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Sample records for inhibitory neuron distribution

  1. Degree of synchronization modulated by inhibitory neurons in clustered excitatory-inhibitory recurrent networks

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    Li, Huiyan; Sun, Xiaojuan; Xiao, Jinghua

    2018-01-01

    An excitatory-inhibitory recurrent neuronal network is established to numerically study the effect of inhibitory neurons on the synchronization degree of neuronal systems. The obtained results show that, with the number of inhibitory neurons and the coupling strength from an inhibitory neuron to an excitatory neuron increasing, inhibitory neurons can not only reduce the synchronization degree when the synchronization degree of the excitatory population is initially higher, but also enhance it when it is initially lower. Meanwhile, inhibitory neurons could also help the neuronal networks to maintain moderate synchronized states. In this paper, we call this effect as modulation effect of inhibitory neurons. With the obtained results, it is further revealed that the ratio of excitatory neurons to inhibitory neurons being nearly 4 : 1 is an economic and affordable choice for inhibitory neurons to realize this modulation effect.

  2. Population activity structure of excitatory and inhibitory neurons.

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    Bittner, Sean R; Williamson, Ryan C; Snyder, Adam C; Litwin-Kumar, Ashok; Doiron, Brent; Chase, Steven M; Smith, Matthew A; Yu, Byron M

    2017-01-01

    Many studies use population analysis approaches, such as dimensionality reduction, to characterize the activity of large groups of neurons. To date, these methods have treated each neuron equally, without taking into account whether neurons are excitatory or inhibitory. We studied population activity structure as a function of neuron type by applying factor analysis to spontaneous activity from spiking networks with balanced excitation and inhibition. Throughout the study, we characterized population activity structure by measuring its dimensionality and the percentage of overall activity variance that is shared among neurons. First, by sampling only excitatory or only inhibitory neurons, we found that the activity structures of these two populations in balanced networks are measurably different. We also found that the population activity structure is dependent on the ratio of excitatory to inhibitory neurons sampled. Finally we classified neurons from extracellular recordings in the primary visual cortex of anesthetized macaques as putative excitatory or inhibitory using waveform classification, and found similarities with the neuron type-specific population activity structure of a balanced network with excitatory clustering. These results imply that knowledge of neuron type is important, and allows for stronger statistical tests, when interpreting population activity structure.

  3. Population activity structure of excitatory and inhibitory neurons.

    Directory of Open Access Journals (Sweden)

    Sean R Bittner

    Full Text Available Many studies use population analysis approaches, such as dimensionality reduction, to characterize the activity of large groups of neurons. To date, these methods have treated each neuron equally, without taking into account whether neurons are excitatory or inhibitory. We studied population activity structure as a function of neuron type by applying factor analysis to spontaneous activity from spiking networks with balanced excitation and inhibition. Throughout the study, we characterized population activity structure by measuring its dimensionality and the percentage of overall activity variance that is shared among neurons. First, by sampling only excitatory or only inhibitory neurons, we found that the activity structures of these two populations in balanced networks are measurably different. We also found that the population activity structure is dependent on the ratio of excitatory to inhibitory neurons sampled. Finally we classified neurons from extracellular recordings in the primary visual cortex of anesthetized macaques as putative excitatory or inhibitory using waveform classification, and found similarities with the neuron type-specific population activity structure of a balanced network with excitatory clustering. These results imply that knowledge of neuron type is important, and allows for stronger statistical tests, when interpreting population activity structure.

  4. Population activity structure of excitatory and inhibitory neurons

    Science.gov (United States)

    Doiron, Brent

    2017-01-01

    Many studies use population analysis approaches, such as dimensionality reduction, to characterize the activity of large groups of neurons. To date, these methods have treated each neuron equally, without taking into account whether neurons are excitatory or inhibitory. We studied population activity structure as a function of neuron type by applying factor analysis to spontaneous activity from spiking networks with balanced excitation and inhibition. Throughout the study, we characterized population activity structure by measuring its dimensionality and the percentage of overall activity variance that is shared among neurons. First, by sampling only excitatory or only inhibitory neurons, we found that the activity structures of these two populations in balanced networks are measurably different. We also found that the population activity structure is dependent on the ratio of excitatory to inhibitory neurons sampled. Finally we classified neurons from extracellular recordings in the primary visual cortex of anesthetized macaques as putative excitatory or inhibitory using waveform classification, and found similarities with the neuron type-specific population activity structure of a balanced network with excitatory clustering. These results imply that knowledge of neuron type is important, and allows for stronger statistical tests, when interpreting population activity structure. PMID:28817581

  5. Inhibitory neurons modulate spontaneous signaling in cultured cortical neurons: density-dependent regulation of excitatory neuronal signaling

    International Nuclear Information System (INIS)

    Serra, Michael; Guaraldi, Mary; Shea, Thomas B

    2010-01-01

    Cortical neuronal activity depends on a balance between excitatory and inhibitory influences. Culturing of neurons on multi-electrode arrays (MEAs) has provided insight into the development and maintenance of neuronal networks. Herein, we seeded MEAs with murine embryonic cortical/hippocampal neurons at different densities ( 1000 cells mm −2 ) and monitored resultant spontaneous signaling. Sparsely seeded cultures displayed a large number of bipolar, rapid, high-amplitude individual signals with no apparent temporal regularity. By contrast, densely seeded cultures instead displayed clusters of signals at regular intervals. These patterns were observed even within thinner and thicker areas of the same culture. GABAergic neurons (25% of total neurons in our cultures) mediated the differential signal patterns observed above, since addition of the inhibitory antagonist bicuculline to dense cultures and hippocampal slice cultures induced the signal pattern characteristic of sparse cultures. Sparsely seeded cultures likely lacked sufficient inhibitory neurons to modulate excitatory activity. Differential seeding of MEAs can provide a unique model for analyses of pertubation in the interaction between excitatory and inhibitory function during aging and neuropathological conditions where dysregulation of GABAergic neurons is a significant component

  6. Inhibitory coherence in a heterogeneous population of subthreshold and suprathreshold type-I neurons

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    Kim, Sang-Yoon; Hong, Duk-Geun; Kim, Jean; Lim, Woochang

    2012-01-01

    We study inhibitory coherence (i.e. collective coherence by synaptic inhibition) in a population of globally coupled type-I neurons, which can fire at arbitrarily low frequency. No inhibitory coherence is observed in a homogeneous population composed of only subthreshold neurons, which exhibit noise-induced firings. In addition to subthreshold neurons, there exist spontaneously firing suprathreshold neurons in a noisy environment of a real brain. To take into consideration the effect of suprathreshold neurons on inhibitory coherence, we consider a heterogeneous population of subthreshold and suprathreshold neurons and investigate the inhibitory coherence by increasing the fraction of suprathreshold neurons P supra . As P supra passes a threshold P* supra , suprathreshold neurons begin to synchronize and play the role of coherent inhibitors for the emergence of inhibitory coherence. Thus, regularly oscillating population-averaged global potential appears for P supra > P* supra . For this coherent case, suprathreshold neurons exhibit sparse spike synchronization (i.e. individual potentials of suprathreshold neurons consist of coherent sparse spikings and coherent subthreshold small-amplitude hoppings). By virtue of their coherent inhibition, sparsely synchronized suprathreshold neurons suppress the noisy activity of subthreshold neurons. Thus, subthreshold neurons exhibit hopping synchronization (i.e. only coherent subthreshold hopping oscillations without spikings appear in the individual potentials of subthreshold neurons). We also characterize the inhibitory coherence in terms of the ‘statistical-mechanical’ spike-based and correlation-based measures, which quantify the average contributions of the microscopic individual spikes and individual potentials to the macroscopic global potential. Finally, the effect of sparse randomness of synaptic connectivity on the inhibitory coherence is briefly discussed. (paper)

  7. [Nonuniform distribution and contribution of the P- and P/Q-type calcium channels to short-term inhibitory synaptic transmission in cultured hippocampal neurons].

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    Mizerna, O P; Fedulova, S A; Veselovs'kyĭ, M S

    2010-01-01

    In the present study, we investigated the sensitivity of GABAergic short-term plasticity to the selective P- and P/Q-type calcium channels blocker omega-agatoxin-IVA. To block the P-type channels we used 30 nM of this toxin and 200 nM of the toxin was used to block the P/Q channel types. The evoked inhibitory postsynaptic currents (eIPSC) were studied using patch-clamp technique in whole-cell configuration in postsynaptic neuron and local extracellular stimulation of single presynaptic axon by rectangular pulse. The present data show that the contribution of P- and P/Q-types channels to GABAergic synaptic transmission in cultured hippocampal neurons are 30% and 45%, respectively. It was shown that the mediate contribution of the P- and P/Q-types channels to the amplitudes of eIPSC is different to every discovered neuron. It means that distribution of these channels is non-uniform. To study the short-term plasticity of inhibitory synaptic transmission, axons of presynaptic neurons were paired-pulse stimulated with the interpulse interval of 150 ms. Neurons demonstrated both the depression and facilitation. The application of 30 nM and 200 nM of the blocker decreased the depression and increased facilitation to 8% and 11%, respectively. In addition, we found that the mediate contribution of the P- and P/Q-types channels to realization of synaptic transmission after the second stimuli is 4% less compared to that after the first one. Therefore, blocking of both P- and P/Q-types calcium channels can change the efficiency of synaptic transmission. In this instance it facilitates realization of the transmission via decreased depression or increased facilitation. These results confirm that the P- and P/Q-types calcium channels are involved in regulation of the short-term inhibitory synaptic plasticity in cultured hippocampal neurons.

  8. Timing control by redundant inhibitory neuronal circuits

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    Tristan, I.; Rulkov, N. F.; Huerta, R.; Rabinovich, M.

    2014-01-01

    Rhythms and timing control of sequential activity in the brain is fundamental to cognition and behavior. Although experimental and theoretical studies support the understanding that neuronal circuits are intrinsically capable of generating different time intervals, the dynamical origin of the phenomenon of functionally dependent timing control is still unclear. Here, we consider a new mechanism that is related to the multi-neuronal cooperative dynamics in inhibitory brain motifs consisting of a few clusters. It is shown that redundancy and diversity of neurons within each cluster enhances the sensitivity of the timing control with the level of neuronal excitation of the whole network. The generality of the mechanism is shown to work on two different neuronal models: a conductance-based model and a map-based model

  9. Timing control by redundant inhibitory neuronal circuits

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    Tristan, I., E-mail: itristan@ucsd.edu; Rulkov, N. F.; Huerta, R.; Rabinovich, M. [BioCircuits Institute, University of California, San Diego, La Jolla, California 92093-0402 (United States)

    2014-03-15

    Rhythms and timing control of sequential activity in the brain is fundamental to cognition and behavior. Although experimental and theoretical studies support the understanding that neuronal circuits are intrinsically capable of generating different time intervals, the dynamical origin of the phenomenon of functionally dependent timing control is still unclear. Here, we consider a new mechanism that is related to the multi-neuronal cooperative dynamics in inhibitory brain motifs consisting of a few clusters. It is shown that redundancy and diversity of neurons within each cluster enhances the sensitivity of the timing control with the level of neuronal excitation of the whole network. The generality of the mechanism is shown to work on two different neuronal models: a conductance-based model and a map-based model.

  10. Spikes matter for phase-locked bursting in inhibitory neurons

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    Jalil, Sajiya; Belykh, Igor; Shilnikov, Andrey

    2012-03-01

    We show that inhibitory networks composed of two endogenously bursting neurons can robustly display several coexistent phase-locked states in addition to stable antiphase and in-phase bursting. This work complements and enhances our recent result [Jalil, Belykh, and Shilnikov, Phys. Rev. EPLEEE81539-375510.1103/PhysRevE.81.045201 81, 045201(R) (2010)] that fast reciprocal inhibition can synchronize bursting neurons due to spike interactions. We reveal the role of spikes in generating multiple phase-locked states and demonstrate that this multistability is generic by analyzing diverse models of bursting networks with various fast inhibitory synapses; the individual cell models include the reduced leech heart interneuron, the Sherman model for pancreatic beta cells, and the Purkinje neuron model.

  11. Sequentially switching cell assemblies in random inhibitory networks of spiking neurons in the striatum.

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    Ponzi, Adam; Wickens, Jeff

    2010-04-28

    The striatum is composed of GABAergic medium spiny neurons with inhibitory collaterals forming a sparse random asymmetric network and receiving an excitatory glutamatergic cortical projection. Because the inhibitory collaterals are sparse and weak, their role in striatal network dynamics is puzzling. However, here we show by simulation of a striatal inhibitory network model composed of spiking neurons that cells form assemblies that fire in sequential coherent episodes and display complex identity-temporal spiking patterns even when cortical excitation is simply constant or fluctuating noisily. Strongly correlated large-scale firing rate fluctuations on slow behaviorally relevant timescales of hundreds of milliseconds are shown by members of the same assembly whereas members of different assemblies show strong negative correlation, and we show how randomly connected spiking networks can generate this activity. Cells display highly irregular spiking with high coefficients of variation, broadly distributed low firing rates, and interspike interval distributions that are consistent with exponentially tailed power laws. Although firing rates vary coherently on slow timescales, precise spiking synchronization is absent in general. Our model only requires the minimal but striatally realistic assumptions of sparse to intermediate random connectivity, weak inhibitory synapses, and sufficient cortical excitation so that some cells are depolarized above the firing threshold during up states. Our results are in good qualitative agreement with experimental studies, consistent with recently determined striatal anatomy and physiology, and support a new view of endogenously generated metastable state switching dynamics of the striatal network underlying its information processing operations.

  12. Dynamics of Time Delay-Induced Multiple Synchronous Behaviors in Inhibitory Coupled Neurons

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    Gu, Huaguang; Zhao, Zhiguo

    2015-01-01

    The inhibitory synapse can induce synchronous behaviors different from the anti-phase synchronous behaviors, which have been reported in recent studies. In the present paper, synchronous behaviors are investigated in the motif model composed of reciprocal inhibitory coupled neurons with endogenous bursting and time delay. When coupling strength is weak, synchronous behavior appears at a single interval of time delay within a bursting period. When coupling strength is strong, multiple synchronous behaviors appear at different intervals of time delay within a bursting period. The different bursting patterns of synchronous behaviors, and time delays and coupling strengths that can induce the synchronous bursting patterns can be well interpreted by the dynamics of the endogenous bursting pattern of isolated neuron, which is acquired by the fast-slow dissection method, combined with the inhibitory coupling current. For an isolated neuron, when a negative impulsive current with suitable strength is applied at different phases of the bursting, multiple different bursting patterns can be induced. For a neuron in the motif, the inhibitory coupling current, of which the application time and strength is modulated by time delay and coupling strength, can cause single or multiple synchronous firing patterns like the negative impulsive current when time delay and coupling strength is suitable. The difference compared to the previously reported multiple synchronous behaviors that appear at time delays wider than a period of the endogenous firing is discussed. The results present novel examples of synchronous behaviors in the neuronal network with inhibitory synapses and provide a reasonable explanation. PMID:26394224

  13. Bistability induces episodic spike communication by inhibitory neurons in neuronal networks.

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    Kazantsev, V B; Asatryan, S Yu

    2011-09-01

    Bistability is one of the important features of nonlinear dynamical systems. In neurodynamics, bistability has been found in basic Hodgkin-Huxley equations describing the cell membrane dynamics. When the neuron is clamped near its threshold, the stable rest potential may coexist with the stable limit cycle describing periodic spiking. However, this effect is often neglected in network computations where the neurons are typically reduced to threshold firing units (e.g., integrate-and-fire models). We found that the bistability may induce spike communication by inhibitory coupled neurons in the spiking network. The communication is realized in the form of episodic discharges with synchronous (correlated) spikes during the episodes. A spiking phase map is constructed to describe the synchronization and to estimate basic spike phase locking modes.

  14. Differential Receptive Field Properties of Parvalbumin and Somatostatin Inhibitory Neurons in Mouse Auditory Cortex.

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    Li, Ling-Yun; Xiong, Xiaorui R; Ibrahim, Leena A; Yuan, Wei; Tao, Huizhong W; Zhang, Li I

    2015-07-01

    Cortical inhibitory circuits play important roles in shaping sensory processing. In auditory cortex, however, functional properties of genetically identified inhibitory neurons are poorly characterized. By two-photon imaging-guided recordings, we specifically targeted 2 major types of cortical inhibitory neuron, parvalbumin (PV) and somatostatin (SOM) expressing neurons, in superficial layers of mouse auditory cortex. We found that PV cells exhibited broader tonal receptive fields with lower intensity thresholds and stronger tone-evoked spike responses compared with SOM neurons. The latter exhibited similar frequency selectivity as excitatory neurons. The broader/weaker frequency tuning of PV neurons was attributed to a broader range of synaptic inputs and stronger subthreshold responses elicited, which resulted in a higher efficiency in the conversion of input to output. In addition, onsets of both the input and spike responses of SOM neurons were significantly delayed compared with PV and excitatory cells. Our results suggest that PV and SOM neurons engage in auditory cortical circuits in different manners: while PV neurons may provide broadly tuned feedforward inhibition for a rapid control of ascending inputs to excitatory neurons, the delayed and more selective inhibition from SOM neurons may provide a specific modulation of feedback inputs on their distal dendrites. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients

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    Sun, Yishan; Paşca, Sergiu P; Portmann, Thomas; Goold, Carleton; Worringer, Kathleen A; Guan, Wendy; Chan, Karen C; Gai, Hui; Vogt, Daniel; Chen, Ying-Jiun J; Mao, Rong; Chan, Karrie; Rubenstein, John LR; Madison, Daniel V; Hallmayer, Joachim; Froehlich-Santino, Wendy M; Bernstein, Jonathan A; Dolmetsch, Ricardo E

    2016-01-01

    Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons. DOI: http://dx.doi.org/10.7554/eLife.13073.001 PMID:27458797

  16. TGF-β Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning

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    Sarah X. Luo

    2016-12-01

    Full Text Available Neural circuits involving midbrain dopaminergic (DA neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor β (TGF-β signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-β type II receptor in DA neurons also disrupts the balance in TGF-β1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-β signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-β in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders.

  17. Development of inhibitory synaptic inputs on layer 2/3 pyramidal neurons in the rat medial prefrontal cortex

    KAUST Repository

    Virtanen, Mari A.; Lacoh, Claudia Marvine; Fiumelli, Hubert; Kosel, Markus; Tyagarajan, Shiva; de Roo, Mathias; Vutskits, Laszlo

    2018-01-01

    Inhibitory control of pyramidal neurons plays a major role in governing the excitability in the brain. While spatial mapping of inhibitory inputs onto pyramidal neurons would provide important structural data on neuronal signaling, studying their distribution at the single cell level is difficult due to the lack of easily identifiable anatomical proxies. Here, we describe an approach where in utero electroporation of a plasmid encoding for fluorescently tagged gephyrin into the precursors of pyramidal cells along with ionotophoretic injection of Lucifer Yellow can reliably and specifically detect GABAergic synapses on the dendritic arbour of single pyramidal neurons. Using this technique and focusing on the basal dendritic arbour of layer 2/3 pyramidal cells of the medial prefrontal cortex, we demonstrate an intense development of GABAergic inputs onto these cells between postnatal days 10 and 20. While the spatial distribution of gephyrin clusters was not affected by the distance from the cell body at postnatal day 10, we found that distal dendritic segments appeared to have a higher gephyrin density at later developmental stages. We also show a transient increase around postnatal day 20 in the percentage of spines that are carrying a gephyrin cluster, indicative of innervation by a GABAergic terminal. Since the precise spatial arrangement of synaptic inputs is an important determinant of neuronal responses, we believe that the method described in this work may allow a better understanding of how inhibition settles together with excitation, and serve as basics for further modelling studies focusing on the geometry of dendritic inhibition during development.

  18. Development of inhibitory synaptic inputs on layer 2/3 pyramidal neurons in the rat medial prefrontal cortex

    KAUST Repository

    Virtanen, Mari A.

    2018-01-10

    Inhibitory control of pyramidal neurons plays a major role in governing the excitability in the brain. While spatial mapping of inhibitory inputs onto pyramidal neurons would provide important structural data on neuronal signaling, studying their distribution at the single cell level is difficult due to the lack of easily identifiable anatomical proxies. Here, we describe an approach where in utero electroporation of a plasmid encoding for fluorescently tagged gephyrin into the precursors of pyramidal cells along with ionotophoretic injection of Lucifer Yellow can reliably and specifically detect GABAergic synapses on the dendritic arbour of single pyramidal neurons. Using this technique and focusing on the basal dendritic arbour of layer 2/3 pyramidal cells of the medial prefrontal cortex, we demonstrate an intense development of GABAergic inputs onto these cells between postnatal days 10 and 20. While the spatial distribution of gephyrin clusters was not affected by the distance from the cell body at postnatal day 10, we found that distal dendritic segments appeared to have a higher gephyrin density at later developmental stages. We also show a transient increase around postnatal day 20 in the percentage of spines that are carrying a gephyrin cluster, indicative of innervation by a GABAergic terminal. Since the precise spatial arrangement of synaptic inputs is an important determinant of neuronal responses, we believe that the method described in this work may allow a better understanding of how inhibition settles together with excitation, and serve as basics for further modelling studies focusing on the geometry of dendritic inhibition during development.

  19. Schaffer collateral inputs to CA1 excitatory and inhibitory neurons follow different connectivity rules.

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    Kwon, Osung; Feng, Linqing; Druckmann, Shaul; Kim, Jinhyun

    2018-05-04

    Neural circuits, governed by a complex interplay between excitatory and inhibitory neurons, are the substrate for information processing, and the organization of synaptic connectivity in neural network is an important determinant of circuit function. Here, we analyzed the fine structure of connectivity in hippocampal CA1 excitatory and inhibitory neurons innervated by Schaffer collaterals (SCs) using mGRASP in male mice. Our previous study revealed spatially structured synaptic connectivity between CA3-CA1 pyramidal cells (PCs). Surprisingly, parvalbumin-positive interneurons (PVs) showed a significantly more random pattern spatial structure. Notably, application of Peters' Rule for synapse prediction by random overlap between axons and dendrites enhanced structured connectivity in PCs, but, by contrast, made the connectivity pattern in PVs more random. In addition, PCs in a deep sublayer of striatum pyramidale appeared more highly structured than PCs in superficial layers, and little or no sublayer specificity was found in PVs. Our results show that CA1 excitatory PCs and inhibitory PVs innervated by the same SC inputs follow different connectivity rules. The different organizations of fine scale structured connectivity in hippocampal excitatory and inhibitory neurons provide important insights into the development and functions of neural networks. SIGNIFICANCE STATEMENT Understanding how neural circuits generate behavior is one of the central goals of neuroscience. An important component of this endeavor is the mapping of fine-scale connection patterns that underlie, and help us infer, signal processing in the brain. Here, using our recently developed synapse detection technology (mGRASP and neuTube), we provide detailed profiles of synaptic connectivity in excitatory (CA1 pyramidal) and inhibitory (CA1 parvalbumin-positive) neurons innervated by the same presynaptic inputs (CA3 Schaffer collaterals). Our results reveal that these two types of CA1 neurons follow

  20. The role of degree distribution in shaping the dynamics in networks of sparsely connected spiking neurons

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    Alex eRoxin

    2011-03-01

    Full Text Available Neuronal network models often assume a fixed probability of connectionbetween neurons. This assumption leads to random networks withbinomial in-degree and out-degree distributions which are relatively narrow. Here I study the effect of broaddegree distributions on network dynamics by interpolating between abinomial and a truncated powerlaw distribution for the in-degree andout-degree independently. This is done both for an inhibitory network(I network as well as for the recurrent excitatory connections in anetwork of excitatory and inhibitory neurons (EI network. In bothcases increasing the width of the in-degree distribution affects theglobal state of the network by driving transitions betweenasynchronous behavior and oscillations. This effect is reproduced ina simplified rate model which includes the heterogeneity in neuronalinput due to the in-degree of cells. On the other hand, broadeningthe out-degree distribution is shown to increase the fraction ofcommon inputs to pairs of neurons. This leads to increases in theamplitude of the cross-correlation (CC of synaptic currents. In thecase of the I network, despite strong oscillatory CCs in the currents, CCs of the membrane potential are low due to filtering and reset effects, leading to very weak CCs of the spikecount. In the asynchronous regime ofthe EI network, broadening the out-degree increases the amplitude ofCCs in the recurrent excitatory currents, while CC of the totalcurrent is essentially unaffected as are pairwise spikingcorrelations. This is due to a dynamic balance between excitatoryand inhibitory synaptic currents. In the oscillatory regime, changesin the out-degree can have a large effect on spiking correlations andeven on the qualitative dynamical state of the network.

  1. Top-down modulation on perceptual decision with balanced inhibition through feedforward and feedback inhibitory neurons.

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    Cheng-Te Wang

    Full Text Available Recent physiological studies have shown that neurons in various regions of the central nervous systems continuously receive noisy excitatory and inhibitory synaptic inputs in a balanced and covaried fashion. While this balanced synaptic input (BSI is typically described in terms of maintaining the stability of neural circuits, a number of experimental and theoretical studies have suggested that BSI plays a proactive role in brain functions such as top-down modulation for executive control. Two issues have remained unclear in this picture. First, given the noisy nature of neuronal activities in neural circuits, how do the modulatory effects change if the top-down control implements BSI with different ratios between inhibition and excitation? Second, how is a top-down BSI realized via only excitatory long-range projections in the neocortex? To address the first issue, we systematically tested how the inhibition/excitation ratio affects the accuracy and reaction times of a spiking neural circuit model of perceptual decision. We defined an energy function to characterize the network dynamics, and found that different ratios modulate the energy function of the circuit differently and form two distinct functional modes. To address the second issue, we tested BSI with long-distance projection to inhibitory neurons that are either feedforward or feedback, depending on whether these inhibitory neurons do or do not receive inputs from local excitatory cells, respectively. We found that BSI occurs in both cases. Furthermore, when relying on feedback inhibitory neurons, through the recurrent interactions inside the circuit, BSI dynamically and automatically speeds up the decision by gradually reducing its inhibitory component in the course of a trial when a decision process takes too long.

  2. Top-down modulation on perceptual decision with balanced inhibition through feedforward and feedback inhibitory neurons.

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    Wang, Cheng-Te; Lee, Chung-Ting; Wang, Xiao-Jing; Lo, Chung-Chuan

    2013-01-01

    Recent physiological studies have shown that neurons in various regions of the central nervous systems continuously receive noisy excitatory and inhibitory synaptic inputs in a balanced and covaried fashion. While this balanced synaptic input (BSI) is typically described in terms of maintaining the stability of neural circuits, a number of experimental and theoretical studies have suggested that BSI plays a proactive role in brain functions such as top-down modulation for executive control. Two issues have remained unclear in this picture. First, given the noisy nature of neuronal activities in neural circuits, how do the modulatory effects change if the top-down control implements BSI with different ratios between inhibition and excitation? Second, how is a top-down BSI realized via only excitatory long-range projections in the neocortex? To address the first issue, we systematically tested how the inhibition/excitation ratio affects the accuracy and reaction times of a spiking neural circuit model of perceptual decision. We defined an energy function to characterize the network dynamics, and found that different ratios modulate the energy function of the circuit differently and form two distinct functional modes. To address the second issue, we tested BSI with long-distance projection to inhibitory neurons that are either feedforward or feedback, depending on whether these inhibitory neurons do or do not receive inputs from local excitatory cells, respectively. We found that BSI occurs in both cases. Furthermore, when relying on feedback inhibitory neurons, through the recurrent interactions inside the circuit, BSI dynamically and automatically speeds up the decision by gradually reducing its inhibitory component in the course of a trial when a decision process takes too long.

  3. Increasing inhibitory input increases neuronal firing rate: why and when? Diffusion process cases

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    Feng Jianfeng [COGS, Sussex University (United Kingdom)]. E-mail: jf218@cam.ac.uk; Wei Gang [Department of Mathematics, Hong Kong Baptist University, Hong Kong (China)]. E-mail gwei@math.hkbu.edu.hk

    2001-09-21

    Increasing inhibitory input to single neuronal models, such as the FitzHugh-Nagumo model and the Hodgkin-Huxley model, can sometimes increase their firing rates, a phenomenon which we term inhibition-boosted firing (IBF). Here we consider neuronal models with diffusion approximation inputs, i.e. they share the identical first- and second-order statistics of the corresponding Poisson process inputs. Using the integrate-and-fire model and the IF-FHN model, we explore theoretically how and when IBF can happen. For both models, it is shown that there is a critical input frequency at which the efferent firing rate is identical when the neuron receives purely excitatory inputs or exactly balanced inhibitory and excitatory inputs. When the input frequency is lower than the critical frequency, IBF occurs. (author)

  4. Adolescent maturation of inhibitory inputs onto cingulate cortex neurons is cell-type specific and TrkB dependent

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    Angela eVandenberg

    2015-02-01

    Full Text Available The maturation of inhibitory circuits during adolescence may be tied to the onset of mental health disorders such as schizophrenia. Neurotrophin signaling likely plays a critical role in supporting inhibitory circuit development and is also implicated in psychiatric disease. Within the neocortex, subcircuits may mature at different times and show differential sensitivity to neurotrophin signaling. We measured miniature inhibitory and excitatory postsynaptic currents (mIPSC and mEPSCs in Layer 5 cell-types in the mouse anterior cingulate across the periadolescent period. We differentiated cell-types mainly by Thy1 YFP transgene expression and also retrobead injection labeling in the contralateral cingulate and ipsilateral pons. We found that YFP- neurons and commissural projecting neurons had lower frequency of mIPSCs than neighboring YFP+ neurons or pons projecting neurons in juvenile mice (P21-25. YFP- neurons and to a lesser extent commissural projecting neurons also showed a significant increase in mIPSC amplitude during the periadolescent period (P21-25 vs. P40-50, which was not seen in YFP+ neurons or pons projecting neurons. Systemic disruption of tyrosine kinase receptor B (TrkB signaling during P23-50 in TrkBF616A mice blocked developmental changes in mIPSC amplitude, without affecting miniature excitatory post synaptic currents (mEPSCs. Our data suggest that the maturation of inhibitory inputs onto layer 5 pyramidal neurons is cell-type specific. These data may inform our understanding of adolescent brain development across species and aid in identifying candidate subcircuits that may show greater vulnerability in mental illness.

  5. Effects of inhibitory neurons on the quorum percolation model and dynamical extension with the Brette-Gerstner model

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    Fardet, Tanguy; Bottani, Samuel; Métens, Stéphane; Monceau, Pascal

    2018-06-01

    The Quorum Percolation model (QP) has been designed in the context of neurobiology to describe the initiation of activity bursts occurring in neuronal cultures from the point of view of statistical physics rather than from a dynamical synchronization approach. This paper aims at investigating an extension of the original QP model by taking into account the presence of inhibitory neurons in the cultures (IQP model). The first part of this paper is focused on an equivalence between the presence of inhibitory neurons and a reduction of the network connectivity. By relying on a simple topological argument, we show that the mean activation behavior of networks containing a fraction η of inhibitory neurons can be mapped onto purely excitatory networks with an appropriately modified wiring, provided that η remains in the range usually observed in neuronal cultures, namely η ⪅ 20%. As a striking result, we show that such a mapping enables to predict the evolution of the critical point of the IQP model with the fraction of inhibitory neurons. In a second part, we bridge the gap between the description of bursts in the framework of percolation and the temporal description of neural networks activity by showing how dynamical simulations of bursts with an adaptive exponential integrate-and-fire model lead to a mean description of bursts activation which is captured by Quorum Percolation.

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

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    Sunggu Yang

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

  7. Dynamical responses to external stimuli for both cases of excitatory and inhibitory synchronization in a complex neuronal network.

    Science.gov (United States)

    Kim, Sang-Yoon; Lim, Woochang

    2017-10-01

    For studying how dynamical responses to external stimuli depend on the synaptic-coupling type, we consider two types of excitatory and inhibitory synchronization (i.e., synchronization via synaptic excitation and inhibition) in complex small-world networks of excitatory regular spiking (RS) pyramidal neurons and inhibitory fast spiking (FS) interneurons. For both cases of excitatory and inhibitory synchronization, effects of synaptic couplings on dynamical responses to external time-periodic stimuli S ( t ) (applied to a fraction of neurons) are investigated by varying the driving amplitude A of S ( t ). Stimulated neurons are phase-locked to external stimuli for both cases of excitatory and inhibitory couplings. On the other hand, the stimulation effect on non-stimulated neurons depends on the type of synaptic coupling. The external stimulus S ( t ) makes a constructive effect on excitatory non-stimulated RS neurons (i.e., it causes external phase lockings in the non-stimulated sub-population), while S ( t ) makes a destructive effect on inhibitory non-stimulated FS interneurons (i.e., it breaks up original inhibitory synchronization in the non-stimulated sub-population). As results of these different effects of S ( t ), the type and degree of dynamical response (e.g., synchronization enhancement or suppression), characterized by the dynamical response factor [Formula: see text] (given by the ratio of synchronization degree in the presence and absence of stimulus), are found to vary in a distinctly different way, depending on the synaptic-coupling type. Furthermore, we also measure the matching degree between the dynamics of the two sub-populations of stimulated and non-stimulated neurons in terms of a "cross-correlation" measure [Formula: see text]. With increasing A , based on [Formula: see text], we discuss the cross-correlations between the two sub-populations, affecting the dynamical responses to S ( t ).

  8. Dexmedetomidine decreases inhibitory but not excitatory neurotransmission to cardiac vagal neurons in the nucleus ambiguus.

    Science.gov (United States)

    Sharp, Douglas B; Wang, Xin; Mendelowitz, David

    2014-07-29

    Dexmedetomidine, an α2 adrenergic agonist, is a useful sedative but can also cause significant bradycardia. This decrease in heart rate may be due to decreased central sympathetic output as well as increased parasympathetic output from brainstem cardiac vagal neurons. In this study, using whole cell voltage clamp methodology, the actions of dexmedetomidine on excitatory glutamatergic and inhibitory GABAergic and glycinergic neurotransmission to parasympathetic cardiac vagal neurons in the rat nucleus ambiguus was determined. The results indicate that dexmedetomidine decreases both GABAergic and glycinergic inhibitory input to cardiac vagal neurons, with no significant effect on excitatory input. These results provide a mechanism for dexmedetomidine induced bradycardia and has implications for the management of this potentially harmful side effect. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder.

    Science.gov (United States)

    Valencia Garcia, Sara; Brischoux, Frédéric; Clément, Olivier; Libourel, Paul-Antoine; Arthaud, Sébastien; Lazarus, Michael; Luppi, Pierre-Hervé; Fort, Patrice

    2018-02-05

    Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients.

  10. Can inhibitory and facilitatory kinesiotaping techniques affect motor neuron excitability? A randomized cross-over trial.

    Science.gov (United States)

    Yoosefinejad, Amin Kordi; Motealleh, Alireza; Abbasalipur, Shekoofeh; Shahroei, Mahan; Sobhani, Sobhan

    2017-04-01

    The aim of this study was to investigate the immediate effects of facilitatory and inhibitory kinesiotaping on motor neuron excitability. Randomized cross-over trial. Twenty healthy people received inhibitory and facilitatory kinesiotaping on two testing days. The H- and M-waves of the lateral gasterocnemius were recorded before and immediately after applying the two modes of taping. The Hmax/Mmax ratio (a measure of motor neuron excitability) was determined and analyzed. The mean Hmax/Mmax ratios were -0.013 (95% CI: -0.033 to 0.007) for inhibitory taping and 0.007 (95% CI: -0.013 to 0.027) for facilitatory taping. The mean difference between groups was -0.020 (95% CI: -0.048 to 0.008). The statistical model revealed no significant differences between the two interventions (P = 0.160). Furthermore, there were no within-group differences in Hmax/Mmax ratio for either group. Our findings did not disclose signs of immediate change in motor neuron excitability in the lateral gasterocnemius. Copyright © 2016. Published by Elsevier Ltd.

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

    Science.gov (United States)

    Tao, Ye; Gu, Huaguang; Ding, Xueli

    2017-10-01

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

  12. Minocycline enhances inhibitory transmission to substantia gelatinosa neurons of the rat spinal dorsal horn.

    Science.gov (United States)

    Peng, H-Z; Ma, L-X; Lv, M-H; Hu, T; Liu, T

    2016-04-05

    Minocycline, a second-generation tetracycline, is well known for its antibiotic, anti-inflammatory, and antinociceptive effects. Modulation of synaptic transmission is one of the analgesic mechanisms of minocycline. Although it has been reported that minocycline may suppress excitatory glutamatergic synaptic transmission, it remains unclear whether it could affect inhibitory synaptic transmission, which also plays a key role in modulating pain signaling. To examine the effect of minocycline on synaptic transmission in rat spinal substantia gelatinosa (SG) neurons, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) using whole-cell patch-clamp recording at a holding potential of 0 mV. Bath application of minocycline significantly increased the frequency but not the amplitude of sIPSCs in a reversible and concentration-dependent manner with an EC50 of 85. The enhancement of inhibitory synaptic transmission produced by minocycline was not affected by the glutamate receptor antagonists CNQX and D-APV or by the voltage-gated sodium channel blocker tetrodotoxin (TTX). Moreover, the potency of minocycline for facilitating sIPSC frequency was the same in both glycinergic and GABAergic sIPSCs without changing their decay phases. However, the facilitatory effect of minocycline on sIPSCs was eliminated in a Ca(2+)-free Krebs solution or by co-administration with calcium channel blockers. In summary, our data demonstrate that baseline inhibitory synaptic transmission in SG neurons is markedly enhanced by minocycline. This may function to decrease the excitability of SG neurons, thus leading to a modulation of nociceptive transmission. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. Contextual Learning Requires Functional Diversity at Excitatory and Inhibitory Synapses onto CA1 Pyramidal Neurons

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    Dai Mitsushima

    2015-01-01

    Full Text Available Although the hippocampus is processing temporal and spatial information in particular context, the encoding rule creating memory is completely unknown. To examine the mechanism, we trained rats on an inhibitory avoidance (IA task, a hippocampus-dependent rapid one-trial contextual learning paradigm. By combining Herpes virus-mediated in vivo gene delivery with in vitro patch-clamp recordings, I reported contextual learning drives GluR1-containing AMPA receptors into CA3-CA1 synapses. The molecular event is required for contextual memory, since bilateral expression of delivery blocker in CA1 successfully blocked IA learning. Moreover, I found a logarithmic correlation between the number of delivery blocking cells and learning performance. Considering that one all-or-none device can process 1-bit of data per clock (Nobert Wiener 1961, the logarithmic correlation may provides evidence that CA1 neurons transmit essential data of contextual information. Further, I recently reported critical role of acetylcholine as an intrinsic trigger of learning-dependent synaptic plasticity. IA training induced ACh release in CA1 that strengthened not only AMPA receptor-mediated excitatory synapses, but also GABAA receptor-mediated inhibitory synapses on each CA1 neuron. More importantly, IA-trained rats showed individually different excitatory and inhibitory synaptic inputs with wide variation on each CA1 neuron. Here I propose a new hypothesis that the diversity of synaptic inputs on CA1 neurons may depict cell-specific outputs processing experienced episodes after training.

  14. Effects of self-coupling and asymmetric output on metastable dynamical transient firing patterns in arrays of neurons with bidirectional inhibitory coupling.

    Science.gov (United States)

    Horikawa, Yo

    2016-04-01

    Metastable dynamical transient patterns in arrays of bidirectionally coupled neurons with self-coupling and asymmetric output were studied. First, an array of asymmetric sigmoidal neurons with symmetric inhibitory bidirectional coupling and self-coupling was considered and the bifurcations of its steady solutions were shown. Metastable dynamical transient spatially nonuniform states existed in the presence of a pair of spatially symmetric stable solutions as well as unstable spatially nonuniform solutions in a restricted range of the output gain of a neuron. The duration of the transients increased exponentially with the number of neurons up to the maximum number at which the spatially nonuniform steady solutions were stabilized. The range of the output gain for which they existed reduced as asymmetry in a sigmoidal output function of a neuron increased, while the existence range expanded as the strength of inhibitory self-coupling increased. Next, arrays of spiking neuron models with slow synaptic inhibitory bidirectional coupling and self-coupling were considered with computer simulation. In an array of Class 1 Hindmarsh-Rose type models, in which each neuron showed a graded firing rate, metastable dynamical transient firing patterns were observed in the presence of inhibitory self-coupling. This agreed with the condition for the existence of metastable dynamical transients in an array of sigmoidal neurons. In an array of Class 2 Bonhoeffer-van der Pol models, in which each neuron had a clear threshold between firing and resting, long-lasting transient firing patterns with bursting and irregular motion were observed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Differential distribution of voltage-gated ion channels in cortical neurons: implications for epilepsy.

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    Child, Nicholas D; Benarroch, Eduardo E

    2014-03-18

    Neurons contain different functional somatodendritic and axonal domains, each with a characteristic distribution of voltage-gated ion channels, synaptic inputs, and function. The dendritic tree of a cortical pyramidal neuron has 2 distinct domains, the basal and the apical dendrites, both containing dendritic spines; the different domains of the axon are the axonal initial segment (AIS), axon proper (which in myelinated axons includes the node of Ranvier, paranodes, juxtaparanodes, and internodes), and the axon terminals. In the cerebral cortex, the dendritic spines of the pyramidal neurons receive most of the excitatory synapses; distinct populations of γ-aminobutyric acid (GABA)ergic interneurons target specific cellular domains and thus exert different influences on pyramidal neurons. The multiple synaptic inputs reaching the somatodendritic region and generating excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) sum and elicit changes in membrane potential at the AIS, the site of initiation of the action potential.

  16. Diversity in Long-Term Synaptic Plasticity at Inhibitory Synapses of Striatal Spiny Neurons

    Science.gov (United States)

    Rueda-Orozco, Pavel E.; Mendoza, Ernesto; Hernandez, Ricardo; Aceves, Jose J.; Ibanez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, Jose

    2009-01-01

    Procedural memories and habits are posited to be stored in the basal ganglia, whose intrinsic circuitries possess important inhibitory connections arising from striatal spiny neurons. However, no information about long-term plasticity at these synapses is available. Therefore, this work describes a novel postsynaptically dependent long-term…

  17. From Quasiperiodic Partial Synchronization to Collective Chaos in Populations of Inhibitory Neurons with Delay.

    Science.gov (United States)

    Pazó, Diego; Montbrió, Ernest

    2016-06-10

    Collective chaos is shown to emerge, via a period-doubling cascade, from quasiperiodic partial synchronization in a population of identical inhibitory neurons with delayed global coupling. This system is thoroughly investigated by means of an exact model of the macroscopic dynamics, valid in the thermodynamic limit. The collective chaotic state is reproduced numerically with a finite population, and persists in the presence of weak heterogeneities. Finally, the relationship of the model's dynamics with fast neuronal oscillations is discussed.

  18. Effects of drugs of abuse on putative rostromedial tegmental neurons, inhibitory afferents to midbrain dopamine cells.

    Science.gov (United States)

    Lecca, Salvatore; Melis, Miriam; Luchicchi, Antonio; Ennas, Maria Grazia; Castelli, Maria Paola; Muntoni, Anna Lisa; Pistis, Marco

    2011-02-01

    Recent findings have underlined the rostromedial tegmental nucleus (RMTg), a structure located caudally to the ventral tegmental area, as an important site involved in the mechanisms of aversion. RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding midbrain dopamine (DA) neurons. One of the key features of drug addiction is the perseverance of drug seeking in spite of negative and unpleasant consequences, likely mediated by response suppression within neural pathways mediating aversion. To investigate whether the RMTg has a function in the mechanisms of addicting drugs, we studied acute effects of morphine, cocaine, the cannabinoid agonist WIN55212-2 (WIN), and nicotine on putative RMTg neurons. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch-clamp recordings in brain slices to identify and characterize putative RMTg neurons and their responses to drugs of abuse. Morphine and WIN inhibited both firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude. Conversely, nicotine robustly excited putative RMTg neurons and enhanced EPSCs, an effect mediated by α7-containing nicotinic acetylcholine receptors. Our results suggest that activity of RMTg neurons is profoundly influenced by drugs of abuse and, as important inhibitory afferents to midbrain DA neurons, they might take place in the complex interplay between the neural circuits mediating aversion and reward.

  19. Inhibitory noise

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    Alain Destexhe

    2010-03-01

    Full Text Available Cortical neurons in vivo may operate in high-conductance states, in which the major part of the neuron's input conductance is due to synaptic activity, sometimes several-fold larger than the resting conductance. We examine here the contribution of inhibition in such high-conductance states. At the level of the absolute conductance values, several studies have shown that cortical neurons in vivo are characterized by strong inhibitory conductances. However, conductances are balanced and spiking activity is mostly determined by fluctuations, but not much is known about excitatory and inhibitory contributions to these fluctuations. Models and dynamic-clamp experiments show that, during high-conductance states, spikes are mainly determined by fluctuations of inhibition, or by inhibitory noise. This stands in contrast to low-conductance states, in which excitatory conductances determine spiking activity. To determine these contributions from experimental data, maximum likelihood methods can be designed and applied to intracellular recordings in vivo. Such methods indicate that action potentials are indeed mostly correlated with inhibitory fluctuations in awake animals. These results argue for a determinant role for inhibitory fluctuations in evoking spikes, and do not support feed-forward modes of processing, for which opposite patterns are predicted.

  20. 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.

  1. Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats.

    Science.gov (United States)

    Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S

    2015-01-01

    Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic-GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP-GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP-GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP-GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP-GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

  2. Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA recording study"

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    Giulia ePuia

    2012-11-01

    Full Text Available The balance between glutamate- and GABA-mediated neurotransmission in the brain is fundamental in the nervous system, but it is regulated by the ‘tonic’ release of a variety of endogenous factors. One such important group of molecules are the neurosteroids (NSs which, similarly to benzodiazepines (BDZs, enhance GABAergic neurotransmission. The purpose of our work was to investigate, at in-vivo physiologically relevant concentrations, the effects of NSs and BDZs as GABA modulators on dissociated neocortical neuron networks grown in long-term culture. We used a multi-electrode array (MEA recording technique and a novel analysis that was able to both identify the action potentials of engaged excitatory and inhibitory neurons and to detect drug-induced network up-states (burst. We found that the NSs tetrahydrodeoxycorticosterone (THDOC and allopregnanolone (ALLO applied at low nM concentrations, produced different modulatory effects on the two neuronal clusters. Conversely, at high concentrations (1 µM, both NSs, decreased excitatory and inhibitory neuron cluster excitability; however, even several hours after washout, the excitability of inhibitory neurons continued to be depressed, leading to a network long term depression (LTD. The BDZs clonazepam (CLZ and midazolam (MDZ also decreased the network excitability, but only MDZ caused LTD of inhibitory neuron cluster. To investigate the origin of the LTD after MDZ application, we tested finasteride (FIN, an inhibitor of endogenous NSs synthesis. FIN did not prevent the LTD induced by MDZ, but surprisingly induced it after application of CLZ. The significance and possible mechanisms underlying these LTD effects of NSs and BDZs are discussed. Taken together, our results not only demonstrate that ex-vivo networks show a sensitivity to NSs and BDZs comparable to that expressed in vivo, but also provide a new global in-vitro description that can help in understanding their activity in more complex

  3. Early-life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats

    Directory of Open Access Journals (Sweden)

    Tomoko eSoga

    2015-11-01

    Full Text Available Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinising hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP-tagged GnIH-transgenic rats. Socially isolated rats were observed for anxious and depressive behaviours. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group -housing. We also inspected serotonergic fibre juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviours. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fibre juxtapositions on EGFP–GnIH neurons was also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

  4. Mutation at Glu23 eliminates the neuron growth inhibitory activity of human metallothionein-3

    International Nuclear Information System (INIS)

    Ding Zhichun; Teng Xinchen; Cai Bin; Wang Hui; Zheng Qi; Wang Yang; Zhou Guoming; Zhang Mingjie; Wu Houming; Sun Hongzhe; Huang Zhongxian

    2006-01-01

    Human metallothionein-3 (hMT3), first isolated and identified as a neuronal growth inhibitory factor (GIF), is a metalloprotein expressed predominantly in brain. However, untill now, the exact mechanism of the bioactivity of hMT3 is still unknown. In order to study the influence of acid-base catalysis on S-nitrosylation of hMT3, we constructed the E23K mutant of hMT3. During the course of bioassay, we found out unexpectedly that mutation at E23 of hMT3 eliminates the neuronal growth inhibitory activity completely. To the best of our knowledge, it is First report that other residues, besides the TCPCP motif, in the β-domain can alter the bioactivity of hMT3. In order to figure out the causes for the loss of bioactivity of the E23K mutant, the biochemical properties were characterized by UV-vis spectroscopy, CD spectroscopy, pH titration, DTNB reaction, EDTA reaction, and SNOC reaction. All data demonstrated that stability of the metal-thiolate cluster and overall structure of the E23K mutant were not altered too much. However, the reaction of the E23K mutant with SNOC exhibited biphasic kinetics and the mutant protein released zinc ions much faster than hMT3 in the initial step, while hMT3 exhibited single kinetic process. The 2D [ 1 H- 15 N] HSQC was also employed to characterize structural changes during the reaction of hMT3 with varying mounts of nitric oxide. It was shown that the resonance of Glu23 disappeared at a molar ratio of NO to protein of 4. Based on these results, we suggest that mutation at Glu23 may alter the NO metabolism and/or affect zinc homeostasis in brain, thus altering the neuronal growth inhibitory activity

  5. The influence of single neuron dynamics and network topology on time delay-induced multiple synchronous behaviors in inhibitory coupled network

    International Nuclear Information System (INIS)

    Zhao, Zhiguo; Gu, Huaguang

    2015-01-01

    Highlights: • Time delay-induced multiple synchronous behaviors was simulated in neuronal networks. • Multiple behaviors appear at time delays shorter than a bursting period of neurons. • The more spikes per burst of bursting, the more synchronous regions of time delay. • From regular to random via small-world networks, synchronous degree becomes weak. • An interpretation of the multiple behaviors and the influence of network are provided. - Abstract: Time delay induced-multiple synchronous behaviors are simulated in neuronal network composed of many inhibitory neurons and appear at different time delays shorter than a period of endogenous bursting of individual neurons. It is different from previous investigations wherein only one of multiple synchronous behaviors appears at time delay shorter than a period of endogenous firing and others appear at time delay longer than the period duration. The bursting patterns of the synchronous behaviors are identified based on the dynamics of an individual neuron stimulated by a signal similar to the inhibitory coupling current, which is applied at the decaying branch of a spike and suitable phase within the quiescent state of the endogenous bursting. If a burst of endogenous bursting contains more spikes, the synchronous behaviors appear at more regions of time delay. As the coupling strength increases, the multiple synchronous behaviors appear in a sequence because the different threshold of coupling current or strength is needed to achieve synchronous behaviors. From regular, to small-world, and to random networks, synchronous degree of the multiple synchronous behaviors becomes weak, and synchronous bursting patterns with lower spikes per burst disappear, which is properly interpreted by the difference of coupling current between neurons induced by different degree and the high threshold of coupling current to achieve synchronization for the absent synchronous bursting patterns. The results of the influence of

  6. Computational Model of a Positive BDNF Feedback Loop in Hippocampal Neurons Following Inhibitory Avoidance Training

    Science.gov (United States)

    Zhang, Yili; Smolen, Paul; Alberini, Cristina M.; Baxter, Douglas A.; Byrne, John H.

    2016-01-01

    Inhibitory avoidance (IA) training in rodents initiates a molecular cascade within hippocampal neurons. This cascade contributes to the transition of short- to long-term memory (i.e., consolidation). Here, a differential equation-based model was developed to describe a positive feedback loop within this molecular cascade. The feedback loop begins…

  7. Inhibitory neuron and hippocampal circuit dysfunction in an aged mouse model of Alzheimer's disease.

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    Anupam Hazra

    Full Text Available In Alzheimer's disease (AD, a decline in explicit memory is one of the earliest signs of disease and is associated with hippocampal dysfunction. Amyloid protein exerts a disruptive impact on neuronal function, but the specific effects on hippocampal network activity are not well known. In this study, fast voltage-sensitive dye imaging and extracellular and whole-cell electrophysiology were used on entorhinal cortical-hippocampal slice preparations to characterize hippocampal network activity in 12-16 month old female APPswe/PSEN1DeltaE9 (APdE9 mice mice. Aged APdE9 mice exhibited profound disruptions in dentate gyrus circuit activation. High frequency stimulation of the perforant pathway in the dentate gyrus (DG area of APdE9 mouse tissue evoked abnormally large field potential responses corresponding to the wider neural activation maps. Whole-cell patch clamp recordings of the identified inhibitory interneurons in the molecular layer of DG revealed that they fail to reliably fire action potentials. Taken together, abnormal DG excitability and an inhibitory neuron failure to generate action potentials are suggested to be important contributors to the underlying cellular mechanisms of early-stage Alzheimer's disease pathophysiology.

  8. Dynamic excitatory and inhibitory gain modulation can produce flexible, robust and optimal decision-making.

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    Ritwik K Niyogi

    Full Text Available Behavioural and neurophysiological studies in primates have increasingly shown the involvement of urgency signals during the temporal integration of sensory evidence in perceptual decision-making. Neuronal correlates of such signals have been found in the parietal cortex, and in separate studies, demonstrated attention-induced gain modulation of both excitatory and inhibitory neurons. Although previous computational models of decision-making have incorporated gain modulation, their abstract forms do not permit an understanding of the contribution of inhibitory gain modulation. Thus, the effects of co-modulating both excitatory and inhibitory neuronal gains on decision-making dynamics and behavioural performance remain unclear. In this work, we incorporate time-dependent co-modulation of the gains of both excitatory and inhibitory neurons into our previous biologically based decision circuit model. We base our computational study in the context of two classic motion-discrimination tasks performed in animals. Our model shows that by simultaneously increasing the gains of both excitatory and inhibitory neurons, a variety of the observed dynamic neuronal firing activities can be replicated. In particular, the model can exhibit winner-take-all decision-making behaviour with higher firing rates and within a significantly more robust model parameter range. It also exhibits short-tailed reaction time distributions even when operating near a dynamical bifurcation point. The model further shows that neuronal gain modulation can compensate for weaker recurrent excitation in a decision neural circuit, and support decision formation and storage. Higher neuronal gain is also suggested in the more cognitively demanding reaction time than in the fixed delay version of the task. Using the exact temporal delays from the animal experiments, fast recruitment of gain co-modulation is shown to maximize reward rate, with a timescale that is surprisingly near the

  9. Spiking Activity of a LIF Neuron in Distributed Delay Framework

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    Saket Kumar Choudhary

    2016-06-01

    Full Text Available Evolution of membrane potential and spiking activity for a single leaky integrate-and-fire (LIF neuron in distributed delay framework (DDF is investigated. DDF provides a mechanism to incorporate memory element in terms of delay (kernel function into a single neuron models. This investigation includes LIF neuron model with two different kinds of delay kernel functions, namely, gamma distributed delay kernel function and hypo-exponential distributed delay kernel function. Evolution of membrane potential for considered models is studied in terms of stationary state probability distribution (SPD. Stationary state probability distribution of membrane potential (SPDV for considered neuron models are found asymptotically similar which is Gaussian distributed. In order to investigate the effect of membrane potential delay, rate code scheme for neuronal information processing is applied. Firing rate and Fano-factor for considered neuron models are calculated and standard LIF model is used for comparative study. It is noticed that distributed delay increases the spiking activity of a neuron. Increase in spiking activity of neuron in DDF is larger for hypo-exponential distributed delay function than gamma distributed delay function. Moreover, in case of hypo-exponential delay function, a LIF neuron generates spikes with Fano-factor less than 1.

  10. Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding.

    Science.gov (United States)

    Suyama, Shigetomo; Maekawa, Fumihiko; Maejima, Yuko; Kubota, Naoto; Kadowaki, Takashi; Yada, Toshihiko

    2016-08-09

    Adiponectin regulates glucose and lipid metabolism, acting against metabolic syndrome and atherosclerosis. Accumulating evidence suggest that adiponectin acts on the brain including hypothalamic arcuate nucleus (ARC), where proopiomelanocortin (POMC) neurons play key roles in feeding regulation. Several studies have examined intracerebroventricular (ICV) injection of adiponectin and reported opposite effects, increase or decrease of food intake. These reports used different nutritional states. The present study aimed to clarify whether adiponectin exerts distinct effects on food intake and ARC POMC neurons depending on the glucose concentration. Adiponectin was ICV injected with or without glucose for feeding experiments and administered to ARC slices with high or low glucose for patch clamp experiments. We found that adiponectin at high glucose inhibited POMC neurons and increased food intake while at low glucose it exerted opposite effects. The results demonstrate that glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding.

  11. Somatostatin-expressing inhibitory interneurons in cortical circuits

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    Iryna Yavorska

    2016-09-01

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

  12. The neurite growth inhibitory effects of soluble TNFα on developing sympathetic neurons are dependent on developmental age.

    Science.gov (United States)

    Nolan, Aoife M; Collins, Louise M; Wyatt, Sean L; Gutierrez, Humberto; O'Keeffe, Gerard W

    2014-01-01

    During development, the growth of neural processes is regulated by an array of cellular and molecular mechanisms which influence growth rate, direction and branching. Recently, many members of the TNF superfamily have been shown to be key regulators of neurite growth during development. The founder member of this family, TNFα can both promote and inhibit neurite growth depending on the cellular context. Specifically, transmembrane TNFα promotes neurite growth, while soluble TNFα inhibits it. While the growth promoting effects of TNFα are restricted to a defined developmental window of early postnatal development, whether the growth inhibitory effects of soluble TNFα occur throughout development is unknown. In this study we used the extensively studied, well characterised neurons of the superior cervical ganglion to show that the growth inhibitory effects of soluble TNFα are restricted to a specific period of late embryonic and early postnatal development. Furthermore, we show that this growth inhibitory effect of soluble TNFα requires NF-κB signalling at all developmental stages at which soluble TNFα inhibits neurite growth. These findings raise the possibility that increases in the amount of soluble TNFα in vivo, for example as a result of maternal inflammation, could negatively affect neurite growth in developing neurons at specific stages of development. Copyright © 2015 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

  13. Recruitment of local inhibitory networks by horizontal connections in layer 2/3 of ferret visual cortex.

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    Tucker, Thomas R; Katz, Lawrence C

    2003-01-01

    To investigate how neurons in cortical layer 2/3 integrate horizontal inputs arising from widely distributed sites, we combined intracellular recording and voltage-sensitive dye imaging to visualize the spatiotemporal dynamics of neuronal activity evoked by electrical stimulation of multiple sites in visual cortex. Individual stimuli evoked characteristic patterns of optical activity, while delivering stimuli at multiple sites generated interacting patterns in the regions of overlap. We observed that neurons in overlapping regions received convergent horizontal activation that generated nonlinear responses due to the emergence of large inhibitory potentials. The results indicate that co-activation of multiple sets of horizontal connections recruit strong inhibition from local inhibitory networks, causing marked deviations from simple linear integration.

  14. 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

  15. The Diversity of Cortical Inhibitory Synapses

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    Yoshiyuki eKubota

    2016-04-01

    Full Text Available The most typical and well known inhibitory action in the cortical microcircuit is a strong inhibition on the target neuron by axo-somatic synapses. However, it has become clear that synaptic inhibition in the cortex is much more diverse and complicated. Firstly, at least ten or more inhibitory non-pyramidal cell subtypes engage in diverse inhibitory functions to produce the elaborate activity characteristic of the different cortical states. Each distinct non-pyramidal cell subtype has its own independent inhibitory function. Secondly, the inhibitory synapses innervate different neuronal domains, such as axons, spines, dendrites and soma, and their IPSP size is not uniform. Thus cortical inhibition is highly complex, with a wide variety of anatomical and physiological modes. Moreover, the functional significance of the various inhibitory synapse innervation styles and their unique structural dynamic behaviors differ from those of excitatory synapses. In this review, we summarize our current understanding of the inhibitory mechanisms of the cortical microcircuit.

