Glutamate-Bound NMDARs Arising from In Vivo-like Network Activity Extend Spatio-temporal Integration in a L5 Cortical Pyramidal Cell Model

PubMed Central

Farinella, Matteo; Ruedt, Daniel T.; Gleeson, Padraig; Lanore, Frederic; Silver, R. Angus

2014-01-01

In vivo, cortical pyramidal cells are bombarded by asynchronous synaptic input arising from ongoing network activity. However, little is known about how such ‘background’ synaptic input interacts with nonlinear dendritic mechanisms. We have modified an existing model of a layer 5 (L5) pyramidal cell to explore how dendritic integration in the apical dendritic tuft could be altered by the levels of network activity observed in vivo. Here we show that asynchronous background excitatory input increases neuronal gain and extends both temporal and spatial integration of stimulus-evoked synaptic input onto the dendritic tuft. Addition of fast and slow inhibitory synaptic conductances, with properties similar to those from dendritic targeting interneurons, that provided a ‘balanced’ background configuration, partially counteracted these effects, suggesting that inhibition can tune spatio-temporal integration in the tuft. Excitatory background input lowered the threshold for NMDA receptor-mediated dendritic spikes, extended their duration and increased the probability of additional regenerative events occurring in neighbouring branches. These effects were also observed in a passive model where all the non-synaptic voltage-gated conductances were removed. Our results show that glutamate-bound NMDA receptors arising from ongoing network activity can provide a powerful spatially distributed nonlinear dendritic conductance. This may enable L5 pyramidal cells to change their integrative properties as a function of local network activity, potentially allowing both clustered and spatially distributed synaptic inputs to be integrated over extended timescales. PMID:24763087

Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia.

PubMed

Lin, Hong; Magrane, Jordi; Clark, Elisia M; Halawani, Sarah M; Warren, Nathan; Rattelle, Amy; Lynch, David R

2017-12-19

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age-matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model. © 2017. Published by The Company of Biologists Ltd.

Balanced Synaptic Input Shapes the Correlation between Neural Spike Trains

PubMed Central

Litwin-Kumar, Ashok; Oswald, Anne-Marie M.; Urban, Nathaniel N.; Doiron, Brent

2011-01-01

Stimulus properties, attention, and behavioral context influence correlations between the spike times produced by a pair of neurons. However, the biophysical mechanisms that modulate these correlations are poorly understood. With a combined theoretical and experimental approach, we show that the rate of balanced excitatory and inhibitory synaptic input modulates the magnitude and timescale of pairwise spike train correlation. High rate synaptic inputs promote spike time synchrony rather than long timescale spike rate correlations, while low rate synaptic inputs produce opposite results. This correlation shaping is due to a combination of enhanced high frequency input transfer and reduced firing rate gain in the high input rate state compared to the low state. Our study extends neural modulation from single neuron responses to population activity, a necessary step in understanding how the dynamics and processing of neural activity change across distinct brain states. PMID:22215995

Activity-dependent control of NMDA receptor subunit composition at hippocampal mossy fibre synapses.

PubMed

Carta, Mario; Srikumar, Bettadapura N; Gorlewicz, Adam; Rebola, Nelson; Mulle, Christophe

2018-02-15

CA3 pyramidal cells display input-specific differences in the subunit composition of synaptic NMDA receptors (NMDARs). Although at low density, GluN2B contributes significantly to NMDAR-mediated EPSCs at mossy fibre synapses. Long-term potentiation (LTP) of NMDARs triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. GluN2B subunits are essential for the expression of LTP of NMDARs at mossy fibre synapses. Single neurons express NMDA receptors (NMDARs) with distinct subunit composition and biophysical properties that can be segregated in an input-specific manner. The dynamic control of the heterogeneous distribution of synaptic NMDARs is crucial to control input-dependent synaptic integration and plasticity. In hippocampal CA3 pyramidal cells from mice of both sexes, we found that mossy fibre (MF) synapses display a markedly lower proportion of GluN2B-containing NMDARs than associative/commissural synapses. The mechanism involved in such heterogeneous distribution of GluN2B subunits is not known. Here we show that long-term potentiation (LTP) of NMDARs, which is selectively expressed at MF-CA3 pyramidal cell synapses, triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. This activity-dependent recruitment of GluN2B at mature MF-CA3 pyramidal cell synapses contrasts with the removal of GluN2B subunits at other glutamatergic synapses during development and in response to activity. Furthermore, although expressed at low levels, GluN2B is necessary for the expression of LTP of NMDARs at MF-CA3 pyramidal cell synapses. Altogether, we reveal a previously unknown activity-dependent regulation and function of GluN2B subunits that may contribute to the heterogeneous plasticity induction rules in CA3 pyramidal cells. © 2017 Centre Nationnal de la Recherche Scientifique. The Journal of Physiology © 2017 The Physiological Society.

Hippocampal ripples down-regulate synapses.

PubMed

Norimoto, Hiroaki; Makino, Kenichi; Gao, Mengxuan; Shikano, Yu; Okamoto, Kazuki; Ishikawa, Tomoe; Sasaki, Takuya; Hioki, Hiroyuki; Fujisawa, Shigeyoshi; Ikegaya, Yuji

2018-03-30

The specific effects of sleep on synaptic plasticity remain unclear. We report that mouse hippocampal sharp-wave ripple oscillations serve as intrinsic events that trigger long-lasting synaptic depression. Silencing of sharp-wave ripples during slow-wave states prevented the spontaneous down-regulation of net synaptic weights and impaired the learning of new memories. The synaptic down-regulation was dependent on the N -methyl-d-aspartate receptor and selective for a specific input pathway. Thus, our findings are consistent with the role of slow-wave states in refining memory engrams by reducing recent memory-irrelevant neuronal activity and suggest a previously unrecognized function for sharp-wave ripples. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Spike Train Auto-Structure Impacts Post-Synaptic Firing and Timing-Based Plasticity

PubMed Central

Scheller, Bertram; Castellano, Marta; Vicente, Raul; Pipa, Gordon

2011-01-01

Cortical neurons are typically driven by several thousand synapses. The precise spatiotemporal pattern formed by these inputs can modulate the response of a post-synaptic cell. In this work, we explore how the temporal structure of pre-synaptic inhibitory and excitatory inputs impact the post-synaptic firing of a conductance-based integrate and fire neuron. Both the excitatory and inhibitory input was modeled by renewal gamma processes with varying shape factors for modeling regular and temporally random Poisson activity. We demonstrate that the temporal structure of mutually independent inputs affects the post-synaptic firing, while the strength of the effect depends on the firing rates of both the excitatory and inhibitory inputs. In a second step, we explore the effect of temporal structure of mutually independent inputs on a simple version of Hebbian learning, i.e., hard bound spike-timing-dependent plasticity. We explore both the equilibrium weight distribution and the speed of the transient weight dynamics for different mutually independent gamma processes. We find that both the equilibrium distribution of the synaptic weights and the speed of synaptic changes are modulated by the temporal structure of the input. Finally, we highlight that the sensitivity of both the post-synaptic firing as well as the spike-timing-dependent plasticity on the auto-structure of the input of a neuron could be used to modulate the learning rate of synaptic modification. PMID:22203800

Asymmetric temporal integration of layer 4 and layer 2/3 inputs in visual cortex.

PubMed

Hang, Giao B; Dan, Yang

2011-01-01

Neocortical neurons in vivo receive concurrent synaptic inputs from multiple sources, including feedforward, horizontal, and feedback pathways. Layer 2/3 of the visual cortex receives feedforward input from layer 4 and horizontal input from layer 2/3. Firing of the pyramidal neurons, which carries the output to higher cortical areas, depends critically on the interaction of these pathways. Here we examined synaptic integration of inputs from layer 4 and layer 2/3 in rat visual cortical slices. We found that the integration is sublinear and temporally asymmetric, with larger responses if layer 2/3 input preceded layer 4 input. The sublinearity depended on inhibition, and the asymmetry was largely attributable to the difference between the two inhibitory inputs. Interestingly, the asymmetric integration was specific to pyramidal neurons, and it strongly affected their spiking output. Thus via cortical inhibition, the temporal order of activation of layer 2/3 and layer 4 pathways can exert powerful control of cortical output during visual processing.

Comparison of glomerular activity patterns by fMRI and wide-field calcium imaging: implications for principles underlying odor mapping

PubMed Central

Sanganahalli, Basavaraju G.; Rebello, Michelle R.; Herman, Peter; Papademetris, Xenophon; Shepherd, Gordon M.; Verhagen, Justus V.; Hyder, Fahmeed

2015-01-01

Functional imaging signals arise from distinct metabolic and hemodynamic events at the neuropil, but how these processes are influenced by pre- and post-synaptic activities need to be understood for quantitative interpretation of stimulus-evoked mapping data. The olfactory bulb (OB) glomeruli, spherical neuropil regions with well-defined neuronal circuitry, can provide insights into this issue. Optical calcium-sensitive fluorescent dye imaging (OICa2+) reflects dynamics of pre-synaptic input to glomeruli, whereas high-resolution functional magnetic resonance imaging (fMRI) using deoxyhemoglobin contrast reveals neuropil function within the glomerular layer where both pre- and post-synaptic activities contribute. We imaged odor-specific activity patterns of the dorsal OB in the same anesthetized rats with fMRI and OICa2+ and then co-registered the respective maps to compare patterns in the same space. Maps by each modality were very reproducible as trial-to-trial patterns for a given odor, overlapping by ~80%. Maps evoked by ethyl butyrate and methyl valerate for a given modality overlapped by ~80%, suggesting activation of similar dorsal glomerular networks by these odors. Comparison of maps generated by both methods for a given odor showed ~70% overlap, indicating similar odor-specific maps by each method. These results suggest that odor-specific glomerular patterns by high-resolution fMRI primarily tracks pre-synaptic input to the OB. Thus combining OICa2+ and fMRI lays the framework for studies of OB processing over a range of spatiotemporal scales, where OICa2+ can feature the fast dynamics of dorsal glomerular clusters and fMRI can map the entire glomerular sheet in the OB. PMID:26631819

Cell-type specific short-term plasticity at auditory nerve synapses controls feed-forward inhibition in the dorsal cochlear nucleus.

PubMed

Sedlacek, Miloslav; Brenowitz, Stephan D

2014-01-01

Feed-forward inhibition (FFI) represents a powerful mechanism by which control of the timing and fidelity of action potentials in local synaptic circuits of various brain regions is achieved. In the cochlear nucleus, the auditory nerve provides excitation to both principal neurons and inhibitory interneurons. Here, we investigated the synaptic circuit associated with fusiform cells (FCs), principal neurons of the dorsal cochlear nucleus (DCN) that receive excitation from auditory nerve fibers and inhibition from tuberculoventral cells (TVCs) on their basal dendrites in the deep layer of DCN. Despite the importance of these inputs in regulating fusiform cell firing behavior, the mechanisms determining the balance of excitation and FFI in this circuit are not well understood. Therefore, we examined the timing and plasticity of auditory nerve driven FFI onto FCs. We find that in some FCs, excitatory and inhibitory components of FFI had the same stimulation thresholds indicating they could be triggered by activation of the same fibers. In other FCs, excitation and inhibition exhibit different stimulus thresholds, suggesting FCs and TVCs might be activated by different sets of fibers. In addition, we find that during repetitive activation, synapses formed by the auditory nerve onto TVCs and FCs exhibit distinct modes of short-term plasticity. Feed-forward inhibitory post-synaptic currents (IPSCs) in FCs exhibit short-term depression because of prominent synaptic depression at the auditory nerve-TVC synapse. Depression of this feedforward inhibitory input causes a shift in the balance of fusiform cell synaptic input towards greater excitation and suggests that fusiform cell spike output will be enhanced by physiological patterns of auditory nerve activity.

Complex-learning Induced Modifications in Synaptic Inhibition: Mechanisms and Functional Significance.

PubMed

Reuveni, Iris; Lin, Longnian; Barkai, Edi

2018-06-15

Following training in a difficult olfactory-discrimination (OD) task rats acquire the capability to perform the task easily, with little effort. This new acquired skill, of 'learning how to learn' is termed 'rule learning'. At the single-cell level, rule learning is manifested in long-term enhancement of intrinsic neuronal excitability of piriform cortex (PC) pyramidal neurons, and in excitatory synaptic connections between these neurons to maintain cortical stability, such long-lasting increase in excitability must be accompanied by paralleled increase in inhibitory processes that would prevent hyper-excitable activation. In this review we describe the cellular and molecular mechanisms underlying complex-learning-induced long-lasting modifications in GABA A -receptors and GABA B -receptor-mediated synaptic inhibition. Subsequently we discuss how such modifications support the induction and preservation of long-term memories in the in the mammalian brain. Based on experimental results, computational analysis and modeling, we propose that rule learning is maintained by doubling the strength of synaptic inputs, excitatory as well as inhibitory, in a sub-group of neurons. This enhanced synaptic transmission, which occurs in all (or almost all) synaptic inputs onto these neurons, activates specific stored memories. At the molecular level, such rule-learning-relevant synaptic strengthening is mediated by doubling the conductance of synaptic channels, but not their numbers. This post synaptic process is controlled by a whole-cell mechanism via particular second messenger systems. This whole-cell mechanism enables memory amplification when required and memory extinction when not relevant. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

All‐optical functional synaptic connectivity mapping in acute brain slices using the calcium integrator CaMPARI

PubMed Central

Sha, Fern; Johenning, Friedrich W.; Schreiter, Eric R.; Looger, Loren L.; Larkum, Matthew E.

2016-01-01

Key points The genetically encoded fluorescent calcium integrator calcium‐modulated photoactivatable ratiobetric integrator (CaMPARI) reports calcium influx induced by synaptic and neural activity. Its fluorescence is converted from green to red in the presence of violet light and calcium.The rate of conversion – the sensitivity to activity – is tunable and depends on the intensity of violet light.Synaptic activity and action potentials can independently initiate significant CaMPARI conversion.The level of conversion by subthreshold synaptic inputs is correlated to the strength of input, enabling optical readout of relative synaptic strength.When combined with optogenetic activation of defined presynaptic neurons, CaMPARI provides an all‐optical method to map synaptic connectivity. Abstract The calcium‐modulated photoactivatable ratiometric integrator (CaMPARI) is a genetically encoded calcium integrator that facilitates the study of neural circuits by permanently marking cells active during user‐specified temporal windows. Permanent marking enables measurement of signals from large swathes of tissue and easy correlation of activity with other structural or functional labels. One potential application of CaMPARI is labelling neurons postsynaptic to specific populations targeted for optogenetic stimulation, giving rise to all‐optical functional connectivity mapping. Here, we characterized the response of CaMPARI to several common types of neuronal calcium signals in mouse acute cortical brain slices. Our experiments show that CaMPARI is effectively converted by both action potentials and subthreshold synaptic inputs, and that conversion level is correlated to synaptic strength. Importantly, we found that conversion rate can be tuned: it is linearly related to light intensity. At low photoconversion light levels CaMPARI offers a wide dynamic range due to slower conversion rate; at high light levels conversion is more rapid and more sensitive to activity. Finally, we employed CaMPARI and optogenetics for functional circuit mapping in ex vivo acute brain slices, which preserve in vivo‐like connectivity of axon terminals. With a single light source, we stimulated channelrhodopsin‐2‐expressing long‐range posteromedial (POm) thalamic axon terminals in cortex and induced CaMPARI conversion in recipient cortical neurons. We found that POm stimulation triggers robust photoconversion of layer 5 cortical neurons and weaker conversion of layer 2/3 neurons. Thus, CaMPARI enables network‐wide, tunable, all‐optical functional circuit mapping that captures supra‐ and subthreshold depolarization. PMID:27861906

Synaptic activity induces input-specific rearrangements in a targeted synaptic protein interaction network.

PubMed

Lautz, Jonathan D; Brown, Emily A; VanSchoiack, Alison A Williams; Smith, Stephen E P

2018-05-27

Cells utilize dynamic, network level rearrangements in highly interconnected protein interaction networks to transmit and integrate information from distinct signaling inputs. Despite the importance of protein interaction network dynamics, the organizational logic underlying information flow through these networks is not well understood. Previously, we developed the quantitative multiplex co-immunoprecipitation platform, which allows for the simultaneous and quantitative measurement of the amount of co-association between large numbers of proteins in shared complexes. Here, we adapt quantitative multiplex co-immunoprecipitation to define the activity dependent dynamics of an 18-member protein interaction network in order to better understand the underlying principles governing glutamatergic signal transduction. We first establish that immunoprecipitation detected by flow cytometry can detect activity dependent changes in two known protein-protein interactions (Homer1-mGluR5 and PSD-95-SynGAP). We next demonstrate that neuronal stimulation elicits a coordinated change in our targeted protein interaction network, characterized by the initial dissociation of Homer1 and SynGAP-containing complexes followed by increased associations among glutamate receptors and PSD-95. Finally, we show that stimulation of distinct glutamate receptor types results in different modular sets of protein interaction network rearrangements, and that cells activate both modules in order to integrate complex inputs. This analysis demonstrates that cells respond to distinct types of glutamatergic input by modulating different combinations of protein co-associations among a targeted network of proteins. Our data support a model of synaptic plasticity in which synaptic stimulation elicits dissociation of preexisting multiprotein complexes, opening binding slots in scaffold proteins and allowing for the recruitment of additional glutamatergic receptors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei

PubMed Central

Pugh, Jason R.; Raman, Indira M.

2009-01-01

Many cerebellar neurons fire spontaneously, generating 10–100 action potentials per second even without synaptic input. This high basal activity correlates with information-coding mechanisms that differ from those of cells that are quiescent until excited synaptically. For example, in the deep cerebellar nuclei, Hebbian patterns of coincident synaptic excitation and postsynaptic firing fail to induce long-term increases in the strength of excitatory inputs. Instead, excitatory synaptic currents are potentiated by combinations of inhibition and excitation that resemble the activity of Purkinje and mossy fiber afferents that is predicted to occur during cerebellar associative learning tasks. Such results indicate that circuits with intrinsically active neurons have rules for information transfer and storage that distinguish them from other brain regions. PMID:19178955

Diversity of neuropsin (KLK8)-dependent synaptic associativity in the hippocampal pyramidal neuron

PubMed Central

Ishikawa, Yasuyuki; Tamura, Hideki; Shiosaka, Sadao

2011-01-01

Abstract Hippocampal early (E-) long-term potentiation (LTP) and long-term depression (LTD) elicited by a weak stimulus normally fades within 90 min. Late (L-) LTP and LTD elicited by strong stimuli continue for >180 min and require new protein synthesis to persist. If a strong tetanus is applied once to synaptic inputs, even a weak tetanus applied to another synaptic input can evoke persistent LTP. A synaptic tag is hypothesized to enable the capture of newly synthesized synaptic molecules. This process, referred to as synaptic tagging, is found between not only the same processes (i.e. E- and L-LTP; E- and L-LTD) but also between different processes (i.e. E-LTP and L-LTD; E-LTD and L-LTP) induced at two independent synaptic inputs (cross-tagging). However, the mechanisms of synaptic tag setting remain unclear. In our previous study, we found that synaptic associativity in the hippocampal Schaffer collateral pathway depended on neuropsin (kallikrein-related peptidase 8 or KLK8), a plasticity-related extracellular protease. In the present study, we investigated how neuropsin participates in synaptic tagging and cross-tagging. We report that neuropsin is involved in synaptic tagging during LTP at basal and apical dendritic inputs. Moreover, neuropsin is involved in synaptic tagging and cross-tagging during LTP at apical dendritic inputs via integrin β1 and calcium/calmodulin-dependent protein kinase II signalling. Thus, neuropsin is a candidate molecule for the LTP-specific tag setting and regulates the transformation of E- to L-LTP during both synaptic tagging and cross-tagging. PMID:21646406

The novel protein kinase C epsilon isoform at the adult neuromuscular synapse: location, regulation by synaptic activity-dependent muscle contraction through TrkB signaling and coupling to ACh release.

PubMed

Obis, Teresa; Besalduch, Núria; Hurtado, Erica; Nadal, Laura; Santafe, Manel M; Garcia, Neus; Tomàs, Marta; Priego, Mercedes; Lanuza, Maria A; Tomàs, Josep

2015-02-10

Protein kinase C (PKC) regulates a variety of neural functions, including neurotransmitter release. Although various PKC isoforms can be expressed at the synaptic sites and specific cell distribution may contribute to their functional diversity, little is known about the isoform-specific functions of PKCs in neuromuscular synapse. The present study is designed to examine the location of the novel isoform nPKCε at the neuromuscular junction (NMJ), their synaptic activity-related expression changes, its regulation by muscle contraction, and their possible involvement in acetylcholine release. We use immunohistochemistry and confocal microscopy to demonstrate that the novel isoform nPKCε is exclusively located in the motor nerve terminals of the adult rat NMJ. We also report that electrical stimulation of synaptic inputs to the skeletal muscle significantly increased the amount of nPKCε isoform as well as its phosphorylated form in the synaptic membrane, and muscle contraction is necessary for these nPKCε expression changes. The results also demonstrate that synaptic activity-induced muscle contraction promotes changes in presynaptic nPKCε through the brain-derived neurotrophic factor (BDNF)-mediated tyrosine kinase receptor B (TrkB) signaling. Moreover, nPKCε activity results in phosphorylation of the substrate MARCKS involved in actin cytoskeleton remodeling and related with neurotransmission. Finally, blocking nPKCε with a nPKCε-specific translocation inhibitor peptide (εV1-2) strongly reduces phorbol ester-induced ACh release potentiation, which further indicates that nPKCε is involved in neurotransmission. Together, these results provide a mechanistic insight into how synaptic activity-induced muscle contraction could regulate the presynaptic action of the nPKCε isoform and suggest that muscle contraction is an important regulatory step in TrkB signaling at the NMJ.

Mapping Inhibitory Neuronal Circuits by Laser Scanning Photostimulation

PubMed Central

Ikrar, Taruna; Olivas, Nicholas D.; Shi, Yulin; Xu, Xiangmin

2011-01-01

Inhibitory neurons are crucial to cortical function. They comprise about 20% of the entire cortical neuronal population and can be further subdivided into diverse subtypes based on their immunochemical, morphological, and physiological properties1-4. Although previous research has revealed much about intrinsic properties of individual types of inhibitory neurons, knowledge about their local circuit connections is still relatively limited3,5,6. Given that each individual neuron's function is shaped by its excitatory and inhibitory synaptic input within cortical circuits, we have been using laser scanning photostimulation (LSPS) to map local circuit connections to specific inhibitory cell types. Compared to conventional electrical stimulation or glutamate puff stimulation, LSPS has unique advantages allowing for extensive mapping and quantitative analysis of local functional inputs to individually recorded neurons3,7-9. Laser photostimulation via glutamate uncaging selectively activates neurons perisomatically, without activating axons of passage or distal dendrites, which ensures a sub-laminar mapping resolution. The sensitivity and efficiency of LSPS for mapping inputs from many stimulation sites over a large region are well suited for cortical circuit analysis. Here we introduce the technique of LSPS combined with whole-cell patch clamping for local inhibitory circuit mapping. Targeted recordings of specific inhibitory cell types are facilitated by use of transgenic mice expressing green fluorescent proteins (GFP) in limited inhibitory neuron populations in the cortex3,10, which enables consistent sampling of the targeted cell types and unambiguous identification of the cell types recorded. As for LSPS mapping, we outline the system instrumentation, describe the experimental procedure and data acquisition, and present examples of circuit mapping in mouse primary somatosensory cortex. As illustrated in our experiments, caged glutamate is activated in a spatially restricted region of the brain slice by UV laser photolysis; simultaneous voltage-clamp recordings allow detection of photostimulation-evoked synaptic responses. Maps of either excitatory or inhibitory synaptic input to the targeted neuron are generated by scanning the laser beam to stimulate hundreds of potential presynaptic sites. Thus, LSPS enables the construction of detailed maps of synaptic inputs impinging onto specific types of inhibitory neurons through repeated experiments. Taken together, the photostimulation-based technique offers neuroscientists a powerful tool for determining the functional organization of local cortical circuits. PMID:22006064

Calcium Signaling in Mitral Cell Dendrites of Olfactory Bulbs of Neonatal Rats and Mice during Olfactory Nerve Stimulation and Beta-Adrenoceptor Activation

ERIC Educational Resources Information Center

Yuan, Qi; Mutoh, Hiroki; Debarbieux, Franck; Knopfel, Thomas

2004-01-01

Synapses formed by the olfactory nerve (ON) provide the source of excitatory synaptic input onto mitral cells (MC) in the olfactory bulb. These synapses, which relay odor-specific inputs, are confined to the distally tufted single primary dendrites of MCs, the first stage of central olfactory processing. Beta-adrenergic modulation of electrical…

Growth of neurites toward neurite- neurite contact sites increases synaptic clustering and secretion and is regulated by synaptic activity.

PubMed

Cove, Joshua; Blinder, Pablo; Abi-Jaoude, Elia; Lafrenière-Roula, Myriam; Devroye, Luc; Baranes, Danny

2006-01-01

The integrative properties of dendrites are determined by several factors, including their morphology and the spatio-temporal patterning of their synaptic inputs. One of the great challenges is to discover the interdependency of these two factors and the mechanisms which sculpt dendrites' fine morphological details. We found a novel form of neurite growth behavior in neuronal cultures of the hippocampus and cortex, when axons and dendrites grew directly toward neurite-neurite contact sites and crossed them, forming multi-neurite intersections (MNIs). MNIs were found at a frequency higher than obtained by computer simulations of randomly distributed dendrites, involved many of the dendrites and were stable for days. They were formed specifically by neurites originating from different neurons and were extremely rare among neurites of individual neurons or among astrocytic processes. Axonal terminals were clustered at MNIs and exhibited higher synaptophysin content and release capability than in those located elsewhere. MNI formation, as well as enhancement of axonal terminal clustering and secretion at MNIs, was disrupted by inhibitors of synaptic activity. Thus, convergence of axons and dendrites to form MNIs is a non-random activity-regulated wiring behavior which shapes dendritic trees and affects the location, clustering level and strength of their presynaptic inputs.

Synaptic Mechanisms of Memory Consolidation during Sleep Slow Oscillations

PubMed Central

Wei, Yina; Krishnan, Giri P.

2016-01-01

Sleep is critical for regulation of synaptic efficacy, memories, and learning. However, the underlying mechanisms of how sleep rhythms contribute to consolidating memories acquired during wakefulness remain unclear. Here we studied the role of slow oscillations, 0.2–1 Hz rhythmic transitions between Up and Down states during stage 3/4 sleep, on dynamics of synaptic connectivity in the thalamocortical network model implementing spike-timing-dependent synaptic plasticity. We found that the spatiotemporal pattern of Up-state propagation determines the changes of synaptic strengths between neurons. Furthermore, an external input, mimicking hippocampal ripples, delivered to the cortical network results in input-specific changes of synaptic weights, which persisted after stimulation was removed. These synaptic changes promoted replay of specific firing sequences of the cortical neurons. Our study proposes a neuronal mechanism on how an interaction between hippocampal input, such as mediated by sharp wave-ripple events, cortical slow oscillations, and synaptic plasticity, may lead to consolidation of memories through preferential replay of cortical cell spike sequences during slow-wave sleep. SIGNIFICANCE STATEMENT Sleep is critical for memory and learning. Replay during sleep of temporally ordered spike sequences related to a recent experience was proposed to be a neuronal substrate of memory consolidation. However, specific mechanisms of replay or how spike sequence replay leads to synaptic changes that underlie memory consolidation are still poorly understood. Here we used a detailed computational model of the thalamocortical system to report that interaction between slow cortical oscillations and synaptic plasticity during deep sleep can underlie mapping hippocampal memory traces to persistent cortical representation. This study provided, for the first time, a mechanistic explanation of how slow-wave sleep may promote consolidation of recent memory events. PMID:27076422

Calcium responses to synaptically activated bursts of action potentials and their synapse-independent replay in cultured networks of hippocampal neurons.

PubMed

Bengtson, C Peter; Kaiser, Martin; Obermayer, Joshua; Bading, Hilmar

2013-07-01

Both synaptic N-methyl-d-aspartate (NMDA) receptors and voltage-operated calcium channels (VOCCs) have been shown to be critical for nuclear calcium signals associated with transcriptional responses to bursts of synaptic input. However the direct contribution to nuclear calcium signals from calcium influx through NMDA receptors and VOCCs has been obscured by their concurrent roles in action potential generation and synaptic transmission. Here we compare calcium responses to synaptically induced bursts of action potentials with identical bursts devoid of any synaptic contribution generated using the pre-recorded burst as the voltage clamp command input to replay the burst in the presence of blockers of action potentials or ionotropic glutamate receptors. Synapse independent replays of bursts produced nuclear calcium responses with amplitudes around 70% of their original synaptically generated signals and were abolished by the L-type VOCC blocker, verapamil. These results identify a major direct source of nuclear calcium from local L-type VOCCs whose activation is boosted by NMDA receptor dependent depolarization. The residual component of synaptically induced nuclear calcium signals which was both VOCC independent and NMDA receptor dependent showed delayed kinetics consistent with a more distal source such as synaptic NMDA receptors or internal stores. The dual requirement of NMDA receptors and L-type VOCCs for synaptic activity-induced nuclear calcium dependent transcriptional responses most likely reflects a direct somatic calcium influx from VOCCs whose activation is amplified by synaptic NMDA receptor-mediated depolarization and whose calcium signal is boosted by a delayed input from distal calcium sources mostly likely entry through NMDA receptors and release from internal stores. This article is part of a Special Issue entitled: 12th European Symposium on Calcium. Copyright © 2013 Elsevier B.V. All rights reserved.

Interactions between behaviorally relevant rhythms and synaptic plasticity alter coding in the piriform cortex

PubMed Central

Urban, Nathaniel N.

2012-01-01

Understanding how neural and behavioral timescales interact to influence cortical activity and stimulus coding is an important issue in sensory neuroscience. In air-breathing animals, voluntary changes in respiratory frequency alter the temporal patterning olfactory input. In the olfactory bulb, these behavioral timescales are reflected in the temporal properties of mitral/tufted (M/T) cell spike trains. As the odor information contained in these spike trains is relayed from the bulb to the cortex, interactions between presynaptic spike timing and short-term synaptic plasticity dictate how stimulus features are represented in cortical spike trains. Here we demonstrate how the timescales associated with respiratory frequency, spike timing and short-term synaptic plasticity interact to shape cortical responses. Specifically, we quantified the timescales of short-term synaptic facilitation and depression at excitatory synapses between bulbar M/T cells and cortical neurons in slices of mouse olfactory cortex. We then used these results to generate simulated M/T population synaptic currents that were injected into real cortical neurons. M/T population inputs were modulated at frequencies consistent with passive respiration or active sniffing. We show how the differential recruitment of short-term plasticity at breathing versus sniffing frequencies alters cortical spike responses. For inputs at sniffing frequencies, cortical neurons linearly encoded increases in presynaptic firing rates with increased phase locked, firing rates. In contrast, at passive breathing frequencies, cortical responses saturated with changes in presynaptic rate. Our results suggest that changes in respiratory behavior can gate the transfer of stimulus information between the olfactory bulb and cortex. PMID:22553016

Input-Specific NMDAR-Dependent Potentiation of Dendritic GABAergic Inhibition.

PubMed

Chiu, Chiayu Q; Martenson, James S; Yamazaki, Maya; Natsume, Rie; Sakimura, Kenji; Tomita, Susumu; Tavalin, Steven J; Higley, Michael J

2018-01-17

Preservation of a balance between synaptic excitation and inhibition is critical for normal brain function. A number of homeostatic cellular mechanisms have been suggested to play a role in maintaining this balance, including long-term plasticity of GABAergic inhibitory synapses. Many previous studies have demonstrated a coupling of postsynaptic spiking with modification of perisomatic inhibition. Here, we demonstrate that activation of NMDA-type glutamate receptors leads to input-specific long-term potentiation of dendritic inhibition mediated by somatostatin-expressing interneurons. This form of plasticity is expressed postsynaptically and requires both CaMKIIα and the β2 subunit of the GABA-A receptor. Importantly, this process may function to preserve dendritic inhibition, as genetic deletion of NMDAR signaling results in a selective weakening of dendritic inhibition. Overall, our results reveal a new mechanism for linking excitatory and inhibitory input in neuronal dendrites and provide novel insight into the homeostatic regulation of synaptic transmission in cortical circuits. Copyright © 2017 Elsevier Inc. All rights reserved.

Synaptic control of the shape of the motoneuron pool input-output function

PubMed Central

Heckman, Charles J.

2017-01-01

Although motoneurons have often been considered to be fairly linear transducers of synaptic input, recent evidence suggests that strong persistent inward currents (PICs) in motoneurons allow neuromodulatory and inhibitory synaptic inputs to induce large nonlinearities in the relation between the level of excitatory input and motor output. To try to estimate the possible extent of this nonlinearity, we developed a pool of model motoneurons designed to replicate the characteristics of motoneuron input-output properties measured in medial gastrocnemius motoneurons in the decerebrate cat with voltage-clamp and current-clamp techniques. We drove the model pool with a range of synaptic inputs consisting of various mixtures of excitation, inhibition, and neuromodulation. We then looked at the relation between excitatory drive and total pool output. Our results revealed that the PICs not only enhance gain but also induce a strong nonlinearity in the relation between the average firing rate of the motoneuron pool and the level of excitatory input. The relation between the total simulated force output and input was somewhat more linear because of higher force outputs in later-recruited units. We also found that the nonlinearity can be increased by increasing neuromodulatory input and/or balanced inhibitory input and minimized by a reciprocal, push-pull pattern of inhibition. We consider the possibility that a flexible input-output function may allow motor output to be tuned to match the widely varying demands of the normal motor repertoire. NEW & NOTEWORTHY Motoneuron activity is generally considered to reflect the level of excitatory drive. However, the activation of voltage-dependent intrinsic conductances can distort the relation between excitatory drive and the total output of a pool of motoneurons. Using a pool of realistic motoneuron models, we show that pool output can be a highly nonlinear function of synaptic input but linearity can be achieved through adjusting the time course of excitatory and inhibitory synaptic inputs. PMID:28053245

Somato-dendritic Synaptic Plasticity and Error-backpropagation in Active Dendrites

PubMed Central

Schiess, Mathieu; Urbanczik, Robert; Senn, Walter

2016-01-01

In the last decade dendrites of cortical neurons have been shown to nonlinearly combine synaptic inputs by evoking local dendritic spikes. It has been suggested that these nonlinearities raise the computational power of a single neuron, making it comparable to a 2-layer network of point neurons. But how these nonlinearities can be incorporated into the synaptic plasticity to optimally support learning remains unclear. We present a theoretically derived synaptic plasticity rule for supervised and reinforcement learning that depends on the timing of the presynaptic, the dendritic and the postsynaptic spikes. For supervised learning, the rule can be seen as a biological version of the classical error-backpropagation algorithm applied to the dendritic case. When modulated by a delayed reward signal, the same plasticity is shown to maximize the expected reward in reinforcement learning for various coding scenarios. Our framework makes specific experimental predictions and highlights the unique advantage of active dendrites for implementing powerful synaptic plasticity rules that have access to downstream information via backpropagation of action potentials. PMID:26841235

Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity

PubMed Central

D'Amico, Jessica M.; Condliffe, Elizabeth G.; Martins, Karen J. B.; Bennett, David J.; Gorassini, Monica A.

2014-01-01

The state of areflexia and muscle weakness that immediately follows a spinal cord injury (SCI) is gradually replaced by the recovery of neuronal and network excitability, leading to both improvements in residual motor function and the development of spasticity. In this review we summarize recent animal and human studies that describe how motoneurons and their activation by sensory pathways become hyperexcitable to compensate for the reduction of functional activation of the spinal cord and the eventual impact on the muscle. Specifically, decreases in the inhibitory control of sensory transmission and increases in intrinsic motoneuron excitability are described. We present the idea that replacing lost patterned activation of the spinal cord by activating synaptic inputs via assisted movements, pharmacology or electrical stimulation may help to recover lost spinal inhibition. This may lead to a reduction of uncontrolled activation of the spinal cord and thus, improve its controlled activation by synaptic inputs to ultimately normalize circuit function. Increasing the excitation of the spinal cord with spared descending and/or peripheral inputs by facilitating movement, instead of suppressing it pharmacologically, may provide the best avenue to improve residual motor function and manage spasticity after SCI. PMID:24860447

Depression-Biased Reverse Plasticity Rule Is Required for Stable Learning at Top-Down Connections

PubMed Central

Burbank, Kendra S.; Kreiman, Gabriel

2012-01-01

Top-down synapses are ubiquitous throughout neocortex and play a central role in cognition, yet little is known about their development and specificity. During sensory experience, lower neocortical areas are activated before higher ones, causing top-down synapses to experience a preponderance of post-synaptic activity preceding pre-synaptic activity. This timing pattern is the opposite of that experienced by bottom-up synapses, which suggests that different versions of spike-timing dependent synaptic plasticity (STDP) rules may be required at top-down synapses. We consider a two-layer neural network model and investigate which STDP rules can lead to a distribution of top-down synaptic weights that is stable, diverse and avoids strong loops. We introduce a temporally reversed rule (rSTDP) where top-down synapses are potentiated if post-synaptic activity precedes pre-synaptic activity. Combining analytical work and integrate-and-fire simulations, we show that only depression-biased rSTDP (and not classical STDP) produces stable and diverse top-down weights. The conclusions did not change upon addition of homeostatic mechanisms, multiplicative STDP rules or weak external input to the top neurons. Our prediction for rSTDP at top-down synapses, which are distally located, is supported by recent neurophysiological evidence showing the existence of temporally reversed STDP in synapses that are distal to the post-synaptic cell body. PMID:22396630

Dendritic integration: 60 years of progress.

PubMed

Stuart, Greg J; Spruston, Nelson

2015-12-01

Understanding how individual neurons integrate the thousands of synaptic inputs they receive is critical to understanding how the brain works. Modeling studies in silico and experimental work in vitro, dating back more than half a century, have revealed that neurons can perform a variety of different passive and active forms of synaptic integration on their inputs. But how are synaptic inputs integrated in the intact brain? With the development of new techniques, this question has recently received substantial attention, with new findings suggesting that many of the forms of synaptic integration observed in vitro also occur in vivo, including in awake animals. Here we review six decades of progress, which collectively highlights the complex ways that single neurons integrate their inputs, emphasizing the critical role of dendrites in information processing in the brain.

Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage

PubMed Central

Prestori, Francesca; Bonardi, Claudia; Mapelli, Lisa; Lombardo, Paola; Goselink, Rianne; De Stefano, Maria Egle; Gandolfi, Daniela; Mapelli, Jonathan; Bertrand, Daniel; Schonewille, Martijn; De Zeeuw, Chris; D’Angelo, Egidio

2013-01-01

The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation. PMID:23741401

Circuit mechanisms of hippocampal reactivation during sleep.

PubMed

Malerba, Paola; Bazhenov, Maxim

2018-05-01

The hippocampus is important for memory and learning, being a brain site where initial memories are formed and where sharp wave - ripples (SWR) are found, which are responsible for mapping recent memories to long-term storage during sleep-related memory replay. While this conceptual schema is well established, specific intrinsic and network-level mechanisms driving spatio-temporal patterns of hippocampal activity during sleep, and specifically controlling off-line memory reactivation are unknown. In this study, we discuss a model of hippocampal CA1-CA3 network generating spontaneous characteristic SWR activity. Our study predicts the properties of CA3 input which are necessary for successful CA1 ripple generation and the role of synaptic interactions and intrinsic excitability in spike sequence replay during SWRs. Specifically, we found that excitatory synaptic connections promote reactivation in both CA3 and CA1, but the different dynamics of sharp waves in CA3 and ripples in CA1 result in a differential role for synaptic inhibition in modulating replay: promoting spike sequence specificity in CA3 but not in CA1 areas. Finally, we describe how awake learning of spatial trajectories leads to synaptic changes sufficient to drive hippocampal cells' reactivation during sleep, as required for sleep-related memory consolidation. Copyright © 2018 Elsevier Inc. All rights reserved.

Identified Serotonergic Modulatory Neurons Have Heterogeneous Synaptic Connectivity within the Olfactory System of Drosophila.

PubMed

Coates, Kaylynn E; Majot, Adam T; Zhang, Xiaonan; Michael, Cole T; Spitzer, Stacy L; Gaudry, Quentin; Dacks, Andrew M

2017-08-02

Modulatory neurons project widely throughout the brain, dynamically altering network processing based on an animal's physiological state. The connectivity of individual modulatory neurons can be complex, as they often receive input from a variety of sources and are diverse in their physiology, structure, and gene expression profiles. To establish basic principles about the connectivity of individual modulatory neurons, we examined a pair of identified neurons, the "contralaterally projecting, serotonin-immunoreactive deutocerebral neurons" (CSDns), within the olfactory system of Drosophila Specifically, we determined the neuronal classes providing synaptic input to the CSDns within the antennal lobe (AL), an olfactory network targeted by the CSDns, and the degree to which CSDn active zones are uniformly distributed across the AL. Using anatomical techniques, we found that the CSDns received glomerulus-specific input from olfactory receptor neurons (ORNs) and projection neurons (PNs), and networkwide input from local interneurons (LNs). Furthermore, we quantified the number of CSDn active zones in each glomerulus and found that CSDn output is not uniform, but rather heterogeneous, across glomeruli and stereotyped from animal to animal. Finally, we demonstrate that the CSDns synapse broadly onto LNs and PNs throughout the AL but do not synapse upon ORNs. Our results demonstrate that modulatory neurons do not necessarily provide purely top-down input but rather receive neuron class-specific input from the networks that they target, and that even a two cell modulatory network has highly heterogeneous, yet stereotyped, pattern of connectivity. SIGNIFICANCE STATEMENT Modulatory neurons often project broadly throughout the brain to alter processing based on physiological state. However, the connectivity of individual modulatory neurons to their target networks is not well understood, as modulatory neuron populations are heterogeneous in their physiology, morphology, and gene expression. In this study, we use a pair of identified serotonergic neurons within the Drosophila olfactory system as a model to establish a framework for modulatory neuron connectivity. We demonstrate that individual modulatory neurons can integrate neuron class-specific input from their target network, which is often nonreciprocal. Additionally, modulatory neuron output can be stereotyped, yet nonuniform, across network regions. Our results provide new insight into the synaptic relationships that underlie network function of modulatory neurons. Copyright © 2017 the authors 0270-6474/17/377318-14$15.00/0.

Neuronal BDNF Signaling Is Necessary for the Effects of Treadmill Exercise on Synaptic Stripping of Axotomized Motoneurons

PubMed Central

Krakowiak, Joey; Liu, Caiyue; Papudesu, Chandana; Ward, P. Jillian; Wilhelm, Jennifer C.; English, Arthur W.

2015-01-01

The withdrawal of synaptic inputs from the somata and proximal dendrites of spinal motoneurons following peripheral nerve injury could contribute to poor functional recovery. Decreased availability of neurotrophins to afferent terminals on axotomized motoneurons has been implicated as one cause of the withdrawal. No reduction in contacts made by synaptic inputs immunoreactive to the vesicular glutamate transporter 1 and glutamic acid decarboxylase 67 is noted on axotomized motoneurons if modest treadmill exercise, which stimulates the production of neurotrophins by spinal motoneurons, is applied after nerve injury. In conditional, neuron-specific brain-derived neurotrophic factor (BDNF) knockout mice, a reduction in synaptic contacts onto motoneurons was noted in intact animals which was similar in magnitude to that observed after nerve transection in wild-type controls. No further reduction in coverage was found if nerves were cut in knockout mice. Two weeks of moderate daily treadmill exercise following nerve injury in these BDNF knockout mice did not affect synaptic inputs onto motoneurons. Treadmill exercise has a profound effect on synaptic inputs to motoneurons after peripheral nerve injury which requires BDNF production by those postsynaptic cells. PMID:25918648

Robustness of sensory-evoked excitation is increased by inhibitory inputs to distal apical tuft dendrites

PubMed Central

Egger, Robert; Schmitt, Arno C.; Wallace, Damian J.; Sakmann, Bert; Oberlaender, Marcel; Kerr, Jason N. D.

2015-01-01

Cortical inhibitory interneurons (INs) are subdivided into a variety of morphologically and functionally specialized cell types. How the respective specific properties translate into mechanisms that regulate sensory-evoked responses of pyramidal neurons (PNs) remains unknown. Here, we investigated how INs located in cortical layer 1 (L1) of rat barrel cortex affect whisker-evoked responses of L2 PNs. To do so we combined in vivo electrophysiology and morphological reconstructions with computational modeling. We show that whisker-evoked membrane depolarization in L2 PNs arises from highly specialized spatiotemporal synaptic input patterns. Temporally L1 INs and L2–5 PNs provide near synchronous synaptic input. Spatially synaptic contacts from L1 INs target distal apical tuft dendrites, whereas PNs primarily innervate basal and proximal apical dendrites. Simulations of such constrained synaptic input patterns predicted that inactivation of L1 INs increases trial-to-trial variability of whisker-evoked responses in L2 PNs. The in silico predictions were confirmed in vivo by L1-specific pharmacological manipulations. We present a mechanism—consistent with the theory of distal dendritic shunting—that can regulate the robustness of sensory-evoked responses in PNs without affecting response amplitude or latency. PMID:26512104

Overnight Fasting Regulates Inhibitory Tone to Cholinergic Neurons of the Dorsomedial Nucleus of the Hypothalamus

PubMed Central

Groessl, Florian; Jeong, Jae Hoon; Talmage, David A.; Role, Lorna W.; Jo, Young-Hwan

2013-01-01

The dorsomedial nucleus of the hypothalamus (DMH) contributes to the regulation of overall energy homeostasis by modulating energy intake as well as energy expenditure. Despite the importance of the DMH in the control of energy balance, DMH-specific genetic markers or neuronal subtypes are poorly defined. Here we demonstrate the presence of cholinergic neurons in the DMH using genetically modified mice that express enhanced green florescent protein (eGFP) selectively in choline acetyltransferase (Chat)-neurons. Overnight food deprivation increases the activity of DMH cholinergic neurons, as shown by induction of fos protein and a significant shift in the baseline resting membrane potential. DMH cholinergic neurons receive both glutamatergic and GABAergic synaptic input, but the activation of these neurons by an overnight fast is due entirely to decreased inhibitory tone. The decreased inhibition is associated with decreased frequency and amplitude of GABAergic synaptic currents in the cholinergic DMH neurons, while glutamatergic synaptic transmission is not altered. As neither the frequency nor amplitude of miniature GABAergic or glutamatergic postsynaptic currents is affected by overnight food deprivation, the fasting-induced decrease in inhibitory tone to cholinergic neurons is dependent on superthreshold activity of GABAergic inputs. This study reveals that cholinergic neurons in the DMH readily sense the availability of nutrients and respond to overnight fasting via decreased GABAergic inhibitory tone. As such, altered synaptic as well as neuronal activity of DMH cholinergic neurons may play a critical role in the regulation of overall energy homeostasis. PMID:23585854

Differences in spike train variability in rat vasopressin and oxytocin neurons and their relationship to synaptic activity

PubMed Central

Li, Chunyan; Tripathi, Pradeep K; Armstrong, William E

2007-01-01

The firing pattern of magnocellular neurosecretory neurons is intimately related to hormone release, but the relative contribution of synaptic versus intrinsic factors to the temporal dispersion of spikes is unknown. In the present study, we examined the firing patterns of vasopressin (VP) and oxytocin (OT) supraoptic neurons in coronal slices from virgin female rats, with and without blockade of inhibitory and excitatory synaptic currents. Inhibitory postsynaptic currents (IPSCs) were twice as prevalent as their excitatory counterparts (EPSCs), and both were more prevalent in OT compared with VP neurons. Oxytocin neurons fired more slowly and irregularly than VP neurons near threshold. Blockade of Cl− currents (including tonic and synaptic currents) with picrotoxin reduced interspike interval (ISI) variability of continuously firing OT and VP neurons without altering input resistance or firing rate. Blockade of EPSCs did not affect firing pattern. Phasic bursting neurons (putative VP neurons) were inconsistently affected by broad synaptic blockade, suggesting that intrinsic factors may dominate the ISI distribution during this mode in the slice. Specific blockade of synaptic IPSCs with gabazine also reduced ISI variability, but only in OT neurons. In all cases, the effect of inhibitory blockade on firing pattern was independent of any consistent change in input resistance or firing rate. Since the great majority of IPSCs are randomly distributed, miniature events (mIPSCs) in the coronal slice, these findings imply that even mIPSCs can impart irregularity to the firing pattern of OT neurons in particular, and could be important in regulating spike patterning in vivo. For example, the increased firing variability that precedes bursting in OT neurons during lactation could be related to significant changes in synaptic activity. PMID:17332000

Heterosynaptic modulation of evoked synaptic potentials in layer II of the entorhinal cortex by activation of the parasubiculum

PubMed Central

Sparks, Daniel W.

2016-01-01

The superficial layers of the entorhinal cortex receive sensory and associational cortical inputs and provide the hippocampus with the majority of its cortical sensory input. The parasubiculum, which receives input from multiple hippocampal subfields, sends its single major output projection to layer II of the entorhinal cortex, suggesting that it may modulate processing of synaptic inputs to the entorhinal cortex. Indeed, stimulation of the parasubiculum can enhance entorhinal responses to synaptic input from the piriform cortex in vivo. Theta EEG activity contributes to spatial and mnemonic processes in this region, and the current study assessed how stimulation of the parasubiculum with either single pulses or short, five-pulse, theta-frequency trains may modulate synaptic responses in layer II entorhinal stellate neurons evoked by stimulation of layer I afferents in vitro. Parasubicular stimulation pulses or trains suppressed responses to layer I stimulation at intervals of 5 ms, and parasubicular stimulation trains facilitated layer I responses at a train-pulse interval of 25 ms. This suggests that firing of parasubicular neurons during theta activity may heterosynaptically enhance incoming sensory inputs to the entorhinal cortex. Bath application of the hyperpolarization-activated cation current (Ih) blocker ZD7288 enhanced the facilitation effect, suggesting that cholinergic inhibition of Ih may contribute. In addition, repetitive pairing of parasubicular trains and layer I stimulation induced a lasting depression of entorhinal responses to layer I stimulation. These findings provide evidence that theta activity in the parasubiculum may promote heterosynaptic modulation effects that may alter sensory processing in the entorhinal cortex. PMID:27146979

Combination of High-density Microelectrode Array and Patch Clamp Recordings to Enable Studies of Multisynaptic Integration.

PubMed

Jäckel, David; Bakkum, Douglas J; Russell, Thomas L; Müller, Jan; Radivojevic, Milos; Frey, Urs; Franke, Felix; Hierlemann, Andreas

2017-04-20

We present a novel, all-electric approach to record and to precisely control the activity of tens of individual presynaptic neurons. The method allows for parallel mapping of the efficacy of multiple synapses and of the resulting dynamics of postsynaptic neurons in a cortical culture. For the measurements, we combine an extracellular high-density microelectrode array, featuring 11'000 electrodes for extracellular recording and stimulation, with intracellular patch-clamp recording. We are able to identify the contributions of individual presynaptic neurons - including inhibitory and excitatory synaptic inputs - to postsynaptic potentials, which enables us to study dendritic integration. Since the electrical stimuli can be controlled at microsecond resolution, our method enables to evoke action potentials at tens of presynaptic cells in precisely orchestrated sequences of high reliability and minimum jitter. We demonstrate the potential of this method by evoking short- and long-term synaptic plasticity through manipulation of multiple synaptic inputs to a specific neuron.

Active Mechanisms of Vibration Encoding and Frequency Filtering in Central Mechanosensory Neurons.

PubMed

Azevedo, Anthony W; Wilson, Rachel I

2017-10-11

To better understand biophysical mechanisms of mechanosensory processing, we investigated two cell types in the Drosophila brain (A2 and B1 cells) that are postsynaptic to antennal vibration receptors. A2 cells receive excitatory synaptic currents in response to both directions of movement: thus, twice per vibration cycle. The membrane acts as a low-pass filter, so that voltage and spiking mainly track the vibration envelope rather than individual cycles. By contrast, B1 cells are excited by only forward or backward movement, meaning they are sensitive to vibration phase. They receive oscillatory synaptic currents at the stimulus frequency, and they bandpass filter these inputs to favor specific frequencies. Different cells prefer different frequencies, due to differences in their voltage-gated conductances. Both Na + and K + conductances suppress low-frequency synaptic inputs, so cells with larger voltage-gated conductances prefer higher frequencies. These results illustrate how membrane properties and voltage-gated conductances can extract distinct stimulus features into parallel channels. Copyright © 2017 Elsevier Inc. All rights reserved.

Parvalbumin interneuron mediated feedforward inhibition controls signal output in the deep layers of the perirhinal‐entorhinal cortex

PubMed Central

Willems, Janske G. P.; Wadman, Wytse J.

2018-01-01

Abstract The perirhinal (PER) and lateral entorhinal (LEC) cortex form an anatomical link between the neocortex and the hippocampus. However, neocortical activity is transmitted through the PER and LEC to the hippocampus with a low probability, suggesting the involvement of the inhibitory network. This study explored the role of interneuron mediated inhibition, activated by electrical stimulation in the agranular insular cortex (AiP), in the deep layers of the PER and LEC. Activated synaptic input by AiP stimulation rarely evoked action potentials in the PER‐LEC deep layer excitatory principal neurons, most probably because the evoked synaptic response consisted of a small excitatory and large inhibitory conductance. Furthermore, parvalbumin positive (PV) interneurons—a subset of interneurons projecting onto the axo‐somatic region of principal neurons—received synaptic input earlier than principal neurons, suggesting recruitment of feedforward inhibition. This synaptic input in PV interneurons evoked varying trains of action potentials, explaining the fast rising, long lasting synaptic inhibition received by deep layer principal neurons. Altogether, the excitatory input from the AiP onto deep layer principal neurons is overruled by strong feedforward inhibition. PV interneurons, with their fast, extensive stimulus‐evoked firing, are able to deliver this fast evoked inhibition in principal neurons. This indicates an essential role for PV interneurons in the gating mechanism of the PER‐LEC network. PMID:29341361

Retrieval Property of Attractor Network with Synaptic Depression

NASA Astrophysics Data System (ADS)

Matsumoto, Narihisa; Ide, Daisuke; Watanabe, Masataka; Okada, Masato

2007-08-01

Synaptic connections are known to change dynamically. High-frequency presynaptic inputs induce decrease of synaptic weights. This process is known as short-term synaptic depression. The synaptic depression controls a gain for presynaptic inputs. However, it remains a controversial issue what are functional roles of this gain control. We propose a new hypothesis that one of the functional roles is to enlarge basins of attraction. To verify this hypothesis, we employ a binary discrete-time associative memory model which consists of excitatory and inhibitory neurons. It is known that the excitatory-inhibitory balance controls an overall activity of the network. The synaptic depression might incorporate an activity control mechanism. Using a mean-field theory and computer simulations, we find that the synaptic depression enlarges the basins at a small loading rate while the excitatory-inhibitory balance enlarges them at a large loading rate. Furthermore the synaptic depression does not affect the steady state of the network if a threshold is set at an appropriate value. These results suggest that the synaptic depression works in addition to the effect of the excitatory-inhibitory balance, and it might improve an error-correcting ability in cortical circuits.

Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli.

PubMed

Tornero, Daniel; Tsupykov, Oleg; Granmo, Marcus; Rodriguez, Cristina; Grønning-Hansen, Marita; Thelin, Jonas; Smozhanik, Ekaterina; Laterza, Cecilia; Wattananit, Somsak; Ge, Ruimin; Tatarishvili, Jemal; Grealish, Shane; Brüstle, Oliver; Skibo, Galina; Parmar, Malin; Schouenborg, Jens; Lindvall, Olle; Kokaia, Zaal

2017-03-01

Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channelrhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

PubMed

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.

Comparing Realistic Subthalamic Nucleus Neuron Models

NASA Astrophysics Data System (ADS)

Njap, Felix; Claussen, Jens C.; Moser, Andreas; Hofmann, Ulrich G.

2011-06-01

The mechanism of action of clinically effective electrical high frequency stimulation is still under debate. However, recent evidence points at the specific activation of GABA-ergic ion channels. Using a computational approach, we analyze temporal properties of the spike trains emitted by biologically realistic neurons of the subthalamic nucleus (STN) as a function of GABA-ergic synaptic input conductances. Our contribution is based on a model proposed by Rubin and Terman and exhibits a wide variety of different firing patterns, silent, low spiking, moderate spiking and intense spiking activity. We observed that most of the cells in our network turn to silent mode when we increase the GABAA input conductance above the threshold of 3.75 mS/cm2. On the other hand, insignificant changes in firing activity are observed when the input conductance is low or close to zero. We thus reproduce Rubin's model with vanishing synaptic conductances. To quantitatively compare spike trains from the original model with the modified model at different conductance levels, we apply four different (dis)similarity measures between them. We observe that Mahalanobis distance, Victor-Purpura metric, and Interspike Interval distribution are sensitive to different firing regimes, whereas Mutual Information seems undiscriminative for these functional changes.

