cfm? ...

  1. MedlinePlus Connect: Email List

    Science.gov (United States)

    ... MedlinePlus Connect → Email List URL of this page: https://medlineplus.gov/connect/emaillist.html MedlinePlus Connect: Email ... will change.) Old URLs New URLs Web Application https://apps.nlm.nih.gov/medlineplus/services/mpconnect.cfm? ...

  2. Connecting multimodality in human communication.

    Science.gov (United States)

    Regenbogen, Christina; Habel, Ute; Kellermann, Thilo

    2013-01-01

    A successful reciprocal evaluation of social signals serves as a prerequisite for social coherence and empathy. In a previous fMRI study we studied naturalistic communication situations by presenting video clips to our participants and recording their behavioral responses regarding empathy and its components. In two conditions, all three channels transported congruent emotional or neutral information, respectively. Three conditions selectively presented two emotional channels and one neutral channel and were thus bimodally emotional. We reported channel-specific emotional contributions in modality-related areas, elicited by dynamic video clips with varying combinations of emotionality in facial expressions, prosody, and speech content. However, to better understand the underlying mechanisms accompanying a naturalistically displayed human social interaction in some key regions that presumably serve as specific processing hubs for facial expressions, prosody, and speech content, we pursued a reanalysis of the data. Here, we focused on two different descriptions of temporal characteristics within these three modality-related regions [right fusiform gyrus (FFG), left auditory cortex (AC), left angular gyrus (AG) and left dorsomedial prefrontal cortex (dmPFC)]. By means of a finite impulse response (FIR) analysis within each of the three regions we examined the post-stimulus time-courses as a description of the temporal characteristics of the BOLD response during the video clips. Second, effective connectivity between these areas and the left dmPFC was analyzed using dynamic causal modeling (DCM) in order to describe condition-related modulatory influences on the coupling between these regions. The FIR analysis showed initially diminished activation in bimodally emotional conditions but stronger activation than that observed in neutral videos toward the end of the stimuli, possibly by bottom-up processes in order to compensate for a lack of emotional information. The

  3. Behavior of concentrically loaded CFT braces connections

    Directory of Open Access Journals (Sweden)

    Maha M. Hassan

    2014-03-01

    Full Text Available Concrete filled tubes (CFTs composite columns have many economical and esthetic advantages, but the behavior of their connections is complicated. Through this study, it is aimed to investigate the performance and behavior of different connection configurations between concrete filled steel tube columns and bracing diagonals through an experimental program. The study included 12 connection subassemblies consisting of a fixed length steel tube and gusset plate connected to the tube end with different details tested under half cyclic loading. A notable effect was observed on the behavior of the connections due to its detailing changes with respect to capacity, failure mode, ductility, and stress distribution.

  4. Are PES connection costs too high?

    International Nuclear Information System (INIS)

    Scott, N.

    1998-01-01

    Windfarm developers often have good reason to question the costs they are quoted by their local distribution company for connection to the system, and these costs can now be challenged under the 'Competition in Connection' initiative. Econnect Ltd specialise in electrical connections for renewable generation throughout the UK and Europe, and have worked on many projects where alternative connections have been designed at more competitive prices. This paper provides some examples which illustrate the importance of acquiring a thorough understanding of all power system issues and PES concerns if the most cost-effective connection is to be realised. (Author)

  5. Twistor connection and the Palatini method

    International Nuclear Information System (INIS)

    Merkulov, S.A.

    1988-01-01

    For the Yang-Mills Lagrangian of the twistor connection, an analog of the Palatini variational method is considered, in which the variations of the twistor connection A m and metric g ab are taken to be independent. It is shown that varying the Lagrangian with respect to the connection establishes a relation between A m and g ab (i.e., defines a standard twistor connection, postulated earlier), while varying with respect to the metric with a subsequent substitution of explicit expressions of the standard twistor connection leads to the Bach vacuum equations, describing the dynamics of conformal gravity

  6. Unity connecting module in SSPF

    Science.gov (United States)

    1998-01-01

    In the Space Station Processing Facility, the Unity connecting module, part of the International Space Station, is shown with Pressurized Mating Adapters 1 (left) and 2 (right) attached. Unity is scheduled to undergo testing of the common berthing mechanism to which other space station elements will dock. Unity is the primary payload on mission STS-88, targeted to launch Dec. 3, 1998. Other testing includes the Pad Demonstration Test to verify the compatibility of the module with the Space Shuttle as well as the ability of the astronauts to send and receive commands to Unity from the flight deck of the orbiter. Unity is expected to be ready for installation into the payload canister on Oct. 25, and transported to Launch Pad 39-A on Oct. 27. The Unity will be mated to the Russian-built Zarya control module which should already be in orbit at that time.

  7. Sprays and Cartan projective connections

    Science.gov (United States)

    Saunders, D. J.

    2004-10-01

    Around 80 years ago, several authors (for instance H. Weyl, T.Y. Thomas, J. Douglas and J.H.C. Whitehead) studied the projective geometry of paths, using the methods of tensor calculus. The principal object of study was a spray, namely a homogeneous second-order differential equation, or more generally a projective equivalence class of sprays. At around the same time, E. Cartan studied the same topic from a different point of view, by imagining a projective space attached to a manifold, or, more generally, attached to a `manifold of elements'; the infinitesimal `glue' may be interpreted in modern language as a Cartan projective connection on a principal bundle. This paper describes the geometrical relationship between these two points of view.

  8. Ultraviolet injury of connective tissue

    International Nuclear Information System (INIS)

    Sengupta, K.P.; Sanyal, Sabitri; Biswas, S.K.; Pal, N.C.