  16. Inhibitory effect of organotin compounds on rat neuronal nitric oxide synthase through interaction with calmodulin

    International Nuclear Information System (INIS)

    Ohashi, Koji; Kominami, Shiro; Yamazaki, Takeshi; Ohta, Shigeru; Kitamura, Shigeyuki

    2004-01-01

    Organotin compounds, triphenyltin (TPT), tributyltin, dibutyltin, and monobutyltin (MBT), showed potent inhibitory effects on both L-arginine oxidation to nitric oxide and L-citrulline, and cytochrome c reduction catalyzed by recombinant rat neuronal nitric oxide synthase (nNOS). The two inhibitory effects were almost parallel. MBT and TPT showed the highest inhibitory effects, followed by tributyltin and dibutyltin; TPT and MBT showed inhibition constant (IC 50 ) values of around 10 μM. Cytochrome c reduction activity was markedly decreased by removal of calmodulin (CaM) from the complete mixture, and the decrease was similar to the extent of inhibition by TPT and MBT. The inhibitory effect of MBT on the cytochrome c reducing activity was rapidly attenuated upon dilution of the inhibitor, and addition of a high concentration of CaM reactivated the cytochrome c reduction activity inhibited by MBT. However, other cofactors such as FAD, FMN or tetrahydrobiopterin had no such ability. The inhibitory effect of organotin compounds (100 μM) on L-arginine oxidation of nNOS almost vanished when the amount of CaM was sufficiently increased (150-300 μM). It was confirmed by CaM-agarose column chromatography that the dissociation of nNOS-CaM complex was induced by organotin compounds. These results indicate that organotin compounds disturb the interaction between CaM and nNOS, thereby inhibiting electron transfer from the reductase domain to cytochrome c and the oxygenase domain

  17. Results on a Binding Neuron Model and Their Implications for Modified Hourglass Model for Neuronal Network

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    Viswanathan Arunachalam

    2013-01-01

    Full Text Available The classical models of single neuron like Hodgkin-Huxley point neuron or leaky integrate and fire neuron assume the influence of postsynaptic potentials to last till the neuron fires. Vidybida (2008 in a refreshing departure has proposed models for binding neurons in which the trace of an input is remembered only for a finite fixed period of time after which it is forgotten. The binding neurons conform to the behaviour of real neurons and are applicable in constructing fast recurrent networks for computer modeling. This paper develops explicitly several useful results for a binding neuron like the firing time distribution and other statistical characteristics. We also discuss the applicability of the developed results in constructing a modified hourglass network model in which there are interconnected neurons with excitatory as well as inhibitory inputs. Limited simulation results of the hourglass network are presented.

  18. Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs.

    Science.gov (United States)

    Spiegel, Ivo; Mardinly, Alan R; Gabel, Harrison W; Bazinet, Jeremy E; Couch, Cameron H; Tzeng, Christopher P; Harmin, David A; Greenberg, Michael E

    2014-05-22

    The nervous system adapts to experience by inducing a transcriptional program that controls important aspects of synaptic plasticity. Although the molecular mechanisms of experience-dependent plasticity are well characterized in excitatory neurons, the mechanisms that regulate this process in inhibitory neurons are only poorly understood. Here, we describe a transcriptional program that is induced by neuronal activity in inhibitory neurons. We find that, while neuronal activity induces expression of early-response transcription factors such as Npas4 in both excitatory and inhibitory neurons, Npas4 activates distinct programs of late-response genes in inhibitory and excitatory neurons. These late-response genes differentially regulate synaptic input to these two types of neurons, promoting inhibition onto excitatory neurons while inducing excitation onto inhibitory neurons. These findings suggest that the functional outcomes of activity-induced transcriptional responses are adapted in a cell-type-specific manner to achieve a circuit-wide homeostatic response. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. The excitatory/inhibitory input to orexin/hypocretin neuron soma undergoes day/night reorganization.

    Science.gov (United States)

    Laperchia, Claudia; Imperatore, Roberta; Azeez, Idris A; Del Gallo, Federico; Bertini, Giuseppe; Grassi-Zucconi, Gigliola; Cristino, Luigia; Bentivoglio, Marina

    2017-11-01

    Orexin (OX)/hypocretin-containing neurons are main regulators of wakefulness stability, arousal, and energy homeostasis. Their activity varies in relation to the animal's behavioral state. We here tested whether such variation is subserved by synaptic plasticity phenomena in basal conditions. Mice were sacrificed during day or night, at times when sleep or wake, respectively, predominates, as assessed by electroencephalography in matched mice. Triple immunofluorescence was used to visualize OX-A perikarya and varicosities containing the vesicular glutamate transporter (VGluT)2 or the vesicular GABA transporter (VGAT) combined with synaptophysin (Syn) as a presynaptic marker. Appositions on OX-A + somata were quantitatively analyzed in pairs of sections in epifluorescence and confocal microscopy. The combined total number of glutamatergic (Syn + /VGluT2 + ) and GABAergic (Syn + /VGAT + ) varicosities apposed to OX-A somata was similar during day and night. However, glutamatergic varicosities were significantly more numerous at night, whereas GABAergic varicosities prevailed in the day. Triple immunofluorescence in confocal microscopy was employed to visualize synapse scaffold proteins as postsynaptic markers and confirmed the nighttime prevalence of VGluT2 + together with postsynaptic density protein 95 + excitatory contacts, and daytime prevalence of VGAT + together with gephyrin + inhibitory contacts, while also showing that they formed synapses on OX-A + cell bodies. The findings reveal a daily reorganization of axosomatic synapses in orexinergic neurons, with a switch from a prevalence of excitatory innervation at a time corresponding to wakefulness to a prevalence of inhibitory innervations in the antiphase, at a time corresponding to sleep. This reorganization could represent a key mechanism of plasticity of the orexinergic network in basal conditions.

  20. Optogenetic stimulation of locus ceruleus neurons augments inhibitory transmission to parasympathetic cardiac vagal neurons via activation of brainstem α1 and β1 receptors.

    Science.gov (United States)

    Wang, Xin; Piñol, Ramón A; Byrne, Peter; Mendelowitz, David

    2014-04-30

    Locus ceruleus (LC) noradrenergic neurons are critical in generating alertness. In addition to inducing cortical arousal, the LC also orchestrates changes in accompanying autonomic system function that compliments increased attention, such as during stress, excitation, and/or exposure to averse or novel stimuli. Although the association between arousal and increased heart rate is well accepted, the neurobiological link between the LC and parasympathetic neurons that control heart rate has not been identified. In this study, we test directly whether activation of noradrenergic neurons in the LC influences brainstem parasympathetic cardiac vagal neurons (CVNs). CVNs were identified in transgenic mice that express channel-rhodopsin-2 (ChR2) in LC tyrosine hydroxylase neurons. Photoactivation evoked a rapid depolarization, increased firing, and excitatory inward currents in ChR2-expressing neurons in the LC. Photostimulation of LC neurons did not alter excitatory currents, but increased inhibitory neurotransmission to CVNs. Optogenetic activation of LC neurons increased the frequency of isolated glycinergic IPSCs by 27 ± 8% (p = 0.003, n = 26) and augmented GABAergic IPSCs in CVNs by 21 ± 5% (p = 0.001, n = 26). Inhibiting α1, but not α2, receptors blocked the evoked responses. Inhibiting β1 receptors prevented the increase in glycinergic, but not GABAergic, IPSCs in CVNs. This study demonstrates LC noradrenergic neurons inhibit the brainstem CVNs that generate parasympathetic activity to the heart. This inhibition of CVNs would increase heart rate and risks associated with tachycardia. The receptors activated within this pathway, α1 and/or β1 receptors, are targets for clinically prescribed antagonists that promote slower, cardioprotective heart rates during heightened vigilant states.

  1. Oscillations, complex spatiotemporal behavior, and information transport in networks of excitatory and inhibitory neurons

    International Nuclear Information System (INIS)

    Destexhe, A.

    1994-01-01

    Various types of spatiotemporal behavior are described for two-dimensional networks of excitatory and inhibitory neurons with time delayed interactions. It is described how the network behaves as several structural parameters are varied, such as the number of neurons, the connectivity, and the values of synaptic weights. A transition from spatially uniform oscillations to spatiotemporal chaos via intermittentlike behavior is observed. The properties of spatiotemporally chaotic solutions are investigated by evaluating the largest positive Lyapunov exponent and the loss of correlation with distance. Finally, properties of information transport are evaluated during uniform oscillations and spatiotemporal chaos. It is shown that the diffusion coefficient increases significantly in the spatiotemporal phase similar to the increase of transport coefficients at the onset of fluid turbulence. It is proposed that such a property should be seen in other media, such as chemical turbulence or networks of oscillators. The possibility of measuring information transport from appropriate experiments is also discussed

  2. Dynamics of excitatory and inhibitory networks are differentially altered by selective attention

    Science.gov (United States)

    Snyder, Adam C.; Morais, Michael J.

    2016-01-01

    Inhibition and excitation form two fundamental modes of neuronal interaction, yet we understand relatively little about their distinct roles in service of perceptual and cognitive processes. We developed a multidimensional waveform analysis to identify fast-spiking (putative inhibitory) and regular-spiking (putative excitatory) neurons in vivo and used this method to analyze how attention affects these two cell classes in visual area V4 of the extrastriate cortex of rhesus macaques. We found that putative inhibitory neurons had both greater increases in firing rate and decreases in correlated variability with attention compared with putative excitatory neurons. Moreover, the time course of attention effects for putative inhibitory neurons more closely tracked the temporal statistics of target probability in our task. Finally, the session-to-session variability in a behavioral measure of attention covaried with the magnitude of this effect. Together, these results suggest that selective targeting of inhibitory neurons and networks is a critical mechanism for attentional modulation. PMID:27466133

  3. Dynamics of excitatory and inhibitory networks are differentially altered by selective attention.

    Science.gov (United States)

    Snyder, Adam C; Morais, Michael J; Smith, Matthew A

    2016-10-01

    Inhibition and excitation form two fundamental modes of neuronal interaction, yet we understand relatively little about their distinct roles in service of perceptual and cognitive processes. We developed a multidimensional waveform analysis to identify fast-spiking (putative inhibitory) and regular-spiking (putative excitatory) neurons in vivo and used this method to analyze how attention affects these two cell classes in visual area V4 of the extrastriate cortex of rhesus macaques. We found that putative inhibitory neurons had both greater increases in firing rate and decreases in correlated variability with attention compared with putative excitatory neurons. Moreover, the time course of attention effects for putative inhibitory neurons more closely tracked the temporal statistics of target probability in our task. Finally, the session-to-session variability in a behavioral measure of attention covaried with the magnitude of this effect. Together, these results suggest that selective targeting of inhibitory neurons and networks is a critical mechanism for attentional modulation. Copyright © 2016 the American Physiological Society.

  4. Nootropic dipeptide noopept enhances inhibitory synaptic transmission in the hippocampus.

    Science.gov (United States)

    Povarov, I S; Kondratenko, R V; Derevyagin, V I; Ostrovskaya, R U; Skrebitskii, V G

    2015-01-01

    Application of nootropic agent Noopept on hippocampal slices from Wistar rats enhanced the inhibitory component of total current induced by stimulation of Shaffer collaterals in CA1 pyramidal neurons, but did not affect the excitatory component. A direct correlation between the increase in the amplitude of inhibitory current and agent concentration was found. The substance did not affect the release of inhibitory transmitters from terminals in the pyramidal neurons, which indicated changes in GABAergic interneurons.

  5. Decorrelation of Neural-Network Activity by Inhibitory Feedback

    Science.gov (United States)

    Einevoll, Gaute T.; Diesmann, Markus

    2012-01-01

    Correlations in spike-train ensembles can seriously impair the encoding of information by their spatio-temporal structure. An inevitable source of correlation in finite neural networks is common presynaptic input to pairs of neurons. Recent studies demonstrate that spike correlations in recurrent neural networks are considerably smaller than expected based on the amount of shared presynaptic input. Here, we explain this observation by means of a linear network model and simulations of networks of leaky integrate-and-fire neurons. We show that inhibitory feedback efficiently suppresses pairwise correlations and, hence, population-rate fluctuations, thereby assigning inhibitory neurons the new role of active decorrelation. We quantify this decorrelation by comparing the responses of the intact recurrent network (feedback system) and systems where the statistics of the feedback channel is perturbed (feedforward system). Manipulations of the feedback statistics can lead to a significant increase in the power and coherence of the population response. In particular, neglecting correlations within the ensemble of feedback channels or between the external stimulus and the feedback amplifies population-rate fluctuations by orders of magnitude. The fluctuation suppression in homogeneous inhibitory networks is explained by a negative feedback loop in the one-dimensional dynamics of the compound activity. Similarly, a change of coordinates exposes an effective negative feedback loop in the compound dynamics of stable excitatory-inhibitory networks. The suppression of input correlations in finite networks is explained by the population averaged correlations in the linear network model: In purely inhibitory networks, shared-input correlations are canceled by negative spike-train correlations. In excitatory-inhibitory networks, spike-train correlations are typically positive. Here, the suppression of input correlations is not a result of the mere existence of correlations between

  6. Prenatal cocaine exposure decreases parvalbumin-immunoreactive neurons and GABA-to-projection neuron ratio in the medial prefrontal cortex.

    Science.gov (United States)

    McCarthy, Deirdre M; Bhide, Pradeep G

    2012-01-01

    Cocaine abuse during pregnancy produces harmful effects not only on the mother but also on the unborn child. The neurotransmitters dopamine and serotonin are known as the principal targets of the action of cocaine in the fetal and postnatal brain. However, recent evidence suggests that cocaine can impair cerebral cortical GABA neuron development and function. We sought to analyze the effects of prenatal cocaine exposure on the number and distribution of GABA and projection neurons (inhibitory interneurons and excitatory output neurons, respectively) in the mouse cerebral cortex. We found that the prenatal cocaine exposure decreased GABA neuron numbers and GABA-to-projection neuron ratio in the medial prefrontal cortex of 60-day-old mice. The neighboring prefrontal cortex did not show significant changes in either of these measures. However, there was a significant increase in projection neuron numbers in the prefrontal cortex but not in the medial prefrontal cortex. Thus, the effects of cocaine on GABA and projection neurons appear to be cortical region specific. The population of parvalbumin-immunoreactive GABA neurons was decreased in the medial prefrontal cortex following the prenatal cocaine exposure. The cocaine exposure also delayed the developmental decline in the volume of the medial prefrontal cortex. Thus, prenatal cocaine exposure produced persisting and region-specific effects on cortical cytoarchitecture and impaired the physiological balance between excitatory and inhibitory neurotransmission. These structural changes may underlie the electrophysiological and behavioral effects of prenatal cocaine exposure observed in animal models and human subjects. Copyright © 2012 S. Karger AG, Basel.

  7. Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

    Science.gov (United States)

    Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

    2015-07-24

    One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

  8. Inhibitory Activity of Yokukansankachimpihange against Nerve Growth Factor-Induced Neurite Growth in Cultured Rat Dorsal Root Ganglion Neurons

    Directory of Open Access Journals (Sweden)

    Chiaki Murayama

    2015-08-01

    Full Text Available Chronic pruritus is a major and distressing symptom of many cutaneous diseases, however, the treatment remains a challenge in the clinic. The traditional Chinese-Japanese medicine (Kampo medicine is a conservative and increasingly popular approach to treat chronic pruritus for both patients and medical providers. Yokukansankachimpihange (YKH, a Kampo formula has been demonstrated to be effective in the treatment of itching of atopic dermatitis in Japan although its pharmacological mechanism is unknown clearly. In an attempt to clarify its pharmacological actions, in this study, we focused on the inhibitory activity of YKH against neurite growth induced with nerve growth factor (NGF in cultured rat dorsal root ganglion (DRG neurons because epidermal hyperinnervation is deeply related to itch sensitization. YKH showed approximately 200-fold inhibitory activity against NGF-induced neurite growth than that of neurotropin (positive control, a drug used clinically for treatment of chronic pruritus. Moreover, it also found that Uncaria hook, Bupleurum root and their chemical constituents rhynchophylline, hirsutine, and saikosaponin a, d showed inhibitory activities against NGF-induced neurite growth, suggesting they should mainly contribute to the inhibitory activity of YKH. Further study on the effects of YKH against epidermal nerve density in “itch-scratch” animal models is under investigation.

  9. Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons.

    Science.gov (United States)

    Mardinly, A R; Spiegel, I; Patrizi, A; Centofante, E; Bazinet, J E; Tzeng, C P; Mandel-Brehm, C; Harmin, D A; Adesnik, H; Fagiolini, M; Greenberg, M E

    2016-03-17

    Inhibitory neurons regulate the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory neuron to regulate cortical plasticity are largely unknown. Here we show that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP)-expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. We identify Igf1 as one of several activity-regulated genes that are specific to VIP neurons, and demonstrate that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons. Our findings further suggest that in cortical VIP neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of IGF1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons.

  10. Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses

    Science.gov (United States)

    Trouche, Stéphanie; Sasaki, Jennifer M.; Tu, Tiffany; Reijmers, Leon G.

    2013-01-01

    SUMMARY A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. PMID:24183705

  11. Response sensitivity of barrel neuron subpopulations to simulated thalamic input.

    Science.gov (United States)

    Pesavento, Michael J; Rittenhouse, Cynthia D; Pinto, David J

    2010-06-01

    Our goal is to examine the relationship between neuron- and network-level processing in the context of a well-studied cortical function, the processing of thalamic input by whisker-barrel circuits in rodent neocortex. Here we focus on neuron-level processing and investigate the responses of excitatory and inhibitory barrel neurons to simulated thalamic inputs applied using the dynamic clamp method in brain slices. Simulated inputs are modeled after real thalamic inputs recorded in vivo in response to brief whisker deflections. Our results suggest that inhibitory neurons require more input to reach firing threshold, but then fire earlier, with less variability, and respond to a broader range of inputs than do excitatory neurons. Differences in the responses of barrel neuron subtypes depend on their intrinsic membrane properties. Neurons with a low input resistance require more input to reach threshold but then fire earlier than neurons with a higher input resistance, regardless of the neuron's classification. Our results also suggest that the response properties of excitatory versus inhibitory barrel neurons are consistent with the response sensitivities of the ensemble barrel network. The short response latency of inhibitory neurons may serve to suppress ensemble barrel responses to asynchronous thalamic input. Correspondingly, whereas neurons acting as part of the barrel circuit in vivo are highly selective for temporally correlated thalamic input, excitatory barrel neurons acting alone in vitro are less so. These data suggest that network-level processing of thalamic input in barrel cortex depends on neuron-level processing of the same input by excitatory and inhibitory barrel neurons.

  12. Neuronal discrimination capacity

    International Nuclear Information System (INIS)

    Deng Yingchun; Williams, Peter; Feng Jianfeng; Liu Feng

    2003-01-01

    We explore neuronal mechanisms of discriminating between masked signals. It is found that when the correlation between input signals is zero, the output signals are separable if and only if input signals are separable. With positively (negatively) correlated signals, the output signals are separable (mixed) even when input signals are mixed (separable). Exact values of discrimination capacity are obtained for two most interesting cases: the exactly balanced inhibitory and excitatory input case and the uncorrelated input case. Interestingly, the discrimination capacity obtained in these cases is independent of model parameters, input distribution and is universal. Our results also suggest a functional role of inhibitory inputs and correlated inputs or, more generally, the large variability of efferent spike trains observed in in vivo experiments: the larger the variability of efferent spike trains, the easier it is to discriminate between masked input signals

  13. Neuronal discrimination capacity

    Energy Technology Data Exchange (ETDEWEB)

    Deng Yingchun [Department of Mathematics, Hunan Normal University 410081, Changsha (China); COGS, University of Sussex at Brighton, BN1 9QH (United Kingdom); Williams, Peter; Feng Jianfeng [COGS, University of Sussex at Brighton, BN1 9QH (United Kingdom); Liu Feng [COGS, University of Sussex at Brighton, BN1 9QH (United Kingdom); Physics Department, Nanjing University (China)

    2003-12-19

    We explore neuronal mechanisms of discriminating between masked signals. It is found that when the correlation between input signals is zero, the output signals are separable if and only if input signals are separable. With positively (negatively) correlated signals, the output signals are separable (mixed) even when input signals are mixed (separable). Exact values of discrimination capacity are obtained for two most interesting cases: the exactly balanced inhibitory and excitatory input case and the uncorrelated input case. Interestingly, the discrimination capacity obtained in these cases is independent of model parameters, input distribution and is universal. Our results also suggest a functional role of inhibitory inputs and correlated inputs or, more generally, the large variability of efferent spike trains observed in in vivo experiments: the larger the variability of efferent spike trains, the easier it is to discriminate between masked input signals.

  14. Distribution of glycinergic neuronal somata in the rat spinal cord.

    Science.gov (United States)

    Hossaini, Mehdi; French, Pim J; Holstege, Jan C

    2007-04-20

    Glycine transporter 2 (GlyT2) mRNA is exclusively expressed in glycinergic neurons, and is presently considered a reliable marker for glycinergic neuronal somata. In this study, we have performed non-radioactive in situ hybridization to localize GlyT2 mRNA in fixed free-floating sections of cervical (C2 and C6), thoracic (T5), lumbar (L2 and L5) and sacral (S1) segments of the rat spinal cord. The results showed that in all segments the majority of the GlyT2 mRNA labeled (glycinergic) neuronal somata was present in the deep dorsal horn and the intermediate zone (laminae III-VIII), with around 50% (range 43.7-70.9%) in laminae VII&VIII. In contrast, the superficial dorsal horn, the motoneuronal cell groups and the area around the central canal contained only few glycinergic neuronal somata. The density (number of glycinergic neuronal somata per mm(2)) was also low in these areas, while the highest densities were found in laminae V to VIII. The lateral spinal nucleus and the lateral cervical nucleus also contained a limited number of glycinergic neurons. Our findings showed that the distribution pattern of the glycinergic neuronal somata is similar in all the examined segments. The few differences that were found in the relative laminar distribution between some of the segments, are most likely due to technical reasons. We therefore conclude that the observed distribution pattern of glycinergic neuronal somata is present throughout the spinal cord. Our findings further showed that the non-radioactive in situ hybridization technique for identifying GlyT2 mRNA in fixed free-floating sections is a highly efficient tool for identifying glycinergic neurons in the spinal cord.

  15. Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses.

    Science.gov (United States)

    Trouche, Stéphanie; Sasaki, Jennifer M; Tu, Tiffany; Reijmers, Leon G

    2013-11-20

    A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos-based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. Copyright © 2013 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Wei-Qun Fang

    2014-12-01

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

  17. Harmane inhibits serotonergic dorsal raphe neurons in the rat.

    Science.gov (United States)

    Touiki, Khalid; Rat, Pascal; Molimard, Robert; Chait, Abderrahman; de Beaurepaire, Renaud

    2005-11-01

    Harmane and norharmane (two beta-carbolines) are tobacco components or products. The effects of harmane and norharmane on serotonergic raphe neurons remain unknown. Harmane and norharmane are inhibitors of the monoamine oxidases A (MAO-A) and B (MAO-B), respectively. To study the effects of harmane, norharmane, befloxatone (MAOI-A), and selegiline (MAOI-B) on the firing of serotonergic neurons. To compare the effects of these compounds to those of nicotine (whose inhibitory action on serotonergic neurons has been previously described). The effects of cotinine, a metabolite of nicotine known to interact with serotonergic systems, are also tested. In vivo electrophysiological recordings of serotonergic dorsal raphe neurons in the anaesthetized rat. Nicotine, harmane, and befloxatone inhibited serotonergic dorsal raphe neurons. The other compounds had no effects. The inhibitory effect of harmane (rapid and long-lasting inhibition) differed from that of nicotine (short and rapidly reversed inhibition) and from that of befloxatone (slow, progressive, and long-lasting inhibition). The inhibitory effects of harmane and befloxatone were reversed by the 5-HT1A antagonist WAY 100 635. Pretreatment of animals with p-chlorophenylalanine abolished the inhibitory effect of befloxatone, but not that of harmane. Nicotine, harmane, and befloxatone inhibit the activity of raphe serotonergic neurons. Therefore, at least two tobacco compounds, nicotine and harmane, inhibit the activity of serotonergic neurons. The mechanism by which harmane inhibits serotonergic dorsal raphe neurons is likely unrelated to a MAO-A inhibitory effect.

  18. Characterization of neurons in the cortical white matter in human temporal lobe epilepsy.

    Science.gov (United States)

    Richter, Zsófia; Janszky, József; Sétáló, György; Horváth, Réka; Horváth, Zsolt; Dóczi, Tamás; Seress, László; Ábrahám, Hajnalka

    2016-10-01

    The aim of the present work was to characterize neurons in the archi- and neocortical white matter, and to investigate their distribution in mesial temporal sclerosis. Immunohistochemistry and quantification of neurons were performed on surgically resected tissue sections of patients with therapy-resistant temporal lobe epilepsy. Temporal lobe tissues of patients with tumor but without epilepsy and that from autopsy were used as controls. Neurons were identified with immunohistochemistry using antibodies against NeuN, calcium-binding proteins, transcription factor Tbr1 and neurofilaments. We found significantly higher density of neurons in the archi- and neocortical white matter of patients with temporal lobe epilepsy than in that of controls. Based on their morphology and neurochemical content, both excitatory and inhibitory cells were present among these neurons. A subset of neurons in the white matter was Tbr-1-immunoreactive and these neurons coexpressed NeuN and neurofilament marker SMI311R. No colocalization of Tbr1 was observed with the inhibitory neuronal markers, calcium-binding proteins. We suggest that a large population of white matter neurons comprises remnants of the subplate. Furthermore, we propose that a subset of white matter neurons was arrested during migration, highlighting the role of cortical maldevelopment in epilepsy associated with mesial temporal sclerosis. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Bifurcation of synchronous oscillations into torus in a system of two reciprocally inhibitory silicon neurons: Experimental observation and modeling

    International Nuclear Information System (INIS)

    Bondarenko, Vladimir E.; Cymbalyuk, Gennady S.; Patel, Girish; DeWeerth, Stephen P.; Calabrese, Ronald L.

    2004-01-01

    Oscillatory activity in the central nervous system is associated with various functions, like motor control, memory formation, binding, and attention. Quasiperiodic oscillations are rarely discussed in the neurophysiological literature yet they may play a role in the nervous system both during normal function and disease. Here we use a physical system and a model to explore scenarios for how quasiperiodic oscillations might arise in neuronal networks. An oscillatory system of two mutually inhibitory neuronal units is a ubiquitous network module found in nervous systems and is called a half-center oscillator. Previously we created a half-center oscillator of two identical oscillatory silicon (analog Very Large Scale Integration) neurons and developed a mathematical model describing its dynamics. In the mathematical model, we have shown that an in-phase limit cycle becomes unstable through a subcritical torus bifurcation. However, the existence of this torus bifurcation in experimental silicon two-neuron system was not rigorously demonstrated or investigated. Here we demonstrate the torus predicted by the model for the silicon implementation of a half-center oscillator using complex time series analysis, including bifurcation diagrams, mapping techniques, correlation functions, amplitude spectra, and correlation dimensions, and we investigate how the properties of the quasiperiodic oscillations depend on the strengths of coupling between the silicon neurons. The potential advantages and disadvantages of quasiperiodic oscillations (torus) for biological neural systems and artificial neural networks are discussed

  20. Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons

    OpenAIRE

    Vong, Linh; Ye, Chianping; Yang, Zongfang; Choi, Brian; Chua, Streamson; Lowell, Bradford B.

    2011-01-01

    Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part due to incomplete knowledge regarding first order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first order neurons. While functionally relevant neurons have been identified, the observed effects have been small suggesting that most first order neurons remain unidentified. Here we take an alternative appro...

  1. Social Isolation Modulates CLOCK Protein and Beta-Catenin Expression Pattern in Gonadotropin-Inhibitory Hormone Neurons in Male Rats

    Directory of Open Access Journals (Sweden)

    Chuin Hau Teo

    2017-09-01

    Full Text Available Postweaning social isolation reduces the amplitude of the daily variation of CLOCK protein in the brain and induces lower reproductive activity. Gonadotropin-inhibitory hormone (GnIH acts as an inhibitor in the reproductive system and has been linked to stress. Social isolation has been shown to lower neuronal activity of GnIH-expressing neurons in the dorsomedial hypothalamus (DMH. The exact mechanism by which social isolation may affect GnIH is still unclear. We investigated the impact of social isolation on regulatory cellular mechanisms in GnIH neurons. We examined via immunohistochemistry the expression of CLOCK protein at four different times throughout the day in GnIH cells tagged with enhanced fluorescent green protein (EGFP-GnIH in 9-week-old adult male rats that have been raised for 6 weeks under postweaning social isolation and compared them with group-raised control rats of the same age. We also studied the expression of β-catenin—which has been shown to be affected by circadian proteins such as Bmal1—in EGFP-GnIH neurons to determine whether it could play a role in linking CLOCK in GnIH neurons. We found that social isolation modifies the pattern of CLOCK expression in GnIH neurons in the DMH. Socially isolated rats displayed greater CLOCK expression in the dark phase, while control rats displayed increased CLOCK expression in the light phase. Furthermore, β-catenin expression pattern in GnIH cells was disrupted by social isolation. This suggests that social isolation triggers changes in CLOCK and GnIH expression, which may be associated with an increase in nuclear β-catenin during the dark phase.

  2. Social Isolation Modulates CLOCK Protein and Beta-Catenin Expression Pattern in Gonadotropin-Inhibitory Hormone Neurons in Male Rats.

    Science.gov (United States)

    Teo, Chuin Hau; Soga, Tomoko; Parhar, Ishwar S

    2017-01-01

    Postweaning social isolation reduces the amplitude of the daily variation of CLOCK protein in the brain and induces lower reproductive activity. Gonadotropin-inhibitory hormone (GnIH) acts as an inhibitor in the reproductive system and has been linked to stress. Social isolation has been shown to lower neuronal activity of GnIH-expressing neurons in the dorsomedial hypothalamus (DMH). The exact mechanism by which social isolation may affect GnIH is still unclear. We investigated the impact of social isolation on regulatory cellular mechanisms in GnIH neurons. We examined via immunohistochemistry the expression of CLOCK protein at four different times throughout the day in GnIH cells tagged with enhanced fluorescent green protein (EGFP-GnIH) in 9-week-old adult male rats that have been raised for 6 weeks under postweaning social isolation and compared them with group-raised control rats of the same age. We also studied the expression of β-catenin-which has been shown to be affected by circadian proteins such as Bmal1-in EGFP-GnIH neurons to determine whether it could play a role in linking CLOCK in GnIH neurons. We found that social isolation modifies the pattern of CLOCK expression in GnIH neurons in the DMH. Socially isolated rats displayed greater CLOCK expression in the dark phase, while control rats displayed increased CLOCK expression in the light phase. Furthermore, β-catenin expression pattern in GnIH cells was disrupted by social isolation. This suggests that social isolation triggers changes in CLOCK and GnIH expression, which may be associated with an increase in nuclear β-catenin during the dark phase.

  3. Physical exercise prevents stress-induced activation of granule neurons and enhances local inhibitory mechanisms in the dentate gyrus.

    Science.gov (United States)

    Schoenfeld, Timothy J; Rada, Pedro; Pieruzzini, Pedro R; Hsueh, Brian; Gould, Elizabeth

    2013-05-01

    Physical exercise is known to reduce anxiety. The ventral hippocampus has been linked to anxiety regulation but the effects of running on this subregion of the hippocampus have been incompletely explored. Here, we investigated the effects of cold water stress on the hippocampus of sedentary and runner mice and found that while stress increases expression of the protein products of the immediate early genes c-fos and arc in new and mature granule neurons in sedentary mice, it has no such effect in runners. We further showed that running enhances local inhibitory mechanisms in the hippocampus, including increases in stress-induced activation of hippocampal interneurons, expression of vesicular GABA transporter (vGAT), and extracellular GABA release during cold water swim stress. Finally, blocking GABAA receptors in the ventral hippocampus, but not the dorsal hippocampus, with the antagonist bicuculline, reverses the anxiolytic effect of running. Together, these results suggest that running improves anxiety regulation by engaging local inhibitory mechanisms in the ventral hippocampus.

  4. Distributed dendritic processing facilitates object detection: a computational analysis on the visual system of the fly.

    Science.gov (United States)

    Hennig, Patrick; Möller, Ralf; Egelhaaf, Martin

    2008-08-28

    Detecting objects is an important task when moving through a natural environment. Flies, for example, may land on salient objects or may avoid collisions with them. The neuronal ensemble of Figure Detection cells (FD-cells) in the visual system of the fly is likely to be involved in controlling these behaviours, as these cells are more sensitive to objects than to extended background structures. Until now the computations in the presynaptic neuronal network of FD-cells and, in particular, the functional significance of the experimentally established distributed dendritic processing of excitatory and inhibitory inputs is not understood. We use model simulations to analyse the neuronal computations responsible for the preference of FD-cells for small objects. We employed a new modelling approach which allowed us to account for the spatial spread of electrical signals in the dendrites while avoiding detailed compartmental modelling. The models are based on available physiological and anatomical data. Three models were tested each implementing an inhibitory neural circuit, but differing by the spatial arrangement of the inhibitory interaction. Parameter optimisation with an evolutionary algorithm revealed that only distributed dendritic processing satisfies the constraints arising from electrophysiological experiments. In contrast to a direct dendro-dendritic inhibition of the FD-cell (Direct Distributed Inhibition model), an inhibition of its presynaptic retinotopic elements (Indirect Distributed Inhibition model) requires smaller changes in input resistance in the inhibited neurons during visual stimulation. Distributed dendritic inhibition of retinotopic elements as implemented in our Indirect Distributed Inhibition model is the most plausible wiring scheme for the neuronal circuit of FD-cells. This microcircuit is computationally similar to lateral inhibition between the retinotopic elements. Hence, distributed inhibition might be an alternative explanation of

  5. Bistability Analysis of Excitatory-Inhibitory Neural Networks in Limited-Sustained-Activity Regime

    International Nuclear Information System (INIS)

    Ni Yun; Wu Liang; Wu Dan; Zhu Shiqun

    2011-01-01

    Bistable behavior of neuronal complex networks is investigated in the limited-sustained-activity regime when the network is composed of excitatory and inhibitory neurons. The standard stability analysis is performed on the two metastable states separately. Both theoretical analysis and numerical simulations show consistently that the difference between time scales of excitatory and inhibitory populations can influence the dynamical behaviors of the neuronal networks dramatically, leading to the transition from bistable behaviors with memory effects to the collapse of bistable behaviors. These results may suggest one possible neuronal information processing by only tuning time scales. (interdisciplinary physics and related areas of science and technology)

  6. Neuronal variability during handwriting: lognormal distribution.

    Directory of Open Access Journals (Sweden)

    Valery I Rupasov

    Full Text Available We examined time-dependent statistical properties of electromyographic (EMG signals recorded from intrinsic hand muscles during handwriting. Our analysis showed that trial-to-trial neuronal variability of EMG signals is well described by the lognormal distribution clearly distinguished from the Gaussian (normal distribution. This finding indicates that EMG formation cannot be described by a conventional model where the signal is normally distributed because it is composed by summation of many random sources. We found that the variability of temporal parameters of handwriting--handwriting duration and response time--is also well described by a lognormal distribution. Although, the exact mechanism of lognormal statistics remains an open question, the results obtained should significantly impact experimental research, theoretical modeling and bioengineering applications of motor networks. In particular, our results suggest that accounting for lognormal distribution of EMGs can improve biomimetic systems that strive to reproduce EMG signals in artificial actuators.

  7. Unsupervised discrimination of patterns in spiking neural networks with excitatory and inhibitory synaptic plasticity.

    Science.gov (United States)

    Srinivasa, Narayan; Cho, Youngkwan

    2014-01-01

    A spiking neural network model is described for learning to discriminate among spatial patterns in an unsupervised manner. The network anatomy consists of source neurons that are activated by external inputs, a reservoir that resembles a generic cortical layer with an excitatory-inhibitory (EI) network and a sink layer of neurons for readout. Synaptic plasticity in the form of STDP is imposed on all the excitatory and inhibitory synapses at all times. While long-term excitatory STDP enables sparse and efficient learning of the salient features in inputs, inhibitory STDP enables this learning to be stable by establishing a balance between excitatory and inhibitory currents at each neuron in the network. The synaptic weights between source and reservoir neurons form a basis set for the input patterns. The neural trajectories generated in the reservoir due to input stimulation and lateral connections between reservoir neurons can be readout by the sink layer neurons. This activity is used for adaptation of synapses between reservoir and sink layer neurons. A new measure called the discriminability index (DI) is introduced to compute if the network can discriminate between old patterns already presented in an initial training session. The DI is also used to compute if the network adapts to new patterns without losing its ability to discriminate among old patterns. The final outcome is that the network is able to correctly discriminate between all patterns-both old and new. This result holds as long as inhibitory synapses employ STDP to continuously enable current balance in the network. The results suggest a possible direction for future investigation into how spiking neural networks could address the stability-plasticity question despite having continuous synaptic plasticity.

  8. Coherent and intermittent ensemble oscillations emerge from networks of irregular spiking neurons.

    Science.gov (United States)

    Hoseini, Mahmood S; Wessel, Ralf

    2016-01-01

    Local field potential (LFP) recordings from spatially distant cortical circuits reveal episodes of coherent gamma oscillations that are intermittent, and of variable peak frequency and duration. Concurrently, single neuron spiking remains largely irregular and of low rate. The underlying potential mechanisms of this emergent network activity have long been debated. Here we reproduce such intermittent ensemble oscillations in a model network, consisting of excitatory and inhibitory model neurons with the characteristics of regular-spiking (RS) pyramidal neurons, and fast-spiking (FS) and low-threshold spiking (LTS) interneurons. We find that fluctuations in the external inputs trigger reciprocally connected and irregularly spiking RS and FS neurons in episodes of ensemble oscillations, which are terminated by the recruitment of the LTS population with concurrent accumulation of inhibitory conductance in both RS and FS neurons. The model qualitatively reproduces experimentally observed phase drift, oscillation episode duration distributions, variation in the peak frequency, and the concurrent irregular single-neuron spiking at low rate. Furthermore, consistent with previous experimental studies using optogenetic manipulation, periodic activation of FS, but not RS, model neurons causes enhancement of gamma oscillations. In addition, increasing the coupling between two model networks from low to high reveals a transition from independent intermittent oscillations to coherent intermittent oscillations. In conclusion, the model network suggests biologically plausible mechanisms for the generation of episodes of coherent intermittent ensemble oscillations with irregular spiking neurons in cortical circuits. Copyright © 2016 the American Physiological Society.

  9. Selective deficiencies in descending inhibitory modulation in neuropathic rats: implications for enhancing noradrenergic tone.

    Science.gov (United States)

    Patel, Ryan; Qu, Chaoling; Xie, Jennifer Y; Porreca, Frank; Dickenson, Anthony H

    2018-05-31

    Pontine noradrenergic neurones form part of a descending inhibitory system that influences spinal nociceptive processing. Weak or absent descending inhibition is a common feature of chronic pain patients. We examined the extent to which the descending noradrenergic system is tonically active, how control of spinal neuronal excitability is integrated into thalamic relays within sensory-discriminative projection pathways, and how this inhibitory control is altered after nerve injury. In vivo electrophysiology was performed in anaesthetised spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range neurones in the ventral posterolateral thalamus (VPL). In sham rats, spinal block of α2-adrenoceptors with atipamezole resulted in enhanced stimulus-evoked and spontaneous firing in the VPL, and produced conditioned place avoidance. However, in SNL rats these conditioned avoidance behaviours were absent. Furthermore, inhibitory control of evoked neuronal responses was lost but spinal atipamezole markedly increased spontaneous firing. Augmenting spinal noradrenergic tone in neuropathic rats with reboxetine, a selective noradrenergic reuptake inhibitor, modestly reinstated inhibitory control of evoked responses in the VPL but had no effect on spontaneous firing. In contrast, clonidine, an α2 agonist, inhibited both evoked and spontaneous firing, and exhibited increased potency in SNL rats compared to sham controls. These data suggest descending noradrenergic inhibitory pathways are tonically active in sham rats. Moreover, in neuropathic states descending inhibitory control is diminished, but not completely absent, and distinguishes between spontaneous and evoked neuronal activity. These observations may have implications for how analgesics targeting the noradrenergic system provide relief.

  10. Distribution, structure and projections of the frog intracardiac neurons.

    Science.gov (United States)

    Batulevicius, Darius; Skripkiene, Gertruda; Batuleviciene, Vaida; Skripka, Valdas; Dabuzinskiene, Anita; Pauza, Dainius H

    2012-05-21

    Histochemistry for acetylcholinesterase was used to determine the distribution of intracardiac neurons in the frog Rana temporaria. Seventy-nine intracardiac neurons from 13 frogs were labelled iontophoretically by the intracellular markers Alexa Fluor 568 and Lucifer Yellow CH to determine their structure and projections. Total neuronal number per frog heart was (Mean ± SE) 1374 ± 56. Largest collections of neurons were found in the interatrial septum (46%), atrioventricular junction (25%) and venal sinus (12%). Among the intracellularly labelled neurons, we found the cells of unipolar (71%), multipolar (20%) and bipolar (9%) types. Multiple processes originated from the neuron soma, hillock and proximal axon. These processes projected onto adjacent neuron somata and cardiac muscle fibers within the interatrial septum. Average total length of the processes from proximal axon was 348 ± 50 μm. Average total length of processes from soma and hillock was less, 118 ± 27 μm and 109 ± 24 μm, respectively. The somata of 59% of neurons had bubble- or flake-shaped extensions. Most neurons from the major nerves in the interatrial septum sent their axons towards the ventricle. In contrast, most neurons from the ventral part of the interatrial septum sent their axons towards the atria. Our findings contradict to a view that the frog intracardiac ganglia contain only non-dendritic neurons of the unipolar type. We conclude that the frog intracardiac neurons are structurally complex and diverse. This diversity may account for the complicated integrative functions of the frog intrinsic cardiac ganglia. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Topographical distribution and morphology of NADPH-diaphorase-stained neurons in the human claustrum

    Science.gov (United States)

    Hinova-Palova, Dimka V.; Edelstein, Lawrence; Landzhov, Boycho; Minkov, Minko; Malinova, Lina; Hristov, Stanislav; Denaro, Frank J.; Alexandrov, Alexandar; Kiriakova, Teodora; Brainova, Ilina; Paloff, Adrian; Ovtscharoff, Wladimir

    2014-01-01

    We studied the topographical distribution and morphological characteristics of NADPH-diaphorase-positive neurons and fibers in the human claustrum. These neurons were seen to be heterogeneously distributed throughout the claustrum. Taking into account the size and shape of stained perikarya as well as dendritic and axonal characteristics, Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPHd)-positive neurons were categorized by diameter into three types: large, medium and small. Large neurons ranged from 25 to 35 μm in diameter and typically displayed elliptical or multipolar cell bodies. Medium neurons ranged from 20 to 25 μm in diameter and displayed multipolar, bipolar and irregular cell bodies. Small neurons ranged from 14 to 20 μm in diameter and most often displayed oval or elliptical cell bodies. Based on dendritic characteristics, these neurons were divided into spiny and aspiny subtypes. Our findings reveal two populations of NADPHd-positive neurons in the human claustrum—one comprised of large and medium cells consistent with a projection neuron phenotype, the other represented by small cells resembling the interneuron phenotype as defined by previous Golgi impregnation studies. PMID:24904317

  12. Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons.

    Science.gov (United States)

    Fujimoto, Takahiro; Itoh, Kyoko; Yaoi, Takeshi; Fushiki, Shinji

    2014-09-12

    The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remain unknown. In this study, we generated a polyclonal antibody against the NH2-terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Inhibitory coupling between inhibitory interneurons in the spinal cord dorsal horn

    Directory of Open Access Journals (Sweden)

    Ribeiro-da-Silva Alfredo

    2009-05-01

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

  14. Different forms of glycine- and GABAA-receptor mediated inhibitory synaptic transmission in mouse superficial and deep dorsal horn neurons

    Directory of Open Access Journals (Sweden)

    Brichta Alan M

    2009-11-01

    Full Text Available Abstract Background Neurons in superficial (SDH and deep (DDH laminae of the spinal cord dorsal horn receive sensory information from skin, muscle, joints and viscera. In both regions, glycine- (GlyR and GABAA-receptors (GABAARs contribute to fast synaptic inhibition. For rat, several types of GABAAR coexist in the two regions and each receptor type provides different contributions to inhibitory tone. Recent work in mouse has discovered an additional type of GlyR, (containing alpha 3 subunits in the SDH. The contribution of differing forms of the GlyR to sensory processing in SDH and DDH is not understood. Methods and Results Here we compare fast inhibitory synaptic transmission in mouse (P17-37 SDH and DDH using patch-clamp electrophysiology in transverse spinal cord slices (L3-L5 segments, 23°C. GlyR-mediated mIPSCs were detected in 74% (25/34 and 94% (25/27 of SDH and DDH neurons, respectively. In contrast, GABAAR-mediated mIPSCs were detected in virtually all neurons in both regions (93%, 14/15 and 100%, 18/18. Several Gly- and GABAAR properties also differed in SDH vs. DDH. GlyR-mediated mIPSC amplitude was smaller (37.1 ± 3.9 vs. 64.7 ± 5.0 pA; n = 25 each, decay time was slower (8.5 ± 0.8 vs. 5.5 ± 0.3 ms, and frequency was lower (0.15 ± 0.03 vs. 0.72 ± 0.13 Hz in SDH vs. DDH neurons. In contrast, GABAAR-mediated mIPSCs had similar amplitudes (25.6 ± 2.4, n = 14 vs. 25. ± 2.0 pA, n = 18 and frequencies (0.21 ± 0.08 vs. 0.18 ± 0.04 Hz in both regions; however, decay times were slower (23.0 ± 3.2 vs. 18.9 ± 1.8 ms in SDH neurons. Mean single channel conductance underlying mIPSCs was identical for GlyRs (54.3 ± 1.6 pS, n = 11 vs. 55.7 ± 1.8, n = 8 and GABAARs (22.7 ± 1.7 pS, n = 10 vs. 22.4 ± 2.0 pS, n = 11 in both regions. We also tested whether the synthetic endocanabinoid, methandamide (methAEA, had direct effects on Gly- and GABAARs in each spinal cord region. MethAEA (5 μM reduced GlyR-mediated mIPSC frequency in SDH

  15. Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons

    Energy Technology Data Exchange (ETDEWEB)

    Fujimoto, Takahiro; Itoh, Kyoko, E-mail: kxi14@koto.kpu-m.ac.jp; Yaoi, Takeshi; Fushiki, Shinji

    2014-09-12

    Highlights: • Identification of dystrophin (Dp) shortest isoform, Dp40, is a neuron-type Dp. • Dp40 expression is temporally and differentially regulated in comparison to Dp71. • Somatodendritic and nuclear localization of Dp40. • Dp40 is localized to excitatory postsynapses. • Dp40 might play roles in dendritic and synaptic functions. - Abstract: The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remain unknown. In this study, we generated a polyclonal antibody against the NH{sub 2}-terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions.

  16. Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons

    International Nuclear Information System (INIS)

    Fujimoto, Takahiro; Itoh, Kyoko; Yaoi, Takeshi; Fushiki, Shinji

    2014-01-01

    Highlights: • Identification of dystrophin (Dp) shortest isoform, Dp40, is a neuron-type Dp. • Dp40 expression is temporally and differentially regulated in comparison to Dp71. • Somatodendritic and nuclear localization of Dp40. • Dp40 is localized to excitatory postsynapses. • Dp40 might play roles in dendritic and synaptic functions. - Abstract: The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remain unknown. In this study, we generated a polyclonal antibody against the NH 2 -terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions

  17. Reciprocal inhibition between motor neurons of the tibialis anterior and triceps surae in humans.

    Science.gov (United States)

    Yavuz, Utku Ş; Negro, Francesco; Diedrichs, Robin; Farina, Dario

    2018-05-01

    Motor neurons innervating antagonist muscles receive reciprocal inhibitory afferent inputs to facilitate the joint movement in the two directions. The present study investigates the mutual transmission of reciprocal inhibitory afferent inputs between the tibialis anterior (TA) and triceps surae (soleus and medial gastrocnemius) motor units. We assessed this mutual mechanism in large populations of motor units for building a statistical distribution of the inhibition amplitudes during standardized input to the motor neuron pools to minimize the effect of modulatory pathways. Single motor unit activities were identified using high-density surface electromyography (HDsEMG) recorded from the TA, soleus (Sol), and medial gastrocnemius (GM) muscles during isometric dorsi- and plantarflexion. Reciprocal inhibition on the antagonist muscle was elicited by electrical stimulation of the tibial (TN) or common peroneal nerves (CPN). The probability density distributions of reflex strength for each muscle were estimated to examine the strength of mutual transmission of reciprocal inhibitory input. The results showed that the strength of reciprocal inhibition in the TA motor units was fourfold greater than for the GM and the Sol motor units. This suggests an asymmetric transmission of reciprocal inhibition between ankle extensor and flexor muscles. This asymmetry cannot be explained by differences in motor unit type composition between the investigated muscles since we sampled low-threshold motor units in all cases. Therefore, the differences observed for the strength of inhibition are presumably due to a differential reciprocal spindle afferent input and the relative contribution of nonreciprocal inhibitory pathways. NEW & NOTEWORTHY We investigated the mutual transmission of reciprocal inhibition in large samples of motor units using a standardized input (electrical stimulation) to the motor neurons. The results demonstrated that the disynaptic reciprocal inhibition exerted

  18. GABA-ergic neurons in the leach central nervous system

    International Nuclear Information System (INIS)

    Cline, H.T.

    1985-01-01

    GABA is a candidate for an inhibitory neurotransmitter in the leech central nervous system because of the well-documented inhibitory action of GABA in other invertebrates. To demonstrate that GABA meets the criteria used to identify a substance as a neurotransmitter, the author examined GABA metabolism and synaptic interactions of inhibitory motor neurons in two leech species, Hirudo medicinalis and Haementeria ghilianii. Segmental ganglia of the leech ventral nerve cord and identified inhibitors have the capacity to synthesize GABA when incubated in the presence of the precursor glutamate. Application of GABA to cell bodies of excitatory motor neurons or muscle fibers innervated by the inhibitors hyperpolarizes the membrane potential of the target cell and activates a chloride ion conductance channel, similar to the inhibitory membrane response following intracellular stimulation of the inhibitor. Bicuculline methiodide (5 x 10 -5 M), GABA receptor antagonist, blocks reversibly the response to applied GABA and the inhibitory synaptic inputs onto the postsynaptic neurons or muscle fibers without interfering with their excitatory inputs. Furthermore, the inhibitors are included among approximately 25 neurons per segmental ganglion that take up GABA by a high affinity uptake system, as revealed by 3 H-GABA-autoradiography. The development of the capacities to synthesize and to take up GABA were examined in leech embryos. The embryos are able to synthesize GABA at early stages of the development of the nervous system, before any neurons have extended neutrites

  19. Optogenetic identification of hypothalamic orexin neuron projections to paraventricular spinally projecting neurons.

    Science.gov (United States)

    Dergacheva, Olga; Yamanaka, Akihiro; Schwartz, Alan R; Polotsky, Vsevolod Y; Mendelowitz, David

    2017-04-01

    Orexin neurons, and activation of orexin receptors, are generally thought to be sympathoexcitatory; however, the functional connectivity between orexin neurons and a likely sympathetic target, the hypothalamic spinally projecting neurons (SPNs) in the paraventricular nucleus of the hypothalamus (PVN) has not been established. To test the hypothesis that orexin neurons project directly to SPNs in the PVN, channelrhodopsin-2 (ChR2) was selectively expressed in orexin neurons to enable photoactivation of ChR2-expressing fibers while examining evoked postsynaptic currents in SPNs in rat hypothalamic slices. Selective photoactivation of orexin fibers elicited short-latency postsynaptic currents in all SPNs tested ( n = 34). These light-triggered responses were heterogeneous, with a majority being excitatory glutamatergic responses (59%) and a minority of inhibitory GABAergic (35%) and mixed glutamatergic and GABAergic currents (6%). Both glutamatergic and GABAergic responses were present in the presence of tetrodotoxin and 4-aminopyridine, suggesting a monosynaptic connection between orexin neurons and SPNs. In addition to generating postsynaptic responses, photostimulation facilitated action potential firing in SPNs (current clamp configuration). Glutamatergic, but not GABAergic, postsynaptic currents were diminished by application of the orexin receptor antagonist almorexant, indicating orexin release facilitates glutamatergic neurotransmission in this pathway. This work identifies a neuronal circuit by which orexin neurons likely exert sympathoexcitatory control of cardiovascular function. NEW & NOTEWORTHY This is the first study to establish, using innovative optogenetic approaches in a transgenic rat model, that there are robust heterogeneous projections from orexin neurons to paraventricular spinally projecting neurons, including excitatory glutamatergic and inhibitory GABAergic neurotransmission. Endogenous orexin release modulates glutamatergic, but not

  20. Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.

    Science.gov (United States)

    Weston, Matthew C; Chen, Hongmei; Swann, John W

    2014-01-01

    The Pten and Tsc1 genes both encode proteins that repress mechanistic target of rapamycin (mTOR) signaling. Disruption of either gene in the brain results in epilepsy and autism-like symptoms in humans and mouse models, therefore it is important to understand the molecular and physiological events that lead from gene disruption to disease phenotypes. Given the similar roles these two molecules play in the regulation of cellular growth and the overlap in the phenotypes that result from their loss, we predicted that the deletion of either the Pten or Tsc1 gene from autaptic hippocampal neurons would have similar effects on neuronal morphology and synaptic transmission. Accordingly, we found that loss of either Pten or Tsc1 caused comparable increases in soma size, dendrite length and action potential properties. However, the effects of Pten and Tsc1 loss on synaptic transmission were different. Loss of Pten lead to an increase in both excitatory and inhibitory neurotransmission, while loss of Tsc1 did not affect excitatory neurotransmission and reduced inhibitory transmission by decreasing mIPSC amplitude. Although the loss of Pten or Tsc1 both increased downstream mTORC1 signaling, phosphorylation of Akt was increased in Pten-ko and decreased in Tsc1-ko neurons, potentially accounting for the different effects on synaptic transmission. Despite the different effects at the synaptic level, our data suggest that loss of Pten or Tsc1 may both lead to an increase in the ratio of excitation to inhibition at the network level, an effect that has been proposed to underlie both epilepsy and autism.

  1. How pattern formation in ring networks of excitatory and inhibitory spiking neurons depends on the input current regime.

    Science.gov (United States)

    Kriener, Birgit; Helias, Moritz; Rotter, Stefan; Diesmann, Markus; Einevoll, Gaute T

    2013-01-01

    Pattern formation, i.e., the generation of an inhomogeneous spatial activity distribution in a dynamical system with translation invariant structure, is a well-studied phenomenon in neuronal network dynamics, specifically in neural field models. These are population models to describe the spatio-temporal dynamics of large groups of neurons in terms of macroscopic variables such as population firing rates. Though neural field models are often deduced from and equipped with biophysically meaningful properties, a direct mapping to simulations of individual spiking neuron populations is rarely considered. Neurons have a distinct identity defined by their action on their postsynaptic targets. In its simplest form they act either excitatorily or inhibitorily. When the distribution of neuron identities is assumed to be periodic, pattern formation can be observed, given the coupling strength is supracritical, i.e., larger than a critical weight. We find that this critical weight is strongly dependent on the characteristics of the neuronal input, i.e., depends on whether neurons are mean- or fluctuation driven, and different limits in linearizing the full non-linear system apply in order to assess stability. In particular, if neurons are mean-driven, the linearization has a very simple form and becomes independent of both the fixed point firing rate and the variance of the input current, while in the very strongly fluctuation-driven regime the fixed point rate, as well as the input mean and variance are important parameters in the determination of the critical weight. We demonstrate that interestingly even in "intermediate" regimes, when the system is technically fluctuation-driven, the simple linearization neglecting the variance of the input can yield the better prediction of the critical coupling strength. We moreover analyze the effects of structural randomness by rewiring individual synapses or redistributing weights, as well as coarse-graining on the formation of

  2. Sleep: The hebbian reinforcement of the local inhibitory synapses.

    Science.gov (United States)

    Touzet, Claude

    2015-09-01

    Sleep is ubiquitous among the animal realm, and represents about 30% of our lives. Despite numerous efforts, the reason behind our need for sleep is still unknown. The Theory of neuronal Cognition (TnC) proposes that sleep is the period of time during which the local inhibitory synapses (in particular the cortical ones) are replenished. Indeed, as long as the active brain stays awake, hebbian learning guarantees that efficient inhibitory synapses lose their efficiency – just because they are efficient at avoiding the activation of the targeted neurons. Since hebbian learning is the only known mechanism of synapse modification, it follows that to replenish the inhibitory synapses' efficiency, source and targeted neurons must be activated together. This is achieved by a local depolarization that may travel (wave). The period of time during which such slow waves are experienced has been named the "slow-wave sleep" (SWS). It is cut into several pieces by shorter periods of paradoxical sleep (REM) which activity resembles that of the awake state. Indeed, SWS – because it only allows local neural activation – decreases the excitatory long distance connections strength. To avoid losing the associations built during the awake state, these long distance activations are played again during the REM sleep. REM and SWS sleeps act together to guarantee that when the subject awakes again, his inhibitory synaptic efficiency is restored and his (excitatory) long distance associations are still there. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Itai Hayut

    2011-10-01

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

  4. An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development

    Directory of Open Access Journals (Sweden)

    Xinglong Gu

    2016-01-01

    Full Text Available In the mammalian brain, GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here, we report that NMDA-type ionotropic glutamate receptors (NMDARs in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, whereas GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABAA receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain.

  5. Are dragon-king neuronal avalanches dungeons for self-organized brain activity?

    Science.gov (United States)

    de Arcangelis, L.

    2012-05-01

    Recent experiments have detected a novel form of spontaneous neuronal activity both in vitro and in vivo: neuronal avalanches. The statistical properties of this activity are typical of critical phenomena, with power laws characterizing the distributions of avalanche size and duration. A critical behaviour for the spontaneous brain activity has important consequences on stimulated activity and learning. Very interestingly, these statistical properties can be altered in significant ways in epilepsy and by pharmacological manipulations. In particular, there can be an increase in the number of large events anticipated by the power law, referred to herein as dragon-king avalanches. This behaviour, as verified by numerical models, can originate from a number of different mechanisms. For instance, it is observed experimentally that the emergence of a critical behaviour depends on the subtle balance between excitatory and inhibitory mechanisms acting in the system. Perturbing this balance, by increasing either synaptic excitation or the incidence of depolarized neuronal up-states causes frequent dragon-king avalanches. Conversely, an unbalanced GABAergic inhibition or long periods of low activity in the network give rise to sub-critical behaviour. Moreover, the existence of power laws, common to other stochastic processes, like earthquakes or solar flares, suggests that correlations are relevant in these phenomena. The dragon-king avalanches may then also be the expression of pathological correlations leading to frequent avalanches encompassing all neurons. We will review the statistics of neuronal avalanches in experimental systems. We then present numerical simulations of a neuronal network model introducing within the self-organized criticality framework ingredients from the physiology of real neurons, as the refractory period, synaptic plasticity and inhibitory synapses. The avalanche critical behaviour and the role of dragon-king avalanches will be discussed in

  6. Local connections of layer 5 GABAergic interneurons to corticospinal neurons

    Directory of Open Access Journals (Sweden)

    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. 

  7. Distribution of spinal neuronal networks controlling forward and backward locomotion.

    Science.gov (United States)

    Merkulyeva, Natalia; Veshchitskii, Aleksandr; Gorsky, Oleg; Pavlova, Natalia; Zelenin, Pavel V; Gerasimenko, Yury; Deliagina, Tatiana G; Musienko, Pavel

    2018-04-20

    Higher vertebrates, including humans, are capable not only of forward (FW) locomotion but also of walking in other directions relative to the body axis [backward (BW), sideways, etc.]. While the neural mechanisms responsible for controlling FW locomotion have been studied in considerable detail, the mechanisms controlling steps in other directions are mostly unknown. The aim of the present study was to investigate the distribution of spinal neuronal networks controlling FW and BW locomotion. First, we applied electrical epidural stimulation (ES) to different segments of the spinal cord from L2 to S2 to reveal zones triggering FW and BW locomotion in decerebrate cats of either sex. Second, to determine the location of spinal neurons activated during FW and BW locomotion, we used c-fos immunostaining. We found that the neuronal networks responsible for FW locomotion were distributed broadly in the lumbosacral spinal cord and could be activated by ES of any segment from L3 to S2. By contrast, networks generating BW locomotion were activated by ES of a limited zone from the caudal part of L5 to the caudal part of L7. In the intermediate part of the gray matter within this zone, a significantly higher number of c- fos -positive interneurons was revealed in BW-stepping cats compared with FW-stepping cats. We suggest that this region of the spinal cord contains the network that determines the BW direction of locomotion. Significance Statement Sequential and single steps in various directions relative to the body axis [forward (FW), backward (BW), sideways, etc.] are used during locomotion and to correct for perturbations, respectively. The mechanisms controlling step direction are unknown. In the present study, for the first time we compared the distributions of spinal neuronal networks controlling FW and BW locomotion. Using a marker to visualize active neurons, we demonstrated that in the intermediate part of the gray matter within L6 and L7 spinal segments

  8. Visualizing Metal Content and Intracellular Distribution in Primary Hippocampal Neurons with Synchrotron X-Ray Fluorescence.