Phasic Firing in Vasopressin Cells: Understanding Its Functional Significance through Computational Models

PubMed Central

MacGregor, Duncan J.; Leng, Gareth

2012-01-01

Vasopressin neurons, responding to input generated by osmotic pressure, use an intrinsic mechanism to shift from slow irregular firing to a distinct phasic pattern, consisting of long bursts and silences lasting tens of seconds. With increased input, bursts lengthen, eventually shifting to continuous firing. The phasic activity remains asynchronous across the cells and is not reflected in the population output signal. Here we have used a computational vasopressin neuron model to investigate the functional significance of the phasic firing pattern. We generated a concise model of the synaptic input driven spike firing mechanism that gives a close quantitative match to vasopressin neuron spike activity recorded in vivo, tested against endogenous activity and experimental interventions. The integrate-and-fire based model provides a simple physiological explanation of the phasic firing mechanism involving an activity-dependent slow depolarising afterpotential (DAP) generated by a calcium-inactivated potassium leak current. This is modulated by the slower, opposing, action of activity-dependent dendritic dynorphin release, which inactivates the DAP, the opposing effects generating successive periods of bursting and silence. Model cells are not spontaneously active, but fire when perturbed by random perturbations mimicking synaptic input. We constructed one population of such phasic neurons, and another population of similar cells but which lacked the ability to fire phasically. We then studied how these two populations differed in the way that they encoded changes in afferent inputs. By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input. Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response. These findings show large differences in information coding between the populations, and apparent functional advantages of asynchronous phasic firing. PMID:23093929

Modelling Feedback Excitation, Pacemaker Properties and Sensory Switching of Electrically Coupled Brainstem Neurons Controlling Rhythmic Activity

PubMed Central

Hull, Michael J.; Soffe, Stephen R.; Willshaw, David J.; Roberts, Alan

2016-01-01

What cellular and network properties allow reliable neuronal rhythm generation or firing that can be started and stopped by brief synaptic inputs? We investigate rhythmic activity in an electrically-coupled population of brainstem neurons driving swimming locomotion in young frog tadpoles, and how activity is switched on and off by brief sensory stimulation. We build a computational model of 30 electrically-coupled conditional pacemaker neurons on one side of the tadpole hindbrain and spinal cord. Based on experimental estimates for neuron properties, population sizes, synapse strengths and connections, we show that: long-lasting, mutual, glutamatergic excitation between the neurons allows the network to sustain rhythmic pacemaker firing at swimming frequencies following brief synaptic excitation; activity persists but rhythm breaks down without electrical coupling; NMDA voltage-dependency doubles the range of synaptic feedback strengths generating sustained rhythm. The network can be switched on and off at short latency by brief synaptic excitation and inhibition. We demonstrate that a population of generic Hodgkin-Huxley type neurons coupled by glutamatergic excitatory feedback can generate sustained asynchronous firing switched on and off synaptically. We conclude that networks of neurons with NMDAR mediated feedback excitation can generate self-sustained activity following brief synaptic excitation. The frequency of activity is limited by the kinetics of the neuron membrane channels and can be stopped by brief inhibitory input. Network activity can be rhythmic at lower frequencies if the neurons are electrically coupled. Our key finding is that excitatory synaptic feedback within a population of neurons can produce switchable, stable, sustained firing without synaptic inhibition. PMID:26824331

Spontaneous Release Regulates Synaptic Scaling in the Embryonic Spinal Network In Vivo

PubMed Central

Garcia-Bereguiain, Miguel Angel; Gonzalez-Islas, Carlos; Lindsly, Casie

2016-01-01

Homeostatic plasticity mechanisms maintain cellular or network spiking activity within a physiologically functional range through compensatory changes in synaptic strength or intrinsic cellular excitability. Synaptic scaling is one form of homeostatic plasticity that is triggered after blockade of spiking or neurotransmission in which the strengths of all synaptic inputs to a cell are multiplicatively scaled upward or downward in a compensatory fashion. We have shown previously that synaptic upscaling could be triggered in chick embryo spinal motoneurons by complete blockade of spiking or GABAA receptor (GABAAR) activation for 2 d in vivo. Here, we alter GABAAR activation in a more physiologically relevant manner by chronically adjusting presynaptic GABA release in vivo using nicotinic modulators or an mGluR2 agonist. Manipulating GABAAR activation in this way triggered scaling in a mechanistically similar manner to scaling induced by complete blockade of GABAARs. Remarkably, we find that altering action-potential (AP)-independent spontaneous release was able to fully account for the observed bidirectional scaling, whereas dramatic changes in spiking activity associated with spontaneous network activity had little effect on quantal amplitude. The reliance of scaling on an AP-independent process challenges the plasticity's relatedness to spiking in the living embryonic spinal network. Our findings have implications for the trigger and function of synaptic scaling and suggest that spontaneous release functions to regulate synaptic strength homeostatically in vivo. SIGNIFICANCE STATEMENT Homeostatic synaptic scaling is thought to prevent inappropriate levels of spiking activity through compensatory adjustments in the strength of synaptic inputs. Therefore, it is thought that perturbations in spike rate trigger scaling. Here, we find that dramatic changes in spiking activity in the embryonic spinal cord have little effect on synaptic scaling; conversely, alterations in GABAA receptor activation due to action-potential-independent GABA vesicle release can trigger scaling. The findings suggest that scaling in the living embryonic spinal cord functions to maintain synaptic strength and challenge the view that scaling acts to regulate spiking activity homeostatically. Finally, the results indicate that fetal exposure to drugs that influence GABA spontaneous release, such as nicotine, could profoundly affect synaptic maturation. PMID:27383600

Increased Cell-Intrinsic Excitability Induces Synaptic Changes in New Neurons in the Adult Dentate Gyrus That Require Npas4

PubMed Central

Sim, Shuyin; Antolin, Salome; Lin, Chia-Wei; Lin, Ying-Xi

2013-01-01

Electrical activity regulates the manner in which neurons mature and form connections to each other. However, it remains unclear whether increased single-cell activity is sufficient to alter the development of synaptic connectivity of that neuron or whether a global increase in circuit activity is necessary. To address this question, we genetically increased neuronal excitability of in vivo individual adult-born neurons in the mouse dentate gyrus via expression of a voltage-gated bacterial sodium channel. We observed that increasing the excitability of new neurons in an otherwise unperturbed circuit leads to changes in both their input and axonal synapses. Furthermore, the activity-dependent transcription factor Npas4 is necessary for the changes in the input synapses of these neurons, but it is not involved in changes to their axonal synapses. Our results reveal that an increase in cell-intrinsic activity during maturation is sufficient to alter the synaptic connectivity of a neuron with the hippocampal circuit and that Npas4 is required for activity-dependent changes in input synapses. PMID:23637184

Spike threshold dynamics in spinal motoneurons during scratching and swimming.

PubMed

Grigonis, Ramunas; Alaburda, Aidas

2017-09-01

Action potential threshold can vary depending on firing history and synaptic inputs. We used an ex vivo carapace-spinal cord preparation from adult turtles to study spike threshold dynamics in motoneurons during two distinct types of functional motor behaviour - fictive scratching and fictive swimming. The threshold potential depolarizes by about 10 mV within each burst of spikes generated during scratch and swim network activity and recovers between bursts to a slightly depolarized level. Slow synaptic integration resulting in a wave of membrane potential depolarization is the factor influencing the threshold potential within firing bursts during motor behaviours. Depolarization of the threshold potential decreases the excitability of motoneurons and may provide a mechanism for stabilization of the response of a motoneuron to intense synaptic inputs to maintain the motor commands within an optimal range for muscle activation. During functional spinal neural network activity motoneurons receive intense synaptic input, and this could modulate the threshold for action potential generation, providing the ability to dynamically adjust the excitability and recruitment order for functional needs. In the present study we investigated the dynamics of action potential threshold during motor network activity. Intracellular recordings from spinal motoneurons in an ex vivo carapace-spinal cord preparation from adult turtles were performed during two distinct types of motor behaviour - fictive scratching and fictive swimming. We found that the threshold of the first spike in episodes of scratching and swimming was the lowest. The threshold potential depolarizes by about 10 mV within each burst of spikes generated during scratch and swim network activity and recovers between bursts to a slightly depolarized level. Depolarization of the threshold potential results in decreased excitability of motoneurons. Synaptic inputs do not modulate the threshold of the first action potential during episodes of scratching or of swimming. There is no correlation between changes in spike threshold and interspike intervals within bursts. Slow synaptic integration that results in a wave of membrane potential depolarization rather than fast synaptic events preceding each spike is the factor influencing the threshold potential within firing bursts during motor behaviours. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Selective Erasure of Distinct Forms of Long-Term Synaptic Plasticity Underlying Different Forms of Memory in the Same Postsynaptic Neuron.

PubMed

Hu, Jiangyuan; Ferguson, Larissa; Adler, Kerry; Farah, Carole A; Hastings, Margaret H; Sossin, Wayne S; Schacher, Samuel

2017-07-10

Generalization of fear responses to non-threatening stimuli is a feature of anxiety disorders. It has been challenging to target maladaptive generalized memories without affecting adaptive memories. Synapse-specific long-term plasticity underlying memory involves the targeting of plasticity-related proteins (PRPs) to activated synapses. If distinct tags and PRPs are used for different forms of plasticity, one could selectively remove distinct forms of memory. Using a stimulation paradigm in which associative long-term facilitation (LTF) occurs at one input and non-associative LTF at another input to the same postsynaptic neuron in an Aplysia sensorimotor preparation, we found that each form of LTF is reversed by inhibiting distinct isoforms of protein kinase M (PKM), putative PRPs, in the postsynaptic neuron. A dominant-negative (dn) atypical PKM selectively reversed associative LTF, while a dn classical PKM selectively reversed non-associative LTF. Although both PKMs are formed from calpain-mediated cleavage of protein kinase C (PKC) isoforms, each form of LTF is sensitive to a distinct dn calpain expressed in the postsynaptic neuron. Associative LTF is blocked by dn classical calpain, whereas non-associative LTF is blocked by dn small optic lobe (SOL) calpain. Interfering with a putative synaptic tag, the adaptor protein KIBRA, which protects the atypical PKM from degradation, selectively erases associative LTF. Thus, the activity of distinct PRPs and tags in a postsynaptic neuron contribute to the maintenance of different forms of synaptic plasticity at separate inputs, allowing for selective reversal of synaptic plasticity and providing a cellular basis for developing therapeutic strategies for selectively reversing maladaptive memories. Copyright © 2017 Elsevier Ltd. All rights reserved.

Different Compartments of Apical CA1 Dendrites Have Different Plasticity Thresholds for Expressing Synaptic Tagging and Capture

ERIC Educational Resources Information Center

Sajikumar, Sreedharan; Korte, Martin

2011-01-01

The consolidation process from short- to long-term memory depends on the type of stimulation received from a specific neuronal network and on the cooperativity and associativity between different synaptic inputs converging onto a specific neuron. We show here that the plasticity thresholds for inducing LTP are different in proximal and distal…

High-frequency stimulation of the temporoammonic pathway induces input-specific long-term potentiation in subicular bursting cells.

PubMed

Fidzinski, Pawel; Wawra, Matthias; Bartsch, Julia; Heinemann, Uwe; Behr, Joachim

2012-01-09

The subiculum (Sub) as a part of the hippocampal formation is thought to play a functional role in learning and memory. In addition to its major input from CA1 pyramidal cells, the subiculum receives input from the entorhinal cortex (EC) via the temporoammonic pathway. Thus far, synaptic plasticity in the subiculum was mainly investigated at CA1-Sub synapses. According to their spiking pattern, pyramidal cells in the subiculum were classified as bursting cells and non-bursting cells. In the present study, we demonstrate that subicular bursting cells show input-specific forms of long-term potentiation (LTP). At CA1-Sub synapses, bursting cells have been shown to express a presynaptic NMDA receptor-dependent LTP that depends on the activation of a cAMP-PKA cascade (Wozny et al., Journal of Physiology 2008). In contrast, at EC-Sub synapses the induction of LTP in bursting cells shows a high induction-threshold and relies on the activation of postsynaptic NMDA receptors, postsynaptic depolarization and postsynaptic Ca(2+) influx. Each form of LTP is input-specific and fails to induce heterosynaptic plasticity. Taken together, our data suggest that distinct, input-specific mechanisms govern high frequency-induced LTP at subicular bursting cells' synapses. Copyright © 2011 Elsevier B.V. All rights reserved.

Compensating Level-Dependent Frequency Representation in Auditory Cortex by Synaptic Integration of Corticocortical Input

PubMed Central

Happel, Max F. K.; Ohl, Frank W.

2017-01-01

Robust perception of auditory objects over a large range of sound intensities is a fundamental feature of the auditory system. However, firing characteristics of single neurons across the entire auditory system, like the frequency tuning, can change significantly with stimulus intensity. Physiological correlates of level-constancy of auditory representations hence should be manifested on the level of larger neuronal assemblies or population patterns. In this study we have investigated how information of frequency and sound level is integrated on the circuit-level in the primary auditory cortex (AI) of the Mongolian gerbil. We used a combination of pharmacological silencing of corticocortically relayed activity and laminar current source density (CSD) analysis. Our data demonstrate that with increasing stimulus intensities progressively lower frequencies lead to the maximal impulse response within cortical input layers at a given cortical site inherited from thalamocortical synaptic inputs. We further identified a temporally precise intercolumnar synaptic convergence of early thalamocortical and horizontal corticocortical inputs. Later tone-evoked activity in upper layers showed a preservation of broad tonotopic tuning across sound levels without shifts towards lower frequencies. Synaptic integration within corticocortical circuits may hence contribute to a level-robust representation of auditory information on a neuronal population level in the auditory cortex. PMID:28046062

Rapid Feedforward Inhibition and Asynchronous Excitation Regulate Granule Cell Activity in the Mammalian Main Olfactory Bulb

PubMed Central

Burton, Shawn D.

2015-01-01

Granule cell-mediated inhibition is critical to patterning principal neuron activity in the olfactory bulb, and perturbation of synaptic input to granule cells significantly alters olfactory-guided behavior. Despite the critical role of granule cells in olfaction, little is known about how sensory input recruits granule cells. Here, we combined whole-cell patch-clamp electrophysiology in acute mouse olfactory bulb slices with biophysical multicompartmental modeling to investigate the synaptic basis of granule cell recruitment. Physiological activation of sensory afferents within single glomeruli evoked diverse modes of granule cell activity, including subthreshold depolarization, spikelets, and suprathreshold responses with widely distributed spike latencies. The generation of these diverse activity modes depended, in part, on the asynchronous time course of synaptic excitation onto granule cells, which lasted several hundred milliseconds. In addition to asynchronous excitation, each granule cell also received synchronous feedforward inhibition. This inhibition targeted both proximal somatodendritic and distal apical dendritic domains of granule cells, was reliably recruited across sniff rhythms, and scaled in strength with excitation as more glomeruli were activated. Feedforward inhibition onto granule cells originated from deep short-axon cells, which responded to glomerular activation with highly reliable, short-latency firing consistent with tufted cell-mediated excitation. Simulations showed that feedforward inhibition interacts with asynchronous excitation to broaden granule cell spike latency distributions and significantly attenuates granule cell depolarization within local subcellular compartments. Collectively, our results thus identify feedforward inhibition onto granule cells as a core feature of olfactory bulb circuitry and establish asynchronous excitation and feedforward inhibition as critical regulators of granule cell activity. SIGNIFICANCE STATEMENT Inhibitory granule cells are involved critically in shaping odor-evoked principal neuron activity in the mammalian olfactory bulb, yet little is known about how sensory input activates granule cells. Here, we show that sensory input to the olfactory bulb evokes a barrage of asynchronous synaptic excitation and highly reliable, short-latency synaptic inhibition onto granule cells via a disynaptic feedforward inhibitory circuit involving deep short-axon cells. Feedforward inhibition attenuates local depolarization within granule cell dendritic branches, interacts with asynchronous excitation to suppress granule cell spike-timing precision, and scales in strength with excitation across different levels of sensory input to normalize granule cell firing rates. PMID:26490853

Extrasynaptic Glutamate Receptor Activation as Cellular Bases for Dynamic Range Compression in Pyramidal Neurons

PubMed Central

Oikonomou, Katerina D.; Short, Shaina M.; Rich, Matthew T.; Antic, Srdjan D.

2012-01-01

Repetitive synaptic stimulation overcomes the ability of astrocytic processes to clear glutamate from the extracellular space, allowing some dendritic segments to become submerged in a pool of glutamate, for a brief period of time. This dynamic arrangement activates extrasynaptic NMDA receptors located on dendritic shafts. We used voltage-sensitive and calcium-sensitive dyes to probe dendritic function in this glutamate-rich location. An excess of glutamate in the extrasynaptic space was achieved either by repetitive synaptic stimulation or by glutamate iontophoresis onto the dendrites of pyramidal neurons. Two successive activations of synaptic inputs produced a typical NMDA spike, whereas five successive synaptic inputs produced characteristic plateau potentials, reminiscent of cortical UP states. While NMDA spikes were coupled with brief calcium transients highly restricted to the glutamate input site, the dendritic plateau potentials were accompanied by calcium influx along the entire dendritic branch. Once initiated, the glutamate-mediated dendritic plateau potentials could not be interrupted by negative voltage pulses. Activation of extrasynaptic NMDA receptors in cellular compartments void of spines is sufficient to initiate and support plateau potentials. The only requirement for sustained depolarizing events is a surplus of free glutamate near a group of extrasynaptic receptors. Highly non-linear dendritic spikes (plateau potentials) are summed in a highly sublinear fashion at the soma, revealing the cellular bases of signal compression in cortical circuits. Extrasynaptic NMDA receptors provide pyramidal neurons with a function analogous to a dynamic range compression in audio engineering. They limit or reduce the volume of “loud sounds” (i.e., strong glutamatergic inputs) and amplify “quiet sounds” (i.e., glutamatergic inputs that barely cross the dendritic threshold for local spike initiation). Our data also explain why consecutive cortical UP states have uniform amplitudes in a given neuron. PMID:22934081

Illuminating the multifaceted roles of neurotransmission in shaping neuronal circuitry.

PubMed

Okawa, Haruhisa; Hoon, Mrinalini; Yoshimatsu, Takeshi; Della Santina, Luca; Wong, Rachel O L

2014-09-17

Across the nervous system, neurons form highly stereotypic patterns of synaptic connections that are designed to serve specific functions. Mature wiring patterns are often attained upon the refinement of early, less precise connectivity. Much work has led to the prevailing view that many developing circuits are sculpted by activity-dependent competition among converging afferents, which results in the elimination of unwanted synapses and the maintenance and strengthening of desired connections. Studies of the vertebrate retina, however, have recently revealed that activity can play a role in shaping developing circuits without engaging competition among converging inputs that differ in their activity levels. Such neurotransmission-mediated processes can produce stereotypic wiring patterns by promoting selective synapse formation rather than elimination. We discuss how the influence of transmission may also be limited by circuit design and further highlight the importance of transmission beyond development in maintaining wiring specificity and synaptic organization of neural circuits. Copyright © 2014 Elsevier Inc. All rights reserved.

The cerebellar Golgi cell and spatiotemporal organization of granular layer activity

PubMed Central

D'Angelo, Egidio; Solinas, Sergio; Mapelli, Jonathan; Gandolfi, Daniela; Mapelli, Lisa; Prestori, Francesca

2013-01-01

The cerebellar granular layer has been suggested to perform a complex spatiotemporal reconfiguration of incoming mossy fiber signals. Central to this role is the inhibitory action exerted by Golgi cells over granule cells: Golgi cells inhibit granule cells through both feedforward and feedback inhibitory loops and generate a broad lateral inhibition that extends beyond the afferent synaptic field. This characteristic connectivity has recently been investigated in great detail and been correlated with specific functional properties of these neurons. These include theta-frequency pacemaking, network entrainment into coherent oscillations and phase resetting. Important advances have also been made in terms of determining the membrane and synaptic properties of the neuron, and clarifying the mechanisms of activation by input bursts. Moreover, voltage sensitive dye imaging and multi-electrode array (MEA) recordings, combined with mathematical simulations based on realistic computational models, have improved our understanding of the impact of Golgi cell activity on granular layer circuit computations. These investigations have highlighted the critical role of Golgi cells in: generating dense clusters of granule cell activity organized in center-surround structures, implementing combinatorial operations on multiple mossy fiber inputs, regulating transmission gain, and cut-off frequency, controlling spike timing and burst transmission, and determining the sign, intensity and duration of long-term synaptic plasticity at the mossy fiber-granule cell relay. This review considers recent advances in the field, highlighting the functional implications of Golgi cells for granular layer network computation and indicating new challenges for cerebellar research. PMID:23730271

Cannabinoids suppress synaptic input to neurones of the rat dorsal motor nucleus of the vagus nerve

PubMed Central

Derbenev, Andrei V; Stuart, Thomas C; Smith, Bret N

2004-01-01

Cannabinoids bind central type 1 receptors (CB1R) and modify autonomic functions, including feeding and anti-emetic behaviours, when administered peripherally or into the dorsal vagal complex. Western blots and immunohistochemistry indicated the expression of CB1R in the rat dorsal vagal complex, and tissue polymerase chain reaction confirmed that CB1R message was made within the region. To identify a cellular substrate for the central autonomic effects of cannabinoids, whole-cell patch-clamp recordings were made in brainstem slices to determine the effects of CB1R activation on synaptic transmission to neurones of the dorsal motor nucleus of the vagus (DMV). A subset of these neurones was identified as gastric related after being labelled retrogradely from the stomach. The CB1R agonists WIN55,212-2 and anandamide decreased the frequency of spontaneous excitatory or inhibitory postsynaptic currents in a concentration-related fashion, an effect that persisted in the presence of tetrodotoxin. Paired pulse ratios of electrically evoked postsynaptic currents were also increased by WIN55,212-2. The effects of WIN55,212-2 were sensitive to the selective CB1R antagonist AM251. Cannabinoid agonist effects on synaptic input originating from neurones in the nucleus tractus solitarius (NTS) were determined by evoking activity in the NTS with local glutamate application. Excitatory and inhibitory synaptic inputs arising from the NTS were attenuated by WIN55,212-2. Our results indicate that cannabinoids inhibit transfer of synaptic information to the DMV, including that arising from the NTS, in part by acting at receptors located on presynaptic terminals contacting DMV neurones. Inhibition of synaptic input to DMV neurones is likely to contribute to the suppression of visceral motor responses by cannabinoids. PMID:15272041

Bidirectional synaptic structural plasticity after chronic cocaine administration occurs through Rap1 small GTPase signaling

PubMed Central

Cahill, Michael E.; Bagot, Rosemary C.; Gancarz, Amy M.; Walker, Deena M.; Sun, HaoSheng; Wang, Zi-Jun; Heller, Elizabeth A.; Feng, Jian; Kennedy, Pamela J.; Koo, Ja Wook; Cates, Hannah M.; Neve, Rachael L.; Shen, Li; Dietz, David M.

2016-01-01

Summary Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens, a primary brain reward region, are seen at early vs. late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local-synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce “metaplasticity” in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner. PMID:26844834

HCN1 channels in cerebellar Purkinje cells promote late stages of learning and constrain synaptic inhibition

PubMed Central

Rinaldi, Arianna; Defterali, Cagla; Mialot, Antoine; Garden, Derek L F; Beraneck, Mathieu; Nolan, Matthew F

2013-01-01

Neural computations rely on ion channels that modify neuronal responses to synaptic inputs. While single cell recordings suggest diverse and neurone type-specific computational functions for HCN1 channels, their behavioural roles in any single neurone type are not clear. Using a battery of behavioural assays, including analysis of motor learning in vestibulo-ocular reflex and rotarod tests, we find that deletion of HCN1 channels from cerebellar Purkinje cells selectively impairs late stages of motor learning. Because deletion of HCN1 modifies only a subset of behaviours involving Purkinje cells, we asked whether the channel also has functional specificity at a cellular level. We find that HCN1 channels in cerebellar Purkinje cells reduce the duration of inhibitory synaptic responses but, in the absence of membrane hyperpolarization, do not affect responses to excitatory inputs. Our results indicate that manipulation of subthreshold computation in a single neurone type causes specific modifications to behaviour. PMID:24000178

Comparison of the dynamics of neural interactions between current-based and conductance-based integrate-and-fire recurrent networks

PubMed Central

Cavallari, Stefano; Panzeri, Stefano; Mazzoni, Alberto

2014-01-01

Models of networks of Leaky Integrate-and-Fire (LIF) neurons are a widely used tool for theoretical investigations of brain function. These models have been used both with current- and conductance-based synapses. However, the differences in the dynamics expressed by these two approaches have been so far mainly studied at the single neuron level. To investigate how these synaptic models affect network activity, we compared the single neuron and neural population dynamics of conductance-based networks (COBNs) and current-based networks (CUBNs) of LIF neurons. These networks were endowed with sparse excitatory and inhibitory recurrent connections, and were tested in conditions including both low- and high-conductance states. We developed a novel procedure to obtain comparable networks by properly tuning the synaptic parameters not shared by the models. The so defined comparable networks displayed an excellent and robust match of first order statistics (average single neuron firing rates and average frequency spectrum of network activity). However, these comparable networks showed profound differences in the second order statistics of neural population interactions and in the modulation of these properties by external inputs. The correlation between inhibitory and excitatory synaptic currents and the cross-neuron correlation between synaptic inputs, membrane potentials and spike trains were stronger and more stimulus-modulated in the COBN. Because of these properties, the spike train correlation carried more information about the strength of the input in the COBN, although the firing rates were equally informative in both network models. Moreover, the network activity of COBN showed stronger synchronization in the gamma band, and spectral information about the input higher and spread over a broader range of frequencies. These results suggest that the second order statistics of network dynamics depend strongly on the choice of synaptic model. PMID:24634645

Comparison of the dynamics of neural interactions between current-based and conductance-based integrate-and-fire recurrent networks.

PubMed

Cavallari, Stefano; Panzeri, Stefano; Mazzoni, Alberto

2014-01-01

Models of networks of Leaky Integrate-and-Fire (LIF) neurons are a widely used tool for theoretical investigations of brain function. These models have been used both with current- and conductance-based synapses. However, the differences in the dynamics expressed by these two approaches have been so far mainly studied at the single neuron level. To investigate how these synaptic models affect network activity, we compared the single neuron and neural population dynamics of conductance-based networks (COBNs) and current-based networks (CUBNs) of LIF neurons. These networks were endowed with sparse excitatory and inhibitory recurrent connections, and were tested in conditions including both low- and high-conductance states. We developed a novel procedure to obtain comparable networks by properly tuning the synaptic parameters not shared by the models. The so defined comparable networks displayed an excellent and robust match of first order statistics (average single neuron firing rates and average frequency spectrum of network activity). However, these comparable networks showed profound differences in the second order statistics of neural population interactions and in the modulation of these properties by external inputs. The correlation between inhibitory and excitatory synaptic currents and the cross-neuron correlation between synaptic inputs, membrane potentials and spike trains were stronger and more stimulus-modulated in the COBN. Because of these properties, the spike train correlation carried more information about the strength of the input in the COBN, although the firing rates were equally informative in both network models. Moreover, the network activity of COBN showed stronger synchronization in the gamma band, and spectral information about the input higher and spread over a broader range of frequencies. These results suggest that the second order statistics of network dynamics depend strongly on the choice of synaptic model.

Active Dendrites and Differential Distribution of Calcium Channels Enable Functional Compartmentalization of Golgi Cells.

PubMed

Rudolph, Stephanie; Hull, Court; Regehr, Wade G

2015-11-25

Interneurons are essential to controlling excitability, timing, and synaptic integration in neuronal networks. Golgi cells (GoCs) serve these roles at the input layer of the cerebellar cortex by releasing GABA to inhibit granule cells (grcs). GoCs are excited by mossy fibers (MFs) and grcs and provide feedforward and feedback inhibition to grcs. Here we investigate two important aspects of GoC physiology: the properties of GoC dendrites and the role of calcium signaling in regulating GoC spontaneous activity. Although GoC dendrites are extensive, previous studies concluded they are devoid of voltage-gated ion channels. Hence, the current view holds that somatic voltage signals decay passively within GoC dendrites, and grc synapses onto distal dendrites are not amplified and are therefore ineffective at firing GoCs because of strong passive attenuation. Using whole-cell recording and calcium imaging in rat slices, we find that dendritic voltage-gated sodium channels allow somatic action potentials to activate voltage-gated calcium channels (VGCCs) along the entire dendritic length, with R-type and T-type VGCCs preferentially located distally. We show that R- and T-type VGCCs located in the dendrites can boost distal synaptic inputs and promote burst firing. Active dendrites are thus critical to the regulation of GoC activity, and consequently, to the processing of input to the cerebellar cortex. In contrast, we find that N-type channels are preferentially located near the soma, and control the frequency and pattern of spontaneous firing through their close association with calcium-activated potassium (KCa) channels. Thus, VGCC types are differentially distributed and serve specialized functions within GoCs. Interneurons are essential to neural processing because they modulate excitability, timing, and synaptic integration within circuits. At the input layer of the cerebellar cortex, a single type of interneuron, the Golgi cell (GoC), carries these functions. The extent of inhibition depends on both spontaneous activity of GoCs and the excitatory synaptic input they receive. In this study, we find that different types of calcium channels are differentially distributed, with dendritic calcium channels being activated by somatic activity, boosting synaptic inputs and enabling bursting, and somatic calcium cannels promoting regular firing. We therefore challenge the current view that GoC dendrites are passive and identify the mechanisms that contribute to GoCs regulating the flow of sensory information in the cerebellar cortex. Copyright © 2015 the authors 0270-6474/15/3515492-13$15.00/0.

Associative memory model with spontaneous neural activity

NASA Astrophysics Data System (ADS)

Kurikawa, Tomoki; Kaneko, Kunihiko

2012-05-01

We propose a novel associative memory model wherein the neural activity without an input (i.e., spontaneous activity) is modified by an input to generate a target response that is memorized for recall upon the same input. Suitable design of synaptic connections enables the model to memorize input/output (I/O) mappings equaling 70% of the total number of neurons, where the evoked activity distinguishes a target pattern from others. Spontaneous neural activity without an input shows chaotic dynamics but keeps some similarity with evoked activities, as reported in recent experimental studies.

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

PubMed Central

Letellier, Mathieu; Park, Yun Kyung; Chater, Thomas E.; Chipman, Peter H.; Gautam, Sunita Ghimire; Oshima-Takago, Tomoko; Goda, Yukiko

2016-01-01

Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-d-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca2+ channels. Intracellular infusion of NMDARs or Ca2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocyte-dependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites. PMID:27118849

Signal processing in local neuronal circuits based on activity-dependent noise and competition

NASA Astrophysics Data System (ADS)

Volman, Vladislav; Levine, Herbert

2009-09-01

We study the characteristics of weak signal detection by a recurrent neuronal network with plastic synaptic coupling. It is shown that in the presence of an asynchronous component in synaptic transmission, the network acquires selectivity with respect to the frequency of weak periodic stimuli. For nonperiodic frequency-modulated stimuli, the response is quantified by the mutual information between input (signal) and output (network's activity) and is optimized by synaptic depression. Introducing correlations in signal structure resulted in the decrease in input-output mutual information. Our results suggest that in neural systems with plastic connectivity, information is not merely carried passively by the signal; rather, the information content of the signal itself might determine the mode of its processing by a local neuronal circuit.

Entorhinal stellate cells show preferred spike phase-locking to theta inputs that is enhanced by correlations in synaptic activity

PubMed Central

Fernandez, Fernando R.; Malerba, Paola; Bressloff, Paul C.; White, John A.

2013-01-01

In active networks, excitatory and inhibitory synaptic inputs generate membrane voltage fluctuations that drive spike activity in a probabilistic manner. Despite this, some cells in vivo show a strong propensity to precisely lock to the local field potential and maintain a specific spike-phase relationship relative to other cells. In recordings from rat medial entorhinal cortical stellate cells, we measured spike phase-locking in response to sinusoidal “test” inputs in the presence of different forms of background membrane voltage fluctuations, generated via dynamic clamp. We find that stellate cells show strong and robust spike phase-locking to theta (4–12 Hz) inputs. This response occurs under a wide variety of background membrane voltage fluctuation conditions that include a substantial increase in overall membrane conductance. Furthermore, the IH current present in stellate cells is critical to the enhanced spike phase-locking response at theta. Finally, we show that correlations between inhibitory and excitatory conductance fluctuations, which can arise through feed-back and feed-forward inhibition, can substantially enhance the spike phase-locking response. The enhancement in locking is a result of a selective reduction in the size of low frequency membrane voltage fluctuations due to cancelation of inhibitory and excitatory current fluctuations with correlations. Hence, our results demonstrate that stellate cells have a strong preference for spike phase-locking to theta band inputs and that the absolute magnitude of locking to theta can be modulated by the properties of background membrane voltage fluctuations. PMID:23554484

Afferent specific role of NMDA receptors for the circuit integration of hippocampal neurogliaform cells.

PubMed

Chittajallu, R; Wester, J C; Craig, M T; Barksdale, E; Yuan, X Q; Akgül, G; Fang, C; Collins, D; Hunt, S; Pelkey, K A; McBain, C J

2017-07-28

Appropriate integration of GABAergic interneurons into nascent cortical circuits is critical for ensuring normal information processing within the brain. Network and cognitive deficits associated with neurological disorders, such as schizophrenia, that result from NMDA receptor-hypofunction have been mainly attributed to dysfunction of parvalbumin-expressing interneurons that paradoxically express low levels of synaptic NMDA receptors. Here, we reveal that throughout postnatal development, thalamic, and entorhinal cortical inputs onto hippocampal neurogliaform cells are characterized by a large NMDA receptor-mediated component. This NMDA receptor-signaling is prerequisite for developmental programs ultimately responsible for the appropriate long-range AMPAR-mediated recruitment of neurogliaform cells. In contrast, AMPAR-mediated input at local Schaffer-collateral synapses on neurogliaform cells remains normal following NMDA receptor-ablation. These afferent specific deficits potentially impact neurogliaform cell mediated inhibition within the hippocampus and our findings reveal circuit loci implicating this relatively understudied interneuron subtype in the etiology of neurodevelopmental disorders characterized by NMDA receptor-hypofunction.Proper brain function depends on the correct assembly of excitatory and inhibitory neurons into neural circuits. Here the authors show that during early postnatal development in mice, NMDAR signaling via activity of long-range synaptic inputs onto neurogliaform cells is required for their appropriate integration into the hippocampal circuitry.

Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex

PubMed Central

McGarry, Laura M.

2016-01-01

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. SIGNIFICANCE STATEMENT 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 with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. PMID:27605614

Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex.

PubMed

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 with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. Copyright © 2016 the authors 0270-6474/16/369391-16$15.00/0.

Decreased spinal synaptic inputs to phrenic motor neurons elicit localized inactivity-induced phrenic motor facilitation

PubMed Central

Streeter, K.A.; Baker-Herman, T.L.

2014-01-01

Phrenic motor neurons receive rhythmic synaptic inputs throughout life. Since even brief disruption in phrenic neural activity is detrimental to life, on-going neural activity may play a key role in shaping phrenic motor output. To test the hypothesis that spinal mechanisms sense and respond to reduced phrenic activity, anesthetized, ventilated rats received micro-injections of procaine in the C2 ventrolateral funiculus (VLF) to transiently (~30 min) block axon conduction in bulbospinal axons from medullary respiratory neurons that innervate one phrenic motor pool; during procaine injections, contralateral phrenic neural activity was maintained. Once axon conduction resumed, a prolonged increase in phrenic burst amplitude was observed in the ipsilateral phrenic nerve, demonstrating inactivity-induced phrenic motor facilitation (iPMF). Inhibition of tumor necrosis factor alpha (TNFα) and atypical PKC (aPKC) activity in spinal segments containing the phrenic motor nucleus impaired ipsilateral iPMF, suggesting a key role for spinal TNFα and aPKC in iPMF following unilateral axon conduction block. A small phrenic burst amplitude facilitation was also observed contralateral to axon conduction block, indicating crossed spinal phrenic motor facilitation (csPMF). csPMF was independent of spinal TNFα and aPKC. Ipsilateral iPMF and csPMF following unilateral withdrawal of phrenic synaptic inputs were associated with proportional increases in phrenic responses to chemoreceptor stimulation (hypercapnia), suggesting iPMF and csPMF increase phrenic dynamic range. These data suggest that local, spinal mechanisms sense and respond to reduced synaptic inputs to phrenic motor neurons. We hypothesize that iPMF and csPMF may represent compensatory mechanisms that assure adequate motor output is maintained in a physiological system in which prolonged inactivity ends life. PMID:24681155

Multi-layer network utilizing rewarded spike time dependent plasticity to learn a foraging task

PubMed Central

2017-01-01

Neural networks with a single plastic layer employing reward modulated spike time dependent plasticity (STDP) are capable of learning simple foraging tasks. Here we demonstrate advanced pattern discrimination and continuous learning in a network of spiking neurons with multiple plastic layers. The network utilized both reward modulated and non-reward modulated STDP and implemented multiple mechanisms for homeostatic regulation of synaptic efficacy, including heterosynaptic plasticity, gain control, output balancing, activity normalization of rewarded STDP and hard limits on synaptic strength. We found that addition of a hidden layer of neurons employing non-rewarded STDP created neurons that responded to the specific combinations of inputs and thus performed basic classification of the input patterns. When combined with a following layer of neurons implementing rewarded STDP, the network was able to learn, despite the absence of labeled training data, discrimination between rewarding patterns and the patterns designated as punishing. Synaptic noise allowed for trial-and-error learning that helped to identify the goal-oriented strategies which were effective in task solving. The study predicts a critical set of properties of the spiking neuronal network with STDP that was sufficient to solve a complex foraging task involving pattern classification and decision making. PMID:28961245

Nitric Oxide Is an Activity-Dependent Regulator of Target Neuron Intrinsic Excitability

PubMed Central

Steinert, Joern R.; Robinson, Susan W.; Tong, Huaxia; Haustein, Martin D.; Kopp-Scheinpflug, Cornelia; Forsythe, Ian D.

2011-01-01

Summary Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nitric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours. PMID:21791288

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

NASA Astrophysics Data System (ADS)

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.

Familiarity Detection is an Intrinsic Property of Cortical Microcircuits with Bidirectional Synaptic Plasticity.

PubMed

Zhang, Xiaoyu; Ju, Han; Penney, Trevor B; VanDongen, Antonius M J

2017-01-01

Humans instantly recognize a previously seen face as "familiar." To deepen our understanding of familiarity-novelty detection, we simulated biologically plausible neural network models of generic cortical microcircuits consisting of spiking neurons with random recurrent synaptic connections. NMDA receptor (NMDAR)-dependent synaptic plasticity was implemented to allow for unsupervised learning and bidirectional modifications. Network spiking activity evoked by sensory inputs consisting of face images altered synaptic efficacy, which resulted in the network responding more strongly to a previously seen face than a novel face. Network size determined how many faces could be accurately recognized as familiar. When the simulated model became sufficiently complex in structure, multiple familiarity traces could be retained in the same network by forming partially-overlapping subnetworks that differ slightly from each other, thereby resulting in a high storage capacity. Fisher's discriminant analysis was applied to identify critical neurons whose spiking activity predicted familiar input patterns. Intriguingly, as sensory exposure was prolonged, the selected critical neurons tended to appear at deeper layers of the network model, suggesting recruitment of additional circuits in the network for incremental information storage. We conclude that generic cortical microcircuits with bidirectional synaptic plasticity have an intrinsic ability to detect familiar inputs. This ability does not require a specialized wiring diagram or supervision and can therefore be expected to emerge naturally in developing cortical circuits.

Familiarity Detection is an Intrinsic Property of Cortical Microcircuits with Bidirectional Synaptic Plasticity

PubMed Central

2017-01-01

Abstract Humans instantly recognize a previously seen face as “familiar.” To deepen our understanding of familiarity-novelty detection, we simulated biologically plausible neural network models of generic cortical microcircuits consisting of spiking neurons with random recurrent synaptic connections. NMDA receptor (NMDAR)-dependent synaptic plasticity was implemented to allow for unsupervised learning and bidirectional modifications. Network spiking activity evoked by sensory inputs consisting of face images altered synaptic efficacy, which resulted in the network responding more strongly to a previously seen face than a novel face. Network size determined how many faces could be accurately recognized as familiar. When the simulated model became sufficiently complex in structure, multiple familiarity traces could be retained in the same network by forming partially-overlapping subnetworks that differ slightly from each other, thereby resulting in a high storage capacity. Fisher’s discriminant analysis was applied to identify critical neurons whose spiking activity predicted familiar input patterns. Intriguingly, as sensory exposure was prolonged, the selected critical neurons tended to appear at deeper layers of the network model, suggesting recruitment of additional circuits in the network for incremental information storage. We conclude that generic cortical microcircuits with bidirectional synaptic plasticity have an intrinsic ability to detect familiar inputs. This ability does not require a specialized wiring diagram or supervision and can therefore be expected to emerge naturally in developing cortical circuits. PMID:28534043

Electrical Advantages of Dendritic Spines

PubMed Central

Gulledge, Allan T.; Carnevale, Nicholas T.; Stuart, Greg J.

2012-01-01

Many neurons receive excitatory glutamatergic input almost exclusively onto dendritic spines. In the absence of spines, the amplitudes and kinetics of excitatory postsynaptic potentials (EPSPs) at the site of synaptic input are highly variable and depend on dendritic location. We hypothesized that dendritic spines standardize the local geometry at the site of synaptic input, thereby reducing location-dependent variability of local EPSP properties. We tested this hypothesis using computational models of simplified and morphologically realistic spiny neurons that allow direct comparison of EPSPs generated on spine heads with EPSPs generated on dendritic shafts at the same dendritic locations. In all morphologies tested, spines greatly reduced location-dependent variability of local EPSP amplitude and kinetics, while having minimal impact on EPSPs measured at the soma. Spine-dependent standardization of local EPSP properties persisted across a range of physiologically relevant spine neck resistances, and in models with variable neck resistances. By reducing the variability of local EPSPs, spines standardized synaptic activation of NMDA receptors and voltage-gated calcium channels. Furthermore, spines enhanced activation of NMDA receptors and facilitated the generation of NMDA spikes and axonal action potentials in response to synaptic input. Finally, we show that dynamic regulation of spine neck geometry can preserve local EPSP properties following plasticity-driven changes in synaptic strength, but is inefficient in modifying the amplitude of EPSPs in other cellular compartments. These observations suggest that one function of dendritic spines is to standardize local EPSP properties throughout the dendritic tree, thereby allowing neurons to use similar voltage-sensitive postsynaptic mechanisms at all dendritic locations. PMID:22532875

Input-output features of anatomically identified CA3 neurons during hippocampal sharp wave/ripple oscillation in vitro.

PubMed

Hájos, Norbert; Karlócai, Mária R; Németh, Beáta; Ulbert, István; Monyer, Hannah; Szabó, Gábor; Erdélyi, Ferenc; Freund, Tamás F; Gulyás, Attila I

2013-07-10

Hippocampal sharp waves and the associated ripple oscillations (SWRs) are implicated in memory processes. These network events emerge intrinsically in the CA3 network. To understand cellular interactions that generate SWRs, we detected first spiking activity followed by recording of synaptic currents in distinct types of anatomically identified CA3 neurons during SWRs that occurred spontaneously in mouse hippocampal slices. We observed that the vast majority of interneurons fired during SWRs, whereas only a small portion of pyramidal cells was found to spike. There were substantial differences in the firing behavior among interneuron groups; parvalbumin-expressing basket cells were one of the most active GABAergic cells during SWRs, whereas ivy cells were silent. Analysis of the synaptic currents during SWRs uncovered that the dominant synaptic input to the pyramidal cell was inhibitory, whereas spiking interneurons received larger synaptic excitation than inhibition. The discharge of all interneurons was primarily determined by the magnitude and the timing of synaptic excitation. Strikingly, we observed that the temporal structure of synaptic excitation and inhibition during SWRs significantly differed between parvalbumin-containing basket cells, axoaxonic cells, and type 1 cannabinoid receptor (CB1)-expressing basket cells, which might explain their distinct recruitment to these synchronous events. Our data support the hypothesis that the active current sources restricted to the stratum pyramidale during SWRs originate from the synaptic output of parvalbumin-expressing basket cells. Thus, in addition to gamma oscillation, these GABAergic cells play a central role in SWR generation.

Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation.

PubMed

Weng, Feng-Ju; Garcia, Rodrigo I; Lutzu, Stefano; Alviña, Karina; Zhang, Yuxiang; Dushko, Margaret; Ku, Taeyun; Zemoura, Khaled; Rich, David; Garcia-Dominguez, Dario; Hung, Matthew; Yelhekar, Tushar D; Sørensen, Andreas Toft; Xu, Weifeng; Chung, Kwanghun; Castillo, Pablo E; Lin, Yingxi

2018-03-07

Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report that the activity-dependent transcription factor Npas4 selectively regulates the structure and strength of MF-CA3 synapses by restricting the number of their functional synaptic contacts without affecting the other synaptic inputs onto CA3 pyramidal neurons. Using an activity-dependent reporter, we identified CA3 pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling the expression of the polo-like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation. Copyright © 2018 Elsevier Inc. All rights reserved.

Conserved neural circuit structure across Drosophila larval development revealed by comparative connectomics.

PubMed

Gerhard, Stephan; Andrade, Ingrid; Fetter, Richard D; Cardona, Albert; Schneider-Mizell, Casey M

2017-10-23

During postembryonic development, the nervous system must adapt to a growing body. How changes in neuronal structure and connectivity contribute to the maintenance of appropriate circuit function remains unclear. Previously , we measured the cellular neuroanatomy underlying synaptic connectivity in Drosophila (Schneider-Mizell et al., 2016). Here, we examined how neuronal morphology and connectivity change between first instar and third instar larval stages using serial section electron microscopy. We reconstructed nociceptive circuits in a larva of each stage and found consistent topographically arranged connectivity between identified neurons. Five-fold increases in each size, number of terminal dendritic branches, and total number of synaptic inputs were accompanied by cell type-specific connectivity changes that preserved the fraction of total synaptic input associated with each pre-synaptic partner. We propose that precise patterns of structural growth act to conserve the computational function of a circuit, for example determining the location of a dangerous stimulus.

Contribution of Ih to the relative facilitation of synaptic responses induced by carbachol in the entorhinal cortex during repetitive stimulation of the parasubiculum.

PubMed

Sparks, D W; Chapman, C A

2014-10-10

Neurons in the superficial layers of the entorhinal cortex provide the hippocampus with the majority of its cortical sensory input, and also receive the major output projection from the parasubiculum. This puts the parasubiculum in a position to modulate the activity of entorhinal neurons that project to the hippocampus. These brain areas receive cholinergic projections that are active during periods of theta- and gamma-frequency electroencephalographic (EEG) activity. The purpose of this study was to investigate how cholinergic receptor activation affects the strength of repetitive synaptic responses at these frequencies in the parasubiculo-entorhinal pathway and the cellular mechanisms involved. Whole-cell patch-clamp recordings of rat layer II medial entorhinal neurons were conducted using an acute slice preparation, and responses to 5-pulse trains of stimulation at theta- and gamma-frequency delivered to the parasubiculum were recorded. The cholinergic agonist carbachol (CCh) suppressed the amplitude of single synaptic responses, but also produced a relative facilitation of synaptic responses evoked during stimulation trains. The N-methyl-d-aspartate (NMDA) glutamate receptor blocker APV did not significantly reduce the relative facilitation effect. However, the hyperpolarization-activated cationic current (Ih) channel blocker ZD7288 mimicked the relative facilitation induced by CCh, suggesting that CCh-induced inhibition of Ih could produce the effect by increasing dendritic input resistance (Rin). Inward-rectifying and leak K(+) currents are known to interact with Ih to affect synaptic excitability. Application of the K(+) channel antagonist Ba(2+) depolarized neurons and enhanced temporal summation, but did not block further facilitation of train-evoked responses by ZD7288. The Ih-dependent facilitation of synaptic responses can therefore occur during reductions in inward-rectifying potassium current (IKir) associated with dendritic depolarization. Thus, in addition to cholinergic reductions in transmitter release that are known to facilitate train-evoked responses, these findings emphasize the role of inhibition of Ih in the integration of synaptic inputs within the entorhinal cortex during cholinergically-induced oscillatory states, likely due to enhanced summation of excitatory postsynaptic potentials (EPSPs) induced by increases in dendritic Rin. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Synaptology of physiologically identified ganglion cells in the cat retina: a comparison of retinal X- and Y-cells.

PubMed

Weber, A J; Stanford, L R

1994-05-15

It has long been known that a number of functionally different types of ganglion cells exist in the cat retina, and that each responds differently to visual stimulation. To determine whether the characteristic response properties of different retinal ganglion cell types might reflect differences in the number and distribution of their bipolar and amacrine cell inputs, we compared the percentages and distributions of the synaptic inputs from bipolar and amacrine cells to the entire dendritic arbors of physiologically characterized retinal X- and Y-cells. Sixty-two percent of the synaptic input to the Y-cell was from amacrine cell terminals, while the X-cells received approximately equal amounts of input from amacrine and bipolar cells. We found no significant difference in the distributions of bipolar or amacrine cell inputs to X- and Y-cells, or ON-center and OFF-center cells, either as a function of dendritic branch order or distance from the origin of the dendritic arbor. While, on the basis of these data, we cannot exclude the possibility that the difference in the proportion of bipolar and amacrine cell input contributes to the functional differences between X- and Y-cells, the magnitude of this difference, and the similarity in the distributions of the input from the two afferent cell types, suggest that mechanisms other than a simple predominance of input from amacrine or bipolar cells underlie the differences in their response properties. More likely, perhaps, is that the specific response features of X- and Y-cells originate in differences in the visual responses of the bipolar and amacrine cells that provide their input, or in the complex synaptic arrangements found among amacrine and bipolar cell terminals and the dendrites of specific types of retinal ganglion cells.

Modulation of synaptic transmission in the rabbit coeliac ganglia by gastric and duodenal mechanoreceptors.

PubMed

Mazet, B; Miolan, J P; Niel, J P; Julé, Y; Roman, C

1989-01-01

The involvement of duodenal and gastric mechanoreceptors in the modulation of synaptic transmission was investigated in a rabbit sympathetic prevertebral ganglion. The present study was performed in vitro on the coeliac plexus connected to the stomach and the duodenum. The electrical activity of ganglionic neurons was recorded using intracellular recording techniques. The patterns of synaptic activation of these ganglionic neurons in response to the activation of mechanoreceptors by gastric or duodenal distension were investigated. Although gastric or duodenal distension was unable to elicit any fast synaptic activity in ganglionic neurons, it produced either an inhibition or a facilitation of the fast nicotinic excitatory postsynaptic potentials elicited by stimulation of the thoracic splanchnic nerves. In addition, this distension triggered long-lasting (3-11 min) modifications in the electrical properties of the ganglionic neurons, i.e. slow depolarizations (6-18 mV) or slow hyperpolarizations (3-6 mV), which were sometimes associated with a decrease in the input membrane resistance. After cooling of the nerves connecting the coeliac ganglia to the stomach, the activation of gastric or duodenal mechanoreceptors was no longer able to modify the fast synaptic activation or the electrical properties of the ganglionic neurons. The results demonstrate that gastric and duodenal mechanoreceptors project onto neurons of the coeliac ganglia and change their excitability as well as the central inputs they receive. The long duration of these modifications suggests that gastric and duodenal mechanoreceptors can modulate the activity of the neurons of the coeliac ganglia.

Learning and retrieval behavior in recurrent neural networks with pre-synaptic dependent homeostatic plasticity

NASA Astrophysics Data System (ADS)

Mizusaki, Beatriz E. P.; Agnes, Everton J.; Erichsen, Rubem; Brunnet, Leonardo G.

2017-08-01

The plastic character of brain synapses is considered to be one of the foundations for the formation of memories. There are numerous kinds of such phenomenon currently described in the literature, but their role in the development of information pathways in neural networks with recurrent architectures is still not completely clear. In this paper we study the role of an activity-based process, called pre-synaptic dependent homeostatic scaling, in the organization of networks that yield precise-timed spiking patterns. It encodes spatio-temporal information in the synaptic weights as it associates a learned input with a specific response. We introduce a correlation measure to evaluate the precision of the spiking patterns and explore the effects of different inhibitory interactions and learning parameters. We find that large learning periods are important in order to improve the network learning capacity and discuss this ability in the presence of distinct inhibitory currents.

Processing Stages Underlying Word Recognition in the Anteroventral Temporal Lobe

PubMed Central

Halgren, Eric; Wang, Chunmao; Schomer, Donald L.; Knake, Susanne; Marinkovic, Ksenija; Wu, Julian; Ulbert, Istvan

2006-01-01

The anteroventral temporal lobe integrates visual, lexical, semantic and mnestic aspects of word-processing, through its reciprocal connections with the ventral visual stream, language areas, and the hippocampal formation. We used linear microelectrode arrays to probe population synaptic currents and neuronal firing in different cortical layers of the anteroventral temporal lobe, during semantic judgments with implicit priming, and overt word recognition. Since different extrinsic and associative inputs preferentially target different cortical layers, this method can help reveal the sequence and nature of local processing stages at a higher resolution than was previously possible. The initial response in inferotemporal and perirhinal cortices is a brief current sink beginning at ~120ms, and peaking at ~170ms. Localization of this initial sink to middle layers suggests that it represents feedforward input from lower visual areas, and simultaneously increased firing implies that it represents excitatory synaptic currents. Until ~800ms, the main focus of transmembrane current sinks alternates between middle and superficial layers, with the superficial focus becoming increasingly dominant after ~550ms. Since superficial layers are the target of local and feedback associative inputs, this suggests an alternation in predominant synaptic input between feedforward and feedback modes. Word repetition does not affect the initial perirhinal and inferotemporal middle layer sink, but does decrease later activity. Entorhinal activity begins later (~200ms), with greater apparent excitatory postsynaptic currents and multiunit activity in neocortically-projecting than hippocampal-projecting layers. In contrast to perirhinal and entorhinal responses, entorhinal responses are larger to repeated words during memory retrieval. These results identify a sequence of physiological activation, beginning with a sharp activation from lower level visual areas carrying specific information to middle layers. This is followed by feedback and associative interactions involving upper cortical layers, which are abbreviated to repeated words. Following bottom-up and associative stages, top-down recollective processes may be driven by entorhinal cortex. Word processing involves a systematic sequence of fast feedforward information transfer from visual areas to anteroventral temporal cortex, followed by prolonged interactions of this feedforward information with local associations, and feedback mnestic information from the medial temporal lobe. PMID:16488158

Dendritic mRNA targeting and translation.

PubMed

Kindler, Stefan; Kreienkamp, Hans-Jürgen

2012-01-01

Selective targeting of specific mRNAs into neuronal dendrites and their locally regulated translation at particular cell contact sites contribute to input-specific synaptic plasticity. Thus, individual synapses become decision-making units, which control gene expression in a spatially restricted and nucleus-independent manner. Dendritic targeting of mRNAs is achieved by active, microtubule-dependent transport. For this purpose, mRNAs are packaged into large ribonucleoprotein (RNP) particles containing an array of trans-acting RNA-binding proteins. These are attached to molecular motors, which move their RNP cargo into dendrites. A variety of proteins may be synthesized in dendrites, including signalling and scaffold proteins of the synapse and neurotransmitter receptors. In some cases, such as the alpha subunit of the calcium/calmodulin-dependent protein kinase II (αCaMKII) and the activity-regulated gene of 3.1 kb (Arg3.1, also referred to as activity-regulated cDNA, Arc), their local synthesis at synapses can modulate long-term changes in synaptic efficiency. Local dendritic translation is regulated by several signalling cascades including Akt/mTOR and Erk/MAP kinase pathways, which are triggered by synaptic activity. More recent findings show that miRNAs also play an important role in protein synthesis at synapses. Disruption of local translation control at synapses, as observed in the fragile X syndrome (FXS) and its mouse models and possibly also in autism spectrum disorders, interferes with cognitive abilities in mice and men.

Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination

PubMed Central

Sahel, Aurélia; Ortiz, Fernando C.; Kerninon, Christophe; Maldonado, Paloma P.; Angulo, María Cecilia; Nait-Oumesmar, Brahim

2015-01-01

Oligodendrocyte precursor cells (OPCs) are a major source of remyelinating oligodendrocytes in demyelinating diseases such as Multiple Sclerosis (MS). While OPCs are innervated by unmyelinated axons in the normal brain, the fate of such synaptic contacts after demyelination is still unclear. By combining electrophysiology and immunostainings in different transgenic mice expressing fluorescent reporters, we studied the synaptic innervation of OPCs in the model of lysolecithin (LPC)-induced demyelination of corpus callosum. Synaptic innervation of reactivated OPCs in the lesion was revealed by the presence of AMPA receptor-mediated synaptic currents, VGluT1+ axon-OPC contacts in 3D confocal reconstructions and synaptic junctions observed by electron microscopy. Moreover, 3D confocal reconstructions of VGluT1 and NG2 immunolabeling showed the existence of glutamatergic axon-OPC contacts in post-mortem MS lesions. Interestingly, patch-clamp recordings in LPC-induced lesions demonstrated a drastic decrease in spontaneous synaptic activity of OPCs early after demyelination that was not caused by an impaired conduction of compound action potentials. A reduction in synaptic connectivity was confirmed by the lack of VGluT1+ axon-OPC contacts in virtually all rapidly proliferating OPCs stained with EdU (50-ethynyl-20-deoxyuridine). At the end of the massive proliferation phase in lesions, the proportion of innervated OPCs rapidly recovers, although the frequency of spontaneous synaptic currents did not reach control levels. In conclusion, our results demonstrate that newly-generated OPCs do not receive synaptic inputs during their active proliferation after demyelination, but gain synapses during the remyelination process. Hence, glutamatergic synaptic inputs may contribute to inhibit OPC proliferation and might have a physiopathological relevance in demyelinating disorders. PMID:25852473

Location-dependent excitatory synaptic interactions in pyramidal neuron dendrites.

PubMed

Behabadi, Bardia F; Polsky, Alon; Jadi, Monika; Schiller, Jackie; Mel, Bartlett W

2012-01-01

Neocortical pyramidal neurons (PNs) receive thousands of excitatory synaptic contacts on their basal dendrites. Some act as classical driver inputs while others are thought to modulate PN responses based on sensory or behavioral context, but the biophysical mechanisms that mediate classical-contextual interactions in these dendrites remain poorly understood. We hypothesized that if two excitatory pathways bias their synaptic projections towards proximal vs. distal ends of the basal branches, the very different local spike thresholds and attenuation factors for inputs near and far from the soma might provide the basis for a classical-contextual functional asymmetry. Supporting this possibility, we found both in compartmental models and electrophysiological recordings in brain slices that the responses of basal dendrites to spatially separated inputs are indeed strongly asymmetric. Distal excitation lowers the local spike threshold for more proximal inputs, while having little effect on peak responses at the soma. In contrast, proximal excitation lowers the threshold, but also substantially increases the gain of distally-driven responses. Our findings support the view that PN basal dendrites possess significant analog computing capabilities, and suggest that the diverse forms of nonlinear response modulation seen in the neocortex, including uni-modal, cross-modal, and attentional effects, could depend in part on pathway-specific biases in the spatial distribution of excitatory synaptic contacts onto PN basal dendritic arbors.