    1975-01-01

    Changes induced by UV irradiation of rat skin could be divided morphologically into prenecrotic, necrotic and regenerating phases. During prenecrotic and necrotic phases, decrease in water content, collagenous protein, citrate buffer soluble fraction, elastin and total lipid and its fractions, and increase in noncollagenous protein nitrogen and fucoglycoprotein were observed. Increase in serum and urinary hydroxyproline and hexosamine, and serum sialic acid and fucose revealed the complicated nature of intrinsic changes occurring systemically. The study revealed that the ground substance was more easily affected while collagen, elastin and fat appeared to be more resistant to injury. This could be due to superficial action of radiation of short duration (30 min) on the dermal connective tissue. (author)

  9. Method for hermetic electrical connections

    Science.gov (United States)

    Monroe, Saundra L [Tijeras, NM; Glass, S Jill [Albuquerque, NM; Stone, Ronnie G [Albuquerque, NM; Bond, Jamey T [Albuquerque, NM; Susan, Donald F [Albuquerque, NM

    2011-12-27

    A method of providing a hermetic, electrical connection between two electrical components by mating at least one metal pin in a glass-ceramic to metal seal connector to two electrical components, wherein the glass-ceramic to metal seal connector incorporates at least one metal pin encased (sealed) in a glass-ceramic material inside of a metal housing, with the glass-ceramic material made from 65-80% SiO.sub.2, 8-16% Li.sub.2O, 2-8% Al.sub.2O.sub.3, 1-5% P.sub.2O.sub.5, 1-8% K.sub.2O, 0.5-7% B.sub.2O.sub.3, and 0-5% ZnO. The connector retains hermeticity at temperatures as high as 700.degree. C. and pressures as high as 500 psi.

  10. Connecting cognition and consumer choice.

    Science.gov (United States)

    Bartels, Daniel M; Johnson, Eric J

    2015-02-01

    We describe what can be gained from connecting cognition and consumer choice by discussing two contexts ripe for interaction between the two fields. The first-context effects on choice-has already been addressed by cognitive science yielding insights about cognitive process but there is promise for more interaction. The second is learning and representation in choice where relevant theories in cognitive science could be informed by consumer choice, and in return, could pose and answer new questions. We conclude by discussing how these two fields of research stand to benefit from more interaction, citing examples of how interfaces of cognitive science with other fields have been illuminating for theories of cognition. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Connected health and multiple sclerosis.

    Science.gov (United States)

    Cohen, M

    2018-04-18

    There is as yet no consensual definition of "connected health". In general, the term refers to the growing use of technology and, in particular, mobile technology in medicine. Over the past 10 years, there have been an increasing number of published reports on the wide-ranging and heterogeneous fields involving the application of technology in medicine, ranging from telemedicine to tools to improve patients' evaluation and monitoring by physicians, as well as a multitude of patient-centered applications. They also represent promising tools in the field of clinical research. This report is a review of the importance of using this technology in the management of multiple sclerosis patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  12. Investigation into Methods for Predicting Connection Temperatures

    Directory of Open Access Journals (Sweden)

    K. Anderson

    2009-01-01

    Full Text Available The mechanical response of connections in fire is largely based on material strength degradation and the interactions between the various components of the connection. In order to predict connection performance in fire, temperature profiles must initially be established in order to evaluate the material strength degradation over time. This paper examines two current methods for predicting connection temperatures: The percentage method, where connection temperatures are calculated as a percentage of the adjacent beam lower-flange, mid-span temperatures; and the lumped capacitance method, based on the lumped mass of the connection. Results from the percentage method do not correlate well with experimental results, whereas the lumped capacitance method shows much better agreement with average connection temperatures. A 3D finite element heat transfer model was also created in Abaqus, and showed good correlation with experimental results. 

  13. Hematopoietic stem cell origin of connective tissues.

    Science.gov (United States)

    Ogawa, Makio; Larue, Amanda C; Watson, Patricia M; Watson, Dennis K

    2010-07-01

    Connective tissue consists of "connective tissue proper," which is further divided into loose and dense (fibrous) connective tissues and "specialized connective tissues." Specialized connective tissues consist of blood, adipose tissue, cartilage, and bone. In both loose and dense connective tissues, the principal cellular element is fibroblasts. It has been generally believed that all cellular elements of connective tissue, including fibroblasts, adipocytes, chondrocytes, and bone cells, are generated solely by mesenchymal stem cells. Recently, a number of studies, including those from our laboratory based on transplantation of single hematopoietic stem cells, strongly suggested a hematopoietic stem cell origin of these adult mesenchymal tissues. This review summarizes the experimental evidence for this new paradigm and discusses its translational implications. Copyright 2010 ISEH - Society for Hematology and Stem Cells. All rights reserved.

  14. Radiotherapy in patients with connective tissue diseases.

    Science.gov (United States)

    Giaj-Levra, Niccolò; Sciascia, Savino; Fiorentino, Alba; Fersino, Sergio; Mazzola, Rosario; Ricchetti, Francesco; Roccatello, Dario; Alongi, Filippo

    2016-03-01

    The decision to offer radiotherapy in patients with connective tissue diseases continues to be challenging. Radiotherapy might trigger the onset of connective tissue diseases by increasing the expression of self-antigens, diminishing regulatory T-cell activity, and activating effectors of innate immunity (dendritic cells) through Toll-like receptor-dependent mechanisms, all of which could potentially lead to breaks of immune tolerance. This potential risk has raised some debate among radiation oncologists about whether patients with connective tissue diseases can tolerate radiation as well as people without connective tissue diseases. Because the number of patients with cancer and connective tissue diseases needing radiotherapy will probably increase due to improvements in medical treatment and longer life expectancy, the issue of interactions between radiotherapy and connective tissue diseases needs to be clearer. In this Review, we discuss available data and evidence for patients with connective tissue diseases treated with radiotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Random geometric graphs with general connection functions

    Science.gov (United States)

    Dettmann, Carl P.; Georgiou, Orestis

    2016-03-01

    In the original (1961) Gilbert model of random geometric graphs, nodes are placed according to a Poisson point process, and links formed between those within a fixed range. Motivated by wireless ad hoc networks "soft" or "probabilistic" connection models have recently been introduced, involving a "connection function" H (r ) that gives the probability that two nodes at distance r are linked (directly connect). In many applications (not only wireless networks), it is desirable that the graph is connected; that is, every node is linked to every other node in a multihop fashion. Here the connection probability of a dense network in a convex domain in two or three dimensions is expressed in terms of contributions from boundary components for a very general class of connection functions. It turns out that only a few quantities such as moments of the connection function appear. Good agreement is found with special cases from previous studies and with numerical simulations.