    Directory of Open Access Journals (Sweden)

    Robert A Colvin

    Full Text Available Increasing evidence suggests that metal dyshomeostasis plays an important role in human neurodegenerative diseases. Although distinctive metal distributions are described for mature hippocampus and cortex, much less is known about metal levels and intracellular distribution in individual hippocampal neuronal somata. To solve this problem, we conducted quantitative metal analyses utilizing synchrotron radiation X-Ray fluorescence on frozen hydrated primary cultured neurons derived from rat embryonic cortex (CTX and two regions of the hippocampus: dentate gyrus (DG and CA1. Comparing average metal contents showed that the most abundant metals were calcium, iron, and zinc, whereas metals such as copper and manganese were less than 10% of zinc. Average metal contents were generally similar when compared across neurons cultured from CTX, DG, and CA1, except for manganese that was larger in CA1. However, each metal showed a characteristic spatial distribution in individual neuronal somata. Zinc was uniformly distributed throughout the cytosol, with no evidence for the existence of previously identified zinc-enriched organelles, zincosomes. Calcium showed a peri-nuclear distribution consistent with accumulation in endoplasmic reticulum and/or mitochondria. Iron showed 2-3 distinct highly concentrated puncta only in peri-nuclear locations. Notwithstanding the small sample size, these analyses demonstrate that primary cultured neurons show characteristic metal signatures. The iron puncta probably represent iron-accumulating organelles, siderosomes. Thus, the metal distributions observed in mature brain structures are likely the result of both intrinsic neuronal factors that control cellular metal content and extrinsic factors related to the synaptic organization, function, and contacts formed and maintained in each region.

  9. Multivesicular Bodies in Neurons: Distribution, Protein Content, and Trafficking Functions

    Science.gov (United States)

    VON BARTHELD, CHRISTOPHER S.; ALTICK, AMY L.

    2011-01-01

    Summary Multivesicular bodies (MVBs) are intracellular endosomal organelles characterized by multiple internal vesicles that are enclosed within a single outer membrane. MVBs were initially regarded as purely prelysosomal structures along the degradative endosomal pathway of internalized proteins. MVBs are now known to be involved in numerous endocytic and trafficking functions, including protein sorting, recycling, transport, storage, and release. This review of neuronal MVBs summarizes their research history, morphology, distribution, accumulation of cargo and constitutive proteins, transport, and theories of functions of MVBs in neurons and glia. Due to their complex morphologies, neurons have expanded trafficking and signaling needs, beyond those of “geometrically simpler” cells, but it is not known whether neuronal MVBs perform additional transport and signaling functions. This review examines the concept of compartment-specific MVB functions in endosomal protein trafficking and signaling within synapses, axons, dendrites and cell bodies. We critically evaluate reports of the accumulation of neuronal MVBs based on evidence of stress-induced MVB formation. Furthermore, we discuss potential functions of neuronal and glial MVBs in development, in dystrophic neuritic syndromes, injury, disease, and aging. MVBs may play a role in Alzheimer’s, Huntington’s, and Niemann-Pick diseases, some types of frontotemporal dementia, prion and virus trafficking, as well as in adaptive responses of neurons to trauma and toxin or drug exposure. Functions of MVBs in neurons have been much neglected, and major gaps in knowledge currently exist. Developing truly MVB-specific markers would help to elucidate the roles of neuronal MVBs in intra- and intercellular signaling of normal and diseased neurons. PMID:21216273

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

    Science.gov (United States)

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

    2011-01-01

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

  11. Neuronal glycosylation differentials in normal, injured and chondroitinase-treated environments

    International Nuclear Information System (INIS)

    Kilcoyne, Michelle; Sharma, Shashank; McDevitt, Niamh; O’Leary, Claire; Joshi, Lokesh; McMahon, Siobhán S.

    2012-01-01

    Highlights: ► Carbohydrates are important in the CNS and ChABC has been used for spinal cord injury (SCI) treatment. ► Neuronal glycosylation in injury and after ChABC treatment is unknown. ► In silico mining verified that glyco-related genes were differentially regulated after SCI. ► In vitro model system revealed abnormal sialylation in an injured environment. ► The model indicated a return to normal neuronal glycosylation after ChABC treatment. -- Abstract: Glycosylation is found ubiquitously throughout the central nervous system (CNS). Chondroitin sulphate proteoglycans (CSPGs) are a group of molecules heavily substituted with glycosaminoglycans (GAGs) and are found in the extracellular matrix (ECM) and cell surfaces. Upon CNS injury, a glial scar is formed, which is inhibitory for axon regeneration. Several CSPGs are up-regulated within the glial scar, including NG2, and these CSPGs are key inhibitory molecules of axonal regeneration. Treatment with chondroitinase ABC (ChABC) can neutralise the inhibitory nature of NG2. A gene expression dataset was mined in silico to verify differentially regulated glycosylation-related genes in neurons after spinal cord injury and identify potential targets for further investigation. To establish the glycosylation differential of neurons that grow in a healthy, inhibitory and ChABC-treated environment, we established an indirect co-culture system where PC12 neurons were grown with primary astrocytes, Neu7 astrocytes (which overexpress NG2) and Neu7 astrocytes treated with ChABC. After 1, 4 and 8 days culture, lectin cytochemistry of the neurons was performed using five fluorescently-labelled lectins (ECA MAA, PNA, SNA-I and WFA). Usually α-(2,6)-linked sialylation scarcely occurs in the CNS but this motif was observed on the neurons in the injured environment only at day 8. Treatment with ChABC was successful in returning neuronal glycosylation to normal conditions at all timepoints for MAA, PNA and SNA-I staining

  12. Neuronal glycosylation differentials in normal, injured and chondroitinase-treated environments

    Energy Technology Data Exchange (ETDEWEB)

    Kilcoyne, Michelle; Sharma, Shashank [Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland, Galway (Ireland); McDevitt, Niamh; O' Leary, Claire [Anatomy, School of Medicine, National University of Ireland, Galway (Ireland); Joshi, Lokesh [Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland, Galway (Ireland); McMahon, Siobhan S., E-mail: siobhan.mcmahon@nuigalway.ie [Anatomy, School of Medicine, National University of Ireland, Galway (Ireland)

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer Carbohydrates are important in the CNS and ChABC has been used for spinal cord injury (SCI) treatment. Black-Right-Pointing-Pointer Neuronal glycosylation in injury and after ChABC treatment is unknown. Black-Right-Pointing-Pointer In silico mining verified that glyco-related genes were differentially regulated after SCI. Black-Right-Pointing-Pointer In vitro model system revealed abnormal sialylation in an injured environment. Black-Right-Pointing-Pointer The model indicated a return to normal neuronal glycosylation after ChABC treatment. -- Abstract: Glycosylation is found ubiquitously throughout the central nervous system (CNS). Chondroitin sulphate proteoglycans (CSPGs) are a group of molecules heavily substituted with glycosaminoglycans (GAGs) and are found in the extracellular matrix (ECM) and cell surfaces. Upon CNS injury, a glial scar is formed, which is inhibitory for axon regeneration. Several CSPGs are up-regulated within the glial scar, including NG2, and these CSPGs are key inhibitory molecules of axonal regeneration. Treatment with chondroitinase ABC (ChABC) can neutralise the inhibitory nature of NG2. A gene expression dataset was mined in silico to verify differentially regulated glycosylation-related genes in neurons after spinal cord injury and identify potential targets for further investigation. To establish the glycosylation differential of neurons that grow in a healthy, inhibitory and ChABC-treated environment, we established an indirect co-culture system where PC12 neurons were grown with primary astrocytes, Neu7 astrocytes (which overexpress NG2) and Neu7 astrocytes treated with ChABC. After 1, 4 and 8 days culture, lectin cytochemistry of the neurons was performed using five fluorescently-labelled lectins (ECA MAA, PNA, SNA-I and WFA). Usually {alpha}-(2,6)-linked sialylation scarcely occurs in the CNS but this motif was observed on the neurons in the injured environment only at day 8. Treatment

  13. Anatomical distribution of estrogen target neurons in turtle brain

    International Nuclear Information System (INIS)

    Kim, Y.S.; Stumpf, W.E.; Sar, M.

    1981-01-01

    Autoradiographic studies with [ 3 H]estradiol-17β in red-eared turtle (Pseudemys scripta elegans) show concentration and retention of radioactivity in nuclei of neurons in certain regions. Accumulations of estrogen target neurons exist in the periventricular brain with relationships to ventral extensions of the forebrain ventricles, including parolfactory, amygdaloid, septal, preoptic, hypothalamic and thalamic areas, as well as the dorsal ventricular ridge, the piriform cortex, and midbrain-pontine periaqueductal structures. The general anatomical pattern of distribution of estrogen target neurons corresponds to those observed not only in another reptile (Anolis carolinensis), but also in birds and mammals, as well as in teleosts and cyclostomes. In Pseudemys, which appears to display an intermediate degree of phylogenetic differentiation, the amygdaloid-septal-preoptic groups of estrogen target neurons constitute a continuum. In phylogenetic ascendency, e.g. in mammals, these cell populations are increasingly separated and distinct, while in phylogenetic descendency, e.g. in teleosts and cyclostomes, an amygdaloid group appears to be absent or contained within the septal-preoptic target cell population. (Auth.)

  14. Anatomical distribution of estrogen target neurons in turtle brain

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Y.S.; Stumpf, W.E.; Sar, M. (North Carolina Univ., Chapel Hill (USA))

    1981-12-28

    Autoradiographic studies with (/sup 3/H)estradiol-17..beta.. in red-eared turtle (Pseudemys scripta elegans) show concentration and retention of radioactivity in nuclei of neurons in certain regions. Accumulations of estrogen target neurons exist in the periventricular brain with relationships to ventral extensions of the forebrain ventricles, including parolfactory, amygdaloid, septal, preoptic, hypothalamic and thalamic areas, as well as the dorsal ventricular ridge, the piriform cortex, and midbrain-pontine periaqueductal structures. The general anatomical pattern of distribution of estrogen target neurons corresponds to those observed not only in another reptile (Anolis carolinensis), but also in birds and mammals, as well as in teleosts and cyclostomes. In Pseudemys, which appears to display an intermediate degree of phylogenetic differentiation, the amygdaloid-septal-preoptic groups of estrogen target neurons constitute a continuum. In phylogenetic ascendency, e.g. in mammals, these cell populations are increasingly separated and distinct, while in phylogenetic descendency, e.g. in teleosts and cyclostomes, an amygdaloid group appears to be absent or contained within the septal-preoptic target cell population.

  15. An investigation into the inhibitory function of serotonin in diffuse noxious inhibitory controls in the neuropathic rat.

    Science.gov (United States)

    Bannister, K; Lockwood, S; Goncalves, L; Patel, R; Dickenson, A H

    2017-04-01

    Following neuropathy α2-adrenoceptor-mediated diffuse noxious inhibitory controls (DNIC), whereby a noxious conditioning stimulus inhibits the activity of spinal wide dynamic range (WDR) neurons, are abolished, and spinal 5-HT7 receptor densities are increased. Here, we manipulate spinal 5-HT content in spinal nerve ligated (SNL) animals and investigate which 5-HT receptor mediated actions predominate. Using in vivo electrophysiology we recorded WDR neuronal responses to von frey filaments applied to the hind paw before, and concurrent to, a noxious ear pinch (the conditioning stimulus) in isoflurane-anaesthetised rats. The expression of DNIC was quantified as a reduction in WDR neuronal firing in the presence of conditioning stimulus and was investigated in SNL rats following spinal application of (1) selective serotonin reuptake inhibitors (SSRIs) citalopram or fluoxetine, or dual application of (2) SSRI plus 5-HT7 receptor antagonist SB269970, or (3) SSRI plus α2 adrenoceptor antagonist atipamezole. DNIC were revealed in SNL animals following spinal application of SSRI, but this effect was abolished upon joint application of SSRI plus SB269970 or atipamezole. We propose that in SNL animals the inhibitory actions (quantified as the presence of DNIC) of excess spinal 5-HT (presumed present following application of SSRI) were mediated via 5-HT7 receptors. The anti-nociception depends upon an underlying tonic noradrenergic inhibitory tone via the α2-adrenoceptor. Following neuropathy enhanced spinal serotonin availability switches the predominant spinal 5-HT receptor-mediated actions but also alters noradrenergic signalling. We highlight the therapeutic complexity of SSRIs and monoamine modulators for the treatment of neuropathic pain. © 2016 European Pain Federation - EFIC®.

  16. Pulsed neural networks consisting of single-flux-quantum spiking neurons

    International Nuclear Information System (INIS)

    Hirose, T.; Asai, T.; Amemiya, Y.

    2007-01-01

    An inhibitory pulsed neural network was developed for brain-like information processing, by using single-flux-quantum (SFQ) circuits. It consists of spiking neuron devices that are coupled to each other through all-to-all inhibitory connections. The network selects neural activity. The operation of the neural network was confirmed by computer simulation. SFQ neuron devices can imitate the operation of the inhibition phenomenon of neural networks

  17. Parallel prefrontal pathways reach distinct excitatory and inhibitory systems in memory-related rhinal cortices.

    Science.gov (United States)

    Bunce, Jamie G; Zikopoulos, Basilis; Feinberg, Marcia; Barbas, Helen

    2013-12-15

    To investigate how prefrontal cortices impinge on medial temporal cortices we labeled pathways from the anterior cingulate cortex (ACC) and posterior orbitofrontal cortex (pOFC) in rhesus monkeys to compare their relationship with excitatory and inhibitory systems in rhinal cortices. The ACC pathway terminated mostly in areas 28 and 35 with a high proportion of large terminals, whereas the pOFC pathway terminated mostly through small terminals in area 36 and sparsely in areas 28 and 35. Both pathways terminated in all layers. Simultaneous labeling of pathways and distinct neurochemical classes of inhibitory neurons, followed by analyses of appositions of presynaptic and postsynaptic fluorescent signal, or synapses, showed overall predominant association with spines of putative excitatory neurons, but also significant interactions with presumed inhibitory neurons labeled for calretinin, calbindin, or parvalbumin. In the upper layers of areas 28 and 35 the ACC pathway was associated with dendrites of neurons labeled with calretinin, which are thought to disinhibit neighboring excitatory neurons, suggesting facilitated hippocampal access. In contrast, in area 36 pOFC axons were associated with dendrites of calbindin neurons, which are poised to reduce noise and enhance signal. In the deep layers, both pathways innervated mostly dendrites of parvalbumin neurons, which strongly inhibit neighboring excitatory neurons, suggesting gating of hippocampal output to other cortices. These findings suggest that the ACC, associated with attention and context, and the pOFC, associated with emotional valuation, have distinct contributions to memory in rhinal cortices, in processes that are disrupted in psychiatric diseases. Copyright © 2013 Wiley Periodicals, Inc.

  18. Generation of functional inhibitory synapses incorporating defined combinations of GABA(A or glycine receptor subunits

    Directory of Open Access Journals (Sweden)

    Christine Laura Dixon

    2015-12-01

    Full Text Available Fast inhibitory neurotransmission in the brain is mediated by wide range of GABAA receptor (GABAAR and glycine receptor (GlyR isoforms, each with different physiological and pharmacological properties. Because multiple isoforms are expressed simultaneously in most neurons, it is difficult to define the properties of inhibitory postsynaptic currents mediated by individual isoforms in vivo. Although recombinant expression systems permit the expression of individual isoforms in isolation, they require exogenous agonist application which cannot mimic the dynamic neurotransmitter profile characteristic of native synapses. We describe a neuron-HEK293 cell co-culture technique for generating inhibitory synapses incorporating defined combinations of GABAAR or GlyR subunits. Primary neuronal cultures, prepared from embryonic rat cerebral cortex or spinal cord, are used to provide presynaptic GABAergic and glycinergic terminals, respectively. When the cultures are mature, HEK293 cells expressing the subunits of interest plus neuroligin 2A are plated onto the neurons, which rapidly form synapses onto HEK293 cells. Patch clamp electrophysiology is then used to analyze the physiological and pharmacological properties of the inhibitory postsynaptic currents mediated by the recombinant receptors. The method is suitable for investigating the kinetic properties or the effects of drugs on inhibitory postsynaptic currents mediated by defined GABAAR or GlyR isoforms of interest, the effects of hereditary disease mutations on the formation and function of both types of synapses, and synaptogenesis and synaptic clustering mechanisms. The entire cell preparation procedure takes 2 – 5 weeks.

  19. Network and neuronal membrane properties in hybrid networks reciprocally regulate selectivity to rapid thalamocortical inputs.

    Science.gov (United States)

    Pesavento, Michael J; Pinto, David J

    2012-11-01

    Rapidly changing environments require rapid processing from sensory inputs. Varying deflection velocities of a rodent's primary facial vibrissa cause varying temporal neuronal activity profiles within the ventral posteromedial thalamic nucleus. Local neuron populations in a single somatosensory layer 4 barrel transform sparsely coded input into a spike count based on the input's temporal profile. We investigate this transformation by creating a barrel-like hybrid network with whole cell recordings of in vitro neurons from a cortical slice preparation, embedding the biological neuron in the simulated network by presenting virtual synaptic conductances via a conductance clamp. Utilizing the hybrid network, we examine the reciprocal network properties (local excitatory and inhibitory synaptic convergence) and neuronal membrane properties (input resistance) by altering the barrel population response to diverse thalamic input. In the presence of local network input, neurons are more selective to thalamic input timing; this arises from strong feedforward inhibition. Strongly inhibitory (damping) network regimes are more selective to timing and less selective to the magnitude of input but require stronger initial input. Input selectivity relies heavily on the different membrane properties of excitatory and inhibitory neurons. When inhibitory and excitatory neurons had identical membrane properties, the sensitivity of in vitro neurons to temporal vs. magnitude features of input was substantially reduced. Increasing the mean leak conductance of the inhibitory cells decreased the network's temporal sensitivity, whereas increasing excitatory leak conductance enhanced magnitude sensitivity. Local network synapses are essential in shaping thalamic input, and differing membrane properties of functional classes reciprocally modulate this effect.

  20. Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit

    Directory of Open Access Journals (Sweden)

    Lisa eMapelli

    2015-05-01

    Full Text Available The way long-term potentiation (LTP and depression (LTD are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network , in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei and correspondingly regulate the function of their three main neurons: granule cells (GrCs, Purkinje cells (PCs and deep cerebellar nuclear (DCN cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

  1. Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

    Science.gov (United States)

    Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

    2015-01-01

    The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

  2. Three-dimensional distribution of sensory stimulation-evoked neuronal activity of spinal dorsal horn neurons analyzed by in vivo calcium imaging.

    Science.gov (United States)

    Nishida, Kazuhiko; Matsumura, Shinji; Taniguchi, Wataru; Uta, Daisuke; Furue, Hidemasa; Ito, Seiji

    2014-01-01

    The spinal dorsal horn comprises heterogeneous populations of interneurons and projection neurons, which form neuronal circuits crucial for processing of primary sensory information. Although electrophysiological analyses have uncovered sensory stimulation-evoked neuronal activity of various spinal dorsal horn neurons, monitoring these activities from large ensembles of neurons is needed to obtain a comprehensive view of the spinal dorsal horn circuitry. In the present study, we established in vivo calcium imaging of multiple spinal dorsal horn neurons by using a two-photon microscope and extracted three-dimensional neuronal activity maps of these neurons in response to cutaneous sensory stimulation. For calcium imaging, a fluorescence resonance energy transfer (FRET)-based calcium indicator protein, Yellow Cameleon, which is insensitive to motion artifacts of living animals was introduced into spinal dorsal horn neurons by in utero electroporation. In vivo calcium imaging following pinch, brush, and heat stimulation suggests that laminar distribution of sensory stimulation-evoked neuronal activity in the spinal dorsal horn largely corresponds to that of primary afferent inputs. In addition, cutaneous pinch stimulation elicited activities of neurons in the spinal cord at least until 2 spinal segments away from the central projection field of primary sensory neurons responsible for the stimulated skin point. These results provide a clue to understand neuronal processing of sensory information in the spinal dorsal horn.

  3. Three-dimensional distribution of sensory stimulation-evoked neuronal activity of spinal dorsal horn neurons analyzed by in vivo calcium imaging.

    Directory of Open Access Journals (Sweden)

    Kazuhiko Nishida

    Full Text Available The spinal dorsal horn comprises heterogeneous populations of interneurons and projection neurons, which form neuronal circuits crucial for processing of primary sensory information. Although electrophysiological analyses have uncovered sensory stimulation-evoked neuronal activity of various spinal dorsal horn neurons, monitoring these activities from large ensembles of neurons is needed to obtain a comprehensive view of the spinal dorsal horn circuitry. In the present study, we established in vivo calcium imaging of multiple spinal dorsal horn neurons by using a two-photon microscope and extracted three-dimensional neuronal activity maps of these neurons in response to cutaneous sensory stimulation. For calcium imaging, a fluorescence resonance energy transfer (FRET-based calcium indicator protein, Yellow Cameleon, which is insensitive to motion artifacts of living animals was introduced into spinal dorsal horn neurons by in utero electroporation. In vivo calcium imaging following pinch, brush, and heat stimulation suggests that laminar distribution of sensory stimulation-evoked neuronal activity in the spinal dorsal horn largely corresponds to that of primary afferent inputs. In addition, cutaneous pinch stimulation elicited activities of neurons in the spinal cord at least until 2 spinal segments away from the central projection field of primary sensory neurons responsible for the stimulated skin point. These results provide a clue to understand neuronal processing of sensory information in the spinal dorsal horn.

  4. Dopaminergic neurons encode a distributed, asymmetric representation of temperature in Drosophila.

    Science.gov (United States)

    Tomchik, Seth M

    2013-01-30

    Dopaminergic circuits modulate a wide variety of innate and learned behaviors in animals, including olfactory associative learning, arousal, and temperature-preference behavior. It is not known whether distinct or overlapping sets of dopaminergic neurons modulate these behaviors. Here, I have functionally characterized the dopaminergic circuits innervating the Drosophila mushroom body with in vivo calcium imaging and conditional silencing of genetically defined subsets of neurons. Distinct subsets of PPL1 dopaminergic neurons innervating the vertical lobes of the mushroom body responded to decreases in temperature, but not increases, with rapidly adapting bursts of activity. PAM neurons innervating the horizontal lobes did not respond to temperature shifts. Ablation of the antennae and maxillary palps reduced, but did not eliminate, the responses. Genetic silencing of dopaminergic neurons innervating the vertical mushroom body lobes substantially reduced behavioral cold avoidance, but silencing smaller subsets of these neurons had no effect. These data demonstrate that overlapping dopaminergic circuits encode a broadly distributed, asymmetric representation of temperature that overlays regions implicated previously in learning, memory, and forgetting. Thus, diverse behaviors engage overlapping sets of dopaminergic neurons that encode multimodal stimuli and innervate a single anatomical target, the mushroom body.

  5. Orexin neurons receive glycinergic innervations.

    Directory of Open Access Journals (Sweden)

    Mari Hondo

    Full Text Available Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation.

  6. Role of inhibitory feedback for information processing in thalamocortical circuits

    International Nuclear Information System (INIS)

    Mayer, Joerg; Schuster, Heinz Georg; Claussen, Jens Christian

    2006-01-01

    The information transfer in the thalamus is blocked dynamically during sleep, in conjunction with the occurrence of spindle waves. In order to describe the dynamic mechanisms which control the sensory transfer of information, it is necessary to have a qualitative model for the response properties of thalamic neurons. As the theoretical understanding of the mechanism remains incomplete, we analyze two modeling approaches for a recent experiment by Le Masson et al. [Nature (London) 417, 854 (2002)] on the thalamocortical loop. We use a conductance based model in order to motivate an extension of the Hindmarsh-Rose model, which mimics experimental observations of Le Masson et al. Typically, thalamic neurons posses two different firing modes, depending on their membrane potential. At depolarized potentials, the cells fire in a single spike mode and relay synaptic inputs in a one-to-one manner to the cortex. If the cell gets hyperpolarized, T-type calcium currents generate burst-mode firing which leads to a decrease in the spike transfer. In thalamocortical circuits, the cell membrane gets hyperpolarized by recurrent inhibitory feedback loops. In the case of reciprocally coupled excitatory and inhibitory neurons, inhibitory feedback leads to metastable self-sustained oscillations, which mask the incoming input, and thereby reduce the information transfer significantly

  7. Intrinsically-generated fluctuating activity in excitatory-inhibitory networks

    Science.gov (United States)

    Mastrogiuseppe, Francesca; Ostojic, Srdjan

    2017-01-01

    Recurrent networks of non-linear units display a variety of dynamical regimes depending on the structure of their synaptic connectivity. A particularly remarkable phenomenon is the appearance of strongly fluctuating, chaotic activity in networks of deterministic, but randomly connected rate units. How this type of intrinsically generated fluctuations appears in more realistic networks of spiking neurons has been a long standing question. To ease the comparison between rate and spiking networks, recent works investigated the dynamical regimes of randomly-connected rate networks with segregated excitatory and inhibitory populations, and firing rates constrained to be positive. These works derived general dynamical mean field (DMF) equations describing the fluctuating dynamics, but solved these equations only in the case of purely inhibitory networks. Using a simplified excitatory-inhibitory architecture in which DMF equations are more easily tractable, here we show that the presence of excitation qualitatively modifies the fluctuating activity compared to purely inhibitory networks. In presence of excitation, intrinsically generated fluctuations induce a strong increase in mean firing rates, a phenomenon that is much weaker in purely inhibitory networks. Excitation moreover induces two different fluctuating regimes: for moderate overall coupling, recurrent inhibition is sufficient to stabilize fluctuations; for strong coupling, firing rates are stabilized solely by the upper bound imposed on activity, even if inhibition is stronger than excitation. These results extend to more general network architectures, and to rate networks receiving noisy inputs mimicking spiking activity. Finally, we show that signatures of the second dynamical regime appear in networks of integrate-and-fire neurons. PMID:28437436

  8. Synaptic Plasticity and Spike Synchronisation in Neuronal Networks

    Science.gov (United States)

    Borges, Rafael R.; Borges, Fernando S.; Lameu, Ewandson L.; Protachevicz, Paulo R.; Iarosz, Kelly C.; Caldas, Iberê L.; Viana, Ricardo L.; Macau, Elbert E. N.; Baptista, Murilo S.; Grebogi, Celso; Batista, Antonio M.

    2017-12-01

    Brain plasticity, also known as neuroplasticity, is a fundamental mechanism of neuronal adaptation in response to changes in the environment or due to brain injury. In this review, we show our results about the effects of synaptic plasticity on neuronal networks composed by Hodgkin-Huxley neurons. We show that the final topology of the evolved network depends crucially on the ratio between the strengths of the inhibitory and excitatory synapses. Excitation of the same order of inhibition revels an evolved network that presents the rich-club phenomenon, well known to exist in the brain. For initial networks with considerably larger inhibitory strengths, we observe the emergence of a complex evolved topology, where neurons sparsely connected to other neurons, also a typical topology of the brain. The presence of noise enhances the strength of both types of synapses, but if the initial network has synapses of both natures with similar strengths. Finally, we show how the synchronous behaviour of the evolved network will reflect its evolved topology.

  9. Short-term Synaptic Depression in the Feedforward Inhibitory Circuit in the Dorsal Lateral Geniculate Nucleus.

    Science.gov (United States)

    Augustinaite, Sigita; Heggelund, Paul

    2018-05-24

    Synaptic short-term plasticity (STP) regulates synaptic transmission in an activity-dependent manner and thereby has important roles in the signal processing in the brain. In some synapses, a presynaptic train of action potentials elicits post-synaptic potentials that gradually increase during the train (facilitation), but in other synapses, these potentials gradually decrease (depression). We studied STP in neurons in the visual thalamic relay, the dorsal lateral geniculate nucleus (dLGN). The dLGN contains two types of neurons: excitatory thalamocortical (TC) neurons, which transfer signals from retinal afferents to visual cortex, and local inhibitory interneurons, which form an inhibitory feedforward loop that regulates the thalamocortical signal transmission. The overall STP in the retino-thalamic relay is short-term depression, but the distinct kind and characteristics of the plasticity at the different types of synapses are unknown. We studied STP in the excitatory responses of interneurons to stimulation of retinal afferents, in the inhibitory responses of TC neurons to stimulation of afferents from interneurons, and in the disynaptic inhibitory responses of TC neurons to stimulation of retinal afferents. Moreover, we studied STP at the direct excitatory input to TC neurons from retinal afferents. The STP at all types of the synapses showed short-term depression. This depression can accentuate rapid changes in the stream of signals and thereby promote detectability of significant features in the sensory input. In vision, detection of edges and contours is essential for object perception, and the synaptic short-term depression in the early visual pathway provides important contributions to this detection process. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Age-Related Gene Expression in the Frontal Cortex Suggests Synaptic Function Changes in Specific Inhibitory Neuron Subtypes

    Directory of Open Access Journals (Sweden)

    Leon French

    2017-05-01

    , and suggest age-related synaptic changes in specific inhibitory neuron subtypes.

  11. Inverse stochastic resonance in networks of spiking neurons.

    Science.gov (United States)

    Uzuntarla, Muhammet; Barreto, Ernest; Torres, Joaquin J

    2017-07-01

    Inverse Stochastic Resonance (ISR) is a phenomenon in which the average spiking rate of a neuron exhibits a minimum with respect to noise. ISR has been studied in individual neurons, but here, we investigate ISR in scale-free networks, where the average spiking rate is calculated over the neuronal population. We use Hodgkin-Huxley model neurons with channel noise (i.e., stochastic gating variable dynamics), and the network connectivity is implemented via electrical or chemical connections (i.e., gap junctions or excitatory/inhibitory synapses). We find that the emergence of ISR depends on the interplay between each neuron's intrinsic dynamical structure, channel noise, and network inputs, where the latter in turn depend on network structure parameters. We observe that with weak gap junction or excitatory synaptic coupling, network heterogeneity and sparseness tend to favor the emergence of ISR. With inhibitory coupling, ISR is quite robust. We also identify dynamical mechanisms that underlie various features of this ISR behavior. Our results suggest possible ways of experimentally observing ISR in actual neuronal systems.

  12. 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

  13. Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex.

    Science.gov (United States)

    McGarry, Laura M; Carter, Adam G

    2016-09-07

    Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared

  14. Death and rebirth of neural activity in sparse inhibitory networks

    Science.gov (United States)

    Angulo-Garcia, David; Luccioli, Stefano; Olmi, Simona; Torcini, Alessandro

    2017-05-01

    Inhibition is a key aspect of neural dynamics playing a fundamental role for the emergence of neural rhythms and the implementation of various information coding strategies. Inhibitory populations are present in several brain structures, and the comprehension of their dynamics is strategical for the understanding of neural processing. In this paper, we clarify the mechanisms underlying a general phenomenon present in pulse-coupled heterogeneous inhibitory networks: inhibition can induce not only suppression of neural activity, as expected, but can also promote neural re-activation. In particular, for globally coupled systems, the number of firing neurons monotonically reduces upon increasing the strength of inhibition (neuronal death). However, the random pruning of connections is able to reverse the action of inhibition, i.e. in a random sparse network a sufficiently strong synaptic strength can surprisingly promote, rather than depress, the activity of neurons (neuronal rebirth). Thus, the number of firing neurons reaches a minimum value at some intermediate synaptic strength. We show that this minimum signals a transition from a regime dominated by neurons with a higher firing activity to a phase where all neurons are effectively sub-threshold and their irregular firing is driven by current fluctuations. We explain the origin of the transition by deriving a mean field formulation of the problem able to provide the fraction of active neurons as well as the first two moments of their firing statistics. The introduction of a synaptic time scale does not modify the main aspects of the reported phenomenon. However, for sufficiently slow synapses the transition becomes dramatic, and the system passes from a perfectly regular evolution to irregular bursting dynamics. In this latter regime the model provides predictions consistent with experimental findings for a specific class of neurons, namely the medium spiny neurons in the striatum.

  15. Differential subcellular distribution of ion channels and the diversity of neuronal function.

    Science.gov (United States)

    Nusser, Zoltan

    2012-06-01

    Following the astonishing molecular diversity of voltage-gated ion channels that was revealed in the past few decades, the ion channel repertoire expressed by neurons has been implicated as the major factor governing their functional heterogeneity. Although the molecular structure of ion channels is a key determinant of their biophysical properties, their subcellular distribution and densities on the surface of nerve cells are just as important for fulfilling functional requirements. Recent results obtained with high resolution quantitative localization techniques revealed complex, subcellular compartment-specific distribution patterns of distinct ion channels. Here I suggest that within a given neuron type every ion channel has a unique cell surface distribution pattern, with the functional consequence that this dramatically increases the computational power of nerve cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Optogenetic activation of serotonergic terminals facilitates GABAergic inhibitory input to orexin/hypocretin neurons

    OpenAIRE

    Chowdhury, Srikanta; Yamanaka, Akihiro

    2016-01-01

    Orexin/hypocretin neurons play a crucial role in the regulation of sleep/wakefulness, primarily in the maintenance of wakefulness. These neurons innervate wide areas of the brain and receive diverse synaptic inputs including those from serotonergic (5-HT) neurons in the raphe nucleus. Previously we showed that pharmacological application of 5-HT directly inhibited orexin neurons via 5-HT1A receptors. However, it was still unclear how 5-HT neurons regulated orexin neurons since 5-HT neurons co...

  17. Optimizing NEURON Simulation Environment Using Remote Memory Access with Recursive Doubling on Distributed Memory Systems.

    Science.gov (United States)

    Shehzad, Danish; Bozkuş, Zeki

    2016-01-01

    Increase in complexity of neuronal network models escalated the efforts to make NEURON simulation environment efficient. The computational neuroscientists divided the equations into subnets amongst multiple processors for achieving better hardware performance. On parallel machines for neuronal networks, interprocessor spikes exchange consumes large section of overall simulation time. In NEURON for communication between processors Message Passing Interface (MPI) is used. MPI_Allgather collective is exercised for spikes exchange after each interval across distributed memory systems. The increase in number of processors though results in achieving concurrency and better performance but it inversely affects MPI_Allgather which increases communication time between processors. This necessitates improving communication methodology to decrease the spikes exchange time over distributed memory systems. This work has improved MPI_Allgather method using Remote Memory Access (RMA) by moving two-sided communication to one-sided communication, and use of recursive doubling mechanism facilitates achieving efficient communication between the processors in precise steps. This approach enhanced communication concurrency and has improved overall runtime making NEURON more efficient for simulation of large neuronal network models.

  18. Optimizing NEURON Simulation Environment Using Remote Memory Access with Recursive Doubling on Distributed Memory Systems

    Directory of Open Access Journals (Sweden)

    Danish Shehzad

    2016-01-01

    Full Text Available Increase in complexity of neuronal network models escalated the efforts to make NEURON simulation environment efficient. The computational neuroscientists divided the equations into subnets amongst multiple processors for achieving better hardware performance. On parallel machines for neuronal networks, interprocessor spikes exchange consumes large section of overall simulation time. In NEURON for communication between processors Message Passing Interface (MPI is used. MPI_Allgather collective is exercised for spikes exchange after each interval across distributed memory systems. The increase in number of processors though results in achieving concurrency and better performance but it inversely affects MPI_Allgather which increases communication time between processors. This necessitates improving communication methodology to decrease the spikes exchange time over distributed memory systems. This work has improved MPI_Allgather method using Remote Memory Access (RMA by moving two-sided communication to one-sided communication, and use of recursive doubling mechanism facilitates achieving efficient communication between the processors in precise steps. This approach enhanced communication concurrency and has improved overall runtime making NEURON more efficient for simulation of large neuronal network models.

  19. Polarized trafficking: the palmitoylation cycle distributes cytoplasmic proteins to distinct neuronal compartments.

    Science.gov (United States)

    Tortosa, Elena; Hoogenraad, Casper C

    2018-02-01

    In neurons, polarized cargo distribution occurs mainly between the soma and axonal and dendritic compartments, and requires coordinated regulation of cytoskeletal remodeling and membrane trafficking. The Golgi complex plays a critical role during neuronal polarization and secretory trafficking has been shown to differentially transport proteins to both axons and dendrites. Besides the Golgi protein sorting, recent data revealed that palmitoylation cycles are an efficient mechanism to localize cytoplasmic, non-transmembrane proteins to particular neuronal compartments, such as the newly formed axon. Palmitoylation allows substrate proteins to bind to and ride with Golgi-derived secretory vesicles to all neuronal compartments. By allowing cytoplasmic proteins to 'hitchhike' on transport carriers in a non-polarized fashion, compartmentalized depalmitoylation may act as a selective retention mechanism. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Neurons in the posterior insular cortex are responsive to gustatory stimulation of the pharyngolarynx, baroreceptor and chemoreceptor stimulation, and tail pinch in rats.

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    Hanamori, T; Kunitake, T; Kato, K; Kannan, H

    1998-02-23

    Extracellular unit responses to gustatory stimulation of the pharyngolaryngeal region, baroreceptor and chemoreceptor stimulation, and tail pinch were recorded from the insular cortex of anesthetized and paralyzed rats. Of the 32 neurons identified, 28 responded to at least one of the nine stimuli used in the present study. Of the 32 neurons, 11 showed an excitatory response to tail pinch, 13 showed an inhibitory response, and the remaining eight had no response. Of the 32 neurons, eight responded to baroreceptor stimulation by an intravenous (i.v.) injection of methoxamine hydrochloride (Mex), four were excitatory and four were inhibitory. Thirteen neurons were excited and six neurons were inhibited by an arterial chemoreceptor stimulation by an i.v. injection of sodium cyanide (NaCN). Twenty-two neurons were responsive to at least one of the gustatory stimuli (deionized water, 1.0 M NaCl, 30 mM HCl, 30 mM quinine HCl, and 1.0 M sucrose); five to 11 excitatory neurons and three to seven inhibitory neurons for each stimulus. A large number of the neurons (25/32) received converging inputs from more than one stimulus among the nine stimuli used in the present study. Most neurons (23/32) received converging inputs from different modalities (gustatory, visceral, and tail pinch). The neurons responded were located in the insular cortex between 2.0 mm anterior and 0.2 mm posterior to the anterior edge of the joining of the anterior commissure (AC); the mean location was 1.2 mm (n=28) anterior to the AC. This indicates that most of the neurons identified in the present study seem to be located in the region posterior to the taste area and anterior to the visceral area in the insular cortex. These results indicate that the insular cortex neurons distributing between the taste area and the visceral area receive convergent inputs from gustatory, baroreceptor, chemoreceptor, and nociceptive organs. Copyright 1998 Elsevier Science B.V.

  1. Histochemical characterization, distribution and morphometric analysis of NADPH diaphorase neurons in the spinal cord of the agouti

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    Marco Aurelio M Freire

    2008-05-01

    Full Text Available We evaluated the neuropil distribution of the enzymes NADPH diaphorase (NADPH-d and cytochrome oxidase (CO in the spinal cord of the agouti, a medium-sized diurnal rodent, together with the distribution pattern and morphometrical characteristics of NADPH-d reactive neurons across different spinal segments. Neuropil labeling pattern was remarkably similar for both enzymes in coronal sections: reactivity was higher in regions involved with pain processing. We found two distinct types of NADPH-d reactive neurons in the agouti’s spinal cord: type I neurons had large, heavily stained cell bodies while type II neurons displayed relatively small and poorly stained somata. We concentrated our analysis on type I neurons. These were found mainly in the dorsal horn and around the central canal of every spinal segment, with a few scattered neurons located in the ventral horn of both cervical and lumbar regions. Overall, type I neurons were more numerous in the cervical region. Type I neurons were also found in the white matter, particularly in the ventral funiculum. Morphometrical analysis revealed that type I neurons located in the cervical region have dendritic trees that are more complex than those located in both lumbar and thoracic regions. In addition, NADPH-d cells located in the ventral horn had a larger cell body, especially in lumbar segments. The resulting pattern of cell body and neuropil distribution is in accordance with proposed schemes of segregation of function in the mammalian spinal cord.

  2. Sonic hedgehog expressing and responding cells generate neuronal diversity in the medial amygdala

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    Machold Robert P

    2010-05-01

    Full Text Available Abstract Background The mammalian amygdala is composed of two primary functional subdivisions, classified according to whether the major output projection of each nucleus is excitatory or inhibitory. The posterior dorsal and ventral subdivisions of the medial amygdala, which primarily contain inhibitory output neurons, modulate specific aspects of innate socio-sexual and aggressive behaviors. However, the development of the neuronal diversity of this complex and important structure remains to be fully elucidated. Results Using a combination of genetic fate-mapping and loss-of-function analyses, we examined the contribution and function of Sonic hedgehog (Shh-expressing and Shh-responsive (Nkx2-1+ and Gli1+ neurons in the medial amygdala. Specifically, we found that Shh- and Nkx2-1-lineage cells contribute differentially to the dorsal and ventral subdivisions of the postnatal medial amygdala. These Shh- and Nkx2-1-lineage neurons express overlapping and non-overlapping inhibitory neuronal markers, such as Calbindin, FoxP2, nNOS and Somatostatin, revealing diverse fate contributions in discrete medial amygdala nuclear subdivisions. Electrophysiological analysis of the Shh-derived neurons additionally reveals an important functional diversity within this lineage in the medial amygdala. Moreover, inducible Gli1CreER(T2 temporal fate mapping shows that early-generated progenitors that respond to Shh signaling also contribute to medial amygdala neuronal diversity. Lastly, analysis of Nkx2-1 mutant mice demonstrates a genetic requirement for Nkx2-1 in inhibitory neuronal specification in the medial amygdala distinct from the requirement for Nkx2-1 in cerebral cortical development. Conclusions Taken together, these data reveal a differential contribution of Shh-expressing and Shh-responding cells to medial amygdala neuronal diversity as well as the function of Nkx2-1 in the development of this important limbic system structure.

  3. Galanin-immunoreactivity identifies a distinct population of inhibitory interneurons in laminae I-III of the rat spinal cord

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    Watanabe Masahiko

    2011-05-01

    Full Text Available Abstract Background Inhibitory interneurons constitute 30-40% of neurons in laminae I-III and have an important anti-nociceptive role. However, because of the difficulty in classifying them we know little about their organisation. Previous studies have identified 3 non-overlapping groups of inhibitory interneuron, which contain neuropeptide Y (NPY, neuronal nitric oxide synthase (nNOS or parvalbumin, and have shown that these differ in postsynaptic targets. Some inhibitory interneurons contain galanin and the first aim of this study was to determine whether these form a different population from those containing NPY, nNOS or parvalbumin. We also estimated the proportion of neurons and GABAergic axons that contain galanin in laminae I-III. Results Galanin cells were concentrated in laminae I-IIo, with few in laminae IIi-III. Galanin showed minimal co-localisation with NPY, nNOS or parvalbumin in laminae I-II, but most galanin-containing cells in lamina III were nNOS-positive. Galanin cells constituted ~7%, 3% and 2% of all neurons in laminae I, II and III, and we estimate that this corresponds to 26%, 10% and 5% of the GABAergic neurons in these laminae. However, galanin was only found in ~6% of GABAergic boutons in laminae I-IIo, and ~1% of those in laminae IIi-III. Conclusions These results show that galanin, NPY, nNOS and parvalbumin can be used to define four distinct neurochemical populations of inhibitory interneurons. Together with results of a recent study, they suggest that the galanin and NPY populations account for around half of the inhibitory interneurons in lamina I and a quarter of those in lamina II.

  4. Fast voltage-sensitive dye imaging of excitatory and inhibitory synaptic transmission in the rat granular retrosplenial cortex.

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    Nixima, Ken'ichi; Okanoya, Kazuo; Ichinohe, Noritaka; Kurotani, Tohru

    2017-09-01

    Rodent granular retrosplenial cortex (GRS) has dense connections between the anterior thalamic nuclei (ATN) and hippocampal formation. GRS superficial pyramidal neurons exhibit distinctive late spiking (LS) firing property and form patchy clusters with prominent apical dendritic bundles. The aim of this study was to investigate spatiotemporal dynamics of signal transduction in the GRS induced by ATN afferent stimulation by using fast voltage-sensitive dye imaging in rat brain slices. In coronal slices, layer 1a stimulation, which presumably activated thalamic fibers, evoked propagation of excitatory synaptic signals from layers 2-4 to layers 5-6 in a direction perpendicular to the layer axis, followed by transverse signal propagation within each layer. In the presence of ionotropic glutamate receptor antagonists, inhibitory responses were observed in superficial layers, induced by direct activation of inhibitory interneurons in layer 1. In horizontal slices, excitatory signals in deep layers propagated transversely mainly from posterior to anterior via superficial layers. Cortical inhibitory responses upon layer 1a stimulation in horizontal slices were weaker than those in the coronal slices. Observed differences between coronal and horizontal planes suggest anisotropy of the intracortical circuitry. In conclusion, ATN inputs are processed differently in coronal and horizontal planes of the GRS and then conveyed to other cortical areas. In both planes, GRS superficial layers play an important role in signal propagation, which suggests that superficial neuronal cascade is crucial in the integration of multiple information sources. NEW & NOTEWORTHY Superficial neurons in the rat granular retrosplenial cortex (GRS) show distinctive late-spiking (LS) firing property. However, little is known about spatiotemporal dynamics of signal transduction in the GRS. We demonstrated LS neuron network relaying thalamic inputs to deep layers and anisotropic distribution of

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

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    Bo Wang

    2015-03-01

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

  6. Dynamic mobility of functional GABAA receptors at inhibitory synapses.

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    Thomas, Philip; Mortensen, Martin; Hosie, Alastair M; Smart, Trevor G

    2005-07-01

    Importing functional GABAA receptors into synapses is fundamental for establishing and maintaining inhibitory transmission and for controlling neuronal excitability. By introducing a binding site for an irreversible inhibitor into the GABAA receptor alpha1 subunit channel lining region that can be accessed only when the receptor is activated, we have determined the dynamics of receptor mobility between synaptic and extrasynaptic locations in hippocampal pyramidal neurons. We demonstrate that the cell surface GABAA receptor population shows no fast recovery after irreversible inhibition. In contrast, after selective inhibition, the synaptic receptor population rapidly recovers by the import of new functional entities within minutes. The trafficking pathways that promote rapid importation of synaptic receptors do not involve insertion from intracellular pools, but reflect receptor diffusion within the plane of the membrane. This process offers the synapse a rapid mechanism to replenish functional GABAA receptors at inhibitory synapses and a means to control synaptic efficacy.

  7. A critical period for experience-dependent remodeling of adult-born neuron connectivity.

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    Bergami, Matteo; Masserdotti, Giacomo; Temprana, Silvio G; Motori, Elisa; Eriksson, Therese M; Göbel, Jana; Yang, Sung Min; Conzelmann, Karl-Klaus; Schinder, Alejandro F; Götz, Magdalena; Berninger, Benedikt

    2015-02-18

    Neurogenesis in the dentate gyrus (DG) of the adult hippocampus is a process regulated by experience. To understand whether experience also modifies the connectivity of new neurons, we systematically investigated changes in their innervation following environmental enrichment (EE). We found that EE exposure between 2-6 weeks following neuron birth, rather than merely increasing the number of new neurons, profoundly affected their pattern of monosynaptic inputs. Both local innervation by interneurons and to even greater degree long-distance innervation by cortical neurons were markedly enhanced. Furthermore, following EE, new neurons received inputs from CA3 and CA1 inhibitory neurons that were rarely observed under control conditions. While EE-induced changes in inhibitory innervation were largely transient, cortical innervation remained increased after returning animals to control conditions. Our findings demonstrate an unprecedented experience-dependent reorganization of connections impinging onto adult-born neurons, which is likely to have important impact on their contribution to hippocampal information processing. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Relationship between the mechanisms of gamma rhythm generation and the magnitude of the macroscopic phase response function in a population of excitatory and inhibitory modified quadratic integrate-and-fire neurons

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    Akao, Akihiko; Ogawa, Yutaro; Jimbo, Yasuhiko; Ermentrout, G. Bard; Kotani, Kiyoshi

    2018-01-01

    Gamma oscillations are thought to play an important role in brain function. Interneuron gamma (ING) and pyramidal interneuron gamma (PING) mechanisms have been proposed as generation mechanisms for these oscillations. However, the relation between the generation mechanisms and the dynamical properties of the gamma oscillation are still unclear. Among the dynamical properties of the gamma oscillation, the phase response function (PRF) is important because it encodes the response of the oscillation to inputs. Recently, the PRF for an inhibitory population of modified theta neurons that generate an ING rhythm was computed by the adjoint method applied to the associated Fokker-Planck equation (FPE) for the model. The modified theta model incorporates conductance-based synapses as well as the voltage and current dynamics. Here, we extended this previous work by creating an excitatory-inhibitory (E-I) network using the modified theta model and described the population dynamics with the corresponding FPE. We conducted a bifurcation analysis of the FPE to find parameter regions which generate gamma oscillations. In order to label the oscillatory parameter regions by their generation mechanisms, we defined ING- and PING-type gamma oscillation in a mathematically plausible way based on the driver of the inhibitory population. We labeled the oscillatory parameter regions by these generation mechanisms and derived PRFs via the adjoint method on the FPE in order to investigate the differences in the responses of each type of oscillation to inputs. PRFs for PING and ING mechanisms are derived and compared. We found the amplitude of the PRF for the excitatory population is larger in the PING case than in the ING case. Finally, the E-I population of the modified theta neuron enabled us to analyze the PRFs of PING-type gamma oscillation and the entrainment ability of E and I populations. We found a parameter region in which PRFs of E and I are both purely positive in the case of

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

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

    2015-01-01

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

  10. [The distribution of NADPH-diaphorase and neuronal no synthase in rat medulla oblongata nuclei].

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    Chertok, V M; Kotsuba, A E

    2013-01-01

    The distribution of nitroxide ergic neurons in the medulla oblongata nuclei in Wistar rats (n = 8) was studied histochemically (NADPH-diaphorase) and using immunohistochemistry with an antiserum against neuronal form of nitric oxide synthase (nNOS). NADPH-diaphorase activity was found in large and small neurons of the sensory, autonomic and motor nuclei. The latter were especially rich in the cells demonstrating the activity of the enzyme. Unlike NADPH-diaphorase, nNOS in the corresponding nuclei was always detected in the fewer number of neurons, predominantly of small sizes. The sensory nuclei (nucleus of solitary tract, reticular parvocellular and lateral nuclei, spinal nucleus of the trigeminal nerve) contained 1.5-3 times more nNOS neurons than in motor nuclei. In some nuclei (nucleus ambiguus, hypoglossal nerve nucleus), containing numerous NADPH-diaphorase-positive neurons, immunoreactive cells were particularly rare.

  11. Excitatory Neuronal Hubs Configure Multisensory Integration of Slow Waves in Association Cortex

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    Satoshi Kuroki

    2018-03-01

    Full Text Available Summary: Multisensory integration (MSI is a fundamental emergent property of the mammalian brain. During MSI, perceptual information encoded in patterned activity is processed in multimodal association cortex. The systems-level neuronal dynamics that coordinate MSI, however, are unknown. Here, we demonstrate intrinsic hub-like network activity in the association cortex that regulates MSI. We engineered calcium reporter mouse lines based on the fluorescence resonance energy transfer sensor yellow cameleon (YC2.60 expressed in excitatory or inhibitory neurons. In medial and parietal association cortex, we observed spontaneous slow waves that self-organized into hubs defined by long-range excitatory and local inhibitory circuits. Unlike directional source/sink-like flows in sensory areas, medial/parietal excitatory and inhibitory hubs had net-zero balanced inputs. Remarkably, multisensory stimulation triggered rapid phase-locking mainly of excitatory hub activity persisting for seconds after the stimulus offset. Therefore, association cortex tends to form balanced excitatory networks that configure slow-wave phase-locking for MSI. Video Abstract: : Kuroki et al. performed cell-type-specific, wide-field FRET-based calcium imaging to visualize cortical network activity induced by multisensory inputs. They observed phase-locking of cortical slow waves in excitatory neuronal hubs in association cortical areas that may underlie multisensory integration. Keywords: wide-field calcium imaging, multisensory integration, cortical slow waves, association cortex, phase locking, fluorescence resonance energy transfer, spontaneous activity, excitatory neuron, inhibitory neuron, mouse

  12. Direct projections from hypothalamic orexin neurons to brainstem cardiac vagal neurons.

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    Dergacheva, Olga; Yamanaka, Akihiro; Schwartz, Alan R; Polotsky, Vsevolod Y; Mendelowitz, David

    2016-12-17

    Orexin neurons are known to augment the sympathetic control of cardiovascular function, however the role of orexin neurons in parasympathetic cardiac regulation remains unclear. To test the hypothesis that orexin neurons contribute to parasympathetic control we selectively expressed channelrhodopsin-2 (ChR2) in orexin neurons in orexin-Cre transgenic rats and examined postsynaptic currents in cardiac vagal neurons (CVNs) in the dorsal motor nucleus of the vagus (DMV). Simultaneous photostimulation and recording in ChR2-expressing orexin neurons in the lateral hypothalamus resulted in reliable action potential firing as well as large whole-cell currents suggesting a strong expression of ChR2 and reliable optogenetic excitation. Photostimulation of ChR2-expressing fibers in the DMV elicited short-latency (ranging from 3.2ms to 8.5ms) postsynaptic currents in 16 out of 44 CVNs tested. These responses were heterogeneous and included excitatory glutamatergic (63%) and inhibitory GABAergic (37%) postsynaptic currents. The results from this study suggest different sub-population of orexin neurons may exert diverse influences on brainstem CVNs and therefore may play distinct functional roles in parasympathetic control of the heart. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. New players tip the scales in the balance between excitatory and inhibitory synapses

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    El-Husseini Alaa

    2005-03-01

    Full Text Available Abstract Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.

  14. Neuronal model with distributed delay: analysis and simulation study for gamma distribution memory kernel.

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    Karmeshu; Gupta, Varun; Kadambari, K V

    2011-06-01

    A single neuronal model incorporating distributed delay (memory)is proposed. The stochastic model has been formulated as a Stochastic Integro-Differential Equation (SIDE) which results in the underlying process being non-Markovian. A detailed analysis of the model when the distributed delay kernel has exponential form (weak delay) has been carried out. The selection of exponential kernel has enabled the transformation of the non-Markovian model to a Markovian model in an extended state space. For the study of First Passage Time (FPT) with exponential delay kernel, the model has been transformed to a system of coupled Stochastic Differential Equations (SDEs) in two-dimensional state space. Simulation studies of the SDEs provide insight into the effect of weak delay kernel on the Inter-Spike Interval(ISI) distribution. A measure based on Jensen-Shannon divergence is proposed which can be used to make a choice between two competing models viz. distributed delay model vis-á-vis LIF model. An interesting feature of the model is that the behavior of (CV(t))((ISI)) (Coefficient of Variation) of the ISI distribution with respect to memory kernel time constant parameter η reveals that neuron can switch from a bursting state to non-bursting state as the noise intensity parameter changes. The membrane potential exhibits decaying auto-correlation structure with or without damped oscillatory behavior depending on the choice of parameters. This behavior is in agreement with empirically observed pattern of spike count in a fixed time window. The power spectral density derived from the auto-correlation function is found to exhibit single and double peaks. The model is also examined for the case of strong delay with memory kernel having the form of Gamma distribution. In contrast to fast decay of damped oscillations of the ISI distribution for the model with weak delay kernel, the decay of damped oscillations is found to be slower for the model with strong delay kernel.

  15. [Effect of pulse magnetic field on distribution of neuronal action potential].

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    Zheng, Yu; Cai, Di; Wang, Jin-Hai; Li, Gang; Lin, Ling

    2014-08-25

    The biological effect on the organism generated by magnetic field is widely studied. The present study was aimed to observe the change of sodium channel under magnetic field in neurons. Cortical neurons of Kunming mice were isolated, subjected to 15 Hz, 1 mT pulse magnetic stimulation, and then the currents of neurons were recorded by whole-cell patch clamp. The results showed that, under magnetic stimulation, the activation process of Na(+) channel was delayed, and the inactivation process was accelerated. Given the classic three-layer model, the polarization diagram of cell membrane potential distribution under pulse magnetic field was simulated, and it was found that the membrane potential induced was associated with the frequency and intensity of magnetic field. Also the effect of magnetic field-induced current on action potential was simulated by Hodgkin-Huxley (H-H) model. The result showed that the generation of action potential was delayed, and frequency and the amplitudes were decreased when working current was between -1.32 μA and 0 μA. When the working current was higher than 0 μA, the generation frequency of action potential was increased, and the change of amplitudes was not obvious, and when the working current was lower than -1.32 μA, the time of rising edge and amplitudes of action potential were decreased drastically, and the action potential was unable to generate. These results suggest that the magnetic field simulation can affect the distribution frequency and amplitude of action potential of neuron via sodium channel mediation.

  16. Segmental distribution and morphometric features of primary sensory neurons projecting to the tibial periosteum in the rat.

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    Tadeusz Cichocki

    2004-07-01

    Full Text Available Previous reports have demonstrated very rich innervation pattern in the periosteum. Most of the periosteal fibers were found to be sensory in nature. The aim of this study was to identify the primary sensory neurons that innervate the tibial periosteum in the adult rat and to describe the morphometric features of their perikarya. To this end, an axonal fluorescent carbocyanine tracer, DiI, was injected into the periosteum on the medial surface of the tibia. The perikarya of the sensory fibers were traced back in the dorsal root ganglia (DRG L1-L6 by means of fluorescent microscopy on cryosections. DiI-containing neurons were counted in each section and their segmental distribution was determined. Using PC-assisted image analysis system, the size and shape of the traced perikarya were analyzed. DiI-labeled sensory neurons innervating the periosteum of the tibia were located in the DRG ipsilateral to the injection site, with the highest distribution in L3 and L4 (57% and 23%, respectively. The majority of the traced neurons were of small size (area < 850 microm2, which is consistent with the size distribution of CGRP- and SP-containing cells, regarded as primary sensory neurons responsible for perception of pain and temperature. A small proportion of labeled cells had large perikarya and probably supplied corpuscular sense receptors observed in the periosteum. No differences were found in the shape distribution of neurons belonging to different size classes.

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

    Science.gov (United States)

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

    2017-04-01

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

  18. Temperature manipulation of neuronal dynamics in a forebrain motor control nucleus.

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    Matías A Goldin

    2017-08-01

    Full Text Available Different neuronal types within brain motor areas contribute to the generation of complex motor behaviors. A widely studied songbird forebrain nucleus (HVC has been recognized as fundamental in shaping the precise timing characteristics of birdsong. This is based, among other evidence, on the stretching and the "breaking" of song structure when HVC is cooled. However, little is known about the temperature effects that take place in its neurons. To address this, we investigated the dynamics of HVC both experimentally and computationally. We developed a technique where simultaneous electrophysiological recordings were performed during temperature manipulation of HVC. We recorded spontaneous activity and found three effects: widening of the spike shape, decrease of the firing rate and change in the interspike interval distribution. All these effects could be explained with a detailed conductance based model of all the neurons present in HVC. Temperature dependence of the ionic channel time constants explained the first effect, while the second was based in the changes of the maximal conductance using single synaptic excitatory inputs. The last phenomenon, only emerged after introducing a more realistic synaptic input to the inhibitory interneurons. Two timescales were present in the interspike distributions. The behavior of one timescale was reproduced with different input balances received form the excitatory neurons, whereas the other, which disappears with cooling, could not be found assuming poissonian synaptic inputs. Furthermore, the computational model shows that the bursting of the excitatory neurons arises naturally at normal brain temperature and that they have an intrinsic delay at low temperatures. The same effect occurs at single synapses, which may explain song stretching. These findings shed light on the temperature dependence of neuronal dynamics and present a comprehensive framework to study neuronal connectivity. This study, which

  19. Neuronal synchrony: peculiarity and generality.

    Science.gov (United States)

    Nowotny, Thomas; Huerta, Ramon; Rabinovich, Mikhail I

    2008-09-01

    Synchronization in neuronal systems is a new and intriguing application of dynamical systems theory. Why are neuronal systems different as a subject for synchronization? (1) Neurons in themselves are multidimensional nonlinear systems that are able to exhibit a wide variety of different activity patterns. Their "dynamical repertoire" includes regular or chaotic spiking, regular or chaotic bursting, multistability, and complex transient regimes. (2) Usually, neuronal oscillations are the result of the cooperative activity of many synaptically connected neurons (a neuronal circuit). Thus, it is necessary to consider synchronization between different neuronal circuits as well. (3) The synapses that implement the coupling between neurons are also dynamical elements and their intrinsic dynamics influences the process of synchronization or entrainment significantly. In this review we will focus on four new problems: (i) the synchronization in minimal neuronal networks with plastic synapses (synchronization with activity dependent coupling), (ii) synchronization of bursts that are generated by a group of nonsymmetrically coupled inhibitory neurons (heteroclinic synchronization), (iii) the coordination of activities of two coupled neuronal networks (partial synchronization of small composite structures), and (iv) coarse grained synchronization in larger systems (synchronization on a mesoscopic scale). (c) 2008 American Institute of Physics.

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

    Science.gov (United States)

    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

  1. Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus.

    Science.gov (United States)

    Puranam, Ram S; He, Xiao Ping; Yao, Lijun; Le, Tri; Jang, Wonjo; Rehder, Catherine W; Lewis, Darrell V; McNamara, James O

    2015-06-10

    We identified a family in which a translocation between chromosomes X and 14 was associated with cognitive impairment and a complex genetic disorder termed "Genetic Epilepsy and Febrile Seizures Plus" (GEFS(+)). We demonstrate that the breakpoint on the X chromosome disrupted a gene that encodes an auxiliary protein of voltage-gated Na(+) channels, fibroblast growth factor 13 (Fgf13). Female mice in which one Fgf13 allele was deleted exhibited hyperthermia-induced seizures and epilepsy. Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of hippocampus. Electrophysiological recordings revealed decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons of Fgf13 mutants. We speculate that reduced expression of Fgf13 impairs excitability of inhibitory interneurons, resulting in enhanced excitability within local circuits of hippocampus and the clinical phenotype of epilepsy. These findings reveal a novel cause of this syndrome and underscore the powerful role of FGF13 in control of neuronal excitability. Copyright © 2015 the authors 0270-6474/15/358866-16$15.00/0.