Distinct Roles of NMDAR and mGluR5 in Light Exposure Reversal of Feedforward Synaptic Strength in V1 of Juvenile Mice after Binocular Vision Deprivation.

PubMed

Tie, Xiaoxiu; Li, Shuo; Feng, Yilin; Lai, Biqin; Liu, Sheng; Jiang, Bin

2018-06-01

In the visual cortex, sensory deprivation causes global augmentation of the amplitude of AMPA receptor-mediated miniature EPSCs in layer 2/3 pyramidal cells and enhancement of NMDA receptor-dependent long-term potentiation (LTP) in cells activated in layer 4, effects that are both rapidly reversed by light exposure. Layer 2/3 pyramidal cells receive both feedforward input from layer 4 and intra-cortical lateral input from the same layer, LTP is mainly induced by the former input. Whether feedforward excitatory synaptic strength is affected by visual deprivation and light exposure, how this synaptic strength correlates with the magnitude of LTP in this pathway, and the underlying mechanism have not been explored. Here, we showed that in juvenile mice, both dark rearing and dark exposure reduced the feedforward excitatory synaptic strength, and the effects can be reversed completely by 10-12 h and 6-8 h light exposure, respectively. However, inhibition of NMDA receptors by CPP or mGluR5 by MPEP, prevented the effect of light exposure on the mice reared in the dark from birth, while only inhibition of NMDAR prevented the effect of light exposure on dark-exposed mice. These results suggested that the activation of both NMDAR and mGluR5 are essential in the light exposure reversal of feedforward excitatory synaptic strength in the dark reared mice from birth; while in the dark exposed mice, only activation of NMDAR is required. Copyright © 2018. Published by Elsevier Ltd.

Estimates of the location of L-type Ca2+ channels in motoneurons of different sizes: a computational study.

PubMed

Grande, Giovanbattista; Bui, Tuan V; Rose, P Ken

2007-06-01

In the presence of monoamines, L-type Ca(2+) channels on the dendrites of motoneurons contribute to persistent inward currents (PICs) that can amplify synaptic inputs two- to sixfold. However, the exact location of the L-type Ca(2+) channels is controversial, and the importance of the location as a means of regulating the input-output properties of motoneurons is unknown. In this study, we used a computational strategy developed previously to estimate the dendritic location of the L-type Ca(2+) channels and test the hypothesis that the location of L-type Ca(2+) channels varies as a function of motoneuron size. Compartmental models were constructed based on dendritic trees of five motoneurons that ranged in size from small to large. These models were constrained by known differences in PIC activation reported for low- and high-conductance motoneurons and the relationship between somatic PIC threshold and the presence or absence of tonic excitatory or inhibitory synaptic activity. Our simulations suggest that L-type Ca(2+) channels are concentrated in hotspots whose distance from the soma increases with the size of the dendritic tree. Moving the hotspots away from these sites (e.g., using the hotspot locations from large motoneurons on intermediate-sized motoneurons) fails to replicate the shifts in PIC threshold that occur experimentally during tonic excitatory or inhibitory synaptic activity. In models equipped with a size-dependent distribution of L-type Ca(2+) channels, the amplification of synaptic current by PICs depends on motoneuron size and the location of the synaptic input on the dendritic tree.

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

PubMed Central

2017-01-01

Abstract 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. PMID:29085896

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

PubMed

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.

Synaptic input correlations leading to membrane potential decorrelation of spontaneous activity in cortex.

PubMed

Graupner, Michael; Reyes, Alex D

2013-09-18

Correlations in the spiking activity of neurons have been found in many regions of the cortex under multiple experimental conditions and are postulated to have important consequences for neural population coding. While there is a large body of extracellular data reporting correlations of various strengths, the subthreshold events underlying the origin and magnitude of signal-independent correlations (called noise or spike count correlations) are unknown. Here we investigate, using intracellular recordings, how synaptic input correlations from shared presynaptic neurons translate into membrane potential and spike-output correlations. Using a pharmacologically activated thalamocortical slice preparation, we perform simultaneous recordings from pairs of layer IV neurons in the auditory cortex of mice and measure synaptic potentials/currents, membrane potentials, and spiking outputs. We calculate cross-correlations between excitatory and inhibitory inputs to investigate correlations emerging from the network. We furthermore evaluate membrane potential correlations near resting potential to study how excitation and inhibition combine and affect spike-output correlations. We demonstrate directly that excitation is correlated with inhibition thereby partially canceling each other and resulting in weak membrane potential and spiking correlations between neurons. Our data suggest that cortical networks are set up to partially cancel correlations emerging from the connections between neurons. This active decorrelation is achieved because excitation and inhibition closely track each other. Our results suggest that the numerous shared presynaptic inputs do not automatically lead to increased spiking correlations.

Learning rules for spike timing-dependent plasticity depend on dendritic synapse location.

PubMed

Letzkus, Johannes J; Kampa, Björn M; Stuart, Greg J

2006-10-11

Previous studies focusing on the temporal rules governing changes in synaptic strength during spike timing-dependent synaptic plasticity (STDP) have paid little attention to the fact that synaptic inputs are distributed across complex dendritic trees. During STDP, propagation of action potentials (APs) back to the site of synaptic input is thought to trigger plasticity. However, in pyramidal neurons, backpropagation of single APs is decremental, whereas high-frequency bursts lead to generation of distal dendritic calcium spikes. This raises the question whether STDP learning rules depend on synapse location and firing mode. Here, we investigate this issue at synapses between layer 2/3 and layer 5 pyramidal neurons in somatosensory cortex. We find that low-frequency pairing of single APs at positive times leads to a distance-dependent shift to long-term depression (LTD) at distal inputs. At proximal sites, this LTD could be converted to long-term potentiation (LTP) by dendritic depolarizations suprathreshold for BAC-firing or by high-frequency AP bursts. During AP bursts, we observed a progressive, distance-dependent shift in the timing requirements for induction of LTP and LTD, such that distal synapses display novel timing rules: they potentiate when inputs are activated after burst onset (negative timing) but depress when activated before burst onset (positive timing). These findings could be explained by distance-dependent differences in the underlying dendritic voltage waveforms driving NMDA receptor activation during STDP induction. Our results suggest that synapse location within the dendritic tree is a crucial determinant of STDP, and that synapses undergo plasticity according to local rather than global learning rules.

Synaptic activation of putative sensory neurons by hexamethonium-sensitive nerve pathways in mouse colon.

PubMed

Hibberd, Timothy J; Travis, Lee; Wiklendt, Lukasz; Costa, Marcello; Brookes, Simon J H; Hu, Hongzhen; Keating, Damien J; Spencer, Nick J

2018-01-01

The gastrointestinal tract contains its own independent population of sensory neurons within the gut wall. These sensory neurons have been referred to as intrinsic primary afferent neurons (IPANs) and can be identified by immunoreactivity to calcitonin gene-related peptide (CGRP) in mice. A common feature of IPANs is a paucity of fast synaptic inputs observed during sharp microelectrode recordings. Whether this is observed using different recording techniques is of particular interest for understanding the physiology of these neurons and neural circuit modeling. Here, we imaged spontaneous and evoked activation of myenteric neurons in isolated whole preparations of mouse colon and correlated recordings with CGRP and nitric oxide synthase (NOS) immunoreactivity, post hoc. Calcium indicator fluo 4 was used for this purpose. Calcium responses were recorded in nerve cell bodies located 5-10 mm oral to transmural electrical nerve stimuli. A total of 618 recorded neurons were classified for CGRP or NOS immunoreactivity. Aboral electrical stimulation evoked short-latency calcium transients in the majority of myenteric neurons, including ~90% of CGRP-immunoreactive Dogiel type II neurons. Activation of Dogiel type II neurons had a time course consistent with fast synaptic transmission and was always abolished by hexamethonium (300 μM) and by low-calcium Krebs solution. The nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (during synaptic blockade) directly activated Dogiel type II neurons. The present study suggests that murine colonic Dogiel type II neurons receive prominent fast excitatory synaptic inputs from hexamethonium-sensitive neural pathways. NEW & NOTEWORTHY Myenteric neurons in isolated mouse colon were recorded using calcium imaging and then neurochemically defined. Short-latency calcium transients were detected in >90% of calcitonin gene-related peptide-immunoreactive neurons to electrical stimulation of hexamethonium-sensitive pathways. Putative sensory Dogiel type II calcitonin gene-related peptide-immunoreactive myenteric neurons may receive widespread fast synaptic inputs in mouse colon.

LIMITED RECOVERY OF PINEAL FUNCTION AFTER REGENERATION OF PREGANGLIONIC SYMPATHETIC AXONS: EVIDENCE FOR LOSS OF GANGLIONIC SYNAPTIC SPECIFICITY

PubMed Central

Lingappa, Jaisri R.; Zigmond, Richard E.

2013-01-01

The cervical sympathetic trunks (CST) contain axons of preganglionic neurons that innervate the superior cervical ganglia (SCG). Since, regeneration of CST fibers can be extensive and can reestablish certain specific patterns of SCG connections, restoration of end organ function would be expected. This expectation was examined with respect to the pineal gland, an organ innervated by the two SCG. The activity of pineal serotonin N-acetyltransferase (NAT) exhibits a large circadian rhythm, with activity high at night, which is dependent on the gland’s sympathetic input. Thirty six hours after the CST were crushed bilaterally, nocturnal NAT was decreased by 99%. Three months later, enzyme activity had recovered only to 15% of control values, a recovery dependent on regeneration of CST fibers. Nevertheless, a small day-night rhythm was present in lesioned animals. Neither the density of the gland’s adrenergic innervation nor the ability of an adrenergic agonist to stimulate NAT activity was reduced in rats with regenerated CST. In addition, stimulation of the regenerated CST at a variety of frequencies was at least as effective in increasing NAT activity as seen with control nerves. These data suggest that the failure of pineal function to recover is not due to a quantitative deficit in the extent of reinnervation or in synaptic efficacy. Rather, we suggest that there is some loss of specificity in the synaptic connections made in the SCG during reinnervation, resulting in a loss of the central neuronal information necessary for directing a normal NAT rhythm and thus normal pineal function. PMID:23486957

Calcium Input Frequency, Duration and Amplitude Differentially Modulate the Relative Activation of Calcineurin and CaMKII

PubMed Central

Li, Lu; Stefan, Melanie I.; Le Novère, Nicolas

2012-01-01

NMDA receptor dependent long-term potentiation (LTP) and long-term depression (LTD) are two prominent forms of synaptic plasticity, both of which are triggered by post-synaptic calcium elevation. To understand how calcium selectively stimulates two opposing processes, we developed a detailed computational model and performed simulations with different calcium input frequencies, amplitudes, and durations. We show that with a total amount of calcium ions kept constant, high frequencies of calcium pulses stimulate calmodulin more efficiently. Calcium input activates both calcineurin and Ca2+/calmodulin-dependent protein kinase II (CaMKII) at all frequencies, but increased frequencies shift the relative activation from calcineurin to CaMKII. Irrespective of amplitude and duration of the inputs, the total amount of calcium ions injected adjusts the sensitivity of the system to calcium input frequencies. At a given frequency, the quantity of CaMKII activated is proportional to the total amount of calcium. Thus, an input of a small amount of calcium at high frequencies can induce the same activation of CaMKII as a larger amount, at lower frequencies. Finally, the extent of activation of CaMKII signals with high calcium frequency is further controlled by other factors, including the availability of calmodulin, and by the potency of phosphatase inhibitors. PMID:22962589

Orientation selectivity and the functional clustering of synaptic inputs in primary visual cortex

PubMed Central

Wilson, Daniel E.; Whitney, David E.; Scholl, Benjamin; Fitzpatrick, David

2016-01-01

The majority of neurons in primary visual cortex are tuned for stimulus orientation, but the factors that account for the range of orientation selectivities exhibited by cortical neurons remain unclear. To address this issue, we used in vivo 2-photon calcium imaging to characterize the orientation tuning and spatial arrangement of synaptic inputs to the dendritic spines of individual pyramidal neurons in layer 2/3 of ferret visual cortex. The summed synaptic input to individual neurons reliably predicted the neuron’s orientation preference, but did not account for differences in orientation selectivity among neurons. These differences reflected a robust input-output nonlinearity that could not be explained by spike threshold alone, and was strongly correlated with the spatial clustering of co-tuned synaptic inputs within the dendritic field. Dendritic branches with more co-tuned synaptic clusters exhibited greater rates of local dendritic calcium events supporting a prominent role for functional clustering of synaptic inputs in dendritic nonlinearities that shape orientation selectivity. PMID:27294510

E-I balance emerges naturally from continuous Hebbian learning in autonomous neural networks.

PubMed

Trapp, Philip; Echeveste, Rodrigo; Gros, Claudius

2018-06-12

Spontaneous brain activity is characterized in part by a balanced asynchronous chaotic state. Cortical recordings show that excitatory (E) and inhibitory (I) drivings in the E-I balanced state are substantially larger than the overall input. We show that such a state arises naturally in fully adapting networks which are deterministic, autonomously active and not subject to stochastic external or internal drivings. Temporary imbalances between excitatory and inhibitory inputs lead to large but short-lived activity bursts that stabilize irregular dynamics. We simulate autonomous networks of rate-encoding neurons for which all synaptic weights are plastic and subject to a Hebbian plasticity rule, the flux rule, that can be derived from the stationarity principle of statistical learning. Moreover, the average firing rate is regulated individually via a standard homeostatic adaption of the bias of each neuron's input-output non-linear function. Additionally, networks with and without short-term plasticity are considered. E-I balance may arise only when the mean excitatory and inhibitory weights are themselves balanced, modulo the overall activity level. We show that synaptic weight balance, which has been considered hitherto as given, naturally arises in autonomous neural networks when the here considered self-limiting Hebbian synaptic plasticity rule is continuously active.

Role of presynaptic inputs to proprioceptive afferents in tuning sensorimotor pathways of an insect joint control network.

PubMed

Sauer, A E; Büschges, A; Stein, W

1997-04-01

The femur-tibia (FT) joint of insects is governed by a neuronal network that controls activity in tibial motoneurons by processing sensory information about tibial position and movement provided by afferents of the femoral chordotonal organ (fCO). We show that central arborizations of fCO afferents receive presynaptic depolarizing synaptic inputs. With an average resting potential of -71.9 +/- 3.72 mV (n = 10), the reversal potential of these potentials is on average -62.8 +/- 2.3 mV (n = 5). These synaptic potentials occur either spontaneously or are related to movements at the fCO. They are thus induced by signals from other fCO afferents. Therefore, the synaptic inputs to fCO afferents are specific and depend on the sensitivity of the individual afferent affected. These potentials reduce the amplitude of concurrent afferent action potentials. Bath application of picrotoxin, a noncompetitive blocker of chloride ion channels, blocks these potentials, which indicates that they are mediated by chloride ions. From these results, it is concluded that these are inhibitory synaptic potentials generated in the central terminals of fCO afferents. Pharmacologic removal of these potentials affects the tuning of the complete FT control system. Following removal, the dependence of the FT control loop on the tibia position increases relative to the dependency on the velocity of tibia movements. This is due to changes in the relative weighting of the position and velocity signals in the parallel interneuronal pathways from the fCO onto tibial motoneurons. Consequently, the FT joint is no longer able to perform twig mimesis (i.e., catalepsy), which is known to rely on a low position compared to the high-velocity dependency of the FT control system.

Hippocampal 5-HT Input Regulates Memory Formation and Schaffer Collateral Excitation.

PubMed

Teixeira, Catia M; Rosen, Zev B; Suri, Deepika; Sun, Qian; Hersh, Marc; Sargin, Derya; Dincheva, Iva; Morgan, Ashlea A; Spivack, Stephen; Krok, Anne C; Hirschfeld-Stoler, Tessa; Lambe, Evelyn K; Siegelbaum, Steven A; Ansorge, Mark S

2018-06-06

The efficacy and duration of memory storage is regulated by neuromodulatory transmitter actions. While the modulatory transmitter serotonin (5-HT) plays an important role in implicit forms of memory in the invertebrate Aplysia, its function in explicit memory mediated by the mammalian hippocampus is less clear. Specifically, the consequences elicited by the spatio-temporal gradient of endogenous 5-HT release are not known. Here we applied optogenetic techniques in mice to gain insight into this fundamental biological process. We find that activation of serotonergic terminals in the hippocampal CA1 region both potentiates excitatory transmission at CA3-to-CA1 synapses and enhances spatial memory. Conversely, optogenetic silencing of CA1 5-HT terminals inhibits spatial memory. We furthermore find that synaptic potentiation is mediated by 5-HT4 receptors and that systemic modulation of 5-HT4 receptor function can bidirectionally impact memory formation. Collectively, these data reveal powerful modulatory influence of serotonergic synaptic input on hippocampal function and memory formation. Copyright © 2018 Elsevier Inc. All rights reserved.

Functional Organization of Cutaneous and Muscle Afferent Synapses onto Immature Spinal Lamina I Projection Neurons

PubMed Central

Li, Jie

2017-01-01

It is well established that sensory afferents innervating muscle are more effective at inducing hyperexcitability within spinal cord circuits compared with skin afferents, which likely contributes to the higher prevalence of chronic musculoskeletal pain compared with pain of cutaneous origin. However, the mechanisms underlying these differences in central nociceptive signaling remain incompletely understood, as nothing is known about how superficial dorsal horn neurons process sensory input from muscle versus skin at the synaptic level. Using a novel ex vivo spinal cord preparation, here we identify the functional organization of muscle and cutaneous afferent synapses onto immature rat lamina I spino-parabrachial neurons, which serve as a major source of nociceptive transmission to the brain. Stimulation of the gastrocnemius nerve and sural nerve revealed significant convergence of muscle and cutaneous afferent synaptic input onto individual projection neurons. Muscle afferents displayed a higher probability of glutamate release, although short-term synaptic plasticity was similar between the groups. Importantly, muscle afferent synapses exhibited greater relative expression of Ca2+-permeable AMPARs compared with cutaneous inputs. In addition, the prevalence and magnitude of spike timing-dependent long-term potentiation were significantly higher at muscle afferent synapses, where it required Ca2+-permeable AMPAR activation. Collectively, these results provide the first evidence for afferent-specific properties of glutamatergic transmission within the superficial dorsal horn. A larger propensity for activity-dependent strengthening at muscle afferent synapses onto developing spinal projection neurons could contribute to the enhanced ability of these sensory inputs to sensitize central nociceptive networks and thereby evoke persistent pain in children following injury. SIGNIFICANCE STATEMENT The neurobiological mechanisms underlying the high prevalence of chronic musculoskeletal pain remain poorly understood, in part because little is known about why sensory neurons innervating muscle appear more capable of sensitizing nociceptive pathways in the CNS compared with skin afferents. The present study identifies, for the first time, the functional properties of muscle and cutaneous afferent synapses onto immature lamina I projection neurons, which convey nociceptive information to the brain. Despite many similarities, an enhanced relative expression of Ca2+-permeable AMPA receptors at muscle afferent synapses drives greater LTP following repetitive stimulation. A preferential ability of the dorsal horn synaptic network to amplify nociceptive input arising from muscle is predicted to favor the generation of musculoskeletal pain following injury. PMID:28069928

Dendritic nonlinearities are tuned for efficient spike-based computations in cortical circuits.

PubMed

Ujfalussy, Balázs B; Makara, Judit K; Branco, Tiago; Lengyel, Máté

2015-12-24

Cortical neurons integrate thousands of synaptic inputs in their dendrites in highly nonlinear ways. It is unknown how these dendritic nonlinearities in individual cells contribute to computations at the level of neural circuits. Here, we show that dendritic nonlinearities are critical for the efficient integration of synaptic inputs in circuits performing analog computations with spiking neurons. We developed a theory that formalizes how a neuron's dendritic nonlinearity that is optimal for integrating synaptic inputs depends on the statistics of its presynaptic activity patterns. Based on their in vivo preynaptic population statistics (firing rates, membrane potential fluctuations, and correlations due to ensemble dynamics), our theory accurately predicted the responses of two different types of cortical pyramidal cells to patterned stimulation by two-photon glutamate uncaging. These results reveal a new computational principle underlying dendritic integration in cortical neurons by suggesting a functional link between cellular and systems--level properties of cortical circuits.

Morphological properties of vestibulospinal neurons in primates

NASA Technical Reports Server (NTRS)

Boyle, Richard; Johanson, Curt

2003-01-01

The lateral and medial vestibulospinal tracts constitute the major descending pathways controlling extensor musculature of the body. We examined the axon morphology and synaptic input patterns and targets in the cervical spinal segments from these tract cells using intracellular recording and biocytin labeling in the squirrel monkey. Lumbosacral projecting cells represent a private, and mostly rapid, communication pathway between the dorsal Deiters' nucleus and the motor circuits controlling the lower limbs and tail. The cervical projecting cells provide both redundant and variable synaptic input to spinal cell groups, suggesting both general and specific control of the head and neck reflexes.

Learning of Precise Spike Times with Homeostatic Membrane Potential Dependent Synaptic Plasticity.

PubMed

Albers, Christian; Westkott, Maren; Pawelzik, Klaus

2016-01-01

Precise spatio-temporal patterns of neuronal action potentials underly e.g. sensory representations and control of muscle activities. However, it is not known how the synaptic efficacies in the neuronal networks of the brain adapt such that they can reliably generate spikes at specific points in time. Existing activity-dependent plasticity rules like Spike-Timing-Dependent Plasticity are agnostic to the goal of learning spike times. On the other hand, the existing formal and supervised learning algorithms perform a temporally precise comparison of projected activity with the target, but there is no known biologically plausible implementation of this comparison. Here, we propose a simple and local unsupervised synaptic plasticity mechanism that is derived from the requirement of a balanced membrane potential. Since the relevant signal for synaptic change is the postsynaptic voltage rather than spike times, we call the plasticity rule Membrane Potential Dependent Plasticity (MPDP). Combining our plasticity mechanism with spike after-hyperpolarization causes a sensitivity of synaptic change to pre- and postsynaptic spike times which can reproduce Hebbian spike timing dependent plasticity for inhibitory synapses as was found in experiments. In addition, the sensitivity of MPDP to the time course of the voltage when generating a spike allows MPDP to distinguish between weak (spurious) and strong (teacher) spikes, which therefore provides a neuronal basis for the comparison of actual and target activity. For spatio-temporal input spike patterns our conceptually simple plasticity rule achieves a surprisingly high storage capacity for spike associations. The sensitivity of the MPDP to the subthreshold membrane potential during training allows robust memory retrieval after learning even in the presence of activity corrupted by noise. We propose that MPDP represents a biophysically plausible mechanism to learn temporal target activity patterns.

Learning of Precise Spike Times with Homeostatic Membrane Potential Dependent Synaptic Plasticity

PubMed Central

Albers, Christian; Westkott, Maren; Pawelzik, Klaus

2016-01-01

Precise spatio-temporal patterns of neuronal action potentials underly e.g. sensory representations and control of muscle activities. However, it is not known how the synaptic efficacies in the neuronal networks of the brain adapt such that they can reliably generate spikes at specific points in time. Existing activity-dependent plasticity rules like Spike-Timing-Dependent Plasticity are agnostic to the goal of learning spike times. On the other hand, the existing formal and supervised learning algorithms perform a temporally precise comparison of projected activity with the target, but there is no known biologically plausible implementation of this comparison. Here, we propose a simple and local unsupervised synaptic plasticity mechanism that is derived from the requirement of a balanced membrane potential. Since the relevant signal for synaptic change is the postsynaptic voltage rather than spike times, we call the plasticity rule Membrane Potential Dependent Plasticity (MPDP). Combining our plasticity mechanism with spike after-hyperpolarization causes a sensitivity of synaptic change to pre- and postsynaptic spike times which can reproduce Hebbian spike timing dependent plasticity for inhibitory synapses as was found in experiments. In addition, the sensitivity of MPDP to the time course of the voltage when generating a spike allows MPDP to distinguish between weak (spurious) and strong (teacher) spikes, which therefore provides a neuronal basis for the comparison of actual and target activity. For spatio-temporal input spike patterns our conceptually simple plasticity rule achieves a surprisingly high storage capacity for spike associations. The sensitivity of the MPDP to the subthreshold membrane potential during training allows robust memory retrieval after learning even in the presence of activity corrupted by noise. We propose that MPDP represents a biophysically plausible mechanism to learn temporal target activity patterns. PMID:26900845

An intracellular characterization of neurones and neural connexions within the left coeliac ganglion of cats.

PubMed Central

Decktor, D L; Weems, W A

1983-01-01

Intracellular recordings were made in vitro from neurones located within the left coeliac ganglion of the cat solar plexus. Thirty percent of the neurones within left coeliac ganglia were identified as efferent neurones. Within this neuronal population, splenic-efferent and renal-efferent neurones were identified specifically. Neurones within left coeliac ganglia were characterized as either phasic (fast adapting) neurones or tonic (slowly adapting) neurones depending upon their prolonged firing behaviour. Electrophysiological properties of neurones varied considerably. The wide range of values obtained for both input resistance and input capacitance suggest that sizeable differences in either specific membrane resistance or cell geometry exist within the over-all neurone population. Frequency distributions of input resistance, time constant, input capacitance and current threshold for tonic and phasic neurones were found to be significantly different. Compound excitatory post-synaptic potentials were produced by stimulation of the ipsilateral splanchnic nerves in 69% of the neurones tested and in 3% of the neurones tested upon stimulation of the contralateral splanchnic nerves. Electrical stimulation of nerve fibres located in the coeliac plexus, the superior mesenteric plexus or the left renal nerves generated excitatory synaptic potentials in neurones located within left coeliac ganglia. It is concluded that neurones within the left coeliac ganglion are innervated by splanchnic nerve fibres primarily contained within the left splanchnic nerves, receive excitatory synaptic input from splenic, renal and other peripheral preganglionic fibres and have extremely varied electrophysiological properties. PMID:6620179

Novel Fast Adapting Interneurons Mediate Cholinergic-Induced Fast GABAA IPSCs In Striatal Spiny Neurons

PubMed Central

Faust, Thomas W.; Assous, Maxime; Shah, Fulva; Tepper, James M.; Koós, Tibor

2015-01-01

Previous work suggests that neostriatal cholinergic interneurons control the activity of several classes of GABAergic interneurons through fast nicotinic receptor mediated synaptic inputs. Although indirect evidence has suggested the existence of several classes of interneurons controlled by this mechanism only one such cell type, the neuropeptide-Y expressing neurogliaform neuron, has been identified to date. Here we tested the hypothesis that in addition to the neurogliaform neurons that elicit slow GABAergic inhibitory responses, another interneuron type exists in the striatum that receives strong nicotinic cholinergic input and elicits conventional fast GABAergic synaptic responses in projection neurons. We obtained in vitro slice recordings from double transgenic mice in which Channelrhodopsin-2 was natively expressed in cholinergic neurons and a population of serotonin receptor-3a-Cre expressing GABAergic interneurons were visualized with tdTomato. We show that among the targeted GABAergic interneurons a novel type of interneuron, termed the fast-adapting interneuron, can be identified that is distinct from previously known interneurons based on immunocytochemical and electrophysiological criteria. We show using optogenetic activation of cholinergic inputs that fast-adapting interneurons receive a powerful supra-threshold nicotinic cholinergic input in vitro. Moreover, fast adapting neurons are densely connected to projection neurons and elicit fast, GABAA receptor mediated inhibitory postsynaptic responses. The nicotinic receptor mediated activation of fast-adapting interneurons may constitute an important mechanism through which cholinergic interneurons control the activity of projection neurons and perhaps the plasticity of their synaptic inputs when animals encounter reinforcing or otherwise salient stimuli. PMID:25865337

A repetitive intracortical microstimulation pattern induces long-lasting synaptic depression in brain slices of the rat primary somatosensory cortex.

PubMed

Heusler, P; Cebulla, B; Boehmer, G; Dinse, H R

2000-12-01

Repetitive intracortical microstimulation (ICMS) applied to the rat primary somatosensory cortex (SI) in vivo was reported to induce reorganization of receptive fields and cortical maps. The present study was designed to examine the effect of such an ICMS pattern applied to layer IV of brain slices containing SI on the efficacy of synaptic input to layer II/III. Effects of ICMS on the synaptic strength was quantified for the first synaptic component (s1) of cortical field potentials (FPs) recorded from layer II/III of SI. FPs were evoked by stimulation in layer IV. The pattern of ICMS was identical to that used in vivo. However, stimulation intensity had to be raised to induce an alteration of synaptic strength. In brain slices superfused with standard ACSF, repetitive ICMS induced a short-lasting (60 min) reduction of the amplitude (-37%) and the slope (-61%) of s1 evoked from the ICMS site, while the amplitude and the slope of s1 evoked from a control stimulation site in cortical layer IV underwent a slow onset increase (13% and 50%, respectively). In brain slices superfused with ACSF containing 1.25 microM bicuculline, ICMS induced an initial strong reduction of the amplitude (-50%) and the slope (-79%) of s1 evoked from the ICMS site. These effects decayed to a sustained level of depression by -30% (amplitude) and -60% (slope). In contrast to experiments using standard ACSF, s1 evoked from the control site was not affected by ICMS. The presynaptic volley was not affected in either of the two groups of experiments. A conventional high frequency stimulation (HFS) protocol induced input-specific long-term potentiation (LTP) of the amplitude and slope of s1 (25% and 76%, respectively). Low frequency stimulation (LFS) induced input-specific long-term depression (LTD) of the amplitude and slope of s1 (24% and 30%, respectively). Application of common forms of conditioning stimulation (HFS and LFS) resulted in LTP or LTD of s1, indicating normal susceptibility of the brain slices studied to the induction of common forms of synaptic plasticity. Therefore, the effects of repetitive ICMS on synaptic FP components were considered ICMS-specific forms of short-lasting (standard ACSF) or long-lasting synaptic depression (ACSF containing bicuculline), the latter resembling neocortical LTD. Results of this study suggest that synaptic depression of excitatory mechanisms are involved in the cortical reorganization induced by repetitive ICMS in vivo. An additional contribution of an ICMS-induced modification of inhibitory mechanisms to cortical reorganization is discussed.

Bilinearity in Spatiotemporal Integration of Synaptic Inputs

PubMed Central

Li, Songting; Liu, Nan; Zhang, Xiao-hui; Zhou, Douglas; Cai, David

2014-01-01

Neurons process information via integration of synaptic inputs from dendrites. Many experimental results demonstrate dendritic integration could be highly nonlinear, yet few theoretical analyses have been performed to obtain a precise quantitative characterization analytically. Based on asymptotic analysis of a two-compartment passive cable model, given a pair of time-dependent synaptic conductance inputs, we derive a bilinear spatiotemporal dendritic integration rule. The summed somatic potential can be well approximated by the linear summation of the two postsynaptic potentials elicited separately, plus a third additional bilinear term proportional to their product with a proportionality coefficient . The rule is valid for a pair of synaptic inputs of all types, including excitation-inhibition, excitation-excitation, and inhibition-inhibition. In addition, the rule is valid during the whole dendritic integration process for a pair of synaptic inputs with arbitrary input time differences and input locations. The coefficient is demonstrated to be nearly independent of the input strengths but is dependent on input times and input locations. This rule is then verified through simulation of a realistic pyramidal neuron model and in electrophysiological experiments of rat hippocampal CA1 neurons. The rule is further generalized to describe the spatiotemporal dendritic integration of multiple excitatory and inhibitory synaptic inputs. The integration of multiple inputs can be decomposed into the sum of all possible pairwise integration, where each paired integration obeys the bilinear rule. This decomposition leads to a graph representation of dendritic integration, which can be viewed as functionally sparse. PMID:25521832

Biophysics of object segmentation in a collision-detecting neuron

PubMed Central

Dewell, Richard Burkett

2018-01-01

Collision avoidance is critical for survival, including in humans, and many species possess visual neurons exquisitely sensitive to objects approaching on a collision course. Here, we demonstrate that a collision-detecting neuron can detect the spatial coherence of a simulated impending object, thereby carrying out a computation akin to object segmentation critical for proper escape behavior. At the cellular level, object segmentation relies on a precise selection of the spatiotemporal pattern of synaptic inputs by dendritic membrane potential-activated channels. One channel type linked to dendritic computations in many neural systems, the hyperpolarization-activated cation channel, HCN, plays a central role in this computation. Pharmacological block of HCN channels abolishes the neuron's spatial selectivity and impairs the generation of visually guided escape behaviors, making it directly relevant to survival. Additionally, our results suggest that the interaction of HCN and inactivating K+ channels within active dendrites produces neuronal and behavioral object specificity by discriminating between complex spatiotemporal synaptic activation patterns. PMID:29667927

Presynaptic Partners of Dorsal Raphe Serotonergic and GABAergic Neurons

PubMed Central

Weissbourd, Brandon; Ren, Jing; DeLoach, Katherine E.; Guenthner, Casey J.; Miyamichi, Kazunari; Luo, Liqun

2016-01-01

SUMMARY The serotonin system powerfully modulates physiology and behavior in health and disease, yet the circuit mechanisms underlying serotonin neuron activity are poorly understood. The major source of forebrain serotonergic innervation is from the dorsal raphe nucleus (DR), which contains both serotonin and GABA neurons. Using viral tracing combined with electrophysiology, we found that GABA and serotonin neurons in the DR receive excitatory, inhibitory, and peptidergic inputs from the same specific brain regions. Embedded in this overall similarity are important differences. Serotonin neurons are more likely to receive synaptic inputs from anterior neocortex while GABA neurons receive disproportionally higher input from the central amygdala. Local input mapping revealed extensive serotonin-serotonin as well as GABA-serotonin connectivity with a distinct spatial organization. Covariance analysis suggests heterogeneity of both serotonin and GABA neurons with respect to the inputs they receive. These analyses provide a foundation for further functional dissection of the serotonin system. PMID:25102560

Ex vivo dissection of optogenetically activated mPFC and hippocampal inputs to neurons in the basolateral amygdala: implications for fear and emotional memory

PubMed Central

Hübner, Cora; Bosch, Daniel; Gall, Andrea; Lüthi, Andreas; Ehrlich, Ingrid

2014-01-01

Many lines of evidence suggest that a reciprocally interconnected network comprising the amygdala, ventral hippocampus (vHC), and medial prefrontal cortex (mPFC) participates in different aspects of the acquisition and extinction of conditioned fear responses and fear behavior. This could at least in part be mediated by direct connections from mPFC or vHC to amygdala to control amygdala activity and output. However, currently the interactions between mPFC and vHC afferents and their specific targets in the amygdala are still poorly understood. Here, we use an ex-vivo optogenetic approach to dissect synaptic properties of inputs from mPFC and vHC to defined neuronal populations in the basal amygdala (BA), the area that we identify as a major target of these projections. We find that BA principal neurons (PNs) and local BA interneurons (INs) receive monosynaptic excitatory inputs from mPFC and vHC. In addition, both these inputs also recruit GABAergic feedforward inhibition in a substantial fraction of PNs, in some neurons this also comprises a slow GABAB-component. Amongst the innervated PNs we identify neurons that project back to subregions of the mPFC, indicating a loop between neurons in mPFC and BA, and a pathway from vHC to mPFC via BA. Interestingly, mPFC inputs also recruit feedforward inhibition in a fraction of INs, suggesting that these inputs can activate dis-inhibitory circuits in the BA. A general feature of both mPFC and vHC inputs to local INs is that excitatory inputs display faster rise and decay kinetics than in PNs, which would enable temporally precise signaling. However, mPFC and vHC inputs to both PNs and INs differ in their presynaptic release properties, in that vHC inputs are more depressing. In summary, our data describe novel wiring, and features of synaptic connections from mPFC and vHC to amygdala that could help to interpret functions of these interconnected brain areas at the network level. PMID:24634648

Input transformation by dendritic spines of pyramidal neurons

PubMed Central

Araya, Roberto

2014-01-01

In the mammalian brain, most inputs received by a neuron are formed on the dendritic tree. In the neocortex, the dendrites of pyramidal neurons are covered by thousands of tiny protrusions known as dendritic spines, which are the major recipient sites for excitatory synaptic information in the brain. Their peculiar morphology, with a small head connected to the dendritic shaft by a slender neck, has inspired decades of theoretical and more recently experimental work in an attempt to understand how excitatory synaptic inputs are processed, stored and integrated in pyramidal neurons. Advances in electrophysiological, optical and genetic tools are now enabling us to unravel the biophysical and molecular mechanisms controlling spine function in health and disease. Here I highlight relevant findings, challenges and hypotheses on spine function, with an emphasis on the electrical properties of spines and on how these affect the storage and integration of excitatory synaptic inputs in pyramidal neurons. In an attempt to make sense of the published data, I propose that the raison d'etre for dendritic spines lies in their ability to undergo activity-dependent structural and molecular changes that can modify synaptic strength, and hence alter the gain of the linearly integrated sub-threshold depolarizations in pyramidal neuron dendrites before the generation of a dendritic spike. PMID:25520626

Active subthreshold dendritic conductances shape the local field potential

PubMed Central

Ness, Torbjørn V.; Remme, Michiel W. H.

2016-01-01

Key points The local field potential (LFP), the low‐frequency part of extracellular potentials recorded in neural tissue, is often used for probing neural circuit activity. Interpreting the LFP signal is difficult, however.While the cortical LFP is thought mainly to reflect synaptic inputs onto pyramidal neurons, little is known about the role of the various subthreshold active conductances in shaping the LFP.By means of biophysical modelling we obtain a comprehensive qualitative understanding of how the LFP generated by a single pyramidal neuron depends on the type and spatial distribution of active subthreshold currents.For pyramidal neurons, the h‐type channels probably play a key role and can cause a distinct resonance in the LFP power spectrum.Our results show that the LFP signal can give information about the active properties of neurons and imply that preferred frequencies in the LFP can result from those cellular properties instead of, for example, network dynamics. Abstract The main contribution to the local field potential (LFP) is thought to stem from synaptic input to neurons and the ensuing subthreshold dendritic processing. The role of active dendritic conductances in shaping the LFP has received little attention, even though such ion channels are known to affect the subthreshold neuron dynamics. Here we used a modelling approach to investigate the effects of subthreshold dendritic conductances on the LFP. Using a biophysically detailed, experimentally constrained model of a cortical pyramidal neuron, we identified conditions under which subthreshold active conductances are a major factor in shaping the LFP. We found that, in particular, the hyperpolarization‐activated inward current, I h, can have a sizable effect and cause a resonance in the LFP power spectral density. To get a general, qualitative understanding of how any subthreshold active dendritic conductance and its cellular distribution can affect the LFP, we next performed a systematic study with a simplified model. We found that the effect on the LFP is most pronounced when (1) the synaptic drive to the cell is asymmetrically distributed (i.e. either basal or apical), (2) the active conductances are distributed non‐uniformly with the highest channel densities near the synaptic input and (3) when the LFP is measured at the opposite pole of the cell relative to the synaptic input. In summary, we show that subthreshold active conductances can be strongly reflected in LFP signals, opening up the possibility that the LFP can be used to characterize the properties and cellular distributions of active conductances. PMID:27079755

SYNAPTIC DEPRESSION IN DEEP NEURAL NETWORKS FOR SPEECH PROCESSING.

PubMed

Zhang, Wenhao; Li, Hanyu; Yang, Minda; Mesgarani, Nima

2016-03-01

A characteristic property of biological neurons is their ability to dynamically change the synaptic efficacy in response to variable input conditions. This mechanism, known as synaptic depression, significantly contributes to the formation of normalized representation of speech features. Synaptic depression also contributes to the robust performance of biological systems. In this paper, we describe how synaptic depression can be modeled and incorporated into deep neural network architectures to improve their generalization ability. We observed that when synaptic depression is added to the hidden layers of a neural network, it reduces the effect of changing background activity in the node activations. In addition, we show that when synaptic depression is included in a deep neural network trained for phoneme classification, the performance of the network improves under noisy conditions not included in the training phase. Our results suggest that more complete neuron models may further reduce the gap between the biological performance and artificial computing, resulting in networks that better generalize to novel signal conditions.

Rational modulation of neuronal processing with applied electric fields.

PubMed

Bikson, Marom; Radman, Thomas; Datta, Abhishek

2006-01-01

Traditional approaches to electrical stimulation, using trains of supra-threshold pulses to trigger action potentials, may be replaced or augmented by using 'rational' sub-threshold stimulation protocols that incorporate knowledge of single neuron geometry, inhomogeneous tissue properties, and nervous system information coding. Sub-threshold stimulation, at intensities (well) below those sufficient to trigger action potentials, may none-the-less exert a profound effect on brain function through modulation of concomitant neuronal activity. For example, small DC fields may coherently polarize a network of neurons and thus modulate the simultaneous processing of afferent synaptic input as well as resulting changes in synaptic plasticity. Through 'activity-dependent plasticity', sub-threshold fields may allow specific targeting of pathological networks and are thus particularly suitable to overcome the poor anatomical focus of noninvasive (transcranial) electrical stimulation. Additional approaches to improve targeting in transcranial stimulation using novel electrode configurations are also introduced.

Distributed synaptic weights in a LIF neural network and learning rules

NASA Astrophysics Data System (ADS)

Perthame, Benoît; Salort, Delphine; Wainrib, Gilles

2017-09-01

Leaky integrate-and-fire (LIF) models are mean-field limits, with a large number of neurons, used to describe neural networks. We consider inhomogeneous networks structured by a connectivity parameter (strengths of the synaptic weights) with the effect of processing the input current with different intensities. We first study the properties of the network activity depending on the distribution of synaptic weights and in particular its discrimination capacity. Then, we consider simple learning rules and determine the synaptic weight distribution it generates. We outline the role of noise as a selection principle and the capacity to memorize a learned signal.

Group II and III metabotropic glutamate receptors and the control of the nucleus reticularis thalami input to rat thalamocortical neurones in vitro.

PubMed

Turner, J P; Salt, T E

2003-01-01

Intracellular recordings were made from neurones in the thalamic reticular nucleus (TRN) and ventro-basal (VB) thalamus in slices of rat midbrain in vitro. Electrical stimulation of the medial lemniscus or TRN resulted in the generation of complex synaptic potentials containing disynaptic inhibitory post-synaptic potentials (IPSPs) in VB thalamocortical neurones. Analysis of the excitatory synaptic responses in TRN neurones indicates they can produce burst output response irrespective of the level of sub-threshold membrane potential. This suggests that network-evoked IPSPs in VB thalamocortical neurones occur following a burst of TRN action potentials. Using ionotropic glutamate receptor antagonists, the activation of these disynaptic events was blocked, and the monosynaptic IPSPs that resulted from the direct activation of the TRN could be isolated. The selective Group II agonists LY354740 (1-10 microM) and N-acetyl-aspartyl-glutamate (NAAG; 100-500 microM) both caused a reversible depression of these monosynaptic TRN IPSPs without any effect on membrane potential or input resistance. Likewise, the specific Group III agonist L-2-amino-4-phosphonobutanoate (10-500 microM), but not (RS)-4-phosphonophenylglycine (1 and 30 microM) also caused a reversible depression of these IPSPs, again without any effect on membrane potential or input resistance.Thus, the IPSPs recorded in VB thalamocortical neurones, evoked by TRN activation, can be depressed by the activation of either Group II or III metabotropic glutamate receptors. This is consistent with the location of these receptor types on the presynaptic terminals of TRN axons in the VB thalamus. This raises the possibility that, during periods of intense excitatory activity, glutamate release could influence the release of GABA from TRN axon terminals in the thalamus. In addition, as NAAG is located in the axons and terminals arising from the TRN, there is the possibility that this dipeptide is also released by these terminals to control the release of GABA during periods of high activity in the TRN.

Post-transcriptional trafficking and regulation of neuronal gene expression.

PubMed

Goldie, Belinda J; Cairns, Murray J

2012-02-01

Intracellular messenger RNA (mRNA) traffic and translation must be highly regulated, both temporally and spatially, within eukaryotic cells to support the complex functional partitioning. This capacity is essential in neurons because it provides a mechanism for rapid input-restricted activity-dependent protein synthesis in individual dendritic spines. While this feature is thought to be important for synaptic plasticity, the structures and mechanisms that support this capability are largely unknown. Certainly specialized RNA binding proteins and binding elements in the 3' untranslated region (UTR) of translationally regulated mRNA are important, but the subtlety and complexity of this system suggests that an intermediate "specificity" component is also involved. Small non-coding microRNA (miRNA) are essential for CNS development and may fulfill this role by acting as the guide strand for mediating complex patterns of post-transcriptional regulation. In this review we examine post-synaptic gene regulation, mRNA trafficking and the emerging role of post-transcriptional gene silencing in synaptic plasticity.

Inhibition to excitation ratio regulates visual system responses and behavior in vivo.

PubMed

Shen, Wanhua; McKeown, Caroline R; Demas, James A; Cline, Hollis T

2011-11-01

The balance of inhibitory to excitatory (I/E) synaptic inputs is thought to control information processing and behavioral output of the central nervous system. We sought to test the effects of the decreased or increased I/E ratio on visual circuit function and visually guided behavior in Xenopus tadpoles. We selectively decreased inhibitory synaptic transmission in optic tectal neurons by knocking down the γ2 subunit of the GABA(A) receptors (GABA(A)R) using antisense morpholino oligonucleotides or by expressing a peptide corresponding to an intracellular loop of the γ2 subunit, called ICL, which interferes with anchoring GABA(A)R at synapses. Recordings of miniature inhibitory postsynaptic currents (mIPSCs) and miniature excitatory PSCs (mEPSCs) showed that these treatments decreased the frequency of mIPSCs compared with control tectal neurons without affecting mEPSC frequency, resulting in an ∼50% decrease in the ratio of I/E synaptic input. ICL expression and γ2-subunit knockdown also decreased the ratio of optic nerve-evoked synaptic I/E responses. We recorded visually evoked responses from optic tectal neurons, in which the synaptic I/E ratio was decreased. Decreasing the synaptic I/E ratio in tectal neurons increased the variance of first spike latency in response to full-field visual stimulation, increased recurrent activity in the tectal circuit, enlarged spatial receptive fields, and lengthened the temporal integration window. We used the benzodiazepine, diazepam (DZ), to increase inhibitory synaptic activity. DZ increased optic nerve-evoked inhibitory transmission but did not affect evoked excitatory currents, resulting in an increase in the I/E ratio of ∼30%. Increasing the I/E ratio with DZ decreased the variance of first spike latency, decreased spatial receptive field size, and lengthened temporal receptive fields. Sequential recordings of spikes and excitatory and inhibitory synaptic inputs to the same visual stimuli demonstrated that decreasing or increasing the I/E ratio disrupted input/output relations. We assessed the effect of an altered I/E ratio on a visually guided behavior that requires the optic tectum. Increasing and decreasing I/E in tectal neurons blocked the tectally mediated visual avoidance behavior. Because ICL expression, γ2-subunit knockdown, and DZ did not directly affect excitatory synaptic transmission, we interpret the results of our study as evidence that partially decreasing or increasing the ratio of I/E disrupts several measures of visual system information processing and visually guided behavior in an intact vertebrate.

Parallel processing of afferent olfactory sensory information

PubMed Central

Vaaga, Christopher E.

2016-01-01

Key points The functional synaptic connectivity between olfactory receptor neurons and principal cells within the olfactory bulb is not well understood.One view suggests that mitral cells, the primary output neuron of the olfactory bulb, are solely activated by feedforward excitation.Using focal, single glomerular stimulation, we demonstrate that mitral cells receive direct, monosynaptic input from olfactory receptor neurons.Compared to external tufted cells, mitral cells have a prolonged afferent‐evoked EPSC, which serves to amplify the synaptic input.The properties of presynaptic glutamate release from olfactory receptor neurons are similar between mitral and external tufted cells.Our data suggest that afferent input enters the olfactory bulb in a parallel fashion. Abstract Primary olfactory receptor neurons terminate in anatomically and functionally discrete cortical modules known as olfactory bulb glomeruli. The synaptic connectivity and postsynaptic responses of mitral and external tufted cells within the glomerulus may involve both direct and indirect components. For example, it has been suggested that sensory input to mitral cells is indirect through feedforward excitation from external tufted cells. We also observed feedforward excitation of mitral cells with weak stimulation of the olfactory nerve layer; however, focal stimulation of an axon bundle entering an individual glomerulus revealed that mitral cells receive monosynaptic afferent inputs. Although external tufted cells had a 4.1‐fold larger peak EPSC amplitude, integration of the evoked currents showed that the synaptic charge was 5‐fold larger in mitral cells, reflecting the prolonged response in mitral cells. Presynaptic afferents onto mitral and external tufted cells had similar quantal amplitude and release probability, suggesting that the larger peak EPSC in external tufted cells was the result of more synaptic contacts. The results of the present study indicate that the monosynaptic afferent input to mitral cells depends on the strength of odorant stimulation. The enhanced spiking that we observed in response to brief afferent input provides a mechanism for amplifying sensory information and contrasts with the transient response in external tufted cells. These parallel input paths may have discrete functions in processing olfactory sensory input. PMID:27377344

Glutamatergic input is selectively increased in dorsal raphe subfield 5-HT neurons: role of morphology, topography and selective innervation.

PubMed

Crawford, LaTasha K; Craige, Caryne P; Beck, Sheryl G

2011-12-01

Characterization of glutamatergic input to dorsal raphe (DR) serotonin (5-HT) neurons is crucial for understanding how the glutamate and 5-HT systems interact in psychiatric disorders. Markers of glutamatergic terminals, vGlut1, 2 and 3, reflect inputs from specific forebrain and midbrain regions. Punctate staining of vGlut2 was homogeneous throughout the mouse DR whereas vGlut1 and vGlut3 puncta were less dense in the lateral wing (lwDR) compared with the ventromedial (vmDR) subregion. The distribution of glutamate terminals was consistent with the lower miniature excitatory postsynaptic current frequency found in the lwDR; however, it was not predictive of glutamatergic synaptic input with local activity intact, as spontaneous excitatory postsynaptic current (sEPSC) frequency was higher in the lwDR. We examined the morphology of recorded cells to determine if variations in dendrite structure contributed to differences in synaptic input. Although lwDR neurons had longer, more complex dendrites than vmDR neurons, glutamatergic input was not correlated with dendrite length in the lwDR, suggesting that dendrite length did not contribute to subregional differences in sEPSC frequency. Overall, glutamatergic input in the DR was the result of selective innervation of subpopulations of 5-HT neurons and was rooted in the topography of DR neurons and the activity of glutamate neurons located within the midbrain slice. Increased glutamatergic input to lwDR cells potentially synergizes with previously reported increased intrinsic excitability of lwDR cells to increase 5-HT output in lwDR target regions. Because the vmDR and lwDR are involved in unique circuits, subregional differences in glutamate modulation may result in diverse effects on 5-HT output in stress-related psychopathology. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Synchronization and long-time memory in neural networks with inhibitory hubs and synaptic plasticity

NASA Astrophysics Data System (ADS)

Bertolotti, Elena; Burioni, Raffaella; di Volo, Matteo; Vezzani, Alessandro

2017-01-01

We investigate the dynamical role of inhibitory and highly connected nodes (hub) in synchronization and input processing of leaky-integrate-and-fire neural networks with short term synaptic plasticity. We take advantage of a heterogeneous mean-field approximation to encode the role of network structure and we tune the fraction of inhibitory neurons fI and their connectivity level to investigate the cooperation between hub features and inhibition. We show that, depending on fI, highly connected inhibitory nodes strongly drive the synchronization properties of the overall network through dynamical transitions from synchronous to asynchronous regimes. Furthermore, a metastable regime with long memory of external inputs emerges for a specific fraction of hub inhibitory neurons, underlining the role of inhibition and connectivity also for input processing in neural networks.

Cell-Specific Activity-Dependent Fractionation of Layer 2/3→5B Excitatory Signaling in Mouse Auditory Cortex

PubMed Central

Joshi, Ankur; Middleton, Jason W.; Anderson, Charles T.; Borges, Katharine; Suter, Benjamin A.; Shepherd, Gordon M. G.

2015-01-01

Auditory cortex (AC) layer 5B (L5B) contains both corticocollicular neurons, a type of pyramidal-tract neuron projecting to the inferior colliculus, and corticocallosal neurons, a type of intratelencephalic neuron projecting to contralateral AC. Although it is known that these neuronal types have distinct roles in auditory processing and different response properties to sound, the synaptic and intrinsic mechanisms shaping their input–output functions remain less understood. Here, we recorded in brain slices of mouse AC from retrogradely labeled corticocollicular and neighboring corticocallosal neurons in L5B. Corticocollicular neurons had, on average, lower input resistance, greater hyperpolarization-activated current (Ih), depolarized resting membrane potential, faster action potentials, initial spike doublets, and less spike-frequency adaptation. In paired recordings between single L2/3 and labeled L5B neurons, the probabilities of connection, amplitude, latency, rise time, and decay time constant of the unitary EPSC were not different for L2/3→corticocollicular and L2/3→corticocallosal connections. However, short trains of unitary EPSCs showed no synaptic depression in L2/3→corticocollicular connections, but substantial depression in L2/3→corticocallosal connections. Synaptic potentials in L2/3→corticocollicular connections decayed faster and showed less temporal summation, consistent with increased Ih in corticocollicular neurons, whereas synaptic potentials in L2/3→corticocallosal connections showed more temporal summation. Extracellular L2/3 stimulation at two different rates resulted in spiking in L5B neurons; for corticocallosal neurons the spike rate was frequency dependent, but for corticocollicular neurons it was not. Together, these findings identify cell-specific intrinsic and synaptic mechanisms that divide intracortical synaptic excitation from L2/3 to L5B into two functionally distinct pathways with different input–output functions. PMID:25698747

Experience-dependent modification of a central amygdala fear circuit

PubMed Central

Li, Haohong; Penzo, Mario A.; Taniguchi, Hiroki; Kopec, Charles D.; Huang, Z. Josh; Li, Bo

2013-01-01

The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, how CeA contributes to the learning and expression of fear is unclear. Here we show in mice that fear conditioning induces robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of CeA (CeL). This experience-dependent plasticity is cell-specific, bidirectional, and expressed presynaptically by inputs from the lateral amygdala. In particular, preventing synaptic potentiation onto somatostatin-positive neurons impairs fear memory formation. Furthermore, activation of these neurons is necessary for fear memory recall and sufficient to drive fear responses. Our findings support a model in which the fear conditioning-induced synaptic modifications in CeL favor the activation of somatostatin-positive neurons, which inhibit CeL output thereby disinhibiting the medial subdivision of CeA and releasing fear expression. PMID:23354330

Asymmetry of Neuronal Combinatorial Codes Arises from Minimizing Synaptic Weight Change.

PubMed

Leibold, Christian; Monsalve-Mercado, Mauro M

2016-08-01

Synaptic change is a costly resource, particularly for brain structures that have a high demand of synaptic plasticity. For example, building memories of object positions requires efficient use of plasticity resources since objects can easily change their location in space and yet we can memorize object locations. But how should a neural circuit ideally be set up to integrate two input streams (object location and identity) in case the overall synaptic changes should be minimized during ongoing learning? This letter provides a theoretical framework on how the two input pathways should ideally be specified. Generally the model predicts that the information-rich pathway should be plastic and encoded sparsely, whereas the pathway conveying less information should be encoded densely and undergo learning only if a neuronal representation of a novel object has to be established. As an example, we consider hippocampal area CA1, which combines place and object information. The model thereby provides a normative account of hippocampal rate remapping, that is, modulations of place field activity by changes of local cues. It may as well be applicable to other brain areas (such as neocortical layer V) that learn combinatorial codes from multiple input streams.

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

PubMed

Muñoz, Fabián; Fuentealba, Pablo

2012-01-01

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

Synaptic loss and firing alterations in Axotomized Motoneurons are restored by vascular endothelial growth factor (VEGF) and VEGF-B.

PubMed

Calvo, Paula M; de la Cruz, Rosa R; Pastor, Angel M

2018-06-01

Vascular endothelial growth factor (VEGF), also known as VEGF-A, was discovered due to its vasculogenic and angiogenic activity, but a neuroprotective role for VEGF was later proven for lesions and disorders. In different models of motoneuronal degeneration, VEGF administration leads to a significant reduction of motoneuronal death. However, there is no information about the physiological state of spared motoneurons. We examined the trophic role of VEGF on axotomized motoneurons with recordings in alert animals using the oculomotor system as the experimental model, complemented with a synaptic study at the confocal microscopy level. Axotomy leads to drastic alterations in the discharge characteristics of abducens motoneurons, as well as to a substantial loss of their synaptic inputs. Retrograde delivery of VEGF completely restored the discharge activity and synaptically-driven signals in injured motoneurons, as demonstrated by correlating motoneuronal firing rate with motor performance. Moreover, VEGF-treated motoneurons recovered a normal density of synaptic boutons around motoneuronal somata and in the neuropil, in contrast to the low levels of synaptic terminals found after axotomy. VEGF also reduced the astrogliosis induced by axotomy in the abducens nucleus to control values. The administration of VEGF-B produced results similar to those of VEGF. This is the first work demonstrating that VEGF and VEGF-B restore the normal operating mode and synaptic inputs on injured motoneurons. Altogether these data indicate that these molecules are relevant synaptotrophic factors for motoneurons and support their clinical potential for the treatment of motoneuronal disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons.

PubMed

Goldie, Belinda J; Dun, Matthew D; Lin, Minjie; Smith, Nathan D; Verrills, Nicole M; Dayas, Christopher V; Cairns, Murray J

2014-08-01

Rapid input-restricted change in gene expression is an important aspect of synaptic plasticity requiring complex mechanisms of post-transcriptional mRNA trafficking and regulation. Small non-coding miRNA are uniquely poised to support these functions by providing a nucleic-acid-based specificity component for universal-sequence-dependent RNA binding complexes. We investigated the subcellular distribution of these molecules in resting and potassium chloride depolarized human neuroblasts, and found both selective enrichment and depletion in neurites. Depolarization was associated with a neurite-restricted decrease in miRNA expression; a subset of these molecules was recovered from the depolarization medium in nuclease resistant extracellular exosomes. These vesicles were enriched with primate specific miRNA and the synaptic-plasticity-associated protein MAP1b. These findings further support a role for miRNA as neural plasticity regulators, as they are compartmentalized in neurons and undergo activity-associated redistribution or release into the extracellular matrix. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Interregional synaptic maps among engram cells underlie memory formation.