  16. Connecting Leadership and Learning: Do Versatile Learners make Connective Leaders?

    Directory of Open Access Journals (Sweden)

    Jill L. Robinson

    2016-03-01

    Full Text Available Abstract Recent failures in leadership, suggest that creating better-quality leadership development programs is critical. In moving from theory to practice, this paper examined the relationship between learning style and leadership style which may enable us to move away from one-size-fits-all leadership development programs. Utilizing Kolb’s Experiential Learning Model and Connective Leadership theory, approximately 3600 college students were analyzed to discover whether versatility in learning styles translates into versatility in leadership styles. One group of versatile learners reported using a wider range of leadership styles suggesting that learning flexibility may transfer to leadership flexibility. Surprisingly, learners of all types reported utilizing Power and Intrinsic styles of leadership above all others. Implications for leadership development include considering individual differences when crafting leadership programs, matching learning styles to leader training, and the need to move beyond one set of leadership behaviors to increase flexibility in dealing with complex situations. Using a large sample rarely seen in management studies, this paper makes key contributions to the literature. 

  17. Structural Connectivity of the Developing Human Amygdala

    Science.gov (United States)

    Saygin, Zeynep M.; Osher, David E.; Koldewyn, Kami; Martin, Rebecca E.; Finn, Amy; Saxe, Rebecca; Gabrieli, John D.E.; Sheridan, Margaret

    2015-01-01

    A large corpus of research suggests that there are changes in the manner and degree to which the amygdala supports cognitive and emotional function across development. One possible basis for these developmental differences could be the maturation of amygdalar connections with the rest of the brain. Recent functional connectivity studies support this conclusion, but the structural connectivity of the developing amygdala and its different nuclei remains largely unstudied. We examined age related changes in the DWI connectivity fingerprints of the amygdala to the rest of the brain in 166 individuals of ages 5-30. We also developed a model to predict age based on individual-subject amygdala connectivity, and identified the connections that were most predictive of age. Finally, we segmented the amygdala into its four main nucleus groups, and examined the developmental changes in connectivity for each nucleus. We observed that with age, amygdalar connectivity becomes increasingly sparse and localized. Age related changes were largely localized to the subregions of the amygdala that are implicated in social inference and contextual memory (the basal and lateral nuclei). The central nucleus’ connectivity also showed differences with age but these differences affected fewer target regions than the basal and lateral nuclei. The medial nucleus did not exhibit any age related changes. These findings demonstrate increasing specificity in the connectivity patterns of amygdalar nuclei across age. PMID:25875758

  18. Courant algebroid connections and string effective actions

    OpenAIRE

    Jurčo, B.

    2017-01-01

    Courant algebroids are a natural generalization of quadratic Lie algebras, appearing in various contexts in mathematical physics. A connection on a Courant algebroid gives an analogue of a covariant derivative compatible with a given fiber-wise metric. Imposing further conditions resembling standard Levi-Civita connections, one obtains a class of connections whose curvature tensor in certain cases gives a new geometrical description of equations of motion of low energy effective action of str...

  19. Robust motion estimation using connected operators

    OpenAIRE

    Salembier Clairon, Philippe Jean; Sanson, H

    1997-01-01

    This paper discusses the use of connected operators for robust motion estimation The proposed strategy involves a motion estimation step extracting the dominant motion and a ltering step relying on connected operators that remove objects that do not fol low the dominant motion. These two steps are iterated in order to obtain an accurate motion estimation and a precise de nition of the objects fol lowing this motion This strategy can be applied on the entire frame or on individual connected c...

  20. Projective Connections and the Algebra of Densities

    International Nuclear Information System (INIS)

    George, Jacob

    2008-01-01

    Projective connections first appeared in Cartan's papers in the 1920's. Since then they have resurfaced periodically in, for example, integrable systems and perhaps most recently in the context of so called projectively equivariant quantisation. We recall the notion of projective connection and describe its relation with the algebra of densities on a manifold. In particular, we construct a Laplace-type operator on functions using a Thomas projective connection and a symmetric contravariant tensor of rank 2 ('upper metric').

  1. Structural Connectivity Asymmetry in the Neonatal Brain

    OpenAIRE

    Ratnarajah, Nagulan; Rifkin-Graboi, Anne; Fortier, Marielle V.; Chong, Yap Seng; Kwek, Kenneth; Saw, Seang-Mei; Godfrey, Keith M; Gluckman, Peter D.; Meaney, Michael J.; Qiu, Anqi

    2013-01-01

    Asymmetry of the neonatal brain is not yet understood at the level of structural connectivity. We utilized DTI deterministic tractography and structural network analysis based on graph theory to determine the pattern of structural connectivity asymmetry in 124 normal neonates. We tracted white matter axonal pathways characterizing interregional connections among brain regions and inferred asymmetry in left and right anatomical network properties. Our findings revealed that in neonates, small-...

  2. Synchronization from Second Order Network Connectivity Statistics

    Science.gov (United States)

    Zhao, Liqiong; Beverlin, Bryce; Netoff, Theoden; Nykamp, Duane Q.

    2011-01-01

    We investigate how network structure can influence the tendency for a neuronal network to synchronize, or its synchronizability, independent of the dynamical model for each neuron. The synchrony analysis takes advantage of the framework of second order networks, which defines four second order connectivity statistics based on the relative frequency of two-connection network motifs. The analysis identifies two of these statistics, convergent connections, and chain connections, as highly influencing the synchrony. Simulations verify that synchrony decreases with the frequency of convergent connections and increases with the frequency of chain connections. These trends persist with simulations of multiple models for the neuron dynamics and for different types of networks. Surprisingly, divergent connections, which determine the fraction of shared inputs, do not strongly influence the synchrony. The critical role of chains, rather than divergent connections, in influencing synchrony can be explained by their increasing the effective coupling strength. The decrease of synchrony with convergent connections is primarily due to the resulting heterogeneity in firing rates. PMID:21779239

  3. Synchronization from second order network connectivity statistics

    Directory of Open Access Journals (Sweden)

    Liqiong eZhao

    2011-07-01

    Full Text Available We investigate how network structure can influence the tendency for a neuronal network to synchronize, or its synchronizability, independent of the dynamical model for each neuron. The synchrony analysis takes advantage of the framework of second order networks (SONETs, which defines four second order connectivity statistics based on the relative frequency of two-connection network motifs. The analysis identifies two of these statistics, convergent connections and chain connections, as highly influencing the synchrony. Simulations verify that synchrony decreases with the frequency of convergent connections and increases with the frequency of chain connections. These trends persist with simulations of multiple models for the neuron dynamics and for different types of networks. Surprisingly, divergent connections, which determine the fraction of shared inputs, do not strongly influence the synchrony. The critical role of chains, rather than divergent connections, in influencing synchrony can be explained by a pool and redistribute mechanism. The pooling of many inputs averages out independent fluctuations, amplifying weak correlations in the inputs. With increased chain connections, neurons with many inputs tend to have many outputs. Hence, chains ensure that the amplified correlations in the neurons with many inputs are redistributed throughout the network, enhancing the development of synchrony across the network.