  2. Distribution of 3H-GABA uptake sites in the nematode Ascaris

    International Nuclear Information System (INIS)

    Guastella, J.; Stretton, A.O.

    1991-01-01

    The distribution of uptake sites for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the nematode Ascaris suum was examined by autoradiography of 3H-GABA uptake. Single neural processes in both the ventral and dorsal nerve cords were labeled with 3H-GABA. Serial section analysis identified the cells of origin of these processes as the RMEV-like and RMED-like neurons. These cells belong to a set of four neurons in the nerve ring, all of which are labeled by 3H-GABA. 3H-GABA labeling of at least two other sets of cephalic neurons was seen. One of these pairs consists of medium-sized lateral ganglia neurons, located at the level of the amphid commissure bundle. A second pair is located in the lateral ganglia at the level of the deirid commissure bundle. The position and size of these lateral ganglia cells suggest that they are the GABA-immunoreactive lateral ganglia cells frequently seen in whole-mount immunocytochemical preparations. Four neuronal cell bodies located in the retrovesicular ganglion were also labeled with 3H-GABA. These cells, which are probably cholinergic excitatory motor neurons, do not contain detectable GABA-like immunoreactivity. Heavy labeling of muscle cells was also observed. The ventral and dorsal nerve cord inhibitory motor neurons, which are known to contain GABA-like immunoreactivity, were not labeled above background with 3H-GABA. Together with the experiments reported previously, these results define three classes of GABA-associated neurons in Ascaris: (1) neurons that contain endogenous GABA and possess a GABA uptake system; (2) neurons that contain endogenous GABA, but that either lack a GABA uptake system or possess a GABA uptake system of low activity; (3) neurons that possess a GABA uptake system, but that lack endogenous GABA

  3. Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses.

    Science.gov (United States)

    Sudhakar, Shyam Kumar; Torben-Nielsen, Benjamin; De Schutter, Erik

    2015-12-01

    Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it.

  4. Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses

    Science.gov (United States)

    Sudhakar, Shyam Kumar; Torben-Nielsen, Benjamin; De Schutter, Erik

    2015-01-01

    Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it. PMID:26630202

  5. [Relation between frequency modulation direction selectivity and forward masking of inferior collicular neurons: a study on in vivo intracellular recording in mice].

    Science.gov (United States)

    Fu, Zi-Ying; Zeng, Hong; Tang, Jia; Li, Jie; Li, Juan; Chen, Qi-Cai

    2013-06-25

    It has been reported that the frequency modulation (FM) or FM direction sensitivity and forward masking of central auditory neurons are related with the neural inhibition, but there are some arguments, because no direct evidence of inhibitory synaptic input was obtained in previous studies using extracellular recording. In the present study, we studied the relation between FM direction sensitivity and forward masking of the inferior collicular (IC) neurons using in vivo intracellular recordings in 20 Mus musculus Km mice. Thirty seven with complete data among 93 neurons were analyzed and discussed. There was an inhibitory area which consisted of inhibitory postsynaptic potentials (IPSP) at high frequency side of frequency tuning of up-sweep FM (FMU) sensitive neurons (n = 12) and at low frequency side of frequency tuning of down-sweep FM (FMD) selective neurons (n = 8), while there was no any inhibitory area at both sides of frequency tuning of non-FM sweep direction (FMN) sensitive neurons (n = 17). Therefore, these results show that the inhibitory area at low or high frequency side of frequency tuning is one of the mechanisms for forming FM sweep direction sensitivity of IC neurons. By comparison of forward masking produced by FMU and FMD sound stimuli in FMU, FMD and FMN neurons, the selective FM sounds could produce stronger forward masking than the non-selective in FMU and FMD neurons, while there was no forward masking difference between FMU and FMD stimuli in the FMN neurons. We suggest that the post-action potential IPSP is a potential mechanism for producing stronger forward masking in FMU and FMD neurons.

  6. Distinct roles of presynaptic dopamine receptors in the differential modulation of the intrinsic synapses of medium-spiny neurons in the nucleus accumbens

    Directory of Open Access Journals (Sweden)

    Schmauss Claudia

    2007-01-01

    Full Text Available Abstract Background In both schizophrenia and addiction, pathological changes in dopamine release appear to induce alterations in the circuitry of the nucleus accumbens that affect coordinated thought and motivation. Dopamine acts principally on medium-spiny GABA neurons, which comprise 95% of accumbens neurons and give rise to the majority of inhibitory synapses in the nucleus. To examine dopamine action at single medium-spiny neuron synapses, we imaged Ca2+ levels in their presynaptic varicosities in the acute brain slice using two-photon microscopy. Results Presynaptic Ca2+ rises were differentially modulated by dopamine. The D1/D5 selective agonist SKF81297 was exclusively facilitatory. The D2/D3 selective agonist quinpirole was predominantly inhibitory, but in some instances it was facilitatory. Studies using D2 and D3 receptor knockout mice revealed that quinpirole inhibition was either D2 or D3 receptor-mediated, while facilitation was mainly D3 receptor-mediated. Subsets of varicosities responded to both D1 and D2 agonists, showing that there was significant co-expression of these receptor families in single medium-spiny neurons. Neighboring presynaptic varicosities showed strikingly heterogeneous responses to DA agonists, suggesting that DA receptors may be differentially trafficked to individual varicosities on the same medium-spiny neuron axon. Conclusion Dopamine receptors are present on the presynaptic varicosities of medium-spiny neurons, where they potently control GABAergic synaptic transmission. While there is significant coexpression of D1 and D2 family dopamine receptors in individual neurons, at the subcellular level, these receptors appear to be heterogeneously distributed, potentially explaining the considerable controversy regarding dopamine action in the striatum, and in particular the degree of dopamine receptor segregation on these neurons. Assuming that post-receptor signaling is restricted to the microdomains of

  7. Early neonatal loss of inhibitory synaptic input to the spinal motor neurons confers spina bifida-like leg dysfunction in a chicken model

    Directory of Open Access Journals (Sweden)

    Md. Sakirul Islam Khan

    2017-12-01

    Full Text Available Spina bifida aperta (SBA, one of the most common congenital malformations, causes lifelong neurological complications, particularly in terms of motor dysfunction. Fetuses with SBA exhibit voluntary leg movements in utero and during early neonatal life, but these disappear within the first few weeks after birth. However, the pathophysiological sequence underlying such motor dysfunction remains unclear. Additionally, because important insights have yet to be obtained from human cases, an appropriate animal model is essential. Here, we investigated the neuropathological mechanisms of progression of SBA-like motor dysfunctions in a neural tube surgery-induced chicken model of SBA at different pathogenesis points ranging from embryonic to posthatch ages. We found that chicks with SBA-like features lose voluntary leg movements and subsequently exhibit lower-limb paralysis within the first 2 weeks after hatching, coinciding with the synaptic change-induced disruption of spinal motor networks at the site of the SBA lesion in the lumbosacral region. Such synaptic changes reduced the ratio of inhibitory-to-excitatory inputs to motor neurons and were associated with a drastic loss of γ-aminobutyric acid (GABAergic inputs and upregulation of the cholinergic activities of motor neurons. Furthermore, most of the neurons in ventral horns, which appeared to be suffering from excitotoxicity during the early postnatal days, underwent apoptosis. However, the triggers of cellular abnormalization and neurodegenerative signaling were evident in the middle- to late-gestational stages, probably attributable to the amniotic fluid-induced in ovo milieu. In conclusion, we found that early neonatal loss of neurons in the ventral horn of exposed spinal cord affords novel insights into the pathophysiology of SBA-like leg dysfunction.

  8. Stochastic Wilson–Cowan models of neuronal network dynamics with memory and delay

    International Nuclear Information System (INIS)

    Goychuk, Igor; Goychuk, Andriy

    2015-01-01

    We consider a simple Markovian class of the stochastic Wilson–Cowan type models of neuronal network dynamics, which incorporates stochastic delay caused by the existence of a refractory period of neurons. From the point of view of the dynamics of the individual elements, we are dealing with a network of non-Markovian stochastic two-state oscillators with memory, which are coupled globally in a mean-field fashion. This interrelation of a higher-dimensional Markovian and lower-dimensional non-Markovian dynamics is discussed in its relevance to the general problem of the network dynamics of complex elements possessing memory. The simplest model of this class is provided by a three-state Markovian neuron with one refractory state, which causes firing delay with an exponentially decaying memory within the two-state reduced model. This basic model is used to study critical avalanche dynamics (the noise sustained criticality) in a balanced feedforward network consisting of the excitatory and inhibitory neurons. Such avalanches emerge due to the network size dependent noise (mesoscopic noise). Numerical simulations reveal an intermediate power law in the distribution of avalanche sizes with the critical exponent around −1.16. We show that this power law is robust upon a variation of the refractory time over several orders of magnitude. However, the avalanche time distribution is biexponential. It does not reflect any genuine power law dependence. (paper)

  9. Mammalian motor neurons corelease glutamate and acetylcholine at central synapses

    DEFF Research Database (Denmark)

    Nishimaru, Hiroshi; Restrepo, Carlos Ernesto; Ryge, Jesper

    2005-01-01

    Motor neurons (MNs) are the principal neurons in the mammalian spinal cord whose activities cause muscles to contract. In addition to their peripheral axons, MNs have central collaterals that contact inhibitory Renshaw cells and other MNs. Since its original discovery > 60 years ago, it has been...

  10. Phase precession through acceleration of local theta rhythm: a biophysical model for the interaction between place cells and local inhibitory neurons.

    Science.gov (United States)

    Castro, Luísa; Aguiar, Paulo

    2012-08-01

    Phase precession is one of the most well known examples within the temporal coding hypothesis. Here we present a biophysical spiking model for phase precession in hippocampal CA1 which focuses on the interaction between place cells and local inhibitory interneurons. The model's functional block is composed of a place cell (PC) connected with a local inhibitory cell (IC) which is modulated by the population theta rhythm. Both cells receive excitatory inputs from the entorhinal cortex (EC). These inputs are both theta modulated and space modulated. The dynamics of the two neuron types are described by integrate-and-fire models with conductance synapses, and the EC inputs are described using non-homogeneous Poisson processes. Phase precession in our model is caused by increased drive to specific PC/IC pairs when the animal is in their place field. The excitation increases the IC's firing rate, and this modulates the PC's firing rate such that both cells precess relative to theta. Our model implies that phase coding in place cells may not be independent from rate coding. The absence of restrictive connectivity constraints in this model predicts the generation of phase precession in any network with similar architecture and subject to a clocking rhythm, independently of the involvement in spatial tasks.

  11. Synaptic Dynamics and Neuronal Network Connectivity are reflected in the Distribution of Times in Up states

    Directory of Open Access Journals (Sweden)

    Khanh eDao Duc

    2015-07-01

    Full Text Available The dynamics of neuronal networks connected by synaptic dynamics can sustain long periods of depolarization that can last for hundreds of milliseconds such as Up states recorded during sleep or anesthesia. Yet the underlying mechanism driving these periods remain unclear. We show here within a mean-field model that the residence times of the neuronal membrane potential in cortical Up states does not follow a Poissonian law, but presents several peaks. Furthermore, the present modeling approach allows extracting some information about the neuronal network connectivity from the time distribution histogram. Based on a synaptic-depression model, we find that these peaks, that can be observed in histograms of patch-clamp recordings are not artifacts of electrophysiological measurements, but rather are an inherent property of the network dynamics. Analysis of the equations reveals a stable focus located close to the unstable limit cycle, delimiting a region that defines the Up state. The model further shows that the peaks observed in the Up state time distribution are due to winding around the focus before escaping from the basin of attraction. Finally, we use in vivo recordings of intracellular membrane potential and we recover from the peak distribution, some information about the network connectivity. We conclude that it is possible to recover the network connectivity from the distribution of times that the neuronal membrane voltage spends in Up states.

  12. Minimum inhibitory concentration distribution in environmental Legionella spp. isolates.

    Science.gov (United States)

    Sandalakis, Vassilios; Chochlakis, Dimosthenis; Goniotakis, Ioannis; Tselentis, Yannis; Psaroulaki, Anna

    2014-12-01

    In Greece standard tests are performed in the watering and cooling systems of hotels' units either as part of the surveillance scheme or following human infection. The purpose of this study was to establish the minimum inhibitory concentration (MIC) distributions of environmental Legionella isolates for six antimicrobials commonly used for the treatment of Legionella infections, by MIC-test methodology. Water samples were collected from 2004 to 2011 from 124 hotels from the four prefectures of Crete (Greece). Sixty-eight (68) Legionella isolates, comprising L. pneumophila serogroups 1, 2, 3, 5, 6, 8, 12, 13, 15, L. anisa, L. rubrilucens, L. maceachernii, L. quinlivanii, L. oakridgensis, and L. taurinensis, were included in the study. MIC-tests were performed on buffered charcoal yeast extract with α-ketoglutarate, L-cysteine, and ferric pyrophosphate. The MICs were read after 2 days of incubation at 36 ± 1 °C at 2.5% CO2. A large distribution in MICs was recorded for each species and each antibiotic tested. Rifampicin proved to be the most potent antibiotic regardless of the Legionella spp.; tetracycline appeared to have the least activity on our environmental isolates. The MIC-test approach is an easy, although not so cost-effective, way to determine MICs in Legionella spp. These data should be kept in mind especially since these Legionella species may cause human disease.

  13. Duration of inhibition of ventral tegmental area dopamine neurons encodes a level of conditioned fear.

    Science.gov (United States)

    Mileykovskiy, Boris; Morales, Marisela

    2011-05-18

    It is widely accepted that midbrain dopamine (DA) neurons encode actual and expected reward values by phasic alterations in firing rate. However, how DA neurons encode negative events in the environment is still unclear because some DA neurons appear to be depressed and others excited by aversive stimuli. Here, we show that exposing fear-conditioned rats to stimuli predicting electrical shock elicited three types of biphasic responses, each of which contained an inhibitory pause, in neurochemically identified ventral tegmental area (VTA) DA neurons. The duration of the inhibitory pause in these responses of VTA DA neurons was in direct proportion to the increase in respiratory rate reflecting the level of conditioned fear. Our results suggest that the duration of inhibition of VTA DA neurons encodes negative emotional values of signals predicting aversive events in the environment.

  14. Brain Distribution and Modulation of Neuronal Excitability by Indicaxanthin From Opuntia Ficus Indica Administered at Nutritionally-Relevant Amounts

    Directory of Open Access Journals (Sweden)

    Giuditta Gambino

    2018-05-01

    Full Text Available Several studies have recently investigated the role of nutraceuticals in complex pathophysiological processes such as oxidative damages, inflammatory conditions and excitotoxicity. In this regard, the effects of nutraceuticals on basic functions of neuronal cells, such as excitability, are still poorly investigated. For this reason, the possible modulation of neuronal excitability by phytochemicals (PhC could represent an interesting field of research given that excitotoxicity phenomena are involved in neurodegenerative alterations leading, for example, to Alzheimer’s disease. The present study was focused on indicaxanthin from Opuntia ficus indica, a bioactive betalain pigment, with a proven antioxidant and anti-inflammatory potential, previously found to cross blood-brain barrier (BBB and to modulate the bioelectric activity of hippocampal neurons. On this basis, we aimed at detecting the specific brain areas where indicaxanthin localizes after oral administration at dietary-achievable amounts and highlighting eventual local effects on the excitability of single neuronal units. HPLC analysis of brain tissue 1 h after ingestion of 2 μmol/kg indicaxanthin indicated that the phytochemical accumulates in cortex, hippocampus, diencephalon, brainstem and cerebellum, but not in the striato-pallidal complex. Then, electrophysiological recordings, applying the microiontophoretic technique, were carried out with different amounts of indicaxanthin (0.34, 0.17, 0.085 ng/neuron to assess whether indicaxanthin influenced the neuronal firing rate. The data showed that the bioelectric activity of neurons belonging to different brain areas was modulated after local injection of indicaxanthin, mainly with dose-related responses. A predominating inhibitory effect was observed, suggesting a possible novel beneficial effect of indicaxanthin in reducing cell excitability. These findings can constitute a new rationale for exploring biological mechanisms through

  15. Brain Distribution and Modulation of Neuronal Excitability by Indicaxanthin From Opuntia Ficus Indica Administered at Nutritionally-Relevant Amounts

    Science.gov (United States)

    Gambino, Giuditta; Allegra, Mario; Sardo, Pierangelo; Attanzio, Alessandro; Tesoriere, Luisa; Livrea, Maria A.; Ferraro, Giuseppe; Carletti, Fabio

    2018-01-01

    Several studies have recently investigated the role of nutraceuticals in complex pathophysiological processes such as oxidative damages, inflammatory conditions and excitotoxicity. In this regard, the effects of nutraceuticals on basic functions of neuronal cells, such as excitability, are still poorly investigated. For this reason, the possible modulation of neuronal excitability by phytochemicals (PhC) could represent an interesting field of research given that excitotoxicity phenomena are involved in neurodegenerative alterations leading, for example, to Alzheimer’s disease. The present study was focused on indicaxanthin from Opuntia ficus indica, a bioactive betalain pigment, with a proven antioxidant and anti-inflammatory potential, previously found to cross blood-brain barrier (BBB) and to modulate the bioelectric activity of hippocampal neurons. On this basis, we aimed at detecting the specific brain areas where indicaxanthin localizes after oral administration at dietary-achievable amounts and highlighting eventual local effects on the excitability of single neuronal units. HPLC analysis of brain tissue 1 h after ingestion of 2 μmol/kg indicaxanthin indicated that the phytochemical accumulates in cortex, hippocampus, diencephalon, brainstem and cerebellum, but not in the striato-pallidal complex. Then, electrophysiological recordings, applying the microiontophoretic technique, were carried out with different amounts of indicaxanthin (0.34, 0.17, 0.085 ng/neuron) to assess whether indicaxanthin influenced the neuronal firing rate. The data showed that the bioelectric activity of neurons belonging to different brain areas was modulated after local injection of indicaxanthin, mainly with dose-related responses. A predominating inhibitory effect was observed, suggesting a possible novel beneficial effect of indicaxanthin in reducing cell excitability. These findings can constitute a new rationale for exploring biological mechanisms through which PhC could

  16. Npas4: Linking Neuronal Activity to Memory.

    Science.gov (United States)

    Sun, Xiaochen; Lin, Yingxi

    2016-04-01

    Immediate-early genes (IEGs) are rapidly activated after sensory and behavioral experience and are believed to be crucial for converting experience into long-term memory. Neuronal PAS domain protein 4 (Npas4), a recently discovered IEG, has several characteristics that make it likely to be a particularly important molecular link between neuronal activity and memory: it is among the most rapidly induced IEGs, is expressed only in neurons, and is selectively induced by neuronal activity. By orchestrating distinct activity-dependent gene programs in different neuronal populations, Npas4 affects synaptic connections in excitatory and inhibitory neurons, neural circuit plasticity, and memory formation. It may also be involved in circuit homeostasis through negative feedback and psychiatric disorders. We summarize these findings and discuss their implications. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Odor-evoked inhibition of olfactory sensory neurons drives olfactory perception in Drosophila.

    Science.gov (United States)

    Cao, Li-Hui; Yang, Dong; Wu, Wei; Zeng, Xiankun; Jing, Bi-Yang; Li, Meng-Tong; Qin, Shanshan; Tang, Chao; Tu, Yuhai; Luo, Dong-Gen

    2017-11-07

    Inhibitory response occurs throughout the nervous system, including the peripheral olfactory system. While odor-evoked excitation in peripheral olfactory cells is known to encode odor information, the molecular mechanism and functional roles of odor-evoked inhibition remain largely unknown. Here, we examined Drosophila olfactory sensory neurons and found that inhibitory odors triggered outward receptor currents by reducing the constitutive activities of odorant receptors, inhibiting the basal spike firing in olfactory sensory neurons. Remarkably, this odor-evoked inhibition of olfactory sensory neurons elicited by itself a full range of olfactory behaviors from attraction to avoidance, as did odor-evoked olfactory sensory neuron excitation. These results indicated that peripheral inhibition is comparable to excitation in encoding sensory signals rather than merely regulating excitation. Furthermore, we demonstrated that a bidirectional code with both odor-evoked inhibition and excitation in single olfactory sensory neurons increases the odor-coding capacity, providing a means of efficient sensory encoding.

  18. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons

    Science.gov (United States)

    Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Padilla, Stephanie L; Palmiter, Richard D

    2016-01-01

    Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1ARH) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1ARH neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1ARH neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1ARH neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1ARH neurons. We propose that Kiss1ARH neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function. DOI: http://dx.doi.org/10.7554/eLife.16246.001 PMID:27549338

  19. Power-law inter-spike interval distributions infer a conditional maximization of entropy in cortical neurons.

    Directory of Open Access Journals (Sweden)

    Yasuhiro Tsubo

    Full Text Available The brain is considered to use a relatively small amount of energy for its efficient information processing. Under a severe restriction on the energy consumption, the maximization of mutual information (MMI, which is adequate for designing artificial processing machines, may not suit for the brain. The MMI attempts to send information as accurate as possible and this usually requires a sufficient energy supply for establishing clearly discretized communication bands. Here, we derive an alternative hypothesis for neural code from the neuronal activities recorded juxtacellularly in the sensorimotor cortex of behaving rats. Our hypothesis states that in vivo cortical neurons maximize the entropy of neuronal firing under two constraints, one limiting the energy consumption (as assumed previously and one restricting the uncertainty in output spike sequences at given firing rate. Thus, the conditional maximization of firing-rate entropy (CMFE solves a tradeoff between the energy cost and noise in neuronal response. In short, the CMFE sends a rich variety of information through broader communication bands (i.e., widely distributed firing rates at the cost of accuracy. We demonstrate that the CMFE is reflected in the long-tailed, typically power law, distributions of inter-spike intervals obtained for the majority of recorded neurons. In other words, the power-law tails are more consistent with the CMFE rather than the MMI. Thus, we propose the mathematical principle by which cortical neurons may represent information about synaptic input into their output spike trains.

  20. Versatile Networks of Simulated Spiking Neurons Displaying Winner-Take-All Behavior

    Directory of Open Access Journals (Sweden)

    Yanqing eChen

    2013-03-01

    Full Text Available We describe simulations of large-scale networks of excitatory and inhibitory spiking neurons that can generate dynamically stable winner-take-all (WTA behavior. The network connectivity is a variant of center-surround architecture that we call center-annular-surround (CAS. In this architecture each neuron is excited by nearby neighbors and inhibited by more distant neighbors in an annular-surround region. The neural units of these networks simulate conductance-based spiking neurons that interact via mechanisms susceptible to both short-term synaptic plasticity and STDP. We show that such CAS networks display robust WTA behavior unlike the center-surround networks and other control architectures that we have studied. We find that a large-scale network of spiking neurons with separate populations of excitatory and inhibitory neurons can give rise to smooth maps of sensory input. In addition, we show that a humanoid Brain-Based-Device (BBD under the control of a spiking WTA neural network can learn to reach to target positions in its visual field, thus demonstrating the acquisition of sensorimotor coordination.

  1. Versatile networks of simulated spiking neurons displaying winner-take-all behavior.

    Science.gov (United States)

    Chen, Yanqing; McKinstry, Jeffrey L; Edelman, Gerald M

    2013-01-01

    We describe simulations of large-scale networks of excitatory and inhibitory spiking neurons that can generate dynamically stable winner-take-all (WTA) behavior. The network connectivity is a variant of center-surround architecture that we call center-annular-surround (CAS). In this architecture each neuron is excited by nearby neighbors and inhibited by more distant neighbors in an annular-surround region. The neural units of these networks simulate conductance-based spiking neurons that interact via mechanisms susceptible to both short-term synaptic plasticity and STDP. We show that such CAS networks display robust WTA behavior unlike the center-surround networks and other control architectures that we have studied. We find that a large-scale network of spiking neurons with separate populations of excitatory and inhibitory neurons can give rise to smooth maps of sensory input. In addition, we show that a humanoid brain-based-device (BBD) under the control of a spiking WTA neural network can learn to reach to target positions in its visual field, thus demonstrating the acquisition of sensorimotor coordination.

  2. The median preoptic nucleus reciprocally modulates activity of arousal-related and sleep-related neurons in the perifornical lateral hypothalamus.

    Science.gov (United States)

    Suntsova, Natalia; Guzman-Marin, Ruben; Kumar, Sunil; Alam, Md Noor; Szymusiak, Ronald; McGinty, Dennis

    2007-02-14

    The perifornical-lateral hypothalamic area (PF/LH) contains neuronal groups playing an important role in control of waking and sleep. Among the brain regions that regulate behavioral states, one of the strongest sources of projections to the PF/LH is the median preoptic nucleus (MnPN) containing a sleep-active neuronal population. To evaluate the role of MnPN afferents in the control of PF/LH neuronal activity, we studied the responses of PF/LH cells to electrical stimulation or local chemical manipulation of the MnPN in freely moving rats. Single-pulse electrical stimulation evoked responses in 79% of recorded PF/LH neurons. No cells were activated antidromically. Direct and indirect transsynaptic effects depended on sleep-wake discharge pattern of PF/LH cells. The majority of arousal-related neurons, that is, cells discharging at maximal rates during active waking (AW) or during AW and rapid eye movement (REM) sleep, exhibited exclusively or initially inhibitory responses to stimulation. Sleep-related neurons, the cells with elevated discharge during non-REM and REM sleep or selectively active in REM sleep, exhibited exclusively or initially excitatory responses. Activation of the MnPN via microdialytic application of L-glutamate or bicuculline resulted in reduced discharge of arousal-related and in excitation of sleep-related PF/LH neurons. Deactivation of the MnPN with muscimol caused opposite effects. The results indicate that the MnPN contains subset(s) of neurons, which exert inhibitory control over arousal-related and excitatory control over sleep-related PF/LH neurons. We hypothesize that MnPN sleep-active neuronal group has both inhibitory and excitatory outputs that participate in the inhibitory control of arousal-promoting PF/LH mechanisms.

  3. Inferring Trial-to-Trial Excitatory and Inhibitory Synaptic Inputs from Membrane Potential using Gaussian Mixture Kalman Filtering

    Directory of Open Access Journals (Sweden)

    Milad eLankarany

    2013-09-01

    Full Text Available Time-varying excitatory and inhibitory synaptic inputs govern activity of neurons and process information in the brain. The importance of trial-to-trial fluctuations of synaptic inputs has recently been investigated in neuroscience. Such fluctuations are ignored in the most conventional techniques because they are removed when trials are averaged during linear regression techniques. Here, we propose a novel recursive algorithm based on Gaussian mixture Kalman filtering for estimating time-varying excitatory and inhibitory synaptic inputs from single trials of noisy membrane potential in current clamp recordings. The Kalman filtering is followed by an expectation maximization algorithm to infer the statistical parameters (time-varying mean and variance of the synaptic inputs in a non-parametric manner. As our proposed algorithm is repeated recursively, the inferred parameters of the mixtures are used to initiate the next iteration. Unlike other recent algorithms, our algorithm does not assume an a priori distribution from which the synaptic inputs are generated. Instead, the algorithm recursively estimates such a distribution by fitting a Gaussian mixture model. The performance of the proposed algorithms is compared to a previously proposed PF-based algorithm (Paninski et al., 2012 with several illustrative examples, assuming that the distribution of synaptic input is unknown. If noise is small, the performance of our algorithms is similar to that of the previous one. However, if noise is large, they can significantly outperform the previous proposal. These promising results suggest that our algorithm is a robust and efficient technique for estimating time varying excitatory and inhibitory synaptic conductances from single trials of membrane potential recordings.

  4. Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders.

    Science.gov (United States)

    Goemaere, Julie; Knoops, Bernard

    2012-02-01

    Redox changes are observed in neurodegenerative diseases, ranging from increased levels of reactive oxygen/nitrogen species and disturbance of antioxidant systems, to nitro-oxidative damage. By reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides, peroxiredoxins (Prdxs) represent a major potential protective barrier against nitro-oxidative insults in the brain. While recent works have investigated the putative role of Prdxs in neurodegenerative disorders, less is known about their expression in the healthy brain. Here we used immunohistochemistry to map basal expression of Prdxs throughout C57BL/6 mouse brain. We first confirmed the neuronal localization of Prdx2-5 and the glial expression of Prdx1, Prdx4, and Prdx6. Then we performed an in-depth analysis of neuronal Prdx distribution in the brain. Our results show that Prdx2-5 are widely detected in the different neuronal populations, and especially well expressed in the olfactory bulb, in the cerebral cortex, in pons nuclei, in the red nucleus, in all cranial nerve nuclei, in the cerebellum, and in motor neurons of the spinal cord. In contrast, Prdx expression is very low in the dopaminergic neurons of substantia nigra pars compacta and in the CA1/2 pyramidal cells of hippocampus. This low basal expression may contribute to the vulnerability of these neurons to nitro-oxidative attacks occurring in Parkinson's disease and Alzheimer's disease. In addition, we found that Prdx expression levels are unevenly distributed among neurons of a determined region and that distinct regional patterns of expression are observed between isoforms, reinforcing the hypothesis of the nonredundant function of Prdxs. Copyright © 2011 Wiley-Liss, Inc.

  5. 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.

  6. Population density models of integrate-and-fire neurons with jumps: well-posedness.

    Science.gov (United States)

    Dumont, Grégory; Henry, Jacques

    2013-09-01

    In this paper we study the well-posedness of different models of population of leaky integrate-and-fire neurons with a population density approach. The synaptic interaction between neurons is modeled by a potential jump at the reception of a spike. We study populations that are self excitatory or self inhibitory. We distinguish the cases where this interaction is instantaneous from the one where there is a repartition of conduction delays. In the case of a bounded density of delays both excitatory and inhibitory population models are shown to be well-posed. But without conduction delay the solution of the model of self excitatory neurons may blow up. We analyze the different behaviours of the model with jumps compared to its diffusion approximation.

  7. Response of spiking neurons to correlated inputs

    International Nuclear Information System (INIS)

    Moreno, Ruben; Rocha, Jaime de la; Renart, Alfonso; Parga, Nestor

    2002-01-01

    The effect of a temporally correlated afferent current on the firing rate of a leaky integrate-and-fire neuron is studied. This current is characterized in terms of rates, autocorrelations, and cross correlations, and correlation time scale τ c of excitatory and inhibitory inputs. The output rate ν out is calculated in the Fokker-Planck formalism in the limit of both small and large τ c compared to the membrane time constant τ of the neuron. By simulations we check the analytical results, provide an interpolation valid for all τ c , and study the neuron's response to rapid changes in the correlation magnitude

  8. Complete synchronization in coupled type-I neurons

    Indian Academy of Sciences (India)

    neural activity has elicited a great deal of interest since it is believed that such ... mechanism in the networks of excitatory (E) and inhibitory (I) neurons both in the ... excitatory–excitatory (EE) and inhibitory–excitatory (IE) bidirectional couplings.

  9. Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis.

    Science.gov (United States)

    Kielar, Catherine; Maddox, Lucy; Bible, Ellen; Pontikis, Charlie C; Macauley, Shannon L; Griffey, Megan A; Wong, Michael; Sands, Mark S; Cooper, Jonathan D

    2007-01-01

    Infantile neuronal ceroid lipofuscinosis (INCL) is caused by deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1). We have investigated the onset and progression of pathological changes in Ppt1 deficient mice (Ppt1-/-) and the development of their seizure phenotype. Surprisingly, cortical atrophy and neuron loss occurred only late in disease progression but were preceded by localized astrocytosis within individual thalamic nuclei and the progressive loss of thalamic neurons that relay different sensory modalities to the cortex. This thalamic neuron loss occurred first within the visual system and only subsequently in auditory and somatosensory relay nuclei or the inhibitory reticular thalamic nucleus. The loss of granule neurons and GABAergic interneurons followed in each corresponding cortical region, before the onset of seizure activity. These findings provide novel evidence for successive neuron loss within the thalamus and cortex in Ppt1-/- mice, revealing the thalamus as an important early focus of INCL pathogenesis.

  10. Distribution of orientation selectivity in recurrent networks of spiking neurons with different random topologies.

    Science.gov (United States)

    Sadeh, Sadra; Rotter, Stefan

    2014-01-01

    Neurons in the primary visual cortex are more or less selective for the orientation of a light bar used for stimulation. A broad distribution of individual grades of orientation selectivity has in fact been reported in all species. A possible reason for emergence of broad distributions is the recurrent network within which the stimulus is being processed. Here we compute the distribution of orientation selectivity in randomly connected model networks that are equipped with different spatial patterns of connectivity. We show that, for a wide variety of connectivity patterns, a linear theory based on firing rates accurately approximates the outcome of direct numerical simulations of networks of spiking neurons. Distance dependent connectivity in networks with a more biologically realistic structure does not compromise our linear analysis, as long as the linearized dynamics, and hence the uniform asynchronous irregular activity state, remain stable. We conclude that linear mechanisms of stimulus processing are indeed responsible for the emergence of orientation selectivity and its distribution in recurrent networks with functionally heterogeneous synaptic connectivity.

  11. 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.

  12. Characteristics and mechanisms of hypothalamic neuronal fatty acid sensing.

    Science.gov (United States)

    Le Foll, Christelle; Irani, Boman G; Magnan, Christophe; Dunn-Meynell, Ambrose A; Levin, Barry E

    2009-09-01

    We assessed the mechanisms by which specialized hypothalamic ventromedial nucleus (VMN) neurons utilize both glucose and long-chain fatty acids as signaling molecules to alter their activity as a potential means of regulating energy homeostasis. Fura-2 calcium (Ca(2+)) and membrane potential dye imaging, together with pharmacological agents, were used to assess the mechanisms by which oleic acid (OA) alters the activity of dissociated VMN neurons from 3- to 4-wk-old rats. OA excited up to 43% and inhibited up to 29% of all VMN neurons independently of glucose concentrations. In those neurons excited by both 2.5 mM glucose and OA, OA had a concentration-dependent effective excitatory concentration (EC(50)) of 13.1 nM. Neurons inhibited by both 2.5 mM glucose and OA had an effective inhibitory concentration (IC(50)) of 93 nM. At 0.5 mM glucose, OA had markedly different effects on these same neurons. Inhibition of carnitine palmitoyltransferase, reactive oxygen species formation, long-chain acetyl-CoA synthetase and ATP-sensitive K(+) channel activity or activation of uncoupling protein 2 (UCP2) accounted for only approximately 20% of OA's excitatory effects and approximately 40% of its inhibitory effects. Inhibition of CD36, a fatty acid transporter that can alter cell function independently of intracellular fatty acid metabolism, reduced the effects of OA by up to 45%. Thus OA affects VMN neuronal activity through multiple pathways. In glucosensing neurons, its effects are glucose dependent. This glucose-OA interaction provides a potential mechanism whereby such "metabolic sensing" neurons can respond to differences in the metabolic states associated with fasting and feeding.

  13. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures

    Science.gov (United States)

    Zhang, Wen; Peterson, Matthew; Beyer, Barbara; Frankel, Wayne N.

    2014-01-01

    Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability. PMID:24523563

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Neuronal specializations for the processing of interaural difference cues in the chick

    Directory of Open Access Journals (Sweden)

    Harunori eOhmori

    2014-05-01

    Full Text Available Sound information is encoded as a series of spikes of the auditory nerve fibers (ANFs, and then transmitted to the brainstem auditory nuclei. Features such as timing and level are extracted from ANFs activity and further processed as the interaural time difference (ITD and the interaural level difference (ILD, respectively. These two interaural difference cues are used for sound source localization by behaving animals. Both cues depend on the head size of animals and are extremely small, requiring specialized neural properties in order to process these cues with precision. Moreover, the sound level and timing cues are not processed independently from one another. Neurons in the nucleus angularis (NA are specialized for coding sound level information in birds and the ILD is processed in the posterior part of the dorsal lateral lemniscus nucleus (LLDp. Processing of ILD is affected by the phase difference of binaural sound. Temporal features of sound are encoded in the pathway starting in nucleus magnocellularis (NM, and ITD is processed in the nucleus laminaris (NL. In this pathway a variety of specializations are found in synapse morphology, neuronal excitability, distribution of ion channels and receptors along the tonotopic axis, which reduces spike timing fluctuation in the ANFs-NM synapse, and imparts precise and stable ITD processing to the NL. Moreover, the contrast of ITD processing in NL is enhanced over a wide range of sound level through the activity of GABAergic inhibitory systems from both the superior olivary nucleus (SON and local inhibitory neurons that follow monosynaptic to NM activity.

  16. Optogenetic Activation of the Sensorimotor Cortex Reveals "Local Inhibitory and Global Excitatory" Inputs to the Basal Ganglia.

    Science.gov (United States)

    Ozaki, Mitsunori; Sano, Hiromi; Sato, Shigeki; Ogura, Mitsuhiro; Mushiake, Hajime; Chiken, Satomi; Nakao, Naoyuki; Nambu, Atsushi

    2017-12-01

    To understand how information from different cortical areas is integrated and processed through the cortico-basal ganglia pathways, we used optogenetics to systematically stimulate the sensorimotor cortex and examined basal ganglia activity. We utilized Thy1-ChR2-YFP transgenic mice, in which channelrhodopsin 2 is robustly expressed in layer V pyramidal neurons. We applied light spots to the sensorimotor cortex in a grid pattern and examined neuronal responses in the globus pallidus (GP) and entopeduncular nucleus (EPN), which are the relay and output nuclei of the basal ganglia, respectively. Light stimulation typically induced a triphasic response composed of early excitation, inhibition, and late excitation in GP/EPN neurons. Other response patterns lacking 1 or 2 of the components were also observed. The distribution of the cortical sites whose stimulation induced a triphasic response was confined, whereas stimulation of the large surrounding areas induced early and late excitation without inhibition. Our results suggest that cortical inputs to the GP/EPN are organized in a "local inhibitory and global excitatory" manner. Such organization seems to be the neuronal basis for information processing through the cortico-basal ganglia pathways, that is, releasing and terminating necessary information at an appropriate timing, while simultaneously suppressing other unnecessary information. © The Author 2017. Published by Oxford University Press.

  17. Area PEc Neurons Use a Multiphasic Pattern of Activity to Signal the Spatial Properties of Optic Flow

    Directory of Open Access Journals (Sweden)

    Milena Raffi

    2017-01-01

    Full Text Available The cortical representation of visual perception requires the integration of several-signal processing distributed across many cortical areas, but the neural substrates of such perception are largely unknown. The type of firing pattern exhibited by single neurons is an important indicator of dynamic circuitry within or across cortical areas. Neurons in area PEc are involved in the spatial mapping of the visual field; thus, we sought to analyze the firing pattern of activity of PEc optic flow neurons to shed some light on the cortical processing of visual signals. We quantified the firing activity of 152 optic flow neurons using a spline interpolation function, which allowed determining onset, end, and latency of each neuronal response. We found that many PEc neurons showed multiphasic activity, which is strictly related to the position of the eye and to the position of the focus of expansion (FOE of the flow field. PEc neurons showed a multiphasic activity comprised of excitatory phases interspersed with inhibitory pauses. This phasic pattern seems to be a very efficient way to signal the spatial location of visual stimuli, given that the same neuron sends different firing patterns according to a specific combination of FOE/eye position.

  18. Distribution and morphology of serotonin-immunoreactive neurons in the brainstem of the New Zealand white rabbit

    DEFF Research Database (Denmark)

    Bjarkam, C R; Sørensen, J C; Geneser, F A

    1997-01-01

    The aim of the present study was to demonstrate the morphology and distribution of the serotonergic neurons in the brainstem of the New Zealand white rabbit by using a highly specific immunocytochemical procedure. It was possible to divide the serotonergic neurons into a rostral group, which......, which were large and multipolar, were morphologically different from the serotonergic neurons in the midline, which were mostly small and relatively nonpolar. The serotonergic system of the New Zealand white rabbit has undergone a major lateralization, like the serotonergic system of man and higher...

  19. Interplay between glucose and leptin signalling 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

    2015-03-26

    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.

  20. 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

  1. Differential expression of alpha-synuclein in hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Katsutoshi Taguchi

    Full Text Available α-Synuclein is the major pathological component of synucleinopathies including Parkinson's disease and dementia with Lewy bodies. Recent studies have demonstrated that α-synuclein also plays important roles in the release of synaptic vesicles and synaptic membrane recycling in healthy neurons. However, the precise relationship between the pathogenicity and physiological functions of α-synuclein remains to be elucidated. To address this issue, we investigated the subcellular localization of α-synuclein in normal and pathological conditions using primary mouse hippocampal neuronal cultures. While some neurons expressed high levels of α-synuclein in presynaptic boutons and cell bodies, other neurons either did not or only very weakly expressed the protein. These α-synuclein-negative cells were identified as inhibitory neurons by immunostaining with specific antibodies against glutamic acid decarboxylase (GAD, parvalbumin, and somatostatin. In contrast, α-synuclein-positive synapses were colocalized with the excitatory synapse marker vesicular glutamate transporter-1. This expression profile of α-synuclein was conserved in the hippocampus in vivo. In addition, we found that while presynaptic α-synuclein colocalizes with synapsin, a marker of presynaptic vesicles, it is not essential for activity-dependent membrane recycling induced by high potassium treatment. Exogenous supply of preformed fibrils generated by recombinant α-synuclein was shown to promote the formation of Lewy body (LB -like intracellular aggregates involving endogenous α-synuclein. GAD-positive neurons did not form LB-like aggregates following treatment with preformed fibrils, however, exogenous expression of human α-synuclein allowed intracellular aggregate formation in these cells. These results suggest the presence of a different mechanism for regulation of the expression of α-synuclein between excitatory and inhibitory neurons. Furthermore, α-synuclein expression

  2. Characteristics of cholinoreceptors on identified TAN neurons of the ground snail Achatina fulica.

    Science.gov (United States)

    Stepanov, I I; Losev, N A

    2000-01-01

    The characteristics of cholinoreceptors located on neurons TAN1, TAN2, and TAN3 of the ground snail Achatina fulica were studied by incubation of the central ganglia in a bath with cholinotropic preparations during intracellular recording of background neuron spike activity. Acetylcholine, nicotine, the selective n-cholinoreceptor agonist suberyldicholine, and the selective n-cholinoreceptor agonist 5-methylfurmethide concentration-dependently inhibited background spike activity to the level of complete blockade at concentrations of 500 microM. The m-cholinoblocker metamizil (500 microM) completely prevented the inhibitory activity of concentrations of 5-methylfurmethide of up to 500 microM. The central n-cholinoblocker etherophen (500 microM) completely blocked the inhibitory activity of 500 microM suberyldicholine. However, metamizil and etherophen added separately only partially decreased the inhibitory effects of acetylcholine but could not completely block the effect of acetylcholine. At the same time, mixtures of metamizil and etherophen (500 microM each) completely blocked the inhibition of background spike activity induced by acetylcholine. These results show that both classes of cholinoreceptors act on TAN neurons in the same direction.

  3. Sleep-Active Neurons: Conserved Motors of Sleep

    Science.gov (United States)

    Bringmann, Henrik

    2018-01-01

    Sleep is crucial for survival and well-being. This behavioral and physiological state has been studied in all major genetically accessible model animals, including rodents, fish, flies, and worms. Genetic and optogenetic studies have identified several neurons that control sleep, making it now possible to compare circuit mechanisms across species. The “motor” of sleep across animal species is formed by neurons that depolarize at the onset of sleep to actively induce this state by directly inhibiting wakefulness. These sleep-inducing neurons are themselves controlled by inhibitory or activating upstream pathways, which act as the “drivers” of the sleep motor: arousal inhibits “sleep-active” neurons whereas various sleep-promoting “tiredness” pathways converge onto sleep-active neurons to depolarize them. This review provides the first overview of sleep-active neurons across the major model animals. The occurrence of sleep-active neurons and their regulation by upstream pathways in both vertebrate and invertebrate species suggests that these neurons are general and ancient components that evolved early in the history of nervous systems. PMID:29618588

  4. Aversive learning shapes neuronal orientation tuning in human visual cortex.

    Science.gov (United States)

    McTeague, Lisa M; Gruss, L Forest; Keil, Andreas

    2015-07-28

    The responses of sensory cortical neurons are shaped by experience. As a result perceptual biases evolve, selectively facilitating the detection and identification of sensory events that are relevant for adaptive behaviour. Here we examine the involvement of human visual cortex in the formation of learned perceptual biases. We use classical aversive conditioning to associate one out of a series of oriented gratings with a noxious sound stimulus. After as few as two grating-sound pairings, visual cortical responses to the sound-paired grating show selective amplification. Furthermore, as learning progresses, responses to the orientations with greatest similarity to the sound-paired grating are increasingly suppressed, suggesting inhibitory interactions between orientation-selective neuronal populations. Changes in cortical connectivity between occipital and fronto-temporal regions mirror the changes in visuo-cortical response amplitudes. These findings suggest that short-term behaviourally driven retuning of human visual cortical neurons involves distal top-down projections as well as local inhibitory interactions.

  5. Structure and function of the amygdaloid NPY system: NPY Y2 receptors regulate excitatory and inhibitory synaptic transmission in the centromedial amygdala.

    Science.gov (United States)

    Wood, J; Verma, D; Lach, G; Bonaventure, P; Herzog, H; Sperk, G; Tasan, R O

    2016-09-01

    The amygdala is essential for generating emotional-affective behaviors. It consists of several nuclei with highly selective, elaborate functions. In particular, the central extended amygdala, consisting of the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST) is an essential component actively controlling efferent connections to downstream effectors like hypothalamus and brain stem. Both, CEA and BNST contain high amounts of different neuropeptides that significantly contribute to synaptic transmission. Among these, neuropeptide Y (NPY) has emerged as an important anxiolytic and fear-reducing neuromodulator. Here, we characterized the expression, connectivity and electrophysiological function of NPY and Y2 receptors within the CEA. We identified several NPY-expressing neuronal populations, including somatostatin- and calretinin-expressing neurons. Furthermore, in the main intercalated nucleus, NPY is expressed primarily in dopamine D1 receptor-expressing neurons but also in interspersed somatostatin-expressing neurons. Interestingly, NPY neurons did not co-localize with the Y2 receptor. Retrograde tract tracing experiments revealed that NPY neurons reciprocally connect the CEA and BNST. Functionally, the Y2 receptor agonist PYY3-36, reduced both, inhibitory as well as excitatory synaptic transmission in the centromedial amygdala (CEm). However, we also provide evidence that lack of NPY or Y2 receptors results in increased GABA release specifically at inhibitory synapses in the CEm. Taken together, our findings suggest that NPY expressed by distinct populations of neurons can modulate afferent and efferent projections of the CEA via presynaptic Y2 receptors located at inhibitory and excitatory synapses.

  6. Curtailing effect of awakening on visual responses of cortical neurons by cholinergic activation of inhibitory circuits.

    Science.gov (United States)

    Kimura, Rui; Safari, Mir-Shahram; Mirnajafi-Zadeh, Javad; Kimura, Rie; Ebina, Teppei; Yanagawa, Yuchio; Sohya, Kazuhiro; Tsumoto, Tadaharu

    2014-07-23

    Visual responsiveness of cortical neurons changes depending on the brain state. Neural circuit mechanism underlying this change is unclear. By applying the method of in vivo two-photon functional calcium imaging to transgenic rats in which GABAergic neurons express fluorescent protein, we analyzed changes in visual response properties of cortical neurons when animals became awakened from anesthesia. In the awake state, the magnitude and reliability of visual responses of GABAergic neurons increased whereas the decay of responses of excitatory neurons became faster. To test whether the basal forebrain (BF) cholinergic projection is involved in these changes, we analyzed effects of electrical and optogenetic activation of BF on visual responses of mouse cortical neurons with in vivo imaging and whole-cell recordings. Electrical BF stimulation in anesthetized animals induced the same direction of changes in visual responses of both groups of neurons as awakening. Optogenetic activation increased the frequency of visually evoked action potentials in GABAergic neurons but induced the delayed hyperpolarization that ceased the late generation of action potentials in excitatory neurons. Pharmacological analysis in slice preparations revealed that photoactivation-induced depolarization of layer 1 GABAergic neurons was blocked by a nicotinic receptor antagonist, whereas non-fast-spiking layer 2/3 GABAergic neurons was blocked only by the application of both nicotinic and muscarinic receptor antagonists. These results suggest that the effect of awakening is mediated mainly through nicotinic activation of layer 1 GABAergic neurons and mixed nicotinic/muscarinic activation of layer 2/3 non-fast-spiking GABAergic neurons, which together curtails the visual responses of excitatory neurons. Copyright © 2014 the authors 0270-6474/14/3410122-12$15.00/0.

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

    Science.gov (United States)

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

    2011-01-01

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

  8. Computational model of neuron-astrocyte interactions during focal seizure generation

    Directory of Open Access Journals (Sweden)

    Davide eReato

    2012-10-01

    Full Text Available Empirical research in the last decade revealed that astrocytes can respond to neurotransmitters with Ca2+ elevations and generate feedback signals to neurons which modulate synaptic transmission and neuronal excitability. This discovery changed our basic understanding of brain function and provided new perspectives for how astrocytes can participate not only to information processing, but also to the genesis of brain disorders, such as epilepsy. Epilepsy is a neurological disorder characterized by recurrent seizures that can arise focally at restricted areas and propagate throughout the brain. Studies in brain slice models suggest that astrocytes contribute to epileptiform activity by increasing neuronal excitability through a Ca2+-dependent release of glutamate. The underlying mechanism remains, however, unclear. In this study, we implemented a parsimonious network model of neurons and astrocytes. The model consists of excitatory and inhibitory neurons described by Izhikevich's neuron dynamics. The experimentally observed Ca2+ change in astrocytes in response to neuronal activity was modeled with linear equations. We considered that glutamate is released from astrocytes above certain intracellular Ca2+ concentrations thus providing a non-linear positive feedback signal to neurons. Propagating seizure-like ictal discharges (IDs were reliably evoked in our computational model by repeatedly exciting a small area of the network, which replicates experimental results in a slice model of focal ID in entorhinal cortex. We found that the threshold of focal ID generation was lowered when an excitatory feedback-loop between astrocytes and neurons was included. Simulations show that astrocytes can contribute to ID generation by directly affecting the excitatory/inhibitory balance of the neuronal network. Our model can be used to obtain mechanistic insights into the distinct contributions of the different signaling pathways to the generation and

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

    Science.gov (United States)

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

    2014-07-16

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

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

    Science.gov (United States)

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

    2015-01-21

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

  11. Subsampling effects in neuronal avalanche distributions recorded in vivo

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    Munk Matthias HJ

    2009-04-01

    Full Text Available Abstract Background Many systems in nature are characterized by complex behaviour where large cascades of events, or avalanches, unpredictably alternate with periods of little activity. Snow avalanches are an example. Often the size distribution f(s of a system's avalanches follows a power law, and the branching parameter sigma, the average number of events triggered by a single preceding event, is unity. A power law for f(s, and sigma = 1, are hallmark features of self-organized critical (SOC systems, and both have been found for neuronal activity in vitro. Therefore, and since SOC systems and neuronal activity both show large variability, long-term stability and memory capabilities, SOC has been proposed to govern neuronal dynamics in vivo. Testing this hypothesis is difficult because neuronal activity is spatially or temporally subsampled, while theories of SOC systems assume full sampling. To close this gap, we investigated how subsampling affects f(s and sigma by imposing subsampling on three different SOC models. We then compared f(s and sigma of the subsampled models with those of multielectrode local field potential (LFP activity recorded in three macaque monkeys performing a short term memory task. Results Neither the LFP nor the subsampled SOC models showed a power law for f(s. Both, f(s and sigma, depended sensitively on the subsampling geometry and the dynamics of the model. Only one of the SOC models, the Abelian Sandpile Model, exhibited f(s and sigma similar to those calculated from LFP activity. Conclusion Since subsampling can prevent the observation of the characteristic power law and sigma in SOC systems, misclassifications of critical systems as sub- or supercritical are possible. Nevertheless, the system specific scaling of f(s and sigma under subsampling conditions may prove useful to select physiologically motivated models of brain function. Models that better reproduce f(s and sigma calculated from the physiological

  12. Mechanisms of Winner-Take-All and Group Selection in Neuronal Spiking Networks.

    Science.gov (United States)

    Chen, Yanqing

    2017-01-01

    A major function of central nervous systems is to discriminate different categories or types of sensory input. Neuronal networks accomplish such tasks by learning different sensory maps at several stages of neural hierarchy, such that different neurons fire selectively to reflect different internal or external patterns and states. The exact mechanisms of such map formation processes in the brain are not completely understood. Here we study the mechanism by which a simple recurrent/reentrant neuronal network accomplish group selection and discrimination to different inputs in order to generate sensory maps. We describe the conditions and mechanism of transition from a rhythmic epileptic state (in which all neurons fire synchronized and indiscriminately to any input) to a winner-take-all state in which only a subset of neurons fire for a specific input. We prove an analytic condition under which a stable bump solution and a winner-take-all state can emerge from the local recurrent excitation-inhibition interactions in a three-layer spiking network with distinct excitatory and inhibitory populations, and demonstrate the importance of surround inhibitory connection topology on the stability of dynamic patterns in spiking neural network.

  13. Neuron Types in the Presumptive Primary Somatosensory Cortex of the Florida Manatee (Trichechus manatus latirostris).

    Science.gov (United States)

    Reyes, Laura D; Stimpson, Cheryl D; Gupta, Kanika; Raghanti, Mary Ann; Hof, Patrick R; Reep, Roger L; Sherwood, Chet C

    2015-01-01

    Within afrotherians, sirenians are unusual due to their aquatic lifestyle, large body size and relatively large lissencephalic brain. However, little is known about the neuron type distributions of the cerebral cortex in sirenians within the context of other afrotherians and aquatic mammals. The present study investigated two cortical regions, dorsolateral cortex area 1 (DL1) and cluster cortex area 2 (CL2), in the presumptive primary somatosensory cortex (S1) in Florida manatees (Trichechus manatus latirostris) to characterize cyto- and chemoarchitecture. The mean neuron density for both cortical regions was 35,617 neurons/mm(3) and fell within the 95% prediction intervals relative to brain mass based on a reference group of afrotherians and xenarthrans. Densities of inhibitory interneuron subtypes labeled against calcium-binding proteins and neuropeptide Y were relatively low compared to afrotherians and xenarthrans and also formed a small percentage of the overall population of inhibitory interneurons as revealed by GAD67 immunoreactivity. Nonphosphorylated neurofilament protein-immunoreactive (NPNFP-ir) neurons comprised a mean of 60% of neurons in layer V across DL1 and CL2. DL1 contained a higher percentage of NPNFP-ir neurons than CL2, although CL2 had a higher variety of morphological types. The mean percentage of NPNFP-ir neurons in the two regions of the presumptive S1 were low compared to other afrotherians and xenarthrans but were within the 95% prediction intervals relative to brain mass, and their morphologies were comparable to those found in other afrotherians and xenarthrans. Although this specific pattern of neuron types and densities sets the manatee apart from other afrotherians and xenarthrans, the manatee isocortex does not appear to be explicitly adapted for an aquatic habitat. Many of the features that are shared between manatees and cetaceans are also shared with a diverse array of terrestrial mammals and likely represent highly conserved

  14. A Computational Analysis of the Function of Three Inhibitory Cell Types in Contextual Visual Processing

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    Jung H. Lee

    2017-04-01

    Full Text Available Most cortical inhibitory cell types exclusively express one of three genes, parvalbumin, somatostatin and 5HT3a. We conjecture that these three inhibitory neuron types possess distinct roles in visual contextual processing based on two observations. First, they have distinctive synaptic sources and targets over different spatial extents and from different areas. Second, the visual responses of cortical neurons are affected not only by local cues, but also by visual context. We use modeling to relate structural information to function in primary visual cortex (V1 of the mouse, and investigate their role in contextual visual processing. Our findings are three-fold. First, the inhibition mediated by parvalbumin positive (PV cells mediates local processing and could underlie their role in boundary detection. Second, the inhibition mediated by somatostatin-positive (SST cells facilitates longer range spatial competition among receptive fields. Third, non-specific top-down modulation to interneurons expressing vasoactive intestinal polypeptide (VIP, a subclass of 5HT3a neurons, can selectively enhance V1 responses.

  15. Effect of Hyperglycemia on Purinergic and Nitrergic Inhibitory Neuromuscular Transmission in the Antrum of the Stomach: Implications for Fast Gastric Emptying

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    Xue-Dao He

    2018-01-01

    Full Text Available BackgroundHyperglycemia has been reported to enhance vagovagal reflex that causes the release of inhibitory neurotransmitter, nitric oxide (NO, at the neuromuscular junction in the antrum to relax the antrum and slow gastric emptying by stimulating glucose-sensitive afferent neurons. However, hyperglycemia has also been reported to cause fast gastric emptying that may be due to suppression of the inhibitory motor neurons.AimsThe purpose of the present study was to investigate changes in inhibitory neuromuscular transmission in the gastric antrum due to hyperglycemia.MethodsInhibitory electrical junction potentials were recorded from gastric antral muscle strips, using intracellular electrodes under non-adrenergic, non-cholinergic conditions. Studies were performed in non-hyperglycemic NOD (NH-NOD, NOD mice as they develop hyperglycemia (H-NOD and their age-matched controls. The purinergic inhibitory junction potential (pIJP and nitrergic IJP (nIJP were isolated pharmacologically.ResultsThe control pIJP was large, around −18 mV and nIJP was small, around −9 mV. In NH-NOD the IJPs were not affected, but in H-NOD pIJP was nearly abolished and nIJP was significantly reduced. In H-NOD mice, membrane hyperpolarization caused by exogenous α,β-MeATP or diethylenetriamine NO adduct was similar to that in wild-type controls (P > 0.05. H-NOD smooth muscles were significantly depolarized as compared to NH-NOD smooth muscles.ConclusionThese observations show that hyperglycemia causes suppression of purinergic and nitrergic transmission by acting on the motor neurons that form the last neuron in the vagovagal circuit. Moreover, the loss the neurotransmission is due to a defect in neurotransmitter release rather than a defect in signal transduction. Hyperglycemia also causes depolarization of smooth muscles that may increase their excitability.

  16. Comparative mapping of GABA-immunoreactive neurons in the central nervous systems of nudibranch molluscs.

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    Gunaratne, Charuni A; Sakurai, Akira; Katz, Paul S

    2014-03-01

    The relative simplicity of certain invertebrate nervous systems, such as those of gastropod molluscs, allows behaviors to be dissected at the level of small neural circuits composed of individually identifiable neurons. Elucidating the neurotransmitter phenotype of neurons in neural circuits is important for understanding how those neural circuits function. In this study, we examined the distribution of γ-aminobutyric-acid;-immunoreactive (GABA-ir) neurons in four species of sea slugs (Mollusca, Gastropoda, Opisthobranchia, Nudibranchia): Tritonia diomedea, Melibe leonina, Dendronotus iris, and Hermissenda crassicornis. We found consistent patterns of GABA immunoreactivity in the pedal and cerebral-pleural ganglia across species. In particular, there were bilateral clusters in the lateral and medial regions of the dorsal surface of the cerebral ganglia as well as a cluster on the ventral surface of the pedal ganglia. There were also individual GABA-ir neurons that were recognizable across species. The invariant presence of these individual neurons and clusters suggests that they are homologous, although there were interspecies differences in the numbers of neurons in the clusters. The GABAergic system was largely restricted to the central nervous system, with the majority of axons confined to ganglionic connectives and commissures, suggesting a central, integrative role for GABA. GABA was a candidate inhibitory neurotransmitter for neurons in central pattern generator (CPG) circuits underlying swimming behaviors in these species, however none of the known swim CPG neurons were GABA-ir. Although the functions of these GABA-ir neurons are not known, it is clear that their presence has been strongly conserved across nudibranchs. Copyright © 2013 Wiley Periodicals, Inc.

  17. Asynchronous Rate Chaos in Spiking Neuronal Circuits.

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    Omri Harish

    2015-07-01

    Full Text Available The brain exhibits temporally complex patterns of activity with features similar to those of chaotic systems. Theoretical studies over the last twenty years have described various computational advantages for such regimes in neuronal systems. Nevertheless, it still remains unclear whether chaos requires specific cellular properties or network architectures, or whether it is a generic property of neuronal circuits. We investigate the dynamics of networks of excitatory-inhibitory (EI spiking neurons with random sparse connectivity operating in the regime of balance of excitation and inhibition. Combining Dynamical Mean-Field Theory with numerical simulations, we show that chaotic, asynchronous firing rate fluctuations emerge generically for sufficiently strong synapses. Two different mechanisms can lead to these chaotic fluctuations. One mechanism relies on slow I-I inhibition which gives rise to slow subthreshold voltage and rate fluctuations. The decorrelation time of these fluctuations is proportional to the time constant of the inhibition. The second mechanism relies on the recurrent E-I-E feedback loop. It requires slow excitation but the inhibition can be fast. In the corresponding dynamical regime all neurons exhibit rate fluctuations on the time scale of the excitation. Another feature of this regime is that the population-averaged firing rate is substantially smaller in the excitatory population than in the inhibitory population. This is not necessarily the case in the I-I mechanism. Finally, we discuss the neurophysiological and computational significance of our results.