PubMed

Choi, Jun-Hyeok; Sim, Su-Eon; Kim, Ji-Il; Choi, Dong Il; Oh, Jihae; Ye, Sanghyun; Lee, Jaehyun; Kim, TaeHyun; Ko, Hyoung-Gon; Lim, Chae-Seok; Kaang, Bong-Kiun

2018-04-27

Memory resides in engram cells distributed across the brain. However, the site-specific substrate within these engram cells remains theoretical, even though it is generally accepted that synaptic plasticity encodes memories. We developed the dual-eGRASP (green fluorescent protein reconstitution across synaptic partners) technique to examine synapses between engram cells to identify the specific neuronal site for memory storage. We found an increased number and size of spines on CA1 engram cells receiving input from CA3 engram cells. In contextual fear conditioning, this enhanced connectivity between engram cells encoded memory strength. CA3 engram to CA1 engram projections strongly occluded long-term potentiation. These results indicate that enhanced structural and functional connectivity between engram cells across two directly connected brain regions forms the synaptic correlate for memory formation. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Dendritic nonlinearities are tuned for efficient spike-based computations in cortical circuits

PubMed Central

Ujfalussy, Balázs B; Makara, Judit K; Branco, Tiago; Lengyel, Máté

2015-01-01

Cortical neurons integrate thousands of synaptic inputs in their dendrites in highly nonlinear ways. It is unknown how these dendritic nonlinearities in individual cells contribute to computations at the level of neural circuits. Here, we show that dendritic nonlinearities are critical for the efficient integration of synaptic inputs in circuits performing analog computations with spiking neurons. We developed a theory that formalizes how a neuron's dendritic nonlinearity that is optimal for integrating synaptic inputs depends on the statistics of its presynaptic activity patterns. Based on their in vivo preynaptic population statistics (firing rates, membrane potential fluctuations, and correlations due to ensemble dynamics), our theory accurately predicted the responses of two different types of cortical pyramidal cells to patterned stimulation by two-photon glutamate uncaging. These results reveal a new computational principle underlying dendritic integration in cortical neurons by suggesting a functional link between cellular and systems--level properties of cortical circuits. DOI: http://dx.doi.org/10.7554/eLife.10056.001 PMID:26705334

Glutamate synaptic inputs to ventral tegmental area neurons in the rat derive primarily from subcortical sources.

PubMed

Omelchenko, N; Sesack, S R

2007-05-25

Dopamine and GABA neurons in the ventral tegmental area project to the nucleus accumbens and prefrontal cortex and modulate locomotor and reward behaviors as well as cognitive and affective processes. Both midbrain cell types receive synapses from glutamate afferents that provide an essential control of behaviorally-linked activity patterns, although the sources of glutamate inputs have not yet been completely characterized. We used antibodies against the vesicular glutamate transporter subtypes 1 and 2 (VGlut1 and VGlut2) to investigate the morphology and synaptic organization of axons containing these proteins as putative markers of glutamate afferents from cortical versus subcortical sites, respectively, in rats. We also characterized the ventral tegmental area cell populations receiving VGlut1+ or VGlut2+ synapses according to their transmitter phenotype (dopamine or GABA) and major projection target (nucleus accumbens or prefrontal cortex). By light and electron microscopic examination, VGlut2+ as opposed to VGlut1+ axon terminals were more numerous, had a larger average size, synapsed more proximally, and were more likely to form convergent synapses onto the same target. Both axon types formed predominantly asymmetric synapses, although VGlut2+ terminals more often formed synapses with symmetric morphology. No absolute selectivity was observed for VGlut1+ or VGlut2+ axons to target any particular cell population. However, the synapses onto mesoaccumbens neurons more often involved VGlut2+ terminals, whereas mesoprefrontal neurons received relatively equal synaptic inputs from VGlut1+ and VGlut2+ profiles. The distinct morphological features of VGlut1 and VGlut2 positive axons suggest that glutamate inputs from presumed cortical and subcortical sources, respectively, differ in the nature and intensity of their physiological actions on midbrain neurons. More specifically, our findings imply that subcortical glutamate inputs to the ventral tegmental area expressing VGlut2 predominate over cortical sources of excitation expressing VGlut1 and are more likely to drive the behaviorally-linked bursts in dopamine cells that signal future expectancy or attentional shifting.

SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

ERIC Educational Resources Information Center

Sinai, Laleh; Duffy, Steven; Roder, John C.

2010-01-01

The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

Sparse Coding and Lateral Inhibition Arising from Balanced and Unbalanced Dendrodendritic Excitation and Inhibition

PubMed Central

Migliore, Michele; Hines, Michael L.; Shepherd, Gordon M.

2014-01-01

The precise mechanism by which synaptic excitation and inhibition interact with each other in odor coding through the unique dendrodendritic synaptic microcircuits present in olfactory bulb is unknown. Here a scaled-up model of the mitral–granule cell network in the rodent olfactory bulb is used to analyze dendrodendritic processing of experimentally determined odor patterns. We found that the interaction between excitation and inhibition is responsible for two fundamental computational mechanisms: (1) a balanced excitation/inhibition in strongly activated mitral cells, leading to a sparse representation of odorant input, and (2) an unbalanced excitation/inhibition (inhibition dominated) in surrounding weakly activated mitral cells, leading to lateral inhibition. These results suggest how both mechanisms can carry information about the input patterns, with optimal level of synaptic excitation and inhibition producing the highest level of sparseness and decorrelation in the network response. The results suggest how the learning process, through the emergent development of these mechanisms, can enhance odor representation of olfactory bulb. PMID:25297097

Coordinate synaptic mechanisms contributing to olfactory cortical adaptation.

PubMed

Best, Aaron R; Wilson, Donald A

2004-01-21

Anterior piriform cortex (aPCX) neurons rapidly filter repetitive odor stimuli despite relatively maintained input from mitral cells. This cortical adaptation is correlated with short-term depression of afferent synapses, in vivo. The purpose of this study was to elucidate mechanisms underlying this nonassociative neural plasticity using in vivo and in vitro preparations and to determine its role in cortical odor adaptation. Lateral olfactory tract (LOT)-evoked responses were recorded in rat aPCX coronal slices. Extracellular and intracellular potentials were recorded before and after simulated odor stimulation of the LOT. Results were compared with in vivo intracellular recordings from aPCX layer II/III neurons and field recordings in urethane-anesthetized rats stimulated with odorants. The onset, time course, and extent of LOT synaptic depression during both in vitro electrical and in vivo odorant stimulation methods were similar. Similar to the odor specificity of cortical odor adaptation in vivo, there was no evidence of heterosynaptic depression between independent inputs in vitro. In vitro evidence suggests at least two mechanisms contribute to this activity-dependent synaptic depression: a rapidly recovering presynaptic depression during the initial 10-20 sec of the post-train recovery period and a longer lasting (approximately 120 sec) depression that can be blocked by the metabotropic glutamate receptor (mGluR) II/III antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) and by the beta-adrenergic receptor agonist isoproterenol. Importantly, in line with the in vitro findings, both adaptation of odor responses in the beta (15-35 Hz) spectral range and the associated synaptic depression can also be blocked by intracortical infusion of CPPG in vivo.

Coordinate Synaptic Mechanisms Contributing to Olfactory Cortical Adaptation

PubMed Central

Best, Aaron R.; Wilson, Donald A.

2008-01-01

Anterior piriform cortex (aPCX) neurons rapidly filter repetitive odor stimuli despite relatively maintained input from mitral cells. This cortical adaptation is correlated with short-term depression of afferent synapses, in vivo. The purpose of this study was to elucidate mechanisms underlying this nonassociative neural plasticity using in vivo and in vitro preparations and to determine its role in cortical odor adaptation. Lateral olfactory tract (LOT)-evoked responses were recorded in rat aPCX coronal slices. Extracellular and intracellular potentials were recorded before and after simulated odor stimulation of the LOT. Results were compared with in vivo intracellular recordings from aPCX layer II/III neurons and field recordings in urethane-anesthetized rats stimulated with odorants. The onset, time course, and extent of LOT synaptic depression during both in vitro electrical and in vivo odorant stimulation methods were similar. Similar to the odor specificity of cortical odor adaptation in vivo, there was no evidence of heterosynaptic depression between independent inputs in vitro. In vitro evidence suggests at least two mechanisms contribute to this activity-dependent synaptic depression: a rapidly recovering presynaptic depression during the initial 10–20 sec of the post-train recovery period and a longer lasting (~120 sec) depression that can be blocked by the metabotropic glutamate receptor (mGluR) II/III antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG) and by the β-adrenergic receptor agonist isoproterenol. Importantly, in line with the in vitro findings, both adaptation of odor responses in the β (15–35 Hz) spectral range and the associated synaptic depression can also be blocked by intracortical infusion of CPPG in vivo. PMID:14736851

Differential Modifications of Synaptic Weights During Odor Rule Learning: Dynamics of Interaction Between the Piriform Cortex with Lower and Higher Brain Areas

PubMed Central

Cohen, Yaniv; Wilson, Donald A.; Barkai, Edi

2015-01-01

Learning of a complex olfactory discrimination (OD) task results in acquisition of rule learning after prolonged training. Previously, we demonstrated enhanced synaptic connectivity between the piriform cortex (PC) and its ascending and descending inputs from the olfactory bulb (OB) and orbitofrontal cortex (OFC) following OD rule learning. Here, using recordings of evoked field postsynaptic potentials in behaving animals, we examined the dynamics by which these synaptic pathways are modified during rule acquisition. We show profound differences in synaptic connectivity modulation between the 2 input sources. During rule acquisition, the ascending synaptic connectivity from the OB to the anterior and posterior PC is simultaneously enhanced. Furthermore, post-training stimulation of the OB enhanced learning rate dramatically. In sharp contrast, the synaptic input in the descending pathway from the OFC was significantly reduced until training completion. Once rule learning was established, the strength of synaptic connectivity in the 2 pathways resumed its pretraining values. We suggest that acquisition of olfactory rule learning requires a transient enhancement of ascending inputs to the PC, synchronized with a parallel decrease in the descending inputs. This combined short-lived modulation enables the PC network to reorganize in a manner that enables it to first acquire and then maintain the rule. PMID:23960200

Computational implications of activity-dependent neuronal processes

NASA Astrophysics Data System (ADS)

Goldman, Mark Steven

Synapses, the connections between neurons, often fail to transmit a large percentage of the action potentials that they receive. I describe several models of synaptic transmission at a single stochastic synapse with an activity-dependent probability of transmission and demonstrate how synaptic transmission failures may increase the efficiency with which a synapse transmits information. Spike trains in the visual cortex of freely viewing monkeys have positive auto correlations that are indicative of a redundant representation of the information they contain. I show how a synapse with activity-dependent transmission failures modeled after those occurring in visual cortical synapses can remove this redundancy by transmitting a decorrelated subset of the spike trains it receives. I suggest that redundancy reduction at individual synapses saves synaptic resources while increasing the sensitivity of the postsynaptic neuron to information arriving along many inputs. For a neuron receiving input from many decorrelating synapses, my analysis leads to a prediction of the number of visual inputs to a neuron and the cross-correlations between these inputs and suggests that the time scale of synaptic dynamics observed in sensory areas corresponds to a fundamental time scale for processing sensory information. Systems with activity-dependent changes in their parameters, or plasticity, often display a wide variability in their individual components that belies the stability of their function, Motivated by experiments demonstrating that identified neurons with stereotyped function can have a large variability in the densities of their ion channels, or ionic conductances, I build a conductance-based model of a single neuron. The neuron's firing activity is relatively insensitive to changes in certain combinations of conductances, but markedly sensitive to changes in other combinations. Using a combined modeling and experimental approach, I show that neuromodulators and regulatory processes target sensitive combinations of conductances. I suggest that the variability observed in conductance measurements occurs along insensitive combinations of conductances and could result from homeostatic processes that allow the neuron's conductances to drift without triggering activity- dependent feedback mechanisms. These results together suggest that plastic systems may have a high degree of flexibility and variability in their components without a loss of robustness in their response properties.

Nonvolatile programmable neural network synaptic array

NASA Technical Reports Server (NTRS)

Tawel, Raoul (Inventor)

1994-01-01

A floating-gate metal oxide semiconductor (MOS) transistor is implemented for use as a nonvolatile analog storage element of a synaptic cell used to implement an array of processing synaptic cells. These cells are based on a four-quadrant analog multiplier requiring both X and Y differential inputs, where one Y input is UV programmable. These nonvolatile synaptic cells are disclosed fully connected in a 32 x 32 synaptic cell array using standard very large scale integration (VLSI) complementary MOS (CMOS) technology.

Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age.

PubMed

McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

2015-11-01

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit-level modifications in middle-age were associated with modest enhancement in contextual fear memory precision, anxiety-like behavior and antidepressant-like behavioral responses. © 2015 Wiley Periodicals, Inc.

Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septo-temporal axis in adulthood and middle age

PubMed Central

McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

2015-01-01

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septo-temporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septo-temporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit-level modifications in middle-age were associated with modest enhancement in contextual fear memory precision, anxiety-like behavior and antidepressant-like behavioral responses. PMID:25850664

Patterns of innervation of neurones in the inferior mesenteric ganglion of the cat.

PubMed Central

Julé, Y; Krier, J; Szurszewski, J H

1983-01-01

The patterns of peripheral and central synaptic input to non-spontaneous, irregular discharging and regular discharging neurones in the inferior mesenteric ganglion of the cat were studied in vitro using intracellular recording techniques. All three types of neurones in rostral and caudal lobes received central synaptic input primarily from L3 and L4 spinal cord segments. Since irregular discharging neurones received synaptic input from intraganglionic regular discharging neurones, some of the central input to irregular discharging neurones may have been relayed through the regular discharging neurones. In the rostral lobes of the ganglion, more than 70% of the non-spontaneous and irregular discharging neurones tested received peripheral synaptic input from the lumbar colonic, intermesenteric and left and right hypogastric nerves. Most of the regular discharging neurones tested received synaptic input from the intermesenteric and lumbar colonic nerves; none of the regular discharging neurones received synaptic input from the hypogastric nerves. Some of the peripheral synaptic input from the lumbar colonic and intermesenteric nerves to irregular discharging neurones may have been relayed through the regular discharging neurones. Axons of non-spontaneous and irregular discharging neurones located in the rostral lobes travelled to the periphery exclusively in the lumbar colonic nerves. Antidromic responses were not observed in regular discharging neurones during stimulation of any of the major peripheral nerve trunks. This suggests these neurones were intraganglionic. In the caudal lobes, irregular discharging neurones received a similar pattern of peripheral synaptic input as did irregular discharging neurones located in the rostral lobes. The majority of irregular discharging neurones in the caudal lobes projected their axons to the periphery through the lumbar colonic nerves. Non-spontaneous neurones in the caudal lobes, in contrast to those located in the rostral lobes, received peripheral synaptic input primarily from the hypogastric nerves. Axons of the majority of non-spontaneous neurones located in the caudal lobes travelled to the periphery through hypogastric nerves. The results suggest that non-spontaneous neurones and irregular discharging neurones in the rostral lobes and the majority of irregular discharging neurones in the caudal lobes transact and integrate neural commands destined for abdominal viscera supplied by the lumbar colonic nerves. Non-spontaneous neurones in the caudal lobes transact and integrate neural commands destined for pelvic viscera supplied by the hypogastric nerves. PMID:6655582

Patterns of innervation of neurones in the inferior mesenteric ganglion of the cat.

PubMed

Julé, Y; Krier, J; Szurszewski, J H

1983-11-01

The patterns of peripheral and central synaptic input to non-spontaneous, irregular discharging and regular discharging neurones in the inferior mesenteric ganglion of the cat were studied in vitro using intracellular recording techniques. All three types of neurones in rostral and caudal lobes received central synaptic input primarily from L3 and L4 spinal cord segments. Since irregular discharging neurones received synaptic input from intraganglionic regular discharging neurones, some of the central input to irregular discharging neurones may have been relayed through the regular discharging neurones. In the rostral lobes of the ganglion, more than 70% of the non-spontaneous and irregular discharging neurones tested received peripheral synaptic input from the lumbar colonic, intermesenteric and left and right hypogastric nerves. Most of the regular discharging neurones tested received synaptic input from the intermesenteric and lumbar colonic nerves; none of the regular discharging neurones received synaptic input from the hypogastric nerves. Some of the peripheral synaptic input from the lumbar colonic and intermesenteric nerves to irregular discharging neurones may have been relayed through the regular discharging neurones. Axons of non-spontaneous and irregular discharging neurones located in the rostral lobes travelled to the periphery exclusively in the lumbar colonic nerves. Antidromic responses were not observed in regular discharging neurones during stimulation of any of the major peripheral nerve trunks. This suggests these neurones were intraganglionic. In the caudal lobes, irregular discharging neurones received a similar pattern of peripheral synaptic input as did irregular discharging neurones located in the rostral lobes. The majority of irregular discharging neurones in the caudal lobes projected their axons to the periphery through the lumbar colonic nerves. Non-spontaneous neurones in the caudal lobes, in contrast to those located in the rostral lobes, received peripheral synaptic input primarily from the hypogastric nerves. Axons of the majority of non-spontaneous neurones located in the caudal lobes travelled to the periphery through hypogastric nerves. The results suggest that non-spontaneous neurones and irregular discharging neurones in the rostral lobes and the majority of irregular discharging neurones in the caudal lobes transact and integrate neural commands destined for abdominal viscera supplied by the lumbar colonic nerves. Non-spontaneous neurones in the caudal lobes transact and integrate neural commands destined for pelvic viscera supplied by the hypogastric nerves.

Morphine treatment enhances glutamatergic input onto neurons of the nucleus accumbens via both disinhibitory and stimulating effect.

PubMed

Yuan, Kejing; Sheng, Huan; Song, Jiaojiao; Yang, Li; Cui, Dongyang; Ma, Qianqian; Zhang, Wen; Lai, Bin; Chen, Ming; Zheng, Ping

2017-11-01

Drug addiction is a chronic brain disorder characterized by the compulsive repeated use of drugs. The reinforcing effect of repeated use of drugs on reward plays an important role in morphine-induced addictive behaviors. The nucleus accumbens (NAc) is an important site where morphine treatment produces its reinforcing effect on reward. However, how morphine treatment produces its reinforcing effect on reward in the NAc remains to be clarified. In the present study, we studied the influence of morphine treatment on the effects of DA and observed whether morphine treatment could directly change glutamatergic synaptic transmission in the NAc. We also explored the functional significance of morphine-induced potentiation of glutamatergic synaptic transmission in the NAc at behavioral level. Our results show that (1) morphine treatment removes the inhibitory effect of DA on glutamatergic input onto NAc neurons; (2) morphine treatment potentiates glutamatergic input onto NAc neurons, especially the one from the basolateral amygdala (BLA) to the NAc; (3) blockade of glutamatergic synaptic transmission in the NAc or ablation of projection neurons from BLA to NAc significantly decreases morphine treatment-induced increase in locomotor activity. These results suggest that morphine treatment enhances glutamatergic input onto neurons of the NAc via both disinhibitory and stimulating effect and therefore increases locomotor activity. © 2016 Society for the Study of Addiction.

Deciphering the contribution of intrinsic and synaptic currents to the effects of transient synaptic inputs on human motor unit discharge

PubMed Central

Powers, Randall K.; Türker, Kemal S.

2010-01-01

The amplitude and time course of synaptic potentials in human motoneurons can be estimated in tonically discharging motor units by measuring stimulus-evoked changes in the rate and probability of motor unit action potentials. However, in spite of the fact that some of these techniques have been used for over thirty years, there is still no consensus on the best way to estimate the characteristics of synaptic potentials or on the accuracy of these estimates. In this review, we compare different techniques for estimating synaptic potentials from human motor unit discharge and also discuss relevant animal models in which estimated synaptic potentials can be compared to those directly measured from intracellular recordings. We also review the experimental evidence on how synaptic noise and intrinsic motoneuron properties influence their responses to synaptic inputs. Finally, we consider to what extent recordings of single motor unit discharge in humans can be used to distinguish the contribution of changes in synaptic inputs versus changes in intrinsic motoneuron properties to altered motoneuron responses following CNS injury. PMID:20427230

Acetylcholine Mediates a Slow Synaptic Potential in Hippocampal Pyramidal Cells

NASA Astrophysics Data System (ADS)

Cole, A. E.; Nicoll, R. A.

1983-09-01

The hippocampal slice preparation was used to study the role of acetylcholine as a synaptic transmitter. Bath-applied acetylcholine had three actions on pyramidal cells: (i) depolarization associated with increased input resistance, (ii) blockade of calcium-activated potassium responses, and (iii) blockade of accommodation of cell discharge. All these actions were reversed by the muscarinic antagonist atropine. Stimulation of sites in the slice known to contain cholinergic fibers mimicked all the actions. Furthermore, these evoked synaptic responses were enhanced by the cholinesterase inhibitor eserine and were blocked by atropine. These findings provide electrophysiological support for the role of acetylcholine as a synaptic transmitter in the brain and demonstrate that nonclassical synaptic responses involving the blockade of membrane conductances exist in the brain.

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

PubMed Central

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. PMID:25566045

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

PubMed

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.

Theta frequency background tunes transmission but not summation of spiking responses.

PubMed

Parameshwaran, Dhanya; Bhalla, Upinder S

2013-01-01

Hippocampal neurons are known to fire as a function of frequency and phase of spontaneous network rhythms, associated with the animal's behaviour. This dependence is believed to give rise to precise rate and temporal codes. However, it is not well understood how these periodic membrane potential fluctuations affect the integration of synaptic inputs. Here we used sinusoidal current injection to the soma of CA1 pyramidal neurons in the rat brain slice to simulate background oscillations in the physiologically relevant theta and gamma frequency range. We used a detailed compartmental model to show that somatic current injection gave comparable results to more physiological synaptically driven theta rhythms incorporating excitatory input in the dendrites, and inhibitory input near the soma. We systematically varied the phase of synaptic inputs with respect to this background, and recorded changes in response and summation properties of CA1 neurons using whole-cell patch recordings. The response of the cell was dependent on both the phase of synaptic inputs and frequency of the background input. The probability of the cell spiking for a given synaptic input was up to 40% greater during the depolarized phases between 30-135 degrees of theta frequency current injection. Summation gain on the other hand, was not affected either by the background frequency or the phasic afferent inputs. This flat summation gain, coupled with the enhanced spiking probability during depolarized phases of the theta cycle, resulted in enhanced transmission of summed inputs during the same phase window of 30-135 degrees. Overall, our study suggests that although oscillations provide windows of opportunity to selectively boost transmission and EPSP size, summation of synaptic inputs remains unaffected during membrane oscillations.

Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization.

PubMed

Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

2014-08-01

An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.

Glutamic Acid Decarboxylase 65: A Link Between GABAergic Synaptic Plasticity in the Lateral Amygdala and Conditioned Fear Generalization

PubMed Central

Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

2014-01-01

An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders. PMID:24663011

Mechanisms for Selective Single-Cell Reactivation during Offline Sharp-Wave Ripples and Their Distortion by Fast Ripples.

PubMed

Valero, Manuel; Averkin, Robert G; Fernandez-Lamo, Ivan; Aguilar, Juan; Lopez-Pigozzi, Diego; Brotons-Mas, Jorge R; Cid, Elena; Tamas, Gabor; Menendez de la Prida, Liset

2017-06-21

Memory traces are reactivated selectively during sharp-wave ripples. The mechanisms of selective reactivation, and how degraded reactivation affects memory, are poorly understood. We evaluated hippocampal single-cell activity during physiological and pathological sharp-wave ripples using juxtacellular and intracellular recordings in normal and epileptic rats with different memory abilities. CA1 pyramidal cells participate selectively during physiological events but fired together during epileptic fast ripples. We found that firing selectivity was dominated by an event- and cell-specific synaptic drive, modulated in single cells by changes in the excitatory/inhibitory ratio measured intracellularly. This mechanism collapses during pathological fast ripples to exacerbate and randomize neuronal firing. Acute administration of a use- and cell-type-dependent sodium channel blocker reduced neuronal collapse and randomness and improved recall in epileptic rats. We propose that cell-specific synaptic inputs govern firing selectivity of CA1 pyramidal cells during sharp-wave ripples. Copyright © 2017 Elsevier Inc. All rights reserved.

Arc expression identifies the lateral amygdala fear memory trace

PubMed Central

Gouty-Colomer, L A; Hosseini, B; Marcelo, I M; Schreiber, J; Slump, D E; Yamaguchi, S; Houweling, A R; Jaarsma, D; Elgersma, Y; Kushner, S A

2016-01-01

Memories are encoded within sparsely distributed neuronal ensembles. However, the defining cellular properties of neurons within a memory trace remain incompletely understood. Using a fluorescence-based Arc reporter, we were able to visually identify the distinct subset of lateral amygdala (LA) neurons activated during auditory fear conditioning. We found that Arc-expressing neurons have enhanced intrinsic excitability and are preferentially recruited into newly encoded memory traces. Furthermore, synaptic potentiation of thalamic inputs to the LA during fear conditioning is learning-specific, postsynaptically mediated and highly localized to Arc-expressing neurons. Taken together, our findings validate the immediate-early gene Arc as a molecular marker for the LA neuronal ensemble recruited during fear learning. Moreover, these results establish a model of fear memory formation in which intrinsic excitability determines neuronal selection, whereas learning-related encoding is governed by synaptic plasticity. PMID:25802982

Genetically increased cell-intrinsic excitability enhances neuronal integration into adult brain circuits

PubMed Central

Lin, Chia-Wei; Sim, Shuyin; Ainsworth, Alice; Okada, Masayoshi; Kelsch, Wolfgang; Lois, Carlos

2009-01-01

New neurons are added to the adult brain throughout life, but only half ultimately integrate into existing circuits. Sensory experience is an important regulator of the selection of new neurons but it remains unknown whether experience provides specific patterns of synaptic input, or simply a minimum level of overall membrane depolarization critical for integration. To investigate this issue, we genetically modified intrinsic electrical properties of adult-generated neurons in the mammalian olfactory bulb. First, we observed that suppressing levels of cell-intrinsic neuronal activity via expression of ESKir2.1 potassium channels decreases, whereas enhancing activity via expression of NaChBac sodium channels increases survival of new neurons. Neither of these modulations affects synaptic formation. Furthermore, even when neurons are induced to fire dramatically altered patterns of action potentials, increased levels of cell-intrinsic activity completely blocks cell death triggered by NMDA receptor deletion. These findings demonstrate that overall levels of cell-intrinsic activity govern survival of new neurons and precise firing patterns are not essential for neuronal integration into existing brain circuits. PMID:20152111

Synaptic Effects of Electric Fields

NASA Astrophysics Data System (ADS)

Rahman, Asif

Learning and sensory processing in the brain relies on the effective transmission of information across synapses. The strength and efficacy of synaptic transmission is modifiable through training and can be modulated with noninvasive electrical brain stimulation. Transcranial electrical stimulation (TES), specifically, induces weak intensity and spatially diffuse electric fields in the brain. Despite being weak, electric fields modulate spiking probability and the efficacy of synaptic transmission. These effects critically depend on the direction of the electric field relative to the orientation of the neuron and on the level of endogenous synaptic activity. TES has been used to modulate a wide range of neuropsychiatric indications, for various rehabilitation applications, and cognitive performance in diverse tasks. How can a weak and diffuse electric field, which simultaneously polarizes neurons across the brain, have precise changes in brain function? Designing therapies to maximize desired outcomes and minimize undesired effects presents a challenging problem. A series of experiments and computational models are used to define the anatomical and functional factors leading to specificity of TES. Anatomical specificity derives from guiding current to targeted brain structures and taking advantage of the direction-sensitivity of neurons with respect to the electric field. Functional specificity originates from preferential modulation of neuronal networks that are already active. Diffuse electric fields may recruit connected brain networks involved in a training task and promote plasticity along active synaptic pathways. In vitro, electric fields boost endogenous synaptic plasticity and raise the ceiling for synaptic learning with repeated stimulation sessions. Synapses undergoing strong plasticity are preferentially modulated over weak synapses. Therefore, active circuits that are involved in a task could be more susceptible to stimulation than inactive circuits. Moreover, stimulation polarity has asymmetric effects on synaptic strength making it easier to enhance ongoing plasticity. These results suggest that the susceptibility of brain networks to an electric field depends on the state of synaptic activity. Combining a training task, which activates specific circuits, with TES may lead to functionally-specific effects. Given the simplicity of TES and the complexity of brain function, understanding the mechanisms leading to specificity is fundamental to the rational advancement of TES.

A model of activity-dependent changes in dendritic spine density and spine structure.

PubMed

Crook, S M; Dur-E-Ahmad, M; Baer, S M

2007-10-01

Recent evidence indicates that the morphology and density of dendritic spines are regulated during synaptic plasticity. See, for instance, a review by Hayashi and Majewska [9]. In this work, we extend previous modeling studies [27] by combining a model for activity-dependent spine density with one for calcium-mediated spine stem restructuring. The model is based on the standard dimensionless cable equation, which represents the change in the membrane potential in a passive dendrite. Additional equations characterize the change in spine density along the dendrite, the current balance equation for an individual spine head, the change in calcium concentration in the spine head, and the dynamics of spine stem resistance. We use computational studies to investigate the changes in spine density and structure for differing synaptic inputs and demonstrate the effects of these changes on the input-output properties of the dendritic branch. Moderate amounts of high-frequency synaptic activation to dendritic spines result in an increase in spine stem resistance that is correlated with spine stem elongation. In addition, the spine density increases both inside and outside the input region. The model is formulated so that this long-term potentiation-inducing stimulus eventually leads to structural stability. In contrast, a prolonged low-frequency stimulation paradigm that would typically induce long-term depression results in a decrease in stem resistance (correlated with stem shortening) and an eventual decrease in spine density.

Electrophysical properties, synaptic transmission and neuromodulation in serotonergic caudal raphe neurons.

PubMed

Li, Y W; Bayliss, D A

1998-06-01

1. We studied electrophysiological properties, synaptic transmission and modulation by 5-hydroxytryptamine (5-HT) of caudal raphe neurons using whole-cell recording in a neonatal rat brain slice preparation; recorded neurons were identified as serotonergic by post-hoc immunohistochemical detection of tryptophan hydroxylase, the 5-HT-synthesizing enzyme. 2. Serotonergic neurons fired spontaneously (approximately 1 Hz), with maximal steady state firing rates of < 4 Hz. 5-Hydroxytryptamine caused hyperpolarization and cessation of spike activity in these neurons by activating inwardly rectifying K+ conductance via somatodendritic 5-HT1A receptors. 3. Unitary glutamatergic excitatory post-synaptic potentials (EPSP) and currents (EPSC) were evoked in serotonergic neurons by local electrical stimulation. Evoked EPSC were potently inhibited by 5-HT, an effect mediated by presynaptic 5-HT1B receptors. 4. In conclusion, serotonergic caudal raphe neurons are spontaneously active in vitro; they receive prominent glutamatergic synaptic inputs. 5-Hydroxytryptamine regulates serotonergic neuronal activity of the caudal raphe by decreasing spontaneous activity via somatodendritic 5-HT1A receptors and by inhibiting excitatory synaptic transmission onto these neurons via presynaptic 5-HT1B receptors. These local modulatory mechanisms provide multiple levels of feedback autoregulation of serotonergic raphe neurons by 5-HT.

The Balance of Excitatory and Inhibitory Synaptic Inputs for Coding Sound Location

PubMed Central

Ono, Munenori

2014-01-01

The localization of high-frequency sounds in the horizontal plane uses an interaural-level difference (ILD) cue, yet little is known about the synaptic mechanisms that underlie processing this cue in the inferior colliculus (IC) of mouse. Here, we study the synaptic currents that process ILD in vivo and use stimuli in which ILD varies around a constant average binaural level (ABL) to approximate sounds on the horizontal plane. Monaural stimulation in either ear produced EPSCs and IPSCs in most neurons. The temporal properties of monaural responses were well matched, suggesting connected functional zones with matched inputs. The EPSCs had three patterns in response to ABL stimuli, preference for the sound field with the highest level stimulus: (1) contralateral; (2) bilateral highly lateralized; or (3) at the center near 0 ILD. EPSCs and IPSCs were well correlated except in center-preferred neurons. Summation of the monaural EPSCs predicted the binaural excitatory response but less well than the summation of monaural IPSCs. Binaural EPSCs often showed a nonlinearity that strengthened the response to specific ILDs. Extracellular spike and intracellular current recordings from the same neuron showed that the ILD tuning of the spikes was sharper than that of the EPSCs. Thus, in the IC, balanced excitatory and inhibitory inputs may be a general feature of synaptic coding for many types of sound processing. PMID:24599475

Dynamics of Action Potential Initiation in the GABAergic Thalamic Reticular Nucleus In Vivo

PubMed Central

Muñoz, Fabián; Fuentealba, Pablo

2012-01-01

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold. PMID:22279567

Emerging feed-forward inhibition allows the robust formation of direction selectivity in the developing ferret visual cortex

PubMed Central

Escobar, Gina M.; Maffei, Arianna; Miller, Paul

2014-01-01

The computation of direction selectivity requires that a cell respond to joint spatial and temporal characteristics of the stimulus that cannot be separated into independent components. Direction selectivity in ferret visual cortex is not present at the time of eye opening but instead develops in the days and weeks following eye opening in a process that requires visual experience with moving stimuli. Classic Hebbian or spike timing-dependent modification of excitatory feed-forward synaptic inputs is unable to produce direction-selective cells from unselective or weakly directionally biased initial conditions because inputs eventually grow so strong that they can independently drive cortical neurons, violating the joint spatial-temporal activation requirement. Furthermore, without some form of synaptic competition, cells cannot develop direction selectivity in response to training with bidirectional stimulation, as cells in ferret visual cortex do. We show that imposing a maximum lateral geniculate nucleus (LGN)-to-cortex synaptic weight allows neurons to develop direction-selective responses that maintain the requirement for joint spatial and temporal activation. We demonstrate that a novel form of inhibitory plasticity, postsynaptic activity-dependent long-term potentiation of inhibition (POSD-LTPi), which operates in the developing cortex at the time of eye opening, can provide synaptic competition and enables robust development of direction-selective receptive fields with unidirectional or bidirectional stimulation. We propose a general model of the development of spatiotemporal receptive fields that consists of two phases: an experience-independent establishment of initial biases, followed by an experience-dependent amplification or modification of these biases via correlation-based plasticity of excitatory inputs that compete against gradually increasing feed-forward inhibition. PMID:24598528

Presynaptic Regulation of Leptin in a Defined Lateral Hypothalamus-Ventral Tegmental Area Neurocircuitry Depends on Energy State.

PubMed

Liu, Jing-Jing; Bello, Nicholas T; Pang, Zhiping P

2017-12-06

Synaptic transmission controls brain activity and behaviors, including food intake. Leptin, an adipocyte-derived hormone, acts on neurons located in the lateral hypothalamic area (LHA) to maintain energy homeostasis and regulate food intake behavior. The specific synaptic mechanisms, cell types, and neural projections mediating this effect remain unclear. In male mice, using pathway-specific retrograde tracing, whole-cell patch-clamp recordings and post hoc cell type identification, we found that leptin reduces excitatory synaptic strength onto both melanin-concentrating hormone- and orexin-expressing neurons projecting from the LHA to the ventral tegmental area (VTA), which may affect dopamine signaling and motivation for feeding. A presynaptic mechanism mediated by distinct intracellular signaling mechanisms may account for this regulation by leptin. The regulatory effects of leptin depend on intact leptin receptor signaling. Interestingly, the synaptic regulatory function of leptin in the LHA-to-VTA neuronal pathway is highly sensitive to energy states: both energy deficiency (acute fasting) and excessive energy storage (high-fat diet-induced obesity) blunt the effect of leptin. These data revealed that leptin may regulate synaptic transmission in the LHA-to-VTA neurocircuitry in an inverted "U-shape" fashion dependent on plasma glucose levels and related to metabolic states. SIGNIFICANCE STATEMENT The lateral hypothalamic area (LHA) to ventral tegmental area (VTA) projection is an important neural pathway involved in balancing whole-body energy states and reward. We found that the excitatory synaptic inputs to both orexin- and melanin-concentrating hormone expressing LHA neurons projecting to the VTA were suppressed by leptin, a peptide hormone derived from adipocytes that signals peripheral energy status to the brain. Interestingly, energy states seem to affect how leptin regulates synaptic transmission since both the depletion of energy induced by acute food deprivation and excessive storage of energy by high-fat diet feeding dampen the suppressive effect of leptin on synaptic transmission. Together, these data show that leptin regulates synaptic transmission and might be important for maintaining energy homeostasis. Copyright © 2017 the authors 0270-6474/17/3711854-13$15.00/0.

Dendritic GIRK Channels Gate the Integration Window, Plateau Potentials, and Induction of Synaptic Plasticity in Dorsal But Not Ventral CA1 Neurons

PubMed Central

2017-01-01

Studies comparing neuronal activity at the dorsal and ventral poles of the hippocampus have shown that the scale of spatial information increases and the precision with which space is represented declines from the dorsal to ventral end. These dorsoventral differences in neuronal output and spatial representation could arise due to differences in computations performed by dorsal and ventral CA1 neurons. In this study, we tested this hypothesis by quantifying the differences in dendritic integration and synaptic plasticity between dorsal and ventral CA1 pyramidal neurons of rat hippocampus. Using a combination of somatic and dendritic patch-clamp recordings, we show that the threshold for LTP induction is higher in dorsal CA1 neurons and that a G-protein-coupled inward-rectifying potassium channel mediated regulation of dendritic plateau potentials and dendritic excitability underlies this gating. By contrast, similar regulation of LTP is absent in ventral CA1 neurons. Additionally, we show that generation of plateau potentials and LTP induction in dorsal CA1 neurons depends on the coincident activation of Schaffer collateral and temporoammonic inputs at the distal apical dendrites. The ventral CA1 dendrites, however, can generate plateau potentials in response to temporally dispersed excitatory inputs. Overall, our results highlight the dorsoventral differences in dendritic computation that could account for the dorsoventral differences in spatial representation. SIGNIFICANCE STATEMENT The dorsal and ventral parts of the hippocampus encode spatial information at very different scales. Whereas the place-specific firing fields are small and precise at the dorsal end of the hippocampus, neurons at the ventral end have comparatively larger place fields. Here, we show that the dorsal CA1 neurons have a higher threshold for LTP induction and require coincident timing of excitatory synaptic inputs for the generation of dendritic plateau potentials. By contrast, ventral CA1 neurons can integrate temporally dispersed inputs and have a lower threshold for LTP. Together, these dorsoventral differences in the threshold for LTP induction could account for the differences in scale of spatial representation at the dorsal and ventral ends of the hippocampus. PMID:28280255

Dendritic GIRK Channels Gate the Integration Window, Plateau Potentials, and Induction of Synaptic Plasticity in Dorsal But Not Ventral CA1 Neurons.

PubMed

Malik, Ruchi; Johnston, Daniel

2017-04-05

Studies comparing neuronal activity at the dorsal and ventral poles of the hippocampus have shown that the scale of spatial information increases and the precision with which space is represented declines from the dorsal to ventral end. These dorsoventral differences in neuronal output and spatial representation could arise due to differences in computations performed by dorsal and ventral CA1 neurons. In this study, we tested this hypothesis by quantifying the differences in dendritic integration and synaptic plasticity between dorsal and ventral CA1 pyramidal neurons of rat hippocampus. Using a combination of somatic and dendritic patch-clamp recordings, we show that the threshold for LTP induction is higher in dorsal CA1 neurons and that a G-protein-coupled inward-rectifying potassium channel mediated regulation of dendritic plateau potentials and dendritic excitability underlies this gating. By contrast, similar regulation of LTP is absent in ventral CA1 neurons. Additionally, we show that generation of plateau potentials and LTP induction in dorsal CA1 neurons depends on the coincident activation of Schaffer collateral and temporoammonic inputs at the distal apical dendrites. The ventral CA1 dendrites, however, can generate plateau potentials in response to temporally dispersed excitatory inputs. Overall, our results highlight the dorsoventral differences in dendritic computation that could account for the dorsoventral differences in spatial representation. SIGNIFICANCE STATEMENT The dorsal and ventral parts of the hippocampus encode spatial information at very different scales. Whereas the place-specific firing fields are small and precise at the dorsal end of the hippocampus, neurons at the ventral end have comparatively larger place fields. Here, we show that the dorsal CA1 neurons have a higher threshold for LTP induction and require coincident timing of excitatory synaptic inputs for the generation of dendritic plateau potentials. By contrast, ventral CA1 neurons can integrate temporally dispersed inputs and have a lower threshold for LTP. Together, these dorsoventral differences in the threshold for LTP induction could account for the differences in scale of spatial representation at the dorsal and ventral ends of the hippocampus. Copyright © 2017 the authors 0270-6474/17/373940-16$15.00/0.

Synaptic depolarization is more effective than back-propagating action potentials during induction of associative long-term potentiation in hippocampal pyramidal neurons.

PubMed

Hardie, Jason; Spruston, Nelson

2009-03-11

Long-term potentiation (LTP) requires postsynaptic depolarization that can result from EPSPs paired with action potentials or larger EPSPs that trigger dendritic spikes. We explored the relative contribution of these sources of depolarization to LTP induction during synaptically driven action potential firing in hippocampal CA1 pyramidal neurons. Pairing of a weak test input with a strong input resulted in large LTP (approximately 75% increase) when the weak and strong inputs were both located in the apical dendrites. This form of LTP did not require somatic action potentials. When the strong input was located in the basal dendrites, the resulting LTP was smaller (< or =25% increase). Pairing the test input with somatically evoked action potentials mimicked this form of LTP. Thus, back-propagating action potentials may contribute to modest LTP, but local synaptic depolarization and/or dendritic spikes mediate a stronger form of LTP that requires spatial proximity of the associated synaptic inputs.

Rebound spiking in layer II medial entorhinal cortex stellate cells: Possible mechanism of grid cell function

PubMed Central

Shay, Christopher F.; Ferrante, Michele; Chapman, G. William; Hasselmo, Michael E.

2015-01-01

Rebound spiking properties of medial entorhinal cortex (mEC) stellate cells induced by inhibition may underlie their functional properties in awake behaving rats, including the temporal phase separation of distinct grid cells and differences in grid cell firing properties. We investigated rebound spiking properties using whole cell patch recording in entorhinal slices, holding cells near spiking threshold and delivering sinusoidal inputs, superimposed with realistic inhibitory synaptic inputs to test the capacity of cells to selectively respond to specific phases of inhibitory input. Stellate cells showed a specific phase range of hyperpolarizing inputs that elicited spiking, but non-stellate cells did not show phase specificity. In both cell types, the phase range of spiking output occurred between the peak and subsequent descending zero crossing of the sinusoid. The phases of inhibitory inputs that induced spikes shifted earlier as the baseline sinusoid frequency increased, while spiking output shifted to later phases. Increases in magnitude of the inhibitory inputs shifted the spiking output to earlier phases. Pharmacological blockade of h-current abolished the phase selectivity of hyperpolarizing inputs eliciting spikes. A network computational model using cells possessing similar rebound properties as found in vitro produces spatially periodic firing properties resembling grid cell firing when a simulated animal moves along a linear track. These results suggest that the ability of mEC stellate cells to fire rebound spikes in response to a specific range of phases of inhibition could support complex attractor dynamics that provide completion and separation to maintain spiking activity of specific grid cell populations. PMID:26385258

Monitoring synaptic and neuronal activity in 3D with synthetic and genetic indicators using a compact acousto-optic lens two-photon microscope☆

PubMed Central

Fernández-Alfonso, Tomás; Nadella, K.M. Naga Srinivas; Iacaruso, M. Florencia; Pichler, Bruno; Roš, Hana; Kirkby, Paul A.; Silver, R. Angus

2014-01-01

Background Two-photon microscopy is widely used to study brain function, but conventional microscopes are too slow to capture the timing of neuronal signalling and imaging is restricted to one plane. Recent development of acousto-optic-deflector-based random access functional imaging has improved the temporal resolution, but the utility of these technologies for mapping 3D synaptic activity patterns and their performance at the excitation wavelengths required to image genetically encoded indicators have not been investigated. New method Here, we have used a compact acousto-optic lens (AOL) two-photon microscope to make high speed [Ca2+] measurements from spines and dendrites distributed in 3D with different excitation wavelengths (800–920 nm). Results We show simultaneous monitoring of activity from many synaptic inputs distributed over the 3D arborisation of a neuronal dendrite using both synthetic as well as genetically encoded indicators. We confirm the utility of AOL-based imaging for fast in vivo recordings by measuring, simultaneously, visually evoked responses in 100 neurons distributed over a 150 μm focal depth range. Moreover, we explore ways to improve the measurement of timing of neuronal activation by choosing specific regions within the cell soma. Comparison with existing methods These results establish that AOL-based 3D random access two-photon microscopy has a wider range of neuroscience applications than previously shown. Conclusions Our findings show that the compact AOL microscope design has the speed, spatial resolution, sensitivity and wavelength flexibility to measure 3D patterns of synaptic and neuronal activity on individual trials. PMID:24200507

Peripheral oxygen-sensing cells directly modulate the output of an identified respiratory central pattern generating neuron.

PubMed

Bell, Harold J; Inoue, Takuya; Shum, Kelly; Luk, Collin; Syed, Naweed I

2007-06-01

Breathing is an essential homeostatic behavior regulated by central neuronal networks, often called central pattern generators (CPGs). Despite ongoing advances in our understanding of the neural control of breathing, the basic mechanisms by which peripheral input modulates the activities of the central respiratory CPG remain elusive. This lack of fundamental knowledge vis-à-vis the role of peripheral influences in the control of the respiratory CPG is due in large part to the complexity of mammalian respiratory control centres. We have therefore developed a simpler invertebrate model to study the basic cellular and synaptic mechanisms by which a peripheral chemosensory input affects the central respiratory CPG. Here we report on the identification and characterization of peripheral chemoreceptor cells (PCRCs) that relay hypoxia-sensitive chemosensory information to the known respiratory CPG neuron right pedal dorsal 1 in the mollusk Lymnaea stagnalis. Selective perfusion of these PCRCs with hypoxic saline triggered bursting activity in these neurons and when isolated in cell culture these cells also demonstrated hypoxic sensitivity that resulted in membrane depolarization and spiking activity. When cocultured with right pedal dorsal 1, the PCRCs developed synapses that exhibited a form of short-term synaptic plasticity in response to hypoxia. Finally, osphradial denervation in intact animals significantly perturbed respiratory activity compared with their sham counterparts. This study provides evidence for direct synaptic connectivity between a peripheral regulatory element and a central respiratory CPG neuron, revealing a potential locus for hypoxia-induced synaptic plasticity underlying breathing behavior.

Prefrontal Cortex HCN1 Channels Enable Intrinsic Persistent Neural Firing and Executive Memory Function

PubMed Central

Thuault, Sébastien J.; Malleret, Gaël; Constantinople, Christine M.; Nicholls, Russell; Chen, Irene; Zhu, Judy; Panteleyev, Andrey; Vronskaya, Svetlana; Nolan, Matthew F.; Bruno, Randy

2013-01-01

In many cortical neurons, HCN1 channels are the major contributors to Ih, the hyperpolarization-activated current, which regulates the intrinsic properties of neurons and shapes their integration of synaptic inputs, paces rhythmic activity, and regulates synaptic plasticity. Here, we examine the physiological role of Ih in deep layer pyramidal neurons in mouse prefrontal cortex (PFC), focusing on persistent activity, a form of sustained firing thought to be important for the behavioral function of the PFC during working memory tasks. We find that HCN1 contributes to the intrinsic persistent firing that is induced by a brief depolarizing current stimulus in the presence of muscarinic agonists. Deletion of HCN1 or acute pharmacological blockade of Ih decreases the fraction of neurons capable of generating persistent firing. The reduction in persistent firing is caused by the membrane hyperpolarization that results from the deletion of HCN1 or Ih blockade, rather than a specific role of the hyperpolarization-activated current in generating persistent activity. In vivo recordings show that deletion of HCN1 has no effect on up states, periods of enhanced synaptic network activity. Parallel behavioral studies demonstrate that HCN1 contributes to the PFC-dependent resolution of proactive interference during working memory. These results thus provide genetic evidence demonstrating the importance of HCN1 to intrinsic persistent firing and the behavioral output of the PFC. The causal role of intrinsic persistent firing in PFC-mediated behavior remains an open question. PMID:23966682

Translocation of CaMKII to dendritic microtubules supports the plasticity of local synapses

PubMed Central

Lemieux, Mado; Labrecque, Simon; Tardif, Christian; Labrie-Dion, Étienne; LeBel, Éric

2012-01-01

The processing of excitatory synaptic inputs involves compartmentalized dendritic Ca2+ oscillations. The downstream signaling evoked by these local Ca2+ transients and their impact on local synaptic development and remodeling are unknown. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an important decoder of Ca2+ signals and mediator of synaptic plasticity. In addition to its known accumulation at spines, we observed with live imaging the dynamic recruitment of CaMKII to dendritic subdomains adjacent to activated synapses in cultured hippocampal neurons. This localized and transient enrichment of CaMKII to dendritic sites coincided spatially and temporally with dendritic Ca2+ transients. We show that it involved an interaction with microtubular elements, required activation of the kinase, and led to localized dendritic CaMKII autophosphorylation. This process was accompanied by the adjacent remodeling of spines and synaptic AMPA receptor insertion. Replacement of endogenous CaMKII with a mutant that cannot translocate within dendrites lessened this activity-dependent synaptic plasticity. Thus, CaMKII could decode compartmental dendritic Ca2+ transients to support remodeling of local synapses. PMID:22965911

Serotonin 1B Receptors Regulate Prefrontal Function by Gating Callosal and Hippocampal Inputs.

PubMed

Kjaerby, Celia; Athilingam, Jegath; Robinson, Sarah E; Iafrati, Jillian; Sohal, Vikaas S

2016-12-13

Both medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety; however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency mPFC activity (4-12 Hz), and reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function, including anxiety-related behaviors. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Cortical network reorganization guided by sensory input features.

PubMed

Kilgard, Michael P; Pandya, Pritesh K; Engineer, Navzer D; Moucha, Raluca

2002-12-01

Sensory experience alters the functional organization of cortical networks. Previous studies using behavioral training motivated by aversive or rewarding stimuli have demonstrated that cortical plasticity is specific to salient inputs in the sensory environment. Sensory experience associated with electrical activation of the basal forebrain (BasF) generates similar input specific plasticity. By directly engaging plasticity mechanisms and avoiding extensive behavioral training, BasF stimulation makes it possible to efficiently explore how specific sensory features contribute to cortical plasticity. This review summarizes our observations that cortical networks employ a variety of strategies to improve the representation of the sensory environment. Different combinations of receptive-field, temporal, and spectrotemporal plasticity were generated in primary auditory cortex neurons depending on the pitch, modulation rate, and order of sounds paired with BasF stimulation. Simple tones led to map expansion, while modulated tones altered the maximum cortical following rate. Exposure to complex acoustic sequences led to the development of combination-sensitive responses. This remodeling of cortical response characteristics may reflect changes in intrinsic cellular mechanisms, synaptic efficacy, and local neuronal connectivity. The intricate relationship between the pattern of sensory activation and cortical plasticity suggests that network-level rules alter the functional organization of the cortex to generate the most behaviorally useful representation of the sensory environment.

Neurophysiological modification of CA1 pyramidal neurons in a transgenic mouse expressing a truncated form of disrupted-in-schizophrenia 1

PubMed Central

Booth, Clair A; Brown, Jonathan T; Randall, Andrew D

2014-01-01

A t(1;11) balanced chromosomal translocation transects the Disc1 gene in a large Scottish family and produces genome-wide linkage to schizophrenia and recurrent major depressive disorder. This study describes our in vitro investigations into neurophysiological function in hippocampal area CA1 of a transgenic mouse (DISC1tr) that expresses a truncated version of DISC1 designed to reproduce aspects of the genetic situation in the Scottish t(1;11) pedigree. We employed both patch-clamp and extracellular recording methods in vitro to compare intrinsic properties and synaptic function and plasticity between DISC1tr animals and wild-type littermates. Patch-clamp analysis of CA1 pyramidal neurons (CA1-PNs) revealed no genotype dependence in multiple subthreshold parameters, including resting potential, input resistance, hyperpolarization-activated ‘sag’ and resonance properties. Suprathreshold stimuli revealed no alteration to action potential (AP) waveform, although the initial rate of AP production was higher in DISC1tr mice. No difference was observed in afterhyperpolarizing potentials following trains of 5–25 APs at 50 Hz. Patch-clamp analysis of synaptic responses in the Schaffer collateral commissural (SC) pathway indicated no genotype-dependence of paired pulse facilitation, excitatory postsynaptic potential summation or AMPA/NMDA ratio. Extracellular recordings also revealed an absence of changes to SC synaptic responses and indicated input–output and short-term plasticity were also unaltered in the temporoammonic (TA) input. However, in DISC1tr mice theta burst-induced long-term potentiation was enhanced in the SC pathway but completely lost in the TA pathway. These data demonstrate that expressing a truncated form of DISC1 affects intrinsic properties of CA1-PNs and produces pathway-specific effects on long-term synaptic plasticity. PMID:24712988

Sequential estimation of intrinsic activity and synaptic input in single neurons by particle filtering with optimal importance density

NASA Astrophysics Data System (ADS)

Closas, Pau; Guillamon, Antoni

2017-12-01

This paper deals with the problem of inferring the signals and parameters that cause neural activity to occur. The ultimate challenge being to unveil brain's connectivity, here we focus on a microscopic vision of the problem, where single neurons (potentially connected to a network of peers) are at the core of our study. The sole observation available are noisy, sampled voltage traces obtained from intracellular recordings. We design algorithms and inference methods using the tools provided by stochastic filtering that allow a probabilistic interpretation and treatment of the problem. Using particle filtering, we are able to reconstruct traces of voltages and estimate the time course of auxiliary variables. By extending the algorithm, through PMCMC methodology, we are able to estimate hidden physiological parameters as well, like intrinsic conductances or reversal potentials. Last, but not least, the method is applied to estimate synaptic conductances arriving at a target cell, thus reconstructing the synaptic excitatory/inhibitory input traces. Notably, the performance of these estimations achieve the theoretical lower bounds even in spiking regimes.

Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus.

PubMed

Zhou, Li; Liu, Ming-Zhe; Li, Qing; Deng, Juan; Mu, Di; Sun, Yan-Gang

2017-03-21

Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN) of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The human motor neuron pools receive a dominant slow‐varying common synaptic input

PubMed Central

Negro, Francesco; Yavuz, Utku Şükrü

2016-01-01

Key points Motor neurons in a pool receive both common and independent synaptic inputs, although the proportion and role of their common synaptic input is debated.Classic correlation techniques between motor unit spike trains do not measure the absolute proportion of common input and have limitations as a result of the non‐linearity of motor neurons.We propose a method that for the first time allows an accurate quantification of the absolute proportion of low frequency common synaptic input (<5 Hz) to motor neurons in humans.We applied the proposed method to three human muscles and determined experimentally that they receive a similar large amount (>60%) of common input, irrespective of their different functional and control properties.These results increase our knowledge about the role of common and independent input to motor neurons in force control. Abstract Motor neurons receive both common and independent synaptic inputs. This observation is classically based on the presence of a significant correlation between pairs of motor unit spike trains. The functional significance of different relative proportions of common input across muscles, individuals and conditions is still debated. One of the limitations in our understanding of correlated input to motor neurons is that it has not been possible so far to quantify the absolute proportion of common input with respect to the total synaptic input received by the motor neurons. Indeed, correlation measures of pairs of output spike trains only allow for relative comparisons. In the present study, we report for the first time an approach for measuring the proportion of common input in the low frequency bandwidth (<5 Hz) to a motor neuron pool in humans. This estimate is based on a phenomenological model and the theoretical fitting of the experimental values of coherence between the permutations of groups of motor unit spike trains. We demonstrate the validity of this theoretical estimate with several simulations. Moreover, we applied this method to three human muscles: the abductor digiti minimi, tibialis anterior and vastus medialis. Despite these muscles having different functional roles and control properties, as confirmed by the results of the present study, we estimate that their motor pools receive a similar and large (>60%) proportion of common low frequency oscillations with respect to their total synaptic input. These results suggest that the central nervous system provides a large amount of common input to motor neuron pools, in a similar way to that for muscles with different functional and control properties. PMID:27151459

Spatially Distributed Dendritic Resonance Selectively Filters Synaptic Input

PubMed Central

Segev, Idan; Shamma, Shihab

2014-01-01

An important task performed by a neuron is the selection of relevant inputs from among thousands of synapses impinging on the dendritic tree. Synaptic plasticity enables this by strenghtening a subset of synapses that are, presumably, functionally relevant to the neuron. A different selection mechanism exploits the resonance of the dendritic membranes to preferentially filter synaptic inputs based on their temporal rates. A widely held view is that a neuron has one resonant frequency and thus can pass through one rate. Here we demonstrate through mathematical analyses and numerical simulations that dendritic resonance is inevitably a spatially distributed property; and therefore the resonance frequency varies along the dendrites, and thus endows neurons with a powerful spatiotemporal selection mechanism that is sensitive both to the dendritic location and the temporal structure of the incoming synaptic inputs. PMID:25144440

The Corticohippocampal Circuit, Synaptic Plasticity, and Memory

PubMed Central

Basu, Jayeeta; Siegelbaum, Steven A.

2015-01-01

Synaptic plasticity serves as a cellular substrate for information storage in the central nervous system. The entorhinal cortex (EC) and hippocampus are interconnected brain areas supporting basic cognitive functions important for the formation and retrieval of declarative memories. Here, we discuss how information flow in the EC–hippocampal loop is organized through circuit design. We highlight recently identified corticohippocampal and intrahippocampal connections and how these long-range and local microcircuits contribute to learning. This review also describes various forms of activity-dependent mechanisms that change the strength of corticohippocampal synaptic transmission. A key point to emerge from these studies is that patterned activity and interaction of coincident inputs gives rise to associational plasticity and long-term regulation of information flow. Finally, we offer insights about how learning-related synaptic plasticity within the corticohippocampal circuit during sensory experiences may enable adaptive behaviors for encoding spatial, episodic, social, and contextual memories. PMID:26525152

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

PubMed

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 respiratory sinus arrhythmia as there is an increase in heart rate during inspiration that occurs via inhibition of premotor parasympathetic cardioinhibitory neurons in the NA during inspiration.