  4. Effect of ionizing radiations on connective tissue

    International Nuclear Information System (INIS)

    Altman, K.I.; Gerber, G.B.

    1980-01-01

    The effects of ionizing radiations on connective tissue in lung, heart, vasculature, kidney, skin, and skeletal tissues are reviewed. Special emphasis is given to the effect of ionizing radiations on vasculo-connective tissue and fibrotic changes following radiation-induced injury to organs and tissues. In order to put the subject matter in proper prospective, the general biochemistry, physiology, and pathology of connective tissue is reviewed briefly together with the participation of connective tissue in disease. The review closes with an assessment of future problems and an enumeration and discussion of important, as yet unanswered questions

  5. Design of Steel Beam-Column Connections

    Directory of Open Access Journals (Sweden)

    Bogatinoski Z.

    2014-05-01

    Full Text Available In this paper a theoretical and experimental research of the steel beam-column connections is presented. Eight types of specimens were being researched, composed of rigid and semi-rigid connections from which 4 connections are with IPE - profile and 4 connections with tube's section for the beam. From the numerical analysis of the researched models, and especially from the experimental research at the Laboratory for Structures in the Faculty of Mechanical Engineering - Skopje, specific conclusions were received that ought to have theoretical and practical usage for researchers in this area of interest.

  6. Essential Connectivity Areas - CEHC, (Raster) [ds620

    Data.gov (United States)

    California Natural Resource Agency — The California Department of Transportation (Caltrans) and California Department of Fish and Game (CDFG) commissioned the California Essential Habitat Connectivity...

  7. Connecting multimodality in human communication

    Directory of Open Access Journals (Sweden)

    Christina eRegenbogen

    2013-11-01

    Full Text Available A successful reciprocal evaluation of social signals serves as a prerequisite for social coherence and empathy. In a previous fMRI study we studied naturalistic communication situations by presenting video clips to our participants and recording their behavioral responses regarding empathy and its components. In two conditions, all three channels transported congruent emotional or neutral information, respectively. Three conditions selectively presented two emotional channels and one neutral channel and were thus bimodally emotional. We reported channel-specific emotional contributions in modality-related areas, elicited by dynamic video clips with varying combinations of emotionality in facial expressions, prosody, and speech content. However, to better understand the underlying mechanisms accompanying a naturalistically displayed human social interaction in some key regions that presumably serve as specific processing hubs for facial expressions, prosody, and speech content, we pursued a reanalysis of the data. In addition to this specificity of these regions to information channels we demonstrated that they were also sensitive to variations of the respective emotional content.Here, we focused on two different descriptions of temporal characteristics within these three modality-related regions (right fusiform gyrus (FFG, left auditory cortex (AC, left angular gyrus (AG and left dorsomedial prefrontal cortex (dmPFC. By means of a finite impulse response (FIR analysis within each of the three regions we examined the post-stimulus time-courses as a description of the temporal characteristics of the BOLD response during the video clips. Second, effective connectivity between these areas and the left dmPFC was analyzed using dynamic causal modeling (DCM in order to describe condition-related modulatory influences on the coupling between these regions. The FIR analysis showed initially diminished activation in bimodally emotional conditions but

  8. 47 CFR 54.506 - Internal connections.

    Science.gov (United States)

    2010-10-01

    ... instructional building of a school or to a non-administrative building of a library. Internal connections do not... SERVICE Universal Service Support for Schools and Libraries § 54.506 Internal connections. (a) A service... necessary to transport information within one or more instructional buildings of a single school campus or...

  9. Aberrant orbitofrontal connectivity in marijuana smoking adolescents

    Directory of Open Access Journals (Sweden)

    Melissa Patricia Lopez-Larson

    2015-12-01

    Discussion: Findings indicate atypical OFC functional connectivity patterns in attentional/executive, motor and reward networks in adolescents with heavy MJ use. These anomalies may be related to suboptimal decision making capacities and increased impulsivity. Results also suggest different OFC connectivity patterns may be present in adolescents with early onset of MJ use and high lifetime exposure to MJ.

  10. Centrifugal separator cascade connected in zigzag manner

    International Nuclear Information System (INIS)

    Kai, Tsunetoshi; Inoue, Yoshiya; Oya, Akio; Nagakura, Masaaki.

    1974-01-01

    Object: To effectively accommodate centrifugal separators of the entire cascade within the available space in a plant by freely selecting perpendicular direction of connection of the centrifugal separator. Structure: Centrifugal separators are connected in zigzag fashion by using a single header for each stage so that in a rectangular shape the entire cascade is arranged. (Kamimura, M.)

  11. Are we connected? : Ports in Global Networks

    NARCIS (Netherlands)

    R.A. Zuidwijk (Rob)

    2015-01-01

    markdownabstractAbstract Global supply chains are built on organizational, information, and logistics networks. Ports are connected via these networks and also need to connect these networks. Synchromodality is an innovative concept for container transportation, and the port plays an important

  12. Connections between quantum chromodynamics and condensed

    Indian Academy of Sciences (India)

    Using examples we discuss some of the connections between the two fields and show how progress can be made by exploiting this connection. Some of the challenges that remain in ... Current Issue : Vol. 90, Issue 6. Current Issue Volume 90 ...

  13. Countering oversegmentation in partitioning-based connectivities

    NARCIS (Netherlands)

    Ouzounis, Georgios K.; Wilkinson, Michael H.F.

    2005-01-01

    A new theoretical development is presented for handling the over-segmentation problem in partitioning-based connected openings. The definition we propose treats singletons generated with the earlier method, as elements of a larger connected component. Unlike the existing formalism, this new method

  14. Connecting Representations: Using Predict, Check, Explain

    Science.gov (United States)

    Roy, George J.; Fueyo, Vivian; Vahey, Philip; Knudsen, Jennifer; Rafanan, Ken; Lara-Meloy, Teresa

    2016-01-01

    Although educators agree that making connections with the real world, as advocated by "Principles to Actions: Ensuring Mathematical Success for All" (NCTM 2014), is important, making such connections while addressing important mathematics is elusive. The authors have found that math content coupled with the instructional strategy of…

  15. Voltage Quality of Grid Connected Wind Turbines

    DEFF Research Database (Denmark)

    Chen, Zhe; Blaabjerg, Frede; Sun, Tao

    2004-01-01

    Grid connected wind turbines may cause quality problems, such as voltage variation and flicker. This paper discusses the voltage variation and flicker emission of grid connected wind turbines with doubly-fed induction generators. A method to compensate flicker by using a voltage source converter...