  18. Asynchronous Rate Chaos in Spiking Neuronal Circuits

    Science.gov (United States)

    Harish, Omri; Hansel, David

    2015-01-01

    The brain exhibits temporally complex patterns of activity with features similar to those of chaotic systems. Theoretical studies over the last twenty years have described various computational advantages for such regimes in neuronal systems. Nevertheless, it still remains unclear whether chaos requires specific cellular properties or network architectures, or whether it is a generic property of neuronal circuits. We investigate the dynamics of networks of excitatory-inhibitory (EI) spiking neurons with random sparse connectivity operating in the regime of balance of excitation and inhibition. Combining Dynamical Mean-Field Theory with numerical simulations, we show that chaotic, asynchronous firing rate fluctuations emerge generically for sufficiently strong synapses. Two different mechanisms can lead to these chaotic fluctuations. One mechanism relies on slow I-I inhibition which gives rise to slow subthreshold voltage and rate fluctuations. The decorrelation time of these fluctuations is proportional to the time constant of the inhibition. The second mechanism relies on the recurrent E-I-E feedback loop. It requires slow excitation but the inhibition can be fast. In the corresponding dynamical regime all neurons exhibit rate fluctuations on the time scale of the excitation. Another feature of this regime is that the population-averaged firing rate is substantially smaller in the excitatory population than in the inhibitory population. This is not necessarily the case in the I-I mechanism. Finally, we discuss the neurophysiological and computational significance of our results. PMID:26230679

  19. Response of Cultured Neuronal Network Activity After High-Intensity Power Frequency Magnetic Field Exposure

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    Atsushi Saito

    2018-03-01

    Full Text Available High-intensity and low frequency (1–100 kHz time-varying electromagnetic fields stimulate the human body through excitation of the nervous system. In power frequency range (50/60 Hz, a frequency-dependent threshold of the external electric field-induced neuronal modulation in cultured neuronal networks was used as one of the biological indicator in international guidelines; however, the threshold of the magnetic field-induced neuronal modulation has not been elucidated. In this study, we exposed rat brain-derived neuronal networks to a high-intensity power frequency magnetic field (hPF-MF, and evaluated the modulation of synchronized bursting activity using a multi-electrode array (MEA-based extracellular recording technique. As a result of short-term hPF-MF exposure (50–400 mT root-mean-square (rms, 50 Hz, sinusoidal wave, 6 s, the synchronized bursting activity was increased in the 400 mT-exposed group. On the other hand, no change was observed in the 50–200 mT-exposed groups. In order to clarify the mechanisms of the 400 mT hPF-MF exposure-induced neuronal response, we evaluated it after blocking inhibitory synapses using bicuculline methiodide (BMI; subsequently, increase in bursting activity was observed with BMI application, and the response of 400 mT hPF-MF exposure disappeared. Therefore, it was suggested that the response of hPF-MF exposure was involved in the inhibitory input. Next, we screened the inhibitory pacemaker-like neuronal activity which showed autonomous 4–10 Hz firing with CNQX and D-AP5 application, and it was confirmed that the activity was reduced after 400 mT hPF-MF exposure. Comparison of these experimental results with estimated values of the induced electric field (E-field in the culture medium revealed that the change in synchronized bursting activity occurred over 0.3 V/m, which was equivalent to the findings of a previous study that used the external electric fields. In addition, the results suggested that

  20. The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster

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    Li, Xianghua; Overton, Ian M.; Baines, Richard A.; Keegan, Liam P.; O’Connell, Mary A.

    2014-01-01

    RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing generates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamorphosis, and Adar5G1 null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomotion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar5G1 mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar5G1 null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions, and vertebrate ADARs may have a relevant evolutionarily conserved control over neuronal excitability. PMID:24137011

  1. Propagated but Topologically Distributed Forebrain Neurons Expressing Alpha-Synuclein in Aged Macaques.

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    Katsuo Kimura

    Full Text Available In neurodegenerative disorders, such as Parkinson's disease (PD, alpha-synuclein (α-syn accumulates to induce cell death and/or form a cytoplasmic inclusion called Lewy body (LB. This α-syn-related pathology is termed synucleinopathy. It remains unclear how α-syn accumulation expands during the progress of synucleinopathy in the human brain. In our study, we investigated the patterns of distribution and propagation of forebrain neurons expressing α-syn in aged macaques. It was found that the occurrence of α-syn-positive neurons proceeded topologically based on the midbrain dopamine pathways arising from the substantia nigra and the ventral tegmental area where they were primarily observed. In the nigrostriatal or mesolimbic dopamine pathway, the age-dependent increase in α-syn-positive neurons was evident in the striatum or the nucleus accumbens, respectively. Concerning the nigrostriatal pathway, a mediolateral or rostrocaudal gradient was seen in the substantia nigra or the striatum, respectively, and a compensatory increase in dopamine transporter occurred in the striatum regardless of the decreased dopamine level. In the mesocortical dopamine pathway, α-syn-positive neurons appeared in the prefrontal and then motor areas of the frontal lobe. Given that neither LB formation nor clinical phenotype manifestation was detected in any of the monkeys examined in the present study, aged macaques may be useful as a potential presymptomatic model for PD and LB-related neuropsychiatric disorders.

  2. Inhibitory Effect of Lycopene on Amyloid-β-Induced Apoptosis in Neuronal Cells.

    Science.gov (United States)

    Hwang, Sinwoo; Lim, Joo Weon; Kim, Hyeyoung

    2017-08-16

    Alzheimer's disease (AD) is a fatal neurodegenerative disease. Brain amyloid-β deposition is a crucial feature of AD, causing neuronal cell death by inducing oxidative damage. Reactive oxygen species (ROS) activate NF-κB, which induces expression of Nucling. Nucling is a pro-apoptotic factor recruiting the apoptosome complex. Lycopene is an antioxidant protecting from oxidative stress-induced cell damage. We investigated whether lycopene inhibits amyloid-β-stimulated apoptosis through reducing ROS and inhibiting mitochondrial dysfunction and NF-κB-mediated Nucling expression in neuronal SH-SY5Y cells. We prepared cells transfected with siRNA for Nucling or nontargeting control siRNA to determine the role of Nucling in amyloid-β-induced apoptosis. The amyloid-β increased intracellular and mitochondrial ROS levels, apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), NF-kB activation and Nucling expression, while cell viability, mitochondrial membrane potential, and oxygen consumption rate decreased in SH-SY5Y cells. Lycopene inhibited these amyloid-β-induced alterations. However, amyloid-β did not induce apoptosis, determined by cell viability and apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), in the cells transfected with siRNA for Nucling. Lycopene inhibited apoptosis by reducing ROS, and by inhibiting mitochondrial dysfunction and NF-κB-target gene Nucling expression in neuronal cells. Lycopene may be beneficial for preventing oxidative stress-mediated neuronal death in patients with neurodegeneration.

  3. Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling.

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    Nagendran, Tharkika; Larsen, Rylan S; Bigler, Rebecca L; Frost, Shawn B; Philpot, Benjamin D; Nudo, Randolph J; Taylor, Anne Marion

    2017-09-20

    Injury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.Spinal cord injury can induce synaptic reorganization and remodeling in the brain. Here the authors study how severed distal axons signal back to the cell body to induce hyperexcitability, loss of inhibition and enhanced presynaptic release through netrin-1.

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

    OpenAIRE

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

    2013-01-01

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

  5. An information theoretic model of information processing in the Drosophila olfactory system: the role of inhibitory neurons for system efficiency.

    Science.gov (United States)

    Faghihi, Faramarz; Kolodziejski, Christoph; Fiala, André; Wörgötter, Florentin; Tetzlaff, Christian

    2013-12-20

    Fruit flies (Drosophila melanogaster) rely on their olfactory system to process environmental information. This information has to be transmitted without system-relevant loss by the olfactory system to deeper brain areas for learning. Here we study the role of several parameters of the fly's olfactory system and the environment and how they influence olfactory information transmission. We have designed an abstract model of the antennal lobe, the mushroom body and the inhibitory circuitry. Mutual information between the olfactory environment, simulated in terms of different odor concentrations, and a sub-population of intrinsic mushroom body neurons (Kenyon cells) was calculated to quantify the efficiency of information transmission. With this method we study, on the one hand, the effect of different connectivity rates between olfactory projection neurons and firing thresholds of Kenyon cells. On the other hand, we analyze the influence of inhibition on mutual information between environment and mushroom body. Our simulations show an expected linear relation between the connectivity rate between the antennal lobe and the mushroom body and firing threshold of the Kenyon cells to obtain maximum mutual information for both low and high odor concentrations. However, contradicting all-day experiences, high odor concentrations cause a drastic, and unrealistic, decrease in mutual information for all connectivity rates compared to low concentration. But when inhibition on the mushroom body is included, mutual information remains at high levels independent of other system parameters. This finding points to a pivotal role of inhibition in fly information processing without which the system efficiency will be substantially reduced.

  6. Time-course of changes in neuronal activity markers following iTBS-TMS of the rat neocortex.

    Science.gov (United States)

    Hoppenrath, Kathrin; Funke, Klaus

    2013-03-01

    In a rat model of transcranial magnetic stimulation we could recently show that intermittent theta-burst stimulation (iTBS) affects the neocortical expression of the immediate early gene products c-Fos and zif268 as well as that of the two glutamic acid decarboxylase isoforms GAD65 and GAD67 and that of the calcium-binding proteins calbindin (CB) and parvalbumin (PV), known as markers of excitatory and inhibitory activity. We now analyzed in more detail the time course of changes in the expression of these proteins at 10, 20, 40, 80 and 160min following a single block of iTBS consisting of 600 stimuli. Initial increase in c-Fos, zif268 and GAD65 (20min) signals transient activation of excitatory and inhibitory neurons, thereafter first followed by a decrease in markers of activity of inhibitory neurons (GAD67, PV, CB: 20-80min) and then by a late decrease in c-Fos and GAD65 expression (160min). The results demonstrate that one iTBS block may have an after-effect of at least two different phases, an early phase with increased neuronal activity (c-Fos, zif268) but also the likelihood of increased GABA-release (GAD65), followed by a late phase (>40min) of reduced neuronal activity in excitatory and inhibitory systems which may indicate a state of reduced excitability. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Excitatory inputs to four types of spinocerebellar tract neurons in the cat and the rat thoraco-lumbar spinal cord

    Science.gov (United States)

    Shrestha, Sony Shakya; Bannatyne, B Anne; Jankowska, Elzbieta; Hammar, Ingela; Nilsson, Elin; Maxwell, David J

    2012-01-01

    The cerebellum receives information from the hindlimbs through several populations of spinocerebellar tract neurons. Although the role of these neurons has been established in electrophysiological experiments, the relative contribution of afferent fibres and central neurons to their excitatory input has only been estimated approximately so far. Taking advantage of differences in the immunohistochemistry of glutamatergic terminals of peripheral afferents and of central neurons (with vesicular glutamate transporters VGLUT1 or VGLUT2, respectively), we compared sources of excitatory input to four populations of spinocerebellar neurons in the thoraco-lumbar spinal cord: dorsal spinocerebellar tract neurons located in Clarke's column (ccDSCT) and in the dorsal horn (dhDSCT) and ventral spinocerebellar tract (VSCT) neurons including spinal border (SB) neurons. This was done on 22 electrophysiologically identified intracellularly labelled neurons in cats and on 80 neurons labelled by retrograde transport of cholera toxin b subunit injected into the cerebellum of rats. In both species distribution of antibodies against VGLUT1 and VGLUT2 on SB neurons (which have dominating inhibitory input from limb muscles), revealed very few VGLUT1 contacts and remarkably high numbers of VGLUT2 contacts. In VSCT neurons with excitatory afferent input, the number of VGLUT1 contacts was relatively high although VGLUT2 contacts likewise dominated, while the proportions of VGLUT1 and VGLUT2 immunoreactive terminals were the reverse on the two populations of DSCT neurons. These findings provide morphological evidence that SB neurons principally receive excitatory inputs from central neurons and provide the cerebellum with information regarding central neuronal activity. PMID:22371473

  8. 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.

  9. Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin.

    Science.gov (United States)

    Butler, Corwin R; Boychuk, Jeffery A; Smith, Bret N

    2017-01-01

    Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.

  10. Distribution and morphology of serotonin-immunoreactive neurons in the brainstem of the New Zealand white rabbit

    DEFF Research Database (Denmark)

    Bjarkam, C R; Sørensen, J C; Geneser, F A

    1997-01-01

    The aim of the present study was to demonstrate the morphology and distribution of the serotonergic neurons in the brainstem of the New Zealand white rabbit by using a highly specific immunocytochemical procedure. It was possible to divide the serotonergic neurons into a rostral group, which......, which were large and multipolar, were morphologically different from the serotonergic neurons in the midline, which were mostly small and relatively nonpolar. The serotonergic system of the New Zealand white rabbit has undergone a major lateralization, like the serotonergic system of man and higher...... and morphology, and this possible subspecialization of the serotonergic system is discussed in the context of present knowledge of serotonergic anatomy and function....

  11. Cerebellins are differentially expressed in selective subsets of neurons throughout the brain.

    Science.gov (United States)

    Seigneur, Erica; Südhof, Thomas C

    2017-10-15

    Cerebellins are secreted hexameric proteins that form tripartite complexes with the presynaptic cell-adhesion molecules neurexins or 'deleted-in-colorectal-cancer', and the postsynaptic glutamate-receptor-related proteins GluD1 and GluD2. These tripartite complexes are thought to regulate synapses. However, cerebellins are expressed in multiple isoforms whose relative distributions and overall functions are not understood. Three of the four cerebellins, Cbln1, Cbln2, and Cbln4, autonomously assemble into homohexamers, whereas the Cbln3 requires Cbln1 for assembly and secretion. Here, we show that Cbln1, Cbln2, and Cbln4 are abundantly expressed in nearly all brain regions, but exhibit strikingly different expression patterns and developmental dynamics. Using newly generated knockin reporter mice for Cbln2 and Cbln4, we find that Cbln2 and Cbln4 are not universally expressed in all neurons, but only in specific subsets of neurons. For example, Cbln2 and Cbln4 are broadly expressed in largely non-overlapping subpopulations of excitatory cortical neurons, but only sparse expression was observed in excitatory hippocampal neurons of the CA1- or CA3-region. Similarly, Cbln2 and Cbln4 are selectively expressed, respectively, in inhibitory interneurons and excitatory mitral projection neurons of the main olfactory bulb; here, these two classes of neurons form dendrodendritic reciprocal synapses with each other. A few brain regions, such as the nucleus of the lateral olfactory tract, exhibit astoundingly high Cbln2 expression levels. Viewed together, our data show that cerebellins are abundantly expressed in relatively small subsets of neurons, suggesting specific roles restricted to subsets of synapses. © 2017 Wiley Periodicals, Inc.

  12. Temporal-pattern recognition by single neurons in a sensory pathway devoted to social communication behavior.

    Science.gov (United States)

    Carlson, Bruce A

    2009-07-29

    Sensory systems often encode stimulus information into the temporal pattern of action potential activity. However, little is known about how the information contained within these patterns is extracted by postsynaptic neurons. Similar to temporal coding by sensory neurons, social information in mormyrid fish is encoded into the temporal patterning of an electric organ discharge. In the current study, sensitivity to temporal patterns of electrosensory stimuli was found to arise within the midbrain posterior exterolateral nucleus (ELp). Whole-cell patch recordings from ELp neurons in vivo revealed three patterns of interpulse interval (IPI) tuning: low-pass neurons tuned to long intervals, high-pass neurons tuned to short intervals, and bandpass neurons tuned to intermediate intervals. Many neurons within each class also responded preferentially to either increasing or decreasing IPIs. Playback of electric signaling patterns recorded from freely behaving fish revealed that the IPI and direction tuning of ELp neurons resulted in selective responses to particular social communication displays characterized by distinct IPI patterns. The postsynaptic potential responses of many neurons indicated a combination of excitatory and inhibitory synaptic input, and the IPI tuning of ELp neurons was directly related to rate-dependent changes in the direction and amplitude of postsynaptic potentials. These results suggest that differences in the dynamics of short-term synaptic plasticity in excitatory and inhibitory pathways may tune central sensory neurons to particular temporal patterns of presynaptic activity. This may represent a general mechanism for the processing of behaviorally relevant stimulus information encoded into temporal patterns of activity by sensory neurons.

  13. Kappe neurons, a novel population of olfactory sensory neurons.

    Science.gov (United States)

    Ahuja, Gaurav; Bozorg Nia, Shahrzad; Zapilko, Veronika; Shiriagin, Vladimir; Kowatschew, Daniel; Oka, Yuichiro; Korsching, Sigrun I

    2014-02-10

    Perception of olfactory stimuli is mediated by distinct populations of olfactory sensory neurons, each with a characteristic set of morphological as well as functional parameters. Beyond two large populations of ciliated and microvillous neurons, a third population, crypt neurons, has been identified in teleost and cartilaginous fishes. We report here a novel, fourth olfactory sensory neuron population in zebrafish, which we named kappe neurons for their characteristic shape. Kappe neurons are identified by their Go-like immunoreactivity, and show a distinct spatial distribution within the olfactory epithelium, similar to, but significantly different from that of crypt neurons. Furthermore, kappe neurons project to a single identified target glomerulus within the olfactory bulb, mdg5 of the mediodorsal cluster, whereas crypt neurons are known to project exclusively to the mdg2 glomerulus. Kappe neurons are negative for established markers of ciliated, microvillous and crypt neurons, but appear to have microvilli. Kappe neurons constitute the fourth type of olfactory sensory neurons reported in teleost fishes and their existence suggests that encoding of olfactory stimuli may require a higher complexity than hitherto assumed already in the peripheral olfactory system.

  14. Altered Chloride Homeostasis Decreases the Action Potential Threshold and Increases Hyperexcitability in Hippocampal Neurons

    DEFF Research Database (Denmark)

    Sørensen, Andreas T; Ledri, Marco; Melis, Miriam

    2017-01-01

    Chloride ions play an important role in controlling excitability of principal neurons in the central nervous system. When neurotransmitter GABA is released from inhibitory interneurons, activated GABA type A (GABAA) receptors on principal neurons become permeable to chloride. Typically, chloride...... neurons, and promote AP generation. It is generally recognized that altered chloride homeostasis per se has no effect on the AP threshold. Here, we demonstrate that chloride overload of mouse principal CA3 pyramidal neurons not only makes these cells more excitable through GABAA receptor activation...

  15. Hyperpolarization-activated current (In is reduced in hippocampal neurons from Gabra5-/- mice.

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    Robert P Bonin

    Full Text Available Changes in the expression of γ-aminobutyric acid type A (GABAA receptors can either drive or mediate homeostatic alterations in neuronal excitability. A homeostatic relationship between α5 subunit-containing GABAA (α5GABAA receptors that generate a tonic inhibitory conductance, and HCN channels that generate a hyperpolarization-activated cation current (Ih was recently described for cortical neurons, where a reduction in Ih was accompanied by a reciprocal increase in the expression of α5GABAA receptors resulting in the preservation of dendritosomatic synaptic function. Here, we report that in mice that lack the α5 subunit gene (Gabra5-/-, cultured embryonic hippocampal pyramidal neurons and ex vivo CA1 hippocampal neurons unexpectedly exhibited a decrease in Ih current density (by 40% and 28%, respectively, compared with neurons from wild-type (WT mice. The resting membrane potential and membrane hyperpolarization induced by blockade of Ih with ZD-7288 were similar in cultured WT and Gabra5-/- neurons. In contrast, membrane hyperpolarization measured after a train of action potentials was lower in Gabra5-/- neurons than in WT neurons. Also, membrane impedance measured in response to low frequency stimulation was greater in cultured Gabra5-/- neurons. Finally, the expression of HCN1 protein that generates Ih was reduced by 41% in the hippocampus of Gabra5-/- mice. These data indicate that loss of a tonic GABAergic inhibitory conductance was followed by a compensatory reduction in Ih. The results further suggest that the maintenance of resting membrane potential is preferentially maintained in mature and immature hippocampal neurons through the homeostatic co-regulation of structurally and biophysically distinct cation and anion channels.

  16. Distribution and chemical coding of neurons in intramural ganglia of the porcine urinary bladder trigone.

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    Zenon Pidsudko

    2004-03-01

    Full Text Available This study presents the distribution and chemical coding of neurons in the porcine intramural ganglia of the urinary bladder trigone (IG-UBT demonstrated using combined retrograde tracing and double-labelling immunohistochemistry. Retrograde fluorescent tracer Fast Blue (FB was injected into the wall of both the left and right side of the bladder trigone during laparotomy performed under pentobarbital anaesthesia. Ten-microm-thick cryostat sections were processed for double-labelling immunofluorescence with antibodies against tyrosine hydroxylase (TH, dopamine beta-hydroxylase (DBH, neuropeptide Y (NPY, somatostatin (SOM, galanin (GAL, vasoactive intestinal polypeptide (VIP, nitric oxide synthase (NOS, calcitonin gene-related peptide (CGRP, substance P (SP, Leu5-enkephalin (LENK and choline acetyltransferase (ChAT. IG-UBT neurons formed characteristic clusters (from a few to tens neuronal cells found under visceral peritoneum or in the outer muscular layer. Immunohistochemistry revealed four main populations of IG-UBT neurons: SOM- (ca. 35%, SP- (ca. 32%, ChAT- and NPY- immunoreactive (-IR (ca. 23% as well as non-adrenergic non-cholinergic nerve cells (ca. 6%. This study has demonstrated a relatively large population of differently coded IG-UBT neurons, which constitute an important element of the complex neuro-endocrine system involved in the regulation of the porcine urogenital organ function.

  17. Modification of CO2 avoidance behaviour in Drosophila by inhibitory odorants.

    Science.gov (United States)

    Turner, Stephanie Lynn; Ray, Anandasankar

    2009-09-10

    The fruitfly Drosophila melanogaster exhibits a robust and innate olfactory-based avoidance behaviour to CO(2), a component of odour emitted from stressed flies. Specialized neurons in the antenna and a dedicated neuronal circuit in the higher olfactory system mediate CO(2) detection and avoidance. However, fruitflies need to overcome this avoidance response in some environments that contain CO(2) such as ripening fruits and fermenting yeast, which are essential food sources. Very little is known about the molecular and neuronal basis of this unique, context-dependent modification of innate olfactory avoidance behaviour. Here we identify a new class of odorants present in food that directly inhibit CO(2)-sensitive neurons in the antenna. Using an in vivo expression system we establish that the odorants act on the Gr21a/Gr63a CO(2) receptor. The presence of these odorants significantly and specifically reduces CO(2)-mediated avoidance behaviour, as well as avoidance mediated by 'Drosophila stress odour'. We propose a model in which behavioural avoidance to CO(2) is directly influenced by inhibitory interactions of the novel odours with CO(2) receptors. Furthermore, we observe differences in the temporal dynamics of inhibition: the effect of one of these odorants lasts several minutes beyond the initial exposure. Notably, animals that have been briefly pre-exposed to this odorant do not respond to the CO(2) avoidance cue even after the odorant is no longer present. We also show that related odorants are effective inhibitors of the CO(2) response in Culex mosquitoes that transmit West Nile fever and filariasis. Our findings have broader implications in highlighting the important role of inhibitory odorants in olfactory coding, and in their potential to disrupt CO(2)-mediated host-seeking behaviour in disease-carrying insects like mosquitoes.

  18. Streptozotocin Inhibits Electrophysiological Determinants of Excitatory and Inhibitory Synaptic Transmission in CA1 Pyramidal Neurons of Rat Hippocampal Slices: Reduction of These Effects by Edaravone

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    Ting Ju

    2016-12-01

    Full Text Available Background: Streptozotocin (STZ has served as an agent to generate an Alzheimer's disease (AD model in rats, while edaravone (EDA, a novel free radical scavenger, has recently emerged as an effective treatment for use in vivo and vitro AD models. However, to date, these beneficial effects of EDA have only been clearly demonstrated within STZ-induced animal models of AD and in cell models of AD. A better understanding of the mechanisms of EDA may provide the opportunity for their clinical application in the treatment of AD. Therefore, the purpose of this study was to investigate the underlying mechanisms of STZ and EDA as assessed upon electrophysiological alterations in CA1 pyramidal neurons of rat hippocampal slices. Methods: Through measures of evoked excitatory postsynaptic currents (eEPSCs, AMPAR-mediated eEPSCs (eEPSCsAMPA, evoked inhibitory postsynaptic currents (eIPSCs, evoked excitatory postsynaptic current paired pulse ratio (eEPSC PPR and evoked inhibitory postsynaptic current paired pulse ratio (eIPSC PPR, it was possible to investigate mechanisms as related to the neurotoxicity of STZ and reductions in these effects by EDA. Results: Our results showed that STZ (1000 µM significantly inhibited peak amplitudes of eEPSCs, eEPSCsAMPA and eIPSCs, while EDA (1000 µM attenuated these STZ-induced changes at holding potentials ranging from -60mV to +40 mV for EPSCs and -60mV to +20 mV for IPSCs. Our work also indicated that mean eEPSC PPR were substantially altered by STZ, effects which were partially restored by EDA. In contrast, no significant effects upon eIPSC PPR were obtained in response to STZ and EDA. Conclusion: Our data suggest that STZ inhibits glutamatergic transmission involving pre-synaptic mechanisms and AMPAR, and that STZ inhibits GABAergic transmission by post-synaptic mechanisms within CA1 pyramidal neurons. These effects are attenuated by EDA.

  19. Spin orbit torque based electronic neuron

    Energy Technology Data Exchange (ETDEWEB)

    Sengupta, Abhronil, E-mail: asengup@purdue.edu; Choday, Sri Harsha; Kim, Yusung; Roy, Kaushik [School of Electrical and Computer Engineering, Purdue University, West Lafayette, Indiana 47907 (United States)

    2015-04-06

    A device based on current-induced spin-orbit torque (SOT) that functions as an electronic neuron is proposed in this work. The SOT device implements an artificial neuron's thresholding (transfer) function. In the first step of a two-step switching scheme, a charge current places the magnetization of a nano-magnet along the hard-axis, i.e., an unstable point for the magnet. In the second step, the SOT device (neuron) receives a current (from the synapses) which moves the magnetization from the unstable point to one of the two stable states. The polarity of the synaptic current encodes the excitatory and inhibitory nature of the neuron input and determines the final orientation of the magnetization. A resistive crossbar array, functioning as synapses, generates a bipolar current that is a weighted sum of the inputs. The simulation of a two layer feed-forward artificial neural network based on the SOT electronic neuron shows that it consumes ∼3× lower power than a 45 nm digital CMOS implementation, while reaching ∼80% accuracy in the classification of 100 images of handwritten digits from the MNIST dataset.

  20. Spin orbit torque based electronic neuron

    International Nuclear Information System (INIS)

    Sengupta, Abhronil; Choday, Sri Harsha; Kim, Yusung; Roy, Kaushik

    2015-01-01

    A device based on current-induced spin-orbit torque (SOT) that functions as an electronic neuron is proposed in this work. The SOT device implements an artificial neuron's thresholding (transfer) function. In the first step of a two-step switching scheme, a charge current places the magnetization of a nano-magnet along the hard-axis, i.e., an unstable point for the magnet. In the second step, the SOT device (neuron) receives a current (from the synapses) which moves the magnetization from the unstable point to one of the two stable states. The polarity of the synaptic current encodes the excitatory and inhibitory nature of the neuron input and determines the final orientation of the magnetization. A resistive crossbar array, functioning as synapses, generates a bipolar current that is a weighted sum of the inputs. The simulation of a two layer feed-forward artificial neural network based on the SOT electronic neuron shows that it consumes ∼3× lower power than a 45 nm digital CMOS implementation, while reaching ∼80% accuracy in the classification of 100 images of handwritten digits from the MNIST dataset

  1. Neurons from the adult human dentate nucleus: neural networks in the neuron classification.

    Science.gov (United States)

    Grbatinić, Ivan; Marić, Dušica L; Milošević, Nebojša T

    2015-04-07

    Topological (central vs. border neuron type) and morphological classification of adult human dentate nucleus neurons according to their quantified histomorphological properties using neural networks on real and virtual neuron samples. In the real sample 53.1% and 14.1% of central and border neurons, respectively, are classified correctly with total of 32.8% of misclassified neurons. The most important result present 62.2% of misclassified neurons in border neurons group which is even greater than number of correctly classified neurons (37.8%) in that group, showing obvious failure of network to classify neurons correctly based on computational parameters used in our study. On the virtual sample 97.3% of misclassified neurons in border neurons group which is much greater than number of correctly classified neurons (2.7%) in that group, again confirms obvious failure of network to classify neurons correctly. Statistical analysis shows that there is no statistically significant difference in between central and border neurons for each measured parameter (p>0.05). Total of 96.74% neurons are morphologically classified correctly by neural networks and each one belongs to one of the four histomorphological types: (a) neurons with small soma and short dendrites, (b) neurons with small soma and long dendrites, (c) neuron with large soma and short dendrites, (d) neurons with large soma and long dendrites. Statistical analysis supports these results (pneurons can be classified in four neuron types according to their quantitative histomorphological properties. These neuron types consist of two neuron sets, small and large ones with respect to their perykarions with subtypes differing in dendrite length i.e. neurons with short vs. long dendrites. Besides confirmation of neuron classification on small and large ones, already shown in literature, we found two new subtypes i.e. neurons with small soma and long dendrites and with large soma and short dendrites. These neurons are

  2. Puerarin exhibits greater distribution and longer retention time in neurons than astrocytes in a co-cultured system

    Directory of Open Access Journals (Sweden)

    Shu-Yong Wei

    2015-01-01

    Full Text Available The phytoestrogen puerarin has been shown to protect neurons and astrocytes in the brain, and is therefore an attractive drug in the treatment of Alzheimer′s disease, Parkinson′s disease and cerebral ischemia. Whether puerarin exhibits the same biological processes in neurons and astrocytes in vitro has rarely been reported. In this study, cortical neurons and astrocytes of newborn Sprague-Dawley rats were separated, identified and co-cultured in a system based on Transwell membranes. The retention time and distribution of puerarin in each cell type was detected by fluorescence spectrophotometry and fluorescence microscope. The concentration of puerarin in both co-cultured and separately cultured neurons was greater than that of astrocytes. Puerarin concentration reached a maximum 20 minutes after it was added. At 60 minutes after its addition, a scant amount of drug was detected in astrocytes; however in both separately cultured and co-cultured neurons, the concentration of puerarin achieved a stable level of about 12.8 ng/mL. The results indicate that puerarin had a higher concentration and longer retention time in neurons than that observed in astrocytes.

  3. TAURINE REGULATION OF VOLTAGE-GATED CHANNELS IN RETINAL NEURONS

    Science.gov (United States)

    Rowan, Matthew JM; Bulley, Simon; Purpura, Lauren; Ripps, Harris; Shen, Wen

    2017-01-01

    Taurine activates not only Cl−-permeable ionotropic receptors, but also receptors that mediate metabotropic responses. The metabotropic property of taurine was revealed in electrophysiological recordings obtained after fully blocking Cl−-permeable receptors with an inhibitory “cocktail” consisting of picrotoxin, SR95531, and strychnine. We found that taurine’s metabotropic effects regulate voltage-gated channels in retinal neurons. After applying the inhibitory cocktail, taurine enhanced delayed outward rectifier K+ channels preferentially in Off-bipolar cells, and the effect was completely blocked by the specific PKC inhibitor, GF109203X. Additionally, taurine also acted through a metabotropic pathway to suppress both L- and N-type Ca2+ channels in retinal neurons, which were insensitive to the potent GABAB receptor inhibitor, CGP55845. This study reinforces our previous finding that taurine in physiological concentrations produces a multiplicity of metabotropic effects that precisely govern the integration of signals being transmitted from the retina to the brain. PMID:23392926

  4. Heat pulse excitability of vestibular hair cells and afferent neurons.

    Science.gov (United States)

    Rabbitt, Richard D; Brichta, Alan M; Tabatabaee, Hessam; Boutros, Peter J; Ahn, JoongHo; Della Santina, Charles C; Poppi, Lauren A; Lim, Rebecca

    2016-08-01

    In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse) and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (ΔT ≈ 0.25°C per pulse). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each infrared heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with Q10 ≈ 2. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise (dT/dt) and an inward conduction current driven by ΔT An iberiotoxin-sensitive inhibitory conduction current was also evoked by ΔT, rising in protein biophysics and manipulate cellular excitability. Copyright © 2016 the American Physiological Society.

  5. Dysregulated Expression of Neuregulin-1 by Cortical Pyramidal Neurons Disrupts Synaptic Plasticity

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    Amit Agarwal

    2014-08-01

    Full Text Available Neuregulin-1 (NRG1 gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an “optimal” level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect.

  6. Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity.

    Science.gov (United States)

    Agarwal, Amit; Zhang, Mingyue; Trembak-Duff, Irina; Unterbarnscheidt, Tilmann; Radyushkin, Konstantin; Dibaj, Payam; Martins de Souza, Daniel; Boretius, Susann; Brzózka, Magdalena M; Steffens, Heinz; Berning, Sebastian; Teng, Zenghui; Gummert, Maike N; Tantra, Martesa; Guest, Peter C; Willig, Katrin I; Frahm, Jens; Hell, Stefan W; Bahn, Sabine; Rossner, Moritz J; Nave, Klaus-Armin; Ehrenreich, Hannelore; Zhang, Weiqi; Schwab, Markus H

    2014-08-21

    Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Wild-type minimal inhibitory concentration distributions in bacteria of animal origin in Argentina

    Directory of Open Access Journals (Sweden)

    Florencia L Pantozzi

    Full Text Available The aim of this study was to determine the antimicrobial resistance profiles of indicator bacteria isolated from domestic animal feces. Minimal inhibitory concentration (MIC was determined by agar dilution. Interpretative criteria on the basis of wild-type MIC distributions and epidemiological cutoff values (ECOFF or ECV were used according to the 'European Committee on Antimicrobial Susceptibility Testing' (EUCAST data. Results from 237 isolates of Escherichia coli showed reduced susceptibility for ampicillin, streptomycin and tetracycline, the antimicrobials commonly used in intensive breeding of pigs and hens. Regarding all the species of the genus Enterococcus spp., there are only ECOFF or ECV for vancomycin. Of the 173 Enterococcus spp. isolated, only one showed reduced susceptibility to vancomycin and was classified as 'non-wild-type' (NWT population. This is the first report in Argentina showing data of epidemiological cutoff values in animal bacteria.

  8. Crosstalks between kisspeptin neurons and somatostatin neurons are not photoperiod dependent in the ewe hypothalamus.

    Science.gov (United States)

    Dufourny, Laurence; Lomet, Didier

    2017-12-01

    Seasonal reproduction is under the control of gonadal steroid feedback, itself synchronized by day-length or photoperiod. As steroid action on GnRH neurons is mostly indirect and therefore exerted through interneurons, we looked for neuroanatomical interactions between kisspeptin (KP) neurons and somatostatin (SOM) neurons, two populations targeted by sex steroids, in three diencephalic areas involved in the central control of ovulation and/or sexual behavior: the arcuate nucleus (ARC), the preoptic area (POA) and the ventrolateral part of the ventromedial hypothalamus (VMHvl). KP is the most potent secretagogue of GnRH secretion while SOM has been shown to centrally inhibit LH pulsatile release. Notably, hypothalamic contents of these two neuropeptides vary with photoperiod in specific seasonal species. Our hypothesis is that SOM inhibits KP neuron activity and therefore indirectly modulate GnRH release and that this effect may be seasonally regulated. We used sections from ovariectomized estradiol-replaced ewes killed after photoperiodic treatment mimicking breeding or anestrus season. We performed triple immunofluorescent labeling to simultaneously detect KP, SOM and synapsin, a marker for synaptic vesicles. Sections from the POA and from the mediobasal hypothalamus were examined using a confocal microscope. Randomly selected KP or SOM neurons were observed in the POA and ARC. SOM neurons were also observed in the VMHvl. In both the ARC and POA, nearly all KP neurons presented numerous SOM contacts. SOM neurons presented KP terminals more frequently in the ARC than in the POA and VMHvl. Quantitative analysis failed to demonstrate major seasonal variations of KP and SOM interactions. Our data suggest a possible inhibitory action of SOM on all KP neurons in both photoperiodic statuses. On the other hand, the physiological significance of KP modulation of SOM neuron activity and vice versa remain to be determined. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. To Break or to Brake Neuronal Network Accelerated by Ammonium Ions?

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    Vladimir V Dynnik

    Full Text Available The aim of present study was to investigate the effects of ammonium ions on in vitro neuronal network activity and to search alternative methods of acute ammonia neurotoxicity prevention.Rat hippocampal neuronal and astrocytes co-cultures in vitro, fluorescent microscopy and perforated patch clamp were used to monitor the changes in intracellular Ca2+- and membrane potential produced by ammonium ions and various modulators in the cells implicated in neural networks.Low concentrations of NH4Cl (0.1-4 mM produce short temporal effects on network activity. Application of 5-8 mM NH4Cl: invariably transforms diverse network firing regimen to identical burst patterns, characterized by substantial neuronal membrane depolarization at plateau phase of potential and high-amplitude Ca2+-oscillations; raises frequency and average for period of oscillations Ca2+-level in all cells implicated in network; results in the appearance of group of «run out» cells with high intracellular Ca2+ and steadily diminished amplitudes of oscillations; increases astrocyte Ca2+-signalling, characterized by the appearance of groups of cells with increased intracellular Ca2+-level and/or chaotic Ca2+-oscillations. Accelerated network activity may be suppressed by the blockade of NMDA or AMPA/kainate-receptors or by overactivation of AMPA/kainite-receptors. Ammonia still activate neuronal firing in the presence of GABA(A receptors antagonist bicuculline, indicating that «disinhibition phenomenon» is not implicated in the mechanisms of networks acceleration. Network activity may also be slowed down by glycine, agonists of metabotropic inhibitory receptors, betaine, L-carnitine, L-arginine, etc.Obtained results demonstrate that ammonium ions accelerate neuronal networks firing, implicating ionotropic glutamate receptors, having preserved the activities of group of inhibitory ionotropic and metabotropic receptors. This may mean, that ammonia neurotoxicity might be prevented by

  10. Understanding metal homeostasis in primary cultured neurons. Studies using single neuron subcellular and quantitative metallomics.

    Science.gov (United States)

    Colvin, Robert A; Lai, Barry; Holmes, William R; Lee, Daewoo

    2015-07-01

    The purpose of this study was to demonstrate how single cell quantitative and subcellular metallomics inform us about both the spatial distribution and cellular mechanisms of metal buffering and homeostasis in primary cultured neurons from embryonic rat brain, which are often used as models of human disease involving metal dyshomeostasis. The present studies utilized synchrotron radiation X-ray fluorescence (SRXRF) and focused primarily on zinc and iron, two abundant metals in neurons that have been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Total single cell contents for calcium, iron, zinc, copper, manganese, and nickel were determined. Resting steady state zinc showed a diffuse distribution in both soma and processes, best defined by the mass profile of the neuron with an enrichment in the nucleus compared with the cytoplasm. Zinc buffering and homeostasis was studied using two modes of cellular zinc loading - transporter and ionophore (pyrithione) mediated. Single neuron zinc contents were shown to statistically significantly increase by either loading method - ionophore: 160 million to 7 billion; transporter 160 million to 280 million atoms per neuronal soma. The newly acquired and buffered zinc still showed a diffuse distribution. Soma and processes have about equal abilities to take up zinc via transporter mediated pathways. Copper levels are distributed diffusely as well, but are relatively higher in the processes relative to zinc levels. Prior studies have observed iron puncta in certain cell types, but others have not. In the present study, iron puncta were characterized in several primary neuronal types. The results show that iron puncta could be found in all neuronal types studied and can account for up to 50% of the total steady state content of iron in neuronal soma. Although other metals can be present in iron puncta, they are predominantly iron containing and do not appear to be

  11. Inhibitory effects of brain-derived neurotrophic factor precursor on viability and neurite growth of murine hippocampal neurons

    Directory of Open Access Journals (Sweden)

    Jia CHEN

    2014-10-01

    Full Text Available Objective To explore the mediation effect of p75 neurotrophin receptor (p75NTR in the effect of brainderived neurotrophic factor precursor (proBDNF on viability and neurite growth of murine hippocampal neurons. Methods  Hippocampal neurons were obtained from p75NTR+/+ and p75NTR-/- 18-day mice and primarily cultured. For p75NTR+/+ neurons, three experimental groups were set, i.e. control, proBDNF (30ng/ml, and proBDNF (30ng/ml+p75/Fc (30µg/ml groups. For p75NTR-/- neurons, two experimental groups were set, i.e. control and proBDNF (30ng/ml groups. MTT assays were performed after 24h to examine the viability of neonatal primary neurons. Immunofluorescent staining was conducted after 72h to investigate the neurite length. Results With MAP2 and DAPI double fluorescent staining it was identified that the neonatal hippocampal neurons were successfully cultured in vitro with high purity. For viability assay of p75NTR+/+ neurons, it was found that the absorbance value at 570nm (A570 in proBDNF group was significantly lower than that in control group (P0.05. With neurite growth assay of p75NTR+/+ neurons, it was found that the neurite length in proBDNF group was significantly shorter than that in control group (P0.05. With neurite growth assay of p75NTR-/- neurons, no difference in neurite length was observed between proBDNF group and control group. Conclusion proBDNF may inhibit the neuronal viability and neurite growth via p75NTR. DOI: 10.11855/j.issn.0577-7402.2014.09.03

  12. The role of GABA in the regulation of GnRH neurons

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    Miho eWatanabe

    2014-11-01

    Full Text Available Gonadotropin-releasing hormone (GnRH neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction.

  13. Inhibition of swallowing reflex following phosphorylation of extracellular signal-regulated kinase in nucleus tractus solitarii neurons in rats with masseter muscle nociception.

    Science.gov (United States)

    Tsujimura, Takanori; Kitagawa, Junichi; Ueda, Koichiro; Iwata, Koichi

    2009-02-06

    Pain is associated with swallowing abnormalities in dysphagic patients. Understanding neuronal mechanisms underlying the swallowing abnormalities associated with orofacial abnormal pain is crucial for developing new methods to treat dysphagic patients. However, how the orofacial abnormal pain is involved in the swallowing abnormalities is not known. In order to evaluate neuronal mechanisms of modulation of the swallows by masticatory muscle pain, here we first induced swallows by topical administration of distilled water to the pharyngolaryngeal region. The swallowing reflex was significantly inhibited after capsaicin (10, 30mM) injection into the masseter muscle compared to vehicle injection. Moreover the number of phosphorylated extracellular signal-regulated kinase-like immunoreactive (pERK-LI) neurons in the nucleus tractus solitarii (NTS) was significantly increased in the rats with capsaicin injection into the masseter muscle compared to that with vehicle injection. Rostro-caudal distribution of pERK-LI neurons in the NTS was peaked at the obex level. The capsaicin-induced inhibitory effect on swallowing reflex was reversed after intrathecal administration of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor, PD98059. The present findings suggest that phosphorylation of ERK in NTS neurons may be involved in capsaicin-induced inhibition of swallowing reflex.

  14. Phase-locking and bistability in neuronal networks with synaptic depression

    Science.gov (United States)

    Akcay, Zeynep; Huang, Xinxian; Nadim, Farzan; Bose, Amitabha

    2018-02-01

    We consider a recurrent network of two oscillatory neurons that are coupled with inhibitory synapses. We use the phase response curves of the neurons and the properties of short-term synaptic depression to define Poincaré maps for the activity of the network. The fixed points of these maps correspond to phase-locked modes of the network. Using these maps, we analyze the conditions that allow short-term synaptic depression to lead to the existence of bistable phase-locked, periodic solutions. We show that bistability arises when either the phase response curve of the neuron or the short-term depression profile changes steeply enough. The results apply to any Type I oscillator and we illustrate our findings using the Quadratic Integrate-and-Fire and Morris-Lecar neuron models.

  15. 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.

  16. Inhibitory Neural Regulation of the Ca2+ Transients in Intramuscular Interstitial Cells of Cajal in the Small Intestine

    Directory of Open Access Journals (Sweden)

    Salah A. Baker

    2018-04-01

    Full Text Available Gastrointestinal motility is coordinated by enteric neurons. Both inhibitory and excitatory motor neurons innervate the syncytium consisting of smooth muscle cells (SMCs interstitial cells of Cajal (ICC and PDGFRα+ cells (SIP syncytium. Confocal imaging of mouse small intestines from animals expressing GCaMP3 in ICC were used to investigate inhibitory neural regulation of ICC in the deep muscular plexus (ICC-DMP. We hypothesized that Ca2+ signaling in ICC-DMP can be modulated by inhibitory enteric neural input. ICC-DMP lie in close proximity to the varicosities of motor neurons and generate ongoing Ca2+ transients that underlie activation of Ca2+-dependent Cl− channels and regulate the excitability of SMCs in the SIP syncytium. Electrical field stimulation (EFS caused inhibition of Ca2+ for the first 2–3 s of stimulation, and then Ca2+ transients escaped from inhibition. The NO donor (DEA-NONOate inhibited Ca2+ transients and Nω-Nitro-L-arginine (L-NNA or a guanylate cyclase inhibitor (ODQ blocked inhibition induced by EFS. Purinergic neurotransmission did not affect Ca2+ transients in ICC-DMP. Purinergic neurotransmission elicits hyperpolarization of the SIP syncytium by activation of K+ channels in PDGFRα+ cells. Generalized hyperpolarization of SIP cells by pinacidil (KATP agonist or MRS2365 (P2Y1 agonist also had no effect on Ca2+ transients in ICC-DMP. Peptidergic transmitter receptors (VIP and PACAP are expressed in ICC and can modulate ICC-DMP Ca2+ transients. In summary Ca2+ transients in ICC-DMP are blocked by enteric inhibitory neurotransmission. ICC-DMP lack a voltage-dependent mechanism for regulating Ca2+ release, and this protects Ca2+ handling in ICC-DMP from membrane potential changes in other SIP cells.

  17. 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.

  18. Spatial distribution of human neocortical neurons and glial cells according to sex and age measured by the saucer method

    DEFF Research Database (Denmark)

    Stark, Anette Kirstine; Petersen, A O; Gardi, Jonathan Eyal

    2007-01-01

    primary neurons in the human neocortex (divided into frontal-, temporal-, parietal- and occipital cortex) of young and old subjects free of neurological or psychological disease to test if age and gender has any influence on the cell distribution in human neocortex. Plots of the spatial distribution...

  19. Morphology, classification, and distribution of the projection neurons in the dorsal lateral geniculate nucleus of the rat.

    Directory of Open Access Journals (Sweden)

    Changying Ling

    Full Text Available The morphology of confirmed projection neurons in the dorsal lateral geniculate nucleus (dLGN of the rat was examined by filling these cells retrogradely with biotinylated dextran amine (BDA injected into the visual cortex. BDA-labeled projection neurons varied widely in the shape and size of their cell somas, with mean cross-sectional areas ranging from 60-340 µm(2. Labeled projection neurons supported 7-55 dendrites that spanned up to 300 µm in length and formed dendritic arbors with cross-sectional areas of up to 7.0 × 10(4 µm(2. Primary dendrites emerged from cell somas in three broad patterns. In some dLGN projection neurons, primary dendrites arise from the cell soma at two poles spaced approximately 180° apart. In other projection neurons, dendrites emerge principally from one side of the cell soma, while in a third group of projection neurons primary dendrites emerge from the entire perimeter of the cell soma. Based on these three distinct patterns in the distribution of primary dendrites from cell somas, we have grouped dLGN projection neurons into three classes: bipolar cells, basket cells and radial cells, respectively. The appendages seen on dendrites also can be grouped into three classes according to differences in their structure. Short "tufted" appendages arise mainly from the distal branches of dendrites; "spine-like" appendages, fine stalks with ovoid heads, typically are seen along the middle segments of dendrites; and "grape-like" appendages, short stalks that terminate in a cluster of ovoid bulbs, appear most often along the proximal segments of secondary dendrites of neurons with medium or large cell somas. While morphologically diverse dLGN projection neurons are intermingled uniformly throughout the nucleus, the caudal pole of the dLGN contains more small projection neurons of all classes than the rostral pole.

  20. Selective serotonergic excitation of callosal projection neurons

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    Daniel eAvesar

    2012-03-01

    Full Text Available Serotonin (5-HT acting as a neurotransmitter in the cerebral cortex is critical for cognitive function, yet how 5-HT regulates information processing in cortical circuits is not well understood. We tested the serotonergic responsiveness of layer 5 pyramidal neurons (L5PNs of the mouse medial prefrontal cortex (mPFC, and found 3 distinct response types: long-lasting 5-HT1A (1A receptor-dependent inhibitory responses (84% of L5PNs, 5-HT2A (2A receptor-dependent excitatory responses (9%, and biphasic responses in which 2A-dependent excitation followed brief inhibition (5%. Relative to 5-HT-inhibited neurons, those excited by 5-HT had physiological properties characteristic of callosal/commissural (COM neurons that project to the contralateral cortex. We tested whether serotonergic responses in cortical pyramidal neurons are correlated with their axonal projection pattern using retrograde fluorescent labeling of COM and corticopontine-projecting (CPn neurons. 5-HT generated excitatory or biphasic responses in all 5-HT-responsive layer 5 COM neurons. Conversely, CPn neurons were universally inhibited by 5-HT. Serotonergic excitation of COM neurons was blocked by the 2A antagonist MDL 11939, while serotonergic inhibition of CPn neurons was blocked by the 1A antagonist WAY 100635, confirming a role for these two receptor subtypes in regulating pyramidal neuron activity. Selective serotonergic excitation of COM neurons was not layer-specific, as COM neurons in layer 2/3 were also selectively excited by 5-HT relative to their non-labeled pyramidal neuron neighbors. Because neocortical 2A receptors are implicated in the etiology and pathophysiology of schizophrenia, we propose that COM neurons may represent a novel cellular target for intervention in psychiatric disease.

  1. Distribution of the octopamine receptor AmOA1 in the honey bee brain.

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    Irina Sinakevitch

    2011-01-01

    Full Text Available Octopamine plays an important role in many behaviors in invertebrates. It acts via binding to G protein coupled receptors located on the plasma membrane of responsive cells. Several distinct subtypes of octopamine receptors have been found in invertebrates, yet little is known about the expression pattern of these different receptor subtypes and how each subtype may contribute to different behaviors. One honey bee (Apis mellifera octopamine receptor, AmOA1, was recently cloned and characterized. Here we continue to characterize the AmOA1 receptor by investigating its distribution in the honey bee brain. We used two independent antibodies produced against two distinct peptides in the carboxyl-terminus to study the distribution of the AmOA1 receptor in the honey bee brain. We found that both anti-AmOA1 antibodies revealed labeling of cell body clusters throughout the brain and within the following brain neuropils: the antennal lobes; the calyces, pedunculus, vertical (alpha, gamma and medial (beta lobes of the mushroom body; the optic lobes; the subesophageal ganglion; and the central complex. Double immunofluorescence staining using anti-GABA and anti-AmOA1 receptor antibodies revealed that a population of inhibitory GABAergic local interneurons in the antennal lobes express the AmOA1 receptor in the cell bodies, axons and their endings in the glomeruli. In the mushroom bodies, AmOA1 receptors are expressed in a subpopulation of inhibitory GABAergic feedback neurons that ends in the visual (outer half of basal ring and collar regions and olfactory (lip and inner basal ring region calyx neuropils, as well as in the collar and lip zones of the vertical and medial lobes. The data suggest that one effect of octopamine via AmOA1 in the antennal lobe and mushroom body is to modulate inhibitory neurons.

  2. Contribution of presynaptic HCN channels to excitatory inputs of spinal substantia gelatinosa neurons.

    Science.gov (United States)

    Peng, S-C; Wu, J; Zhang, D-Y; Jiang, C-Y; Xie, C-N; Liu, T

    2017-09-01

    Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are pathological pain-associated voltage-gated ion channels. They are widely expressed in central nervous system including spinal lamina II (also named the substantia gelatinosa, SG). Here, we examined the distribution of HCN channels in glutamatergic synaptic terminals as well as their role in the modulation of synaptic transmission in SG neurons from SD rats and glutamic acid decarboxylase-67 (GAD67)-GFP mice. We found that the expression of the HCN channel isoforms was varied in SG. The HCN4 isoform showed the highest level of co-localization with VGLUT2 (23±3%). In 53% (n=21/40 neurons) of the SG neurons examined in SD rats, application of HCN channel blocker, ZD7288 (10μM), decreased the frequency of spontaneous (s) and miniature (m) excitatory postsynaptic currents (EPSCs) by 37±4% and 33±4%, respectively. Consistently, forskolin (FSK) (an activator of adenylate cyclase) significantly increased the frequency of mEPSCs by 225±34%, which could be partially inhibited by ZD7288. Interestingly, the effects of ZD7288 and FSK on sEPSC frequency were replicated in non-GFP-expressing neurons, but not in GFP-expressing GABAergic SG neurons, in GAD67-GFP transgenic C57/BL6 mice. In summary, our results represent a previously unknown cellular mechanism by which presynaptic HCN channels, especially HCN4, regulate the glutamate release from presynaptic terminals that target excitatory, but not inhibitory SG interneurons. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Synchronization in a non-uniform network of excitatory spiking neurons

    Science.gov (United States)

    Echeveste, Rodrigo; Gros, Claudius

    Spontaneous synchronization of pulse coupled elements is ubiquitous in nature and seems to be of vital importance for life. Networks of pacemaker cells in the heart, extended populations of southeast asian fireflies, and neuronal oscillations in cortical networks, are examples of this. In the present work, a rich repertoire of dynamical states with different degrees of synchronization are found in a network of excitatory-only spiking neurons connected in a non-uniform fashion. In particular, uncorrelated and partially correlated states are found without the need for inhibitory neurons or external currents. The phase transitions between these states, as well the robustness, stability, and response of the network to external stimulus are studied.

  4. Stochastic models for spike trains of single neurons

    CERN Document Server

    Sampath, G

    1977-01-01

    1 Some basic neurophysiology 4 The neuron 1. 1 4 1. 1. 1 The axon 7 1. 1. 2 The synapse 9 12 1. 1. 3 The soma 1. 1. 4 The dendrites 13 13 1. 2 Types of neurons 2 Signals in the nervous system 14 2. 1 Action potentials as point events - point processes in the nervous system 15 18 2. 2 Spontaneous activi~ in neurons 3 Stochastic modelling of single neuron spike trains 19 3. 1 Characteristics of a neuron spike train 19 3. 2 The mathematical neuron 23 4 Superposition models 26 4. 1 superposition of renewal processes 26 4. 2 Superposition of stationary point processe- limiting behaviour 34 4. 2. 1 Palm functions 35 4. 2. 2 Asymptotic behaviour of n stationary point processes superposed 36 4. 3 Superposition models of neuron spike trains 37 4. 3. 1 Model 4. 1 39 4. 3. 2 Model 4. 2 - A superposition model with 40 two input channels 40 4. 3. 3 Model 4. 3 4. 4 Discussion 41 43 5 Deletion models 5. 1 Deletion models with 1nd~endent interaction of excitatory and inhibitory sequences 44 VI 5. 1. 1 Model 5. 1 The basic de...

  5. 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.

  6. Differential Expression of Dopamine D5 Receptors across Neuronal Subtypes in Macaque Frontal Eye Field

    Directory of Open Access Journals (Sweden)

    Adrienne Mueller

    2018-02-01

    Full Text Available Dopamine signaling in the prefrontal cortex (PFC is important for cognitive functions, yet very little is known about the expression of the D5 class of dopamine receptors (D5Rs in this region. To address this, we co-stained for D5Rs, pyramidal neurons (neurogranin+, putative long-range projection pyramidal neurons (SMI-32+, and several classes of inhibitory interneuron (parvalbumin+, calbindin+, calretinin+, somatostatin+ within the frontal eye field (FEF: an area within the PFC involved in the control of visual spatial attention. We then quantified the co-expression of D5Rs with markers of different cell types across different layers of the FEF. We show that: (1 D5Rs are more prevalent on pyramidal neurons than on inhibitory interneurons. (2 D5Rs are disproportionately expressed on putative long-range projecting pyramidal neurons. The disproportionately high expression of D5Rs on long-range projecting pyramidals, compared to interneurons, was particularly pronounced in layers II–III. Together these results indicate that the engagement of D5R-dependent mechanisms in the FEF varies depending on cell type and cortical layer, and suggests that non-locally projecting neurons contribute disproportionately to functions involving the D5R subtype.

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

    OpenAIRE

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

    2015-01-01

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

  8. Spatial interactions reveal inhibitory cortical networks in human amblyopia.

    Science.gov (United States)

    Wong, Erwin H; Levi, Dennis M; McGraw, Paul V

    2005-10-01

    Humans with amblyopia have a well-documented loss of sensitivity for first-order, or luminance defined, visual information. Recent studies show that they also display a specific loss of sensitivity for second-order, or contrast defined, visual information; a type of image structure encoded by neurons found predominantly in visual area A18/V2. In the present study, we investigate whether amblyopia disrupts the normal architecture of spatial interactions in V2 by determining the contrast detection threshold of a second-order target in the presence of second-order flanking stimuli. Adjacent flanks facilitated second-order detectability in normal observers. However, in marked contrast, they suppressed detection in each eye of the majority of amblyopic observers. Furthermore, strabismic observers with no loss of visual acuity show a similar pattern of detection suppression. We speculate that amblyopia results in predominantly inhibitory cortical interactions between second-order neurons.

  9. Heat pulse excitability of vestibular hair cells and afferent neurons

    Science.gov (United States)

    Brichta, Alan M.; Tabatabaee, Hessam; Boutros, Peter J.; Ahn, JoongHo; Della Santina, Charles C.; Poppi, Lauren A.; Lim, Rebecca

    2016-01-01

    In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse) and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (ΔT ≈ 0.25°C per pulse). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each infrared heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with Q10 ≈ 2. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise (dT/dt) and an inward conduction current driven by ΔT. An iberiotoxin-sensitive inhibitory conduction current was also evoked by ΔT, rising in heat pulse excitability in vestibular sensory organs and provide quantitative methods for rational application of optical heat pulses to examine protein biophysics and manipulate cellular excitability. PMID:27226448

  10. The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release.

    Science.gov (United States)

    Rau, Andrew R; Hentges, Shane T

    2017-08-02

    Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of μ-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation. SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons play an important role in driving food intake, while proopiomelanocortin (POMC) neurons inhibit feeding. Despite the importance of these two well characterized neuron types in maintaining metabolic homeostasis, communication between these

  11. Muscarinic receptors modulate dendrodendritic inhibitory synapses to sculpt glomerular output.

    Science.gov (United States)

    Liu, Shaolin; Shao, Zuoyi; Puche, Adam; Wachowiak, Matt; Rothermel, Markus; Shipley, Michael T

    2015-04-08

    Cholinergic [acetylcholine (ACh)] axons from the basal forebrain innervate olfactory bulb glomeruli, the initial site of synaptic integration in the olfactory system. Both nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs) are expressed in glomeruli. The activation of nAChRs directly excites both mitral/tufted cells (MTCs) and external tufted cells (ETCs), the two major excitatory neurons that transmit glomerular output. The functional roles of mAChRs in glomerular circuits are unknown. We show that the restricted glomerular application of ACh causes rapid, brief nAChR-mediated excitation of both MTCs and ETCs in the mouse olfactory bulb. This excitation is followed by mAChR-mediated inhibition, which is blocked by GABAA receptor antagonists, indicating the engagement of periglomerular cells (PGCs) and/or short axon cells (SACs), the two major glomerular inhibitory neurons. Indeed, selective activation of glomerular mAChRs, with ionotropic GluRs and nAChRs blocked, increased IPSCs in MTCs and ETCs, indicating that mAChRs recruit glomerular inhibitory circuits. Selective activation of glomerular mAChRs in the presence of tetrodotoxin increased IPSCs in all glomerular neurons, indicating action potential-independent enhancement of GABA release from PGC and/or SAC dendrodendritic synapses. mAChR-mediated enhancement of GABA release also presynaptically suppressed the first synapse of the olfactory system via GABAB receptors on sensory terminals. Together, these results indicate that cholinergic modulation of glomerular circuits is biphasic, involving an initial excitation of MTC/ETCs mediated by nAChRs followed by inhibition mediated directly by mAChRs on PGCs/SACs. This may phasically enhance the sensitivity of glomerular outputs to odorants, an action that is consistent with recent in vivo findings. Copyright © 2015 the authors 0270-6474/15/355680-13$15.00/0.