Transient Response in a Dendritic Neuron Model for Current Injected at One Branch

PubMed Central

Rinzel, John; Rall, Wilfrid

1974-01-01

Mathematical expressions are obtained for the response function corresponding to an instantaneous pulse of current injected to a single dendritic branch in a branched dendritic neuron model. The theoretical model assumes passive membrane properties and the equivalent cylinder constraint on branch diameters. The response function when used in a convolution formula enables one to compute the voltage transient at any specified point in the dendritic tree for an arbitrary current injection at a given input location. A particular numerical example, for a brief current injection at a branch terminal, illustrates the attenuation and delay characteristics of the depolarization peak as it spreads throughout the neuron model. In contrast to the severe attenuation of voltage transients from branch input sites to the soma, the fraction of total input charge actually delivered to the soma and other trees is calculated to be about one-half. This fraction is independent of the input time course. Other numerical examples, which compare a branch terminal input site with a soma input site, demonstrate that, for a given transient current injection, the peak depolarization is not proportional to the input resistance at the injection site and, for a given synaptic conductance transient, the effective synaptic driving potential can be significantly reduced, resulting in less synaptic current flow and charge, for a branch input site. Also, for the synaptic case, the two inputs are compared on the basis of the excitatory post-synaptic potential (EPSP) seen at the soma and the total charge delivered to the soma. PMID:4424185

Noise Suppression and Surplus Synchrony by Coincidence Detection

PubMed Central

Schultze-Kraft, Matthias; Diesmann, Markus; Grün, Sonja; Helias, Moritz

2013-01-01

The functional significance of correlations between action potentials of neurons is still a matter of vivid debate. In particular, it is presently unclear how much synchrony is caused by afferent synchronized events and how much is intrinsic due to the connectivity structure of cortex. The available analytical approaches based on the diffusion approximation do not allow to model spike synchrony, preventing a thorough analysis. Here we theoretically investigate to what extent common synaptic afferents and synchronized inputs each contribute to correlated spiking on a fine temporal scale between pairs of neurons. We employ direct simulation and extend earlier analytical methods based on the diffusion approximation to pulse-coupling, allowing us to introduce precisely timed correlations in the spiking activity of the synaptic afferents. We investigate the transmission of correlated synaptic input currents by pairs of integrate-and-fire model neurons, so that the same input covariance can be realized by common inputs or by spiking synchrony. We identify two distinct regimes: In the limit of low correlation linear perturbation theory accurately determines the correlation transmission coefficient, which is typically smaller than unity, but increases sensitively even for weakly synchronous inputs. In the limit of high input correlation, in the presence of synchrony, a qualitatively new picture arises. As the non-linear neuronal response becomes dominant, the output correlation becomes higher than the total correlation in the input. This transmission coefficient larger unity is a direct consequence of non-linear neural processing in the presence of noise, elucidating how synchrony-coded signals benefit from these generic properties present in cortical networks. PMID:23592953

Stimulus-specific adaptation in a recurrent network model of primary auditory cortex

PubMed Central

2017-01-01

Stimulus-specific adaptation (SSA) occurs when neurons decrease their responses to frequently-presented (standard) stimuli but not, or not as much, to other, rare (deviant) stimuli. SSA is present in all mammalian species in which it has been tested as well as in birds. SSA confers short-term memory to neuronal responses, and may lie upstream of the generation of mismatch negativity (MMN), an important human event-related potential. Previously published models of SSA mostly rely on synaptic depression of the feedforward, thalamocortical input. Here we study SSA in a recurrent neural network model of primary auditory cortex. When the recurrent, intracortical synapses display synaptic depression, the network generates population spikes (PSs). SSA occurs in this network when deviants elicit a PS but standards do not, and we demarcate the regions in parameter space that allow SSA. While SSA based on PSs does not require feedforward depression, we identify feedforward depression as a mechanism for expanding the range of parameters that support SSA. We provide predictions for experiments that could help differentiate between SSA due to synaptic depression of feedforward connections and SSA due to synaptic depression of recurrent connections. Similar to experimental data, the magnitude of SSA in the model depends on the frequency difference between deviant and standard, probability of the deviant, inter-stimulus interval and input amplitude. In contrast to models based on feedforward depression, our model shows true deviance sensitivity as found in experiments. PMID:28288158

Stabilization of memory States by stochastic facilitating synapses.

PubMed

Miller, Paul

2013-12-06

Bistability within a small neural circuit can arise through an appropriate strength of excitatory recurrent feedback. The stability of a state of neural activity, measured by the mean dwelling time before a noise-induced transition to another state, depends on the neural firing-rate curves, the net strength of excitatory feedback, the statistics of spike times, and increases exponentially with the number of equivalent neurons in the circuit. Here, we show that such stability is greatly enhanced by synaptic facilitation and reduced by synaptic depression. We take into account the alteration in times of synaptic vesicle release, by calculating distributions of inter-release intervals of a synapse, which differ from the distribution of its incoming interspike intervals when the synapse is dynamic. In particular, release intervals produced by a Poisson spike train have a coefficient of variation greater than one when synapses are probabilistic and facilitating, whereas the coefficient of variation is less than one when synapses are depressing. However, in spite of the increased variability in postsynaptic input produced by facilitating synapses, their dominant effect is reduced synaptic efficacy at low input rates compared to high rates, which increases the curvature of neural input-output functions, leading to wider regions of bistability in parameter space and enhanced lifetimes of memory states. Our results are based on analytic methods with approximate formulae and bolstered by simulations of both Poisson processes and of circuits of noisy spiking model neurons.

Clarinet (CLA-1), a novel active zone protein required for synaptic vesicle clustering and release

PubMed Central

Nelson, Jessica; Richmond, Janet E; Colón-Ramos, Daniel A; Shen, Kang

2017-01-01

Active zone proteins cluster synaptic vesicles at presynaptic terminals and coordinate their release. In forward genetic screens, we isolated a novel Caenorhabditis elegans active zone gene, clarinet (cla-1). cla-1 mutants exhibit defects in synaptic vesicle clustering, active zone structure and synapse number. As a result, they have reduced spontaneous vesicle release and increased synaptic depression. cla-1 mutants show defects in vesicle distribution near the presynaptic dense projection, with fewer undocked vesicles contacting the dense projection and more docked vesicles at the plasma membrane. cla-1 encodes three isoforms containing common C-terminal PDZ and C2 domains with homology to vertebrate active zone proteins Piccolo and RIM. The C-termini of all isoforms localize to the active zone. Specific loss of the ~9000 amino acid long isoform results in vesicle clustering defects and increased synaptic depression. Our data indicate that specific isoforms of clarinet serve distinct functions, regulating synapse development, vesicle clustering and release. PMID:29160205

RhoGTPase Regulators Orchestrate Distinct Stages of Synaptic Development

PubMed Central

Martin-Vilchez, Samuel; Whitmore, Leanna; Asmussen, Hannelore; Zareno, Jessica; Horwitz, Rick; Newell-Litwa, Karen

2017-01-01

Small RhoGTPases regulate changes in post-synaptic spine morphology and density that support learning and memory. They are also major targets of synaptic disorders, including Autism. Here we sought to determine whether upstream RhoGTPase regulators, including GEFs, GAPs, and GDIs, sculpt specific stages of synaptic development. The majority of examined molecules uniquely regulate either early spine precursor formation or later maturation. Specifically, an activator of actin polymerization, the Rac1 GEF β-PIX, drives spine precursor formation, whereas both FRABIN, a Cdc42 GEF, and OLIGOPHRENIN-1, a RhoA GAP, regulate spine precursor elongation. However, in later development, a novel Rac1 GAP, ARHGAP23, and RhoGDIs inactivate actomyosin dynamics to stabilize mature synapses. Our observations demonstrate that specific combinations of RhoGTPase regulatory proteins temporally balance RhoGTPase activity during post-synaptic spine development. PMID:28114311

Directional hearing by linear summation of binaural inputs at the medial superior olive

PubMed Central

van der Heijden, Marcel; Lorteije, Jeannette A. M.; Plauška, Andrius; Roberts, Michael T.; Golding, Nace L.; Borst, J. Gerard G.

2013-01-01

SUMMARY Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own “best ITD” to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible. PMID:23764292

Synaptic State Matching: A Dynamical Architecture for Predictive Internal Representation and Feature Detection

PubMed Central

Tavazoie, Saeed

2013-01-01

Here we explore the possibility that a core function of sensory cortex is the generation of an internal simulation of sensory environment in real-time. A logical elaboration of this idea leads to a dynamical neural architecture that oscillates between two fundamental network states, one driven by external input, and the other by recurrent synaptic drive in the absence of sensory input. Synaptic strength is modified by a proposed synaptic state matching (SSM) process that ensures equivalence of spike statistics between the two network states. Remarkably, SSM, operating locally at individual synapses, generates accurate and stable network-level predictive internal representations, enabling pattern completion and unsupervised feature detection from noisy sensory input. SSM is a biologically plausible substrate for learning and memory because it brings together sequence learning, feature detection, synaptic homeostasis, and network oscillations under a single unifying computational framework. PMID:23991161

Variability in common synaptic input to motor neurons modulates both force steadiness and pegboard time in young and older adults.

PubMed

Feeney, Daniel F; Mani, Diba; Enoka, Roger M

2018-06-07

We investigated the associations between grooved pegboard times, force steadiness (coefficient of variation for force), and variability in an estimate of the common synaptic input to motor neurons innervating the wrist extensor muscles during steady contractions performed by young and older adults. The discharge times of motor units were derived from recordings obtained with high-density surface electrodes while participants performed steady isometric contractions at 10% and 20% of maximal voluntary contraction (MVC) force. The steady contractions were performed with a pinch grip and wrist extension, both independently (single action) and concurrently (double action). The variance in common synaptic input to motor neurons was estimated with a state-space model of the latent common input dynamics. There was a statistically significant association between the coefficient of variation for force during the steady contractions and the estimated variance in common synaptic input in young (r 2 = 0.31) and older (r 2 = 0.39) adults, but not between either the mean or the coefficient of variation for interspike interval of single motor units with the coefficient of variation for force. Moreover, the estimated variance in common synaptic input during the double-action task with the wrist extensors at the 20% target was significantly associated with grooved pegboard time (r 2 = 0.47) for older adults, but not young adults. These findings indicate that longer pegboard times of older adults were associated with worse force steadiness and greater fluctuations in the estimated common synaptic input to motor neurons during steady contractions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Short-Term Memory Trace in Rapidly Adapting Synapses of Inferior Temporal Cortex

PubMed Central

Sugase-Miyamoto, Yasuko; Liu, Zheng; Wiener, Matthew C.; Optican, Lance M.; Richmond, Barry J.

2008-01-01

Visual short-term memory tasks depend upon both the inferior temporal cortex (ITC) and the prefrontal cortex (PFC). Activity in some neurons persists after the first (sample) stimulus is shown. This delay-period activity has been proposed as an important mechanism for working memory. In ITC neurons, intervening (nonmatching) stimuli wipe out the delay-period activity; hence, the role of ITC in memory must depend upon a different mechanism. Here, we look for a possible mechanism by contrasting memory effects in two architectonically different parts of ITC: area TE and the perirhinal cortex. We found that a large proportion (80%) of stimulus-selective neurons in area TE of macaque ITCs exhibit a memory effect during the stimulus interval. During a sequential delayed matching-to-sample task (DMS), the noise in the neuronal response to the test image was correlated with the noise in the neuronal response to the sample image. Neurons in perirhinal cortex did not show this correlation. These results led us to hypothesize that area TE contributes to short-term memory by acting as a matched filter. When the sample image appears, each TE neuron captures a static copy of its inputs by rapidly adjusting its synaptic weights to match the strength of their individual inputs. Input signals from subsequent images are multiplied by those synaptic weights, thereby computing a measure of the correlation between the past and present inputs. The total activity in area TE is sufficient to quantify the similarity between the two images. This matched filter theory provides an explanation of what is remembered, where the trace is stored, and how comparison is done across time, all without requiring delay period activity. Simulations of a matched filter model match the experimental results, suggesting that area TE neurons store a synaptic memory trace during short-term visual memory. PMID:18464917

Effects of dopamine and glutamate on synaptic plasticity: a computational modeling approach for drug abuse as comorbidity in mood disorders.

PubMed

Qi, Z; Kikuchi, S; Tretter, F; Voit, E O

2011-05-01

Major depressive disorder (MDD) affects about 16% of the general population and is a leading cause of death in the United States and around the world. Aggravating the situation is the fact that "drug use disorders" are highly comorbid in MDD patients, and VICE VERSA. Drug use and MDD share a common component, the dopamine system, which is critical in many motivation and reward processes, as well as in the regulation of stress responses in MDD. A potentiating mechanism in drug use disorders appears to be synaptic plasticity, which is regulated by dopamine transmission. In this article, we describe a computational model of the synaptic plasticity of GABAergic medium spiny neurons in the nucleus accumbens, which is critical in the reward system. The model accounts for effects of both dopamine and glutamate transmission. Model simulations show that GABAergic medium spiny neurons tend to respond to dopamine stimuli with synaptic potentiation and to glutamate signals with synaptic depression. Concurrent dopamine and glutamate signals cause various types of synaptic plasticity, depending on input scenarios. Interestingly, the model shows that a single 0.5 mg/kg dose of amphetamine can cause synaptic potentiation for over 2 h, a phenomenon that makes synaptic plasticity of medium spiny neurons behave quasi as a bistable system. The model also identifies mechanisms that could potentially be critical to correcting modifications of synaptic plasticity caused by drugs in MDD patients. An example is the feedback loop between protein kinase A, phosphodiesterase, and the second messenger cAMP in the postsynapse. Since reward mechanisms activated by psychostimulants could be crucial in establishing addiction comorbidity in patients with MDD, this model might become an aid for identifying and targeting specific modules within the reward system and lead to a better understanding and potential treatment of comorbid drug use disorders in MDD. © Georg Thieme Verlag KG Stuttgart · New York.

Synaptic depression in the CA1 region of freely behaving mice is highly dependent on afferent stimulation parameters

PubMed Central

Goh, Jinzhong J.; Manahan-Vaughan, Denise

2012-01-01

Persistent synaptic plasticity has been subjected to intense study in the decades since it was first described. Occurring in the form of long-term potentiation (LTP) and long-term depression (LTD), it shares many cellular and molecular properties with hippocampus-dependent forms of persistent memory. Recent reports of both LTP and LTD occurring endogenously under specific learning conditions provide further support that these forms of synaptic plasticity may comprise the cellular correlates of memory. Most studies of synaptic plasticity are performed using in vitro or in vivo preparations where patterned electrical stimulation of afferent fibers is implemented to induce changes in synaptic strength. This strategy has proven very effective in inducing LTP, even under in vivo conditions. LTD in vivo has proven more elusive: although LTD occurs endogenously under specific learning conditions in both rats and mice, its induction has not been successfully demonstrated with afferent electrical stimulation alone. In this study we screened a large spectrum of protocols that are known to induce LTD either in hippocampal slices or in the intact rat hippocampus, to clarify if LTD can be induced by sole afferent stimulation in the mouse CA1 region in vivo. Low frequency stimulation at 1, 2, 3, 5, 7, or 10 Hz given in the range of 100 through 1800 pulses produced, at best, short-term depression (STD) that lasted for up to 60 min. Varying the administration pattern of the stimuli (e.g., 900 pulses given twice at 5 min intervals), or changing the stimulation intensity did not improve the persistency of synaptic depression. LTD that lasts for at least 24 h occurs under learning conditions in mice. We conclude that a coincidence of factors, such as afferent activity together with neuromodulatory inputs, play a decisive role in the enablement of LTD under more naturalistic (e.g., learning) conditions. PMID:23355815

Synaptic Efficacy as a Function of Ionotropic Receptor Distribution: A Computational Study

PubMed Central

Allam, Sushmita L.; Bouteiller, Jean-Marie C.; Hu, Eric Y.; Ambert, Nicolas; Greget, Renaud; Bischoff, Serge; Baudry, Michel; Berger, Theodore W.

2015-01-01

Glutamatergic synapses are the most prevalent functional elements of information processing in the brain. Changes in pre-synaptic activity and in the function of various post-synaptic elements contribute to generate a large variety of synaptic responses. Previous studies have explored postsynaptic factors responsible for regulating synaptic strength variations, but have given far less importance to synaptic geometry, and more specifically to the subcellular distribution of ionotropic receptors. We analyzed the functional effects resulting from changing the subsynaptic localization of ionotropic receptors by using a hippocampal synaptic computational framework. The present study was performed using the EONS (Elementary Objects of the Nervous System) synaptic modeling platform, which was specifically developed to explore the roles of subsynaptic elements as well as their interactions, and that of synaptic geometry. More specifically, we determined the effects of changing the localization of ionotropic receptors relative to the presynaptic glutamate release site, on synaptic efficacy and its variations following single pulse and paired-pulse stimulation protocols. The results indicate that changes in synaptic geometry do have consequences on synaptic efficacy and its dynamics. PMID:26480028

Synaptic Efficacy as a Function of Ionotropic Receptor Distribution: A Computational Study.

PubMed

Allam, Sushmita L; Bouteiller, Jean-Marie C; Hu, Eric Y; Ambert, Nicolas; Greget, Renaud; Bischoff, Serge; Baudry, Michel; Berger, Theodore W

2015-01-01

Glutamatergic synapses are the most prevalent functional elements of information processing in the brain. Changes in pre-synaptic activity and in the function of various post-synaptic elements contribute to generate a large variety of synaptic responses. Previous studies have explored postsynaptic factors responsible for regulating synaptic strength variations, but have given far less importance to synaptic geometry, and more specifically to the subcellular distribution of ionotropic receptors. We analyzed the functional effects resulting from changing the subsynaptic localization of ionotropic receptors by using a hippocampal synaptic computational framework. The present study was performed using the EONS (Elementary Objects of the Nervous System) synaptic modeling platform, which was specifically developed to explore the roles of subsynaptic elements as well as their interactions, and that of synaptic geometry. More specifically, we determined the effects of changing the localization of ionotropic receptors relative to the presynaptic glutamate release site, on synaptic efficacy and its variations following single pulse and paired-pulse stimulation protocols. The results indicate that changes in synaptic geometry do have consequences on synaptic efficacy and its dynamics.

The Slow Dynamics of Intracellular Sodium Concentration Increase the Time Window of Neuronal Integration: A Simulation Study

PubMed Central

Zylbertal, Asaph; Yarom, Yosef; Wagner, Shlomo

2017-01-01

Changes in intracellular Na+ concentration ([Na+]i) are rarely taken into account when neuronal activity is examined. As opposed to Ca2+, [Na+]i dynamics are strongly affected by longitudinal diffusion, and therefore they are governed by the morphological structure of the neurons, in addition to the localization of influx and efflux mechanisms. Here, we examined [Na+]i dynamics and their effects on neuronal computation in three multi-compartmental neuronal models, representing three distinct cell types: accessory olfactory bulb (AOB) mitral cells, cortical layer V pyramidal cells, and cerebellar Purkinje cells. We added [Na+]i as a state variable to these models, and allowed it to modulate the Na+ Nernst potential, the Na+-K+ pump current, and the Na+-Ca2+ exchanger rate. Our results indicate that in most cases [Na+]i dynamics are significantly slower than [Ca2+]i dynamics, and thus may exert a prolonged influence on neuronal computation in a neuronal type specific manner. We show that [Na+]i dynamics affect neuronal activity via three main processes: reduction of EPSP amplitude in repeatedly active synapses due to reduction of the Na+ Nernst potential; activity-dependent hyperpolarization due to increased activity of the Na+-K+ pump; specific tagging of active synapses by extended Ca2+ elevation, intensified by concurrent back-propagating action potentials or complex spikes. Thus, we conclude that [Na+]i dynamics should be considered whenever synaptic plasticity, extensive synaptic input, or bursting activity are examined. PMID:28970791

Dendritic excitability modulates dendritic information processing in a purkinje cell model.

PubMed

Coop, Allan D; Cornelis, Hugo; Santamaria, Fidel

2010-01-01

Using an electrophysiological compartmental model of a Purkinje cell we quantified the contribution of individual active dendritic currents to processing of synaptic activity from granule cells. We used mutual information as a measure to quantify the information from the total excitatory input current (I(Glu)) encoded in each dendritic current. In this context, each active current was considered an information channel. Our analyses showed that most of the information was encoded by the calcium (I(CaP)) and calcium activated potassium (I(Kc)) currents. Mutual information between I(Glu) and I(CaP) and I(Kc) was sensitive to different levels of excitatory and inhibitory synaptic activity that, at the same time, resulted in the same firing rate at the soma. Since dendritic excitability could be a mechanism to regulate information processing in neurons we quantified the changes in mutual information between I(Glu) and all Purkinje cell currents as a function of the density of dendritic Ca (g(CaP)) and Kca (g(Kc)) conductances. We extended our analysis to determine the window of temporal integration of I(Glu) by I(CaP) and I(Kc) as a function of channel density and synaptic activity. The window of information integration has a stronger dependence on increasing values of g(Kc) than on g(CaP), but at high levels of synaptic stimulation information integration is reduced to a few milliseconds. Overall, our results show that different dendritic conductances differentially encode synaptic activity and that dendritic excitability and the level of synaptic activity regulate the flow of information in dendrites.

Differential conserted activity induced regulation of Nogo receptors (1-3), LOTUS and Nogo mRNA in mouse brain.

PubMed

Karlsson, Tobias E; Koczy, Josefin; Brené, Stefan; Olson, Lars; Josephson, Anna

2013-01-01

Nogo Receptor 1 (NgR1) mRNA is downregulated in hippocampal and cortical regions by increased neuronal activity such as a kainic acid challenge or by exposing rats to running wheels. Plastic changes in cerebral cortex in response to loss of specific sensory inputs caused by spinal cord injury are also associated with downregulation of NgR1 mRNA. Here we investigate the possible regulation by neuronal activity of the homologous receptors NgR2 and NgR3 as well as the endogenous NgR1 antagonist LOTUS and the ligand Nogo. The investigated genes respond to kainic acid by gene-specific, concerted alterations of transcript levels, suggesting a role in the regulation of synaptic plasticity, Downregulation of NgR1, coupled to upregulation of the NgR1 antagonist LOTUS, paired with upregulation of NgR2 and 3 in the dentate gyrus suggest a temporary decrease of Nogo/OMgp sensitivity while CSPG and MAG sensitivity could remain. It is suggested that these activity-synchronized temporary alterations may serve to allow structural alterations at the level of local synaptic circuitry in gray matter, while maintaining white matter pathways and that subsequent upregulation of Nogo-A and NgR1 transcript levels signals the end of such a temporarily opened window of plasticity.

Differential Conserted Activity Induced Regulation of Nogo Receptors (1–3), LOTUS and Nogo mRNA in Mouse Brain

PubMed Central

Karlsson, Tobias E.; Koczy, Josefin; Brené, Stefan; Olson, Lars; Josephson, Anna

2013-01-01

Nogo Receptor 1 (NgR1) mRNA is downregulated in hippocampal and cortical regions by increased neuronal activity such as a kainic acid challenge or by exposing rats to running wheels. Plastic changes in cerebral cortex in response to loss of specific sensory inputs caused by spinal cord injury are also associated with downregulation of NgR1 mRNA. Here we investigate the possible regulation by neuronal activity of the homologous receptors NgR2 and NgR3 as well as the endogenous NgR1 antagonist LOTUS and the ligand Nogo. The investigated genes respond to kainic acid by gene-specific, concerted alterations of transcript levels, suggesting a role in the regulation of synaptic plasticity, Downregulation of NgR1, coupled to upregulation of the NgR1 antagonist LOTUS, paired with upregulation of NgR2 and 3 in the dentate gyrus suggest a temporary decrease of Nogo/OMgp sensitivity while CSPG and MAG sensitivity could remain. It is suggested that these activity-synchronized temporary alterations may serve to allow structural alterations at the level of local synaptic circuitry in gray matter, while maintaining white matter pathways and that subsequent upregulation of Nogo-A and NgR1 transcript levels signals the end of such a temporarily opened window of plasticity. PMID:23593344

Conditional bistability, a generic cellular mnemonic mechanism for robust and flexible working memory computations.

PubMed

Rodriguez, Guillaume; Sarazin, Matthieu; Clemente, Alexandra; Holden, Stephanie; Paz, Jeanne T; Delord, Bruno

2018-04-30

Persistent neural activity, the substrate of working memory, is thought to emerge from synaptic reverberation within recurrent networks. However, reverberation models do not robustly explain fundamental dynamics of persistent activity, including high-spiking irregularity, large intertrial variability, and state transitions. While cellular bistability may contribute to persistent activity, its rigidity appears incompatible with persistent activity labile characteristics. Here, we unravel in a cellular model a form of spike-mediated conditional bistability that is robust, generic and provides a rich repertoire of mnemonic computations. Under asynchronous synaptic inputs of the awakened state, conditional bistability generates spiking/bursting episodes, accounting for the irregularity, variability and state transitions characterizing persistent activity. This mechanism has likely been overlooked because of the sub-threshold input it requires and we predict how to assess it experimentally. Our results suggest a reexamination of the role of intrinsic properties in the collective network dynamics responsible for flexible working memory. SIGNIFICANCE STATEMENT This study unravels a novel form of intrinsic neuronal property, i.e. conditional bistability. We show that, thanks of its conditional character, conditional bistability favors the emergence of flexible and robust forms of persistent activity in PFC neural networks, in opposition to previously studied classical forms of absolute bistability. Specifically, we demonstrate for the first time that conditional bistability 1) is a generic biophysical spike-dependent mechanism of layer V pyramidal neurons in the PFC and that 2) it accounts for essential neurodynamical features for the organisation and flexibility of PFC persistent activity (the large irregularity and intertrial variability of the discharge and its organization under discrete stable states), which remain unexplained in a robust fashion by current models. Copyright © 2018 the authors.

Distribution and Function of HCN Channels in the Apical Dendritic Tuft of Neocortical Pyramidal Neurons

PubMed Central

Harnett, Mark T.; Magee, Jeffrey C.

2015-01-01

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. PMID:25609619

Activity Regulates the Incidence of Heteronymous Sensory-Motor Connections

PubMed Central

Mendelsohn, Alana I.; Simon, Christian M.; Abbott, L. F.; Mentis, George Z.; Jessell, Thomas M.

2015-01-01

Summary The construction of spinal sensory-motor circuits involves the selection of appropriate synaptic partners and the allocation of precise synaptic input densities. Many aspects of spinal sensory-motor selectivity appear to be preserved when peripheral sensory activation is blocked, which has led to a view that sensory-motor circuits are assembled in an activity-independent manner. Yet it remains unclear whether activity-dependent refinement has a role in the establishment of connections between sensory afferents and those motor pools that have synergistic biomechanical functions. We show here that genetically abolishing central sensory-motor neurotransmission leads to a selective enhancement in the number and density of such “heteronymous” connections, whereas other aspects of sensory-motor connectivity are preserved. Spike-timing dependent synaptic refinement represents one possible mechanism for the changes in connectivity observed after activity blockade. Our findings therefore reveal that sensory activity does have a limited and selective role in the establishment of patterned monosynaptic sensory-motor connections. PMID:26094608

Excitatory and inhibitory synaptic mechanisms at the first stage of integration in the electroreception system of the shark

PubMed Central

Rotem, Naama; Sestieri, Emanuel; Hounsgaard, Jorn; Yarom, Yosef

2014-01-01

High impulse rate in afferent nerves is a common feature in many sensory systems that serve to accommodate a wide dynamic range. However, the first stage of integration should be endowed with specific properties that enable efficient handling of the incoming information. In elasmobranches, the afferent nerve originating from the ampullae of Lorenzini targets specific neurons located at the Dorsal Octavolateral Nucleus (DON), the first stage of integration in the electroreception system. Using intracellular recordings in an isolated brainstem preparation from the shark we analyze the properties of this afferent pathway. We found that stimulating the afferent nerve activates a mixture of excitatory and inhibitory synapses mediated by AMPA-like and GABAA receptors, respectively. The excitatory synapses that are extremely efficient in activating the postsynaptic neurons display unusual voltage dependence, enabling them to operate as a current source. The inhibitory input is powerful enough to completely eliminate the excitatory action of the afferent nerve but is ineffective regarding other excitatory inputs. These observations can be explained by the location and efficiency of the synapses. We conclude that the afferent nerve provides powerful and reliable excitatory input as well as a feed-forward inhibitory input, which is partially presynaptic in origin. These results question the cellular location within the DON where cancelation of expected incoming signals occurs. PMID:24639631

A latent low-dimensional common input drives a pool of motor neurons: a probabilistic latent state-space model.

PubMed

Feeney, Daniel F; Meyer, François G; Noone, Nicholas; Enoka, Roger M

2017-10-01

Motor neurons appear to be activated with a common input signal that modulates the discharge activity of all neurons in the motor nucleus. It has proven difficult for neurophysiologists to quantify the variability in a common input signal, but characterization of such a signal may improve our understanding of how the activation signal varies across motor tasks. Contemporary methods of quantifying the common input to motor neurons rely on compiling discrete action potentials into continuous time series, assuming the motor pool acts as a linear filter, and requiring signals to be of sufficient duration for frequency analysis. We introduce a space-state model in which the discharge activity of motor neurons is modeled as inhomogeneous Poisson processes and propose a method to quantify an abstract latent trajectory that represents the common input received by motor neurons. The approach also approximates the variation in synaptic noise in the common input signal. The model is validated with four data sets: a simulation of 120 motor units, a pair of integrate-and-fire neurons with a Renshaw cell providing inhibitory feedback, the discharge activity of 10 integrate-and-fire neurons, and the discharge times of concurrently active motor units during an isometric voluntary contraction. The simulations revealed that a latent state-space model is able to quantify the trajectory and variability of the common input signal across all four conditions. When compared with the cumulative spike train method of characterizing common input, the state-space approach was more sensitive to the details of the common input current and was less influenced by the duration of the signal. The state-space approach appears to be capable of detecting rather modest changes in common input signals across conditions. NEW & NOTEWORTHY We propose a state-space model that explicitly delineates a common input signal sent to motor neurons and the physiological noise inherent in synaptic signal transmission. This is the first application of a deterministic state-space model to represent the discharge characteristics of motor units during voluntary contractions. Copyright © 2017 the American Physiological Society.

Contributions of diverse excitatory and inhibitory neurons to recurrent network activity in cerebral cortex.

PubMed

Neske, Garrett T; Patrick, Saundra L; Connors, Barry W

2015-01-21

The recurrent synaptic architecture of neocortex allows for self-generated network activity. One form of such activity is the Up state, in which neurons transiently receive barrages of excitatory and inhibitory synaptic inputs that depolarize many neurons to spike threshold before returning to a relatively quiescent Down state. The extent to which different cell types participate in Up states is still unclear. Inhibitory interneurons have particularly diverse intrinsic properties and synaptic connections with the local network, suggesting that different interneurons might play different roles in activated network states. We have studied the firing, subthreshold behavior, and synaptic conductances of identified cell types during Up and Down states in layers 5 and 2/3 in mouse barrel cortex in vitro. We recorded from pyramidal cells and interneurons expressing parvalbumin (PV), somatostatin (SOM), vasoactive intestinal peptide (VIP), or neuropeptide Y. PV cells were the most active interneuron subtype during the Up state, yet the other subtypes also received substantial synaptic conductances and often generated spikes. In all cell types except PV cells, the beginning of the Up state was dominated by synaptic inhibition, which decreased thereafter; excitation was more persistent, suggesting that inhibition is not the dominant force in terminating Up states. Compared with barrel cortex, SOM and VIP cells were much less active in entorhinal cortex during Up states. Our results provide a measure of functional connectivity of various neuron types in barrel cortex and suggest differential roles for interneuron types in the generation and control of persistent network activity. Copyright © 2015 the authors 0270-6474/15/351089-17$15.00/0.

Synaptic Mechanisms Generating Orientation Selectivity in the ON Pathway of the Rabbit Retina

PubMed Central

Venkataramani, Sowmya

2016-01-01

Neurons that signal the orientation of edges within the visual field have been widely studied in primary visual cortex. Much less is known about the mechanisms of orientation selectivity that arise earlier in the visual stream. Here we examine the synaptic and morphological properties of a subtype of orientation-selective ganglion cell in the rabbit retina. The receptive field has an excitatory ON center, flanked by excitatory OFF regions, a structure similar to simple cell receptive fields in primary visual cortex. Examination of the light-evoked postsynaptic currents in these ON-type orientation-selective ganglion cells (ON-OSGCs) reveals that synaptic input is mediated almost exclusively through the ON pathway. Orientation selectivity is generated by larger excitation for preferred relative to orthogonal stimuli, and conversely larger inhibition for orthogonal relative to preferred stimuli. Excitatory orientation selectivity arises in part from the morphology of the dendritic arbors. Blocking GABAA receptors reduces orientation selectivity of the inhibitory synaptic inputs and the spiking responses. Negative contrast stimuli in the flanking regions produce orientation-selective excitation in part by disinhibition of a tonic NMDA receptor-mediated input arising from ON bipolar cells. Comparison with earlier studies of OFF-type OSGCs indicates that diverse synaptic circuits have evolved in the retina to detect the orientation of edges in the visual input. SIGNIFICANCE STATEMENT A core goal for visual neuroscientists is to understand how neural circuits at each stage of the visual system extract and encode features from the visual scene. This study documents a novel type of orientation-selective ganglion cell in the retina and shows that the receptive field structure is remarkably similar to that of simple cells in primary visual cortex. However, the data indicate that, unlike in the cortex, orientation selectivity in the retina depends on the activity of inhibitory interneurons. The results further reveal the physiological basis for feature detection in the visual system, elucidate the synaptic mechanisms that generate orientation selectivity at an early stage of visual processing, and illustrate a novel role for NMDA receptors in retinal processing. PMID:26985041

Synaptic Mechanisms Generating Orientation Selectivity in the ON Pathway of the Rabbit Retina.

PubMed

Venkataramani, Sowmya; Taylor, W Rowland

2016-03-16

Neurons that signal the orientation of edges within the visual field have been widely studied in primary visual cortex. Much less is known about the mechanisms of orientation selectivity that arise earlier in the visual stream. Here we examine the synaptic and morphological properties of a subtype of orientation-selective ganglion cell in the rabbit retina. The receptive field has an excitatory ON center, flanked by excitatory OFF regions, a structure similar to simple cell receptive fields in primary visual cortex. Examination of the light-evoked postsynaptic currents in these ON-type orientation-selective ganglion cells (ON-OSGCs) reveals that synaptic input is mediated almost exclusively through the ON pathway. Orientation selectivity is generated by larger excitation for preferred relative to orthogonal stimuli, and conversely larger inhibition for orthogonal relative to preferred stimuli. Excitatory orientation selectivity arises in part from the morphology of the dendritic arbors. Blocking GABAA receptors reduces orientation selectivity of the inhibitory synaptic inputs and the spiking responses. Negative contrast stimuli in the flanking regions produce orientation-selective excitation in part by disinhibition of a tonic NMDA receptor-mediated input arising from ON bipolar cells. Comparison with earlier studies of OFF-type OSGCs indicates that diverse synaptic circuits have evolved in the retina to detect the orientation of edges in the visual input. A core goal for visual neuroscientists is to understand how neural circuits at each stage of the visual system extract and encode features from the visual scene. This study documents a novel type of orientation-selective ganglion cell in the retina and shows that the receptive field structure is remarkably similar to that of simple cells in primary visual cortex. However, the data indicate that, unlike in the cortex, orientation selectivity in the retina depends on the activity of inhibitory interneurons. The results further reveal the physiological basis for feature detection in the visual system, elucidate the synaptic mechanisms that generate orientation selectivity at an early stage of visual processing, and illustrate a novel role for NMDA receptors in retinal processing. Copyright © 2016 the authors 0270-6474/16/363336-14$15.00/0.

Spinal Endocannabinoids and CB1 Receptors Mediate C-Fiber-Induced Heterosynaptic Pain Plasticity

PubMed Central

Pernía-Andrade, Alejandro J.; Kato, Ako; Witschi, Robert; Nyilas, Rita; Katona, István; Freund, Tamás F.; Watanabe, Masahiko; Filitz, Jörg; Koppert, Wolfgang; Schüttler, Jürgen; Ji, Guangchen; Neugebauer, Volker; Marsicano, Giovanni; Lutz, Beat; Vanegas, Horacio; Zeilhofer, Hanns Ulrich

2010-01-01

Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain. Pathways, which reduce synaptic inhibition in inflammatory and neuropathic pain states, have been identified, but central hyperalgesia and diminished dorsal horn synaptic inhibition also occur in the absence of inflammation or neuropathy, solely triggered by intense nociceptive (C–fiber) input to the spinal dorsal horn. We found that endocannabinoids produced upon strong nociceptive stimulation activated CB1 receptors on inhibitory dorsal horn neurons to reduce the synaptic release of GABA and glycine and thus rendered nociceptive neurons excitable by non-painful stimuli. Spinal endocannabinoids and CB1 receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain controlling circuits. PMID:19661434

Functional Differences between Global Pre- and Postsynaptic Inhibition in the Drosophila Olfactory Circuit.

PubMed

Oizumi, Masafumi; Satoh, Ryota; Kazama, Hokto; Okada, Masato

2012-01-01

The Drosophila antennal lobe is subdivided into multiple glomeruli, each of which represents a unique olfactory information processing channel. In each glomerulus, feedforward input from olfactory receptor neurons (ORNs) is transformed into activity of projection neurons (PNs), which represent the output. Recent investigations have indicated that lateral presynaptic inhibitory input from other glomeruli controls the gain of this transformation. Here, we address why this gain control acts "pre"-synaptically rather than "post"-synaptically. Postsynaptic inhibition could work similarly to presynaptic inhibition with regard to regulating the firing rates of PNs depending on the stimulus intensity. We investigate the differences between pre- and postsynaptic gain control in terms of odor discriminability by simulating a network model of the Drosophila antennal lobe with experimental data. We first demonstrate that only presynaptic inhibition can reproduce the type of gain control observed in experiments. We next show that presynaptic inhibition decorrelates PN responses whereas postsynaptic inhibition does not. Due to this effect, presynaptic gain control enhances the accuracy of odor discrimination by a linear decoder while its postsynaptic counterpart only diminishes it. Our results provide the reason gain control operates "pre"-synaptically but not "post"-synaptically in the Drosophila antennal lobe.

Push-Pull Receptive Field Organization and Synaptic Depression: Mechanisms for Reliably Encoding Naturalistic Stimuli in V1

PubMed Central

Kremkow, Jens; Perrinet, Laurent U.; Monier, Cyril; Alonso, Jose-Manuel; Aertsen, Ad; Frégnac, Yves; Masson, Guillaume S.

2016-01-01

Neurons in the primary visual cortex are known for responding vigorously but with high variability to classical stimuli such as drifting bars or gratings. By contrast, natural scenes are encoded more efficiently by sparse and temporal precise spiking responses. We used a conductance-based model of the visual system in higher mammals to investigate how two specific features of the thalamo-cortical pathway, namely push-pull receptive field organization and fast synaptic depression, can contribute to this contextual reshaping of V1 responses. By comparing cortical dynamics evoked respectively by natural vs. artificial stimuli in a comprehensive parametric space analysis, we demonstrate that the reliability and sparseness of the spiking responses during natural vision is not a mere consequence of the increased bandwidth in the sensory input spectrum. Rather, it results from the combined impacts of fast synaptic depression and push-pull inhibition, the later acting for natural scenes as a form of “effective” feed-forward inhibition as demonstrated in other sensory systems. Thus, the combination of feedforward-like inhibition with fast thalamo-cortical synaptic depression by simple cells receiving a direct structured input from thalamus composes a generic computational mechanism for generating a sparse and reliable encoding of natural sensory events. PMID:27242445

Role of Immediate-Early Genes in Synaptic Plasticity and Neuronal Ensembles Underlying the Memory Trace

PubMed Central

Minatohara, Keiichiro; Akiyoshi, Mika; Okuno, Hiroyuki

2016-01-01

In the brain, neuronal gene expression is dynamically changed in response to neuronal activity. In particular, the expression of immediate-early genes (IEGs) such as egr-1, c-fos, and Arc is rapidly and selectively upregulated in subsets of neurons in specific brain regions associated with learning and memory formation. IEG expression has therefore been widely used as a molecular marker for neuronal populations that undergo plastic changes underlying formation of long-term memory. In recent years, optogenetic and pharmacogenetic studies of neurons expressing c-fos or Arc have revealed that, during learning, IEG-positive neurons encode and store information that is required for memory recall, suggesting that they may be involved in formation of the memory trace. However, despite accumulating evidence for the role of IEGs in synaptic plasticity, the molecular and cellular mechanisms associated with this process remain unclear. In this review, we first summarize recent literature concerning the role of IEG-expressing neuronal ensembles in organizing the memory trace. We then focus on the physiological significance of IEGs, especially Arc, in synaptic plasticity, and describe our hypotheses about the importance of Arc expression in various types of input-specific circuit reorganization. Finally, we offer perspectives on Arc function that would unveil the role of IEG-expressing neurons in the formation of memory traces in the hippocampus and other brain areas. PMID:26778955

Anoxia increases potassium conductance in hippocampal nerve cells.

PubMed

Hansen, A J; Hounsgaard, J; Jahnsen, H

1982-07-01

The effect of anoxia on nerve cell function was studied by intra- and extracellular microelectrode recordings from the CA1 and CA3 region in guinea pig hippocampal slices. Hyperpolarization and concomitant reduction of the nerve cell input resistance was observed early during anoxia. During this period the spontaneous activity first disappeared, then the evoked activity gradually disappeared. The hyperpolarization was followed by depolarization and an absence of a measurable input resistance. All the induced changes were reversed when the slice was reoxygenated. Reversal of the electro-chemical gradient for Cl- across the nerve cell membrane did not affect the course of events during anoxia. Aminopyridines blocked the anoxic hyperpolarization and attenuated the decrease of membrane resistance, but had no effect on the later depolarization. Blockers of synaptic transmission. Mn++, Mg++ and of Na+-channels (TTX) were without effect on the nerve cell changes during anoxia. It is suggested that the reduction of nerve cell excitability in anoxia is primarily due to increased K+-conductance. Thus, the nerve cells are hyperpolarized and the input resistance reduced, causing higher threshold and reduction of synaptic potentials. The mechanism of the K+-conductance activation is unknown at present.

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

PubMed

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

2017-12-20

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

Quantifying the Number of Discriminable Coincident Dendritic Input Patterns through Dendritic Tree Morphology

PubMed Central

Zippo, Antonio G.; Biella, Gabriele E. M.

2015-01-01

Current developments in neuronal physiology are unveiling novel roles for dendrites. Experiments have shown mechanisms of non-linear synaptic NMDA dependent activations, able to discriminate input patterns through the waveforms of the excitatory postsynaptic potentials. Contextually, the synaptic clustering of inputs is the principal cellular strategy to separate groups of common correlated inputs. Dendritic branches appear to work as independent discriminating units of inputs potentially reflecting an extraordinary repertoire of pattern memories. However, it is unclear how these observations could impact our comprehension of the structural correlates of memory at the cellular level. This work investigates the discrimination capabilities of neurons through computational biophysical models to extract a predicting law for the dendritic input discrimination capability (M). By this rule we compared neurons from a neuron reconstruction repository (neuromorpho.org). Comparisons showed that primate neurons were not supported by an equivalent M preeminence and that M is not uniformly distributed among neuron types. Remarkably, neocortical neurons had substantially less memory capacity in comparison to those from non-cortical regions. In conclusion, the proposed rule predicts the inherent neuronal spatial memory gathering potentially relevant anatomical and evolutionary considerations about the brain cytoarchitecture. PMID:26100354

Spontaneously emerging direction selectivity maps in visual cortex through STDP.

PubMed

Wenisch, Oliver G; Noll, Joachim; Hemmen, J Leo van

2005-10-01

It is still an open question as to whether, and how, direction-selective neuronal responses in primary visual cortex are generated by feedforward thalamocortical or recurrent intracortical connections, or a combination of both. Here we present an investigation that concentrates on and, only for the sake of simplicity, restricts itself to intracortical circuits, in particular, with respect to the developmental aspects of direction selectivity through spike-timing-dependent synaptic plasticity. We show that directional responses can emerge in a recurrent network model of visual cortex with spiking neurons that integrate inputs mainly from a particular direction, thus giving rise to an asymmetrically shaped receptive field. A moving stimulus that enters the receptive field from this (preferred) direction will activate a neuron most strongly because of the increased number and/or strength of inputs from this direction and since delayed isotropic inhibition will neither overlap with, nor cancel excitation, as would be the case for other stimulus directions. It is demonstrated how direction-selective responses result from spatial asymmetries in the distribution of synaptic contacts or weights of inputs delivered to a neuron by slowly conducting intracortical axonal delay lines. By means of spike-timing-dependent synaptic plasticity with an asymmetric learning window this kind of coupling asymmetry develops naturally in a recurrent network of stochastically spiking neurons in a scenario where the neurons are activated by unidirectionally moving bar stimuli and even when only intrinsic spontaneous activity drives the learning process. We also present simulation results to show the ability of this model to produce direction preference maps similar to experimental findings.

Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons

PubMed Central

Cristino, Luigia; Busetto, Giuseppe; Imperatore, Roberta; Ferrandino, Ida; Palomba, Letizia; Silvestri, Cristoforo; Petrosino, Stefania; Orlando, Pierangelo; Bentivoglio, Marina; Mackie, Kenneth; Di Marzo, Vincenzo

2013-01-01

Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB1)-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB1-expressing excitatory vs. inhibitory inputs to orexin-A–containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin-knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB1-expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB1-expressing axon terminals. Patch-clamp recordings also showed increased CB1-sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB1-mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB1-mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity. PMID:23630288

Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus

PubMed Central

Dennis, Siobhan H.; Pasqui, Francesca; Colvin, Ellen M.; Sanger, Helen; Mogg, Adrian J.; Felder, Christian C.; Broad, Lisa M.; Fitzjohn, Steve M.; Isaac, John T.R.; Mellor, Jack R.

2016-01-01

Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans. PMID:26472558

Unitary synaptic connections among substantia nigra pars reticulata neurons

PubMed Central

Wilson, Charles J.

2016-01-01

Neurons in substantia nigra pars reticulata (SNr) are synaptically coupled by local axon collaterals, providing a potential mechanism for local signal processing. Because SNr neurons fire spontaneously, these synapses are constantly active. To investigate their properties, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from SNr neurons in brain slices, in which afferents from upstream nuclei are severed, and the cells fire rhythmically. The sIPSC trains contained a mixture of periodic and aperiodic events. Autocorrelation analysis of sIPSC trains showed that a majority of cells had one to four active unitary inputs. The properties of the unitary IPSCs (uIPSCs) were analyzed for cells with one unitary input, using a model of periodic presynaptic firing and stochastic synaptic transmission. The inferred presynaptic firing rates and coefficient of variation of interspike intervals (ISIs) corresponded well with direct measurements of spiking in SNr neurons. Methods were developed to estimate the success probability, amplitude distributions, and kinetics of the uIPSCs, while removing the contribution from aperiodic sIPSCs. The sIPSC amplitudes were not increased upon release from halorhodopsin silencing, suggesting that most synapses were not depressed at the spontaneous firing rate. Gramicidin perforated-patch recordings indicated that the average reversal potential of spontaneous inhibitory postsynaptic potentials was −64 mV. Because of the change in driving force across the ISI, the unitary inputs are predicted to have a larger postsynaptic impact when they arrive late in the ISI. Simulations of network activity suggest that this very sparse inhibitory coupling may act to desynchronize the activity of SNr neurons while having only a small effect on firing rate. PMID:26961101

Propagating waves can explain irregular neural dynamics.

PubMed

Keane, Adam; Gong, Pulin

2015-01-28

Cortical neurons in vivo fire quite irregularly. Previous studies about the origin of such irregular neural dynamics have given rise to two major models: a balanced excitation and inhibition model, and a model of highly synchronized synaptic inputs. To elucidate the network mechanisms underlying synchronized synaptic inputs and account for irregular neural dynamics, we investigate a spatially extended, conductance-based spiking neural network model. We show that propagating wave patterns with complex dynamics emerge from the network model. These waves sweep past neurons, to which they provide highly synchronized synaptic inputs. On the other hand, these patterns only emerge from the network with balanced excitation and inhibition; our model therefore reconciles the two major models of irregular neural dynamics. We further demonstrate that the collective dynamics of propagating wave patterns provides a mechanistic explanation for a range of irregular neural dynamics, including the variability of spike timing, slow firing rate fluctuations, and correlated membrane potential fluctuations. In addition, in our model, the distributions of synaptic conductance and membrane potential are non-Gaussian, consistent with recent experimental data obtained using whole-cell recordings. Our work therefore relates the propagating waves that have been widely observed in the brain to irregular neural dynamics. These results demonstrate that neural firing activity, although appearing highly disordered at the single-neuron level, can form dynamical coherent structures, such as propagating waves at the population level. Copyright © 2015 the authors 0270-6474/15/351591-15$15.00/0.

Generating synchrony from the asynchronous: compensation for cochlear traveling wave delays by the dendrites of individual brainstem neurons

PubMed Central

McGinley, Matthew J.; Liberman, M. Charles; Bal, Ramazan; Oertel, Donata

2012-01-01

Broadband transient sounds, such as clicks and consonants, activate a traveling wave in the cochlea. This wave evokes firing in auditory nerve fibers that are tuned to high frequencies several milliseconds earlier than in fibers tuned to low frequencies. Despite this substantial traveling wave delay, octopus cells in the brainstem receive broadband input and respond to clicks with submillisecond temporal precision. The dendrites of octopus cells lie perpendicular to the tonotopically organized array of auditory nerve fibers, placing the earliest arriving inputs most distally and the latest arriving closest to the soma. Here, we test the hypothesis that the topographic arrangement of synaptic inputs on dendrites of octopus cells allows octopus cells to compensate the traveling wave delay. We show that in mice the full cochlear traveling wave delay is 1.6 ms. Because the dendrites of each octopus cell spread across about one third of the tonotopic axis, a click evokes a soma directed sweep of synaptic input lasting 0.5 ms in individual octopus cells. Morphologically and biophysically realistic, computational models of octopus cells show that soma-directed sweeps with durations matching in vivo measurements result in the largest and sharpest somatic excitatory postsynaptic potentials (EPSPs). A low input resistance and activation of a low-voltage-activated potassium conductance that are characteristic of octopus cells are important determinants of sweep sensitivity. We conclude that octopus cells have dendritic morphologies and biophysics tailored to accomplish the precise encoding of broadband transient sounds. PMID:22764237

Cell-type specific circuit connectivity of hippocampal CA1 revealed through Cre-dependent rabies tracing

PubMed Central

Sun, Yanjun; Nguyen, Amanda; Nguyen, Joseph; Le, Luc; Saur, Dieter; Choi, Jiwon; Callaway, Edward M.; Xu, Xiangmin

2014-01-01

Summary We applied a new Cre-dependent, genetically modified rabies-based tracing system to map direct synaptic connections to CA1 excitatory and inhibitory neuron types in mouse hippocampus. We found common inputs to excitatory and inhibitory CA1 neurons from CA3, CA2, entorhinal cortex and the medial septum (MS), and unexpectedly also from the subiculum. Excitatory CA1 neurons receive inputs from both cholinergic and GABAergic MS neurons while inhibitory CA1 neurons receive a great majority of input from GABAergic MS neurons; both cell types also receive weaker input from glutamatergic MS neurons. Comparisons of inputs to CA1 PV+ interneurons versus SOM+ interneurons showed similar strengths of input from the subiculum, but PV+ interneurons receive much stronger input than SOM+ neurons from CA3, entorhinal cortex and MS. Differential input from CA3 to specific CA1 cell types was also demonstrated functionally using laser scanning photostimulation and whole cell recordings. PMID:24656815

Role of the site of synaptic competition and the balance of learning forces for Hebbian encoding of probabilistic Markov sequences

PubMed Central

Bouchard, Kristofer E.; Ganguli, Surya; Brainard, Michael S.

2015-01-01

The majority of distinct sensory and motor events occur as temporally ordered sequences with rich probabilistic structure. Sequences can be characterized by the probability of transitioning from the current state to upcoming states (forward probability), as well as the probability of having transitioned to the current state from previous states (backward probability). Despite the prevalence of probabilistic sequencing of both sensory and motor events, the Hebbian mechanisms that mold synapses to reflect the statistics of experienced probabilistic sequences are not well understood. Here, we show through analytic calculations and numerical simulations that Hebbian plasticity (correlation, covariance, and STDP) with pre-synaptic competition can develop synaptic weights equal to the conditional forward transition probabilities present in the input sequence. In contrast, post-synaptic competition can develop synaptic weights proportional to the conditional backward probabilities of the same input sequence. We demonstrate that to stably reflect the conditional probability of a neuron's inputs and outputs, local Hebbian plasticity requires balance between competitive learning forces that promote synaptic differentiation and homogenizing learning forces that promote synaptic stabilization. The balance between these forces dictates a prior over the distribution of learned synaptic weights, strongly influencing both the rate at which structure emerges and the entropy of the final distribution of synaptic weights. Together, these results demonstrate a simple correspondence between the biophysical organization of neurons, the site of synaptic competition, and the temporal flow of information encoded in synaptic weights by Hebbian plasticity while highlighting the utility of balancing learning forces to accurately encode probability distributions, and prior expectations over such probability distributions. PMID:26257637

Hybrid Scheme for Modeling Local Field Potentials from Point-Neuron Networks.

PubMed

Hagen, Espen; Dahmen, David; Stavrinou, Maria L; Lindén, Henrik; Tetzlaff, Tom; van Albada, Sacha J; Grün, Sonja; Diesmann, Markus; Einevoll, Gaute T

2016-12-01

With rapidly advancing multi-electrode recording technology, the local field potential (LFP) has again become a popular measure of neuronal activity in both research and clinical applications. Proper understanding of the LFP requires detailed mathematical modeling incorporating the anatomical and electrophysiological features of neurons near the recording electrode, as well as synaptic inputs from the entire network. Here we propose a hybrid modeling scheme combining efficient point-neuron network models with biophysical principles underlying LFP generation by real neurons. The LFP predictions rely on populations of network-equivalent multicompartment neuron models with layer-specific synaptic connectivity, can be used with an arbitrary number of point-neuron network populations, and allows for a full separation of simulated network dynamics and LFPs. We apply the scheme to a full-scale cortical network model for a ∼1 mm 2 patch of primary visual cortex, predict laminar LFPs for different network states, assess the relative LFP contribution from different laminar populations, and investigate effects of input correlations and neuron density on the LFP. The generic nature of the hybrid scheme and its public implementation in hybridLFPy form the basis for LFP predictions from other and larger point-neuron network models, as well as extensions of the current application with additional biological detail. © The Author 2016. Published by Oxford University Press.

Input- and subunit-specific AMPA receptor trafficking underlying long-term potentiation at hippocampal CA3 synapses.

PubMed

Kakegawa, Wataru; Tsuzuki, Keisuke; Yoshida, Yukari; Kameyama, Kimihiko; Ozawa, Seiji

2004-07-01

Hippocampal CA3 pyramidal neurons receive synaptic inputs from both mossy fibres (MFs) and associational fibres (AFs). Long-term potentiation (LTP) at these synapses differs in its induction sites and N-methyl-D-aspartate receptor (NMDAR) dependence. Most evidence favours the presynaptic and postsynaptic mechanisms for induction of MF LTP and AF LTP, respectively. This implies that molecular and functional properties differ between MF and AF synapses at both presynaptic and postsynaptic sites. In this study, we focused on the difference in the postsynaptic trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) between these synapses. To trace the subunit-specific trafficking of AMPARs at each synapse, GluR1 and GluR2 subunits were introduced into CA3 pyramidal neurons in hippocampal organotypic cultures using the Sindbis viral expression system. The electrophysiologically-tagged GluR2 AMPARs, produced by the viral-mediated transfer of the unedited form of GluR2 (GluR2Q), were inserted into both MF and AF postsynaptic sites in a neuronal activity-independent manner. Endogenous Ca(2+)-impermeable AMPARs at these synapses were replaced with exogenous Ca(2+)-permeable receptors, and Ca(2+) influx via the newly expressed postsynaptic AMPARs induced NMDAR-independent LTP at AF synapses. In contrast, no GluR1 AMPAR produced by the gene transfer was constitutively incorporated into AF postsynaptic sites, and only a small amount into MF postsynaptic sites. The synaptic trafficking of GluR1 AMPARs was triggered by the activity of Ca(2+)/calmodulin-dependent kinase II or high-frequency stimulation to induce LTP at AF synapses, but not at MF synapses. These results indicate that MF and AF postsynaptic sites possess distinct properties for AMPAR trafficking in CA3 pyramidal neurons.

Viral-genetic tracing of the input-output organization of a central noradrenaline circuit.

PubMed

Schwarz, Lindsay A; Miyamichi, Kazunari; Gao, Xiaojing J; Beier, Kevin T; Weissbourd, Brandon; DeLoach, Katherine E; Ren, Jing; Ibanes, Sandy; Malenka, Robert C; Kremer, Eric J; Luo, Liqun

2015-08-06

Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For example, locus coeruleus noradrenaline (also known as norepinephrine) (LC-NE) neurons receive input from and send output to broad regions of the brain and spinal cord, and regulate diverse functions including arousal, attention, mood and sensory gating. However, it is unclear how LC-NE neurons divide up their brain-wide projection patterns and whether different LC-NE neurons receive differential input. Here we developed a set of viral-genetic tools to quantitatively analyse the input-output relationship of neural circuits, and applied these tools to dissect the LC-NE circuit in mice. Rabies-virus-based input mapping indicated that LC-NE neurons receive convergent synaptic input from many regions previously identified as sending axons to the locus coeruleus, as well as from newly identified presynaptic partners, including cerebellar Purkinje cells. The 'tracing the relationship between input and output' method (or TRIO method) enables trans-synaptic input tracing from specific subsets of neurons based on their projection and cell type. We found that LC-NE neurons projecting to diverse output regions receive mostly similar input. Projection-based viral labelling revealed that LC-NE neurons projecting to one output region also project to all brain regions we examined. Thus, the LC-NE circuit overall integrates information from, and broadcasts to, many brain regions, consistent with its primary role in regulating brain states. At the same time, we uncovered several levels of specificity in certain LC-NE sub-circuits. These tools for mapping output architecture and input-output relationship are applicable to other neuronal circuits and organisms. More broadly, our viral-genetic approaches provide an efficient intersectional means to target neuronal populations based on cell type and projection pattern.