  16. Simple clamped connection for bamboo truss systems

    NARCIS (Netherlands)

    Blok, R.

    2016-01-01

    “How to make fast and simple tension connections for truss systems?” The Solution: The innovation is a connection that uses only widely available base components (boltsand threaded steel bars) and simple hand tools to install it. With a handsaw and aspanner, the bamboo stems can be combined into to

  17. IDRC Connect | IDRC - International Development Research Centre

    International Development Research Centre (IDRC) Digital Library (Canada)

    2015-07-20

    All IDRC-funded researchers have access to IDRC Connect, our project portal and collaborative workspace. For projects approved after July 20, 2015, IDRC Connect must be used to submit technical reports project outputs funding requests for open access journal publishing charges You need a password to access IDRC ...

  18. Connecting Functions in Geometry and Algebra

    Science.gov (United States)

    Steketee, Scott; Scher, Daniel

    2016-01-01

    One goal of a mathematics education is that students make significant connections among different branches of mathematics. Connections--such as those between arithmetic and algebra, between two-dimensional and three-dimensional geometry, between compass-and-straight-edge constructions and transformations, and between calculus and analytic…

  19. Natural Connections on Riemannian Product Manifolds

    OpenAIRE

    Gribacheva, Dobrinka

    2011-01-01

    A Riemannian almost product manifold with integrable almost product structure is called a Riemannian product manifold. In the present paper the natural connections on such manifolds are studied, i.e. the linear connections preserving the almost product structure and the Riemannian metric.

  20. Connectivity: Performance Portable Algorithms for graph connectivity v. 0.1

    Energy Technology Data Exchange (ETDEWEB)

    2017-09-21

    Graphs occur in several places in real world from road networks, social networks and scientific simulations. Connectivity is a graph analysis software to graph connectivity in modern architectures like multicore CPUs, Xeon Phi and GPUs.

  1. Directional connectivity in hydrology and ecology

    Science.gov (United States)

    Larsen, Laurel G.; Choi, Jungyill; Nungesser, Martha K.; Harvey, Judson W.

    2012-01-01

    Quantifying hydrologic and ecological connectivity has contributed to understanding transport and dispersal processes and assessing ecosystem degradation or restoration potential. However, there has been little synthesis across disciplines. The growing field of ecohydrology and recent recognition that loss of hydrologic connectivity is leading to a global decline in biodiversity underscore the need for a unified connectivity concept. One outstanding need is a way to quantify directional connectivity that is consistent, robust to variations in sampling, and transferable across scales or environmental settings. Understanding connectivity in a particular direction (e.g., streamwise, along or across gradient, between sources and sinks, along cardinal directions) provides critical information for predicting contaminant transport, planning conservation corridor design, and understanding how landscapes or hydroscapes respond to directional forces like wind or water flow. Here we synthesize progress on quantifying connectivity and develop a new strategy for evaluating directional connectivity that benefits from use of graph theory in ecology and percolation theory in hydrology. The directional connectivity index (DCI) is a graph-theory based, multiscale metric that is generalizable to a range of different structural and functional connectivity applications. It exhibits minimal sensitivity to image rotation or resolution within a given range and responds intuitively to progressive, unidirectional change. Further, it is linearly related to the integral connectivity scale length—a metric common in hydrology that correlates well with actual fluxes—but is less computationally challenging and more readily comparable across different landscapes. Connectivity-orientation curves (i.e., directional connectivity computed over a range of headings) provide a quantitative, information-dense representation of environmental structure that can be used for comparison or detection of

  2. Directional connectivity in hydrology and ecology.

    Science.gov (United States)

    Larsen, Laurel G; Choi, Jungyill; Nungesser, Martha K; Harvey, Judson W

    2012-12-01

    Quantifying hydrologic and ecological connectivity has contributed to understanding transport and dispersal processes and assessing ecosystem degradation or restoration potential. However, there has been little synthesis across disciplines. The growing field of ecohydrology and recent recognition that loss of hydrologic connectivity is leading to a global decline in biodiversity underscore the need for a unified connectivity concept. One outstanding need is a way to quantify directional connectivity that is consistent, robust to variations in sampling, and transferable across scales or environmental settings. Understanding connectivity in a particular direction (e.g., streamwise, along or across gradient, between sources and sinks, along cardinal directions) provides critical information for predicting contaminant transport, planning conservation corridor design, and understanding how landscapes or hydroscapes respond to directional forces like wind or water flow. Here we synthesize progress on quantifying connectivity and develop a new strategy for evaluating directional connectivity that benefits from use of graph theory in ecology and percolation theory in hydrology. The directional connectivity index (DCI) is a graph-theory based, multiscale metric that is generalizable to a range of different structural and functional connectivity applications. It exhibits minimal sensitivity to image rotation or resolution within a given range and responds intuitively to progressive, unidirectional change. Further, it is linearly related to the integral connectivity scale length--a metric common in hydrology that correlates well with actual fluxes--but is less computationally challenging and more readily comparable across different landscapes. Connectivity-orientation curves (i.e., directional connectivity computed over a range of headings) provide a quantitative, information-dense representation of environmental structure that can be used for comparison or detection of

  3. The TANF/SSI connection.

    Science.gov (United States)