  12. Latency modulation of collicular neurons induced by electric stimulation of the auditory cortex in Hipposideros pratti: In vivo intracellular recording.

    Directory of Open Access Journals (Sweden)

    Kang Peng

    Full Text Available In the auditory pathway, the inferior colliculus (IC receives and integrates excitatory and inhibitory inputs from the lower auditory nuclei, contralateral IC, and auditory cortex (AC, and then uploads these inputs to the thalamus and cortex. Meanwhile, the AC modulates the sound signal processing of IC neurons, including their latency (i.e., first-spike latency. Excitatory and inhibitory corticofugal projections to the IC may shorten and prolong the latency of IC neurons, respectively. However, the synaptic mechanisms underlying the corticofugal latency modulation of IC neurons remain unclear. Thus, this study probed these mechanisms via in vivo intracellular recording and acoustic and focal electric stimulation. The AC latency modulation of IC neurons is possibly mediated by pre-spike depolarization duration, pre-spike hyperpolarization duration, and spike onset time. This study suggests an effective strategy for the timing sequence determination of auditory information uploaded to the thalamus and cortex.

  13. Spiking irregularity and frequency modulate the behavioral report of single-neuron stimulation.

    Science.gov (United States)

    Doron, Guy; von Heimendahl, Moritz; Schlattmann, Peter; Houweling, Arthur R; Brecht, Michael

    2014-02-05

    The action potential activity of single cortical neurons can evoke measurable sensory effects, but it is not known how spiking parameters and neuronal subtypes affect the evoked sensations. Here, we examined the effects of spike train irregularity, spike frequency, and spike number on the detectability of single-neuron stimulation in rat somatosensory cortex. For regular-spiking, putative excitatory neurons, detectability increased with spike train irregularity and decreasing spike frequencies but was not affected by spike number. Stimulation of single, fast-spiking, putative inhibitory neurons led to a larger sensory effect compared to regular-spiking neurons, and the effect size depended only on spike irregularity. An ideal-observer analysis suggests that, under our experimental conditions, rats were using integration windows of a few hundred milliseconds or more. Our data imply that the behaving animal is sensitive to single neurons' spikes and even to their temporal patterning. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Beyond the frontiers of neuronal types

    Science.gov (United States)

    Battaglia, Demian; Karagiannis, Anastassios; Gallopin, Thierry; Gutch, Harold W.; Cauli, Bruno

    2012-01-01

    Cortical neurons and, particularly, inhibitory interneurons display a large diversity of morphological, synaptic, electrophysiological, and molecular properties, as well as diverse embryonic origins. Various authors have proposed alternative classification schemes that rely on the concomitant observation of several multimodal features. However, a broad variability is generally observed even among cells that are grouped into a same class. Furthermore, the attribution of specific neurons to a single defined class is often difficult, because individual properties vary in a highly graded fashion, suggestive of continua of features between types. Going beyond the description of representative traits of distinct classes, we focus here on the analysis of atypical cells. We introduce a novel paradigm for neuronal type classification, assuming explicitly the existence of a structured continuum of diversity. Our approach, grounded on the theory of fuzzy sets, identifies a small optimal number of model archetypes. At the same time, it quantifies the degree of similarity between these archetypes and each considered neuron. This allows highlighting archetypal cells, which bear a clear similarity to a single model archetype, and edge cells, which manifest a convergence of traits from multiple archetypes. PMID:23403725

  15. Beyond the frontiers of neuronal types

    Directory of Open Access Journals (Sweden)

    Demian eBattaglia

    2013-02-01

    Full Text Available Cortical neurons and, particularly, inhibitory interneurons display a large diversity of morphological, synaptic, electrophysiological and molecular properties, as well as diverse embryonic origins. Various authors have proposed alternative classification schemes that rely on the concomitant observation of several multimodal features. However, a broad variability is generally observed even among cells that are grouped into a same class. Furthermore, the attribution of specific neurons to a single defined class is often difficult, because individual properties vary in a highly graded fashion, suggestive of continua of features between types. Going beyond the description of representative traits of distinct classes, we focus here on the analysis of atypical cells. We introduce a novel paradigm for neuronal type classification, assuming explicitly the existence of a structured continuum of diversity. Our approach, grounded on the theory of fuzzy sets, identifies a small optimal number of model archetypes. At the same time, it quantifies the degree of similarity between these archetypes and each considered neuron. This allows highlighting archetypal cells, which bear a clear similarity to a single model archetype, and edge cells, which manifest a convergence of traits from multiple archetypes.

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

    Science.gov (United States)

    Lemieux, Maxime; Chauvette, Sylvain; Timofeev, Igor

    2015-02-01

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

  17. Spatial distribution of intermingling pools of projection neurons with distinct targets: A 3D analysis of the commissural ganglia in Cancer borealis.

    Science.gov (United States)

    Follmann, Rosangela; Goldsmith, Christopher John; Stein, Wolfgang

    2017-06-01

    Projection neurons play a key role in carrying long-distance information between spatially distant areas of the nervous system and in controlling motor circuits. Little is known about how projection neurons with distinct anatomical targets are organized, and few studies have addressed their spatial organization at the level of individual cells. In the paired commissural ganglia (CoGs) of the stomatogastric nervous system of the crab Cancer borealis, projection neurons convey sensory, motor, and modulatory information to several distinct anatomical regions. While the functions of descending projection neurons (dPNs) which control downstream motor circuits in the stomatogastric ganglion are well characterized, their anatomical distribution as well as that of neurons projecting to the labrum, brain, and thoracic ganglion have received less attention. Using cell membrane staining, we investigated the spatial distribution of CoG projection neurons in relation to all CoG neurons. Retrograde tracing revealed that somata associated with different axonal projection pathways were not completely spatially segregated, but had distinct preferences within the ganglion. Identified dPNs had diameters larger than 70% of CoG somata and were restricted to the most medial and anterior 25% of the ganglion. They were contained within a cluster of motor neurons projecting through the same nerve to innervate the labrum, indicating that soma position was independent of function and target area. Rather, our findings suggest that CoG neurons projecting to a variety of locations follow a generalized rule: for all nerve pathway origins, the soma cluster centroids in closest proximity are those whose axons project down that pathway. © 2017 Wiley Periodicals, Inc.

  18. Most superficial sublamina of rat superior colliculus: neuronal response properties and correlates with perceptual figure-ground segregation.

    Science.gov (United States)

    Girman, S V; Lund, R D

    2007-07-01

    The uppermost layer (stratum griseum superficiale, SGS) of the superior colliculus (SC) provides an important gateway from the retina to the visual extrastriate and visuomotor systems. The majority of attention has been given to the role of this "visual" SC in saccade generation and target selection and it is generally considered to be less important in visual perception. We have found, however, that in the rat SGS1, the most superficial division of the SGS, the neurons perform very sophisticated analysis of visual information. First, in studying their responses with a variety of flashing stimuli we found that the neurons respond not to brightness changes per se, but to the appearance and/or disappearance of visual shapes in their receptive fields (RFs). Contrary to conventional RFs of neurons at the early stages of visual processing, the RFs in SGS1 cannot be described in terms of fixed spatial distribution of excitatory and inhibitory inputs. Second, SGS1 neurons showed robust orientation tuning to drifting gratings and orientation-specific modulation of the center response from surround. These are features previously seen only in visual cortical neurons and are considered to be involved in "contour" perception and figure-ground segregation. Third, responses of SGS1 neurons showed complex dynamics; typically the response tuning became progressively sharpened with repetitive grating periods. We conclude that SGS1 neurons are involved in considerably more complex analysis of retinal input than was previously thought. SGS1 may participate in early stages of figure-ground segregation and have a role in low-resolution nonconscious vision as encountered after visual decortication.

  19. Reward, interrupted: Inhibitory control and its relevance to addictions.

    Science.gov (United States)

    Jentsch, James David; Pennington, Zachary T

    2014-01-01

    There are broad individual differences in the ability to voluntarily and effortfully suppress motivated, reward-seeking behaviors, and this review presents the hypothesis that these individual differences are relevant to addictive disorders. On one hand, cumulative experience with drug abuse appears to alter the molecular, cellular and circuit mechanisms that mediate inhibitory abilities, leading to increasingly uncontrolled patterns of drug-seeking and -taking. On the other, native inter-individual differences in inhibitory control are apparently a risk factor for aspects of drug-reinforced responding and substance use disorders. In both cases, the behavioral manifestation of poor inhibitory abilities is linked to relatively low striatal dopamine D2-like receptor availability, and evidence is accumulating for a more direct contribution of striatopallidal neurons to cognitive control processes. Mechanistic research is now identifying genes upstream of dopamine transmission that mediate these relationships, as well as the involvement of other neurotransmitter systems, acting alone and in concert with dopamine. The reviewed research stands poised to identify new mechanisms that can be targeted by pharmacotherapies and/or by behavioral interventions that are designed to prevent or treat addictive behaviors and associated behavioral pathology. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats

    OpenAIRE

    Urakawa, Susumu; Takamoto, Kouich; Hori, Etsuro; Sakai, Natsuko; Ono, Taketoshi; Nishijo, Hisao

    2013-01-01

    Background Early life experiences including physical exercise, sensory stimulation, and social interaction can modulate development of the inhibitory neuronal network and modify various behaviors. In particular, alteration of parvalbumin-expressing neurons, a gamma-aminobutyric acid (GABA)ergic neuronal subpopulation, has been suggested to be associated with psychiatric disorders. Here we investigated whether rearing in enriched environment could modify the expression of parvalbumin-positive ...

  1. Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission

    Science.gov (United States)

    Accardi, Michael V.; Daniels, Bryan A.; Brown, Patricia M. G. E.; Fritschy, Jean-Marc; Tyagarajan, Shiva K.; Bowie, Derek

    2014-01-01

    Neuronal communication imposes a heavy metabolic burden in maintaining ionic gradients essential for action potential firing and synaptic signalling. Although cellular metabolism is known to regulate excitatory neurotransmission, it is still unclear whether the brain’s energy supply affects inhibitory signalling. Here we show that mitochondrial-derived reactive oxygen species (mROS) regulate the strength of postsynaptic GABAA receptors at inhibitory synapses of cerebellar stellate cells. Inhibition is strengthened through a mechanism that selectively recruits α3-containing GABAA receptors into synapses with no discernible effect on resident α1-containing receptors. Since mROS promotes the emergence of postsynaptic events with unique kinetic properties, we conclude that newly recruited α3-containing GABAA receptors are activated by neurotransmitter released onto discrete postsynaptic sites. Although traditionally associated with oxidative stress in neurodegenerative disease, our data identify mROS as a putative homeostatic signalling molecule coupling cellular metabolism to the strength of inhibitory transmission.

  2. Distribution of Fos-Like Immunoreactivity, Catecholaminergic and Serotoninergic Neurons Activated by the Laryngeal Chemoreflex in the Medulla Oblongata of Rats.

    Science.gov (United States)

    Wang, Xiaolu; Guo, Ruichen; Zhao, Wenjing

    2015-01-01

    The laryngeal chemoreflex (LCR) induces apnea, glottis closure, bradycardia and hypertension in young and maturing mammals. We examined the distribution of medullary nuclei that are activated by the LCR and used immunofluorescent detection of Fos protein as a cellular marker for neuronal activation to establish that the medullary catecholaminergic and serotoninergic neurons participate in the modulation of the LCR. The LCR was elicited by the infusion of KCl-HCl solution into the laryngeal lumen of adult rats in the experimental group, whereas the control group received the same surgery but no infusion. In comparison, the number of regions of Fos-like immunoreactivity (FLI) that were activated by the LCR significantly increased in the nucleus of the solitary tract (NTS), the vestibular nuclear complex (VNC), the loose formation of the nucleus ambiguus (AmbL), the rostral ventral respiratory group (RVRG), the ventrolateral reticular complex (VLR), the pre-Bötzinger complex (PrBöt), the Bötzinger complex (Böt), the spinal trigeminal nucleus (SP5), and the raphe obscurus nucleus (ROb) bilaterally from the medulla oblongata. Furthermore, 12.71% of neurons with FLI in the dorsolateral part of the nucleus of the solitary tract (SolDL) showed tyrosine hydroxylase-immunoreactivity (TH-ir, catecholaminergic), and 70.87% of neurons with FLI in the ROb were serotoninergic. Our data demonstrated the distribution of medullary nuclei that were activated by the LCR, and further demonstrated that catecholaminergic neurons of the SolDL and serotoninergic neurons of the ROb were activated by the LCR, indicating the potential central pathway of the LCR.

  3. Distribution of Fos-Like Immunoreactivity, Catecholaminergic and Serotoninergic Neurons Activated by the Laryngeal Chemoreflex in the Medulla Oblongata of Rats.

    Directory of Open Access Journals (Sweden)

    Xiaolu Wang

    Full Text Available The laryngeal chemoreflex (LCR induces apnea, glottis closure, bradycardia and hypertension in young and maturing mammals. We examined the distribution of medullary nuclei that are activated by the LCR and used immunofluorescent detection of Fos protein as a cellular marker for neuronal activation to establish that the medullary catecholaminergic and serotoninergic neurons participate in the modulation of the LCR. The LCR was elicited by the infusion of KCl-HCl solution into the laryngeal lumen of adult rats in the experimental group, whereas the control group received the same surgery but no infusion. In comparison, the number of regions of Fos-like immunoreactivity (FLI that were activated by the LCR significantly increased in the nucleus of the solitary tract (NTS, the vestibular nuclear complex (VNC, the loose formation of the nucleus ambiguus (AmbL, the rostral ventral respiratory group (RVRG, the ventrolateral reticular complex (VLR, the pre-Bötzinger complex (PrBöt, the Bötzinger complex (Böt, the spinal trigeminal nucleus (SP5, and the raphe obscurus nucleus (ROb bilaterally from the medulla oblongata. Furthermore, 12.71% of neurons with FLI in the dorsolateral part of the nucleus of the solitary tract (SolDL showed tyrosine hydroxylase-immunoreactivity (TH-ir, catecholaminergic, and 70.87% of neurons with FLI in the ROb were serotoninergic. Our data demonstrated the distribution of medullary nuclei that were activated by the LCR, and further demonstrated that catecholaminergic neurons of the SolDL and serotoninergic neurons of the ROb were activated by the LCR, indicating the potential central pathway of the LCR.

  4. Modulation of Apoptosis Controls Inhibitory Interneuron Number in the Cortex

    Directory of Open Access Journals (Sweden)

    Myrto Denaxa

    2018-02-01

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

  5. VTA GABA neurons modulate specific learning behaviours through the control of dopamine and cholinergic systems

    Directory of Open Access Journals (Sweden)

    Meaghan C Creed

    2014-01-01

    Full Text Available The mesolimbic reward system is primarily comprised of the ventral tegmental area (VTA and the nucleus accumbens (NAc as well as their afferent and efferent connections. This circuitry is essential for learning about stimuli associated with motivationally-relevant outcomes. Moreover, addictive drugs affect and remodel this system, which may underlie their addictive properties. In addition to DA neurons, the VTA also contains approximately 30% ɣ-aminobutyric acid (GABA neurons. The task of signalling both rewarding and aversive events from the VTA to the NAc has mostly been ascribed to DA neurons and the role of GABA neurons has been largely neglected until recently. GABA neurons provide local inhibition of DA neurons and also long-range inhibition of projection regions, including the NAc. Here we review studies using a combination of in vivo and ex vivo electrophysiology, pharmacogenetic and optogenetic manipulations that have characterized the functional neuroanatomy of inhibitory circuits in the mesolimbic system, and describe how GABA neurons of the VTA regulate reward and aversion-related learning. We also discuss pharmacogenetic manipulation of this system with benzodiazepines (BDZs, a class of addictive drugs, which act directly on GABAA receptors located on GABA neurons of the VTA. The results gathered with each of these approaches suggest that VTA GABA neurons bi-directionally modulate activity of local DA neurons, underlying reward or aversion at the behavioural level. Conversely, long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons (CINs to pause their firing and temporarily reduce cholinergic tone in the NAc, which modulates associative learning. Further characterization of inhibitory circuit function within and beyond the VTA is needed in order to fully understand the function of the mesolimbic system under normal and pathological conditions.

  6. Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea.

    Science.gov (United States)

    Sulk, Mathias; Seeliger, Stephan; Aubert, Jerome; Schwab, Verena D; Cevikbas, Ferda; Rivier, Michel; Nowak, Pawel; Voegel, Johannes J; Buddenkotte, Jörg; Steinhoff, Martin

    2012-04-01

    Rosacea is a frequent chronic inflammatory skin disease of unknown etiology. Because early rosacea reveals all characteristics of neurogenic inflammation, a central role of sensory nerves in its pathophysiology has been discussed. Neuroinflammatory mediators and their receptors involved in rosacea are poorly defined. Good candidates may be transient receptor potential (TRP) ion channels of vanilloid type (TRPV), which can be activated by many trigger factors of rosacea. Interestingly, TRPV2, TRPV3, and TRPV4 are expressed by both neuronal and non-neuronal cells. Here, we analyzed the expression and distribution of TRPV receptors in the various subtypes of rosacea on non-neuronal cells using immunohistochemistry, morphometry, double immunoflourescence, and quantitative real-time PCR (qRT-PCR) as compared with healthy skin and lupus erythematosus. Our results show that dermal immunolabeling of TRPV2 and TRPV3 and gene expression of TRPV1 is significantly increased in erythematotelangiectatic rosacea (ETR). Papulopustular rosacea (PPR) displayed an enhanced immunoreactivity for TRPV2, TRPV4, and also of TRPV2 gene expression. In phymatous rosacea (PhR)-affected skin, dermal immunostaining of TRPV3 and TRPV4 and gene expression of TRPV1 and TRPV3 was enhanced, whereas epidermal TRPV2 staining was decreased. Thus, dysregulation of TRPV channels also expressed by non-neuronal cells may be critically involved in the initiation and/or development of rosacea. TRP ion channels may be targets for the treatment of rosacea.

  7. Eigenvalue distributions for a class of covariance matrices with application to Bienenstock-Cooper-Munro neurons under noisy conditions.

    Science.gov (United States)

    Bazzani, Armando; Castellani, Gastone C; Cooper, Leon N

    2010-05-01

    We analyze the effects of noise correlations in the input to, or among, Bienenstock-Cooper-Munro neurons using the Wigner semicircular law to construct random, positive-definite symmetric correlation matrices and compute their eigenvalue distributions. In the finite dimensional case, we compare our analytic results with numerical simulations and show the effects of correlations on the lifetimes of synaptic strengths in various visual environments. These correlations can be due either to correlations in the noise from the input lateral geniculate nucleus neurons, or correlations in the variability of lateral connections in a network of neurons. In particular, we find that for fixed dimensionality, a large noise variance can give rise to long lifetimes of synaptic strengths. This may be of physiological significance.

  8. Enhancing action of LSD on neuronal responsiveness to serotonin in a brain structure involved in obsessive-compulsive disorder.

    Science.gov (United States)

    Zghoul, Tarek; Blier, Pierre

    2003-03-01

    Potent serotonin (5-HT) reuptake inhibitors are the only drugs that consistently exert a therapeutic action in obsessive-compulsive disorder (OCD). Given that some hallucinogens were reported to exert an anti-OCD effect outlasting their psychotomimetic action, possible modifications of neuronal responsiveness to 5-HT by LSD were examined in two rat brain structures: one associated with OCD, the orbitofrontal cortex (OFC), and another linked to depression, the hippocampus. The effects of concurrent microiontophoretic application of LSD and 5-HT were examined on neuronal firing rate in the rat OFC and hippocampus under chloral hydrate anaesthesia. In order to determine whether LSD could also exert a modification of 5-HT neuronal responsiveness upon systemic administration, after a delay when hallucinosis is presumably no longer present, it was given once daily (100 microg/kg i.p.) for 4 d and the experiments were carried out 24 h after the last dose. LSD attenuated the firing activity of OFC neurons, and enhanced the inhibitory effect of 5-HT when concomitantly ejected on the same neurons. In the hippocampus, LSD also decreased firing rate by itself but decreased the inhibitory action of 5-HT. The inhibitory action of 5-HT was significantly greater in the OFC, but smaller in the hippocampus, when examined after subacute systemic administration of LSD. It is postulated that some hallucinogens could have a beneficial action in OCD by enhancing the responsiveness to 5-HT in the OFC, and not necessarily in direct relation to hallucinosis. The latter observation may have theoretical implications for the pharmacotherapy of OCD.

  9. The distribution of excitatory amino acid receptors on acutely dissociated dorsal horn neurons from postnatal rats.

    Science.gov (United States)

    Arancio, O; Yoshimura, M; Murase, K; MacDermott, A B

    1993-01-01

    Excitatory amino acid receptor distribution was mapped on acutely dissociated neurons from postnatal rat spinal cord dorsal horn. N-methyl D-aspartate, quisqualate and kainate were applied to multiple locations along the somal and dendritic surfaces of voltage-clamped neurons by means of a pressure application system. To partially compensate for the decrement of response amplitude due to current loss between the site of activation on the dendrite and the recording electrode at the soma, a solution containing 0.15 M KCl was applied on the cell bodies and dendrites of some cells to estimate an empirical length constant. In the majority of the cells tested, the dendritic membrane had regions of higher sensitivity to excitatory amino acid agonists than the somatic membrane, with dendritic response amplitudes reaching more than seven times those at the cell body. A comparison of the relative changes in sensitivity between each combination of two of the three excitatory amino acid agonists along the same dendrite showed different patterns of agonist sensitivity along the dendrite in the majority of the cells. These data were obtained from dorsal horn neurons that had developed and formed synaptic connections in vivo. They demonstrate that in contrast to observations made on ventral horn neurons, receptor density for all the excitatory amino acid receptors on dorsal horn neurons, including the N-methyl-D-aspartate receptor, are generally higher on the dendrites than on the soma. Further, these results are similar to those obtained from dorsal horn neurons grown in culture.

  10. Synthetic ciguatoxin CTX 3C induces a rapid imbalance in neuronal excitability.

    Science.gov (United States)

    Martín, Victor; Vale, Carmen; Hirama, Masahiro; Yamashita, Shuji; Rubiolo, Juan Andrés; Vieytes, Mercedes R; Botana, Luis M

    2015-06-15

    Ciguatera is a human global disease caused by the consumption of contaminated fish that have accumulated ciguatoxins (CTXs), sodium channel activator toxins. Symptoms of ciguatera include neurological alterations such as paraesthesiae, dysaesthesiae, depression, and heightened nociperception, among others. An important issue to understand these long-term neurological alterations is to establish the role that changes in activity produced by CTX 3C represent to neurons. Here, the effects of synthetic ciguatoxin CTX 3C on membrane potential, spontaneous spiking, and properties of synaptic transmission in cultured cortical neurons of 11-18 days in vitro (DIV) were evaluated using electrophysiological approaches. CTX 3C induced a large depolarization that decreased neuronal firing and caused a rapid inward tonic current that was primarily GABAergic. Moreover, the toxin enhanced the amplitude of miniature postsynaptic inhibitory currents (mIPSCs), whereas it decreased the amplitude of miniature postsynaptic excitatory currents (mEPSCs). The frequency of mIPSCs increased, whereas the frequency of mEPSCs remained unaltered. We describe, for the first time, that a rapid membrane depolarization caused by CTX 3C in cortical neurons activates mechanisms that tend to suppress electrical activity by shifting the balance between excitatory and inhibitory synaptic transmission toward inhibition. Indeed, these results suggest that the acute effects of CTX on synaptic transmission could underlie some of the neurological symptoms caused by ciguatera in humans.

  11. Extrasynaptic glycine receptors of rodent dorsal raphe serotonergic neurons:a sensitive target for ethanol

    OpenAIRE

    Maguire, Edward P.; Mitchell, Elizabeth A.; Greig, Scott J.; Corteen, Nicole; Balfour, David J. K.; Swinny, Jerome; Lambert, Jeremy J.; Belelli, Delia

    2014-01-01

    Alcohol abuse is a significant medical and social problem. Several neurotransmitter systems are implicated in ethanol's actions, with certain receptors and ion channels emerging as putative targets. The dorsal raphe (DR) nucleus is associated with the behavioral actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterize DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inh...

  12. Organization of left-right coordination of neuronal activity in the mammalian spinal cord

    DEFF Research Database (Denmark)

    Shevtsova, Natalia A.; Talpalar, Adolfo E.; Markin, Sergey N.

    2015-01-01

    and the left-right synchronous hopping-like pattern in mutants lacking specific neuron classes, and speed-dependent asymmetric changes of flexor and extensor phase durations. The models provide insights into the architecture of spinal network and the organization of parallel inhibitory and excitatory CIN....... In this study, we construct and analyse two computational models of spinal locomotor circuits consisting of left and right rhythm generators interacting bilaterally via several neuronal pathways mediated by different CINs. The CIN populations incorporated in the models include the genetically identified...... inhibitory (V0D) and excitatory (V0V) subtypes of V0 CINs and excitatory V3 CINs. The model also includes the ipsilaterally projecting excitatory V2a interneurons mediating excitatory drive to the V0V CINs. The proposed network architectures and CIN connectivity allow the models to closely reproduce...

  13. Interactions between superficial and deep dorsal horn spinal cord neurons in the processing of nociceptive information.

    Science.gov (United States)

    Petitjean, Hugues; Rodeau, Jean-Luc; Schlichter, Rémy

    2012-12-01

    In acute rat spinal cord slices, the application of capsaicin (5 μm, 90 s), an agonist of transient receptor potential vanilloid 1 receptors expressed by a subset of nociceptors that project to laminae I-II of the spinal cord dorsal horn, induced an increase in the frequency of spontaneous excitatory and spontaneous inhibitory postsynaptic currents in about half of the neurons in laminae II, III-IV and V. In the presence of tetrodotoxin, which blocks action potential generation and polysynaptic transmission, capsaicin increased the frequency of miniature excitatory postsynaptic currents in only 30% of lamina II neurons and had no effect on the frequency of miniature excitatory postsynaptic currents in laminae III-V or on the frequency of miniature inhibitory postsynaptic currents in laminae II-V. When the communication between lamina V and more superficial laminae was interrupted by performing a mechanical section between laminae IV and V, capsaicin induced an increase in spontaneous excitatory postsynaptic current frequency in laminae II-IV and an increase in spontaneous inhibitory postsynaptic current frequency in lamina II that were similar to those observed in intact slices. However, in laminae III-IV of transected slices, the increase in spontaneous inhibitory postsynaptic current frequency was virtually abolished. Our results indicate that nociceptive information conveyed by transient receptor potential vanilloid 1-expressing nociceptors is transmitted from lamina II to deeper laminae essentially by an excitatory pathway and that deep laminae exert a 'feedback' control over neurons in laminae III-IV by increasing inhibitory synaptic transmission in these laminae. Moreover, we provide evidence that laminae III-IV might play an important role in the processing of nociceptive information in the dorsal horn. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  14. Involvement of ERK phosphorylation in brainstem neurons in modulation of swallowing reflex in rats

    Science.gov (United States)

    Tsujimura, Takanori; Kondo, Masahiro; Kitagawa, Junichi; Tsuboi, Yoshiyuki; Saito, Kimiko; Tohara, Haruka; Ueda, Koichiro; Sessle, Barry J; Iwata, Koichi

    2009-01-01

    In order to evaluate the neuronal mechanisms underlying functional abnormalities of swallowing in orofacial pain patients, this study investigated the effects of noxious orofacial stimulation on the swallowing reflex, phosphorylated extracellular signal-regulated kinase (pERK) and γ-aminobutyric acid (GABA) immunohistochemical features in brainstem neurons, and also analysed the effects of brainstem lesioning and of microinjection of GABA receptor agonist or antagonist into the nucleus tractus solitarii (NTS) on the swallowing reflex in anaesthetized rats. The swallowing reflex elicited by topical administration of distilled water to the pharyngolaryngeal region was inhibited after capsaicin injection into the facial (whisker pad) skin or lingual muscle. The capsaicin-induced inhibitory effect on the swallowing reflex was itself depressed after the intrathecal administration of MAPK kinase (MEK) inhibitor. No change in the capsaicin-induced inhibitory effect was observed after trigeminal spinal subnucleus caudalis lesioning, but the inhibitory effect was diminished by paratrigeminal nucleus (Pa5) lesioning. Many pERK-like immunoreactive neurons in the NTS showed GABA immunoreactivity. The local microinjection of the GABAA receptor agonist muscimol into the NTS produced a significant reduction in swallowing reflex, and the capsaicin-induced depression of the swallowing reflex was abolished by microinjection of the GABAA receptor antagonist bicuculline into the NTS. The present findings suggest that facial skin–NTS, lingual muscle–NTS and lingual muscle–Pa5–NTS pathways are involved in the modulation of swallowing reflex by facial and lingual pain, respectively, and that the activation of GABAergic NTS neurons is involved in the inhibition of the swallowing reflex following noxious stimulation of facial and intraoral structures. PMID:19124539

  15. Involvement of ERK phosphorylation in brainstem neurons in modulation of swallowing reflex in rats.

    Science.gov (United States)

    Tsujimura, Takanori; Kondo, Masahiro; Kitagawa, Junichi; Tsuboi, Yoshiyuki; Saito, Kimiko; Tohara, Haruka; Ueda, Koichiro; Sessle, Barry J; Iwata, Koichi

    2009-02-15

    In order to evaluate the neuronal mechanisms underlying functional abnormalities of swallowing in orofacial pain patients, this study investigated the effects of noxious orofacial stimulation on the swallowing reflex, phosphorylated extracellular signal-regulated kinase (pERK) and gamma-aminobutyric acid (GABA) immunohistochemical features in brainstem neurons, and also analysed the effects of brainstem lesioning and of microinjection of GABA receptor agonist or antagonist into the nucleus tractus solitarii (NTS) on the swallowing reflex in anaesthetized rats. The swallowing reflex elicited by topical administration of distilled water to the pharyngolaryngeal region was inhibited after capsaicin injection into the facial (whisker pad) skin or lingual muscle. The capsaicin-induced inhibitory effect on the swallowing reflex was itself depressed after the intrathecal administration of MAPK kinase (MEK) inhibitor. No change in the capsaicin-induced inhibitory effect was observed after trigeminal spinal subnucleus caudalis lesioning, but the inhibitory effect was diminished by paratrigeminal nucleus (Pa5) lesioning. Many pERK-like immunoreactive neurons in the NTS showed GABA immunoreactivity. The local microinjection of the GABA(A) receptor agonist muscimol into the NTS produced a significant reduction in swallowing reflex, and the capsaicin-induced depression of the swallowing reflex was abolished by microinjection of the GABA(A) receptor antagonist bicuculline into the NTS. The present findings suggest that facial skin-NTS, lingual muscle-NTS and lingual muscle-Pa5-NTS pathways are involved in the modulation of swallowing reflex by facial and lingual pain, respectively, and that the activation of GABAergic NTS neurons is involved in the inhibition of the swallowing reflex following noxious stimulation of facial and intraoral structures.

  16. Efficient Coding and Energy Efficiency Are Promoted by Balanced Excitatory and Inhibitory Synaptic Currents in Neuronal Network.

    Science.gov (United States)

    Yu, Lianchun; Shen, Zhou; Wang, Chen; Yu, Yuguo

    2018-01-01

    Selective pressure may drive neural systems to process as much information as possible with the lowest energy cost. Recent experiment evidence revealed that the ratio between synaptic excitation and inhibition (E/I) in local cortex is generally maintained at a certain value which may influence the efficiency of energy consumption and information transmission of neural networks. To understand this issue deeply, we constructed a typical recurrent Hodgkin-Huxley network model and studied the general principles that governs the relationship among the E/I synaptic current ratio, the energy cost and total amount of information transmission. We observed in such a network that there exists an optimal E/I synaptic current ratio in the network by which the information transmission achieves the maximum with relatively low energy cost. The coding energy efficiency which is defined as the mutual information divided by the energy cost, achieved the maximum with the balanced synaptic current. Although background noise degrades information transmission and imposes an additional energy cost, we find an optimal noise intensity that yields the largest information transmission and energy efficiency at this optimal E/I synaptic transmission ratio. The maximization of energy efficiency also requires a certain part of energy cost associated with spontaneous spiking and synaptic activities. We further proved this finding with analytical solution based on the response function of bistable neurons, and demonstrated that optimal net synaptic currents are capable of maximizing both the mutual information and energy efficiency. These results revealed that the development of E/I synaptic current balance could lead a cortical network to operate at a highly efficient information transmission rate at a relatively low energy cost. The generality of neuronal models and the recurrent network configuration used here suggest that the existence of an optimal E/I cell ratio for highly efficient energy

  17. Synchronous behavior of two coupled electronic neurons

    International Nuclear Information System (INIS)

    Pinto, R. D.; Varona, P.; Volkovskii, A. R.; Szuecs, A.; Abarbanel, Henry D. I.; Rabinovich, M. I.

    2000-01-01

    We report on experimental studies of synchronization phenomena in a pair of analog electronic neurons (ENs). The ENs were designed to reproduce the observed membrane voltage oscillations of isolated biological neurons from the stomatogastric ganglion of the California spiny lobster Panulirus interruptus. The ENs are simple analog circuits which integrate four-dimensional differential equations representing fast and slow subcellular mechanisms that produce the characteristic regular/chaotic spiking-bursting behavior of these cells. In this paper we study their dynamical behavior as we couple them in the same configurations as we have done for their counterpart biological neurons. The interconnections we use for these neural oscillators are both direct electrical connections and excitatory and inhibitory chemical connections: each realized by analog circuitry and suggested by biological examples. We provide here quantitative evidence that the ENs and the biological neurons behave similarly when coupled in the same manner. They each display well defined bifurcations in their mutual synchronization and regularization. We report briefly on an experiment on coupled biological neurons and four-dimensional ENs, which provides further ground for testing the validity of our numerical and electronic models of individual neural behavior. Our experiments as a whole present interesting new examples of regularization and synchronization in coupled nonlinear oscillators. (c) 2000 The American Physical Society

  18. Glucose-monitoring neurons in the mediodorsal prefrontal cortex.

    Science.gov (United States)

    Nagy, Bernadett; Szabó, István; Papp, Szilárd; Takács, Gábor; Szalay, Csaba; Karádi, Zoltán

    2012-03-20

    The mediodorsal prefrontal cortex (mdPFC), a key structure of the limbic neural circuitry, plays important roles in the central regulation of feeding. As an integrant part of the forebrain dopamine (DA) system, it performs complex roles via interconnections with various brain areas where glucose-monitoring (GM) neurons have been identified. The main goal of the present experiments was to examine whether similar GM neurons exist in the mediodorsal prefrontal cortex. To search for such chemosensory cells here, and to estimate their involvement in the DA circuitry, extracellular single neuron activity of the mediodorsal prefrontal cortex of anesthetized Wistar and Sprague-Dawley rats was recorded by means of tungsten wire multibarreled glass microelectrodes during microelectrophoretic administration of d-glucose and DA. One fourth of the neurons tested changed in firing rate in response to glucose, thus, proved to be elements of the forebrain GM neural network. DA responsive neurons in the mdPFC were found to represent similar proportion of all cells; the glucose-excited units were shown to display excitatory whereas the glucose-inhibited neurons were demonstrated to exert mainly inhibitory responses to dopamine. The glucose-monitoring neurons of the mdPFC and their distinct DA sensitivity are suggested to be of particular significance in adaptive processes of the central feeding control. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Inactivation of the infragranular striate cortex broadens orientation tuning of supragranular visual neurons in the cat.

    Science.gov (United States)

    Allison, J D; Bonds, A B

    1994-01-01

    Intracortical inhibition is believed to enhance the orientation tuning of striate cortical neurons, but the origin of this inhibition is unclear. To examine the possible influence of ascending inhibitory projections from the infragranular layers of striate cortex on the orientation selectivity of neurons in the supragranular layers, we measured the spatiotemporal response properties of 32 supragranular neurons in the cat before, during, and after neural activity in the infragranular layers beneath the recorded cells was inactivated by iontophoretic administration of GABA. During GABA iontophoresis, the orientation tuning bandwidth of 15 (46.9%) supragranular neurons broadened as a result of increases in response amplitude to stimuli oriented about +/- 20 degrees away from the preferred stimulus angle. The mean (+/- SD) baseline orientation tuning bandwidth (half width at half height) of these neurons was 13.08 +/- 2.3 degrees. Their mean tuning bandwidth during inactivation of the infragranular layers increased to 19.59 +/- 2.54 degrees, an increase of 49.7%. The mean percentage increase in orientation tuning bandwidth of the individual neurons was 47.4%. Four neurons exhibited symmetrical changes in their orientation tuning functions, while 11 neurons displayed asymmetrical changes. The change in form of the orientation tuning functions appeared to depend on the relative vertical alignment of the recorded neuron and the infragranular region of inactivation. Neurons located in close vertical register with the inactivated infragranular tissue exhibited symmetric changes in their orientation tuning functions. The neurons exhibiting asymmetric changes in their orientation tuning functions were located just outside the vertical register. Eight of these 11 neurons also demonstrated a mean shift of 6.67 +/- 5.77 degrees in their preferred stimulus orientation. The magnitude of change in the orientation tuning functions increased as the delivery of GABA was prolonged

  20. A reanalysis of "Two types of asynchronous activity in networks of excitatory and inhibitory spiking neurons".

    Science.gov (United States)

    Engelken, Rainer; Farkhooi, Farzad; Hansel, David; van Vreeswijk, Carl; Wolf, Fred

    2016-01-01

    Neuronal activity in the central nervous system varies strongly in time and across neuronal populations. It is a longstanding proposal that such fluctuations generically arise from chaotic network dynamics. Various theoretical studies predict that the rich dynamics of rate models operating in the chaotic regime can subserve circuit computation and learning. Neurons in the brain, however, communicate via spikes and it is a theoretical challenge to obtain similar rate fluctuations in networks of spiking neuron models. A recent study investigated spiking balanced networks of leaky integrate and fire (LIF) neurons and compared their dynamics to a matched rate network with identical topology, where single unit input-output functions were chosen from isolated LIF neurons receiving Gaussian white noise input. A mathematical analogy between the chaotic instability in networks of rate units and the spiking network dynamics was proposed. Here we revisit the behavior of the spiking LIF networks and these matched rate networks. We find expected hallmarks of a chaotic instability in the rate network: For supercritical coupling strength near the transition point, the autocorrelation time diverges. For subcritical coupling strengths, we observe critical slowing down in response to small external perturbations. In the spiking network, we found in contrast that the timescale of the autocorrelations is insensitive to the coupling strength and that rate deviations resulting from small input perturbations rapidly decay. The decay speed even accelerates for increasing coupling strength. In conclusion, our reanalysis demonstrates fundamental differences between the behavior of pulse-coupled spiking LIF networks and rate networks with matched topology and input-output function. In particular there is no indication of a corresponding chaotic instability in the spiking network.

  1. Generation of Induced Neuronal Cells by the Single Reprogramming Factor ASCL1

    Directory of Open Access Journals (Sweden)

    Soham Chanda

    2014-08-01

    Full Text Available Direct conversion of nonneural cells to functional neurons holds great promise for neurological disease modeling and regenerative medicine. We previously reported rapid reprogramming of mouse embryonic fibroblasts (MEFs into mature induced neuronal (iN cells by forced expression of three transcription factors: ASCL1, MYT1L, and BRN2. Here, we show that ASCL1 alone is sufficient to generate functional iN cells from mouse and human fibroblasts and embryonic stem cells, indicating that ASCL1 is the key driver of iN cell reprogramming in different cell contexts and that the role of MYT1L and BRN2 is primarily to enhance the neuronal maturation process. ASCL1-induced single-factor neurons (1F-iN expressed mature neuronal markers, exhibited typical passive and active intrinsic membrane properties, and formed functional pre- and postsynaptic structures. Surprisingly, ASCL1-induced iN cells were predominantly excitatory, demonstrating that ASCL1 is permissive but alone not deterministic for the inhibitory neuronal lineage.

  2. Short-Term Depression, Temporal Summation, and Onset Inhibition Shape Interval Tuning in Midbrain Neurons

    Science.gov (United States)

    Baker, Christa A.

    2014-01-01

    A variety of synaptic mechanisms can contribute to single-neuron selectivity for temporal intervals in sensory stimuli. However, it remains unknown how these mechanisms interact to establish single-neuron sensitivity to temporal patterns of sensory stimulation in vivo. Here we address this question in a circuit that allows us to control the precise temporal patterns of synaptic input to interval-tuned neurons in behaviorally relevant ways. We obtained in vivo intracellular recordings under multiple levels of current clamp from midbrain neurons in the mormyrid weakly electric fish Brienomyrus brachyistius during stimulation with electrosensory pulse trains. To reveal the excitatory and inhibitory inputs onto interval-tuned neurons, we then estimated the synaptic conductances underlying responses. We found short-term depression in excitatory and inhibitory pathways onto all interval-tuned neurons. Short-interval selectivity was associated with excitation that depressed less than inhibition at short intervals, as well as temporally summating excitation. Long-interval selectivity was associated with long-lasting onset inhibition. We investigated tuning after separately nullifying the contributions of temporal summation and depression, and found the greatest diversity of interval selectivity among neurons when both mechanisms were at play. Furthermore, eliminating the effects of depression decreased sensitivity to directional changes in interval. These findings demonstrate that variation in depression and summation of excitation and inhibition helps to establish tuning to behaviorally relevant intervals in communication signals, and that depression contributes to neural coding of interval sequences. This work reveals for the first time how the interplay between short-term plasticity and temporal summation mediates the decoding of temporal sequences in awake, behaving animals. PMID:25339741

  3. Detection of 5-hydroxytryptamine (5-HT) in vitro using a hippocampal neuronal network-based biosensor with extracellular potential analysis of neurons.

    Science.gov (United States)

    Hu, Liang; Wang, Qin; Qin, Zhen; Su, Kaiqi; Huang, Liquan; Hu, Ning; Wang, Ping

    2015-04-15

    5-hydroxytryptamine (5-HT) is an important neurotransmitter in regulating emotions and related behaviors in mammals. To detect and monitor the 5-HT, effective and convenient methods are demanded in investigation of neuronal network. In this study, hippocampal neuronal networks (HNNs) endogenously expressing 5-HT receptors were employed as sensing elements to build an in vitro neuronal network-based biosensor. The electrophysiological characteristics were analyzed in both neuron and network levels. The firing rates and amplitudes were derived from signal to determine the biosensor response characteristics. The experimental results demonstrate a dose-dependent inhibitory effect of 5-HT on hippocampal neuron activities, indicating the effectiveness of this hybrid biosensor in detecting 5-HT with a response range from 0.01μmol/L to 10μmol/L. In addition, the cross-correlation analysis of HNNs activities suggests 5-HT could weaken HNN connectivity reversibly, providing more specificity of this biosensor in detecting 5-HT. Moreover, 5-HT induced spatiotemporal firing pattern alterations could be monitored in neuron and network levels simultaneously by this hybrid biosensor in a convenient and direct way. With those merits, this neuronal network-based biosensor will be promising to be a valuable and utility platform for the study of neurotransmitter in vitro. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network

    Science.gov (United States)

    Weick, Jason P.; Liu, Yan; Zhang, Su-Chun

    2011-01-01

    Whether hESC-derived neurons can fully integrate with and functionally regulate an existing neural network remains unknown. Here, we demonstrate that hESC-derived neurons receive unitary postsynaptic currents both in vitro and in vivo and adopt the rhythmic firing behavior of mouse cortical networks via synaptic integration. Optical stimulation of hESC-derived neurons expressing Channelrhodopsin-2 elicited both inhibitory and excitatory postsynaptic currents and triggered network bursting in mouse neurons. Furthermore, light stimulation of hESC-derived neurons transplanted to the hippocampus of adult mice triggered postsynaptic currents in host pyramidal neurons in acute slice preparations. Thus, hESC-derived neurons can participate in and modulate neural network activity through functional synaptic integration, suggesting they are capable of contributing to neural network information processing both in vitro and in vivo. PMID:22106298

  5. Orientation selectivity of synaptic input to neurons in mouse and cat primary visual cortex.

    Science.gov (United States)

    Tan, Andrew Y Y; Brown, Brandon D; Scholl, Benjamin; Mohanty, Deepankar; Priebe, Nicholas J

    2011-08-24

    Primary visual cortex (V1) is the site at which orientation selectivity emerges in mammals: visual thalamus afferents to V1 respond equally to all stimulus orientations, whereas their target V1 neurons respond selectively to stimulus orientation. The emergence of orientation selectivity in V1 has long served as a model for investigating cortical computation. Recent evidence for orientation selectivity in mouse V1 opens cortical computation to dissection by genetic and imaging tools, but also raises two essential questions: (1) How does orientation selectivity in mouse V1 neurons compare with that in previously described species? (2) What is the synaptic basis for orientation selectivity in mouse V1? A comparison of orientation selectivity in mouse and in cat, where such measures have traditionally been made, reveals that orientation selectivity in mouse V1 is weaker than in cat V1, but that spike threshold plays a similar role in narrowing selectivity between membrane potential and spike rate. To uncover the synaptic basis for orientation selectivity, we made whole-cell recordings in vivo from mouse V1 neurons, comparing neuronal input selectivity-based on membrane potential, synaptic excitation, and synaptic inhibition-to output selectivity based on spiking. We found that a neuron's excitatory and inhibitory inputs are selective for the same stimulus orientations as is its membrane potential response, and that inhibitory selectivity is not broader than excitatory selectivity. Inhibition has different dynamics than excitation, adapting more rapidly. In neurons with temporally modulated responses, the timing of excitation and inhibition was different in mice and cats.

  6. Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma

    NARCIS (Netherlands)

    Maarsingh, H; Leusink, J; Bos, I Sophie T; Zaagsma, J; Meurs, H

    2006-01-01

    Background: Using guinea pig tracheal preparations, we have recently shown that endogenous arginase activity attenuates inhibitory nonadrenergic noncholinergic (iNANC) nerve-mediated airway smooth muscle relaxation by reducing nitric oxide (NO) production - due to competition with neuronal

  7. Transmitter modulation of spike-evoked calcium transients in arousal related neurons

    DEFF Research Database (Denmark)

    Kohlmeier, Kristi Anne; Leonard, Christopher S

    2006-01-01

    Nitric oxide synthase (NOS)-containing cholinergic neurons in the laterodorsal tegmentum (LDT) influence behavioral and motivational states through their projections to the thalamus, ventral tegmental area and a brainstem 'rapid eye movement (REM)-induction' site. Action potential-evoked intracel......Nitric oxide synthase (NOS)-containing cholinergic neurons in the laterodorsal tegmentum (LDT) influence behavioral and motivational states through their projections to the thalamus, ventral tegmental area and a brainstem 'rapid eye movement (REM)-induction' site. Action potential......-evoked intracellular calcium transients dampen excitability and stimulate NO production in these neurons. In this study, we investigated the action of several arousal-related neurotransmitters and the role of specific calcium channels in these LDT Ca(2+)-transients by simultaneous whole-cell recording and calcium...... of cholinergic LDT neurons and that inhibition of spike-evoked Ca(2+)-transients is a common action of neurotransmitters that also activate GIRK channels in these neurons. Because spike-evoked calcium influx dampens excitability, our findings suggest that these 'inhibitory' transmitters could boost firing rate...

  8. Transcriptional dysregulation of γ-aminobutyric acid transporter in parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia.

    Science.gov (United States)

    Bitanihirwe, Byron K Y; Woo, Tsung-Ung W

    2014-12-30

    Parvalbumin (PV)-containing neurons are functionally compromised in schizophrenia. Using double in situ hybridization in postmortem human prefrontal cortex, we found that the messenger RNA (mRNA) for the γ-aminobutyric acid (GABA) transporter GAT-1 was undetectable in 22-41% of PV neurons in layers 3-4 in schizophrenia. In the remaining PV neurons with detectable GAT-1 mRNA, transcript expression was decreased by 26% in layer 3. Hence, the dysfunction of PV neurons involves the molecular dysregulation of presynaptic GABA reuptake. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. A unified framework for spiking and gap-junction interactions in distributed neuronal network simulations

    Directory of Open Access Journals (Sweden)

    Jan eHahne

    2015-09-01

    Full Text Available Contemporary simulators for networks of point and few-compartment model neurons come with a plethora of ready-to-use neuron and synapse models and support complex network topologies. Recent technological advancements have broadened the spectrum of application further to the efficient simulation of brain-scale networks on supercomputers. In distributed network simulations the amount of spike data that accrues per millisecond and process is typically low, such that a common optimization strategy is to communicate spikes at relatively long intervals, where the upper limit is given by the shortest synaptic transmission delay in the network. This approach is well-suited for simulations that employ only chemical synapses but it has so far impeded the incorporation of gap-junction models, which require instantaneous neuronal interactions. Here, we present a numerical algorithm based on a waveform-relaxation technique which allows for network simulations with gap junctions in a way that is compatible with the delayed communication strategy. Using a reference implementation in the NEST simulator, we demonstrate that the algorithm and the required data structures can be smoothly integrated with existing code such that they complement the infrastructure for spiking connections. To show that the unified framework for gap-junction and spiking interactions achieves high performance and delivers high accuracy...

  10. The signaling role for chloride in the bidirectional communication between neurons and astrocytes.

    Science.gov (United States)

    Wilson, Corinne S; Mongin, Alexander A

    2018-01-09

    It is well known that the electrical signaling in neuronal networks is modulated by chloride (Cl - ) fluxes via the inhibitory GABA A and glycine receptors. Here, we discuss the putative contribution of Cl - fluxes and intracellular Cl - to other forms of information transfer in the CNS, namely the bidirectional communication between neurons and astrocytes. The manuscript (i) summarizes the generic functions of Cl - in cellular physiology, (ii) recaps molecular identities and properties of Cl - transporters and channels in neurons and astrocytes, and (iii) analyzes emerging studies implicating Cl - in the modulation of neuroglial communication. The existing literature suggests that neurons can alter astrocytic Cl - levels in a number of ways; via (a) the release of neurotransmitters and activation of glial transporters that have intrinsic Cl - conductance, (b) the metabotropic receptor-driven changes in activity of the electroneutral cation-Cl - cotransporter NKCC1, and (c) the transient, activity-dependent changes in glial cell volume which open the volume-regulated Cl - /anion channel VRAC. Reciprocally, astrocytes are thought to alter neuronal [Cl - ] i through either (a) VRAC-mediated release of the inhibitory gliotransmitters, GABA and taurine, which open neuronal GABA A and glycine receptor/Cl - channels, or (b) the gliotransmitter-driven stimulation of NKCC1. The most important recent developments in this area are the identification of the molecular composition and functional heterogeneity of brain VRAC channels, and the discovery of a new cytosolic [Cl - ] sensor - the Wnk family protein kinases. With new work in the field, our understanding of the role of Cl - in information processing within the CNS is expected to be significantly updated. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Motor Neurons

    DEFF Research Database (Denmark)

    Hounsgaard, Jorn

    2017-01-01

    Motor neurons translate synaptic input from widely distributed premotor networks into patterns of action potentials that orchestrate motor unit force and motor behavior. Intercalated between the CNS and muscles, motor neurons add to and adjust the final motor command. The identity and functional...... in in vitro preparations is far from complete. Nevertheless, a foundation has been provided for pursuing functional significance of intrinsic response properties in motoneurons in vivo during motor behavior at levels from molecules to systems....

  12. Balance of excitation and inhibition determines 1/f power spectrum in neuronal networks.

    Science.gov (United States)

    Lombardi, F; Herrmann, H J; de Arcangelis, L

    2017-04-01

    The 1/f-like decay observed in the power spectrum of electro-physiological signals, along with scale-free statistics of the so-called neuronal avalanches, constitutes evidence of criticality in neuronal systems. Recent in vitro studies have shown that avalanche dynamics at criticality corresponds to some specific balance of excitation and inhibition, thus suggesting that this is a basic feature of the critical state of neuronal networks. In particular, a lack of inhibition significantly alters the temporal structure of the spontaneous avalanche activity and leads to an anomalous abundance of large avalanches. Here, we study the relationship between network inhibition and the scaling exponent β of the power spectral density (PSD) of avalanche activity in a neuronal network model inspired in Self-Organized Criticality. We find that this scaling exponent depends on the percentage of inhibitory synapses and tends to the value β = 1 for a percentage of about 30%. More specifically, β is close to 2, namely, Brownian noise, for purely excitatory networks and decreases towards values in the interval [1, 1.4] as the percentage of inhibitory synapses ranges between 20% and 30%, in agreement with experimental findings. These results indicate that the level of inhibition affects the frequency spectrum of resting brain activity and suggest the analysis of the PSD scaling behavior as a possible tool to study pathological conditions.

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

    Science.gov (United States)

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

    2018-05-23

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

  14. Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis.

    Science.gov (United States)

    Guerrero-Alba, Raquel; Valdez-Morales, Eduardo E; Jimenez-Vargas, Nestor N; Lopez-Lopez, Cintya; Jaramillo-Polanco, Josue; Okamoto, Takanobu; Nasser, Yasmin; Bunnett, Nigel W; Lomax, Alan E; Vanner, Stephen J

    2017-12-01

    Psychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways. Mouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca 2+ imaging techniques. Supernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca 2+ responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits. Stress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. Dopamine D1-D2 receptor heteromer in dual phenotype GABA/glutamate-coexpressing striatal medium spiny neurons: regulation of BDNF, GAD67 and VGLUT1/2.

    Directory of Open Access Journals (Sweden)

    Melissa L Perreault

    Full Text Available In basal ganglia a significant subset of GABAergic medium spiny neurons (MSNs coexpress D1 and D2 receptors (D1R and D2R along with the neuropeptides dynorphin (DYN and enkephalin (ENK. These coexpressing neurons have been recently shown to have a region-specific distribution throughout the mesolimbic and basal ganglia circuits. While the functional relevance of these MSNs remains relatively unexplored, they have been shown to exhibit the unique property of expressing the dopamine D1-D2 receptor heteromer, a novel receptor complex with distinct pharmacology and cell signaling properties. Here we showed that MSNs coexpressing the D1R and D2R also exhibited a dual GABA/glutamate phenotype. Activation of the D1R-D2R heteromer in these neurons resulted in the simultaneous, but differential regulation of proteins involved in GABA and glutamate production or vesicular uptake in the nucleus accumbens (NAc, ventral tegmental area (VTA, caudate putamen and substantia nigra (SN. Additionally, activation of the D1R-D2R heteromer in NAc shell, but not NAc core, differentially altered protein expression in VTA and SN, regions rich in dopamine cell bodies. The identification of a MSN with dual inhibitory and excitatory intrinsic functions provides new insights into the neuroanatomy of the basal ganglia and demonstrates a novel source of glutamate in this circuit. Furthermore, the demonstration of a dopamine receptor complex with the potential to differentially regulate the expression of proteins directly involved in GABAergic inhibitory or glutamatergic excitatory activation in VTA and SN may potentially provide new insights into the regulation of dopamine neuron activity. This could have broad implications in understanding how dysregulation of neurotransmission within basal ganglia contributes to dopamine neuronal dysfunction.

  16. Synchronization of the small-world neuronal network with unreliable synapses

    International Nuclear Information System (INIS)

    Li, Chunguang; Zheng, Qunxian

    2010-01-01

    As is well known, synchronization phenomena are ubiquitous in neuronal systems. Recently a lot of work concerning the synchronization of the neuronal network has been accomplished. In these works, the synapses are usually considered reliable, but experimental results show that, in biological neuronal networks, synapses are usually unreliable. In our previous work, we have studied the synchronization of the neuronal network with unreliable synapses; however, we have not paid attention to the effect of topology on the synchronization of the neuronal network. Several recent studies have found that biological neuronal networks have typical properties of small-world networks, characterized by a short path length and high clustering coefficient. In this work, mainly based on the small-world neuronal network (SWNN) with inhibitory neurons, we study the effect of network topology on the synchronization of the neuronal network with unreliable synapses. Together with the network topology, the effects of the GABAergic reversal potential, time delay and noise are also considered. Interestingly, we found a counter-intuitive phenomenon for the SWNN with specific shortcut adding probability, that is, the less reliable the synapses, the better the synchronization performance of the SWNN. We also consider the effects of both local noise and global noise in this work. It is shown that these two different types of noise have distinct effects on the synchronization: one is negative and the other is positive

  17. ELECTROPHYSIOLOGICAL CHARACTERIZATION OF DOPAMINERGIC AND NONDOPAMINERGIC NEURONS IN ORGANOTYPIC SLICE CULTURES OF THE RAT VENTRAL MESENCEPHALON

    DEFF Research Database (Denmark)

    STEENSEN, BH; NEDERGAARD, S; OSTERGAARD, K

    1995-01-01

    -old organotypic slice cultures of the ventral mesencephalon prepared from newborn rats. Dopaminergic neurones were distinguished from non-dopaminergic neurones by staining with the autofluorescent serotonin analogue 5,7-dihydroxytryptamine and briefly viewing the preparation with short exposures to ultraviolet...... 81 M Omega), were silent or fired spontaneously at a low frequency (0-9 Hz), and no spontaneous GABA(A)-ergic inhibitory postsynaptic potentials or inward rectification were present. In contrast, non-dopaminergic neurones had fast action potentials (0.6-3.2 ms), low input resistance (mean 32 M Omega...

  18. A single-neuron tracing study of arkypallidal and prototypic neurons in healthy rats.

    Science.gov (United States)

    Fujiyama, Fumino; Nakano, Takashi; Matsuda, Wakoto; Furuta, Takahiro; Udagawa, Jun; Kaneko, Takeshi

    2016-12-01

    The external globus pallidus (GP) is known as a relay nucleus of the indirect pathway of the basal ganglia. Recent studies in dopamine-depleted and healthy rats indicate that the GP comprises two main types of pallidofugal neurons: the so-called "prototypic" and "arkypallidal" neurons. However, the reconstruction of complete arkypallidal neurons in healthy rats has not been reported. Here we visualized the entire axonal arborization of four single arkypallidal neurons and six single prototypic neurons in rat brain using labeling with a viral vector expressing membrane-targeted green fluorescent protein and examined the distribution of axon boutons in the target nuclei. Results revealed that not only the arkypallidal neurons but nearly all of the prototypic neurons projected to the striatum with numerous axon varicosities. Thus, the striatum is a major target nucleus for pallidal neurons. Arkypallidal and prototypic GP neurons located in the calbindin-positive and calbindin-negative regions mainly projected to the corresponding positive and negative regions in the striatum. Because the GP and striatum calbindin staining patterns reflect the topographic organization of the striatopallidal projection, the striatal neurons in the sensorimotor and associative regions constitute the reciprocal connection with the GP neurons in the corresponding regions.

  19. Differential Activation of Fast-Spiking and Regular-Firing Neuron Populations During Movement and Reward in the Dorsal Medial Frontal Cortex

    Science.gov (United States)

    Insel, Nathan; Barnes, Carol A.

    2015-01-01

    The medial prefrontal cortex is thought to be important for guiding behavior according to an animal's expectations. Efforts to decode the region have focused not only on the question of what information it computes, but also how distinct circuit components become engaged during behavior. We find that the activity of regular-firing, putative projection neurons contains rich information about behavioral context and firing fields cluster around reward sites, while activity among putative inhibitory and fast-spiking neurons is most associated with movement and accompanying sensory stimulation. These dissociations were observed even between adjacent neurons with apparently reciprocal, inhibitory–excitatory connections. A smaller population of projection neurons with burst-firing patterns did not show clustered firing fields around rewards; these neurons, although heterogeneous, were generally less selective for behavioral context than regular-firing cells. The data suggest a network that tracks an animal's behavioral situation while, at the same time, regulating excitation levels to emphasize high valued positions. In this scenario, the function of fast-spiking inhibitory neurons is to constrain network output relative to incoming sensory flow. This scheme could serve as a bridge between abstract sensorimotor information and single-dimensional codes for value, providing a neural framework to generate expectations from behavioral state. PMID:24700585

  20. Inhibitory Control in the Cortico-Basal Ganglia-Thalamocortical Loop: Complex Regulation and Interplay with Memory and Decision Processes.

    Science.gov (United States)

    Wei, Wei; Wang, Xiao-Jing

    2016-12-07

    We developed a circuit model of spiking neurons that includes multiple pathways in the basal ganglia (BG) and is endowed with feedback mechanisms at three levels: cortical microcircuit, corticothalamic loop, and cortico-BG-thalamocortical system. We focused on executive control in a stop signal task, which is known to depend on BG across species. The model reproduces a range of experimental observations and shows that the newly discovered feedback projection from external globus pallidus to striatum is crucial for inhibitory control. Moreover, stopping process is enhanced by the cortico-subcortical reverberatory dynamics underlying persistent activity, establishing interdependence between working memory and inhibitory control. Surprisingly, the stop signal reaction time (SSRT) can be adjusted by weights of certain connections but is insensitive to other connections in this complex circuit, suggesting novel circuit-based intervention for inhibitory control deficits associated with mental illness. Our model provides a unified framework for inhibitory control, decision making, and working memory. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. When is an Inhibitory Synapse Effective?

    Science.gov (United States)

    Qian, Ning; Sejnowski, Terrence J.