Tissue Plasminogen Activator Induction in Purkinje Neurons After Cerebellar Motor Learning

NASA Astrophysics Data System (ADS)

Seeds, Nicholas W.; Williams, Brian L.; Bickford, Paula C.

1995-12-01

The cerebellar cortex is implicated in the learning of complex motor skills. This learning may require synaptic remodeling of Purkinje cell inputs. An extracellular serine protease, tissue plasminogen activator (tPA), is involved in remodeling various nonneural tissues and is associated with developing and regenerating neurons. In situ hybridization showed that expression of tPA messenger RNA was increased in the Purkinje neurons of rats within an hour of their being trained for a complex motor task. Antibody to tPA also showed the induction of tPA protein associated with cerebellar Purkinje cells. Thus, the induction of tPA during motor learning may play a role in activity-dependent synaptic plasticity.

Cell-specific gain modulation by synaptically released zinc in cortical circuits of audition.

PubMed

Anderson, Charles T; Kumar, Manoj; Xiong, Shanshan; Tzounopoulos, Thanos

2017-09-09

In many excitatory synapses, mobile zinc is found within glutamatergic vesicles and is coreleased with glutamate. Ex vivo studies established that synaptically released (synaptic) zinc inhibits excitatory neurotransmission at lower frequencies of synaptic activity but enhances steady state synaptic responses during higher frequencies of activity. However, it remains unknown how synaptic zinc affects neuronal processing in vivo. Here, we imaged the sound-evoked neuronal activity of the primary auditory cortex in awake mice. We discovered that synaptic zinc enhanced the gain of sound-evoked responses in CaMKII-expressing principal neurons, but it reduced the gain of parvalbumin- and somatostatin-expressing interneurons. This modulation was sound intensity-dependent and, in part, NMDA receptor-independent. By establishing a previously unknown link between synaptic zinc and gain control of auditory cortical processing, our findings advance understanding about cortical synaptic mechanisms and create a new framework for approaching and interpreting the role of the auditory cortex in sound processing.

The effects of dynamical synapses on firing rate activity: a spiking neural network model.

PubMed

Khalil, Radwa; Moftah, Marie Z; Moustafa, Ahmed A

2017-11-01

Accumulating evidence relates the fine-tuning of synaptic maturation and regulation of neural network activity to several key factors, including GABA A signaling and a lateral spread length between neighboring neurons (i.e., local connectivity). Furthermore, a number of studies consider short-term synaptic plasticity (STP) as an essential element in the instant modification of synaptic efficacy in the neuronal network and in modulating responses to sustained ranges of external Poisson input frequency (IF). Nevertheless, evaluating the firing activity in response to the dynamical interaction between STP (triggered by ranges of IF) and these key parameters in vitro remains elusive. Therefore, we designed a spiking neural network (SNN) model in which we incorporated the following parameters: local density of arbor essences and a lateral spread length between neighboring neurons. We also created several network scenarios based on these key parameters. Then, we implemented two classes of STP: (1) short-term synaptic depression (STD) and (2) short-term synaptic facilitation (STF). Each class has two differential forms based on the parametric value of its synaptic time constant (either for depressing or facilitating synapses). Lastly, we compared the neural firing responses before and after the treatment with STP. We found that dynamical synapses (STP) have a critical differential role on evaluating and modulating the firing rate activity in each network scenario. Moreover, we investigated the impact of changing the balance between excitation (E) and inhibition (I) on stabilizing this firing activity. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Molecular underpinnings of neurodegenerative disorders: striatal-enriched protein tyrosine phosphatase signaling and synaptic plasticity

PubMed Central

Lombroso, Paul J.; Ogren, Marilee; Kurup, Pradeep; Nairn, Angus C.

2016-01-01

This commentary focuses on potential molecular mechanisms related to the dysfunctional synaptic plasticity that is associated with neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Specifically, we focus on the role of striatal-enriched protein tyrosine phosphatase (STEP) in modulating synaptic function in these illnesses. STEP affects neuronal communication by opposing synaptic strengthening and does so by dephosphorylating several key substrates known to control synaptic signaling and plasticity. STEP levels are elevated in brains from patients with Alzheimer’s and Parkinson’s disease. Studies in model systems have found that high levels of STEP result in internalization of glutamate receptors as well as inactivation of ERK1/2, Fyn, Pyk2, and other STEP substrates necessary for the development of synaptic strengthening. We discuss the search for inhibitors of STEP activity that may offer potential treatments for neurocognitive disorders that are characterized by increased STEP activity. Future studies are needed to examine the mechanisms of differential and region-specific changes in STEP expression pattern, as such knowledge could lead to targeted therapies for disorders involving disrupted STEP activity. PMID:29098072

Hypothalamic modulation of the arterial chemoreceptor reflex in the anaesthetized cat: role of the nucleus tractus solitarii.

PubMed Central

Silva-Carvalho, L; Dawid-Milner, M S; Goldsmith, G E; Spyer, K M

1995-01-01

1. There is evidence in the literature of a mutual facilitatory interaction between the arterial chemoreceptor reflex and the alerting stage of the defence reaction, particularly in relation to the patterning of cardiorespiratory activity. The present study has been designed to test the hypothesis that a portion of this interaction involves synaptic interactions within the nucleus tractus solitarii (NTS). 2. The study has involved an analysis of the effective interactions between the stimulation of the arterial chemoreceptors and the hypothalamic defence area (HDA) on the activity of NTS neurones recorded in anaesthetized, paralysed and artificially ventilated cats. 3. A group of eighteen NTS neurones was classified as chemosensitive, on the basis of displaying EPSPs on sinus nerve stimulation (SN) and their failure to show an excitatory response to baroreceptor stimulation. Thirteen of these neurones displayed pronounced excitatory responses to chemoreceptor stimulation. In sixteen of these neurones HDA stimulation elicited an EPSP; in four of these sixteen neurones this early EPSP was followed by an IPSP. In the remaining two (of 18) neurones HDA stimulation provoked no obvious synaptic response but facilitated the efficacy of both chemoreceptor inputs and SN stimulation. 4. Neurones shown to receive convergent inputs from the arterial chemoreceptors (and SN stimulation) and HDA, often displayed excitatory responses to stimulation of other peripheral inputs. Vagally evoked EPSPs were observed in nine neurones, SLN-evoked responses in seven neurones and aortic nerve-evoked EPSPs in three neurones. 5. The organization of these synaptic interactions is discussed and these data are used to explain the pattern of interaction between chemoreceptor, baroreceptor and HDA inputs within the NTS. Conclusions are drawn regarding the functional role of different classes of NTS neurone, based on the findings in this and the accompanying two papers. PMID:8544136

Ultrastructure of spines and associated terminals on brainstem neurons controlling auditory input

PubMed Central

Brown, M. Christian; Lee, Daniel J.; Benson, Thane E.

2013-01-01

Spines are unique cellular appendages that isolate synaptic input to neurons and play a role in synaptic plasticity. Using the electron microscope, we studied spines and their associated synaptic terminals on three groups of brainstem neurons: tensor tympani motoneurons, stapedius motoneurons, and medial olivocochlear neurons, all of which exert reflexive control of processes in the auditory periphery. These spines are generally simple in shape; they are infrequent and found on the somata as well as the dendrites. Spines do not differ in volume among the three groups of neurons. In all cases, the spines are associated with a synaptic terminal that engulfs the spine rather than abuts its head. The positions of the synapses are variable, and some are found at a distance from the spine, suggesting that the isolation of synaptic input is of diminished importance for these spines. Each group of neurons receives three common types of synaptic terminals. The type of terminal associated with spines of the motoneurons contains pleomorphic vesicles, whereas the type associated with spines of olivocochlear neurons contains large round vesicles. Thus, spine-associated terminals in the motoneurons appear to be associated with inhibitory processes but in olivocochlear neurons they are associated with excitatory processes. PMID:23602963

A 2D Material based Gate Tunable Memristive Device for Emulating Modulatory Input-dependent Hetero-synaptic Plasticity.

NASA Astrophysics Data System (ADS)

Yan, Xiaodong; Tian, He; Xie, Yujun; Kostelec, Andrew; Zhao, Huan; Cha, Judy J.; Tice, Jesse; Wang, Han

Modulatory input-dependent plasticity is a well-known type of hetero-synaptic response where the release of neuromodulators can alter the efficacy of neurotransmission in a nearby chemical synapse. Solid-state devices that can mimic such phenomenon are desirable for enhancing the functionality and reconfigurability of neuromorphic electronics. In this work, we demonstrated a tunable artificial synaptic device concept based on the properties of graphene and tin oxide that can mimic the modulatory input-dependent plasticity. By using graphene as the contact electrode, a third electrode terminal can be used to modulate the conductive filament formation in the vertical tin oxide based resistive memory device. The resulting synaptic characteristics of this device, in terms of the profile of synaptic weight change and the spike-timing-dependent-plasticity, is tunable with the bias at the modulating terminal. Furthermore, the synaptic response can be reconfigured between excitatory and inhibitory modes by this modulating bias. The operation mechanism of the device is studied with combined experimental and theoretical analysis. The device is attractive for application in neuromorphic electronics. This work is supported by ARO and NG-ION2 at USC.

Self-Organization of Microcircuits in Networks of Spiking Neurons with Plastic Synapses.

PubMed

Ocker, Gabriel Koch; Litwin-Kumar, Ashok; Doiron, Brent

2015-08-01

The synaptic connectivity of cortical networks features an overrepresentation of certain wiring motifs compared to simple random-network models. This structure is shaped, in part, by synaptic plasticity that promotes or suppresses connections between neurons depending on their joint spiking activity. Frequently, theoretical studies focus on how feedforward inputs drive plasticity to create this network structure. We study the complementary scenario of self-organized structure in a recurrent network, with spike timing-dependent plasticity driven by spontaneous dynamics. We develop a self-consistent theory for the evolution of network structure by combining fast spiking covariance with a slow evolution of synaptic weights. Through a finite-size expansion of network dynamics we obtain a low-dimensional set of nonlinear differential equations for the evolution of two-synapse connectivity motifs. With this theory in hand, we explore how the form of the plasticity rule drives the evolution of microcircuits in cortical networks. When potentiation and depression are in approximate balance, synaptic dynamics depend on weighted divergent, convergent, and chain motifs. For additive, Hebbian STDP these motif interactions create instabilities in synaptic dynamics that either promote or suppress the initial network structure. Our work provides a consistent theoretical framework for studying how spiking activity in recurrent networks interacts with synaptic plasticity to determine network structure.

Self-Organization of Microcircuits in Networks of Spiking Neurons with Plastic Synapses

PubMed Central

Ocker, Gabriel Koch; Litwin-Kumar, Ashok; Doiron, Brent

2015-01-01

The synaptic connectivity of cortical networks features an overrepresentation of certain wiring motifs compared to simple random-network models. This structure is shaped, in part, by synaptic plasticity that promotes or suppresses connections between neurons depending on their joint spiking activity. Frequently, theoretical studies focus on how feedforward inputs drive plasticity to create this network structure. We study the complementary scenario of self-organized structure in a recurrent network, with spike timing-dependent plasticity driven by spontaneous dynamics. We develop a self-consistent theory for the evolution of network structure by combining fast spiking covariance with a slow evolution of synaptic weights. Through a finite-size expansion of network dynamics we obtain a low-dimensional set of nonlinear differential equations for the evolution of two-synapse connectivity motifs. With this theory in hand, we explore how the form of the plasticity rule drives the evolution of microcircuits in cortical networks. When potentiation and depression are in approximate balance, synaptic dynamics depend on weighted divergent, convergent, and chain motifs. For additive, Hebbian STDP these motif interactions create instabilities in synaptic dynamics that either promote or suppress the initial network structure. Our work provides a consistent theoretical framework for studying how spiking activity in recurrent networks interacts with synaptic plasticity to determine network structure. PMID:26291697

Pathway and Cell-Specific Kappa-Opioid Receptor Modulation of Excitatory-Inhibitory Balance Differentially Gates D1 and D2 Accumbens Neuron Activity

PubMed Central

Tejeda, Hugo A.; Wu, Jocelyn; Kornspun, Alana R.; Pignatelli, Marco; Kashtelyan, Vadim; Krashes, Michael J.; Lowell, Brad B.; Carlezon, William A.; Bonci, Antonello

2018-01-01

Endogenous dynorphin signaling via the kappa-opioid receptor (KOR) in the nucleus accumbens (NAcc) powerfully mediates negative affective states and stress reactivity. Excitatory inputs from the hippocampus and amygdala play a fundamental role in shaping the activity of both NAcc D1 and D2 MSNs, which encode positive and negative motivational valences, respectively. However, a circuit-based mechanism by which KOR modulation of excitation-inhibition balance modifies D1 and D2 MSN activity is lacking. Here, we provide a comprehensive synaptic framework wherein presynaptic KOR inhibition decreases excitatory drive of D1 MSN activity by the amygdala, but not hippocampus. Conversely, presynaptic inhibition by KORs of inhibitory synapses on D2 MSNs enhances integration of excitatory drive by the amygdala and hippocampus. In conclusion, we describe a circuit-based mechanism showing differential gating of afferent control of D1 and D2 MSN activity by KORs in a pathway specific manner. PMID:28056342

Long-term modifications of synaptic efficacy in the human inferior and middle temporal cortex

NASA Technical Reports Server (NTRS)

Chen, W. R.; Lee, S.; Kato, K.; Spencer, D. D.; Shepherd, G. M.; Williamson, A.

1996-01-01

The primate temporal cortex has been demonstrated to play an important role in visual memory and pattern recognition. It is of particular interest to investigate whether activity-dependent modification of synaptic efficacy, a presumptive mechanism for learning and memory, is present in this cortical region. Here we address this issue by examining the induction of synaptic plasticity in surgically resected human inferior and middle temporal cortex. The results show that synaptic strength in the human temporal cortex could undergo bidirectional modifications, depending on the pattern of conditioning stimulation. High frequency stimulation (100 or 40 Hz) in layer IV induced long-term potentiation (LTP) of both intracellular excitatory postsynaptic potentials and evoked field potentials in layers II/III. The LTP induced by 100 Hz tetanus was blocked by 50-100 microM DL-2-amino-5-phosphonovaleric acid, suggesting that N-methyl-D-aspartate receptors were responsible for its induction. Long-term depression (LTD) was elicited by prolonged low frequency stimulation (1 Hz, 15 min). It was reduced, but not completely blocked, by DL-2-amino-5-phosphonovaleric acid, implying that some other mechanisms in addition to N-methyl-DL-aspartate receptors were involved in LTD induction. LTD was input-specific, i.e., low frequency stimulation of one pathway produced LTD of synaptic transmission in that pathway only. Finally, the LTP and LTD could reverse each other, suggesting that they can act cooperatively to modify the functional state of cortical network. These results suggest that LTP and LTD are possible mechanisms for the visual memory and pattern recognition functions performed in the human temporal cortex.

A review of the integrate-and-fire neuron model: II. Inhomogeneous synaptic input and network properties.

PubMed

Burkitt, A N

2006-08-01

The integrate-and-fire neuron model describes the state of a neuron in terms of its membrane potential, which is determined by the synaptic inputs and the injected current that the neuron receives. When the membrane potential reaches a threshold, an action potential (spike) is generated. This review considers the model in which the synaptic input varies periodically and is described by an inhomogeneous Poisson process, with both current and conductance synapses. The focus is on the mathematical methods that allow the output spike distribution to be analyzed, including first passage time methods and the Fokker-Planck equation. Recent interest in the response of neurons to periodic input has in part arisen from the study of stochastic resonance, which is the noise-induced enhancement of the signal-to-noise ratio. Networks of integrate-and-fire neurons behave in a wide variety of ways and have been used to model a variety of neural, physiological, and psychological phenomena. The properties of the integrate-and-fire neuron model with synaptic input described as a temporally homogeneous Poisson process are reviewed in an accompanying paper (Burkitt in Biol Cybern, 2006).

An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger.

PubMed

Krashes, Michael J; Shah, Bhavik P; Madara, Joseph C; Olson, David P; Strochlic, David E; Garfield, Alastair S; Vong, Linh; Pei, Hongjuan; Watabe-Uchida, Mitsuko; Uchida, Naoshige; Liberles, Stephen D; Lowell, Bradford B

2014-03-13

Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

The Bermuda Triangle of cocaine-induced neuroadaptations.

PubMed

Wolf, Marina E

2010-09-01

Activation of medium spiny neurons (MSNs) of the nucleus accumbens is critical for goal-directed behaviors including cocaine seeking. Studies in cocaine-experienced rodents have revealed three major categories of neuroadaptations that influence the ability of glutamate inputs to activate MSNs: changes in synaptic AMPA receptor levels, changes in extracellular non-synaptic glutamate levels and changes in MSN intrinsic membrane excitability. Most studies have focused on one of these adaptations. This review will consider the possibility that they are causally related and speculate about how time-dependent changes in their interactions may regulate MSN output during early and late withdrawal from repeated cocaine exposure. Copyright 2010 Elsevier Ltd. All rights reserved.

The Bermuda Triangle of Cocaine-Induced Neuroadaptations

PubMed Central

Wolf, Marina E.

2010-01-01

Activation of medium spiny neurons (MSN) of the nucleus accumbens is critical for goal-directed behaviors including cocaine seeking. Studies in cocaine-experienced rodents have revealed three major categories of neuroadaptations that influence the ability of glutamate inputs to activate MSN: changes in synaptic AMPA receptor levels, changes in extracellular non-synaptic glutamate levels, and changes in MSN intrinsic membrane excitability. Most studies have focused on one of these adaptations. Here, we consider the possibility that they are causally related and speculate about how time-dependent changes in their interactions may regulate MSN output during early and late withdrawal from repeated cocaine exposure. PMID:20655604

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

PubMed

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.

Attention Enhances Synaptic Efficacy and Signal-to-Noise in Neural Circuits

PubMed Central

Briggs, Farran; Mangun, George R.; Usrey, W. Martin

2013-01-01

Summary Attention is a critical component of perception. However, the mechanisms by which attention modulates neuronal communication to guide behavior are poorly understood. To elucidate the synaptic mechanisms of attention, we developed a sensitive assay of attentional modulation of neuronal communication. In alert monkeys performing a visual spatial attention task, we probed thalamocortical communication by electrically stimulating neurons in the lateral geniculate nucleus of the thalamus while simultaneously recording shock-evoked responses from monosynaptically connected neurons in primary visual cortex. We found that attention enhances neuronal communication by (1) increasing the efficacy of presynaptic input in driving postsynaptic responses, (2) increasing synchronous responses among ensembles of postsynaptic neurons receiving independent input, and (3) decreasing redundant signals between postsynaptic neurons receiving common input. These results demonstrate that attention finely tunes neuronal communication at the synaptic level by selectively altering synaptic weights, enabling enhanced detection of salient events in the noisy sensory milieu. PMID:23803766

Basal Forebrain Gating by Somatostatin Neurons Drives Prefrontal Cortical Activity.

PubMed

Espinosa, Nelson; Alonso, Alejandra; Morales, Cristian; Espinosa, Pedro; Chávez, Andrés E; Fuentealba, Pablo

2017-11-17

The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing neurons constitute a heterogeneous GABAergic population known to functionally inhibit basal forebrain cortically projecting cells thus favoring sleep and cortical synchronization. However, it remains unclear if somatostatin cells can regulate population activity patterns in the basal forebrain and modulate cortical dynamics. Here, we demonstrate that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo rapidly modified neural activity in the basal forebrain, with the consequent enhancement and desynchronization of activity in the prefrontal cortex, reflected in both neuronal spiking and network oscillations. Cortical activation was partially dependent on cholinergic transmission, suppressing slow waves and potentiating gamma oscillations. In addition, recruitment dynamics was cell type-specific, with interneurons showing similar temporal profiles, but stronger responses than pyramidal cells. Finally, optogenetic stimulation of quiescent animals during resting periods prompted locomotor activity, suggesting generalized cortical activation and increased arousal. Altogether, we provide physiological and behavioral evidence indicating that somatostatin neurons are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain.

PubMed

Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru

2013-01-01

In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca(2+) indicator in the MBs, we investigated synaptic transmission and plasticity at the AL-MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca(2+) responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca(2+) responses were mediated through Drosophila NMDA receptors (dNRs). AL-MB synaptic transmission was enhanced more than 2 h after the simultaneous 'associative-stimulation' of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL-MB synapses but not at the AFV-MB synapses. AL-MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL-MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL-MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL-MB LTE might be a relevant cellular model for olfactory memory.

Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain

PubMed Central

Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru

2013-01-01

In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca2+ indicator in the MBs, we investigated synaptic transmission and plasticity at the AL–MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca2+ responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca2+ responses were mediated through Drosophila NMDA receptors (dNRs). AL–MB synaptic transmission was enhanced more than 2 h after the simultaneous ‘associative-stimulation’ of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL–MB synapses but not at the AFV–MB synapses. AL–MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL–MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL–MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL–MB LTE might be a relevant cellular model for olfactory memory. PMID:23027817

Synergistic control of protein kinase Cgamma activity by ionotropic and metabotropic glutamate receptor inputs in hippocampal neurons.

PubMed

Codazzi, Franca; Di Cesare, Alessandra; Chiulli, Nino; Albanese, Alberto; Meyer, Tobias; Zacchetti, Daniele; Grohovaz, Fabio

2006-03-29

Conventional protein kinase C (PKC) isoforms are abundant neuronal signaling proteins with important roles in regulating synaptic plasticity and other neuronal processes. Here, we investigate the role of ionotropic and metabotropic glutamate receptor (iGluR and mGluR, respectively) activation on the generation of Ca2+ and diacylglycerol (DAG) signals and the subsequent activation of the neuron-specific PKCgamma isoform in hippocampal neurons. By combining Ca2+ imaging with total internal reflection microscopy analysis of specific biosensors, we show that elevation of both Ca2+ and DAG is necessary for sustained translocation and activation of EGFP (enhanced green fluorescent protein)-PKCgamma. Both DAG production and PKCgamma translocation were localized processes, typically observed within discrete microdomains along the dendritic branches. Markedly, intermediate-strength NMDA receptor (NMDAR) activation or moderate electrical stimulation generated Ca2+ but no DAG signals, whereas mGluR activation generated DAG but no Ca2+ signals. Both receptors were needed for PKCgamma activation. This suggests that a coincidence detection process exists between iGluRs and mGluRs that relies on a molecular coincidence detection process based on the corequirement of Ca2+ and DAG for PKCgamma activation. Nevertheless, the requirement for costimulation with mGluRs could be overcome for maximal NMDAR stimulation through a direct production of DAG via activation of the Ca2+-sensitive PLCdelta (phospholipase Cdelta) isoform. In a second important exception, mGluRs were sufficient for PKCgamma activation in neurons in which Ca2+ stores were loaded by previous electrical activity. Together, the dual activation requirement for PKCgamma provides a plausible molecular interpretation for different synergistic contributions of mGluRs to long-term potentiation and other synaptic plasticity processes.

Adrenoceptor-Mediated Post- and Pre-Synaptic Regulations of the Reticulospinal Neurons in Rat Caudal Pontine Reticular Nucleus.

PubMed

Yang, Nian; Qiao, Qi-Cheng; Liu, Yu-Hui; Zhang, Ji-Qiang; Hu, Zhi-An; Zhang, Jun

2016-12-01

The central noradrenergic system participates in diverse nervous functions. Nevertheless, our knowledge of the action of adrenoceptors in motor regulation is still lacking. Intriguingly, reticulospinal neurons in the caudal pontine reticular nucleus (PnC) receive fairly dense noradrenergic innervation and play an important role in motor control. Here, after demonstrating the expression of α1- and α2-adrenoceptors in the PnC, we found that noradrenaline elicited a post-synaptic effect (inward or outward whole-cell current at -70 mV holding) on PnC reticulospinal neurons. The α1- and α2-adrenoceptors were co-expressed in individual PnC reticulospinal neurons to mediate an inward and an outward current component at -70 mV holding, respectively, which, when superposed, produced the overall post-synaptic effects of noradrenaline (NA). More importantly, the activation of post-synaptic α1- or α2-adrenoceptors indeed exerted opposing modulations (excitation vs. inhibition) on the firing activities of individual PnC reticulospinal neurons. Furthermore, the activation and inhibition of the Na + -permeable non-selective cationic conductance (NSCC) were demonstrated to be coupled to α1- and α2-adrenoceptors, respectively. Additionally, the activation of α2-adrenoceptors activated K + conductance. Pre-synaptically, the α2-adrenoceptors were expressed to attenuate the miniature excitatory postsynaptic current (mEPSC) in PnC reticulospinal neurons, but not to affect the miniature inhibitory postsynaptic current (mIPSC). Consistently, the evoked EPSC in PnC reticulospinal neurons was suppressed after the activation of pre-synaptic α2-adrenoceptors. Thus, the excitatory input and post-synaptic dynamics of PnC reticulospinal neurons are indeed intricately modulated by the activation of α1- and α2-adrenoceptors, through which motor control may be regulated in an adaptive manner by the central noradrenergic system.

Task-Driven Activity Reduces the Cortical Activity Space of the Brain: Experiment and Whole-Brain Modeling

PubMed Central

Hagmann, Patric; Deco, Gustavo

2015-01-01

How a stimulus or a task alters the spontaneous dynamics of the brain remains a fundamental open question in neuroscience. One of the most robust hallmarks of task/stimulus-driven brain dynamics is the decrease of variability with respect to the spontaneous level, an effect seen across multiple experimental conditions and in brain signals observed at different spatiotemporal scales. Recently, it was observed that the trial-to-trial variability and temporal variance of functional magnetic resonance imaging (fMRI) signals decrease in the task-driven activity. Here we examined the dynamics of a large-scale model of the human cortex to provide a mechanistic understanding of these observations. The model allows computing the statistics of synaptic activity in the spontaneous condition and in putative tasks determined by external inputs to a given subset of brain regions. We demonstrated that external inputs decrease the variance, increase the covariances, and decrease the autocovariance of synaptic activity as a consequence of single node and large-scale network dynamics. Altogether, these changes in network statistics imply a reduction of entropy, meaning that the spontaneous synaptic activity outlines a larger multidimensional activity space than does the task-driven activity. We tested this model’s prediction on fMRI signals from healthy humans acquired during rest and task conditions and found a significant decrease of entropy in the stimulus-driven activity. Altogether, our study proposes a mechanism for increasing the information capacity of brain networks by enlarging the volume of possible activity configurations at rest and reliably settling into a confined stimulus-driven state to allow better transmission of stimulus-related information. PMID:26317432

Post-synaptic Density-95 (PSD-95) Binding Capacity of G-protein-coupled Receptor 30 (GPR30), an Estrogen Receptor That Can Be Identified in Hippocampal Dendritic Spines*

PubMed Central

Akama, Keith T.; Thompson, Louisa I.; Milner, Teresa A.; McEwen, Bruce S.

2013-01-01

The estrogen 17β-estradiol (E2) modulates dendritic spine plasticity in the cornu ammonis 1 (CA1) region of the hippocampus, and GPR30 (G-protein coupled estrogen receptor 1 (GPER1)) is an estrogen-sensitive G-protein-coupled receptor (GPCR) that is expressed in the mammalian brain and in specific subregions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30, however, remains unclear. Here, we demonstrate that GPR30 immunoreactivity is detected in dendritic spines of rat CA1 hippocampal neurons in vivo and that GPR30 protein can be found in rat brain synaptosomes. GPR30 immunoreactivity is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail that is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity. PMID:23300088

Post-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines.

PubMed

Akama, Keith T; Thompson, Louisa I; Milner, Teresa A; McEwen, Bruce S

2013-03-01

The estrogen 17β-estradiol (E2) modulates dendritic spine plasticity in the cornu ammonis 1 (CA1) region of the hippocampus, and GPR30 (G-protein coupled estrogen receptor 1 (GPER1)) is an estrogen-sensitive G-protein-coupled receptor (GPCR) that is expressed in the mammalian brain and in specific subregions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30, however, remains unclear. Here, we demonstrate that GPR30 immunoreactivity is detected in dendritic spines of rat CA1 hippocampal neurons in vivo and that GPR30 protein can be found in rat brain synaptosomes. GPR30 immunoreactivity is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail that is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity.

Bidirectional Hebbian Plasticity Induced by Low-Frequency Stimulation in Basal Dendrites of Rat Barrel Cortex Layer 5 Pyramidal Neurons.

PubMed

Díez-García, Andrea; Barros-Zulaica, Natali; Núñez, Ángel; Buño, Washington; Fernández de Sevilla, David

2017-01-01

According to Hebb's original hypothesis (Hebb, 1949), synapses are reinforced when presynaptic activity triggers postsynaptic firing, resulting in long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) is a use-dependent decrease in synaptic strength that is thought to be due to synaptic input causing a weak postsynaptic effect. Although the mechanisms that mediate long-term synaptic plasticity have been investigated for at least three decades not all question have as yet been answered. Therefore, we aimed at determining the mechanisms that generate LTP or LTD with the simplest possible protocol. Low-frequency stimulation of basal dendrite inputs in Layer 5 pyramidal neurons of the rat barrel cortex induces LTP. This stimulation triggered an EPSP, an action potential (AP) burst, and a Ca 2+ spike. The same stimulation induced LTD following manipulations that reduced the Ca 2+ spike and Ca 2+ signal or the AP burst. Low-frequency whisker deflections induced similar bidirectional plasticity of action potential evoked responses in anesthetized rats. These results suggest that both in vitro and in vivo similar mechanisms regulate the balance between LTP and LTD. This simple induction form of bidirectional hebbian plasticity could be present in the natural conditions to regulate the detection, flow, and storage of sensorimotor information.

Bidirectional Hebbian Plasticity Induced by Low-Frequency Stimulation in Basal Dendrites of Rat Barrel Cortex Layer 5 Pyramidal Neurons

PubMed Central

Díez-García, Andrea; Barros-Zulaica, Natali; Núñez, Ángel; Buño, Washington; Fernández de Sevilla, David

2017-01-01

According to Hebb's original hypothesis (Hebb, 1949), synapses are reinforced when presynaptic activity triggers postsynaptic firing, resulting in long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) is a use-dependent decrease in synaptic strength that is thought to be due to synaptic input causing a weak postsynaptic effect. Although the mechanisms that mediate long-term synaptic plasticity have been investigated for at least three decades not all question have as yet been answered. Therefore, we aimed at determining the mechanisms that generate LTP or LTD with the simplest possible protocol. Low-frequency stimulation of basal dendrite inputs in Layer 5 pyramidal neurons of the rat barrel cortex induces LTP. This stimulation triggered an EPSP, an action potential (AP) burst, and a Ca2+ spike. The same stimulation induced LTD following manipulations that reduced the Ca2+ spike and Ca2+ signal or the AP burst. Low-frequency whisker deflections induced similar bidirectional plasticity of action potential evoked responses in anesthetized rats. These results suggest that both in vitro and in vivo similar mechanisms regulate the balance between LTP and LTD. This simple induction form of bidirectional hebbian plasticity could be present in the natural conditions to regulate the detection, flow, and storage of sensorimotor information. PMID:28203145

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

PubMed

Luo, Sarah X; Timbang, Leah; Kim, Jae-Ick; Shang, Yulei; Sandoval, Kadellyn; Tang, Amy A; Whistler, Jennifer L; Ding, Jun B; Huang, Eric J

2016-12-20

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. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

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

PubMed

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.

A Postsynaptic AMPK→p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons.

PubMed

Kong, Dong; Dagon, Yossi; Campbell, John N; Guo, Yikun; Yang, Zongfang; Yi, Xinchi; Aryal, Pratik; Wellenstein, Kerry; Kahn, Barbara B; Sabatini, Bernardo L; Lowell, Bradford B

2016-07-06

AMP-activated protein kinase (AMPK) plays an important role in regulating food intake. The downstream AMPK substrates and neurobiological mechanisms responsible for this, however, are ill defined. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus regulate hunger. Their firing increases with fasting, and once engaged they cause feeding. AgRP neuron activity is regulated by state-dependent synaptic plasticity: fasting increases dendritic spines and excitatory synaptic activity; feeding does the opposite. The signaling mechanisms underlying this, however, are also unknown. Using neuron-specific approaches to measure and manipulate kinase activity specifically within AgRP neurons, we establish that fasting increases AMPK activity in AgRP neurons, that increased AMPK activity in AgRP neurons is both necessary and sufficient for fasting-induced spinogenesis and excitatory synaptic activity, and that the AMPK phosphorylation target mediating this plasticity is p21-activated kinase. This provides a signaling and neurobiological basis for both AMPK regulation of energy balance and AgRP neuron state-dependent plasticity. Copyright © 2016 Elsevier Inc. All rights reserved.

Active action potential propagation but not initiation in thalamic interneuron dendrites

PubMed Central

Casale, Amanda E.; McCormick, David A.

2012-01-01

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

The Influence of Synaptic Weight Distribution on Neuronal Population Dynamics

PubMed Central

Buice, Michael; Koch, Christof; Mihalas, Stefan

2013-01-01

The manner in which different distributions of synaptic weights onto cortical neurons shape their spiking activity remains open. To characterize a homogeneous neuronal population, we use the master equation for generalized leaky integrate-and-fire neurons with shot-noise synapses. We develop fast semi-analytic numerical methods to solve this equation for either current or conductance synapses, with and without synaptic depression. We show that its solutions match simulations of equivalent neuronal networks better than those of the Fokker-Planck equation and we compute bounds on the network response to non-instantaneous synapses. We apply these methods to study different synaptic weight distributions in feed-forward networks. We characterize the synaptic amplitude distributions using a set of measures, called tail weight numbers, designed to quantify the preponderance of very strong synapses. Even if synaptic amplitude distributions are equated for both the total current and average synaptic weight, distributions with sparse but strong synapses produce higher responses for small inputs, leading to a larger operating range. Furthermore, despite their small number, such synapses enable the network to respond faster and with more stability in the face of external fluctuations. PMID:24204219

Membrane Properties and the Balance between Excitation and Inhibition Control Gamma-Frequency Oscillations Arising from Feedback Inhibition

PubMed Central

Economo, Michael N.; White, John A.

2012-01-01

Computational studies as well as in vivo and in vitro results have shown that many cortical neurons fire in a highly irregular manner and at low average firing rates. These patterns seem to persist even when highly rhythmic signals are recorded by local field potential electrodes or other methods that quantify the summed behavior of a local population. Models of the 30–80 Hz gamma rhythm in which network oscillations arise through ‘stochastic synchrony’ capture the variability observed in the spike output of single cells while preserving network-level organization. We extend upon these results by constructing model networks constrained by experimental measurements and using them to probe the effect of biophysical parameters on network-level activity. We find in simulations that gamma-frequency oscillations are enabled by a high level of incoherent synaptic conductance input, similar to the barrage of noisy synaptic input that cortical neurons have been shown to receive in vivo. This incoherent synaptic input increases the emergent network frequency by shortening the time scale of the membrane in excitatory neurons and by reducing the temporal separation between excitation and inhibition due to decreased spike latency in inhibitory neurons. These mechanisms are demonstrated in simulations and in vitro current-clamp and dynamic-clamp experiments. Simulation results further indicate that the membrane potential noise amplitude has a large impact on network frequency and that the balance between excitatory and inhibitory currents controls network stability and sensitivity to external inputs. PMID:22275859

Emergence of network structure due to spike-timing-dependent plasticity in recurrent neuronal networks IV: structuring synaptic pathways among recurrent connections.

PubMed

Gilson, Matthieu; Burkitt, Anthony N; Grayden, David B; Thomas, Doreen A; van Hemmen, J Leo

2009-12-01

In neuronal networks, the changes of synaptic strength (or weight) performed by spike-timing-dependent plasticity (STDP) are hypothesized to give rise to functional network structure. This article investigates how this phenomenon occurs for the excitatory recurrent connections of a network with fixed input weights that is stimulated by external spike trains. We develop a theoretical framework based on the Poisson neuron model to analyze the interplay between the neuronal activity (firing rates and the spike-time correlations) and the learning dynamics, when the network is stimulated by correlated pools of homogeneous Poisson spike trains. STDP can lead to both a stabilization of all the neuron firing rates (homeostatic equilibrium) and a robust weight specialization. The pattern of specialization for the recurrent weights is determined by a relationship between the input firing-rate and correlation structures, the network topology, the STDP parameters and the synaptic response properties. We find conditions for feed-forward pathways or areas with strengthened self-feedback to emerge in an initially homogeneous recurrent network.

Social stress alters inhibitory synaptic input to distinct subpopulations of raphe serotonin neurons.

PubMed

Crawford, LaTasha K; Rahman, Shumaia F; Beck, Sheryl G

2013-01-16

Anxiety disorders are among the most prevalent psychiatric disorders, yet much is unknown about the underlying mechanisms. The dorsal raphe (DR) is at the crux of the anxiety-inducing effects of uncontrollable stress, a key component of models of anxiety. Though DR serotonin (5-HT) neurons play a prominent role, anxiety-associated changes in the physiology of 5-HT neurons remain poorly understood. A 5-day social defeat model of anxiety produced a multifaceted, anxious phenotype in intruder mice that included increased avoidance behavior in the open field test, increased stress-evoked grooming, and increased bladder and heart weights when compared to control mice. Intruders were further compared to controls using electrophysiology recordings conducted in midbrain slices wherein recordings targeted 5-HT neurons of the ventromedial (vmDR) and lateral wing (lwDR) subfields of the DR. Though defining membrane characteristics of 5-HT neurons were unchanged, γ-aminobutyric-acid-mediated (GABAergic) synaptic regulation of 5-HT neurons was altered in a topographically specific way. In the vmDR of intruders, there was a decrease in the frequency and amplitude of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs). However, in the lwDR, there was an increase in the strength of inhibitory signals due to slower sIPSC kinetics. Synaptic changes were selective for GABAergic input, as glutamatergic synaptic input was unchanged in intruders. The distinct inhibitory regulation of DR subfields provides a mechanism for increased 5-HT output in vmDR target regions and decreased 5-HT output in lwDR target regions, divergent responses to uncontrollable stress that have been reported in the literature but were previously poorly understood.

Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive.

PubMed

Williams, Michael R; DeSpenza, Tyrone; Li, Meijie; Gulledge, Allan T; Luikart, Bryan W

2015-01-21

Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either "birthdate" or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons. Copyright © 2015 the authors 0270-6474/15/350943-17$15.00/0.

Anesthetic Agent-Specific Effects on Synaptic Inhibition

PubMed Central

MacIver, M. Bruce

2014-01-01

Background Anesthetics enhance gamma-aminobutyric acid (GABA)-mediated inhibition in the central nervous system. Different agents have been shown to act on tonic versus synaptic GABA receptors to different degrees, but it remains unknown whether different forms of synaptic inhibition are also differentially engaged. With this in mind, we tested the hypothesis that different types of GABA-mediated synapses exhibit different anesthetic sensitivities. The present study compared effects produced by isoflurane, halothane, pentobarbital, thiopental and propofol on paired pulse GABAA receptor-mediated synaptic inhibition. Effects on glutamate-mediated facilitation were also studied. Methods Synaptic responses were measured in rat hippocampal brain slices. Orthodromic paired pulse stimulation was used to assess anesthetic effects on either glutamate-mediated excitatory inputs or GABA-mediated inhibitory inputs to CA1 neurons. Antidromic stimulation was used to assess anesthetic effects on CA1 background excitability. Agents were studied at equi-effective concentrations for population spike depression to compare their relative degree of effect on synaptic inhibition. Results Differing degrees of anesthetic effect on paired pulse facilitation at excitatory glutamate synapses were evident, and blocking GABA inhibition revealed a previously unseen presynaptic action for pentobarbital. Although all five anesthetics depressed synaptically evoked excitation of CA1 neurons, the involvement of enhanced GABA-mediated inhibition differed considerably among agents. Single pulse inhibition was enhanced by propofol, thiopental and pentobarbital, but only marginally by halothane and isoflurane. In contrast, isoflurane enhanced paired pulse inhibition strongly, as did thiopental, but propofol, pentobarbital and halothane were less effective. Conclusions These observations support the idea that different GABA synapses use receptors with differing subunit compositions, and that anesthetics exhibit differing degrees of selectivity for these receptors. The differing anesthetic sensitivities seen in the present study, at glutamate and GABA synapses, help explain the unique behavioral/clinical profiles produced by different classes of anesthetics, and indicate that there are selective targets for new agent development. PMID:24977633

Anesthetic agent-specific effects on synaptic inhibition.

PubMed

MacIver, M Bruce

2014-09-01

Anesthetics enhance γ-aminobutyric acid (GABA)-mediated inhibition in the central nervous system. Different agents have been shown to act on tonic versus synaptic GABA receptors to different degrees, but it remains unknown whether different forms of synaptic inhibition are also differentially engaged. With this in mind, we tested the hypothesis that different types of GABA-mediated synapses exhibit different anesthetic sensitivities. The present study compared effects produced by isoflurane, halothane, pentobarbital, thiopental, and propofol on paired-pulse GABAA receptor-mediated synaptic inhibition. Effects on glutamate-mediated facilitation were also studied. Synaptic responses were measured in rat hippocampal brain slices. Orthodromic paired-pulse stimulation was used to assess anesthetic effects on either glutamate-mediated excitatory inputs or GABA-mediated inhibitory inputs to CA1 neurons. Antidromic stimulation was used to assess anesthetic effects on CA1 background excitability. Agents were studied at equieffective concentrations for population spike depression to compare their relative degree of effect on synaptic inhibition. Differing degrees of anesthetic effect on paired-pulse facilitation at excitatory glutamate synapses were evident, and blocking GABA inhibition revealed a previously unseen presynaptic action for pentobarbital. Although all 5 anesthetics depressed synaptically evoked excitation of CA1 neurons, the involvement of enhanced GABA-mediated inhibition differed considerably among agents. Single-pulse inhibition was enhanced by propofol, thiopental, and pentobarbital, but only marginally by halothane and isoflurane. In contrast, isoflurane enhanced paired-pulse inhibition strongly, as did thiopental, but propofol, pentobarbital, and halothane were less effective. These observations support the idea that different GABA synapses use receptors with differing subunit compositions and that anesthetics exhibit differing degrees of selectivity for these receptors. The differing anesthetic sensitivities seen in the present study, at glutamate and GABA synapses, help explain the unique behavioral/clinical profiles produced by different classes of anesthetics and indicate that there are selective targets for new agent development.

Synaptic communication between neurons and NG2+ cells.

PubMed

Paukert, Martin; Bergles, Dwight E

2006-10-01

Chemical synaptic transmission provides the basis for much of the rapid signaling that occurs within neuronal networks. However, recent studies have provided compelling evidence that synapses are not used exclusively for communication between neurons. Physiological and anatomical studies indicate that a distinct class of glia known as NG2(+) cells also forms direct synaptic junctions with both glutamatergic and GABAergic neurons. Glutamatergic signaling can influence intracellular Ca(2+) levels in NG2(+) cells by activating Ca(2+) permeable AMPA receptors, and these inputs can be potentiated through high frequency stimulation. Although the significance of this highly differentiated form of communication remains to be established, these neuro-glia synapses might enable neurons to influence rapidly the behavior of this ubiquitous class of glial progenitors.

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

PubMed

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.

Firing rate of noisy integrate-and-fire neurons with synaptic current dynamics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andrieux, David; Monnai, Takaaki; Department of Applied Physics, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555

2009-08-15

We derive analytical formulas for the firing rate of integrate-and-fire neurons endowed with realistic synaptic dynamics. In particular, we include the possibility of multiple synaptic inputs as well as the effect of an absolute refractory period into the description. The latter affects the firing rate through its interaction with the synaptic dynamics.

The Role of Short Term Synaptic Plasticity in Temporal Coding of Neuronal Networks

ERIC Educational Resources Information Center

Chandrasekaran, Lakshmi

2008-01-01

Short term synaptic plasticity is a phenomenon which is commonly found in the central nervous system. It could contribute to functions of signal processing namely, temporal integration and coincidence detection by modulating the input synaptic strength. This dissertation has two parts. First, we study the effects of short term synaptic plasticity…

A new simple /spl infin/OH neuron model as a biologically plausible principal component analyzer.

PubMed

Jankovic, M V

2003-01-01

A new approach to unsupervised learning in a single-layer neural network is discussed. An algorithm for unsupervised learning based upon the Hebbian learning rule is presented. A simple neuron model is analyzed. A dynamic neural model, which contains both feed-forward and feedback connections between the input and the output, has been adopted. The, proposed learning algorithm could be more correctly named self-supervised rather than unsupervised. The solution proposed here is a modified Hebbian rule, in which the modification of the synaptic strength is proportional not to pre- and postsynaptic activity, but instead to the presynaptic and averaged value of postsynaptic activity. It is shown that the model neuron tends to extract the principal component from a stationary input vector sequence. Usually accepted additional decaying terms for the stabilization of the original Hebbian rule are avoided. Implementation of the basic Hebbian scheme would not lead to unrealistic growth of the synaptic strengths, thanks to the adopted network structure.

Frequency-selective augmenting responses by short-term synaptic depression in cat neocortex

PubMed Central

Houweling, Arthur R; Bazhenov, Maxim; Timofeev, Igor; Grenier, François; Steriade, Mircea; Sejnowski, Terrence J

2002-01-01

Thalamic stimulation at frequencies between 5 and 15 Hz elicits incremental or ‘augmenting’ cortical responses. Augmenting responses can also be evoked in cortical slices and isolated cortical slabs in vivo. Here we show that a realistic network model of cortical pyramidal cells and interneurones including short-term plasticity of inhibitory and excitatory synapses replicates the main features of augmenting responses as obtained in isolated slabs in vivo. Repetitive stimulation of synaptic inputs at frequencies around 10 Hz produced postsynaptic potentials that grew in size and carried an increasing number of action potentials resulting from the depression of inhibitory synaptic currents. Frequency selectivity was obtained through the relatively weak depression of inhibitory synapses at low frequencies, and strong depression of excitatory synapses together with activation of a calcium-activated potassium current at high frequencies. This network resonance is a consequence of short-term synaptic plasticity in a network of neurones without intrinsic resonances. These results suggest that short-term plasticity of cortical synapses could shape the dynamics of synchronized oscillations in the brain. PMID:12122156

Neural principles of memory and a neural theory of analogical insight

NASA Astrophysics Data System (ADS)

Lawson, David I.; Lawson, Anton E.

1993-12-01

Grossberg's principles of neural modeling are reviewed and extended to provide a neural level theory to explain how analogies greatly increase the rate of learning and can, in fact, make learning and retention possible. In terms of memory, the key point is that the mind is able to recognize and recall when it is able to match sensory input from new objects, events, or situations with past memory records of similar objects, events, or situations. When a match occurs, an adaptive resonance is set up in which the synaptic strengths of neurons are increased; thus a long term record of the new input is formed in memory. Systems of neurons called outstars and instars are presumably the underlying units that enable this to occur. Analogies can greatly facilitate learning and retention because they activate the outstars (i.e., the cells that are sampling the to-be-learned pattern) and cause the neural activity to grow exponentially by forming feedback loops. This increased activity insures the boost in synaptic strengths of neurons, thus causing storage and retention in long-term memory (i.e., learning).

Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb.

PubMed

Vaaga, Christopher E; Yorgason, Jordan T; Williams, John T; Westbrook, Gary L

2017-03-01

In the olfactory bulb, lateral inhibition mediated by local juxtaglomerular interneurons has been proposed as a gain control mechanism, important for decorrelating odorant responses. Among juxtaglomerular interneurons, short axon cells are unique as dual-transmitter neurons that release dopamine and GABA. To examine their intraglomerular function, we expressed channelrhodopsin under control of the DAT-cre promoter and activated olfactory afferents within individual glomeruli. Optical stimulation of labeled cells triggered endogenous dopamine release as measured by cyclic voltammetry and GABA release as measured by whole cell GABA A receptor currents. Activation of short axon cells reduced the afferent presynaptic release probability via D 2 and GABA B receptor activation, resulting in reduced spiking in both mitral and external tufted cells. Our results suggest that short axon cells influence glomerular activity not only by direct inhibition of external tufted cells but also by inhibition of afferent inputs to external tufted and mitral cells. NEW & NOTEWORTHY Sensory systems, including the olfactory system, encode information across a large dynamic range, making synaptic mechanisms of gain control critical to proper function. Here we demonstrate that a dual-transmitter interneuron in the olfactory bulb controls the gain of intraglomerular afferent input via two distinct mechanisms, presynaptic inhibition as well as inhibition of a principal neuron subtype, and thereby potently controls the synaptic gain of afferent inputs. Copyright © 2017 the American Physiological Society.

Sensory Regulation of Network Components Underlying Ciliary Locomotion in Hermissenda

PubMed Central

Crow, Terry; Tian, Lian-Ming

2008-01-01

Ciliary locomotion in the nudibranch mollusk Hermissenda is modulated by the visual and graviceptive systems. Components of the neural network mediating ciliary locomotion have been identified including aggregates of polysensory interneurons that receive monosynaptic input from identified photoreceptors and efferent neurons that activate cilia. Illumination produces an inhibition of type Ii (off-cell) spike activity, excitation of type Ie (on-cell) spike activity, decreased spike activity in type IIIi inhibitory interneurons, and increased spike activity of ciliary efferent neurons. Here we show that pairs of type Ii interneurons and pairs of type Ie interneurons are electrically coupled. Neither electrical coupling or synaptic connections were observed between Ie and Ii interneurons. Coupling is effective in synchronizing dark-adapted spontaneous firing between pairs of Ie and pairs of Ii interneurons. Out-of-phase burst activity, occasionally observed in dark-adapted and light-adapted pairs of Ie and Ii interneurons, suggests that they receive synaptic input from a common presynaptic source or sources. Rhythmic activity is typically not a characteristic of dark-adapted, light-adapted, or light-evoked firing of type I interneurons. However, burst activity in Ie and Ii interneurons may be elicited by electrical stimulation of pedal nerves or generated at the offset of light. Our results indicate that type I interneurons can support the generation of both rhythmic activity and changes in tonic firing depending on sensory input. This suggests that the neural network supporting ciliary locomotion may be multifunctional. However, consistent with the nonmuscular and nonrhythmic characteristics of visually modulated ciliary locomotion, type I interneurons exhibit changes in tonic activity evoked by illumination. PMID:18768639

Auditory cortical plasticity induced by intracortical microstimulation under pharmacological blockage of inhibitory synapses.

PubMed

Yokota, R; Takahashi, H; Funamizu, A; Uchihara, M; Suzurikawa, J; Kanzaki, R

2006-01-01

Electrical stimulation that can reorganize our neural system has a potential for promising neurorehabilitation. We previously demonstrated that temporally controlled intracortical microstimulation (ICMS) could induce the spike time-dependant plasticity and modify tuning properties of cortical neurons as desired. A 'pairing' ICMS following tone-induced excitatory post-synaptic potentials (EPSPs) produced potentiation in response to the paired tones, while an 'anti-pairing' ICMS preceding the tone-induced EPSPs resulted in depression. However, the conventional ICMS affected both excitatory and inhibitory synapses, and thereby could not quantify net excitatory synaptic effects. In the present work, we evaluated the ICMS effects under a pharmacological blockage of inhibitory inputs. The pharmacological blockage enhanced the ICMS effects, suggesting that inhibitory inputs determine a plastic degree of the neural system. Alternatively, the conventional ICMS had an inadequate timing to control excitatory synaptic inputs, because inhibitory synapse determined the latency of total neural inputs.

Optimal degrees of synaptic connectivity

PubMed Central

Litwin-Kumar, Ashok; Harris, Kameron Decker; Axel, Richard; Sompolinsky, Haim; Abbott, L. F.

2017-01-01

Summary Synaptic connectivity varies widely across neuronal types. Cerebellar granule cells receive five orders of magnitude fewer inputs than the Purkinje cells they innervate, and cerebellum-like circuits including the insect mushroom body also exhibit large divergences in connectivity. In contrast, the number of inputs per neuron in cerebral cortex is more uniform and large. We investigate how the dimension of a representation formed by a population of neurons depends on how many inputs they each receive and what this implies for learning associations. Our theory predicts that the dimensions of the cerebellar granule-cell and Drosophila Kenyon-cell representations are maximized at degrees of synaptic connectivity that match those observed anatomically, showing that sparse connectivity is sometimes superior to dense connectivity. When input synapses are subject to supervised plasticity, however, dense wiring becomes advantageous, suggesting that the type of plasticity exhibited by a set of synapses is a major determinant of connection density. PMID:28215558

Inter-synaptic learning of combination rules in a cortical network model

PubMed Central

Lavigne, Frédéric; Avnaïm, Francis; Dumercy, Laurent

2014-01-01

Selecting responses in working memory while processing combinations of stimuli depends strongly on their relations stored in long-term memory. However, the learning of XOR-like combinations of stimuli and responses according to complex rules raises the issue of the non-linear separability of the responses within the space of stimuli. One proposed solution is to add neurons that perform a stage of non-linear processing between the stimuli and responses, at the cost of increasing the network size. Based on the non-linear integration of synaptic inputs within dendritic compartments, we propose here an inter-synaptic (IS) learning algorithm that determines the probability of potentiating/depressing each synapse as a function of the co-activity of the other synapses within the same dendrite. The IS learning is effective with random connectivity and without either a priori wiring or additional neurons. Our results show that IS learning generates efficacy values that are sufficient for the processing of XOR-like combinations, on the basis of the sole correlational structure of the stimuli and responses. We analyze the types of dendrites involved in terms of the number of synapses from pre-synaptic neurons coding for the stimuli and responses. The synaptic efficacy values obtained show that different dendrites specialize in the detection of different combinations of stimuli. The resulting behavior of the cortical network model is analyzed as a function of inter-synaptic vs. Hebbian learning. Combinatorial priming effects show that the retrospective activity of neurons coding for the stimuli trigger XOR-like combination-selective prospective activity of neurons coding for the expected response. The synergistic effects of inter-synaptic learning and of mixed-coding neurons are simulated. The results show that, although each mechanism is sufficient by itself, their combined effects improve the performance of the network. PMID:25221529

Acetylcholine, ATP, and proteoglycan are common to synaptic vesicles isolated from the electric organs of electric eel and electric catfish as well as from rat diaphragm.

PubMed

Volknandt, W; Zimmermann, H

1986-11-01

Cholinergic synaptic vesicles were isolated from the electric organs of the electric eel (Electrophorus electricus) and the electric catfish (Malapterurus electricus) as well as from the diaphragm of the rat by density gradient centrifugation followed by column chromatography on Sephacryl-1000. This was verified by both biochemical and electron microscopic criteria. Differences in size between synaptic vesicles from the various tissue sources were reflected by their elution pattern from the Sephacryl column. Specific activities of acetylcholine (ACh; in nmol/mg of protein) of chromatography-purified vesicle fractions were 36 (electric eel), 2 (electric catfish), and 1 (rat diaphragm). Synaptic vesicles from all three sources contained ATP in addition to ACh (molar ratios of ACh/ATP, 9-12) as well as binding activity for an antibody raised against Torpedo cholinergic synaptic vesicle proteoglycan. Synaptic vesicles from rat diaphragm contained binding activity for the monoclonal antibody asv 48 raised against a rat brain 65-kilodalton synaptic vesicle protein. Antibody asv 48 binding was absent from electric eel and electric catfish synaptic vesicles. These antibody binding results, which were obtained by a dot blot assay on isolated vesicles, directly correspond to the immunocytochemical results demonstrating fluorescein isothiocyanate staining in the respective nerve terminals. Our results imply that ACh, ATP, and proteoglycan are common molecular constituents of motor nerve terminal-derived synaptic vesicles from Torpedo to rat. In addition to ACh, both ATP and proteoglycan may play a specific role in the process of cholinergic signal transmission.

Feedforward Inhibition and Synaptic Scaling – Two Sides of the Same Coin?

PubMed Central

Lücke, Jörg

2012-01-01

Feedforward inhibition and synaptic scaling are important adaptive processes that control the total input a neuron can receive from its afferents. While often studied in isolation, the two have been reported to co-occur in various brain regions. The functional implications of their interactions remain unclear, however. Based on a probabilistic modeling approach, we show here that fast feedforward inhibition and synaptic scaling interact synergistically during unsupervised learning. In technical terms, we model the input to a neural circuit using a normalized mixture model with Poisson noise. We demonstrate analytically and numerically that, in the presence of lateral inhibition introducing competition between different neurons, Hebbian plasticity and synaptic scaling approximate the optimal maximum likelihood solutions for this model. Our results suggest that, beyond its conventional use as a mechanism to remove undesired pattern variations, input normalization can make typical neural interaction and learning rules optimal on the stimulus subspace defined through feedforward inhibition. Furthermore, learning within this subspace is more efficient in practice, as it helps avoid locally optimal solutions. Our results suggest a close connection between feedforward inhibition and synaptic scaling which may have important functional implications for general cortical processing. PMID:22457610

Feedforward inhibition and synaptic scaling--two sides of the same coin?

PubMed

Keck, Christian; Savin, Cristina; Lücke, Jörg

2012-01-01

Feedforward inhibition and synaptic scaling are important adaptive processes that control the total input a neuron can receive from its afferents. While often studied in isolation, the two have been reported to co-occur in various brain regions. The functional implications of their interactions remain unclear, however. Based on a probabilistic modeling approach, we show here that fast feedforward inhibition and synaptic scaling interact synergistically during unsupervised learning. In technical terms, we model the input to a neural circuit using a normalized mixture model with Poisson noise. We demonstrate analytically and numerically that, in the presence of lateral inhibition introducing competition between different neurons, Hebbian plasticity and synaptic scaling approximate the optimal maximum likelihood solutions for this model. Our results suggest that, beyond its conventional use as a mechanism to remove undesired pattern variations, input normalization can make typical neural interaction and learning rules optimal on the stimulus subspace defined through feedforward inhibition. Furthermore, learning within this subspace is more efficient in practice, as it helps avoid locally optimal solutions. Our results suggest a close connection between feedforward inhibition and synaptic scaling which may have important functional implications for general cortical processing.