    Wamhoff, Steve; Wiseman, Michael

    Interactions and overlap of social assistance programs across clients interest policymakers because such interactions affect both the clients' well-being and the programs' efficiency. This article investigates the connections between Supplemental Security Income (SSI) and Temporary Assistance for Needy Families (TANF) and TANF's predecessor, the Aid to Families with Dependent Children (AFDC) program. Connections between receipt of TANF and SSI are widely discussed in both disability policy and poverty research literatures because many families receiving TANF report disabilities. For both states and the individuals involved, it is generally financially advantageous for adults and children with disabilities to transfer from TANF to SSI. States gain because the federal government pays for the SSI benefit, and states can then use the TANF savings for other purposes. The families gain because the SSI benefits they acquire are greater than the TANF benefits they lose. The payoff to states from transferring welfare recipients to SSI was substantially increased when Congress replaced AFDC with TANF in 1996. States retained less than half of any savings achieved through such transfers under AFDC, but they retain all of the savings under TANF. Also, the work participation requirements under TANF have obligated states to address the work support needs of adults with disabilities who remain in TANF, and states can avoid these costs if adults have disabilities that satisfy SSI eligibility requirements. The incentive for TANF recipients to apply for SSI has increased over time as inflation has caused real TANF benefits to fall relative to payments received by SSI recipients. Trends in the financial incentives for transfer to SSI have not been studied in detail, and reliable general data on the extent of the interaction between TANF and SSI are scarce. In addition, some estimates of the prevalence of TANF receipt among SSI awardees are flawed because they fail to include adults

  4. Social media and (dis)connectivity

    DEFF Research Database (Denmark)

    Tække, Jesper

    The paper discuss the relation between media of communication and societal (dis)connectivity. The question is how communication media provide society with different possibilities for (dis)connectivity in different historical media societies. The paper draws on Luhmann’s theory of social systems...... for social systems to develop structures with new forms of communicative connections. Even though society only is possible because of communication media and gets new possibilities for the formation of new structures providing it with new connection possibilities, in the beginning a new communication medium....... In the present society we also see signs of new dis-connectivity, i.e. fake news, political polarization, and economic and democratic inequality. In the final section the paper analyse such problems triggered by digital media. Also the paper point out some new possibilities triggered by the acquisition of social...

  5. Study on the Connecting Length of CFRP

    Science.gov (United States)

    Liu, Xiongfei; Li, Yue; Li, Zhanguo

    2018-05-01

    The paper studied the varying mode of shear stress in the connecting zone of CFRP. Using epoxy resin (EP) as bond material, performance of specimens with different connecting length of CFRP was tested to obtain the conclusion. CFRP-confined concrete column was tested subsequently to verify the conclusion. The results show that: (1) The binding properties of modified epoxy resin with CFRP is good; (2) As the connecting length increased, the ultimate tensile strength of CFRP increased as well in the range of the experiment parameters; (3) Tensile strength of CFRP can reach the ultimate strength when the connecting length is 90mm;(4) The connecting length of 90mm of CFRP meet the reinforcement requirements.

  6. Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease? The Potential Role of Zolpidem in the Treatment of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Antonio Daniele

    2016-01-01

    Full Text Available At present, patients with advanced Parkinson’s disease (PD are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only for GABAA receptors containing the α-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation of GABAA receptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr, it was hypothesized that in PD patients zolpidem may induce through GABAA receptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also, resulting in an increased activity of motor cortical areas (such as supplementary motor area, which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD.

  7. Enhancement of cortical network activity in vitro and promotion of GABAergic neurogenesis by stimulation with an electromagnetic field with a 150 MHz carrier wave pulsed with an alternating 10 and 16 Hz modulation.

    Directory of Open Access Journals (Sweden)

    Alexandra eGramowski-Voss

    2015-07-01

    Full Text Available In recent years, various stimuli were identified capable of enhancing neurogenesis, a process which is dysfunctional in the senescent brain and in neurodegenerative and certain neuropsychiatric diseases. Applications of electromagnetic fields to brain tissue have been shown to affect cellular properties and their importance for therapies in medicine is recognized.In this study, differentiating murine cortical networks on multiwell microelectrode arrays were repeatedly exposed to an extremely low electromagnetic field (ELEMF with alternating 10 and 16 Hz frequencies piggy-backed onto a 150 MHz carrier frequency. The ELEMF exposure stimulated the electrical network activity and intensified the structure of bursts. Further, the exposure with an electromagnetic field within the first 28 days of the differentiation the network activity induced also reorganization within the burst structure. This effect was already most pronounced at 14 days in vitro after 10 days of exposure. Overall, the development of cortical activity under these conditions was accelerated. These functional electrophysiological changes were accompanied by morphological ones. The percentage of neurons in the neuron glia co-culture was increased without affecting the total number of cells, indicating an enhancement of neurogenesis. The ELEMF exposure selectively promoted the proliferation of a particular population of neurons, evidenced by the increased proportion of GABAergic neurons. The results support the initial hypothesis that this kind of ELEMF stimulation is a treatment option for specific indications with promising potential for CNS applications, especially for degenerative diseases such as Alzheimer’s disease and other dementias.

  8. Ecological connectivity networks in rapidly expanding cities.

    Science.gov (United States)

    Nor, Amal Najihah M; Corstanje, Ron; Harris, Jim A; Grafius, Darren R; Siriwardena, Gavin M

    2017-06-01

    Urban expansion increases fragmentation of the landscape. In effect, fragmentation decreases connectivity, causes green space loss and impacts upon the ecology and function of green space. Restoration of the functionality of green space often requires restoring the ecological connectivity of this green space within the city matrix. However, identifying ecological corridors that integrate different structural and functional connectivity of green space remains vague. Assessing connectivity for developing an ecological network by using efficient models is essential to improve these networks under rapid urban expansion. This paper presents a novel methodological approach to assess and model connectivity for the Eurasian tree sparrow ( Passer montanus ) and Yellow-vented bulbul ( Pycnonotus goiavier ) in three cities (Kuala Lumpur, Malaysia; Jakarta, Indonesia and Metro Manila, Philippines). The approach identifies potential priority corridors for ecological connectivity networks. The study combined circuit models, connectivity analysis and least-cost models to identify potential corridors by integrating structure and function of green space patches to provide reliable ecological connectivity network models in the cities. Relevant parameters such as landscape resistance and green space structure (vegetation density, patch size and patch distance) were derived from an expert and literature-based approach based on the preference of bird behaviour. The integrated models allowed the assessment of connectivity for both species using different measures of green space structure revealing the potential corridors and least-cost pathways for both bird species at the patch sites. The implementation of improvements to the identified corridors could increase the connectivity of green space. This study provides examples of how combining models can contribute to the improvement of ecological networks in rapidly expanding cities and demonstrates the usefulness of such models for

  9. Ecological connectivity networks in rapidly expanding cities

    Directory of Open Access Journals (Sweden)