    1990-10-01

    Interactions between excitatory and inhibitory synaptic inputs on dendrites determine the level of activity in neurons. Models based on the cable equation predict that silent shunting inhibition can strongly veto the effect of an excitatory input. The cable model assumes that ionic concentrations do not change during the electrical activity, which may not be a valid assumption, especially for small structures such as dendritic spines. We present here an analysis and computer simulations to show that for large Cl^- conductance changes, the more general Nernst-Planck electrodiffusion model predicts that shunting inhibition on spines should be much less effective than that predicted by the cable model. This is a consequence of the large changes in the intracellular ionic concentration of Cl^- that can occur in small structures, which would alter the reversal potential and reduce the driving force for Cl^-. Shunting inhibition should therefore not be effective on spines, but it could be significantly more effective on the dendritic shaft at the base of the spine. In contrast to shunting inhibition, hyperpolarizing synaptic inhibition mediated by K^+ currents can be very effective in reducing the excitatory synaptic potentials on the same spine if the excitatory conductance change is less than 10 nS. We predict that if the inhibitory synapses found on cortical spines are to be effective, then they should be mediated by K^+ through GABA_B receptors.

  2. Acetylcholine release and inhibitory interneuron activity in hippocampal CA1

    Directory of Open Access Journals (Sweden)

    A. Rory McQuiston

    2014-09-01

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

  3. BDNF regulates the expression and distribution of vesicular glutamate transporters in cultured hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Carlos V Melo

    Full Text Available BDNF is a pro-survival protein involved in neuronal development and synaptic plasticity. BDNF strengthens excitatory synapses and contributes to LTP, presynaptically, through enhancement of glutamate release, and postsynaptically, via phosphorylation of neurotransmitter receptors, modulation of receptor traffic and activation of the translation machinery. We examined whether BDNF upregulated vesicular glutamate receptor (VGLUT 1 and 2 expression, which would partly account for the increased glutamate release in LTP. Cultured rat hippocampal neurons were incubated with 100 ng/ml BDNF, for different periods of time, and VGLUT gene and protein expression were assessed by real-time PCR and immunoblotting, respectively. At DIV7, exogenous application of BDNF rapidly increased VGLUT2 mRNA and protein levels, in a dose-dependent manner. VGLUT1 expression also increased but only transiently. However, at DIV14, BDNF stably increased VGLUT1 expression, whilst VGLUT2 levels remained low. Transcription inhibition with actinomycin-D or α-amanitine, and translation inhibition with emetine or anisomycin, fully blocked BDNF-induced VGLUT upregulation. Fluorescence microscopy imaging showed that BDNF stimulation upregulates the number, integrated density and intensity of VGLUT1 and VGLUT2 puncta in neurites of cultured hippocampal neurons (DIV7, indicating that the neurotrophin also affects the subcellular distribution of the transporter in developing neurons. Increased VGLUT1 somatic signals were also found 3 h after stimulation with BDNF, further suggesting an increased de novo transcription and translation. BDNF regulation of VGLUT expression was specifically mediated by BDNF, as no effect was found upon application of IGF-1 or bFGF, which activate other receptor tyrosine kinases. Moreover, inhibition of TrkB receptors with K252a and PLCγ signaling with U-73122 precluded BDNF-induced VGLUT upregulation. Hippocampal neurons express both isoforms during

  4. Estradiol-Dependent Stimulation and Suppression of Gonadotropin-Releasing Hormone Neuron Firing Activity by Corticotropin-Releasing Hormone in Female Mice.

    Science.gov (United States)

    Phumsatitpong, Chayarndorn; Moenter, Suzanne M

    2018-01-01

    Gonadotropin-releasing hormone (GnRH) neurons are the final central regulators of reproduction, integrating various inputs that modulate fertility. Stress typically inhibits reproduction but can be stimulatory; stress effects can also be modulated by steroid milieu. Corticotropin-releasing hormone (CRH) released during the stress response may suppress reproduction independent of downstream glucocorticoids. We hypothesized CRH suppresses fertility by decreasing GnRH neuron firing activity. To test this, mice were ovariectomized (OVX) and either implanted with an estradiol capsule (OVX+E) or not treated further to examine the influence of estradiol on GnRH neuron response to CRH. Targeted extracellular recordings were used to record firing activity from green fluorescent protein-identified GnRH neurons in brain slices before and during CRH treatment; recordings were done in the afternoon when estradiol has a positive feedback effect to increase GnRH neuron firing. In OVX mice, CRH did not affect the firing rate of GnRH neurons. In contrast, CRH exhibited dose-dependent stimulatory (30 nM) or inhibitory (100 nM) effects on GnRH neuron firing activity in OVX+E mice; both effects were reversible. The dose-dependent effects of CRH appear to result from activation of different receptor populations; a CRH receptor type-1 agonist increased firing activity in GnRH neurons, whereas a CRH receptor type-2 agonist decreased firing activity. CRH and specific agonists also differentially regulated short-term burst frequency and burst properties, including burst duration, spikes/burst, and/or intraburst interval. These results indicate that CRH alters GnRH neuron activity and that estradiol is required for CRH to exert both stimulatory and inhibitory effects on GnRH neurons. Copyright © 2018 Endocrine Society.

  5. Inference of topology and the nature of synapses, and the flow of information in neuronal networks

    Science.gov (United States)

    Borges, F. S.; Lameu, E. L.; Iarosz, K. C.; Protachevicz, P. R.; Caldas, I. L.; Viana, R. L.; Macau, E. E. N.; Batista, A. M.; Baptista, M. S.

    2018-02-01

    The characterization of neuronal connectivity is one of the most important matters in neuroscience. In this work, we show that a recently proposed informational quantity, the causal mutual information, employed with an appropriate methodology, can be used not only to correctly infer the direction of the underlying physical synapses, but also to identify their excitatory or inhibitory nature, considering easy to handle and measure bivariate time series. The success of our approach relies on a surprising property found in neuronal networks by which nonadjacent neurons do "understand" each other (positive mutual information), however, this exchange of information is not capable of causing effect (zero transfer entropy). Remarkably, inhibitory connections, responsible for enhancing synchronization, transfer more information than excitatory connections, known to enhance entropy in the network. We also demonstrate that our methodology can be used to correctly infer directionality of synapses even in the presence of dynamic and observational Gaussian noise, and is also successful in providing the effective directionality of intermodular connectivity, when only mean fields can be measured.

  6. Electroacupuncture reduces the evoked responses of the spinal dorsal horn neurons in ankle-sprained rats

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    Kim, Jae Hyo; Kim, Hee Young; Chung, Kyungsoon

    2011-01-01

    Acupuncture is shown to be effective in producing analgesia in ankle sprain pain in humans and animals. To examine the underlying mechanisms of the acupuncture-induced analgesia, the effects of electroacupuncture (EA) on weight-bearing forces (WBR) of the affected foot and dorsal horn neuron activities were examined in a rat model of ankle sprain. Ankle sprain was induced manually by overextending ligaments of the left ankle in the rat. Dorsal horn neuron responses to ankle movements or compression were recorded from the lumbar spinal cord using an in vivo extracellular single unit recording setup 1 day after ankle sprain. EA was applied to the SI-6 acupoint on the right forelimb (contralateral to the sprained ankle) by trains of electrical pulses (10 Hz, 1-ms pulse width, 2-mA intensity) for 30 min. After EA, WBR of the sprained foot significantly recovered and dorsal horn neuron activities were significantly suppressed in ankle-sprained rats. However, EA produced no effect in normal rats. The inhibitory effect of EA on hyperactivities of dorsal horn neurons of ankle-sprained rats was blocked by the α-adrenoceptor antagonist phentolamine (5 mg/kg ip) but not by the opioid receptor antagonist naltrexone (10 mg/kg ip). These data suggest that EA-induced analgesia in ankle sprain pain is mediated mainly by suppressing dorsal horn neuron activities through α-adrenergic descending inhibitory systems at the spinal level. PMID:21389301

  7. Mathematical Relationships between Neuron Morphology and Neurite Growth Dynamics in Drosophila melanogaster Larva Class IV Sensory Neurons

    Science.gov (United States)

    Ganguly, Sujoy; Liang, Xin; Grace, Michael; Lee, Daniel; Howard, Jonathon

    The morphology of neurons is diverse and reflects the diversity of neuronal functions, yet the principles that govern neuronal morphogenesis are unclear. In an effort to better understand neuronal morphogenesis we will be focusing on the development of the dendrites of class IV sensory neuron in Drosophila melanogaster. In particular we attempt to determine how the the total length, and the number of branches of dendrites are mathematically related to the dynamics of neurite growth and branching. By imaging class IV neurons during early embryogenesis we are able to measure the change in neurite length l (t) as a function of time v (t) = dl / dt . We found that the distribution of v (t) is well characterized by a hyperbolic secant distribution, and that the addition of new branches per unit time is well described by a Poisson process. Combining these measurements with the assumption that branching occurs with equal probability anywhere along the dendrite we were able to construct a mathematical model that provides reasonable agreement with the observed number of branches, and total length of the dendrites of the class IV sensory neuron.

  8. Segmental Bayesian estimation of gap-junctional and inhibitory conductance of inferior olive neurons from spike trains with complicated dynamics

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    Huu eHoang

    2015-05-01

    Full Text Available The inverse problem for estimating model parameters from brain spike data is an ill-posed problem because of a huge mismatch in the system complexity between the model and the brain as well as its non-stationary dynamics, and needs a stochastic approach that finds the most likely solution among many possible solutions. In the present study, we developed a segmental Bayesian method to estimate the two parameters of interest, the gap-junctional (gc and inhibitory conductance (gi from inferior olive spike data. Feature vectors were estimated for the spike data in a segment-wise fashion to compensate for the non-stationary firing dynamics. Hierarchical Bayesian estimation was conducted to estimate the gc and gi for every spike segment using a forward model constructed in the principal component analysis (PCA space of the feature vectors, and to merge the segmental estimates into single estimates for every neuron. The segmental Bayesian estimation gave smaller fitting errors than the conventional Bayesian inference, which finds the estimates once across the entire spike data, or the minimum error method, which directly finds the closest match in the PCA space. The segmental Bayesian inference has the potential to overcome the problem of non-stationary dynamics and resolve the ill-posedness of the inverse problem because of the mismatch between the model and the brain under the constraints based, and it is a useful tool to evaluate parameters of interest for neuroscience from experimental spike train data.

  9. DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons.

    Science.gov (United States)

    Wei, Jing; Graziane, Nicholas M; Gu, Zhenglin; Yan, Zhen

    2015-11-13

    Association studies have suggested that Disrupted-in-Schizophrenia 1 (DISC1) confers a genetic risk at the level of endophenotypes that underlies many major mental disorders. Despite the progress in understanding the significance of DISC1 at neural development, the mechanisms underlying DISC1 regulation of synaptic functions remain elusive. Because alterations in the cortical GABA system have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the GABAA receptor (GABAAR). We found that cellular knockdown of DISC1 significantly reduced GABAAR-mediated synaptic and whole-cell current, whereas overexpression of wild-type DISC1, but not the C-terminal-truncated DISC1 (a schizophrenia-related mutant), significantly increased GABAAR currents in pyramidal neurons of the prefrontal cortex. These effects were accompanied by DISC1-induced changes in surface GABAAR expression. Moreover, the regulation of GABAARs by DISC1 knockdown or overexpression depends on the microtubule motor protein kinesin 1 (KIF5). Our results suggest that DISC1 exerts an important effect on GABAergic inhibitory transmission by regulating KIF5/microtubule-based GABAAR trafficking in the cortex. The knowledge gained from this study would shed light on how DISC1 and the GABA system are linked mechanistically and how their interactions are critical for maintaining a normal mental state. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Effects of weak electric fields on the activity of neurons and neuronal networks

    International Nuclear Information System (INIS)

    Jeffreys, J.G.R.; Deans, J.; Bikson, M.; Fox, J.

    2003-01-01

    Electric fields applied to brain tissue will affect cellular properties. They will hyperpolarise the ends of cells closest to the positive part of the field, and depolarise ends closest to the negative. In the case of neurons this affects excitability. How these changes in transmembrane potential are distributed depends on the length constant of the neuron, and on its geometry; if the neuron is electrically compact, the change in transmembrane potential becomes an almost linear function of distance in the direction of the field. Neurons from the mammalian hippocampus, maintained in tissue slices in vitro, are significantly affected by fields of around 1-5 Vm -1 . (author)

  11. Pain-related increase of excitatory transmission and decrease of inhibitory transmission in the central nucleus of the amygdala are mediated by mGluR1

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    Neugebauer Volker

    2010-12-01

    Full Text Available Abstract Neuroplasticity in the central nucleus of the amygdala (CeA, particularly its latero-capsular division (CeLC, is an important contributor to the emotional-affective aspects of pain. Previous studies showed synaptic plasticity of excitatory transmission to the CeLC in different pain models, but pain-related changes of inhibitory transmission remain to be determined. The CeLC receives convergent excitatory inputs from the parabrachial nucleus in the brainstem and from the basolateral amygdala (BLA. In addition, feedforward inhibition of CeA neurons is driven by glutamatergic projections from the BLA area to a cluster of GABAergic neurons in the intercalated cell masses (ITC. Using patch-clamp in rat brain slices we measured monosynaptic excitatory postsynaptic currents (EPSCs and polysynaptic inhibitory currents (IPSCs that were evoked by electrical stimulation in the BLA. In brain slices from arthritic rats, input-output functions of excitatory synaptic transmission were enhanced whereas inhibitory synaptic transmission was decreased compared to control slices from normal untreated rats. A non-NMDA receptor antagonist (NBQX blocked the EPSCs and reduced the IPSCs, suggesting that non-NMDA receptors mediate excitatory transmission and also contribute to glutamate-driven feed-forward inhibition of CeLC neurons. IPSCs were blocked by a GABAA receptor antagonist (bicuculline. Bicuculline increased EPSCs under normal conditions but not in slices from arthritic rats, which indicates a loss of GABAergic control of excitatory transmission. A metabotropic glutamate receptor subtype 1 (mGluR1 antagonist (LY367385 reversed both the increase of excitatory transmission and the decrease of inhibitory transmission in the arthritis pain model but had no effect on basal synaptic transmission in control slices from normal rats. The inhibitory effect of LY367385 on excitatory transmission was blocked by bicuculline suggesting the involvement of a GABAergic

  12. Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset.

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    Christine Vande Velde

    Full Text Available Mutations in superoxide dismutase (SOD1 are causative for inherited amyotrophic lateral sclerosis. A proportion of SOD1 mutant protein is misfolded onto the cytoplasmic face of mitochondria in one or more spinal cord cell types. By construction of mice in which mitochondrially targeted enhanced green fluorescent protein is selectively expressed in motor neurons, we demonstrate that axonal mitochondria of motor neurons are primary in vivo targets for misfolded SOD1. Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning pre-symptomatically and increasing in severity as disease progresses. Somal mitochondria are altered by mutant SOD1, with loss of the characteristic cylindrical, networked morphology and its replacement by a less elongated, more spherical shape. These data indicate that mutant SOD1 binding to mitochondria disrupts normal mitochondrial distribution and size homeostasis as early pathogenic features of SOD1 mutant-mediated ALS.

  13. Optogenetic Stimulation of Locus Ceruleus Neurons Augments Inhibitory Transmission to Parasympathetic Cardiac Vagal Neurons via Activation of Brainstem α1 and β1 Receptors

    OpenAIRE

    Wang, Xin; Piñol, Ramón A.; Byrne, Peter; Mendelowitz, David

    2014-01-01

    Locus ceruleus (LC) noradrenergic neurons are critical in generating alertness. In addition to inducing cortical arousal, the LC also orchestrates changes in accompanying autonomic system function that compliments increased attention, such as during stress, excitation, and/or exposure to averse or novel stimuli. Although the association between arousal and increased heart rate is well accepted, the neurobiological link between the LC and parasympathetic neurons that control heart rate has not...

  14. The ciliogenic transcription factor RFX3 regulates early midline distribution of guidepost neurons required for corpus callosum development.

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    Carine Benadiba

    Full Text Available The corpus callosum (CC is the major commissure that bridges the cerebral hemispheres. Agenesis of the CC is associated with human ciliopathies, but the origin of this default is unclear. Regulatory Factor X3 (RFX3 is a transcription factor involved in the control of ciliogenesis, and Rfx3-deficient mice show several hallmarks of ciliopathies including left-right asymmetry defects and hydrocephalus. Here we show that Rfx3-deficient mice suffer from CC agenesis associated with a marked disorganisation of guidepost neurons required for axon pathfinding across the midline. Using transplantation assays, we demonstrate that abnormalities of the mutant midline region are primarily responsible for the CC malformation. Conditional genetic inactivation shows that RFX3 is not required in guidepost cells for proper CC formation, but is required before E12.5 for proper patterning of the cortical septal boundary and hence accurate distribution of guidepost neurons at later stages. We observe focused but consistent ectopic expression of Fibroblast growth factor 8 (Fgf8 at the rostro commissural plate associated with a reduced ratio of GLIoma-associated oncogene family zinc finger 3 (GLI3 repressor to activator forms. We demonstrate on brain explant cultures that ectopic FGF8 reproduces the guidepost neuronal defects observed in Rfx3 mutants. This study unravels a crucial role of RFX3 during early brain development by indirectly regulating GLI3 activity, which leads to FGF8 upregulation and ultimately to disturbed distribution of guidepost neurons required for CC morphogenesis. Hence, the RFX3 mutant mouse model brings novel understandings of the mechanisms that underlie CC agenesis in ciliopathies.

  15. GABA regulates synaptic integration of newly generated neurons in the adult brain

    Science.gov (United States)

    Ge, Shaoyu; Goh, Eyleen L. K.; Sailor, Kurt A.; Kitabatake, Yasuji; Ming, Guo-Li; Song, Hongjun

    2006-02-01

    Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

  16. Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model.

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    Mohsen, Zaid; Sim, Hosung; Garcia-Galiano, David; Han, Xingfa; Bellefontaine, Nicole; Saunders, Thomas L; Elias, Carol F

    2017-12-01

    Prokineticin receptor 2 (PROKR2) is predominantly expressed in the mammalian central nervous system. Loss-of-function mutations of PROKR2 in humans are associated with Kallmann syndrome due to the disruption of gonadotropin releasing hormone neuronal migration and deficient olfactory bulb morphogenesis. PROKR2 has been also implicated in the neuroendocrine control of GnRH neurons post-migration and other physiological systems. However, the brain circuitry and mechanisms associated with these actions have been difficult to investigate mainly due to the widespread distribution of Prokr2-expressing cells, and the lack of animal models and molecular tools. Here, we describe the generation, validation and characterization of a new mouse model that expresses Cre recombinase driven by the Prokr2 promoter, using CRISPR-Cas9 technology. Cre expression was visualized using reporter genes, tdTomato and GFP, in males and females. Expression of Cre-induced reporter genes was found in brain sites previously described to express Prokr2, e.g., the paraventricular and the suprachiasmatic nuclei, and the area postrema. The Prokr2-Cre mouse model was further validated by colocalization of Cre-induced GFP and Prokr2 mRNA. No disruption of Prokr2 expression, GnRH neuronal migration or fertility was observed. Comparative analysis of Prokr2-Cre expression in male and female brains revealed a sexually dimorphic distribution confirmed by in situ hybridization. In females, higher Cre activity was found in the medial preoptic area, ventromedial nucleus of the hypothalamus, arcuate nucleus, medial amygdala and lateral parabrachial nucleus. In males, Cre was higher in the amygdalo-hippocampal area. The sexually dimorphic pattern of Prokr2 expression indicates differential roles in reproductive function and, potentially, in other physiological systems.

  17. Inhibitory actions of the gamma-aminobutyric acid in pediatric Sturge-Weber syndrome.

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    Tyzio, Roman; Khalilov, Ilgam; Represa, Alfonso; Crepel, Valerie; Zilberter, Yuri; Rheims, Sylvain; Aniksztejn, Laurent; Cossart, Rosa; Nardou, Romain; Mukhtarov, Marat; Minlebaev, Marat; Epsztein, Jérôme; Milh, Mathieu; Becq, Helene; Jorquera, Isabel; Bulteau, Christine; Fohlen, Martine; Oliver, Viviana; Dulac, Olivier; Dorfmüller, Georg; Delalande, Olivier; Ben-Ari, Yehezkel; Khazipov, Roustem

    2009-08-01

    The mechanisms of epileptogenesis in Sturge-Weber syndrome (SWS) are unknown. We explored the properties of neurons from human pediatric SWS cortex in vitro and tested in particular whether gamma-aminobutyric acid (GABA) excites neurons in SWS cortex, as has been suggested for various types of epilepsies. Patch-clamp and field potential recordings and dynamic biphoton imaging were used to analyze cortical tissue samples obtained from four 6- to 14-month-old pediatric SWS patients during surgery. Neurons in SWS cortex were characterized by a relatively depolarized resting membrane potential, as was estimated from cell-attached recordings of N-methyl-D-aspartate channels. Many cells spontaneously fired action potentials at a rate proportional to the level of neuronal depolarization. The reversal potential for GABA-activated currents, assessed by cell-attached single channel recordings, was close to the resting membrane potential. All spontaneously firing neurons recorded in cell-attached mode or imaged with biphoton microscopy were inhibited by GABA. Spontaneous epileptiform activity in the form of recurrent population bursts was suppressed by glutamate receptor antagonists, the GABA(A) receptor agonist isoguvacine, and the positive allosteric GABA(A) modulator diazepam. Blockade of GABA(A) receptors aggravated spontaneous epileptiform activity. The NKCC1 antagonist bumetanide had little effect on epileptiform activity. SWS cortical neurons have a relatively depolarized resting membrane potential and spontaneously fire action potentials that may contribute to increased network excitability. In contrast to previous data depicting excitatory and proconvulsive actions of GABA in certain pediatric and adult epilepsies, GABA plays mainly an inhibitory and anticonvulsive role in SWS pediatric cortex.

  18. Effects of Neuromodulation on Excitatory-Inhibitory Neural Network Dynamics Depend on Network Connectivity Structure

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    Rich, Scott; Zochowski, Michal; Booth, Victoria

    2018-01-01

    Acetylcholine (ACh), one of the brain's most potent neuromodulators, can affect intrinsic neuron properties through blockade of an M-type potassium current. The effect of ACh on excitatory and inhibitory cells with this potassium channel modulates their membrane excitability, which in turn affects their tendency to synchronize in networks. Here, we study the resulting changes in dynamics in networks with inter-connected excitatory and inhibitory populations (E-I networks), which are ubiquitous in the brain. Utilizing biophysical models of E-I networks, we analyze how the network connectivity structure in terms of synaptic connectivity alters the influence of ACh on the generation of synchronous excitatory bursting. We investigate networks containing all combinations of excitatory and inhibitory cells with high (Type I properties) or low (Type II properties) modulatory tone. To vary network connectivity structure, we focus on the effects of the strengths of inter-connections between excitatory and inhibitory cells (E-I synapses and I-E synapses), and the strengths of intra-connections among excitatory cells (E-E synapses) and among inhibitory cells (I-I synapses). We show that the presence of ACh may or may not affect the generation of network synchrony depending on the network connectivity. Specifically, strong network inter-connectivity induces synchronous excitatory bursting regardless of the cellular propensity for synchronization, which aligns with predictions of the PING model. However, when a network's intra-connectivity dominates its inter-connectivity, the propensity for synchrony of either inhibitory or excitatory cells can determine the generation of network-wide bursting.

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

    Science.gov (United States)

    Li, Jun-Ping; Wang, Xi-Yu; Gao, Chang-Jun; Liao, Yong-Hui; Qu, Juan; He, Zhong-Yi; Zhang, Ting; Wang, Guo-Du; Li, Yun-Qing

    2014-01-01

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

  20. Analysis of nonlocal neural fields for both general and gamma-distributed connectivities

    Science.gov (United States)

    Hutt, Axel; Atay, Fatihcan M.

    2005-04-01

    This work studies the stability of equilibria in spatially extended neuronal ensembles. We first derive the model equation from statistical properties of the neuron population. The obtained integro-differential equation includes synaptic and space-dependent transmission delay for both general and gamma-distributed synaptic connectivities. The latter connectivity type reveals infinite, finite, and vanishing self-connectivities. The work derives conditions for stationary and nonstationary instabilities for both kernel types. In addition, a nonlinear analysis for general kernels yields the order parameter equation of the Turing instability. To compare the results to findings for partial differential equations (PDEs), two typical PDE-types are derived from the examined model equation, namely the general reaction-diffusion equation and the Swift-Hohenberg equation. Hence, the discussed integro-differential equation generalizes these PDEs. In the case of the gamma-distributed kernels, the stability conditions are formulated in terms of the mean excitatory and inhibitory interaction ranges. As a novel finding, we obtain Turing instabilities in fields with local inhibition-lateral excitation, while wave instabilities occur in fields with local excitation and lateral inhibition. Numerical simulations support the analytical results.

  1. Minimal inhibitory concentration distributions and epidemiological cutoff values of five antifungal agents against Sporothrix brasiliensis

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    Rodrigo Almeida-Paes

    Full Text Available BACKGROUND Sporothrix brasiliensis is the most virulent sporotrichosis agent. This species usually responds to antifungal drugs, but therapeutic failure can occur in some patients. Antifungal susceptibility tests have been performed on this species, but no clinical breakpoints (CBPs are available. In this situation, minimal inhibitory concentration (MIC distributions and epidemiological cutoff values (ECVs support the detection of identification of resistant strains. OBJECTIVES To study the MIC distributions of five antifungal drugs against S. brasiliensis and to propose tentative ECVs. METHODS MICs of amphotericin B (AMB, itraconazole (ITR, ketoconazole (KET, posaconazole (POS, and terbinafine (TRB against 335 S. brasiliensis strains were determined by the Clinical and Laboratory Standards Institute broth microdilution method. FINDINGS The proposed ECV, in µg/mL, for AMB, ITR, KET, POS, and TRB were 4.0, 2.0, 1.0, 2.0, and 0.25, respectively. Percentages of wild-type strains in our population for the above antifungal drugs were 98.48, 95.22, 95.33, 100, and 97.67%, respectively. MAIN CONCLUSIONS These ECVs will be useful to detect strains with resistance, to define CBPs, and to elaborate specific therapeutic guidelines for S. brasiliensis. Rational use of antifungals is strongly recommended to avoid the emergence of resistant strains and ensure the therapeutic effectiveness of sporotrichosis.

  2. Dynorphin-dependent reduction of excitability and attenuation of inhibitory afferents of NPS neurons in the pericoerulear region of mice

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    Kay eJuengling

    2016-03-01

    Full Text Available The Neuropeptide S system, consisting of the 20-amino acid peptide neuropeptide S (NPS and its G-protein coupled receptor (NPSR, modulates arousal, wakefulness, anxiety, and fear-extinction in mice. In addition, recent evidence indicates that the NPS system attenuates stress-dependent impairment of fear extinction, and that NPS-expressing neurons in close proximity to the locus coeruleus (pericoerulear, periLC region are activated by stress. Furthermore, periLC NPS neurons receive afferents from neurons of the centrolateral nucleus of the amygdala (CeL, of which a substantial population expresses the kappa opioid receptor (KOR ligand precursor prodynorphin. This study aims to identify the effect of the dynorphinergic system on NPS neurons in the periLC via pre- and postsynaptic mechanisms. Using electrophysiological recordings in mouse brain slices, we provide evidence that NPS neurons in the periLC region are directly inhibited by dynorphin A via activation of κ-opioid receptor 1 (KOR1 and a subsequent increase of potassium conductances. Thus, the dynorphinergic system is suited to inactivate NPS neurons in the periLC. In addition to this direct, somatic effect, dynorphin A reduces the efficacy of GABAergic synapses on NPS neurons via KOR1 and KOR2. In conclusion, the present study provides evidence for the interaction of the NPS and the kappa opioid system in the periLC. Therefore, the endogenous opioid dynorphin is suited to inhibit NPS neurons with a subsequent decrease in NPS release in putative target regions leading to a variety of physiological consequences such as increased anxiety or vulnerability to stress exposure.

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

    Science.gov (United States)

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

    2007-11-01

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

  4. Computational modeling of seizure dynamics using coupled neuronal networks: factors shaping epileptiform activity.

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    Sebastien Naze

    2015-05-01

    Full Text Available Epileptic seizure dynamics span multiple scales in space and time. Understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. Mathematical models have been developed to reproduce seizure dynamics across scales ranging from the single neuron to the neural population. In this study, we develop a network model of spiking neurons and systematically investigate the conditions, under which the network displays the emergent dynamic behaviors known from the Epileptor, which is a well-investigated abstract model of epileptic neural activity. This approach allows us to study the biophysical parameters and variables leading to epileptiform discharges at cellular and network levels. Our network model is composed of two neuronal populations, characterized by fast excitatory bursting neurons and regular spiking inhibitory neurons, embedded in a common extracellular environment represented by a slow variable. By systematically analyzing the parameter landscape offered by the simulation framework, we reproduce typical sequences of neural activity observed during status epilepticus. We find that exogenous fluctuations from extracellular environment and electro-tonic couplings play a major role in the progression of the seizure, which supports previous studies and further validates our model. We also investigate the influence of chemical synaptic coupling in the generation of spontaneous seizure-like events. Our results argue towards a temporal shift of typical spike waves with fast discharges as synaptic strengths are varied. We demonstrate that spike waves, including interictal spikes, are generated primarily by inhibitory neurons, whereas fast discharges during the wave part are due to excitatory neurons. Simulated traces are compared with in vivo experimental data from rodents at different stages of the disorder. We draw the conclusion

  5. β-Nicotinamide adenine dinucleotide acts at prejunctional adenosine A1 receptors to suppress inhibitory musculomotor neurotransmission in guinea pig colon and human jejunum

    Science.gov (United States)

    Wang, Guo-Du; Wang, Xi-Yu; Liu, Sumei; Xia, Yun; Zou, Fei; Qu, Meihua; Needleman, Bradley J.; Mikami, Dean J.

    2015-01-01

    Intracellular microelectrodes were used to record neurogenic inhibitory junction potentials in the intestinal circular muscle coat. Electrical field stimulation was used to stimulate intramural neurons and evoke contraction of the smooth musculature. Exposure to β-nicotinamide adenine dinucleotide (β-NAD) did not alter smooth muscle membrane potential in guinea pig colon or human jejunum. ATP, ADP, β-NAD, and adenosine, as well as the purinergic P2Y1 receptor antagonists MRS 2179 and MRS 2500 and the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine, each suppressed inhibitory junction potentials in guinea pig and human preparations. β-NAD suppressed contractile force of twitch-like contractions evoked by electrical field stimulation in guinea pig and human preparations. P2Y1 receptor antagonists did not reverse this action. Stimulation of adenosine A1 receptors with 2-chloro-N6-cyclopentyladenosine suppressed the force of twitch contractions evoked by electrical field stimulation in like manner to the action of β-NAD. Blockade of adenosine A1 receptors with 8-cyclopentyl-1,3-dipropylxanthine suppressed the inhibitory action of β-NAD on the force of electrically evoked contractions. The results do not support an inhibitory neurotransmitter role for β-NAD at intestinal neuromuscular junctions. The data suggest that β-NAD is a ligand for the adenosine A1 receptor subtype expressed by neurons in the enteric nervous system. The influence of β-NAD on intestinal motility emerges from adenosine A1 receptor-mediated suppression of neurotransmitter release at inhibitory neuromuscular junctions. PMID:25813057

  6. Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons.

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    Jun Hu

    Full Text Available Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+, EPSC(-, and EPSC(+/- based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs, using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+ neurons, but increased it in EPSC(- neurons. Unlike EPSC(+ and EPSC(- neurons, EPSC(+/- neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/- neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals.

  7. Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons.

    Science.gov (United States)

    Hu, Jun; Jiang, Lin; Low, Malcolm J; Rui, Liangyou

    2014-01-01

    Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+), EPSC(-), and EPSC(+/-)) based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs), using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+) neurons, but increased it in EPSC(-) neurons. Unlike EPSC(+) and EPSC(-) neurons, EPSC(+/-) neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/-) neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals.

  8. Signal transfer within a cultured asymmetric cortical neuron circuit.

    Science.gov (United States)

    Isomura, Takuya; Shimba, Kenta; Takayama, Yuzo; Takeuchi, Akimasa; Kotani, Kiyoshi; Jimbo, Yasuhiko

    2015-12-01

    Simplified neuronal circuits are required for investigating information representation in nervous systems and for validating theoretical neural network models. Here, we developed patterned neuronal circuits using micro fabricated devices, comprising a micro-well array bonded to a microelectrode-array substrate. The micro-well array consisted of micrometre-scale wells connected by tunnels, all contained within a silicone slab called a micro-chamber. The design of the micro-chamber confined somata to the wells and allowed axons to grow through the tunnels bidirectionally but with a designed, unidirectional bias. We guided axons into the point of the arrow structure where one of the two tunnel entrances is located, making that the preferred direction. When rat cortical neurons were cultured in the wells, their axons grew through the tunnels and connected to neurons in adjoining wells. Unidirectional burst transfers and other asymmetric signal-propagation phenomena were observed via the substrate-embedded electrodes. Seventy-nine percent of burst transfers were in the forward direction. We also observed rapid propagation of activity from sites of local electrical stimulation, and significant effects of inhibitory synapse blockade on bursting activity. These results suggest that this simple, substrate-controlled neuronal circuit can be applied to develop in vitro models of the function of cortical microcircuits or deep neural networks, better to elucidate the laws governing the dynamics of neuronal networks.

  9. Signal transfer within a cultured asymmetric cortical neuron circuit

    Science.gov (United States)

    Isomura, Takuya; Shimba, Kenta; Takayama, Yuzo; Takeuchi, Akimasa; Kotani, Kiyoshi; Jimbo, Yasuhiko

    2015-12-01

    Objective. Simplified neuronal circuits are required for investigating information representation in nervous systems and for validating theoretical neural network models. Here, we developed patterned neuronal circuits using micro fabricated devices, comprising a micro-well array bonded to a microelectrode-array substrate. Approach. The micro-well array consisted of micrometre-scale wells connected by tunnels, all contained within a silicone slab called a micro-chamber. The design of the micro-chamber confined somata to the wells and allowed axons to grow through the tunnels bidirectionally but with a designed, unidirectional bias. We guided axons into the point of the arrow structure where one of the two tunnel entrances is located, making that the preferred direction. Main results. When rat cortical neurons were cultured in the wells, their axons grew through the tunnels and connected to neurons in adjoining wells. Unidirectional burst transfers and other asymmetric signal-propagation phenomena were observed via the substrate-embedded electrodes. Seventy-nine percent of burst transfers were in the forward direction. We also observed rapid propagation of activity from sites of local electrical stimulation, and significant effects of inhibitory synapse blockade on bursting activity. Significance. These results suggest that this simple, substrate-controlled neuronal circuit can be applied to develop in vitro models of the function of cortical microcircuits or deep neural networks, better to elucidate the laws governing the dynamics of neuronal networks.

  10. Astrocytes Modulate a Postsynaptic NMDA–GABAA-Receptor Crosstalk in Hypothalamic Neurosecretory Neurons

    Science.gov (United States)

    Potapenko, Evgeniy S.; Biancardi, Vinicia C.; Zhou, Yiqiang

    2013-01-01

    A dynamic balance between the excitatory and inhibitory neurotransmitters glutamate and GABA is critical for maintaining proper neuronal activity in the brain. This balance is partly achieved via presynaptic interactions between glutamatergic and GABAAergic synapses converging into the same targets. Here, we show that in hypothalamic magnocellular neurosecretory neurons (MNCs), a direct crosstalk between postsynaptic NMDA receptors (NMDARs) and GABAA receptors (GABAARs) contributes to the excitatory/inhibitory balance in this system. We found that activation of NMDARs by endogenous glutamate levels controlled by astrocyte glutamate transporters, evokes a transient and reversible potentiation of postsynaptic GABAARs. This inter-receptor crosstalk is calcium-dependent and involves a kinase-dependent phosphorylation mechanism, but does not require nitric oxide as an intermediary signal. Finally, we found the NMDAR–GABAAR crosstalk to be blunted in rats with heart failure, a pathological condition in which the hypothalamic glutamate–GABA balance is tipped toward an excitatory predominance. Together, our findings support a novel form of glutamate–GABA interactions in MNCs, which involves crosstalk between NMDA and GABAA postsynaptic receptors, whose strength is controlled by the activity of local astrocytes. We propose this inter-receptor crosstalk to act as a compensatory, counterbalancing mechanism to dampen glutamate-mediated overexcitation. Finally, we propose that an uncoupling between NMDARs and GABAARs may contribute to exacerbated neuronal activity and, consequently, sympathohumoral activation in such disease conditions as heart failure. PMID:23303942

  11. Ontogeny of Biochemical, Morphological and Functional Parameters of Synaptogenesis in Primary Cultures of Rat Hippocampal and Cortical Neurons

    Science.gov (United States)

    AbstractBackground: Synaptogenesis is a critical neurodevelopmental process whereby pre-and postsynaptic neurons form apposed sites of contact specialized for excitatory and inhibitory neurotransmission. Many neurodevelopmental disorders are thought to reflect altered patterns of...

  12. Dynamics of Competition between Subnetworks of Spiking Neuronal Networks in the Balanced State

    Science.gov (United States)

    Lagzi, Fereshteh; Rotter, Stefan

    2015-01-01

    We explore and analyze the nonlinear switching dynamics of neuronal networks with non-homogeneous connectivity. The general significance of such transient dynamics for brain function is unclear; however, for instance decision-making processes in perception and cognition have been implicated with it. The network under study here is comprised of three subnetworks of either excitatory or inhibitory leaky integrate-and-fire neurons, of which two are of the same type. The synaptic weights are arranged to establish and maintain a balance between excitation and inhibition in case of a constant external drive. Each subnetwork is randomly connected, where all neurons belonging to a particular population have the same in-degree and the same out-degree. Neurons in different subnetworks are also randomly connected with the same probability; however, depending on the type of the pre-synaptic neuron, the synaptic weight is scaled by a factor. We observed that for a certain range of the “within” versus “between” connection weights (bifurcation parameter), the network activation spontaneously switches between the two sub-networks of the same type. This kind of dynamics has been termed “winnerless competition”, which also has a random component here. In our model, this phenomenon is well described by a set of coupled stochastic differential equations of Lotka-Volterra type that imply a competition between the subnetworks. The associated mean-field model shows the same dynamical behavior as observed in simulations of large networks comprising thousands of spiking neurons. The deterministic phase portrait is characterized by two attractors and a saddle node, its stochastic component is essentially given by the multiplicative inherent noise of the system. We find that the dwell time distribution of the active states is exponential, indicating that the noise drives the system randomly from one attractor to the other. A similar model for a larger number of populations might

  13. Dynamics of Competition between Subnetworks of Spiking Neuronal Networks in the Balanced State.

    Science.gov (United States)

    Lagzi, Fereshteh; Rotter, Stefan

    2015-01-01

    We explore and analyze the nonlinear switching dynamics of neuronal networks with non-homogeneous connectivity. The general significance of such transient dynamics for brain function is unclear; however, for instance decision-making processes in perception and cognition have been implicated with it. The network under study here is comprised of three subnetworks of either excitatory or inhibitory leaky integrate-and-fire neurons, of which two are of the same type. The synaptic weights are arranged to establish and maintain a balance between excitation and inhibition in case of a constant external drive. Each subnetwork is randomly connected, where all neurons belonging to a particular population have the same in-degree and the same out-degree. Neurons in different subnetworks are also randomly connected with the same probability; however, depending on the type of the pre-synaptic neuron, the synaptic weight is scaled by a factor. We observed that for a certain range of the "within" versus "between" connection weights (bifurcation parameter), the network activation spontaneously switches between the two sub-networks of the same type. This kind of dynamics has been termed "winnerless competition", which also has a random component here. In our model, this phenomenon is well described by a set of coupled stochastic differential equations of Lotka-Volterra type that imply a competition between the subnetworks. The associated mean-field model shows the same dynamical behavior as observed in simulations of large networks comprising thousands of spiking neurons. The deterministic phase portrait is characterized by two attractors and a saddle node, its stochastic component is essentially given by the multiplicative inherent noise of the system. We find that the dwell time distribution of the active states is exponential, indicating that the noise drives the system randomly from one attractor to the other. A similar model for a larger number of populations might suggest a

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

    Science.gov (United States)

    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...

  15. Neurokinin-1 enables measles virus trans-synaptic spread in neurons

    International Nuclear Information System (INIS)

    Makhortova, Nina R.; Askovich, Peter; Patterson, Catherine E.; Gechman, Lisa A.; Gerard, Norma P.; Rall, Glenn F.

    2007-01-01

    Measles virus (MV), a morbillivirus that remains a significant human pathogen, can infect the central nervous system, resulting in rare but often fatal diseases, such as subacute sclerosing panencephalitis. Previous work demonstrated that MV was transmitted trans-synaptically and that, while a cellular receptor for the hemagglutinin (H) protein was required for MV entry, it was dispensable for subsequent cell-to-cell spread. Here, we explored what role the other envelope protein, fusion (F), played in trans-synaptic transport. We made the following observations: (1) MV-F expression in infected neurons was similar to that seen in infected fibroblasts; (2) fusion inhibitory peptide (FIP), an inhibitor of MV fusion, prevented both infection and spread in primary neurons; (3) Substance P, a neurotransmitter with the same active site as FIP, also blocked neuronal MV spread; and (4) both genetic deletion and pharmacological inhibition of the Substance P receptor, neurokinin-1 (NK-1), reduced infection of susceptible mice. Together, these data implicate a role for NK-1 in MV CNS infection and spread, perhaps serving as an MV-F receptor or co-receptor on neurons

  16. Alterations of cortical GABA neurons and network oscillations in schizophrenia.

    Science.gov (United States)

    Gonzalez-Burgos, Guillermo; Hashimoto, Takanori; Lewis, David A

    2010-08-01

    The hypothesis that alterations of cortical inhibitory gamma-aminobutyric acid (GABA) neurons are a central element in the pathology of schizophrenia has emerged from a series of postmortem studies. How such abnormalities may contribute to the clinical features of schizophrenia has been substantially informed by a convergence with basic neuroscience studies revealing complex details of GABA neuron function in the healthy brain. Importantly, activity of the parvalbumin-containing class of GABA neurons has been linked to the production of cortical network oscillations. Furthermore, growing knowledge supports the concept that gamma band oscillations (30-80 Hz) are an essential mechanism for cortical information transmission and processing. Herein we review recent studies further indicating that inhibition from parvalbumin-positive GABA neurons is necessary to produce gamma oscillations in cortical circuits; provide an update on postmortem studies documenting that deficits in the expression of glutamic acid decarboxylase67, which accounts for most GABA synthesis in the cortex, are widely observed in schizophrenia; and describe studies using novel, noninvasive approaches directly assessing potential relations between alterations in GABA, oscillations, and cognitive function in schizophrenia.

  17. Gap junctions and inhibitory synapses modulate inspiratory motoneuron synchronization.

    Science.gov (United States)

    Bou-Flores, C; Berger, A J

    2001-04-01

    Interneuronal electrical coupling via gap junctions and chemical synaptic inhibitory transmission are known to have roles in the generation and synchronization of activity in neuronal networks. Uncertainty exists regarding the roles of these two modes of interneuronal communication in the central respiratory rhythm-generating system. To assess their roles, we performed studies on both the neonatal mouse medullary slice and en bloc brain stem-spinal cord preparations where rhythmic inspiratory motor activity can readily be recorded from both hypoglossal and phrenic nerve roots. The rhythmic inspiratory activity observed had two temporal characteristics: the basic respiratory frequency occurring on a long time scale and the synchronous neuronal discharge within the inspiratory burst occurring on a short time scale. In both preparations, we observed that bath application of gap-junction blockers, including 18 alpha-glycyrrhetinic acid, 18 beta-glycyrrhetinic acid, and carbenoxolone, all caused a reduction in respiratory frequency. In contrast, peak integrated phrenic and hypoglossal inspiratory activity was not significantly changed by gap-junction blockade. On a short-time-scale, gap-junction blockade increased the degree of synchronization within an inspiratory burst observed in both nerves. In contrast, opposite results were observed with blockade of GABA(A) and glycine receptors. We found that respiratory frequency increased with receptor blockade, and simultaneous blockade of both receptors consistently resulted in a reduction in short-time-scale synchronized activity observed in phrenic and hypoglossal inspiratory bursts. These results support the concept that the central respiratory system has two components: a rhythm generator responsible for the production of respiratory cycle timing and an inspiratory pattern generator that is involved in short-time-scale synchronization. In the neonatal rodent, properties of both components can be regulated by interneuronal

  18. Characterization of neuronal intrinsic properties and synaptic transmission in layer I of anterior cingulate cortex from adult mice

    Directory of Open Access Journals (Sweden)

    Li Xiang-Yao

    2012-07-01

    Full Text Available Abstract The neurons in neocortex layer I (LI provide inhibition to the cortical networks. Despite increasing use of mice for the study of brain functions, few studies were reported about mouse LI neurons. In the present study, we characterized intrinsic properties of LI neurons of the anterior cingulate cortex (ACC, a key cortical area for sensory and cognitive functions, by using whole-cell patch clamp recording approach. Seventy one neurons in LI and 12 pyramidal neurons in LII/III were recorded. Although all of the LI neurons expressed continuous adapting firing characteristics, the unsupervised clustering results revealed five groups in the ACC, including: Spontaneous firing neurons; Delay-sAHP neurons, Delay-fAHP neurons, and two groups of neurons with ADP, named ADP1 and ADP2, respectively. Using pharmacological approaches, we found that LI neurons received both excitatory (mediated by AMPA, kainate and NMDA receptors, and inhibitory inputs (which were mediated by GABAA receptors. Our studies provide the first report characterizing the electrophysiological properties of neurons in LI of the ACC from adult mice.

  19. Injection of fully-defined signal mixtures: a novel high-throughput tool to study neuronal encoding and computations.

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    Vladimir Ilin

    Full Text Available Understanding of how neurons transform fluctuations of membrane potential, reflecting input activity, into spike responses, which communicate the ultimate results of single-neuron computation, is one of the central challenges for cellular and computational neuroscience. To study this transformation under controlled conditions, previous work has used a signal immersed in noise paradigm where neurons are injected with a current consisting of fluctuating noise that mimics on-going synaptic activity and a systematic signal whose transmission is studied. One limitation of this established paradigm is that it is designed to examine the encoding of only one signal under a specific, repeated condition. As a result, characterizing how encoding depends on neuronal properties, signal parameters, and the interaction of multiple inputs is cumbersome. Here we introduce a novel fully-defined signal mixture paradigm, which allows us to overcome these problems. In this paradigm, current for injection is synthetized as a sum of artificial postsynaptic currents (PSCs resulting from the activity of a large population of model presynaptic neurons. PSCs from any presynaptic neuron(s can be now considered as "signal", while the sum of all other inputs is considered as "noise". This allows us to study the encoding of a large number of different signals in a single experiment, thus dramatically increasing the throughput of data acquisition. Using this novel paradigm, we characterize the detection of excitatory and inhibitory PSCs from neuronal spike responses over a wide range of amplitudes and firing-rates. We show, that for moderately-sized neuronal populations the detectability of individual inputs is higher for excitatory than for inhibitory inputs during the 2-5 ms following PSC onset, but becomes comparable after 7-8 ms. This transient imbalance of sensitivity in favor of excitation may enhance propagation of balanced signals through neuronal networks. Finally, we

  20. Traveling wave front solutions in lateral-excitatory neuronal networks

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    Sittipong Ruktamatakul

    2008-05-01

    Full Text Available In this paper, we discuss the shape of traveling wave front solutions to a neuronal model with the connection function to be of lateral excitation type. This means that close connecting cells have an inhibitory influence, while cells that aremore distant have an excitatory influence. We give results on the shape of the wave fronts solutions, which exhibit different shapes depend ing on the size of a threshold parameter.

  1. Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons

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    Ada eLedonne

    2011-07-01

    Full Text Available Trace amines (TAs are a class of endogenous compounds strictly related to classic monoamine neurotransmitters with regard to their structure, metabolism and tissue distribution. Although the presence of TAs in mammalian brain has been recognized for decades, until recently they were considered to be by-products of amino acid metabolism or as ‘false’ neurotransmitters. The discovery in 2001 of a new family of G protein-coupled receptors (GPCRs, namely trace amines receptors, has re-ignited interest in TAs. In particular, two members of the family, trace amine receptor 1 (TA1 and trace amine receptor 2 (TA2, were shown to be highly sensitive to these endogenous compounds. Experimental evidence suggests that TAs modulate the activity of catecholaminergic neurons and that TA dysregulation may contribute to neuropsychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder, depression and Parkinson’s disease, all of which are characterised by altered monoaminergic networks. Here we review recent data concerning the electrophysiological effects of TAs on the activity of mesencephalic dopaminergic neurons. In the context of recent data obtained with TA1 receptor knockout mice, we also discuss the mechanisms by which the activation of these receptors modulates the activity of these neurons. Three important new aspects of TAs action have recently emerged: (a inhibition of firing due to increased release of dopamine; (b reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to dysinhibition; and (c a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. While the first two effects have been well documented in our laboratory, the direct activation of GIRK channels by TA1 receptors has been reported by others, but has not been seen in our laboratory (Geracitano et al., 2004. Further research is needed to address this point, and to further

  2. Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity

    KAUST Repository

    Orlando, Marta

    2017-10-17

    Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABAA Receptors (GABAARs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABAAR clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABAAR clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

  3. Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity

    KAUST Repository

    Orlando, Marta; Ravasenga, Tiziana; Petrini, Enrica Maria; Falqui, Andrea; Marotta, Roberto; Barberis, Andrea

    2017-01-01

    Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABAA Receptors (GABAARs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABAAR clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABAAR clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

  4. Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity.

    Science.gov (United States)

    Orlando, Marta; Ravasenga, Tiziana; Petrini, Enrica Maria; Falqui, Andrea; Marotta, Roberto; Barberis, Andrea

    2017-10-23

    Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABA A Receptors (GABA A Rs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABA A R clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABA A R clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

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

    Science.gov (United States)

    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

  6. Asynchronous Cholinergic Drive Correlates with Excitation-Inhibition Imbalance via a Neuronal Ca2+ Sensor Protein

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    Keming Zhou

    2017-05-01

    Full Text Available Excitation-inhibition imbalance in neural networks is widely linked to neurological and neuropsychiatric disorders. However, how genetic factors alter neuronal activity, leading to excitation-inhibition imbalance, remains unclear. Here, using the C. elegans locomotor circuit, we examine how altering neuronal activity for varying time periods affects synaptic release pattern and animal behavior. We show that while short-duration activation of excitatory cholinergic neurons elicits a reversible enhancement of presynaptic strength, persistent activation results to asynchronous and reduced cholinergic drive, inducing imbalance between endogenous excitation and inhibition. We find that the neuronal calcium sensor protein NCS-2 is required for asynchronous cholinergic release in an activity-dependent manner and dampens excitability of inhibitory neurons non-cell autonomously. The function of NCS-2 requires its Ca2+ binding and membrane association domains. These results reveal a synaptic mechanism implicating asynchronous release in regulation of excitation-inhibition balance.

  7. Photoperiodic plasticity in circadian clock neurons in insects

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    Sakiko eShiga

    2013-08-01

    Full Text Available Since Bünning’s observation of circadian rhythms and photoperiodism in the runner bean Phaseolus multiflorus in 1936, many studies have shown that photoperiodism is based on the circadian clock system. In insects, involvement of circadian clock genes or neurons has been recently shown in the photoperiodic control of developmental arrests, diapause. Based on molecular and neuronal studies in Drosophila melanogaster, photoperiodic changes have been reported for expression patterns of the circadian clock genes, subcellular distribution of clock proteins, fiber distribution, or the number of plausible clock neurons in different species. Photoperiod sets peaks of per or tim mRNA abundance at lights-off in Sarcophaga crassipalpis, Chymomyza costata and Protophormia terraenovae. Abundance of per and Clock mRNA changes by photoperiod in Pyrrhocoris apterus. Subcellular Per distribution in circadian clock neurons changes with photoperiod in P. terraenovae. Although photoperiodism is not known in Leucophaea maderae, under longer day length, more stomata and longer commissural fibers of circadian clock neurons have been found. These plastic changes in the circadian clock neurons could be an important constituent for photoperiodic clock mechanisms to integrate repetitive photoperiodic information and produce different outputs based on day length.

  8. Distribution and female reproductive state differences in orexigenic and anorexigenic neurons in the brain of the mouth brooding African cichlid fish, Astatotilapia burtoni.

    Science.gov (United States)

    Porter, Danielle T; Roberts, David A; Maruska, Karen P

    2017-10-01

    Integration of reproduction and metabolism is necessary for species survival. While the neural circuits controlling energy homeostasis are well-characterized, the signals controlling the relay of nutritional information to the reproductive axis are less understood. The cichlid fish Astatotilapia burtoni is ideal for studying the neural regulation of feeding and reproduction because females cycle between a feeding gravid state and a period of forced starvation while they brood developing young inside their mouths. To test the hypothesis that candidate neuropeptide-containing neurons known to be involved in feeding and energy homeostasis in mammals show conserved distribution patterns, we performed immunohistochemistry and in situ hybridization to localize appetite-stimulating (neuropeptide Y, NPY; agouti-related protein, AGRP) and appetite-inhibiting (cocaine and amphetamine-regulated transcript, CART; pro-opiomelanocortin, pomc1a) neurons in the brain. NPY, AGRP, CART, and pomc1a somata showed distribution patterns similar to other teleosts, which included localization to the lateral tuberal nucleus (NLT), the putative homolog of the mammalian arcuate nucleus. Gravid females also had larger NPY and AGRP neurons in the NLT compared to brooding females, but brooding females had larger pomc1a neurons compared to gravid females. Hypothalamic agrp mRNA levels were also higher in gravid compared to brooding females. Thus, larger appetite-stimulating neurons (NPY, AGRP) likely promote feeding while females are gravid, while larger pomc1a neurons may act as a signal to inhibit food intake during mouth brooding. Collectively, our data suggest a potential role for NPY, AGRP, POMC, and CART in regulating energetic status in A. burtoni females during varying metabolic and reproductive demands. © 2017 Wiley Periodicals, Inc.

  9. Glycogen distribution in adult and geriatric mice brains

    KAUST Repository

    Alrabeh, Rana

    2017-05-01

    Astrocytes, the most abundant glial cell type in the brain, undergo a number of roles in brain physiology; among them, the energetic support of neurons is the best characterized. Contained within astrocytes is the brain’s obligate energy store, glycogen. Through glycogenolysis, glycogen, a storage form of glucose, is converted to pyruvate that is further reduced to lactate and transferred to neurons as an energy source via MCTs. Glycogen is a multi-branched polysaccharide synthesized from the glucose uptaken in astrocytes. It has been shown that glycogen accumulates with age and contributes to the physiological ageing process in the brain. In this study, we compared glycogen distribution between young adults and geriatric mice to understand the energy consumption of synaptic terminals during ageing using computational tools. We segmented and densely reconstructed neuropil and glycogen granules within six (three 4 month old old and three 24 month old) volumes of Layer 1 somatosensory cortex mice brains from FIB-SEM stacks, using a combination of semi-automated and manual tools, ilastik and TrakEM2. Finally, the 3D visualization software, Blender, was used to analyze the dataset using the DBSCAN and KDTree Nearest neighbor algorithms to study the distribution of glycogen granules compared to synapses, using a plugin that was developed for this purpose. The Nearest Neighbors and clustering results of 6 datasets show that glycogen clusters around excitatory synapses more than inhibitory synapses and that, in general, glycogen is found around axonal boutons more than dendritic spines. There was no significant accumulation of glycogen with ageing within our admittedly small dataset. However, there was a homogenization of glycogen distribution with age and that is consistent with published literature. We conclude that glycogen distribution in the brain is not a random process but follows a function distribution.

  10. Extracellular Ca²⁺ acts as a mediator of communication from neurons to glia.

    Science.gov (United States)

    Torres, Arnulfo; Wang, Fushun; Xu, Qiwu; Fujita, Takumi; Dobrowolski, Radoslaw; Willecke, Klaus; Takano, Takahiro; Nedergaard, Maiken

    2012-01-24

    Defining the pathways through which neurons and astrocytes communicate may contribute to the elucidation of higher central nervous system functions. We investigated the possibility that decreases in extracellular calcium ion concentration ([Ca(2+)](e)) that occur during synaptic transmission might mediate signaling from neurons to glia. Using noninvasive photolysis of the photolabile Ca(2+) buffer diazo-2 {N-[2-[2-[2-[bis(carboxymethyl)amino]-5-(diazoacetyl)phenoxy]ethoxy]-4-methylphenyl]-N-(carboxymethyl)-, tetrapotassium salt} to reduce [Ca(2+)](e) or caged glutamate to simulate glutamatergic transmission, we found that a local decline in extracellular Ca(2+) triggered astrocytic adenosine triphosphate (ATP) release and astrocytic Ca(2+) signaling. In turn, activation of purinergic P2Y1 receptors on a subset of inhibitory interneurons initiated the generation of action potentials by these interneurons, thereby enhancing synaptic inhibition. Thus, astrocytic ATP release evoked by an activity-associated decrease in [Ca(2+)](e) may provide a negative feedback mechanism that potentiates inhibitory transmission in response to local hyperexcitability.

  11. GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia.

    Science.gov (United States)

    Gonzalez-Burgos, Guillermo; Lewis, David A

    2008-09-01

    Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical gamma-aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type-specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value.

  12. Glucose Rapidly Induces Different Forms of Excitatory Synaptic Plasticity in Hypothalamic POMC Neurons

    Science.gov (United States)

    Hu, Jun; Jiang, Lin; Low, Malcolm J.; Rui, Liangyou

    2014-01-01

    Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+), EPSC(−), and EPSC(+/−)) based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs), using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+) neurons, but increased it in EPSC(−) neurons. Unlike EPSC(+) and EPSC(−) neurons, EPSC(+/−) neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/−) neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals. PMID:25127258

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

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    Sun Qian-Quan

    2009-10-01

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

  14. Enhanced astroglial GABA uptake attenuates tonic GABAA inhibition of the presympathetic hypothalamic paraventricular nucleus neurons in heart failure.

    Science.gov (United States)

    Pandit, Sudip; Jo, Ji Yoon; Lee, Sang Ung; Lee, Young Jae; Lee, So Yeong; Ryu, Pan Dong; Lee, Jung Un; Kim, Hyun-Woo; Jeon, Byeong Hwa; Park, Jin Bong

    2015-08-01

    γ-Aminobutyric acid (GABA) generates persistent tonic inhibitory currents (Itonic) and conventional inhibitory postsynaptic currents in the hypothalamic paraventricular nucleus (PVN) via activation of GABAA receptors (GABAARs). We investigated the pathophysiological significance of astroglial GABA uptake in the regulation of Itonic in the PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM). The Itonic of PVN-RVLM neurons were significantly reduced in heart failure (HF) compared with sham-operated (SHAM) rats. Reduced Itonic sensitivity to THIP argued for the decreased function of GABAAR δ subunits in HF, whereas similar Itonic sensitivity to benzodiazepines argued against the difference of γ2 subunit-containing GABAARs in SHAM and HF rats. HF Itonic attenuation was reversed by a nonselective GABA transporter (GAT) blocker (nipecotic acid, NPA) and a GAT-3 selective blocker, but not by a GAT-1 blocker, suggesting that astroglial GABA clearance increased in HF. Similar and minimal Itonic responses to bestrophin-1 blockade in SHAM and HF neurons further argued against a role for astroglial GABA release in HF Itonic attenuation. Finally, the NPA-induced inhibition of spontaneous firing was greater in HF than in SHAM PVN-RVLM neurons, whereas diazepam induced less inhibition of spontaneous firing in HF than in SHAM neurons. Overall, our results showed that combined with reduced GABAARs function, the enhanced astroglial GABA uptake-induced attenuation of Itonic in HF PVN-RVLM neurons explains the deficit in tonic GABAergic inhibition and increased sympathetic outflow from the PVN during heart failure. Copyright © 2015 the American Physiological Society.

  15. Inhibitory Control of Feature Selectivity in an Object Motion Sensitive Circuit of the Retina

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    Tahnbee Kim

    2017-05-01

    Full Text Available Object motion sensitive (OMS W3-retinal ganglion cells (W3-RGCs in mice respond to local movements in a visual scene but remain silent during self-generated global image motion. The excitatory inputs that drive responses of W3-RGCs to local motion were recently characterized, but which inhibitory neurons suppress W3-RGCs’ responses to global motion, how these neurons encode motion information, and how their connections are organized along the excitatory circuit axis remains unknown. Here, we find that a genetically identified amacrine cell (AC type, TH2-AC, exhibits fast responses to global motion and slow responses to local motion. Optogenetic stimulation shows that TH2-ACs provide strong GABAA receptor-mediated input to W3-RGCs but only weak input to upstream excitatory neurons. Cell-type-specific silencing reveals that temporally coded inhibition from TH2-ACs cancels W3-RGC spike responses to global but not local motion stimuli and, thus, controls the feature selectivity of OMS signals sent to the brain.