Complementary functions of SK and Kv7/M potassium channels in excitability control and synaptic integration in rat hippocampal dentate granule cells

PubMed Central

Mateos-Aparicio, Pedro; Murphy, Ricardo; Storm, Johan F

2014-01-01

The dentate granule cells (DGCs) form the most numerous neuron population of the hippocampal memory system, and its gateway for cortical input. Yet, we have only limited knowledge of the intrinsic membrane properties that shape their responses. Since SK and Kv7/M potassium channels are key mechanisms of neuronal spiking and excitability control, afterhyperpolarizations (AHPs) and synaptic integration, we studied their functions in DGCs. The specific SK channel blockers apamin or scyllatoxin increased spike frequency (excitability), reduced early spike frequency adaptation, fully blocked the medium-duration AHP (mAHP) after a single spike or spike train, and increased postsynaptic EPSP summation after spiking, but had no effect on input resistance (Rinput) or spike threshold. In contrast, blockade of Kv7/M channels by XE991 increased Rinput, lowered the spike threshold, and increased excitability, postsynaptic EPSP summation, and EPSP–spike coupling, but only slightly reduced mAHP after spike trains (and not after single spikes). The SK and Kv7/M channel openers 1-EBIO and retigabine, respectively, had effects opposite to the blockers. Computational modelling reproduced many of these effects. We conclude that SK and Kv7/M channels have complementary roles in DGCs. These mechanisms may be important for the dentate network function, as CA3 neurons can be activated or inhibition recruited depending on DGC firing rate. PMID:24366266

Dynamics of self-sustained asynchronous-irregular activity in random networks of spiking neurons with strong synapses

PubMed Central

Kriener, Birgit; Enger, Håkon; Tetzlaff, Tom; Plesser, Hans E.; Gewaltig, Marc-Oliver; Einevoll, Gaute T.

2014-01-01

Random networks of integrate-and-fire neurons with strong current-based synapses can, unlike previously believed, assume stable states of sustained asynchronous and irregular firing, even without external random background or pacemaker neurons. We analyze the mechanisms underlying the emergence, lifetime and irregularity of such self-sustained activity states. We first demonstrate how the competition between the mean and the variance of the synaptic input leads to a non-monotonic firing-rate transfer in the network. Thus, by increasing the synaptic coupling strength, the system can become bistable: In addition to the quiescent state, a second stable fixed-point at moderate firing rates can emerge by a saddle-node bifurcation. Inherently generated fluctuations of the population firing rate around this non-trivial fixed-point can trigger transitions into the quiescent state. Hence, the trade-off between the magnitude of the population-rate fluctuations and the size of the basin of attraction of the non-trivial rate fixed-point determines the onset and the lifetime of self-sustained activity states. During self-sustained activity, individual neuronal activity is moreover highly irregular, switching between long periods of low firing rate to short burst-like states. We show that this is an effect of the strong synaptic weights and the finite time constant of synaptic and neuronal integration, and can actually serve to stabilize the self-sustained state. PMID:25400575

Dynamics of self-sustained asynchronous-irregular activity in random networks of spiking neurons with strong synapses.

PubMed

Kriener, Birgit; Enger, Håkon; Tetzlaff, Tom; Plesser, Hans E; Gewaltig, Marc-Oliver; Einevoll, Gaute T

2014-01-01

Random networks of integrate-and-fire neurons with strong current-based synapses can, unlike previously believed, assume stable states of sustained asynchronous and irregular firing, even without external random background or pacemaker neurons. We analyze the mechanisms underlying the emergence, lifetime and irregularity of such self-sustained activity states. We first demonstrate how the competition between the mean and the variance of the synaptic input leads to a non-monotonic firing-rate transfer in the network. Thus, by increasing the synaptic coupling strength, the system can become bistable: In addition to the quiescent state, a second stable fixed-point at moderate firing rates can emerge by a saddle-node bifurcation. Inherently generated fluctuations of the population firing rate around this non-trivial fixed-point can trigger transitions into the quiescent state. Hence, the trade-off between the magnitude of the population-rate fluctuations and the size of the basin of attraction of the non-trivial rate fixed-point determines the onset and the lifetime of self-sustained activity states. During self-sustained activity, individual neuronal activity is moreover highly irregular, switching between long periods of low firing rate to short burst-like states. We show that this is an effect of the strong synaptic weights and the finite time constant of synaptic and neuronal integration, and can actually serve to stabilize the self-sustained state.

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

PubMed Central

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

Dendritic nonlinearities reduce network size requirements and mediate ON and OFF states of persistent activity in a PFC microcircuit model.

PubMed

Papoutsi, Athanasia; Sidiropoulou, Kyriaki; Poirazi, Panayiota

2014-07-01

Technological advances have unraveled the existence of small clusters of co-active neurons in the neocortex. The functional implications of these microcircuits are in large part unexplored. Using a heavily constrained biophysical model of a L5 PFC microcircuit, we recently showed that these structures act as tunable modules of persistent activity, the cellular correlate of working memory. Here, we investigate the mechanisms that underlie persistent activity emergence (ON) and termination (OFF) and search for the minimum network size required for expressing these states within physiological regimes. We show that (a) NMDA-mediated dendritic spikes gate the induction of persistent firing in the microcircuit. (b) The minimum network size required for persistent activity induction is inversely proportional to the synaptic drive of each excitatory neuron. (c) Relaxation of connectivity and synaptic delay constraints eliminates the gating effect of NMDA spikes, albeit at a cost of much larger networks. (d) Persistent activity termination by increased inhibition depends on the strength of the synaptic input and is negatively modulated by dADP. (e) Slow synaptic mechanisms and network activity contain predictive information regarding the ability of a given stimulus to turn ON and/or OFF persistent firing in the microcircuit model. Overall, this study zooms out from dendrites to cell assemblies and suggests a tight interaction between dendritic non-linearities and network properties (size/connectivity) that may facilitate the short-memory function of the PFC.

When is an Inhibitory Synapse Effective?

NASA Astrophysics Data System (ADS)

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.

Glycinergic dysfunction in a subpopulation of dorsal horn interneurons in a rat model of neuropathic pain

PubMed Central

Imlach, Wendy L.; Bhola, Rebecca F.; Mohammadi, Sarasa A.; Christie, Macdonald J.

2016-01-01

The development of neuropathic pain involves persistent changes in signalling within pain pathways. Reduced inhibitory signalling in the spinal cord following nerve-injury has been used to explain sensory signs of neuropathic pain but specific circuits that lose inhibitory input have not been identified. This study shows a specific population of spinal cord interneurons, radial neurons, lose glycinergic inhibitory input in a rat partial sciatic nerve ligation (PNL) model of neuropathic pain. Radial neurons are excitatory neurons located in lamina II of the dorsal horn, and are readily identified by their morphology. The amplitude of electrically-evoked glycinergic inhibitory post-synaptic currents (eIPSCs) was greatly reduced in radial neurons following nerve-injury associated with increased paired-pulse ratio. There was also a reduction in frequency of spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSC) in radial neurons without significantly affecting mIPSC amplitude. A subtype selective receptor antagonist and western blots established reversion to expression of the immature glycine receptor subunit GlyRα2 in radial neurons after PNL, consistent with slowed decay times of IPSCs. This study has important implications as it identifies a glycinergic synaptic connection in a specific population of dorsal horn neurons where loss of inhibitory signalling may contribute to signs of neuropathic pain. PMID:27841371

Hox2 Genes Are Required for Tonotopic Map Precision and Sound Discrimination in the Mouse Auditory Brainstem.

PubMed

Karmakar, Kajari; Narita, Yuichi; Fadok, Jonathan; Ducret, Sebastien; Loche, Alberto; Kitazawa, Taro; Genoud, Christel; Di Meglio, Thomas; Thierry, Raphael; Bacelo, Joao; Lüthi, Andreas; Rijli, Filippo M

2017-01-03

Tonotopy is a hallmark of auditory pathways and provides the basis for sound discrimination. Little is known about the involvement of transcription factors in brainstem cochlear neurons orchestrating the tonotopic precision of pre-synaptic input. We found that in the absence of Hoxa2 and Hoxb2 function in Atoh1-derived glutamatergic bushy cells of the anterior ventral cochlear nucleus, broad input topography and sound transmission were largely preserved. However, fine-scale synaptic refinement and sharpening of isofrequency bands of cochlear neuron activation upon pure tone stimulation were impaired in Hox2 mutants, resulting in defective sound-frequency discrimination in behavioral tests. These results establish a role for Hox factors in tonotopic refinement of connectivity and in ensuring the precision of sound transmission in the mammalian auditory circuit. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The modeling and simulation of visuospatial working memory

PubMed Central

Liang, Lina; Zhang, Zhikang

2010-01-01

Camperi and Wang (Comput Neurosci 5:383–405, 1998) presented a network model for working memory that combines intrinsic cellular bistability with the recurrent network architecture of the neocortex. While Fall and Rinzel (Comput Neurosci 20:97–107, 2006) replaced this intrinsic bistability with a biological mechanism-Ca2+ release subsystem. In this study, we aim to further expand the above work. We integrate the traditional firing-rate network with Ca2+ subsystem-induced bistability, amend the synaptic weights and suggest that Ca2+ concentration only increase the efficacy of synaptic input but has nothing to do with the external input for the transient cue. We found that our network model maintained the persistent activity in response to a brief transient stimulus like that of the previous two models and the working memory performance was resistant to noise and distraction stimulus if Ca2+ subsystem was tuned to be bistable. PMID:22132045

Layer- and cell-type-specific subthreshold and suprathreshold effects of long-term monocular deprivation in rat visual cortex.

PubMed

Medini, Paolo

2011-11-23

Connectivity and dendritic properties are determinants of plasticity that are layer and cell-type specific in the neocortex. However, the impact of experience-dependent plasticity at the level of synaptic inputs and spike outputs remains unclear along vertical cortical microcircuits. Here I compared subthreshold and suprathreshold sensitivity to prolonged monocular deprivation (MD) in rat binocular visual cortex in layer 4 and layer 2/3 pyramids (4Ps and 2/3Ps) and in thick-tufted and nontufted layer 5 pyramids (5TPs and 5NPs), which innervate different extracortical targets. In normal rats, 5TPs and 2/3Ps are the most binocular in terms of synaptic inputs, and 5NPs are the least. Spike responses of all 5TPs were highly binocular, whereas those of 2/3Ps were dominated by either the contralateral or ipsilateral eye. MD dramatically shifted the ocular preference of 2/3Ps and 4Ps, mostly by depressing deprived-eye inputs. Plasticity was profoundly different in layer 5. The subthreshold ocular preference shift was sevenfold smaller in 5TPs because of smaller depression of deprived inputs combined with a generalized loss of responsiveness, and was undetectable in 5NPs. Despite their modest ocular dominance change, spike responses of 5TPs consistently lost their typically high binocularity during MD. The comparison of MD effects on 2/3Ps and 5TPs, the main affected output cells of vertical microcircuits, indicated that subthreshold plasticity is not uniquely determined by the initial degree of input binocularity. The data raise the question of whether 5TPs are driven solely by 2/3Ps during MD. The different suprathreshold plasticity of the two cell populations could underlie distinct functional deficits in amblyopia.

Closing the gate in the limbic striatum: prefrontal suppression of hippocampal and thalamic inputs

PubMed Central

Calhoon, Gwendolyn G.; O’Donnell, Patricio

2013-01-01

SUMMARY Many brain circuits control behavior by integrating information arising from separate inputs onto a common target neuron. Neurons in the ventral striatum (VS) receive converging excitatory afferents from the prefrontal cortex (PFC), hippocampus (HP), and thalamus, among other structures, and the integration of these inputs is critical for shaping goal-directed behaviors. Although HP inputs have been described as gating PFC throughput in the VS, recent data reveal that the VS desynchronizes from the HP during epochs of burst-like PFC activity related to decision-making. It is therefore possible that PFC inputs locally attenuate responses to other glutamatergic inputs to the VS. Here, we found that delivering trains of stimuli to the PFC suppresses HP- and thalamus-evoked synaptic responses in the VS, in part through activation of inhibitory processes. This interaction may enable the PFC to exert influence on basal ganglia loops during decision-making instances with minimal disturbance from ongoing contextual inputs. PMID:23583113

The Synaptic and Morphological Basis of Orientation Selectivity in a Polyaxonal Amacrine Cell of the Rabbit Retina.

PubMed

Murphy-Baum, Benjamin L; Taylor, W Rowland

2015-09-30

Much of the computational power of the retina derives from the activity of amacrine cells, a large and diverse group of GABAergic and glycinergic inhibitory interneurons. Here, we identify an ON-type orientation-selective, wide-field, polyaxonal amacrine cell (PAC) in the rabbit retina and demonstrate how its orientation selectivity arises from the structure of the dendritic arbor and the pattern of excitatory and inhibitory inputs. Excitation from ON bipolar cells and inhibition arising from the OFF pathway converge to generate a quasi-linear integration of visual signals in the receptive field center. This serves to suppress responses to high spatial frequencies, thereby improving sensitivity to larger objects and enhancing orientation selectivity. Inhibition also regulates the magnitude and time course of excitatory inputs to this PAC through serial inhibitory connections onto the presynaptic terminals of ON bipolar cells. This presynaptic inhibition is driven by graded potentials within local microcircuits, similar in extent to the size of single bipolar cell receptive fields. Additional presynaptic inhibition is generated by spiking amacrine cells on a larger spatial scale covering several hundred microns. The orientation selectivity of this PAC may be a substrate for the inhibition that mediates orientation selectivity in some types of ganglion cells. Significance statement: The retina comprises numerous excitatory and inhibitory circuits that encode specific features in the visual scene, such as orientation, contrast, or motion. Here, we identify a wide-field inhibitory neuron that responds to visual stimuli of a particular orientation, a feature selectivity that is primarily due to the elongated shape of the dendritic arbor. Integration of convergent excitatory and inhibitory inputs from the ON and OFF visual pathways suppress responses to small objects and fine textures, thus enhancing selectivity for larger objects. Feedback inhibition regulates the strength and speed of excitation on both local and wide-field spatial scales. This study demonstrates how different synaptic inputs are regulated to tune a neuron to respond to specific features in the visual scene. Copyright © 2015 the authors 0270-6474/15/3513336-15$15.00/0.

Flexible Proton-Gated Oxide Synaptic Transistors on Si Membrane.

PubMed

Zhu, Li Qiang; Wan, Chang Jin; Gao, Ping Qi; Liu, Yang Hui; Xiao, Hui; Ye, Ji Chun; Wan, Qing

2016-08-24

Ion-conducting materials have received considerable attention for their applications in fuel cells, electrochemical devices, and sensors. Here, flexible indium zinc oxide (InZnO) synaptic transistors with multiple presynaptic inputs gated by proton-conducting phosphorosilicate glass-based electrolyte films are fabricated on ultrathin Si membranes. Transient characteristics of the proton gated InZnO synaptic transistors are investigated, indicating stable proton-gating behaviors. Short-term synaptic plasticities are mimicked on the proposed proton-gated synaptic transistors. Furthermore, synaptic integration regulations are mimicked on the proposed synaptic transistor networks. Spiking logic modulations are realized based on the transition between superlinear and sublinear synaptic integration. The multigates coupled flexible proton-gated oxide synaptic transistors may be interesting for neuroinspired platforms with sophisticated spatiotemporal information processing.

Target-specific expression of presynaptic NMDA receptors in neocortical microcircuits.

PubMed

Buchanan, Katherine A; Blackman, Arne V; Moreau, Alexandre W; Elgar, Dale; Costa, Rui P; Lalanne, Txomin; Tudor Jones, Adam A; Oyrer, Julia; Sjöström, P Jesper

2012-08-09

Traditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns. Copyright © 2012 Elsevier Inc. All rights reserved.

Using Inspiration from Synaptic Plasticity Rules to Optimize Traffic Flow in Distributed Engineered Networks.

PubMed

Suen, Jonathan Y; Navlakha, Saket

2017-05-01

Controlling the flow and routing of data is a fundamental problem in many distributed networks, including transportation systems, integrated circuits, and the Internet. In the brain, synaptic plasticity rules have been discovered that regulate network activity in response to environmental inputs, which enable circuits to be stable yet flexible. Here, we develop a new neuro-inspired model for network flow control that depends only on modifying edge weights in an activity-dependent manner. We show how two fundamental plasticity rules, long-term potentiation and long-term depression, can be cast as a distributed gradient descent algorithm for regulating traffic flow in engineered networks. We then characterize, both by simulation and analytically, how different forms of edge-weight-update rules affect network routing efficiency and robustness. We find a close correspondence between certain classes of synaptic weight update rules derived experimentally in the brain and rules commonly used in engineering, suggesting common principles to both.

BDNF-TrkB Signaling Coupled to nPKCε and cPKCβI Modulate the Phosphorylation of the Exocytotic Protein Munc18-1 During Synaptic Activity at the Neuromuscular Junction.

PubMed

Simó, Anna; Just-Borràs, Laia; Cilleros-Mañé, Víctor; Hurtado, Erica; Nadal, Laura; Tomàs, Marta; Garcia, Neus; Lanuza, Maria A; Tomàs, Josep

2018-01-01

Munc18-1, a neuron-specific member of the Sec1/Munc18 family, is involved in neurotransmitter release by binding tightly to syntaxin. Munc18-1 is phosphorylated by PKC on Ser-306 and Ser-313 in vitro which reduces the amount of Munc18-1 able to bind syntaxin. We have previously identified that PKC is involved in neurotransmitter release when continuous electrical stimulation imposes a moderate activity on the NMJ and that muscle contraction through TrkB has an important impact on presynaptic PKC isoforms levels, specifically cPKCβI and nPKCε. Therefore, the present study was designed to understand how Munc18-1 phosphorylation is affected by (1) synaptic activity at the neuromuscular junction, (2) nPKCε and cPKCβI isoforms activity, (3) muscle contraction per se , and (4) the BDNF/TrkB signaling in a neuromuscular activity-dependent manner. We performed immunohistochemistry and confocal techniques to evidence the presynaptic location of Munc18-1 in the rat diaphragm muscle. To study synaptic activity, we stimulated the phrenic nerve (1 Hz, 30 min) with or without contraction (abolished by μ-conotoxin GIIIB). Specific inhibitory reagents were used to block nPKCε and cPKCβI activity and to modulate the tropomyosin receptor kinase B (TrkB). Main results obtained from Western blot experiments showed that phosphorylation of Munc18-1 at Ser-313 increases in response to a signaling mechanism initiated by synaptic activity and directly mediated by nPKCε. Otherwise, cPKCβI and TrkB activities work together to prevent this synaptic activity-induced Munc18-1 phosphorylation by a negative regulation of cPKCβI over nPKCε. Therefore, a balance between the activities of these PKC isoforms could be a relevant cue in the regulation of the exocytotic apparatus. The results also demonstrate that muscle contraction prevents the synaptic activity-induced Munc18-1 phosphorylation through a mechanism that opposes the TrkB/cPKCβI/nPKCε signaling.

Effects of Calcium Spikes in the Layer 5 Pyramidal Neuron on Coincidence Detection and Activity Propagation

PubMed Central

Chua, Yansong; Morrison, Abigail

2016-01-01

The role of dendritic spiking mechanisms in neural processing is so far poorly understood. To investigate the role of calcium spikes in the functional properties of the single neuron and recurrent networks, we investigated a three compartment neuron model of the layer 5 pyramidal neuron with calcium dynamics in the distal compartment. By performing single neuron simulations with noisy synaptic input and occasional large coincident input at either just the distal compartment or at both somatic and distal compartments, we show that the presence of calcium spikes confers a substantial advantage for coincidence detection in the former case and a lesser advantage in the latter. We further show that the experimentally observed critical frequency phenomenon, in which action potentials triggered by stimuli near the soma above a certain frequency trigger a calcium spike at distal dendrites, leading to further somatic depolarization, is not exhibited by a neuron receiving realistically noisy synaptic input, and so is unlikely to be a necessary component of coincidence detection. We next investigate the effect of calcium spikes in propagation of spiking activities in a feed-forward network (FFN) embedded in a balanced recurrent network. The excitatory neurons in the network are again connected to either just the distal, or both somatic and distal compartments. With purely distal connectivity, activity propagation is stable and distinguishable for a large range of recurrent synaptic strengths if the feed-forward connections are sufficiently strong, but propagation does not occur in the absence of calcium spikes. When connections are made to both the somatic and the distal compartments, activity propagation is achieved for neurons with active calcium dynamics at a much smaller number of neurons per pool, compared to a network of passive neurons, but quickly becomes unstable as the strength of recurrent synapses increases. Activity propagation at higher scaling factors can be stabilized by increasing network inhibition or introducing short term depression in the excitatory synapses, but the signal to noise ratio remains low. Our results demonstrate that the interaction of synchrony with dendritic spiking mechanisms can have profound consequences for the dynamics on the single neuron and network level. PMID:27499740

Effects of Calcium Spikes in the Layer 5 Pyramidal Neuron on Coincidence Detection and Activity Propagation.

PubMed

Chua, Yansong; Morrison, Abigail

2016-01-01

The role of dendritic spiking mechanisms in neural processing is so far poorly understood. To investigate the role of calcium spikes in the functional properties of the single neuron and recurrent networks, we investigated a three compartment neuron model of the layer 5 pyramidal neuron with calcium dynamics in the distal compartment. By performing single neuron simulations with noisy synaptic input and occasional large coincident input at either just the distal compartment or at both somatic and distal compartments, we show that the presence of calcium spikes confers a substantial advantage for coincidence detection in the former case and a lesser advantage in the latter. We further show that the experimentally observed critical frequency phenomenon, in which action potentials triggered by stimuli near the soma above a certain frequency trigger a calcium spike at distal dendrites, leading to further somatic depolarization, is not exhibited by a neuron receiving realistically noisy synaptic input, and so is unlikely to be a necessary component of coincidence detection. We next investigate the effect of calcium spikes in propagation of spiking activities in a feed-forward network (FFN) embedded in a balanced recurrent network. The excitatory neurons in the network are again connected to either just the distal, or both somatic and distal compartments. With purely distal connectivity, activity propagation is stable and distinguishable for a large range of recurrent synaptic strengths if the feed-forward connections are sufficiently strong, but propagation does not occur in the absence of calcium spikes. When connections are made to both the somatic and the distal compartments, activity propagation is achieved for neurons with active calcium dynamics at a much smaller number of neurons per pool, compared to a network of passive neurons, but quickly becomes unstable as the strength of recurrent synapses increases. Activity propagation at higher scaling factors can be stabilized by increasing network inhibition or introducing short term depression in the excitatory synapses, but the signal to noise ratio remains low. Our results demonstrate that the interaction of synchrony with dendritic spiking mechanisms can have profound consequences for the dynamics on the single neuron and network level.

COMPENSATION FOR VARIABLE INTRINSIC NEURONAL EXCITABILITY BY CIRCUIT-SYNAPTIC INTERACTIONS

PubMed Central

Grashow, Rachel; Brookings, Ted; Marder, Eve

2010-01-01

Recent theoretical and experimental work indicates that neurons tune themselves to maintain target levels of excitation by modulating ion channel expression and synaptic strengths. As a result, functionally equivalent circuits can produce similar activity despite disparate underlying network and cellular properties. To experimentally test the extent to which synaptic and intrinsic conductances can produce target activity in the presence of variability in neuronal intrinsic properties, we used the dynamic clamp to create hybrid two-cell circuits built from four types of stomatogastric (STG) neurons coupled to the same model Morris-Lecar neuron by reciprocal inhibition. We measured six intrinsic properties (input resistance, minimum membrane potential, firing rate in response to +1nA of injected current, slope of the FI curve, spike height and spike voltage threshold) of Dorsal Gastric (DG), Gastric Mill (GM), Lateral Pyloric (LP) and Pyloric Dilator (PD) neurons from male crabs, Cancer borealis. The intrinsic properties varied two to seven-fold in each cell type. We coupled each biological neuron to the Morris-Lecar model with seven different values of inhibitory synaptic conductance, and also used the dynamic clamp to add seven different values of an artificial h-conductance, thus creating 49 different circuits for each biological neuron. Despite the variability in intrinsic excitability, networks formed from each neuron produced similar circuit performance at some values of synaptic and h-conductances. This work experimentally confirms results from previous modeling studies; tuning synaptic and intrinsic conductances can yield similar circuit output from neurons with variable intrinsic excitability. PMID:20610748

Presynaptic modulation of tonic and respiratory inputs to cardiovagal motoneurons by substance P.

PubMed

Hou, Lili; Tang, Hongtai; Chen, Yonghua; Wang, Lin; Zhou, Xujiao; Rong, Weifang; Wang, Jijiang

2009-08-11

Substance P (SP) has been implicated in vagal control of heart rate and cardiac functions, but the mechanisms of SP actions on cardiac vagal activity remain obscure. The present study has investigated the effects of SP on the synaptic inputs of preganglionic cardiovagal motoneurons (CVNs) in brainstem slices of neonatal rat. Whole-cell voltage-clamp recordings were performed on retrogradely labeled CVNs in the nucleus ambiguus. The results show that in thin slices (400 microm thickness) without respiratory-like rhythm, globally applied SP (1 microM) significantly enhanced both the GABAergic and the glycinergic inputs, but had no effect on the glutamatergic inputs, of CVNs. Since inspiratory-related augmentation of the inhibitory inputs of CVNs in individual respiratory cycles is known to play an important role in the genesis of respiratory sinus arrhythmia, the effects of SP on the inhibitory inputs of CVNs were further examined in thick slices (500-800 microm thickness) with respiratory-like rhythm, and SP (1 microM) was focally applied to the CVNs under patch-clamp recording. Focally applied SP caused frequency increases of the GABAergic and the glycinergic inputs both during inspiratory bursts and during inspiratory intervals. However, the inspiratory-related augmentation of the GABAergic and the glycinergic inputs of CVNs, measured by the frequency increases during inspiratory bursts in percentage of the frequency during inspiratory intervals, was significantly decreased by SP. These results suggest that SP inhibits CVNs via enhancement of their inhibitory synaptic inputs, and SP diminishes the respiratory-related fluctuation of cardiac vagal activity in individual respiratory cycles. These results also indicate that SP may play a role in altering the vagal control of the heart in some cardiovascular diseases such as myocardial ischemia and hypertension, since these diseases are characterized by weakened cardiac vagal tone and heart rate variability, and have been found to have increased central release and receptor binding of SP.

Myelination: an overlooked mechanism of synaptic plasticity?

PubMed

Fields, R Douglas

2005-12-01

Myelination of the brain continues through childhood into adolescence and early adulthood--the question is, Why? Two new articles provide intriguing evidence that myelination may be an underappreciated mechanism of activity-dependent nervous system plasticity: one study reported increased myelination associated with extensive piano playing, another indicated that rats have increased myelination of the corpus callosum when raised in environments providing increased social interaction and cognitive stimulation. These articles make it clear that activity-dependent effects on myelination cannot be considered strictly a developmental event. They raise the question of whether myelination is an overlooked mechanism of activity-dependent plasticity, extending in humans until at least age 30. It has been argued that regulating the speed of conduction across long fiber tracts would have a major influence on synaptic response, by coordinating the timing of afferent input to maximize temporal summation. The increase in synaptic amplitude could be as large as neurotransmitter-based mechanisms of plasticity, such as LTP. These new findings raise a larger question: How did the oligodendrocytes know they were practicing the piano or that their environment was socially complex?

Development of feedforward receptive field structure of a simple cell and its contribution to the orientation selectivity: a modeling study.

PubMed

Garg, Akhil R; Obermayer, Klaus; Bhaumik, Basabi

2005-01-01

Recent experimental studies of hetero-synaptic interactions in various systems have shown the role of signaling in the plasticity, challenging the conventional understanding of Hebb's rule. It has also been found that activity plays a major role in plasticity, with neurotrophins acting as molecular signals translating activity into structural changes. Furthermore, role of synaptic efficacy in biasing the outcome of competition has also been revealed recently. Motivated by these experimental findings we present a model for the development of simple cell receptive field structure based on the competitive hetero-synaptic interactions for neurotrophins combined with cooperative hetero-synaptic interactions in the spatial domain. We find that with proper balance in competition and cooperation, the inputs from two populations (ON/OFF) of LGN cells segregate starting from the homogeneous state. We obtain segregated ON and OFF regions in simple cell receptive field. Our modeling study supports the experimental findings, suggesting the role of synaptic efficacy and the role of spatial signaling. We find that using this model we obtain simple cell RF, even for positively correlated activity of ON/OFF cells. We also compare different mechanism of finding the response of cortical cell and study their possible role in the sharpening of orientation selectivity. We find that degree of selectivity improvement in individual cells varies from case to case depending upon the structure of RF field and type of sharpening mechanism.

Glycine inhibits startle-mediating neurons in the caudal pontine reticular formation but is not involved in synaptic depression underlying short-term habituation of startle.

PubMed

Geis, Hans-Ruediger; Schmid, Susanne

2011-10-01

The mammalian startle response is controlled by glycine inhibition in the spinal cord. Evidence for additional glycine inhibition on the level of the brainstem, namely in the caudal pontine reticular nucleus (PnC), is controversial. Startle mediating PnC neurons receive fast input from sensory pathways and project to cranial and spinal motoneurons. Synaptic depression in the sensory synapses in the PnC has been indicated as underlying mechanism of short-term habituation of startle. We here performed patch-clamp recordings of PnC giant neurons in rat brain slices to test the hypothesis that the activation of glycine receptors inhibits PnC neurons and that this inhibition is involved in synaptic depression in the PnC. Glycine strongly inhibited PnC neuron activity and synaptic signalling, indicating that functional glycine receptors mediate a powerful inhibition of PnC neurons over a wide range of glycine concentrations. Strychnine reversed all glycine effects, but had no effect on PnC neurons itself. Thus, we found no evidence for a tonic glycine inhibition or for glycine activation within the primary startle pathway indicating that baseline startle reactions are unlikely to be controlled by glycine in the PnC. Most importantly, synaptic depression underlying short-term habituation was not affected by glycine or strychnine. Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Amplitude Normalization of Dendritic EPSPs at the Soma of Binaural Coincidence Detector Neurons of the Medial Superior Olive

PubMed Central

Winters, Bradley D.; Jin, Shan-Xue; Ledford, Kenneth R.

2017-01-01

The principal neurons of the medial superior olive (MSO) encode cues for horizontal sound localization through comparisons of the relative timing of EPSPs. To understand how the timing and amplitude of EPSPs are maintained during propagation in the dendrites, we made dendritic and somatic whole-cell recordings from MSO principal neurons in brain slices from Mongolian gerbils. In somatic recordings, EPSP amplitudes were largely uniform following minimal stimulation of excitatory synapses at visualized locations along the dendrites. Similar results were obtained when excitatory synaptic transmission was eliminated in a low calcium solution and then restored at specific dendritic sites by pairing input stimulation and focal application of a higher calcium solution. We performed dual dendritic and somatic whole-cell recordings to measure spontaneous EPSPs using a dual-channel template-matching algorithm to separate out those events initiated at or distal to the dendritic recording location. Local dendritic spontaneous EPSP amplitudes increased sharply in the dendrite with distance from the soma (length constant, 53.6 μm), but their attenuation during propagation resulted in a uniform amplitude of ∼0.2 mV at the soma. The amplitude gradient of dendritic EPSPs was also apparent in responses to injections of identical simulated excitatory synaptic currents in the dendrites. Compartmental models support the view that these results extensively reflect the influence of dendritic cable properties. With relatively few excitatory axons innervating MSO neurons, the normalization of dendritic EPSPs at the soma would increase the importance of input timing versus location during the processing of interaural time difference cues in vivo. SIGNIFICANCE STATEMENT The neurons of the medial superior olive analyze cues for sound localization by detecting the coincidence of binaural excitatory synaptic inputs distributed along the dendrites. Previous studies have shown that dendritic voltages undergo severe attenuation as they propagate to the soma, potentially reducing the influence of distal inputs. However, using dendritic and somatic patch recordings, we found that dendritic EPSP amplitude increased with distance from the soma, compensating for dendritic attenuation and normalizing EPSP amplitude at the soma. Much of this normalization reflected the influence of dendritic morphology. As different combinations of presynaptic axons may be active during consecutive cycles of sound stimuli, somatic EPSP normalization renders spike initiation more sensitive to synapse timing than dendritic location. PMID:28213442

Effect of CDP-choline on age-dependent modifications of energy- and glutamate-linked enzyme activities in synaptic and non-synaptic mitochondria from rat cerebral cortex.

PubMed

Villa, Roberto Federico; Ferrari, Federica; Gorini, Antonella

2012-12-01

The effect of aging and CDP-choline treatment (20 mg kg⁻¹ body weight i.p. for 28 days) on the maximal rates (V(max)) of representative mitochondrial enzyme activities related to Krebs' cycle (citrate synthase, α-ketoglutarate dehydrogenase, malate dehydrogenase), glutamate and related amino acid metabolism (glutamate dehydrogenase, glutamate-oxaloacetate- and glutamate-pyruvate transaminases) were evaluated in non-synaptic and intra-synaptic "light" and "heavy" mitochondria from frontal cerebral cortex of male Wistar rats aged 4, 12, 18 and 24 months. During aging, enzyme activities vary in a complex way respect to the type of mitochondria, i.e. non-synaptic and intra-synaptic. This micro-heterogeneity is an important factor, because energy-related mitochondrial enzyme catalytic properties cause metabolic modifications of physiopathological significance in cerebral tissue in vivo, also discriminating pre- and post-synaptic sites of action for drugs and affecting tissue responsiveness to noxious stimuli. Results show that CDP-choline in vivo treatment enhances cerebral energy metabolism selectively at 18 months, specifically modifying enzyme catalytic activities in non-synaptic and intra-synaptic "light" mitochondrial sub-populations. This confirms that the observed changes in enzyme catalytic activities during aging reflect the bioenergetic state at each single age and the corresponding energy requirements, further proving that in vivo drug treatment is able to interfere with the neuronal energy metabolism. Copyright © 2012. Published by Elsevier Ltd.

Neural coding using telegraphic switching of magnetic tunnel junction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suh, Dong Ik; Bae, Gi Yoon; Oh, Heong Sik

2015-05-07

In this work, we present a synaptic transmission representing neural coding with spike trains by using a magnetic tunnel junction (MTJ). Telegraphic switching generates an artificial neural signal with both the applied magnetic field and the spin-transfer torque that act as conflicting inputs for modulating the number of spikes in spike trains. The spiking probability is observed to be weighted with modulation between 27.6% and 99.8% by varying the amplitude of the voltage input or the external magnetic field. With a combination of the reverse coding scheme and the synaptic characteristic of MTJ, an artificial function for the synaptic transmissionmore » is achieved.« less

Impact of Fast Sodium Channel Inactivation on Spike Threshold Dynamics and Synaptic Integration

PubMed Central

Platkiewicz, Jonathan; Brette, Romain

2011-01-01

Neurons spike when their membrane potential exceeds a threshold value. In central neurons, the spike threshold is not constant but depends on the stimulation. Thus, input-output properties of neurons depend both on the effect of presynaptic spikes on the membrane potential and on the dynamics of the spike threshold. Among the possible mechanisms that may modulate the threshold, one strong candidate is Na channel inactivation, because it specifically impacts spike initiation without affecting the membrane potential. We collected voltage-clamp data from the literature and we found, based on a theoretical criterion, that the properties of Na inactivation could indeed cause substantial threshold variability by itself. By analyzing simple neuron models with fast Na inactivation (one channel subtype), we found that the spike threshold is correlated with the mean membrane potential and negatively correlated with the preceding depolarization slope, consistent with experiments. We then analyzed the impact of threshold dynamics on synaptic integration. The difference between the postsynaptic potential (PSP) and the dynamic threshold in response to a presynaptic spike defines an effective PSP. When the neuron is sufficiently depolarized, this effective PSP is briefer than the PSP. This mechanism regulates the temporal window of synaptic integration in an adaptive way. Finally, we discuss the role of other potential mechanisms. Distal spike initiation, channel noise and Na activation dynamics cannot account for the observed negative slope-threshold relationship, while adaptive conductances (e.g. K+) and Na inactivation can. We conclude that Na inactivation is a metabolically efficient mechanism to control the temporal resolution of synaptic integration. PMID:21573200

Input/output properties of the lateral vestibular nucleus

NASA Technical Reports Server (NTRS)

Boyle, R.; Bush, G.; Ehsanian, R.

2004-01-01

This article is a review of work in three species, squirrel monkey, cat, and rat studying the inputs and outputs from the lateral vestibular nucleus (LVN). Different electrophysiological shock paradigms were used to determine the synaptic inputs derived from thick to thin diameter vestibular nerve afferents. Angular and linear mechanical stimulations were used to activate and study the combined and individual contribution of inner ear organs and neck afferents. The spatio-temporal properties of LVN neurons in the decerebrated rat were studied in response to dynamic acceleration inputs using sinusoidal linear translation in the horizontal head plane. Outputs were evaluated using antidromic identification techniques and identified LVN neurons were intracellularly injected with biocytin and their morphology studied.

Heterogeneity of Intrinsic and Synaptic Properties of Neurons in the Ventral and Dorsal Parts of the Ventral Nucleus of the Lateral Lemniscus

PubMed Central

Caspari, Franziska; Baumann, Veronika J.; Garcia-Pino, Elisabet; Koch, Ursula

2015-01-01

The ventral nucleus of the lateral lemniscus (VNLL) provides a major inhibitory projection to the inferior colliculus (IC). Neurons in the VNLL respond with various firing patterns and different temporal precision to acoustic stimulation. The present study investigates the underlying intrinsic and synaptic properties of various cell types in different regions of the VNLL, using in vitro electrophysiological recordings from acute brain slices of mice and immunohistochemistry. We show that the biophysical membrane properties and excitatory input characteristics differed between dorsal and ventral VNLL neurons. Neurons in the ventral VNLL displayed an onset-type firing pattern and little hyperpolarization-activated current (Ih). Stimulation of lemniscal inputs evoked a large all-or-none excitatory response similar to Calyx of Held synapses in neurons in the lateral part of the ventral VNLL. Neurons that were located within the fiber tract of the lateral lemniscus, received several and weak excitatory input fibers. In the dorsal VNLL onset-type and sustained firing neurons were intermingled. These neurons showed large Ih and were strongly immunopositive for the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) subunit. Both neuron types received several excitatory inputs that were weaker and slower compared to ventrolateral VNLL neurons. Using a mouse model that expresses channelrhodopsin under the promotor of the vesicular GABA transporter (VGAT) suggests that dorsal and ventral neurons were inhibitory since they were all depolarized by light stimulation. The diverse membrane and input properties in dorsal and ventral VNLL neurons suggest differential roles of these neurons for sound processing. PMID:26635535

Processing of central and reflex vagal drives by rat cardiac ganglion neurones: an intracellular analysis

PubMed Central

McAllen, Robin M; Salo, Lauren M; Paton, Julian F R; Pickering, Anthony E

2011-01-01

Abstract Cardiac vagal tone is an important indicator of cardiovascular health, and its loss is an independent risk factor for arrhythmias and mortality. Several studies suggest that this loss of vagal tone can occur at the cardiac ganglion but the factors affecting ganglionic transmissionin vivoare poorly understood. We have employed a novel approach allowing intracellular recordings from functionally connected cardiac vagal ganglion cells in the working heart–brainstem preparation. The atria were stabilisedin situpreserving their central neural connections, and ganglion cells (n = 32) were impaled with sharp microelectrodes. Cardiac ganglion cells with vagal synaptic inputs (spontaneous, n = 10; or electrically evoked from the vagus, n = 3) were identified as principal neurones and showed tonic firing responses to current injected to their somata. Cells lacking vagal inputs (n = 19, presumed interneurones) were quiescent but showed phasic firing responses to depolarising current. In principal cells the ongoing action potentials and EPSPs exhibited respiratory modulation, with peak frequency in post-inspiration. Action potentials arose from unitary EPSPs and autocorrelation of those events showed that each ganglion cell received inputs from a single active preganglionic source. Peripheral chemoreceptor, arterial baroreceptor and diving response activation all evoked high frequency synaptic barrages in these cells, always from the same single preganglionic source. EPSP amplitudes showed frequency dependent depression, leading to more spike failures at shorter inter-event intervals. These findings indicate that rather than integrating convergent inputs, cardiac vagal postganglionic neurones gate preganglionic inputs, so regulating the proportion of central parasympathetic tone that is transmitted on to the heart. PMID:22005679

The microRNA miR-1 regulates a MEF-2 dependent retrograde signal at neuromuscular junctions

PubMed Central

Simon, David J.; Madison, Jon M.; Conery, Annie L.; Thompson-Peer, Katherine L.; Soskis, Michael; Ruvkun, Gary B.; Kaplan, Joshua M.; Kim, John K.

2008-01-01

Summary We show that miR-1, a conserved muscle specific microRNA, regulates aspects of both pre- and post-synaptic function at C. elegans neuromuscular junctions. miR-1 regulates the expression level of two nicotinic acetylcholine receptor (nAChR) subunits (UNC-29 and UNC-63), thereby altering muscle sensitivity to acetylcholine (ACh). miR-1 also regulates the muscle transcription factor MEF-2, which results in altered pre-synaptic ACh secretion, suggesting that MEF-2 activity in muscles controls a retrograde signal. The effect of the MEF-2-dependent retrograde signal on secretion is mediated by the synaptic vesicle protein RAB-3. Finally, acute activation of levamisole-sensitive nAChRs stimulates MEF-2-dependent transcriptional responses, and induces the MEF-2-dependent retrograde signal. We propose that miR-1 refines synaptic function by coupling changes in muscle activity to changes in pre-synaptic function. PMID:18510933

Acute Fasting Regulates Retrograde Synaptic Enhancement through a 4E-BP-Dependent Mechanism.

PubMed

Kauwe, Grant; Tsurudome, Kazuya; Penney, Jay; Mori, Megumi; Gray, Lindsay; Calderon, Mario R; Elazouzzi, Fatima; Chicoine, Nicole; Sonenberg, Nahum; Haghighi, A Pejmun

2016-12-21

While beneficial effects of fasting on organismal function and health are well appreciated, we know little about the molecular details of how fasting influences synaptic function and plasticity. Our genetic and electrophysiological experiments demonstrate that acute fasting blocks retrograde synaptic enhancement that is normally triggered as a result of reduction in postsynaptic receptor function at the Drosophila larval neuromuscular junction (NMJ). This negative regulation critically depends on transcriptional enhancement of eukaryotic initiation factor 4E binding protein (4E-BP) under the control of the transcription factor Forkhead box O (Foxo). Furthermore, our findings indicate that postsynaptic 4E-BP exerts a constitutive negative input, which is counteracted by a positive regulatory input from the Target of Rapamycin (TOR). This combinatorial retrograde signaling plays a key role in regulating synaptic strength. Our results provide a mechanistic insight into how cellular stress and nutritional scarcity could acutely influence synaptic homeostasis and functional stability in neural circuits. Copyright © 2016 Elsevier Inc. All rights reserved.

Ta2O5-memristor synaptic array with winner-take-all method for neuromorphic pattern matching

NASA Astrophysics Data System (ADS)

Truong, Son Ngoc; Van Pham, Khoa; Yang, Wonsun; Min, Kyeong-Sik; Abbas, Yawar; Kang, Chi Jung; Shin, Sangho; Pedrotti, Ken

2016-08-01

Pattern matching or pattern recognition is one of the elemental components that constitute the very complicated recalling and remembering process in human's brain. To realize this neuromorphic pattern matching, we fabricated and tested a 3 × 3 memristor synaptic array with the winner-take-all method in this research. In the measurement, first, the 3 × 3 Ta2O5 memristor array is programmed to store [LLL], [LHH], and [HLH], where L is a low-resistance state and H is a high-resistance state, at the 1st, 2nd, and 3rd columns, respectively. After the programming, three input patterns, [111], [100], and [010], are applied to the memristor synaptic array. From the measurement results, we confirm that all three input patterns can be recognized well by using a twin memristor crossbar with synaptic arrays. This measurement can be thought of as the first real verification of the twin memristor crossbar with memristive synaptic arrays for neuromorphic pattern recognition.

Reversing the Outcome of Synapse Elimination at Developing Neuromuscular Junctions In Vivo: Evidence for Synaptic Competition and Its Mechanism

PubMed Central

Turney, Stephen G.; Lichtman, Jeff W.

2012-01-01

During mammalian development, neuromuscular junctions and some other postsynaptic cells transition from multiple- to single-innervation as synaptic sites are exchanged between different axons. It is unclear whether one axon invades synaptic sites to drive off other inputs or alternatively axons expand their territory in response to sites vacated by other axons. Here we show that soon-to-be-eliminated axons rapidly reverse fate and grow to occupy vacant sites at a neuromuscular junction after laser removal of a stronger input. This reversal supports the idea that axons take over sites that were previously vacated. Indeed, during normal development we observed withdrawal followed by takeover. The stimulus for axon growth is not postsynaptic cell inactivity because axons grow into unoccupied sites even when target cells are functionally innervated. These results demonstrate competition at the synaptic level and enable us to provide a conceptual framework for understanding this form of synaptic plasticity. PMID:22745601

BDNF-TrkB Signaling Coupled to nPKCε and cPKCβI Modulate the Phosphorylation of the Exocytotic Protein Munc18-1 During Synaptic Activity at the Neuromuscular Junction

PubMed Central

Simó, Anna; Just-Borràs, Laia; Cilleros-Mañé, Víctor; Hurtado, Erica; Nadal, Laura; Tomàs, Marta; Garcia, Neus; Lanuza, Maria A.; Tomàs, Josep

2018-01-01

Munc18-1, a neuron-specific member of the Sec1/Munc18 family, is involved in neurotransmitter release by binding tightly to syntaxin. Munc18-1 is phosphorylated by PKC on Ser-306 and Ser-313 in vitro which reduces the amount of Munc18-1 able to bind syntaxin. We have previously identified that PKC is involved in neurotransmitter release when continuous electrical stimulation imposes a moderate activity on the NMJ and that muscle contraction through TrkB has an important impact on presynaptic PKC isoforms levels, specifically cPKCβI and nPKCε. Therefore, the present study was designed to understand how Munc18-1 phosphorylation is affected by (1) synaptic activity at the neuromuscular junction, (2) nPKCε and cPKCβI isoforms activity, (3) muscle contraction per se, and (4) the BDNF/TrkB signaling in a neuromuscular activity-dependent manner. We performed immunohistochemistry and confocal techniques to evidence the presynaptic location of Munc18-1 in the rat diaphragm muscle. To study synaptic activity, we stimulated the phrenic nerve (1 Hz, 30 min) with or without contraction (abolished by μ-conotoxin GIIIB). Specific inhibitory reagents were used to block nPKCε and cPKCβI activity and to modulate the tropomyosin receptor kinase B (TrkB). Main results obtained from Western blot experiments showed that phosphorylation of Munc18-1 at Ser-313 increases in response to a signaling mechanism initiated by synaptic activity and directly mediated by nPKCε. Otherwise, cPKCβI and TrkB activities work together to prevent this synaptic activity–induced Munc18-1 phosphorylation by a negative regulation of cPKCβI over nPKCε. Therefore, a balance between the activities of these PKC isoforms could be a relevant cue in the regulation of the exocytotic apparatus. The results also demonstrate that muscle contraction prevents the synaptic activity–induced Munc18-1 phosphorylation through a mechanism that opposes the TrkB/cPKCβI/nPKCε signaling. PMID:29946239

Color opponent receptive fields self-organize in a biophysical model of visual cortex via spike-timing dependent plasticity

PubMed Central

Eguchi, Akihiro; Neymotin, Samuel A.; Stringer, Simon M.

2014-01-01

Although many computational models have been proposed to explain orientation maps in primary visual cortex (V1), it is not yet known how similar clusters of color-selective neurons in macaque V1/V2 are connected and develop. In this work, we address the problem of understanding the cortical processing of color information with a possible mechanism of the development of the patchy distribution of color selectivity via computational modeling. Each color input is decomposed into a red, green, and blue representation and transmitted to the visual cortex via a simulated optic nerve in a luminance channel and red–green and blue–yellow opponent color channels. Our model of the early visual system consists of multiple topographically-arranged layers of excitatory and inhibitory neurons, with sparse intra-layer connectivity and feed-forward connectivity between layers. Layers are arranged based on anatomy of early visual pathways, and include a retina, lateral geniculate nucleus, and layered neocortex. Each neuron in the V1 output layer makes synaptic connections to neighboring neurons and receives the three types of signals in the different channels from the corresponding photoreceptor position. Synaptic weights are randomized and learned using spike-timing-dependent plasticity (STDP). After training with natural images, the neurons display heightened sensitivity to specific colors. Information-theoretic analysis reveals mutual information between particular stimuli and responses, and that the information reaches a maximum with fewer neurons in the higher layers, indicating that estimations of the input colors can be done using the output of fewer cells in the later stages of cortical processing. In addition, cells with similar color receptive fields form clusters. Analysis of spiking activity reveals increased firing synchrony between neurons when particular color inputs are presented or removed (ON-cell/OFF-cell). PMID:24659956

Spine Calcium Transients Induced by Synaptically-Evoked Action Potentials Can Predict Synapse Location and Establish Synaptic Democracy

PubMed Central

Meredith, Rhiannon M.; van Ooyen, Arjen

2012-01-01

CA1 pyramidal neurons receive hundreds of synaptic inputs at different distances from the soma. Distance-dependent synaptic scaling enables distal and proximal synapses to influence the somatic membrane equally, a phenomenon called “synaptic democracy”. How this is established is unclear. The backpropagating action potential (BAP) is hypothesised to provide distance-dependent information to synapses, allowing synaptic strengths to scale accordingly. Experimental measurements show that a BAP evoked by current injection at the soma causes calcium currents in the apical shaft whose amplitudes decay with distance from the soma. However, in vivo action potentials are not induced by somatic current injection but by synaptic inputs along the dendrites, which creates a different excitable state of the dendrites. Due to technical limitations, it is not possible to study experimentally whether distance information can also be provided by synaptically-evoked BAPs. Therefore we adapted a realistic morphological and electrophysiological model to measure BAP-induced voltage and calcium signals in spines after Schaffer collateral synapse stimulation. We show that peak calcium concentration is highly correlated with soma-synapse distance under a number of physiologically-realistic suprathreshold stimulation regimes and for a range of dendritic morphologies. Peak calcium levels also predicted the attenuation of the EPSP across the dendritic tree. Furthermore, we show that peak calcium can be used to set up a synaptic democracy in a homeostatic manner, whereby synapses regulate their synaptic strength on the basis of the difference between peak calcium and a uniform target value. We conclude that information derived from synaptically-generated BAPs can indicate synapse location and can subsequently be utilised to implement a synaptic democracy. PMID:22719238

The gut-brain axis rewired: adding a functional vagal nicotinic "sensory synapse".

PubMed

Perez-Burgos, Azucena; Mao, Yu-Kang; Bienenstock, John; Kunze, Wolfgang A

2014-07-01

It is generally accepted that intestinal sensory vagal fibers are primary afferent, responding nonsynaptically to luminal stimuli. The gut also contains intrinsic primary afferent neurons (IPANs) that respond to luminal stimuli. A psychoactive Lactobacillus rhamnosus (JB-1) that affects brain function excites both vagal fibers and IPANs. We wondered whether, contrary to its primary afferent designation, the sensory vagus response to JB-1 might depend on IPAN to vagal fiber synaptic transmission. We recorded ex vivo single- and multiunit afferent action potentials from mesenteric nerves supplying mouse jejunal segments. Intramural synaptic blockade with Ca(2+) channel blockers reduced constitutive or JB-1-evoked vagal sensory discharge. Firing of 60% of spontaneously active units was reduced by synaptic blockade. Synaptic or nicotinic receptor blockade reduced firing in 60% of vagal sensory units that were stimulated by luminal JB-1. In control experiments, increasing or decreasing IPAN excitability, respectively increased or decreased nerve firing that was abolished by synaptic blockade or vagotomy. We conclude that >50% of vagal afferents function as interneurons for stimulation by JB-1, receiving input from an intramural functional "sensory synapse." This was supported by myenteric plexus nicotinic receptor immunohistochemistry. These data offer a novel therapeutic target to modify pathological gut-brain axis activity.-Perez-Burgos, A., Mao, Y.-K., Bienenstock, J., Kunze, W. A. The gut-brain axis rewired: adding a functional vagal nicotinic "sensory synapse." © FASEB.

Preferential distribution of nociceptive input to motoneurons with muscle units in the cranial portion of the upper trapezius muscle.

PubMed

Dideriksen, Jakob L; Holobar, Ales; Falla, Deborah

2016-08-01

Pain is associated with changes in the neural drive to muscles. For the upper trapezius muscle, surface electromyography (EMG) recordings have indicated that acute noxious stimulation in either the cranial or the caudal region of the muscle leads to a relative decrease in muscle activity in the cranial region. It is, however, not known if this adaption reflects different recruitment thresholds of the upper trapezius motor units in the cranial and caudal region or a nonuniform nociceptive input to the motor units of both regions. This study investigated these potential mechanisms by direct motor unit identification. Motor unit activity was investigated with high-density surface EMG signals recorded from the upper trapezius muscle of 12 healthy volunteers during baseline, control (intramuscular injection of isotonic saline), and painful (hypertonic saline) conditions. The EMG was decomposed into individual motor unit spike trains. Motor unit discharge rates decreased significantly from control to pain conditions by 4.0 ± 3.6 pulses/s (pps) in the cranial region but not in the caudal region (1.4 ± 2.8 pps; not significant). These changes were compatible with variations in the synaptic input to the motoneurons of the two regions. These adjustments were observed, irrespective of the location of noxious stimulation. These results strongly indicate that the nociceptive synaptic input is distributed in a nonuniform way across regions of the upper trapezius muscle. Copyright © 2016 the American Physiological Society.

Preferential distribution of nociceptive input to motoneurons with muscle units in the cranial portion of the upper trapezius muscle

PubMed Central

Dideriksen, Jakob L.; Holobar, Ales

2016-01-01

Pain is associated with changes in the neural drive to muscles. For the upper trapezius muscle, surface electromyography (EMG) recordings have indicated that acute noxious stimulation in either the cranial or the caudal region of the muscle leads to a relative decrease in muscle activity in the cranial region. It is, however, not known if this adaption reflects different recruitment thresholds of the upper trapezius motor units in the cranial and caudal region or a nonuniform nociceptive input to the motor units of both regions. This study investigated these potential mechanisms by direct motor unit identification. Motor unit activity was investigated with high-density surface EMG signals recorded from the upper trapezius muscle of 12 healthy volunteers during baseline, control (intramuscular injection of isotonic saline), and painful (hypertonic saline) conditions. The EMG was decomposed into individual motor unit spike trains. Motor unit discharge rates decreased significantly from control to pain conditions by 4.0 ± 3.6 pulses/s (pps) in the cranial region but not in the caudal region (1.4 ± 2.8 pps; not significant). These changes were compatible with variations in the synaptic input to the motoneurons of the two regions. These adjustments were observed, irrespective of the location of noxious stimulation. These results strongly indicate that the nociceptive synaptic input is distributed in a nonuniform way across regions of the upper trapezius muscle. PMID:27226455

Maintaining Consistency of Spatial Information in the Hippocampal Network: A Combinatorial Geometry Model.

PubMed

Dabaghian, Y

2016-06-01

Place cells in the rat hippocampus play a key role in creating the animal's internal representation of the world. During active navigation, these cells spike only in discrete locations, together encoding a map of the environment. Electrophysiological recordings have shown that the animal can revisit this map mentally during both sleep and awake states, reactivating the place cells that fired during its exploration in the same sequence in which they were originally activated. Although consistency of place cell activity during active navigation is arguably enforced by sensory and proprioceptive inputs, it remains unclear how a consistent representation of space can be maintained during spontaneous replay. We propose a model that can account for this phenomenon and suggest that a spatially consistent replay requires a number of constraints on the hippocampal network that affect its synaptic architecture and the statistics of synaptic connection strengths.

Synaptic activation patterns of the perirhinal-entorhinal inter-connections.

PubMed

de Villers-Sidani, E; Tahvildari, B; Alonso, A

2004-01-01

Ample neuropsychological evidence supports the role of rhinal cortices in memory. The perirhinal cortex (PRC) represents one of the main conduits for the bi-directional flow of information between the entorhinal-hippocampal network and the cortical mantle, a process essential in memory formation. However, despite anatomical evidence for a robust reciprocal connectivity between the perirhinal and entorhinal cortices, neurophysiological understanding of this circuitry is lacking. We now present the results of a series of electrophysiological experiments in rats that demonstrate robust synaptic activation patterns of the perirhinal-entorhinal inter-connections. First, using silicon multi-electrode arrays placed under visual guidance in vivo we performed current source density (CSD) analysis of lateral entorhinal cortex (LEC) responses to PRC stimulation, which demonstrated a current sink in layers II-III of the LEC with a latency consistent with monosynaptic activation. To further substantiate and extend this conclusion, we developed a PRC-LEC slice preparation where CSD analysis also revealed a current sink in superficial LEC layers in response to PRC stimulation. Importantly, intracellular recording of superficial LEC layer neurons confirmed that they receive a major monosynaptic excitatory input from the PRC. Finally, CSD analysis of the LEC to PRC projection in vivo also allowed us to document robust feedback synaptic activation of PRC neurons to deep LEC layer activation. We conclude that a clear bidirectional pattern of synaptic interactions exists between the PRC and LEC that would support a dynamic flow of information subserving memory function in the temporal lobe.