    Amal Najihah M. Nor

    2017-06-01

    Full Text Available Urban expansion increases fragmentation of the landscape. In effect, fragmentation decreases connectivity, causes green space loss and impacts upon the ecology and function of green space. Restoration of the functionality of green space often requires restoring the ecological connectivity of this green space within the city matrix. However, identifying ecological corridors that integrate different structural and functional connectivity of green space remains vague. Assessing connectivity for developing an ecological network by using efficient models is essential to improve these networks under rapid urban expansion. This paper presents a novel methodological approach to assess and model connectivity for the Eurasian tree sparrow (Passer montanus and Yellow-vented bulbul (Pycnonotus goiavier in three cities (Kuala Lumpur, Malaysia; Jakarta, Indonesia and Metro Manila, Philippines. The approach identifies potential priority corridors for ecological connectivity networks. The study combined circuit models, connectivity analysis and least-cost models to identify potential corridors by integrating structure and function of green space patches to provide reliable ecological connectivity network models in the cities. Relevant parameters such as landscape resistance and green space structure (vegetation density, patch size and patch distance were derived from an expert and literature-based approach based on the preference of bird behaviour. The integrated models allowed the assessment of connectivity for both species using different measures of green space structure revealing the potential corridors and least-cost pathways for both bird species at the patch sites. The implementation of improvements to the identified corridors could increase the connectivity of green space. This study provides examples of how combining models can contribute to the improvement of ecological networks in rapidly expanding cities and demonstrates the usefulness of such

  10. Abnormal interhemispheric connectivity in male psychopathic offenders.

    Science.gov (United States)

    Hoppenbrouwers, Sylco S; De Jesus, Danilo R; Sun, Yinming; Stirpe, Tania; Hofman, Dennis; McMaster, Jeff; Hughes, Ginny; Daskalakis, Zafiris J; Schutter, Dennis J L G

    2014-01-01

    Psychopathic offenders inevitably violate interpersonal norms and frequently resort to aggressive and criminal behaviour. The affective and cognitive deficits underlying these behaviours have been linked to abnormalities in functional interhemispheric connectivity. However, direct neurophysiological evidence for dysfunctional connectivity in psychopathic offenders is lacking. We used transcranial magnetic stimulation combined with electroencephalography to examine interhemispheric connectivity in the dorsolateral and motor cortex in a sample of psychopathic offenders and healthy controls. We also measured intracortical inhibition and facilitation over the left and right motor cortex to investigate the effects of local cortical processes on interhemispheric connectivity. We enrolled 17 psychopathic offenders and 14 controls in our study. Global abnormalities in right to left functional connectivity were observed in psychopathic offenders compared with controls. Furthermore, in contrast to controls, psychopathic offenders showed increased intracortical inhibition in the right, but not the left, hemisphere. The relatively small sample size limited the sensitivity to show that the abnormalities in interhemispheric connectivity were specifically related to the dorsolateral prefrontal cortex in psychopathic offenders. To our knowledge, this study provides the first neurophysiological evidence for abnormal interhemispheric connectivity in psychopathic offenders and may further our understanding of the disruptive antisocial behaviour of these offenders.

  11. Structural and effective connectivity in focal epilepsy

    Directory of Open Access Journals (Sweden)

    Christopher S. Parker

    2018-01-01

    Full Text Available Patients with medically-refractory focal epilepsy may be candidates for neurosurgery and some may require placement of intracranial EEG electrodes to localise seizure onset. Assessing cerebral responses to single pulse electrical stimulation (SPES may give diagnostically useful data. SPES produces cortico-cortical evoked potentials (CCEPs, which infer effective brain connectivity. Diffusion-weighted images and tractography may be used to estimate structural brain connectivity. This combination provides the opportunity to observe seizure onset and its propagation throughout the brain, spreading contiguously along the cortex explored with electrodes, or non-contiguously. We analysed CCEPs and diffusion tractography in seven focal epilepsy patients and reconstructed the effective and structural brain networks. We aimed to assess the inter-modal similarity of the networks at a large scale across the cortex, the effective and structural connectivity of the ictal-onset zone, and investigate potential mechanisms of non-contiguous seizure spread. We found a significant overlap between structural and effective networks. Effective network CCEP amplitude, baseline variation, and outward connectivity was higher at ictal-onset zones, while structural connection strength within the ictal-onset zone tended to be higher. These findings support the concept of hyperexcitable cortex being associated with seizure generation. The high prevalence of structural and effective connections from the ictal-onset zone to sites of non-contiguous spread suggests that macroscopic structural and effective connections are plausible routes for non-contiguous seizure spread.

  12. Altered thalamic functional connectivity in multiple sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yaou; Liang, Peipeng; Duan, Yunyun; Huang, Jing; Ren, Zhuoqiong; Jia, Xiuqin [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Dong, Huiqing; Ye, Jing [Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Shi, Fu-Dong [Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052 (China); Butzkueven, Helmut [Department of Medicine, University of Melbourne, Parkville 3010 (Australia); Li, Kuncheng, E-mail: kunchengli55@gmail.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)

    2015-04-15

    Highlights: •We demonstrated decreased connectivity between thalamus and cortical regions in MS. •Increased intra- and inter-thalamic connectivity was also observed in MS. •The increased functional connectivity is attenuated by increasing disease duration. -- Abstract: Objective: To compare thalamic functional connectivity (FC) in patients with multiple sclerosis (MS) and healthy controls (HC), and correlate these connectivity measures with other MRI and clinical variables. Methods: We employed resting-state functional MRI (fMRI) to examine changes in thalamic connectivity by comparing thirty-five patients with MS and 35 age- and sex-matched HC. Thalamic FC was investigated by correlating low frequency fMRI signal fluctuations in thalamic voxels with voxels in all other brain regions. Additionally thalamic volume fraction (TF), T2 lesion volume (T2LV), EDSS and disease duration were recorded and correlated with the FC changes. Results: MS patients were found to have a significantly lower TF than HC in bilateral thalami. Compared to HC, the MS group showed significantly decreased FC between thalamus and several brain regions including right middle frontal and parahippocampal gyri, and the left inferior parietal lobule. Increased intra- and inter-thalamic FC was observed in the MS group compared to HC. These FC alterations were not correlated with T2LV, thalamic volume or lesions. In the MS group, however, there was a negative correlation between disease duration and inter-thalamic connectivity (r = −0.59, p < 0.001). Conclusion: We demonstrated decreased FC between thalamus and several cortical regions, while increased intra- and inter-thalamic connectivity in MS patients. These complex functional changes reflect impairments and/or adaptations that are independent of T2LV, thalamic volume or presence of thalamic lesions. The negative correlation between disease duration and inter-thalamic connectivity could indicate an adaptive role of thalamus that is