  16. Distribution of binding sites for the plant lectin Ulex europaeus agglutinin I on primary sensory neurones in seven different mammalian species.

    Science.gov (United States)

    Gerke, Michelle B; Plenderleith, Mark B

    2002-01-01

    There is an increasing body of evidence to suggest that different functional classes of neurones express characteristic cell-surface carbohydrates. Previous studies have shown that the plant lectin Ulex europaeus agglutinin-I (UEA) binds to a population of small to medium diameter primary sensory neurones in rabbits and humans. This suggests that a fucose-containing glycoconjugate may be expressed by nociceptive primary sensory neurones. In order to determine the extent to which this glycoconjugate is expressed by other species, in the current study, we have examined the distribution of UEA-binding sites on primary sensory neurones in seven different mammals. Binding sites for UEA were associated with the plasma membrane and cytoplasmic granules of small to medium dorsal root ganglion cells and their axon terminals in laminae I-III of the grey matter of the spinal cord, in the rabbit, cat and marmoset monkey. However, no binding was observed in either the dorsal root ganglia or spinal cord in the mouse, rat, guinea pig or flying fox. These results indicate an inter-species variation in the expression of cell-surface glycoconjugates on mammalian primary sensory neurones.

  17. Understanding the Generation of Network Bursts by Adaptive Oscillatory Neurons

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    Tanguy Fardet

    2018-02-01

    Full Text Available Experimental and numerical studies have revealed that isolated populations of oscillatory neurons can spontaneously synchronize and generate periodic bursts involving the whole network. Such a behavior has notably been observed for cultured neurons in rodent's cortex or hippocampus. We show here that a sufficient condition for this network bursting is the presence of an excitatory population of oscillatory neurons which displays spike-driven adaptation. We provide an analytic model to analyze network bursts generated by coupled adaptive exponential integrate-and-fire neurons. We show that, for strong synaptic coupling, intrinsically tonic spiking neurons evolve to reach a synchronized intermittent bursting state. The presence of inhibitory neurons or plastic synapses can then modulate this dynamics in many ways but is not necessary for its appearance. Thanks to a simple self-consistent equation, our model gives an intuitive and semi-quantitative tool to understand the bursting behavior. Furthermore, it suggests that after-hyperpolarization currents are sufficient to explain bursting termination. Through a thorough mapping between the theoretical parameters and ion-channel properties, we discuss the biological mechanisms that could be involved and the relevance of the explored parameter-space. Such an insight enables us to propose experimentally-testable predictions regarding how blocking fast, medium or slow after-hyperpolarization channels would affect the firing rate and burst duration, as well as the interburst interval.

  18. Tonotopic alterations in inhibitory input to the medial nucleus of the trapezoid body in a mouse model of Fragile X syndrome.

    Science.gov (United States)

    McCullagh, Elizabeth A; Salcedo, Ernesto; Huntsman, Molly M; Klug, Achim

    2017-11-01

    Hyperexcitability and the imbalance of excitation/inhibition are one of the leading causes of abnormal sensory processing in Fragile X syndrome (FXS). The precise timing and distribution of excitation and inhibition is crucial for auditory processing at the level of the auditory brainstem, which is responsible for sound localization ability. Sound localization is one of the sensory abilities disrupted by loss of the Fragile X Mental Retardation 1 (Fmr1) gene. Using triple immunofluorescence staining we tested whether there were alterations in the number and size of presynaptic structures for the three primary neurotransmitters (glutamate, glycine, and GABA) in the auditory brainstem of Fmr1 knockout mice. We found decreases in either glycinergic or GABAergic inhibition to the medial nucleus of the trapezoid body (MNTB) specific to the tonotopic location within the nucleus. MNTB is one of the primary inhibitory nuclei in the auditory brainstem and participates in the sound localization process with fast and well-timed inhibition. Thus, a decrease in inhibitory afferents to MNTB neurons should lead to greater inhibitory output to the projections from this nucleus. In contrast, we did not see any other significant alterations in balance of excitation/inhibition in any of the other auditory brainstem nuclei measured, suggesting that the alterations observed in the MNTB are both nucleus and frequency specific. We furthermore show that glycinergic inhibition may be an important contributor to imbalances in excitation and inhibition in FXS and that the auditory brainstem is a useful circuit for testing these imbalances. © 2017 Wiley Periodicals, Inc.

  19. On the number of preganglionic neurones driving human postganglionic sympathetic neurones: a comparison of modelling and empirical data

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    Vaughan G Macefield

    2011-12-01

    Full Text Available Postganglionic sympathetic axons in awake healthy human subjects, regardless of their identity as muscle vasoconstrictor, cutaneous vasoconstrictor or sudomotor neurones, discharge with a low firing probability (~30%, generate low firing rates (~0.5 Hz and typically fire only once per cardiac interval. The purpose of the present study was to use modelling of spike trains in an attempt to define the number of preganglionic neurones that drive an individual postganglionic neurone. Artificial spike trains were generated in 1-3 preganglionic neurones converging onto a single postganglionic neurone. Each preganglionic input fired with a mean interval distribution of either 1000, 1500, 2000, 2500 or 3000 ms and the standard deviation varied between 0.5, 1.0 and 2.0 x the mean interval; the discharge frequency of each preganglionic neurone exhibited positive skewness and kurtosis. Of the 45 patterns examined, the mean discharge properties of the postganglionic neurone could only be explained by it being driven by, on average, two preganglionic neurones firing with a mean interspike interval of 2500 ms and SD of 5000 ms. The mean firing rate resulting from this pattern was 0.22 Hz, comparable to that of spontaneously active muscle vasoconstrictor neurones in healthy subjects (0.40 Hz. Likewise, the distribution of the number of spikes per cardiac interval was similar between the modelled and actual data: 0 spikes (69.5 vs 66.6 %, 1 spike (25.6 vs 21.2 %, 2 spikes (4.3 vs 6.4 %, 3 spikes (0.5 vs 1.7 % and 4 spikes (0.1 vs 0.7 %. Although some features of the firing patterns could be explained by the postganglionic neurone being driven by a single preganglionic neurone, none of the emulated firing patterns generated by the firing of three preganglionic neurones matched the discharge of the real neurones. These modelling data indicate that, on average, human postganglionic sympathetic neurones are driven by two preganglionic inputs.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    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

  2. The changing roles of neurons in the cortical subplate

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    Michael J Friedlander

    2009-08-01

    Full Text Available Neurons may serve different functions over the course of an organism’s life. Recent evidence suggests that cortical subplate neurons including those that reside in the white matter may perform longitudinal multi-tasking at different stages of development. These cells play a key role in early cortical development in coordinating thalamocortical reciprocal innervation. At later stages of development, they become integrated within the cortical microcircuitry. This type of longitudinal multi-tasking can enhance the capacity for information processing by populations of cells serving different functions over the lifespan. Subplate cells are initially derived when cells from the ventricular zone underlying the cortex migrate to the cortical preplate that is subsequently split by the differentiating neurons of the cortical plate with some neurons locating in the marginal zone and others settling below in the subplate (SP. While the cortical plate neurons form most of the cortical layers (layers 2-6, the marginal zone neurons form layer 1 and the SP neurons become interstitial cells of the white matter as well as forming a compact sublayer along the bottom of layer 6. After serving as transient innervation targets for thalamocortical axons, most of these cells die and layer 4 neurons become innervated by thalamic axons. However, 10-20% survives, remaining into adulthood along the bottom of layer 6 and as a scattered population of interstitial neurons in the white matter. Surviving subplate cells’ axons project throughout the overlying laminae, reaching layer 1 and issuing axon collaterals within white matter and in lower layer 6. This suggests that they participate in local synaptic networks, as well. Moreover, they receive excitatory and inhibitory synaptic inputs, potentially monitoring outputs from axon collaterals of cortical efferents, from cortical afferents and/or from each other. We explore our understanding of the functional connectivity of

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

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    Yun-Qing eLi

    2014-12-01

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

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

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    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.

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

    Science.gov (United States)

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

    2015-01-01

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

  6. Organization of left–right coordination of neuronal activity in the mammalian spinal cord: Insights from computational modelling

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    Shevtsova, Natalia A; Talpalar, Adolfo E; Markin, Sergey N; Harris-Warrick, Ronald M; Kiehn, Ole; Rybak, Ilya A

    2015-01-01

    Different locomotor gaits in mammals, such as walking or galloping, are produced by coordinated activity in neuronal circuits in the spinal cord. Coordination of neuronal activity between left and right sides of the cord is provided by commissural interneurons (CINs), whose axons cross the midline. In this study, we construct and analyse two computational models of spinal locomotor circuits consisting of left and right rhythm generators interacting bilaterally via several neuronal pathways mediated by different CINs. The CIN populations incorporated in the models include the genetically identified inhibitory (V0D) and excitatory (V0V) subtypes of V0 CINs and excitatory V3 CINs. The model also includes the ipsilaterally projecting excitatory V2a interneurons mediating excitatory drive to the V0V CINs. The proposed network architectures and CIN connectivity allow the models to closely reproduce and suggest mechanistic explanations for several experimental observations. These phenomena include: different speed-dependent contributions of V0D and V0V CINs and V2a interneurons to left–right alternation of neural activity, switching gaits between the left–right alternating walking-like activity and the left–right synchronous hopping-like pattern in mutants lacking specific neuron classes, and speed-dependent asymmetric changes of flexor and extensor phase durations. The models provide insights into the architecture of spinal network and the organization of parallel inhibitory and excitatory CIN pathways and suggest explanations for how these pathways maintain alternating and synchronous gaits at different locomotor speeds. The models propose testable predictions about the neural organization and operation of mammalian locomotor circuits. Key points Coordination of neuronal activity between left and right sides of the mammalian spinal cord is provided by several sets of commissural interneurons (CINs) whose axons cross the midline. Genetically identified inhibitory V

  7. A million-plus neuron model of the hippocampal dentate gyrus: Dependency of spatio-temporal network dynamics on topography.

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    Hendrickson, Phillip J; Yu, Gene J; Song, Dong; Berger, Theodore W

    2015-01-01

    This paper describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons. The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions. Modeling excitatory input from the entorhinal cortex was guided by axonal transport studies documenting the topographical organization of projections from subregions of the medial and lateral entorhinal cortex, plus other important details of the distribution of glutamatergic inputs to the dentate gyrus. Results showed that when medial and lateral entorhinal cortical neurons maintained Poisson random firing, dentate granule cells expressed, throughout the million-cell network, a robust, non-random pattern of spiking best described as spatiotemporal "clustering". To identify the network property or properties responsible for generating such firing "clusters", we progressively eliminated from the model key mechanisms such as feedforward and feedback inhibition, intrinsic membrane properties underlying rhythmic burst firing, and/or topographical organization of entorhinal afferents. Findings conclusively identified topographical organization of inputs as the key element responsible for generating a spatio-temporal distribution of clustered firing. These results uncover a functional organization of perforant path afferents to the dentate gyrus not previously recognized: topography-dependent clusters of granule cell activity as "functional units" that organize the processing of entorhinal signals.

  8. Enzyme inhibitory activity of selected Philippine plants

    International Nuclear Information System (INIS)

    Sasotona, Joseph S.; Hernandez, Christine C.

    2015-01-01

    In the Philippines, the number one cause of death are cardiovascular diseases. Diseases linked with inflammation are proliferating. This research aims to identify plant extracts that have potential activity of cholesterol-lowering, anti-hypertension, anti-gout, anti-inflammatory and fat blocker agents. Although there are commercially available drugs to treat the aforementioned illnesses, these medicine have adverse side-effects, aside from the fact that they are expensive. The results of this study will serve as added knowledge to contribute to the development of cheaper, more readily available, and effective alternative medicine. 100 plant extracts from different areas in the Philippines have been tested for potential inhibitory activity against Hydroxymethylglutaryl-coenzyme A (HMG-CoA), Lipoxygenase, and Xanthine Oxidase. The plant samples were labeled with codes and distributed to laboratories for blind testing. The effective concentration of the samples tested for Xanthine oxidase is 100 ppm. Samples number 9, 11, 14, 29, 43, 46, and 50 have shown significant inhibitory activity at 78.7%, 78.4%, 70%, 89.2%, 79%, 67.4%, and 67.5% respectively. Samples tested for Lipoxygenase inhibition were set at 33ppm. Samples number 2, 37, 901, 1202, and 1204 have shown significant inhibitory activity at 66, 84.9%, 88.55%, 93.3%, and 84.7% respectively. For HMG-CoA inhibition, the effective concentration of the samples used was 100 ppm. Samples number 1 and 10 showed significant inhibitory activity at 90.1% and 81.8% respectively. (author)

  9. Leaders of neuronal cultures in a quorum percolation model

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Eckmann

    2010-09-01

    Full Text Available We present a theoretical framework using quorum-percolation for describing the initiation of activity in a neural culture. The cultures are modeled as random graphs, whose nodes are neurons with $kin$ inputs and $kout$ outputs, and whose input degrees $kin=k$ obey given distribution functions $p_k$. We examine the firing activity of the population of neurons according to their input degree ($k$ classes and calculate for each class its firing probability $Phi_k(t$ as a function of $t$. The probability of a node to fire is found to be determined by its in-degree $k$, and the first-to-fire neurons are those that have a high $k$. A small minority of high-$k$ classes may be called ``Leaders,'' as they form an inter-connected subnetwork that consistently fires much before the rest of the culture. Once initiated, the activity spreads from the Leaders to the less connected majority of the culture. We then use the distribution of in-degree of the Leaders to study the growth rate of the number of neurons active in a burst, which was experimentally measured to be initially exponential. We find that this kind of growth rate is best described by a population that has an in-degree distribution that is a Gaussian centered around $k=75$ with width $sigma=31$ for the majority of the neurons, but also has a power law tail with exponent $-2$ for ten percent of the population. Neurons in the tail may have as many as $k=4,700$ inputs. We explore and discuss the correspondence between the degree distribution and a dynamic neuronal threshold, showing that from the functional point of view, structure and elementary dynamics are interchangeable. We discuss possible geometric origins of this distribution, and comment on the importance of size, or of having a large number of neurons, in the culture.

  10. Acupuncture-like stimulation at auricular point Heart evokes cardiovascular inhibition via activating the cardiac-related neurons in the nucleus tractus solitarius.

    Science.gov (United States)

    Gao, Xin Yan; Li, Yan Hua; Liu, Kun; Rong, Pei Jing; Ben, Hui; Li, Liang; Zhu, Bing; Zhang, Shi Ping

    2011-06-23

    Fifty-eight male Sprague-Dawley rats used in the present study to investigate the role of baroreceptor sensitive neurons of the nucleus tractus solitarius (NTS) in the regulation of cardiovascular inhibition during acupuncture at the auricular point Heart, single unit recording was made in anesthetized Sprague-Dawley rats. A neuron was considered to be excited or inhibited by acupuncture stimulation if it displayed 15% more or less spikes s(-1), respectively. NTS neurons were classified into cardiac-related (CR) neurons and non-cardiac-related neurons based on whether their rhythmic discharges were synchronized with the R-waves and responding to sodium nitroprusside (NP; 20 μg/kg, i.v.) administration. Manual acupuncture was applied at the auricular point Heart and somatic acupuncture points ST36 and PC6. Acupuncture at auricular point Heart showed a more significant inhibitory effect on arterial pressure (-22.1±2.4mm Hg; Pheart rate (-12.7±1.7 bpm; PHeart also increased the level of response of CR neurons in the NTS (93.8%±26.0% increase in discharge rate; Pneurons evoked by auricular acupuncture, but had no effect on the same responses evoked by somatic acupuncture. Inactivation of the NTS with local anesthetics also decreased the cardiovascular inhibitory responses evoked by auricular acupuncture. Our results show that acupuncture at the auricular point Heart regulates cardiovascular function by activating baroreceptor sensitive neurons in the NTS in a similar manner as the baroreceptor reflex in cardiovascular inhibition. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Connections between EM2-containing terminals and GABA/μ-opioid receptor co-expressing neurons in the rat spinal trigeminal caudal nucleus

    Science.gov (United States)

    Li, Meng-Ying; Wu, Zhen-Yu; Lu, Ya-Cheng; Yin, Jun-Bin; Wang, Jian; Zhang, Ting; Dong, Yu-Lin; Wang, Feng

    2014-01-01

    Endomorphin-2 (EM2) demonstrates a potent antinociceptive effect via the μ-opioid receptor (MOR). To provide morphological evidence for the pain control effect of EM2, the synaptic connections between EM2-immunoreactive (IR) axonal terminals and γ-amino butyric acid (GABA)/MOR co-expressing neurons in lamina II of the spinal trigeminal caudal nucleus (Vc) were investigated in the rat. Dense EM2-, MOR- and GABA-IR fibers and terminals were mainly observed in lamina II of the Vc. Within lamina II, GABA- and MOR-neuronal cell bodies were also encountered. The results of immunofluorescent histochemical triple-staining showed that approximately 14.2 or 18.9% of GABA-IR or MOR-IR neurons also showed MOR- or GABA-immunopositive staining in lamina II; approximately 45.2 and 36.1% of the GABA-IR and MOR-IR neurons, respectively, expressed FOS protein in their nuclei induced by injecting formalin into the left lower lip of the mouth. Most of the GABA/MOR, GABA/FOS, and MOR/FOS double-labeled neurons made close contacts with EM2-IR fibers and terminals. Immuno-electron microscopy confirmed that the EM2-IR terminals formed synapses with GABA-IR or MOR-IR dendritic processes and neuronal cell bodies in lamina II of the Vc. These results suggest that EM2 might participate in pain transmission and modulation by binding to MOR-IR and GABAergic inhibitory interneuron in lamina II of the Vc to exert inhibitory effect on the excitatory interneuron in lamina II and projection neurons in laminae I and III. PMID:25386121

  12. Comparative study of the distribution of the alpha-subunits of voltage-gated sodium channels in normal and axotomized rat dorsal root ganglion neurons.

    Science.gov (United States)

    Fukuoka, Tetsuo; Kobayashi, Kimiko; Yamanaka, Hiroki; Obata, Koichi; Dai, Yi; Noguchi, Koichi

    2008-09-10

    We compared the distribution of the alpha-subunit mRNAs of voltage-gated sodium channels Nav1.1-1.3 and Nav1.6-1.9 and a related channel, Nax, in histochemically identified neuronal subpopulations of the rat dorsal root ganglia (DRG). In the naïve DRG, the expression of Nav1.1 and Nav1.6 was restricted to A-fiber neurons, and they were preferentially expressed by TrkC neurons, suggesting that proprioceptive neurons possess these channels. Nav1.7, -1.8, and -1.9 mRNAs were more abundant in C-fiber neurons compared with A-fiber ones. Nax was evenly expressed in both populations. Although Nav1.8 and -1.9 were preferentially expressed by TrkA neurons, other alpha-subunits were expressed independently of TrkA expression. Actually, all IB4(+) neurons expressed both Nav1.8 and -1.9, and relatively limited subpopulations of IB4(+) neurons (3% and 12%, respectively) expressed Nav1.1 and/or Nav1.6. These findings provide useful information in interpreting the electrophysiological characteristics of some neuronal subpopulations of naïve DRG. After L5 spinal nerve ligation, Nav1.3 mRNA was up-regulated mainly in A-fiber neurons in the ipsilateral L5 DRG. Although previous studies demonstrated that nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF) reversed this up-regulation, the Nav1.3 induction was independent of either TrkA or GFRalpha1 expression, suggesting that the induction of Nav1.3 may be one of the common responses of axotomized DRG neurons without a direct relationship to NGF/GDNF supply. (c) 2008 Wiley-Liss, Inc.

  13. Possibilities of introducing different functional circuits on top of a structural neuron triplet: Where do the gains lie?

    International Nuclear Information System (INIS)

    Franović, Igor; Miljković, Vladimir

    2012-01-01

    Highlights: ► We identify different types of functional circuits in structural triplets. ► The approach utilizes the properties of synapses with fast-threshold modulation. ► We observe correspondence between sequences in the time series and the triads. ► Triads are assigned roles with respect to synchronization. ► Regularization of bursting series is explained by classifying all the bursts. - Abstract: Instigated by the research on clusterization phenomena in complex neural networks, we study a triplet of bursting Rulkov map neurons connected via inhibitory synapses with delay. It is demonstrated how on a background of structural motif one can build different types of functional circuits. The approach is based on utilizing the properties of the chemical synapses, whose gating is modeled by the fast threshold modulation, in conjunction with the phase plane analysis, allowing the system state to be represented in terms of maps the neurons reside on. For both the dynamical configurations, monitoring the layout of active neurons, and the functional motifs, following the maps where the synchronized neurons lie, we establish a one-on-one correspondence between sequences in the time series and the triads, making up the subgraphs of the original graph. By introducing the appropriate sets of quantities, one obtains not only the distributions of triads as a function of synaptic parameters, but is also able to identify a distinct triad whose presence may be viewed as a signature of the burst synchronization process. In another setup, the regularization of burst cycles for an arbitrary neuron is explained by classifying all the bursts as long or short, with their fractions linked to the abundances of triads under variation of synaptic parameters.

  14. Dual Actions of Mammalian and Piscine Gonadotropin-Inhibitory Hormones, RFamide-Related Peptides and LPXRFamide Peptides, in the Hypothalamic–Pituitary–Gonadal Axis

    Directory of Open Access Journals (Sweden)

    Takayoshi Ubuka

    2018-01-01

    Full Text Available Gonadotropin-inhibitory hormone (GnIH is a hypothalamic neuropeptide that decreases gonadotropin synthesis and release by directly acting on the gonadotrope or by decreasing the activity of gonadotropin-releasing hormone (GnRH neurons. GnIH is also called RFamide-related peptide in mammals or LPXRFamide peptide in fishes due to its characteristic C-terminal structure. The primary receptor for GnIH is GPR147 that inhibits cAMP production in target cells. Although most of the studies in mammals, birds, and fish have shown the inhibitory action of GnIH in the hypothalamic–pituitary–gonadal (HPG axis, several in vivo studies in mammals and many in vivo and in vitro studies in fish have shown its stimulatory action. In mouse, although the firing rate of the majority of GnRH neurons is decreased, a small population of GnRH neurons is stimulated by GnIH. In hamsters, GnIH inhibits luteinizing hormone (LH release in the breeding season when their endogenous LH level is high but stimulates LH release in non-breeding season when their LH level is basal. Besides different effects of GnIH on the HPG axis depending on the reproductive stages in fish, higher concentration or longer duration of GnIH administration can stimulate their HPG axis. These results suggest that GnIH action in the HPG axis is modulated by sex-steroid concentration, the action of neuroestrogen synthesized by the activity of aromatase stimulated by GnIH, estrogen membrane receptor, heteromerization and internalization of GnIH, GnRH, and estrogen membrane receptors. The inhibitory and stimulatory action of GnIH in the HPG axis may have a physiological role to maintain reproductive homeostasis according to developmental and reproductive stages.

  15. Activation of the Basal Forebrain by the Orexin/Hypocretin Neurons: Orexin International Symposium

    Science.gov (United States)

    Arrigoni, Elda; Mochizuki, Takatoshi; Scammell, Thomas E.

    2010-01-01

    The orexin neurons play an essential role in driving arousal and in maintaining normal wakefulness. Lack of orexin neurotransmission produces a chronic state of hypoarousal characterized by excessive sleepiness, frequent transitions between wake and sleep, and episodes of cataplexy. A growing body of research now suggests that the basal forebrain (BF) may be a key site through which the orexin-producing neurons promote arousal. Here we review anatomical, pharmacological and electrophysiological studies on how the orexin neurons may promote arousal by exciting cortically-projecting neurons of the BF. Orexin fibers synapse on BF cholinergic neurons and orexin-A is released in the BF during waking. Local application of orexins excites BF cholinergic neurons, induces cortical release of acetylcholine, and promotes wakefulness. The orexin neurons also contain and probably co-release the inhibitory neuropeptide dynorphin. We found that orexin-A and dynorphin have specific effects on different classes of BF neurons that project to the cortex. Cholinergic neurons were directly excited by orexin-A, but did not respond to dynorphin. Non-cholinergic BF neurons that project to the cortex seem to comprise at least two populations with some directly excited by orexin that may represent wake-active, GABAergic neurons, whereas others did not respond to orexin but were inhibited by dynorphin and may be sleep-active, GABAergic neurons. This evidence suggests that the BF is a key site through which orexins activate the cortex and promotes behavioral arousal. In addition, orexins and dynorphin may act synergistically in the BF to promote arousal and improve cognitive performance. PMID:19723027

  16. Inhibitory effects of aspirin-triggered resolvin D1 on spinal nociceptive processing in rat pain models.

    Science.gov (United States)

    Meesawatsom, Pongsatorn; Burston, James; Hathway, Gareth; Bennett, Andrew; Chapman, Victoria

    2016-09-02

    Harnessing the actions of the resolvin pathways has the potential for the treatment of a wide range of conditions associated with overt inflammatory signalling. Aspirin-triggered resolvin D1 (AT-RvD1) has robust analgesic effects in behavioural models of pain; however, the potential underlying spinal neurophysiological mechanisms contributing to these inhibitory effects in vivo are yet to be determined. This study investigated the acute effects of spinal AT-RvD1 on evoked responses of spinal neurones in vivo in a model of acute inflammatory pain and chronic osteoarthritic (OA) pain and the relevance of alterations in spinal gene expression to these neurophysiological effects. Pain behaviour was assessed in rats with established carrageenan-induced inflammatory or monosodium iodoacetate (MIA)-induced OA pain, and changes in spinal gene expression of resolvin receptors and relevant enzymatic pathways were examined. At timepoints of established pain behaviour, responses of deep dorsal horn wide dynamic range (WDR) neurones to transcutaneous electrical stimulation of the hind paw were recorded pre- and post direct spinal administration of AT-RvD1 (15 and 150 ng/50 μl). AT-RvD1 (15 ng/50 μl) significantly inhibited WDR neurone responses to electrical stimuli at C- (29 % inhibition) and Aδ-fibre (27 % inhibition) intensities. Both wind-up (53 %) and post-discharge (46 %) responses of WDR neurones in carrageenan-treated animals were significantly inhibited by AT-RvD1, compared to pre-drug response (p < 0.05). These effects were abolished by spinal pre-administration of a formyl peptide receptor 2 (FPR2/ALX) antagonist, butoxy carbonyl-Phe-Leu-Phe-Leu-Phe (BOC-2) (50 μg/50 μl). AT-RvD1 did not alter evoked WDR neurone responses in non-inflamed or MIA-treated rats. Electrophysiological effects in carrageenan-inflamed rats were accompanied by a significant increase in messenger RNA (mRNA) for chemerin (ChemR23) receptor and 5-lipoxygenase

  17. Preschool Inhibitory Control Predicts ADHD Group Status and Inhibitory Weakness in School.

    Science.gov (United States)

    Jacobson, Lisa A; Schneider, Heather; Mahone, E Mark

    2017-12-26

    Discriminative utility of performance measures of inhibitory control was examined in preschool children with and without ADHD to determine whether performance measures added to diagnostic prediction and to prediction of informant-rated day-to-day executive function. Children ages 4-5 years (N = 105, 61% boys; 54 ADHD, medication-naïve) were assessed using performance measures (Auditory Continuous Performance Test for Preschoolers-Commission errors, Conflicting Motor Response Test, NEPSY Statue) and caregiver (parent, teacher) ratings of inhibition (Behavior Rating Inventory of Executive Function-Preschool version). Performance measures and parent and teacher reports of inhibitory control significantly and uniquely predicted ADHD group status; however, performance measures did not add to prediction of group status beyond parent reports. Performance measures did significantly predict classroom inhibitory control (teacher ratings), over and above parent reports of inhibitory control. Performance measures of inhibitory control may be adequate predictors of ADHD status and good predictors of young children's classroom inhibitory control, demonstrating utility as components of clinical assessments. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Firing dynamics of an autaptic neuron

    International Nuclear Information System (INIS)

    Wang Heng-Tong; Chen Yong

    2015-01-01

    Autapses are synapses that connect a neuron to itself in the nervous system. Previously, both experimental and theoretical studies have demonstrated that autaptic connections in the nervous system have a significant physiological function. Autapses in nature provide self-delayed feedback, thus introducing an additional timescale to neuronal activities and causing many dynamic behaviors in neurons. Recently, theoretical studies have revealed that an autapse provides a control option for adjusting the response of a neuron: e.g., an autaptic connection can cause the electrical activities of the Hindmarsh–Rose neuron to switch between quiescent, periodic, and chaotic firing patterns; an autapse can enhance or suppress the mode-locking status of a neuron injected with sinusoidal current; and the firing frequency and interspike interval distributions of the response spike train can also be modified by the autapse. In this paper, we review recent studies that showed how an autapse affects the response of a single neuron. (topical review)

  19. Ketamine Causes Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Neurons

    Science.gov (United States)

    Ito, Hiroyuki; Uchida, Tokujiro; Makita, Koshi

    2015-01-01

    Purpose Ketamine toxicity has been demonstrated in nonhuman mammalian neurons. To study the toxic effect of ketamine on human neurons, an experimental model of cultured neurons from human induced pluripotent stem cells (iPSCs) was examined, and the mechanism of its toxicity was investigated. Methods Human iPSC-derived dopaminergic neurons were treated with 0, 20, 100 or 500 μM ketamine for 6 and 24 h. Ketamine toxicity was evaluated by quantification of caspase 3/7 activity, reactive oxygen species (ROS) production, mitochondrial membrane potential, ATP concentration, neurotransmitter reuptake activity and NADH/NAD+ ratio. Mitochondrial morphological change was analyzed by transmission electron microscopy and confocal microscopy. Results Twenty-four-hour exposure of iPSC-derived neurons to 500 μM ketamine resulted in a 40% increase in caspase 3/7 activity (P ketamine (100 μM) decreased the ATP level (22%, P ketamine concentration, which suggests that mitochondrial dysfunction preceded ROS generation and caspase activation. Conclusions We established an in vitro model for assessing the neurotoxicity of ketamine in iPSC-derived neurons. The present data indicate that the initial mitochondrial dysfunction and autophagy may be related to its inhibitory effect on the mitochondrial electron transport system, which underlies ketamine-induced neural toxicity. Higher ketamine concentration can induce ROS generation and apoptosis in human neurons. PMID:26020236

  20. Adrenergic receptors inhibit TRPV1 activity in the dorsal root ganglion neurons of rats.

    Science.gov (United States)

    Matsushita, Yumi; Manabe, Miki; Kitamura, Naoki; Shibuya, Izumi

    2018-01-01

    Transient receptor potential vanilloid type 1 (TRPV1) is a polymodal receptor channel that responds to multiple types of stimuli, such as heat, acid, mechanical pressure and some vanilloids. Capsaicin is the most commonly used vanilloid to stimulate TRPV1. TRPV1 channels are expressed in dorsal root ganglion neurons that extend to Aδ- and C-fibers and have a role in the transduction of noxious inputs to the skin into the electrical signals of the sensory nerve. Although noradrenergic nervous systems, including the descending antinociceptive system and the sympathetic nervous system, are known to modulate pain sensation, the functional association between TRPV1 and noradrenaline in primary sensory neurons has rarely been examined. In the present study, we examined the effects of noradrenaline on capsaicin-evoked currents in cultured dorsal root ganglion neurons of the rat by the whole-cell voltage clamp method. Noradrenaline at concentrations higher than 0.1 pM significantly reduced the amplitudes of the inward capsaicin currents recorded at -60 mV holding potential. This inhibitory action was reversed by either yohimbine (an α2 antagonist, 10 nM) or propranolol (a β antagonist, 10 nM). The α2 agonists, clonidine (1 pM) and dexmedetomidine (1 pM) inhibited capsaicin currents, and yohimbine (1 nM) reversed the effects of clonidine. The inhibitory action of noradrenaline was not seen in the neurons pretreated with pertussis toxin (100 μg/ml for 24 h) and the neurons dialyzed intracellularly with guanosine 5'- [β-thio] diphosphate (GDPβS, 200 μM), the catalytic subunit of protein kinase A (250 U/ml) or okadaic acid (1 μM). These results suggest that noradrenaline directly acts on dorsal root ganglion neurons to inhibit the activity of TRPV1 depending on the activation of α2-adrenoceptors followed by the inhibition of the adenylate cyclase/cAMP/protein kinase A pathway.

  1. Gene Expression and the Diversity of Identified Neurons

    OpenAIRE

    Buck, L.; Stein, R.; Palazzolo, M.; Anderson, D. J.; Axel, R.

    1983-01-01

    Nervous systems consist of diverse populations of neurons that are anatomically and functionally distinct. The diversity of neurons and the precision with which they are interconnected suggest that specific genes or sets of genes are activated in some neurons but not expressed in others. Experimentally, this problem may be considered at two levels. First, what is the total number of genes expressed in the brain, and how are they distributed among the different populations of neurons? Second, ...

  2. [Effect of electromagnetic radiation on discharge activity of neurons in the hippocampus CA1 in rats].

    Science.gov (United States)

    Tong, Jun; Chen, Su; Liu, Xiang-Ming; Hao, Dong-Mei

    2013-09-01

    In order to explore effect of electromagnetic radiation on learning and memory ability of hippocampus neuron in rats, the changes in discharge patterns and overall electrical activity of hippocampus neuron after electromagnetic radiation were observed. Rat neurons discharge was recorded with glass electrode extracellular recording technology and a polygraph respectively. Radiation frequency of electromagnetic wave was 900 MHZ and the power was 10 W/m2. In glass electrode extracellular recording, the rats were separately irradiated for 10, 20, 30, 40, 50 and 60 min, every points repeated 10 times and updated interval of 1h, observing the changes in neuron discharge and spontaneous discharge patterns after electromagnetic radiation. In polygraph recording experiments, irradiation group rats for five days a week, 6 hours per day, repeatedly for 10 weeks, memory electrical changes in control group and irradiation group rats when they were feeding were repeatedly monitored by the implanted electrodes, observing the changes in peak electric digits and the largest amplitude in hippocampal CA1 area, and taking some electromagnetic radiation sampling sequence for correlation analysis. (1) Electromagnetic radiation had an inhibitory role on discharge frequency of the hippocampus CA1 region neurons. After electromagnetic radiation, discharge frequency of the hippocampus CA1 region neurons was reduced, but the changes in scale was not obvious. (2) Electromagnetic radiation might change the spontaneous discharge patterns of hippocampus CA1 region neurons, which made the explosive discharge pattern increased obviously. (3) Peak potential total number within 5 min in irradiation group was significantly reduced, the largest amplitude was less than that of control group. (4) Using mathematical method to make the correlation analysis of the electromagnetic radiation sampling sequence, that of irradiation group was less than that of control group, indicating that there was a tending

  3. Neurons other than motor neurons in motor neuron disease.

    Science.gov (United States)

    Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

  4. Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia.

    Science.gov (United States)

    Joshi, Dipesh; Fung, Samantha J; Rothwell, Alice; Weickert, Cynthia Shannon

    2012-11-01

    In the orbitofrontal cortex (OFC), reduced gray matter volume and reduced glutamic acid decarboxylase 67kDa isoform (GAD67) messenger (m)RNA are found in schizophrenia; however, how these alterations relate to developmental pathology of interneurons is unclear. The present study therefore aimed to determine if increased interstitial white matter neuron (IWMN) density exists in the OFC; whether gamma-aminobutyric acid (GABA)ergic neuron density in OFC white matter was altered; and how IWMN density may be related to an early-expressed inhibitory neuron marker, Dlx1, in OFC gray matter in schizophrenia. IWMN densities were determined (38 schizophrenia and 38 control subjects) for neuronal nuclear antigen (NeuN+) and 65/67 kDa isoform of glutamic acid decarboxylase immunopositive (GAD65/67+) neurons. In situ hybridization was performed to determine Dlx1 and GAD67 mRNA expression in the OFC gray matter. NeuN and GAD65/67 immunopositive cell density was significantly increased in the superficial white matter in schizophrenia. Gray matter Dlx1 and GAD67 mRNA expression were reduced in schizophrenia. Dlx1 mRNA levels were negatively correlated with GAD65/67 IWMN density. Our study provides evidence that pathology of IWMNs in schizophrenia includes GABAergic interneurons and that increased IWMN density may be related to GABAergic deficits in the overlying gray matter. These findings provide evidence at the cellular level that the OFC is a site of pathology in schizophrenia and support the hypothesis that inappropriate migration of cortical inhibitory interneurons occurs in schizophrenia. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Neuron class-specific requirements for Fragile X Mental Retardation Protein in critical period development of calcium signaling in learning and memory circuitry.

    Science.gov (United States)

    Doll, Caleb A; Broadie, Kendal

    2016-05-01

    Neural circuit optimization occurs through sensory activity-dependent mechanisms that refine synaptic connectivity and information processing during early-use developmental critical periods. Fragile X Mental Retardation Protein (FMRP), the gene product lost in Fragile X syndrome (FXS), acts as an activity sensor during critical period development, both as an RNA-binding translation regulator and channel-binding excitability regulator. Here, we employ a Drosophila FXS disease model to assay calcium signaling dynamics with a targeted transgenic GCaMP reporter during critical period development of the mushroom body (MB) learning/memory circuit. We find FMRP regulates depolarization-induced calcium signaling in a neuron-specific manner within this circuit, suppressing activity-dependent calcium transients in excitatory cholinergic MB input projection neurons and enhancing calcium signals in inhibitory GABAergic MB output neurons. Both changes are restricted to the developmental critical period and rectified at maturity. Importantly, conditional genetic (dfmr1) rescue of null mutants during the critical period corrects calcium signaling defects in both neuron classes, indicating a temporally restricted FMRP requirement. Likewise, conditional dfmr1 knockdown (RNAi) during the critical period replicates constitutive null mutant defects in both neuron classes, confirming cell-autonomous requirements for FMRP in developmental regulation of calcium signaling dynamics. Optogenetic stimulation during the critical period enhances depolarization-induced calcium signaling in both neuron classes, but this developmental change is eliminated in dfmr1 null mutants, indicating the activity-dependent regulation requires FMRP. These results show FMRP shapes neuron class-specific calcium signaling in excitatory vs. inhibitory neurons in developing learning/memory circuitry, and that FMRP mediates activity-dependent regulation of calcium signaling specifically during the early

  6. Visual patch clamp recording of neurons in thick portions of the adult spinal cord

    DEFF Research Database (Denmark)

    Munch, Anders Sonne; Smith, Morten; Moldovan, Mihai

    2010-01-01

    The study of visually identified neurons in slice preparations from the central nervous system offers considerable advantages over in vivo preparations including high mechanical stability in the absence of anaesthesia and full control of the extracellular medium. However, because of their relative...... remain alive and capable of generating action potentials. By stimulating the lateral funiculus we can evoke intense synaptic activity associated with large increases in conductance of the recorded neurons. The conductance increases substantially more in neurons recorded in thick slices suggesting...... that the size of the network recruited with the stimulation increases with the thickness of the slices. We also find that that the number of spontaneous excitatory postsynaptic currents (EPSCs) is higher in thick slices compared with thin slices while the number of spontaneous inhibitory postsynaptic currents...

  7. BACE1 Deficiency Causes Abnormal Neuronal Clustering in the Dentate Gyrus

    Directory of Open Access Journals (Sweden)

    Hailong Hou

    2017-07-01

    Full Text Available BACE1 is validated as Alzheimer's β-secretase and a therapeutic target for Alzheimer's disease. In examining BACE1-null mice, we discovered that BACE1 deficiency develops abnormal clusters of immature neurons, forming doublecortin-positive neuroblasts, in the developing dentate gyrus, mainly in the subpial zone (SPZ. Such clusters were rarely observed in wild-type SPZ and not reported in other mouse models. To understand their origins and fates, we examined how neuroblasts in BACE1-null SPZ mature and migrate during early postnatal development. We show that such neuroblasts are destined to form Prox1-positive granule cells in the dentate granule cell layer, and mainly mature to form excitatory neurons, but not inhibitory neurons. Mechanistically, higher levels of reelin potentially contribute to abnormal neurogenesis and timely migration in BACE1-null SPZ. Altogether, we demonstrate that BACE1 is a critical regulator in forming the dentate granule cell layer through timely maturation and migration of SPZ neuroblasts.

  8. Differential distribution of glutamate- and GABA-gated chloride channels in the housefly Musca domestica.

    Science.gov (United States)

    Kita, Tomo; Ozoe, Fumiyo; Azuma, Masaaki; Ozoe, Yoshihisa

    2013-09-01

    l-Glutamic acid (glutamate) mediates fast inhibitory neurotransmission by affecting glutamate-gated chloride channels (GluCls) in invertebrates. The molecular function and pharmacological properties of GluCls have been well studied, but not much is known about their physiological role and localization in the insect body. The distribution of GluCls in the housefly (Musca domestica L.) was thus compared with the distribution of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls). Quantitative PCR and ligand-binding experiments indicate that the GluCl and GABACl transcripts and proteins are predominantly expressed in the adult head. Intense GluCl immunostaining was detected in the lamina, leg motor neurons, and legs of adult houseflies. The GABACl (Rdl) immunostaining was more widely distributed, and was found in the medulla, lobula, lobula plate, mushroom body, antennal lobe, and ellipsoid body. The present findings suggest that GluCls have physiological roles in different tissues than GABACls. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Effects of penicillin on procaine-elicited bursts of potential in central neuron of snail, Achatina fulica.

    Science.gov (United States)

    Chen, Yi-Hung; Lu, Kuan-Ling; Hsiao, Ru-Wan; Lee, Ya-Ling; Tsai, Hong-Chieh; Lin, Chia Hsien; Tsai, Ming-Cheng

    2008-08-01

    Effects of penicillin on changes in procaine-elicited bursts of potential (BoP) were studied in a central neuron (RP4) of snail, Achatina fulica Ferussac. Procaine elicited BoP in the RP4 neuron while penicillin elicited depolarization of the neuron. Penicillin decreased the BoP elicited by procaine in a concentration-dependent manner. The effect of penicillin on the procaine-elicited BoP was not altered in the preparations treated with ascorbate or L-NAME (N-nitro-L-arginine methyl ester). However, the inhibitory effect of penicillin on the procaine-elicited BoP was enhanced with a decrease in extracellular sodium ion. Sodium ion was one of the important ions contributing to the action potential of the neuron. Two-electrode voltage-clamp studies revealed that penicillin decreased the fast sodium inward current of the neuron. It is concluded that penicillin inhibited the BoP elicited by procaine and sodium ion altered the effect of penicillin on procaine-elicited BoP.

  10. [The characteristics of the cholinoreceptors on the identified TAN neuron of the giant African snail Achatina fulica].

    Science.gov (United States)

    Stepanov, I I; Losev, N A

    1999-04-01

    Acetylcholine, nicotine, a selective agonist of N-cholinoreceptors suberildicholine dibromide, as well as a selective agonist of M-cholinoreceptors 5-methylfurmethide inhibited spike discharges in a dose-dependent manner up to a complete ceasing of the firing in cholinoreceptors situated on the identified neurone TAN of African giant snail Achatina fulica. M-cholinoblocker metamizylum completely prevented the inhibitory effect of methylfurmethide. Central cholinoblocker aetherophen completely prevented the inhibitory effect of suberildicholine dibromide. Metamizylum or aetherophen used alone were only able to decrease the inhibitory effect of acetylcholine, whereas a mixture of these agents suppressed completely the acetylcholine-induced inhibition. The findings suggest that, on the TAN membrane, nicotinic and muscarinic cholinoreceptors co-exist and function in one and the same direction.

  11. Identification of distinct telencephalic progenitor pools for neuronal diversity in the amygdala.

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    Hirata, Tsutomu; Li, Peijun; Lanuza, Guillermo M; Cocas, Laura A; Huntsman, Molly M; Corbin, Joshua G

    2009-02-01

    The development of the amygdala, a central structure of the limbic system, remains poorly understood. We found that two spatially distinct and early-specified telencephalic progenitor pools marked by the homeodomain transcription factor Dbx1 are major sources of neuronal cell diversity in the mature mouse amygdala. We found that Dbx1-positive cells of the ventral pallium generate the excitatory neurons of the basolateral complex and cortical amygdala nuclei. Moreover, Dbx1-derived cells comprise a previously unknown migratory stream that emanates from the preoptic area (POA), a ventral telencephalic domain adjacent to the diencephalic border. The Dbx1-positive, POA-derived population migrated specifically to the amygdala and, as defined by both immunochemical and electrophysiological criteria, generated a unique subclass of inhibitory neurons in the medial amygdala nucleus. Thus, this POA-derived population represents a previously unknown progenitor pool dedicated to the limbic system.

  12. Bottom-up and Top-down Input Augment the Variability of Cortical Neurons

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    Nassi, Jonathan J.; Kreiman, Gabriel; Born, Richard T.

    2016-01-01

    SUMMARY Neurons in the cerebral cortex respond inconsistently to a repeated sensory stimulus, yet they underlie our stable sensory experiences. Although the nature of this variability is unknown, its ubiquity has encouraged the general view that each cell produces random spike patterns that noisily represent its response rate. In contrast, here we show that reversibly inactivating distant sources of either bottom-up or top-down input to cortical visual areas in the alert primate reduces both the spike train irregularity and the trial-to-trial variability of single neurons. A simple model in which a fraction of the pre-synaptic input is silenced can reproduce this reduction in variability, provided that there exist temporal correlations primarily within, but not between, excitatory and inhibitory input pools. A large component of the variability of cortical neurons may therefore arise from synchronous input produced by signals arriving from multiple sources. PMID:27427459

  13. Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction.

    Science.gov (United States)

    Wu, Min; Dumalska, Iryna; Morozova, Elena; van den Pol, Anthony; Alreja, Meenakshi

    2009-10-06

    A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile. MCH also modulates sleep, drug abuse behavior, and mood, and MCH receptor antagonists are currently being developed as antiobesity and antidepressant drugs. Despite the clinical implications of MCH, the direct postsynaptic effects of MCH have never been reported in CNS neurons. Using patch-clamp recordings in brain slices from multiple lines of transgenic GFP mice, we demonstrate a strong inhibitory effect of MCH on an exclusive population of septal vGluT2-GnRH neurons that is activated by the puberty-triggering and preovulatory luteinizing hormone surge-mediating peptide, kisspeptin. MCH has no effect on kisspeptin-insensitive GnRH, vGluT2, cholinergic, or GABAergic neurons located within the same nucleus. The inhibitory effects of MCH are reproducible and nondesensitizing and are mediated via a direct postsynaptic Ba(2+)-sensitive K(+) channel mechanism involving the MCHR1 receptor. MCH immunoreactive fibers are in close proximity to vGluT2-GFP and GnRH-GFP neurons. Importantly, MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. Considering the role of MCH in regulating energy balance and of GnRH and kisspeptin in triggering puberty and maintaining fertility, MCH may provide a critical link between energy balance and reproduction directly at the level of the kisspeptin-activated vGluT2-GnRH neuron.

  14. Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area

    NARCIS (Netherlands)

    Dremencov, Eliyahu; El Mansari, Mostafa; Blier, Pierre

    Background: Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are efficacious in depression because of their ability to increase 5-HT neurotransmission. However, owing to a purported inhibitory effect of 5- HT on dopamine (DA) neuronal activity in the ventral tegmental area (VTA), this increase

  15. The human cerebral cortex is neither one nor many: Neuronal distribution reveals two quantitatively different zones in the grey matter, three in the white matter, and explains local variations in cortical folding

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    Pedro F. M. Ribeiro

    2013-09-01

    Full Text Available The human prefrontal cortex has been considered different in several aspects and relatively enlarged compared to the rest of the cortical areas. Here we determine whether the white and gray matter of the prefrontal portion of the human cerebral cortex have similar or different cellular compositions relative to the rest of the cortical regions by applying the Isotropic Fractionator to analyze the distribution of neurons along the entire anteroposterior axis of the cortex, and its relationship with the degree of gyrification, number of neurons under the cortical surface, and other parameters. The prefrontal region shares with the remainder of the cerebral cortex (except for occipital cortex the same relationship between cortical volume and number of neurons. In contrast, both occipital and prefrontal areas vary from other cortical areas in their connectivity through the white matter, with a systematic reduction of cortical connectivity through the white matter and an increase of the mean axon caliber along the anteroposterior axis. These two parameters explain local differences in the distribution of neurons underneath the cortical surface. We also show that local variations in cortical folding are neither a function of local numbers of neurons nor of cortical thickness, but correlate with properties of the white matter, and are best explained by the folding of the white matter surface. Our results suggest that the human cerebral cortex is divided in two zones (occipital and non-occipital that differ in how neurons distributed across their grey matter volume and in three zones (prefrontal, occipital, and non-occipital that differ in how neurons are connected through the white matter. Thus, the human prefrontal cortex has the largest fraction of neuronal connectivity through the white matter and the smallest average axonal caliber in the white matter within the cortex, although its neuronal composition fits the pattern found for other, non

  16. Neuronal gain modulability is determined by dendritic morphology: A computational optogenetic study.

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    Jarvis, Sarah; Nikolic, Konstantin; Schultz, Simon R

    2018-03-01

    The mechanisms by which the gain of the neuronal input-output function may be modulated have been the subject of much investigation. However, little is known of the role of dendrites in neuronal gain control. New optogenetic experimental paradigms based on spatial profiles or patterns of light stimulation offer the prospect of elucidating many aspects of single cell function, including the role of dendrites in gain control. We thus developed a model to investigate how competing excitatory and inhibitory input within the dendritic arbor alters neuronal gain, incorporating kinetic models of opsins into our modeling to ensure it is experimentally testable. To investigate how different topologies of the neuronal dendritic tree affect the neuron's input-output characteristics we generate branching geometries which replicate morphological features of most common neurons, but keep the number of branches and overall area of dendrites approximately constant. We found a relationship between a neuron's gain modulability and its dendritic morphology, with neurons with bipolar dendrites with a moderate degree of branching being most receptive to control of the gain of their input-output relationship. The theory was then tested and confirmed on two examples of realistic neurons: 1) layer V pyramidal cells-confirming their role in neural circuits as a regulator of the gain in the circuit in addition to acting as the primary excitatory neurons, and 2) stellate cells. In addition to providing testable predictions and a novel application of dual-opsins, our model suggests that innervation of all dendritic subdomains is required for full gain modulation, revealing the importance of dendritic targeting in the generation of neuronal gain control and the functions that it subserves. Finally, our study also demonstrates that neurophysiological investigations which use direct current injection into the soma and bypass the dendrites may miss some important neuronal functions, such as gain

  17. Enhanced inhibitory control by neuropeptide Y Y5 receptor blockade in rats.

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    Bari, A; Dec, A; Lee, A W; Lee, J; Song, D; Dale, E; Peterson, J; Zorn, S; Huang, X; Campbell, B; Robbins, T W; West, A R

    2015-03-01

    The neuropeptide Y (NPY) system acts in synergy with the classic neurotransmitters to regulate a large variety of functions including autonomic, affective, and cognitive processes. Research on the effects of NPY in the central nervous system has focused on food intake control and affective processes, but growing evidence of NPY involvement in attention-deficit/hyperactivity disorder (ADHD) and other psychiatric conditions motivated the present study. We tested the effects of the novel and highly selective NPY Y5 receptor antagonist Lu AE00654 on impulsivity and the underlying cortico-striatal circuitry in rats to further explore the possible involvement of the NPY system in pathologies characterized by inattention and impulsive behavior. A low dose of Lu AE00654 (0.03 mg/kg) selectively facilitated response inhibition as measured by the stop-signal task, whereas no effects were found at higher doses (0.3 and 3 mg/kg). Systemic administration of Lu AE00654 also enhanced the inhibitory influence of the dorsal frontal cortex on neurons in the caudate-putamen, this fronto-striatal circuitry being implicated in the executive control of behavior. Finally, by locally injecting a Y5 agonist, we observed reciprocal activation between dorsal frontal cortex and caudate-putamen neurons. Importantly, the effects of the Y5 agonist were attenuated by pretreatment with Lu AE00654, confirming the presence of Y5 binding sites modulating functional interactions within frontal-subcortical circuits. These results suggest that the NPY system modulates inhibitory neurotransmission in brain areas important for impulse control, and may be relevant for the treatment of pathologies such as ADHD and drug abuse.

  18. Intraindividual variability in inhibitory function in adults with ADHD--an ex-Gaussian approach.

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    Dennis Gmehlin

    Full Text Available OBJECTIVE: Attention deficit disorder (ADHD is commonly associated with inhibitory dysfunction contributing to typical behavioral symptoms like impulsivity or hyperactivity. However, some studies analyzing intraindividual variability (IIV of reaction times in children with ADHD (cADHD question a predominance of inhibitory deficits. IIV is a measure of the stability of information processing and provides evidence that longer reaction times (RT in inhibitory tasks in cADHD are due to only a few prolonged responses which may indicate deficits in sustained attention rather than inhibitory dysfunction. We wanted to find out, whether a slowing in inhibitory functioning in adults with ADHD (aADHD is due to isolated slow responses. METHODS: Computing classical RT measures (mean RT, SD, ex-Gaussian parameters of IIV (which allow a better separation of reaction time (mu, variability (sigma and abnormally slow responses (tau than classical measures as well as errors of omission and commission, we examined response inhibition in a well-established GoNogo task in a sample of aADHD subjects without medication and healthy controls matched for age, gender and education. RESULTS: We did not find higher numbers of commission errors in aADHD, while the number of omissions was significantly increased compared with controls. In contrast to increased mean RT, the distributional parameter mu did not document a significant slowing in aADHD. However, subjects with aADHD were characterized by increased IIV throughout the entire RT distribution as indicated by the parameters sigma and tau as well as the SD of reaction time. Moreover, we found a significant correlation between tau and the number of omission errors. CONCLUSIONS: Our findings question a primacy of inhibitory deficits in aADHD and provide evidence for attentional dysfunction. The present findings may have theoretical implications for etiological models of ADHD as well as more practical implications for

  19. Modulation of inhibitory activity markers by intermittent theta-burst stimulation in rat cortex is NMDA-receptor dependent.

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    Labedi, Adnan; Benali, Alia; Mix, Annika; Neubacher, Ute; Funke, Klaus

    2014-01-01

    Intermittent theta-burst stimulation (iTBS) applied via transcranial magnetic stimulation has been shown to increase cortical excitability in humans. In the rat brain it strongly reduced the number of neurons expressing the 67-kD isoform of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) and those expressing the calcium-binding proteins parvalbumin (PV) and calbindin (CB), specific markers of fast-spiking (FS) and non-FS inhibitory interneurons, respectively, an indication of modified cortical inhibition. Since iTBS effects in humans have been shown to be NMDA receptor sensitive, we wondered whether the iTBS-induced changes in the molecular phenotype of interneurons may be also sensitive to glutamatergic synaptic transmission mediated by NMDA receptors. In a sham-controlled fashion, five iTBS-blocks of 600 stimuli were applied to rats either lightly anesthetized by only urethane or by an additional low (subnarcotic) or high dose of the NMDA receptor antagonist ketamine before immunohistochemical analysis. iTBS reduced the number of neurons expressing GAD67, PV and CB. Except for CB, a low dose of ketamine partially prevented these effects while a higher dose almost completely abolished the iTBS effects. Our findings indicate that iTBS modulates the molecular, and likely also the electric, activity of cortical inhibitory interneurons and that the modulation of FS-type but less that of non-FS-type neurons is mediated by NMDA receptors. A combination of iTBS with pharmacological interventions affecting distinct receptor subtypes may thus offer options to enhance its selectivity in modulating the activity of distinct cell types and preventing others from being modulated. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Minocycline inhibits D-amphetamine-elicited action potential bursts in a central snail neuron.

    Science.gov (United States)

    Chen, Y-H; Lin, P-L; Wong, R-W; Wu, Y-T; Hsu, H-Y; Tsai, M-C; Lin, M-J; Hsu, Y-C; Lin, C-H

    2012-10-25

    Minocycline is a second-generation tetracycline that has been reported to have powerful neuroprotective properties. In our previous studies, we found that d-amphetamine (AMPH) elicited action potential bursts in an identifiable RP4 neuron of the African snail, Achatina fulica Ferussac. This study sought to determine the effects of minocycline on the AMPH-elicited action potential pattern changes in the central snail neuron, using the two-electrode voltage clamping method. Extracellular application of AMPH at 300 μM elicited action potential bursts in the RP4 neuron. Minocycline dose-dependently (300-900 μM) inhibited the action potential bursts elicited by AMPH. The inhibitory effects of minocycline on AMPH-elicited action potential bursts were restored by forskolin (50 μM), an adenylate cyclase activator, and by dibutyryl cAMP (N(6),2'-O-Dibutyryladenosine 3',5'-cyclic monophosphate; 1mM), a membrane-permeable cAMP analog. Co-administration of forskolin (50 μM) plus tetraethylammonium chloride (TEA; 5mM) or co-administration of TEA (5mM) plus dibutyryl cAMP (1mM) also elicited action potential bursts, which were prevented and inhibited by minocycline. In addition, minocycline prevented and inhibited forskolin (100 μM)-elicited action potential bursts. Notably, TEA (50mM)-elicited action potential bursts in the RP4 neuron were not affected by minocycline. Minocycline did not affect steady-state outward currents of the RP4 neuron. However, minocycline did decrease the AMPH-elicited steady-state current changes. Similarly, minocycline decreased the effects of forskolin-elicited steady-state current changes. Pretreatment with H89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride; 10 μM), a protein kinase A inhibitor, inhibited AMPH-elicited action potential bursts and decreased AMPH-elicited steady-state current changes. These results suggest that the cAMP-protein kinase A signaling pathway and the steady-state current are involved in

  1. Stability versus neuronal specialization for STDP: long-tail weight distributions solve the dilemma.

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    Matthieu Gilson

    Full Text Available Spike-timing-dependent plasticity (STDP modifies the weight (or strength of synaptic connections between neurons and is considered to be crucial for generating network structure. It has been observed in physiology that, in addition to spike timing, the weight update also depends on the current value of the weight. The functional implications of this feature are still largely unclear. Additive STDP gives rise to strong competition among synapses, but due to the absence of weight dependence, it requires hard boundaries to secure the stability of weight dynamics. Multiplicative STDP with linear weight dependence for depression ensures stability, but it lacks sufficiently strong competition required to obtain a clear synaptic specialization. A solution to this stability-versus-function dilemma can be found with an intermediate parametrization between additive and multiplicative STDP. Here we propose a novel solution to the dilemma, named log-STDP, whose key feature is a sublinear weight dependence for depression. Due to its specific weight dependence, this new model can produce significantly broad weight distributions with no hard upper bound, similar to those recently observed in experiments. Log-STDP induces graded competition between synapses, such that synapses receiving stronger input correlations are pushed further in the tail of (very large weights. Strong weights are functionally important to enhance the neuronal response to synchronous spike volleys. Depending on the input configuration, multiple groups of correlated synaptic inputs exhibit either winner-share-all or winner-take-all behavior. When the configuration of input correlations changes, individual synapses quickly and robustly readapt to represent the new configuration. We also demonstrate the advantages of log-STDP for generating a stable structure of strong weights in a recurrently connected network. These properties of log-STDP are compared with those of previous models. Through

  2. Perforin Promotes Amyloid Beta Internalisation in Neurons.

    Science.gov (United States)

    Lana, Erica; Khanbolouki, Mahbod; Degavre, Charline; Samuelsson, Eva-Britt; Åkesson, Elisabet; Winblad, Bengt; Alici, Evren; Lithner, Christina Unger; Behbahani, Homira

    2017-03-01

    Studies on the mechanisms of neuronal amyloid-β (Aβ) internalisation are crucial for understanding the neuropathological progression of Alzheimer's disease (AD). We here investigated how extracellular Aβ peptides are internalised and focused on three different pathways: (i) via endocytic mechanisms, (ii) via the receptor for advanced glycation end products (RAGE) and (iii) via the pore-forming protein perforin. Both Aβ 40 and Aβ 42 were internalised in retinoic acid differentiated neuroblastoma (RA-SH-SY5Y) cells. A higher concentration was required for Aβ 40 (250 nM) compared with Aβ 42 (100 nM). The internalised Aβ 40 showed a dot-like pattern of distribution whereas Aβ 42 accumulated in larger and distinct formations. By confocal microscopy, we showed that Aβ 40 and Aβ 42 co-localised with mitochondria, endoplasmic reticulum (ER) and lysosomes. Aβ treatment of human primary cortical neurons (hPCN) confirmed our findings in RA-SH-SY5Y cells, but hPCN were less sensitive to Aβ; therefore, a 20 (Aβ 40 ) and 50 (Aβ 42 ) times higher concentration was needed for inducing uptake. The blocking of endocytosis completely inhibited the internalisation of Aβ peptides in RA-SH-SY5Y cells and hPCN, indicating that this is a major pathway by which Aβ enters the cells. In addition, the internalisation of Aβ 42 , but not Aβ 40 , was reduced by 55 % by blocking RAGE. Finally, for the first time we showed that pore formation in cell membranes by perforin led to Aβ internalisation in hPCN. Understanding how Aβ is internalised sheds light on the pathological role of Aβ and provides further ideas of inh