  13. Depression: a psychiatric nursing theory of connectivity.

    Science.gov (United States)

    Feely, M; Long, A

    2009-10-01

    This paper presents a theory of connectivity, which was formulated from the findings of a Classical Grounded Theory study that was designed to capture a sample of people's perceptions of living with depression or caring for individuals with depression. Data were collected from: (1) a focus group consisting of people with depression (n = 7), of which five were patients in the community and two were nurses; (2) one-to-one interviews with patients in the community (n = 5) and nurses (n = 5), three of whom had experienced depression from both sides of the caring process; and (3) two 'happy accident' focus groups (n = 25; n = 18) comprising of healthcare workers with a shared understanding of depression. Purposeful sampling was used initially. Thereafter, in keeping with one of the key tenets of grounded theory, theoretical sampling was used until theoretical saturation occurred. Data were analysed using the constant comparative approach together with the NVivo qualitative analysis software package. The core category that emerged was 'connectivity' relating to the connections and disconnections, which people make in their lives. Six key categories emerged all of which were integrated with the core category. Hence, connectivity provided a significant platform for understanding and responding to the life experience of depression. They were: (1) life encounters on the journey to naming; (2) depression: What's in a name? The silent thief; (3) tentative steps to health care; (4) connective encounters and challenges; (5) connecting with self; and (6) self-connection maintenance. Subsequently, a theory, 'Depression: a psychiatric nursing theory of connectivity', surfaced from the overall findings. We argue that this theory of connectivity provides a framework that people working in the field of holistic treatment and care could use to better understand and respond to the life experience of people living with depression.

  14. Detecting Functional Connectivity During Audiovisual Integration with MEG: A Comparison of Connectivity Metrics.

    Science.gov (United States)

    Ard, Tyler; Carver, Frederick W; Holroyd, Tom; Horwitz, Barry; Coppola, Richard

    2015-08-01

    In typical magnetoencephalography and/or electroencephalography functional connectivity analysis, researchers select one of several methods that measure a relationship between regions to determine connectivity, such as coherence, power correlations, and others. However, it is largely unknown if some are more suited than others for various types of investigations. In this study, the authors investigate seven connectivity metrics to evaluate which, if any, are sensitive to audiovisual integration by contrasting connectivity when tracking an audiovisual object versus connectivity when tracking a visual object uncorrelated with the auditory stimulus. The authors are able to assess the metrics' performances at detecting audiovisual integration by investigating connectivity between auditory and visual areas. Critically, the authors perform their investigation on a whole-cortex all-to-all mapping, avoiding confounds introduced in seed selection. The authors find that amplitude-based connectivity measures in the beta band detect strong connections between visual and auditory areas during audiovisual integration, specifically between V4/V5 and auditory cortices in the right hemisphere. Conversely, phase-based connectivity measures in the beta band as well as phase and power measures in alpha, gamma, and theta do not show connectivity between audiovisual areas. The authors postulate that while beta power correlations detect audiovisual integration in the current experimental context, it may not always be the best measure to detect connectivity. Instead, it is likely that the brain utilizes a variety of mechanisms in neuronal communication that may produce differential types of temporal relationships.

  15. Are people more connective than political actions?

    DEFF Research Database (Denmark)

    Shehata, Mostafa

    2017-01-01

    The recent wave of Internet-based social movements in the Arab Spring countries and elsewhere has considerably changed the organizational structure of contentious action. One of the current and most significant theories that has handled this change is the logic of connective action, which...... distinguishes between two major types of contentious action: collective and connective. In the context of this theory, this article puts forward a new conception of political action participants and attempts to classify them along the categories of collective or connective. This conception, which consists...

  16. Transit signal priority with connected vehicle technology.

    Science.gov (United States)

    2014-01-01

    A new TSP logic was proposed, taking advantage of the resources provided by Connected Vehicle (CV) : technology, including two-way communication between the bus and the traffic signal controller, accurate bus : location detection and prediction, and ...

  17. Connected Vehicle Technologies for Efficient Urban Transportation

    Science.gov (United States)

    2016-10-24

    Connected vehicle technology is employed to optimize the vehicle's control system in real-time to reduce congestion, improve fuel economy, and reduce emissions. This project's goal was to develop a two-way communication system to upload vehicle data ...

  18. PROCESS OF ELECTRICAL CONNECTION OF PHOTOVOLTAIC DEVICES

    DEFF Research Database (Denmark)

    2012-01-01

    A photovoltaic cell module comprising at least two serially connected photovoltaic cells on a common substrate, wherein the cells each comprise a first electrode layer, a first charge selective layer, a light harvesting layer which comprises an organic conjugated polymer, and a second charge...... of the pair, which connection is made through the light harvesting layer common to the at least one pair of cells, without forming an electrical connection with the first electrode of the first cell or the second charge selective layer of the second cell; and a method of making such a photovoltaic cell module....... selective layer is formed such that the second charge selective layer of one cell has no direct electrical connection to the second charge selective layer of any other cell, and wherein the light-harvesting layer is formed such that it is common to at least one pair of adjacent cells of the module; wherein...

  19. Low-stress bicycling and network connectivity.

    Science.gov (United States)

    2012-05-01

    For a bicycling network to attract the widest possible segment of the population, its most fundamental attribute should be low-stress connectivity, that is, providing routes between peoples origins and destinations that do not require cyclists to ...

  20. Switch-connected HyperX network

    Science.gov (United States)

    Chen, Dong; Heidelberger, Philip

    2018-02-13

    A network system includes a plurality of sub-network planes and global switches. The sub-network planes have a same network topology as each other. Each of the sub-network planes includes edge switches. Each of the edge switches has N ports. Each of the global switches is configured to connect a group of edge switches at a same location in the sub-network planes. In each of the sub-network planes, some of the N ports of each of the edge switches are connected to end nodes, and others of the N ports are connected to other edge switches in the same sub-network plane, other of the N ports are connected to at least one of the global switches.