Synaptic physiology of the flow of information in the cat's visual cortex in vivo

PubMed Central

Hirsch, Judith A; Martinez, Luis M; Alonso, José-Manuel; Desai, Komal; Pillai, Cinthi; Pierre, Carhine

2002-01-01

Each stage of the striate cortical circuit extracts novel information about the visual environment. We asked if this analytic process reflected laminar variations in synaptic physiology by making whole-cell recording with dye-filled electrodes from the cat's visual cortex and thalamus; the stimuli were flashed spots. Thalamic afferents terminate in layer 4, which contains two types of cell, simple and complex, distinguished by the spatial structure of the receptive field. Previously, we had found that the postsynaptic and spike responses of simple cells reliably followed the time course of flash-evoked thalamic activity. Here we report that complex cells in layer 4 (or cells intermediate between simple and complex) similarly reprised thalamic activity (response/trial, 99 ± 1.9 %; response duration 159 ± 57 ms; latency 25 ± 4 ms; average ± standard deviation; n = 7). Thus, all cells in layer 4 share a common synaptic physiology that allows secure integration of thalamic input. By contrast, at the second cortical stage (layer 2+3), where layer 4 directs its output, postsynaptic responses did not track simple patterns of antecedent activity. Typical responses to the static stimulus were intermittent and brief (response/trial, 31 ± 40 %; response duration 72 ± 60 ms, latency 39 ± 7 ms; n = 11). Only richer stimuli like those including motion evoked reliable responses. All told, the second level of cortical processing differs markedly from the first. At that later stage, ascending information seems strongly gated by connections between cortical neurons. Inputs must be combined in newly specified patterns to influence intracortical stages of processing. PMID:11927691

Investigating the influence of PFC transection and nicotine on dynamics of AMPA and NMDA receptors of VTA dopaminergic neurons.

PubMed

Chen, Ting; Zhang, Die; Dragomir, Andrei; Kobayashi, Kunikazu; Akay, Yasemin; Akay, Metin

2011-10-21

All drugs of abuse, including nicotine, activate the mesocorticolimbic system that plays critical roles in nicotine reward and reinforcement development and triggers glutamatergic synaptic plasticity on the dopamine (DA) neurons in the ventral tegmental area (VTA). The addictive behavior and firing pattern of the VTA DA neurons are thought to be controlled by the glutamatergic synaptic input from prefrontal cortex (PFC). Interrupted functional input from PFC to VTA was shown to decrease the effects of the drug on the addiction process. Nicotine treatment could enhance the AMPA/NMDA ratio in VTA DA neurons, which is thought as a common addiction mechanism. In this study, we investigate whether or not the lack of glutamate transmission from PFC to VTA could make any change in the effects of nicotine. We used the traditional AMPA/NMDA peak ratio, AMPA/NMDA area ratio, and KL (Kullback-Leibler) divergence analysis method for the present study. Our results using AMPA/NMDA peak ratio showed insignificant difference between PFC intact and transected and treated with saline. However, using AMPA/NMDA area ratio and KL divergence method, we observed a significant difference when PFC is interrupted with saline treatment. One possible reason for the significant effect that the PFC transection has on the synaptic responses (as indicated by the AMPA/NMDA area ratio and KL divergence) may be the loss of glutamatergic inputs. The glutamatergic input is one of the most important factors that contribute to the peak ratio level. Our results suggested that even within one hour after a single nicotine injection, the peak ratio of AMPA/NMDA on VTA DA neurons could be enhanced.

Differential effects of natural rewards and pain on vesicular glutamate transporter expression in the nucleus accumbens.

PubMed

Tukey, David S; Lee, Michelle; Xu, Duo; Eberle, Sarah E; Goffer, Yossef; Manders, Toby R; Ziff, Edward B; Wang, Jing

2013-07-09

Pain and natural rewards such as food elicit different behavioral effects. Both pain and rewards, however, have been shown to alter synaptic activities in the nucleus accumbens (NAc), a key component of the brain reward system. Mechanisms by which external stimuli regulate plasticity at NAc synapses are largely unexplored. Medium spiny neurons (MSNs) from the NAc receive excitatory glutamatergic inputs and modulatory dopaminergic and cholinergic inputs from a variety of cortical and subcortical structures. Glutamate inputs to the NAc arise primarily from prefrontal cortex, thalamus, amygdala, and hippocampus, and different glutamate projections provide distinct synaptic and ultimately behavioral functions. The family of vesicular glutamate transporters (VGLUTs 1-3) plays a key role in the uploading of glutamate into synaptic vesicles. VGLUT1-3 isoforms have distinct expression patterns in the brain, but the effects of external stimuli on their expression patterns have not been studied. In this study, we use a sucrose self-administration paradigm for natural rewards, and spared nerve injury (SNI) model for chronic pain. We examine the levels of VGLUTs (1-3) in synaptoneurosomes of the NAc in these two behavioral models. We find that chronic pain leads to a decrease of VGLUT1, likely reflecting decreased projections from the cortex. Pain also decreases VGLUT3 levels, likely representing a decrease in projections from GABAergic, serotonergic, and/or cholinergic interneurons. In contrast, chronic consumption of sucrose increases VGLUT3 in the NAc, possibly reflecting an increase from these interneuron projections. Our study shows that natural rewards and pain have distinct effects on the VGLUT expression pattern in the NAc, indicating that glutamate inputs to the NAc are differentially modulated by rewards and pain.

Spermidine Suppresses Age-Associated Memory Impairment by Preventing Adverse Increase of Presynaptic Active Zone Size and Release

PubMed Central

Gupta, Varun K.; Pech, Ulrike; Fulterer, Andreas; Ender, Anatoli; Mauermann, Stephan F.; Andlauer, Till F. M.; Beuschel, Christine; Thriene, Kerstin; Quentin, Christine; Schwärzel, Martin; Mielke, Thorsten; Madeo, Frank; Dengjel, Joern; Fiala, André; Sigrist, Stephan J.

2016-01-01

Memories are assumed to be formed by sets of synapses changing their structural or functional performance. The efficacy of forming new memories declines with advancing age, but the synaptic changes underlying age-induced memory impairment remain poorly understood. Recently, we found spermidine feeding to specifically suppress age-dependent impairments in forming olfactory memories, providing a mean to search for synaptic changes involved in age-dependent memory impairment. Here, we show that a specific synaptic compartment, the presynaptic active zone (AZ), increases the size of its ultrastructural elaboration and releases significantly more synaptic vesicles with advancing age. These age-induced AZ changes, however, were fully suppressed by spermidine feeding. A genetically enforced enlargement of AZ scaffolds (four gene-copies of BRP) impaired memory formation in young animals. Thus, in the Drosophila nervous system, aging AZs seem to steer towards the upper limit of their operational range, limiting synaptic plasticity and contributing to impairment of memory formation. Spermidine feeding suppresses age-dependent memory impairment by counteracting these age-dependent changes directly at the synapse. PMID:27684064

Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice

PubMed Central

Hasan, Mazahir T.; Hernández-González, Samuel; Dogbevia, Godwin; Treviño, Mario; Bertocchi, Ilaria; Gruart, Agnès; Delgado-García, José M.

2013-01-01

The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning. PMID:23978820

The response of cortical neurons to in vivo-like input current: theory and experiment: II. Time-varying and spatially distributed inputs.

PubMed

Giugliano, Michele; La Camera, Giancarlo; Fusi, Stefano; Senn, Walter

2008-11-01

The response of a population of neurons to time-varying synaptic inputs can show a rich phenomenology, hardly predictable from the dynamical properties of the membrane's inherent time constants. For example, a network of neurons in a state of spontaneous activity can respond significantly more rapidly than each single neuron taken individually. Under the assumption that the statistics of the synaptic input is the same for a population of similarly behaving neurons (mean field approximation), it is possible to greatly simplify the study of neural circuits, both in the case in which the statistics of the input are stationary (reviewed in La Camera et al. in Biol Cybern, 2008) and in the case in which they are time varying and unevenly distributed over the dendritic tree. Here, we review theoretical and experimental results on the single-neuron properties that are relevant for the dynamical collective behavior of a population of neurons. We focus on the response of integrate-and-fire neurons and real cortical neurons to long-lasting, noisy, in vivo-like stationary inputs and show how the theory can predict the observed rhythmic activity of cultures of neurons. We then show how cortical neurons adapt on multiple time scales in response to input with stationary statistics in vitro. Next, we review how it is possible to study the general response properties of a neural circuit to time-varying inputs by estimating the response of single neurons to noisy sinusoidal currents. Finally, we address the dendrite-soma interactions in cortical neurons leading to gain modulation and spike bursts, and show how these effects can be captured by a two-compartment integrate-and-fire neuron. Most of the experimental results reviewed in this article have been successfully reproduced by simple integrate-and-fire model neurons.

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

PubMed

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.

Dopamine-Modulated Recurrent Corticoefferent Feedback in Primary Sensory Cortex Promotes Detection of Behaviorally Relevant Stimuli

PubMed Central

Handschuh, Juliane

2014-01-01

Dopaminergic neurotransmission in primary auditory cortex (AI) has been shown to be involved in learning and memory functions. Moreover, dopaminergic projections and D1/D5 receptor distributions display a layer-dependent organization, suggesting specific functions in the cortical circuitry. However, the circuit effects of dopaminergic neurotransmission in sensory cortex and their possible roles in perception, learning, and memory are largely unknown. Here, we investigated layer-specific circuit effects of dopaminergic neuromodulation using current source density (CSD) analysis in AI of Mongolian gerbils. Pharmacological stimulation of D1/D5 receptors increased auditory-evoked synaptic currents in infragranular layers, prolonging local thalamocortical input via positive feedback between infragranular output and granular input. Subsequently, dopamine promoted sustained cortical activation by prolonged recruitment of long-range corticocortical networks. A detailed circuit analysis combining layer-specific intracortical microstimulation (ICMS), CSD analysis, and pharmacological cortical silencing revealed that cross-laminar feedback enhanced by dopamine relied on a positive, fast-acting recurrent corticoefferent loop, most likely relayed via local thalamic circuits. Behavioral signal detection analysis further showed that activation of corticoefferent output by infragranular ICMS, which mimicked auditory activation under dopaminergic influence, was most effective in eliciting a behaviorally detectable signal. Our results show that D1/D5-mediated dopaminergic modulation in sensory cortex regulates positive recurrent corticoefferent feedback, which enhances states of high, persistent activity in sensory cortex evoked by behaviorally relevant stimuli. In boosting horizontal network interactions, this potentially promotes the readout of task-related information from cortical synapses and improves behavioral stimulus detection. PMID:24453315

Sexually dimorphic differentiation of a C. elegans hub neuron is cell-autonomously controlled by a conserved transcription factor

PubMed Central

Serrano-Saiz, Esther; Oren-Suissa, Meital; Bayer, Emily A.; Hobert, Oliver

2018-01-01

SUMMARY Functional and anatomical sexual dimorphisms in the brain are either the result of cells that are generated only in one sex, or a manifestation of sex-specific differentiation of neurons present in both sexes. The PHC neurons of the nematode C. elegans differentiate in a strikingly sex-specific manner. While in hermaphrodites the PHC neurons display a canonical pattern of synaptic connectivity similar to that of other sensory neurons, PHC differentiates into a densely connected hub sensory/interneuron in males, integrating a large number of male-specific synaptic inputs and conveying them to both male-specific and sex-shared circuitry. We show that the differentiation into such a hub neuron involves the sex-specific scaling of several components of the synaptic vesicle machinery, including the vesicular glutamate transporter eat-4/VGLUT, induction of neuropeptide expression, changes in axonal projection morphology and a switch in neuronal function. We demonstrate that these molecular and anatomical remodeling events are controlled cell-autonomously by the phylogenetically conserved Doublesex homolog dmd-3, which is both required and sufficient for sex-specific PHC differentiation. Cellular specificity of dmd-3 action is ensured by its collaboration with non-sex specific terminal selector-type transcription factors whereas sex-specificity of dmd-3 action is ensured by the hermaphrodite-specific, transcriptional master regulator of hermaphroditic cell identity, tra-1, which represses transcription of dmd-3 in hermaphrodite PHC. Taken together, our studies provide mechanistic insights into how neurons are specified in a sexually dimorphic manner. PMID:28065609

Active Sampling State Dynamically Enhances Olfactory Bulb Odor Representation.

PubMed

Jordan, Rebecca; Fukunaga, Izumi; Kollo, Mihaly; Schaefer, Andreas T

2018-06-27

The olfactory bulb (OB) is the first site of synaptic odor information processing, yet a wealth of contextual and learned information has been described in its activity. To investigate the mechanistic basis of contextual modulation, we use whole-cell recordings to measure odor responses across rapid learning episodes in identified mitral/tufted cells (MTCs). Across these learning episodes, diverse response changes occur already during the first sniff cycle. Motivated mice develop active sniffing strategies across learning that robustly correspond to the odor response changes, resulting in enhanced odor representation. Evoking fast sniffing in different behavioral states demonstrates that response changes during active sampling exceed those predicted from feedforward input alone. Finally, response changes are highly correlated in tufted cells, but not mitral cells, indicating there are cell-type-specific effects on odor representation during active sampling. Altogether, we show that active sampling is strongly associated with enhanced OB responsiveness on rapid timescales. Copyright © 2018 The Francis Crick Institute. Published by Elsevier Inc. All rights reserved.

Activation properties of trigeminal motoneurons in participants with and without bruxism

PubMed Central

D'Amico, Jessica M.; Yavuz, Ş. Utku; Saraçoğlu, Ahmet; Atiş, Elif Sibel; Türker, Kemal S.

2013-01-01

In animals, sodium- and calcium-mediated persistent inward currents (PICs), which produce long-lasting periods of depolarization under conditions of low synaptic drive, can be activated in trigeminal motoneurons following the application of the monoamine serotonin. Here we examined if PICs are activated in human trigeminal motoneurons during voluntary contractions and under physiological levels of monoaminergic drive (e.g., serotonin and norepinephrine) using a paired motor unit analysis technique. We also examined if PICs activated during voluntary contractions are larger in participants who demonstrate involuntary chewing during sleep (bruxism), which is accompanied by periods of high monoaminergic drive. In control participants, during a slowly increasing and then decreasing isometric contraction, the firing rate of an earlier-recruited masseter motor unit, which served as a measure of synaptic input to a later-recruited test unit, was consistently lower during derecruitment of the test unit compared with at recruitment (ΔF = 4.6 ± 1.5 imp/s). The ΔF, therefore, is a measure of the reduction in synaptic input needed to counteract the depolarization from the PIC to provide an indirect estimate of PIC amplitude. The range of ΔF values measured in the bruxer participants during similar voluntary contractions was the same as in controls, suggesting that abnormally high levels of monoaminergic drive are not continually present in the absence of involuntary motor activity. We also observed a consistent “onion skin effect” during the moderately sized contractions (<20% of maximal), whereby the firing rate of higher threshold motor units discharged at slower rates (by 4–7 imp/s) compared with motor units with relatively lower thresholds. The presence of lower firing rates in the more fatigue-prone, higher threshold trigeminal motoneurons, in addition to the activation of PICs, likely facilitates the activation of the masseter muscle during motor activities such as eating, nonnutritive chewing, clenching, and yawning. PMID:24068753

Mechanisms of potentiation of mossy fiber EPSCs in the cerebellar nuclei by coincident synaptic excitation and inhibition

PubMed Central

Pugh, Jason R.; Raman, Indira M.

2008-01-01

Neurons of the cerebellar nuclei receive synaptic excitation from cerebellar mossy fibers. Unlike in many principal neurons, coincident presynaptic activity and postsynaptic depolarization do not generate long-term potentiation at these synapses. Instead, EPSCs are potentiated by high-frequency trains of presynaptic activity applied with postsynaptic hyperpolarization, in patterns resembling the mossy fiber-mediated excitation and Purkinje cell-mediated inhibition predicted to occur during delay eyelid conditioning. Here, we have used electrophysiology and Ca imaging to test how synaptic excitation and inhibition interact to generate long-lasting synaptic plasticity in nuclear cells in cerebellar slices. We find that the extent of plasticity varies with the relative timing of synaptic excitation and hyperpolarization. Potentiation is most effective when synaptic stimuli precede the post-inhibitory rebound by ~400 ms, whereas with longer intervals, or with a reverse sequence, EPSCs tend to depress. When basal intracellular Ca is raised by spontaneous firing or reduced by voltage-clamping at subthreshold potentials, potentiation is induced as long as the synaptic-rebound temporal sequence is maintained, suggesting that plasticity does not require Ca levels to exceed a threshold or attain a specific concentration. Although rebound and spike-dependent Ca influx are global, potentiation is synapse-specific, and is disrupted by inhibitors of calcineurin or CaMKII, but not PKC. When IPSPs replace the hyperpolarizing step in the induction protocol, potentiation proceeds normally. These results lead us to propose that synaptic and inhibitory/rebound stimuli initiate separate processes, with local NMDA-receptor-mediated Ca influx “priming” synapses, and Ca changes from the inhibition and rebound “triggering” potentiation at recently activated synapses. PMID:18923031

Presynaptic muscarinic receptors, calcium channels, and protein kinase C modulate the functional disconnection of weak inputs at polyinnervated neonatal neuromuscular synapses.

PubMed

Santafe, M M; Garcia, N; Lanuza, M A; Tomàs, M; Besalduch, N; Tomàs, J

2009-04-01

We studied the relation among calcium inflows, voltage-dependent calcium channels (VDCC), presynaptic muscarinic acetylcholine receptors (mAChRs), and protein kinase C (PKC) activity in the modulation of synapse elimination. We used intracellular recording to determine the synaptic efficacy in dually innervated endplates of the levator auris longus muscle of newborn rats during axonal competition in the postnatal synaptic elimination period. In these dual junctions, the weak nerve terminal was potentiated by partially reducing calcium entry (P/Q-, N-, or L-type VDCC-specific block or 500 muM magnesium ions), M1- or M4-type selective mAChR block, or PKC block. Moreover, reducing calcium entry or blocking PKC or mAChRs results in unmasking functionally silent nerve endings that now recover neurotransmitter release. Our results show interactions between these molecules and indicate that there is a release inhibition mechanism based on an mAChR-PKC-VDCC intracellular cascade. When it is fully active in certain weak motor axons, it can depress ACh release and even disconnect synapses. We suggest that this mechanism plays a central role in the elimination of redundant neonatal synapses, because functional axonal withdrawal can indeed be reversed by mAChRs, VDCCs, or PKC block.

Effects of 17beta-estradiol on glutamate synaptic transmission and neuronal excitability in the rat medial vestibular nuclei.

PubMed

Grassi, S; Frondaroli, A; Scarduzio, M; Dutia, M B; Dieni, C; Pettorossi, V E

2010-02-17

We investigated the effects of the neurosteroid 17beta-estradiol (E(2)) on the evoked and spontaneous activity of rat medial vestibular nucleus (MVN) neurons in brainstem slices. E(2) enhances the synaptic response to vestibular nerve stimulation in type B neurons and depresses the spontaneous discharge in both type A and B neurons. The amplitude of the field potential, as well as the excitatory post-synaptic potential (EPSP) and current (EPSC), in type B neurons, are enhanced by E(2). Both effects are long-term phenomena since they outlast the drug washout. The enhancement of synaptic response is mainly due to facilitation of glutamate release mediated by pre-synaptic N-methyl-D-aspartate receptors (NMDARs), since the reduction of paired pulse ratio (PPR) and the increase of miniature EPSC frequency after E(2) are abolished under D-(-)-2-amino-5-phosphonopentanoic acid (AP-5). E(2) also facilitates post-synaptic NMDARs, but it does not affect directly alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and group I-metabotropic glutamate receptors (mGluRs-I). In contrast, the depression of the spontaneous discharge of type A and type B neurons appears to depend on E(2) modulation of intrinsic ion conductances, as the effect remains after blockade of glutamate, GABA and glycine receptors (GlyRs). The net effect of E(2) is to enhance the signal-to-noise ratio of the synaptic response in type B neurons, relative to resting activity of all MVN neurons. These findings provide evidence for a novel potential mechanism to modulate the responsiveness of vestibular neurons to afferent inputs, and so regulate vestibular function in vivo.

Anesthesia modifies subthreshold critical slowing down in a stochastic Hodgkin-Huxley-like model with inhibitory synaptic input

NASA Astrophysics Data System (ADS)

Bukoski, Alex; Steyn-Ross, D. A.; Pickett, Ashley F.; Steyn-Ross, Moira L.

2018-06-01

The dynamics of a stochastic type-I Hodgkin-Huxley-like point neuron model exposed to inhibitory synaptic noise are investigated as a function of distance from spiking threshold and the inhibitory influence of the general anesthetic agent propofol. The model is biologically motivated and includes the effects of intrinsic ion-channel noise via a stochastic differential equation description as well as inhibitory synaptic noise modeled as multiple Poisson-distributed impulse trains with saturating response functions. The effect of propofol on these synapses is incorporated through this drug's principal influence on fast inhibitory neurotransmission mediated by γ -aminobutyric acid (GABA) type-A receptors via reduction of the synaptic response decay rate. As the neuron model approaches spiking threshold from below, we track membrane voltage fluctuation statistics of numerically simulated stochastic trajectories. We find that for a given distance from spiking threshold, increasing the magnitude of anesthetic-induced inhibition is associated with augmented signatures of critical slowing: fluctuation amplitudes and correlation times grow as spectral power is increasingly focused at 0 Hz. Furthermore, as a function of distance from threshold, anesthesia significantly modifies the power-law exponents for variance and correlation time divergences observable in stochastic trajectories. Compared to the inverse square root power-law scaling of these quantities anticipated for the saddle-node bifurcation of type-I neurons in the absence of anesthesia, increasing anesthetic-induced inhibition results in an observable exponent <-0.5 for variance and >-0.5 for correlation time divergences. However, these behaviors eventually break down as distance from threshold goes to zero with both the variance and correlation time converging to common values independent of anesthesia. Compared to the case of no synaptic input, linearization of an approximating multivariate Ornstein-Uhlenbeck model reveals these effects to be the consequence of an additional slow eigenvalue associated with synaptic activity that competes with those of the underlying point neuron in a manner that depends on distance from spiking threshold.

LRRTM1 underlies synaptic convergence in visual thalamus

PubMed Central

Monavarfeshani, Aboozar; Stanton, Gail; Van Name, Jonathan; Su, Kaiwen; Mills, William A; Swilling, Kenya; Kerr, Alicia; Huebschman, Natalie A; Su, Jianmin

2018-01-01

It has long been thought that the mammalian visual system is organized into parallel pathways, with incoming visual signals being parsed in the retina based on feature (e.g. color, contrast and motion) and then transmitted to the brain in unmixed, feature-specific channels. To faithfully convey feature-specific information from retina to cortex, thalamic relay cells must receive inputs from only a small number of functionally similar retinal ganglion cells. However, recent studies challenged this by revealing substantial levels of retinal convergence onto relay cells. Here, we sought to identify mechanisms responsible for the assembly of such convergence. Using an unbiased transcriptomics approach and targeted mutant mice, we discovered a critical role for the synaptic adhesion molecule Leucine Rich Repeat Transmembrane Neuronal 1 (LRRTM1) in the emergence of retinothalamic convergence. Importantly, LRRTM1 mutant mice display impairment in visual behaviors, suggesting a functional role of retinothalamic convergence in vision. PMID:29424692

Generation of field potentials and modulation of their dynamics through volume integration of cortical activity.

PubMed

Kajikawa, Yoshinao; Schroeder, Charles E

2015-01-01

Field potentials (FPs) recorded within the brain, often called "local field potentials" (LFPs), are useful measures of net synaptic activity in a neuronal ensemble. However, due to volume conduction, FPs spread beyond regions of underlying synaptic activity, and thus an "LFP" signal may not accurately reflect the temporal patterns of synaptic activity in the immediately surrounding neuron population. To better understand the physiological processes reflected in FPs, we explored the relationship between the FP and its membrane current generators using current source density (CSD) analysis in conjunction with a volume conductor model. The model provides a quantitative description of the spatiotemporal summation of immediate local and more distant membrane currents to produce the FP. By applying the model to FPs in the macaque auditory cortex, we have investigated a critical issue that has broad implications for FP research. We have shown that FP responses in particular cortical layers are differentially susceptible to activity in other layers. Activity in the supragranular layers has the strongest contribution to FPs in other cortical layers, and infragranular FPs are most susceptible to contributions from other layers. To define the physiological processes generating FPs recorded in loci of relatively weak synaptic activity, strong effects produced by synaptic events in the vicinity have to be taken into account. While outlining limitations and caveats inherent to FP measurements, our results also suggest specific peak and frequency band components of FPs can be related to activity in specific cortical layers. These results may help improving the interpretability of FPs. Copyright © 2015 the American Physiological Society.

Generation of field potentials and modulation of their dynamics through volume integration of cortical activity

PubMed Central

Schroeder, Charles E.

2014-01-01

Field potentials (FPs) recorded within the brain, often called “local field potentials” (LFPs), are useful measures of net synaptic activity in a neuronal ensemble. However, due to volume conduction, FPs spread beyond regions of underlying synaptic activity, and thus an “LFP” signal may not accurately reflect the temporal patterns of synaptic activity in the immediately surrounding neuron population. To better understand the physiological processes reflected in FPs, we explored the relationship between the FP and its membrane current generators using current source density (CSD) analysis in conjunction with a volume conductor model. The model provides a quantitative description of the spatiotemporal summation of immediate local and more distant membrane currents to produce the FP. By applying the model to FPs in the macaque auditory cortex, we have investigated a critical issue that has broad implications for FP research. We have shown that FP responses in particular cortical layers are differentially susceptible to activity in other layers. Activity in the supragranular layers has the strongest contribution to FPs in other cortical layers, and infragranular FPs are most susceptible to contributions from other layers. To define the physiological processes generating FPs recorded in loci of relatively weak synaptic activity, strong effects produced by synaptic events in the vicinity have to be taken into account. While outlining limitations and caveats inherent to FP measurements, our results also suggest specific peak and frequency band components of FPs can be related to activity in specific cortical layers. These results may help improving the interpretability of FPs. PMID:25274348

T-type calcium channels cause bursts of spikes in motor but not sensory thalamic neurons during mimicry of natural patterns of synaptic input.

PubMed

Kim, Haram R; Hong, Su Z; Fiorillo, Christopher D

2015-01-01

Although neurons within intact nervous systems can be classified as 'sensory' or 'motor,' it is not known whether there is any general distinction between sensory and motor neurons at the cellular or molecular levels. Here, we extend and test a theory according to which activation of certain subtypes of voltage-gated ion channel (VGC) generate patterns of spikes in neurons of motor systems, whereas VGC are proposed to counteract patterns in sensory neurons. We previously reported experimental evidence for the theory from visual thalamus, where we found that T-type calcium channels (TtCCs) did not cause bursts of spikes but instead served the function of 'predictive homeostasis' to maximize the causal and informational link between retinogeniculate excitation and spike output. Here, we have recorded neurons in brain slices from eight sensory and motor regions of rat thalamus while mimicking key features of natural excitatory and inhibitory post-synaptic potentials. As predicted by theory, TtCC did cause bursts of spikes in motor thalamus. TtCC-mediated responses in motor thalamus were activated at more hyperpolarized potentials and caused larger depolarizations with more spikes than in visual and auditory thalamus. Somatosensory thalamus is known to be more closely connected to motor regions relative to auditory and visual thalamus, and likewise the strength of its TtCC responses was intermediate between these regions and motor thalamus. We also observed lower input resistance, as well as limited evidence of stronger hyperpolarization-induced ('H-type') depolarization, in nuclei closer to motor output. These findings support our theory of a specific difference between sensory and motor neurons at the cellular level.

Control of neuronal polarity and plasticity--a renaissance for microtubules?

PubMed

Hoogenraad, Casper C; Bradke, Frank

2009-12-01

Microtubules have been regarded as essential structures for stable neuronal morphology but new studies are highlighting their role in dynamic neuronal processes. Recent work demonstrates that the microtubule cytoskeleton has an active role during different phases of neuronal polarization - microtubules and their stability determine axon formation, they maintain the identity of axons and they regulate the dynamics of dendritic spines, the major sites of excitatory synaptic input. Although microtubules fulfill distinct cellular functions at different developmental stages, the underlying molecular mechanisms are remarkably similar. Reccurring themes are that microtubules direct specific membrane traffic and affect actin dynamics to locally organize axon growth and spine dynamics. We review the novel role of microtubules during neuronal development and discuss models for microtubule-dependent signaling in neuronal plasticity.

Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase

PubMed Central

Qiu, Shenfeng; Anderson, Charles T.; Levitt, Pat; Shepherd, Gordon M. G.

2011-01-01

Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium derived, conditional knockout (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes this pathway was stronger by a factor of ~2. This increase was both sub-layer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B, and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk. PMID:21490227

Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.

PubMed

Qiu, Shenfeng; Anderson, Charles T; Levitt, Pat; Shepherd, Gordon M G

2011-04-13

Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium-derived, conditional knock-out (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes, this pathway was stronger by a factor of approximately 2. This increase was both sublayer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk.

Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping.

PubMed

Beier, Kevin T; Steinberg, Elizabeth E; DeLoach, Katherine E; Xie, Stanley; Miyamichi, Kazunari; Schwarz, Lindsay; Gao, Xiaojing J; Kremer, Eric J; Malenka, Robert C; Luo, Liqun

2015-07-30

Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) integrate complex inputs to encode multiple signals that influence motivated behaviors via diverse projections. Here, we combine axon-initiated viral transduction with rabies-mediated trans-synaptic tracing and Cre-based cell-type-specific targeting to systematically map input-output relationships of VTA-DA neurons. We found that VTA-DA (and VTA-GABA) neurons receive excitatory, inhibitory, and modulatory input from diverse sources. VTA-DA neurons projecting to different forebrain regions exhibit specific biases in their input selection. VTA-DA neurons projecting to lateral and medial nucleus accumbens innervate largely non-overlapping striatal targets, with the latter also sending extensive extra-striatal axon collaterals. Using electrophysiology and behavior, we validated new circuits identified in our tracing studies, including a previously unappreciated top-down reinforcing circuit from anterior cortex to lateral nucleus accumbens via VTA-DA neurons. This study highlights the utility of our viral-genetic tracing strategies to elucidate the complex neural substrates that underlie motivated behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Influence of asymmetric attenuation of single and paired dendritic inputs on summation of synaptic potentials and initiation of action potentials.

PubMed

Fortier, Pierre A; Bray, Chelsea

2013-04-16

Previous studies revealed mechanisms of dendritic inputs leading to action potential initiation at the axon initial segment and backpropagation into the dendritic tree. This interest has recently expanded toward the communication between different parts of the dendritic tree which could preprocess information before reaching the soma. This study tested for effects of asymmetric voltage attenuation between different sites in the dendritic tree on summation of synaptic inputs and action potential initiation using the NEURON simulation environment. Passive responses due to the electrical equivalent circuit of the three-dimensional neuron architecture with leak channels were examined first, followed by the responses after adding voltage-gated channels and finally synaptic noise. Asymmetric attenuation of voltage, which is a function of asymmetric input resistance, was seen between all pairs of dendritic sites but the transfer voltages (voltage recorded at the opposite site from stimulation among a pair of dendritic sites) were equal and also summed linearly with local voltage responses during simultaneous stimulation of both sites. In neurons with voltage-gated channels, we reproduced the observations where a brief stimulus to the proximal ascending dendritic branch of a pyramidal cell triggers a local action potential but a long stimulus triggers a somal action potential. Combined stimulation of a pair of sites in this proximal dendrite did not alter this pattern. The attraction of the action potential onset toward the soma with a long stimulus in the absence of noise was due to the higher density of voltage-gated sodium channels at the axon initial segment. This attraction was, however, negligible at the most remote distal dendritic sites and was replaced by an effect due to high input resistance. Action potential onset occurred at the dendritic site of higher input resistance among a pair of remote dendritic sites, irrespective of which of these two sites received the synaptic input. Exploration of the parameter space showed how the gradient of voltage-gated channel densities and input resistances along a dendrite could draw the action potential onset away from the stimulation site. The attraction of action potential onset toward the higher density of voltage-gated channels in the soma during stimulation of the proximal dendrite was, however, reduced after the addition of synaptic noise. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons.

PubMed

Hight, Ariel E; Kalluri, Radha

2016-08-01

The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182-187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41-51, 1986). Kalluri et al. (J Neurophysiol 104: 2034-2051, 2010) proposed that regularity is controlled by the density of low-voltage-activated potassium currents (IKL). To examine the impact of IKL on spike timing regularity, we implemented a single-compartment model with three conductances known to be present in the vestibular ganglion: transient sodium (gNa), low-voltage-activated potassium (gKL), and high-voltage-activated potassium (gKH). Consistent with in vitro observations, removing gKL depolarized resting potential, increased input resistance and membrane time constant, and converted current step-evoked firing patterns from transient (1 spike at current onset) to sustained (many spikes). Modeled neurons were driven with a time-varying synaptic conductance that captured the random arrival times and amplitudes of glutamate-driven synaptic events. In the presence of gKL, spiking occurred only in response to large events with fast onsets. Models without gKL exhibited greater integration by responding to the superposition of rapidly arriving events. Three synaptic conductance were modeled, each with different kinetics to represent a variety of different synaptic processes. In response to all three types of synaptic conductance, models containing gKL produced spike trains with irregular interspike intervals. Only models lacking gKL when driven by rapidly arriving small excitatory postsynaptic currents were capable of generating regular spiking. Copyright © 2016 the American Physiological Society.

Schizophrenia-Related Microdeletion Impairs Emotional Memory through MicroRNA-Dependent Disruption of Thalamic Inputs to the Amygdala.

PubMed

Eom, Tae-Yeon; Bayazitov, Ildar T; Anderson, Kara; Yu, Jing; Zakharenko, Stanislav S

2017-05-23

Individuals with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing psychiatric diseases such as schizophrenia. Individuals with 22q11DS and schizophrenia are impaired in emotional memory, anticipating, recalling, and assigning a correct context to emotions. The neuronal circuits responsible for these emotional memory deficits are unknown. Here, we show that 22q11DS mouse models have disrupted synaptic transmission at thalamic inputs to the lateral amygdala (thalamo-LA projections). This synaptic deficit is caused by haploinsufficiency of the 22q11DS gene Dgcr8, which is involved in microRNA processing, and is mediated by the increased dopamine receptor Drd2 levels in the thalamus and by reduced probability of glutamate release from thalamic inputs. This deficit in thalamo-LA synaptic transmission is sufficient to cause fear memory deficits. Our results suggest that dysregulation of the Dgcr8-Drd2 mechanism at thalamic inputs to the amygdala underlies emotional memory deficits in 22q11DS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Preparation of Horizontal Slices of Adult Mouse Retina for Electrophysiological Studies.

PubMed

Feigenspan, Andreas; Babai, Norbert Zsolt

2017-01-27

Vertical slice preparations are well established to study circuitry and signal transmission in the adult mammalian retina. The plane of sectioning in these preparations is perpendicular to the retinal surface, making it ideal for the study of radially oriented neurons like photoreceptors and bipolar cells. However, the large dendritic arbors of horizontal cells, wide-field amacrine cells, and ganglion cells are mostly truncated, leaving markedly reduced synaptic activity in these cells. Whereas ganglion cells and displaced amacrine cells can be studied in a whole-mounted preparation of the retina, horizontal cells and amacrine cells located in the inner nuclear layer are only poorly accessible for electrodes in whole retina tissue. To achieve maximum accessibility and synaptic integrity, we developed a horizontal slice preparation of the mouse retina, and studied signal transmission at the synapse between photoreceptors and horizontal cells. Horizontal sectioning allows (1) easy and unambiguous visual identification of horizontal cell bodies for electrode targeting, and (2) preservation of the extended horizontal cell dendritic fields, as a prerequisite for intact and functional cone synaptic input to horizontal cell dendrites. Horizontal cells from horizontal slices exhibited tonic synaptic activity in the dark, and they responded to brief flashes of light with a reduction of inward current and diminished synaptic activity. Immunocytochemical evidence indicates that almost all cones within the dendritic field of a horizontal cell establish synapses with its peripheral dendrites. The horizontal slice preparation is therefore well suited to study the physiological properties of horizontally extended retinal neurons as well as sensory signal transmission and integration across selected synapses.

The Plasminogen Activation System Promotes Dendritic Spine Recovery and Improvement in Neurological Function After an Ischemic Stroke

PubMed Central

Jeanneret, Valerie; Yepes, Manuel

2016-01-01

Advances in neurocritical care and interventional neuroradiology have led to a significant decrease in acute ischemic stroke (AIS) mortality. In contrast, due to the lack of an effective therapeutic strategy to promote neuronal recovery among AIS survivors, cerebral ischemia is still a leading cause of disability in the world. Ischemic stroke has a harmful impact on synaptic structure and function, and plasticity-mediated synaptic recovery is associated with neurological improvement following an AIS. Dendritic spines (DSs) are specialized dendritic protrusions that receive most of the excitatory input in the brain. The deleterious effect of cerebral ischemia on DSs morphology and function has been associated with impaired synaptic transmission and neurological deterioration. However, these changes are reversible if cerebral blood flow is restored on time, and this recovery has been associated with neurological improvement following an AIS. Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are two serine proteases that besides catalyzing the conversion of plasminogen into plasmin in the intravascular and pericellular environment, respectively, are also are efficient inductors of synaptic plasticity. Accordingly, recent evidence indicates that both, tPA and uPA, protect DSs from the metabolic stress associated with the ischemic injury, and promote their morphological and functional recovery during the recovery phase from an AIS. Here we will review data indicating that plasticity-induced changes in DSs and the associated post-synaptic density play a pivotal role in the recovery process from AIS, making special emphasis on the role of tPA and uPA in this process. PMID:26846991

In vivo voltage-dependent influences on summation of synaptic potentials in neurons of the lateral nucleus of the amygdala

PubMed Central

Rosenkranz, J. Amiel

2012-01-01

The amygdala has a fundamental role in driving affective behaviors in response to sensory cues. To accomplish this, neurons of the lateral nucleus (LAT) must integrate a large number of synaptic inputs. A wide range of factors influence synaptic integration, including membrane potential, voltage-gated ion channels and GABAergic inhibition. However, little is known about how these factors modulate integration of synaptic inputs in LAT neurons in vivo. The purpose of this study was to determine the voltage-dependent factors that modify in vivo integration of synaptic inputs in the soma of LAT neurons. In vivo intracellular recordings from anesthetized rats were used to measure post-synaptic potentials (PSPs) and clusters of PSPs across a range of membrane potentials. These studies found that the relationship between membrane potential and PSP clusters was sublinear, due to a reduction of cluster amplitude and area at depolarized membrane potentials. In combination with intracellular delivery of pharmacological agents, it was found that the voltage-dependent suppression of PSP clusters was sensitive to tetraethylammonium (TEA), but not cesium or a blocker of fast GABAergic inhibition. These findings indicate that integration of PSPs in LAT neurons in vivo is strongly modified by somatic membrane potential, likely through voltage-dependent TEA-sensitive potassium channels. Conditions that lead to a shift in membrane potential, or a modulation of the number or function of these ion channels will lead to a more uniform capacity for integration across voltages, and perhaps greatly facilitate amygdala-dependent behaviors. PMID:22989917

Regulation of C. elegans presynaptic differentiation and neurite branching via a novel signaling pathway initiated by SAM-10

PubMed Central

Zheng, Qun; Schaefer, Anneliese M.; Nonet, Michael L.

2011-01-01

Little is known about transcriptional control of neurite branching or presynaptic differentiation, events that occur relatively late in neuronal development. Using the Caenorhabditis elegans mechanosensory circuit as an in vivo model, we show that SAM-10, an ortholog of mammalian single-stranded DNA-binding protein (SSDP), functions cell-autonomously in the nucleus to regulate synaptic differentiation, as well as positioning of, a single neurite branch. PLM mechanosensory neurons in sam-10 mutants exhibit abnormal placement of the neurite branch point, and defective synaptogenesis, characterized by an overextended synaptic varicosity, underdeveloped synaptic morphology and disrupted colocalization of active zone and synaptic vesicles. SAM-10 functions coordinately with Lim domain-binding protein 1 (LDB-1), demonstrated by our observations that: (1) mutations in either gene show similar defects in PLM neurons; and (2) LDB-1 is required for SAM-10 nuclear localization. SAM-10 regulates PLM synaptic differentiation by suppressing transcription of prk-2, which encodes an ortholog of the mammalian Pim kinase family. PRK-2-mediated activities of SAM-10 are specifically involved in PLM synaptic differentiation, but not other sam-10 phenotypes such as neurite branching. Thus, these data reveal a novel transcriptional signaling pathway that regulates neuronal specification of neurite branching and presynaptic differentiation. PMID:21115607

Regulation of C. elegans presynaptic differentiation and neurite branching via a novel signaling pathway initiated by SAM-10.

PubMed

Zheng, Qun; Schaefer, Anneliese M; Nonet, Michael L

2011-01-01

Little is known about transcriptional control of neurite branching or presynaptic differentiation, events that occur relatively late in neuronal development. Using the Caenorhabditis elegans mechanosensory circuit as an in vivo model, we show that SAM-10, an ortholog of mammalian single-stranded DNA-binding protein (SSDP), functions cell-autonomously in the nucleus to regulate synaptic differentiation, as well as positioning of, a single neurite branch. PLM mechanosensory neurons in sam-10 mutants exhibit abnormal placement of the neurite branch point, and defective synaptogenesis, characterized by an overextended synaptic varicosity, underdeveloped synaptic morphology and disrupted colocalization of active zone and synaptic vesicles. SAM-10 functions coordinately with Lim domain-binding protein 1 (LDB-1), demonstrated by our observations that: (1) mutations in either gene show similar defects in PLM neurons; and (2) LDB-1 is required for SAM-10 nuclear localization. SAM-10 regulates PLM synaptic differentiation by suppressing transcription of prk-2, which encodes an ortholog of the mammalian Pim kinase family. PRK-2-mediated activities of SAM-10 are specifically involved in PLM synaptic differentiation, but not other sam-10 phenotypes such as neurite branching. Thus, these data reveal a novel transcriptional signaling pathway that regulates neuronal specification of neurite branching and presynaptic differentiation.

Acute pancreatitis decreases the sensitivity of pancreas-projecting dorsal motor nucleus of the vagus neurones to group II metabotropic glutamate receptor agonists in rats

PubMed Central

Babic, Tanja; Travagli, R Alberto

2014-01-01

Recent studies have shown that pancreatic exocrine secretions (PES) are modulated by dorsal motor nucleus of the vagus (DMV) neurones, whose activity is finely tuned by GABAergic and glutamatergic synaptic inputs. Group II metabotropic glutamate receptors (mGluR) decrease synaptic transmission to pancreas-projecting DMV neurones and increase PES. In the present study, we used a combination of in vivo and in vitro approaches aimed at characterising the effects of caerulein-induced acute pancreatitis (AP) on the vagal neurocircuitry modulating pancreatic functions. In control rats, microinjection of bicuculline into the DMV increased PES, whereas microinjections of kynurenic acid had no effect. Conversely, in AP rats, microinjection of bicuculline had no effect, whereas kynurenic acid decreased PES. DMV microinjections of the group II mGluR agonist APDC and whole cell recordings of excitatory currents in identified pancreas-projecting DMV neurones showed a reduced functional response in AP rats compared to controls. Moreover, these changes persisted up to 3 weeks following the induction of AP. These data demonstrate that AP increases the excitatory input to pancreas-projecting DMV neurones by decreasing the response of excitatory synaptic terminals to group II mGluR agonist. PMID:24445314

Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking.

PubMed

Heinsbroek, Jasper A; Neuhofer, Daniela N; Griffin, William C; Siegel, Griffin S; Bobadilla, Ana-Clara; Kupchik, Yonatan M; Kalivas, Peter W

2017-01-25

Distinct populations of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accumbens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1- and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1- or D2-MSNs. Because D1- and D2-MSNs innervate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1- versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A μ opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic μ opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTD GABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking. More than 90% of ventral striatum is composed of two cell types, those expressing dopamine D1 or D2 receptors, which exert opposing roles on motivated behavior. Both cell types send GABAergic projections to the ventral pallidum and were found to differentially promote cue-induced reinstatement of cocaine seeking via the ventral pallidum. Furthermore, after cocaine self-administration, synaptic plasticity was selectively lost in D2, but not D1 inputs to the ventral pallidum. The selective impairment in D2 afferents may promote the influence of D1 inputs to drive relapse to cocaine seeking. Copyright © 2017 the authors 0270-6474/17/370757-11$15.00/0.

Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking

PubMed Central

Neuhofer, Daniela N.; Griffin, William C.; Siegel, Griffin S.; Bobadilla, Ana-Clara; Kupchik, Yonatan M.

2017-01-01

Distinct populations of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accumbens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1- and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1- or D2-MSNs. Because D1- and D2-MSNs innervate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1- versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A μ opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic μ opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTDGABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking. SIGNIFICANCE STATEMENT More than 90% of ventral striatum is composed of two cell types, those expressing dopamine D1 or D2 receptors, which exert opposing roles on motivated behavior. Both cell types send GABAergic projections to the ventral pallidum and were found to differentially promote cue-induced reinstatement of cocaine seeking via the ventral pallidum. Furthermore, after cocaine self-administration, synaptic plasticity was selectively lost in D2, but not D1 inputs to the ventral pallidum. The selective impairment in D2 afferents may promote the influence of D1 inputs to drive relapse to cocaine seeking. PMID:28123013

Synaptic dynamics contribute to long-term single neuron response fluctuations.

PubMed

Reinartz, Sebastian; Biro, Istvan; Gal, Asaf; Giugliano, Michele; Marom, Shimon

2014-01-01

Firing rate variability at the single neuron level is characterized by long-memory processes and complex statistics over a wide range of time scales (from milliseconds up to several hours). Here, we focus on the contribution of non-stationary efficacy of the ensemble of synapses-activated in response to a given stimulus-on single neuron response variability. We present and validate a method tailored for controlled and specific long-term activation of a single cortical neuron in vitro via synaptic or antidromic stimulation, enabling a clear separation between two determinants of neuronal response variability: membrane excitability dynamics vs. synaptic dynamics. Applying this method we show that, within the range of physiological activation frequencies, the synaptic ensemble of a given neuron is a key contributor to the neuronal response variability, long-memory processes and complex statistics observed over extended time scales. Synaptic transmission dynamics impact on response variability in stimulation rates that are substantially lower compared to stimulation rates that drive excitability resources to fluctuate. Implications to network embedded neurons are discussed.

Reorganization of Learning-Associated Prefrontal Synaptic Plasticity between the Recall of Recent and Remote Fear Extinction Memory

ERIC Educational Resources Information Center

Hugues, Sandrine; Garcia, Rene

2007-01-01

We have previously shown that fear extinction is accompanied by an increase of synaptic efficacy in inputs from the ventral hippocampus (vHPC) and mediodorsal thalamus (MD) to the medial prefrontal cortex (mPFC) and that disrupting these changes to mPFC synaptic transmission compromises extinction processes. The aim of this study was to examine…

Response of integrate-and-fire neurons to noisy inputs filtered by synapses with arbitrary timescales: firing rate and correlations.

PubMed

Moreno-Bote, Rubén; Parga, Néstor

2010-06-01

Delivery of neurotransmitter produces on a synapse a current that flows through the membrane and gets transmitted into the soma of the neuron, where it is integrated. The decay time of the current depends on the synaptic receptor's type and ranges from a few (e.g., AMPA receptors) to a few hundred milliseconds (e.g., NMDA receptors). The role of the variety of synaptic timescales, several of them coexisting in the same neuron, is at present not understood. A prime question to answer is which is the effect of temporal filtering at different timescales of the incoming spike trains on the neuron's response. Here, based on our previous work on linear synaptic filtering, we build a general theory for the stationary firing response of integrate-and-fire (IF) neurons receiving stochastic inputs filtered by one, two, or multiple synaptic channels, each characterized by an arbitrary timescale. The formalism applies to arbitrary IF model neurons and arbitrary forms of input noise (i.e., not required to be gaussian or to have small amplitude), as well as to any form of synaptic filtering (linear or nonlinear). The theory determines with exact analytical expressions the firing rate of an IF neuron for long synaptic time constants using the adiabatic approach. The correlated spiking (cross-correlations function) of two neurons receiving common as well as independent sources of noise is also described. The theory is illustrated using leaky, quadratic, and noise-thresholded IF neurons. Although the adiabatic approach is exact when at least one of the synaptic timescales is long, it provides a good prediction of the firing rate even when the timescales of the synapses are comparable to that of the leak of the neuron; it is not required that the synaptic time constants are longer than the mean interspike intervals or that the noise has small variance. The distribution of the potential for general IF neurons is also characterized. Our results provide powerful analytical tools that can allow a quantitative description of the dynamics of neuronal networks with realistic synaptic dynamics.

Learning place cells, grid cells and invariances with excitatory and inhibitory plasticity

PubMed Central

2018-01-01

Neurons in the hippocampus and adjacent brain areas show a large diversity in their tuning to location and head direction, and the underlying circuit mechanisms are not yet resolved. In particular, it is unclear why certain cell types are selective to one spatial variable, but invariant to another. For example, place cells are typically invariant to head direction. We propose that all observed spatial tuning patterns – in both their selectivity and their invariance – arise from the same mechanism: Excitatory and inhibitory synaptic plasticity driven by the spatial tuning statistics of synaptic inputs. Using simulations and a mathematical analysis, we show that combined excitatory and inhibitory plasticity can lead to localized, grid-like or invariant activity. Combinations of different input statistics along different spatial dimensions reproduce all major spatial tuning patterns observed in rodents. Our proposed model is robust to changes in parameters, develops patterns on behavioral timescales and makes distinctive experimental predictions. PMID:29465399

Endogenous GABA and Glutamate Finely Tune the Bursting of Olfactory Bulb External Tufted Cells

PubMed Central

Hayar, Abdallah; Ennis, Matthew

2008-01-01

In rat olfactory bulb slices, external tufted (ET) cells spontaneously generate spike bursts. Although ET cell bursting is intrinsically generated, its strength and precise timing may be regulated by synaptic input. We tested this hypothesis by analyzing whether the burst properties are modulated by activation of ionotropic γ-aminobutyric acid (GABA) and glutamate receptors. Blocking GABAA receptors increased—whereas blocking ionotropic glutamate receptors decreased—the number of spikes/burst without changing the interburst frequency. The GABAA agonist (isoguvacine, 10 μM) completely inhibited bursting or reduced the number of spikes/burst, suggesting a shunting effect. These findings indicate that the properties of ET cell spontaneous bursting are differentially controlled by GABAergic and glutamatergic fast synaptic transmission. We suggest that ET cell excitatory and inhibitory inputs may be encoded as a change in the pattern of spike bursting in ET cells, which together with mitral/tufted cells constitute the output circuit of the olfactory bulb. PMID:17567771

Endogenous GABA and glutamate finely tune the bursting of olfactory bulb external tufted cells.

PubMed

Hayar, Abdallah; Ennis, Matthew

2007-08-01

In rat olfactory bulb slices, external tufted (ET) cells spontaneously generate spike bursts. Although ET cell bursting is intrinsically generated, its strength and precise timing may be regulated by synaptic input. We tested this hypothesis by analyzing whether the burst properties are modulated by activation of ionotropic gamma-aminobutyric acid (GABA) and glutamate receptors. Blocking GABA(A) receptors increased--whereas blocking ionotropic glutamate receptors decreased--the number of spikes/burst without changing the interburst frequency. The GABA(A) agonist (isoguvacine, 10 microM) completely inhibited bursting or reduced the number of spikes/burst, suggesting a shunting effect. These findings indicate that the properties of ET cell spontaneous bursting are differentially controlled by GABAergic and glutamatergic fast synaptic transmission. We suggest that ET cell excitatory and inhibitory inputs may be encoded as a change in the pattern of spike bursting in ET cells, which together with mitral/tufted cells constitute the output circuit of the olfactory bulb.

pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract

PubMed Central

McCrimmon, Donald R.; Martina, Marco

2013-01-01

The nucleus of the solitary tract (NTS) is the major site for termination of visceral sensory afferents contributing to homeostatic regulation of, for example, arterial pressure, gastric motility, and breathing. Whereas much is known about how different neuronal populations influence these functions, information about the role of glia remains scant. In this article, we propose that glia may contribute to NTS functions by modulating excitatory neurotransmission. We found that acidification (pH 7.0) depolarizes NTS glia by inhibiting K+-selective membrane currents. NTS glia also showed functional expression of voltage-sensitive glutamate transporters, suggesting that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake. To test this hypothesis, we evoked glutamatergic slow excitatory potentials (SEPs) in NTS neurons with repetitive stimulation (20 pulses at 10 Hz) of the solitary tract. This SEP depends on accumulation of glutamate following repetitive stimulation, since it was potentiated by blocking glutamate uptake with dl-threo-β-benzyloxyaspartic acid (TBOA) or a glia-specific glutamate transport blocker, dihydrokainate (DHK). Importantly, extracellular acidification (pH 7.0) also potentiated the SEP. This effect appeared to be mediated through a depolarization-induced inhibition of glial transporter activity, because it was occluded by TBOA and DHK. In agreement, pH 7.0 did not directly alter d-aspartate-induced responses in NTS glia or properties of presynaptic glutamate release. Thus acidification-dependent regulation of glial function affects synaptic transmission within the NTS. These results suggest that glia play a modulatory role in the NTS by integrating local tissue signals (such as pH) with synaptic inputs from peripheral afferents. PMID:23615553

The A-Current Modulates Learning via NMDA Receptors Containing the NR2B Subunit

PubMed Central

Fontán-Lozano, Ángela; Suárez-Pereira, Irene; González-Forero, David; Carrión, Ángel Manuel

2011-01-01

Synaptic plasticity involves short- and long-term events, although the molecular mechanisms that underlie these processes are not fully understood. The transient A-type K+ current (IA) controls the excitability of the dendrites from CA1 pyramidal neurons by regulating the back-propagation of action potentials and shaping synaptic input. Here, we have studied how decreases in IA affect cognitive processes and synaptic plasticity. Using wild-type mice treated with 4-AP, an IA inhibitor, and mice lacking the DREAM protein, a transcriptional repressor and modulator of the IA, we demonstrate that impairment of IA decreases the stimulation threshold for learning and the induction of early-LTP. Hippocampal electrical recordings in both models revealed alterations in basal electrical oscillatory properties toward low-theta frequencies. In addition, we demonstrated that the facilitated learning induced by decreased IA requires the activation of NMDA receptors containing the NR2B subunit. Together, these findings point to a balance between the IA and the activity of NR2B-containing NMDA receptors in the regulation of learning. PMID:21966384

Neuronal activity in the isolated mouse spinal cord during spontaneous deletions in fictive locomotion: insights into locomotor central pattern generator organization

PubMed Central

Zhong, Guisheng; Shevtsova, Natalia A; Rybak, Ilya A; Harris-Warrick, Ronald M

2012-01-01

We explored the organization of the spinal central pattern generator (CPG) for locomotion by analysing the activity of spinal interneurons and motoneurons during spontaneous deletions occurring during fictive locomotion in the isolated neonatal mouse spinal cord, following earlier work on locomotor deletions in the cat. In the isolated mouse spinal cord, most spontaneous deletions were non-resetting, with rhythmic activity resuming after an integer number of cycles. Flexor and extensor deletions showed marked asymmetry: flexor deletions were accompanied by sustained ipsilateral extensor activity, whereas rhythmic flexor bursting was not perturbed during extensor deletions. Rhythmic activity on one side of the cord was not perturbed during non-resetting spontaneous deletions on the other side, and these deletions could occur with no input from the other side of the cord. These results suggest that the locomotor CPG has a two-level organization with rhythm-generating (RG) and pattern-forming (PF) networks, in which only the flexor RG network is intrinsically rhythmic. To further explore the neuronal organization of the CPG, we monitored activity of motoneurons and selected identified interneurons during spontaneous non-resetting deletions. Motoneurons lost rhythmic synaptic drive during ipsilateral deletions. Flexor-related commissural interneurons continued to fire rhythmically during non-resetting ipsilateral flexor deletions. Deletion analysis revealed two classes of rhythmic V2a interneurons. Type I V2a interneurons retained rhythmic synaptic drive and firing during ipsilateral motor deletions, while type II V2a interneurons lost rhythmic synaptic input and fell silent during deletions. This suggests that the type I neurons are components of the RG, whereas the type II neurons are components of the PF network. We propose a computational model of the spinal locomotor CPG that reproduces our experimental results. The results may provide novel insights into the organization of spinal locomotor networks. PMID:22869012

Neuroligin-1 links neuronal activity to sleep-wake regulation.

PubMed

El Helou, Janine; Bélanger-Nelson, Erika; Freyburger, Marlène; Dorsaz, Stéphane; Curie, Thomas; La Spada, Francesco; Gaudreault, Pierre-Olivier; Beaumont, Éric; Pouliot, Philippe; Lesage, Frédéric; Frank, Marcos G; Franken, Paul; Mongrain, Valérie

2013-06-11

Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-d-aspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strain-specific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation.

Neuroligin-1 links neuronal activity to sleep-wake regulation

PubMed Central

El Helou, Janine; Bélanger-Nelson, Erika; Freyburger, Marlène; Dorsaz, Stéphane; Curie, Thomas; La Spada, Francesco; Gaudreault, Pierre-Olivier; Beaumont, Éric; Pouliot, Philippe; Lesage, Frédéric; Frank, Marcos G.; Franken, Paul; Mongrain, Valérie

2013-01-01

Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-d-aspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strain-specific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation. PMID:23716671

Somatostatin-Expressing Inhibitory Interneurons in Cortical Circuits

PubMed Central

Yavorska, Iryna; Wehr, Michael

2016-01-01

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. PMID:27746722

A neuronal model of predictive coding accounting for the mismatch negativity.

PubMed

Wacongne, Catherine; Changeux, Jean-Pierre; Dehaene, Stanislas

2012-03-14

The mismatch negativity (MMN) is thought to index the activation of specialized neural networks for active prediction and deviance detection. However, a detailed neuronal model of the neurobiological mechanisms underlying the MMN is still lacking, and its computational foundations remain debated. We propose here a detailed neuronal model of auditory cortex, based on predictive coding, that accounts for the critical features of MMN. The model is entirely composed of spiking excitatory and inhibitory neurons interconnected in a layered cortical architecture with distinct input, predictive, and prediction error units. A spike-timing dependent learning rule, relying upon NMDA receptor synaptic transmission, allows the network to adjust its internal predictions and use a memory of the recent past inputs to anticipate on future stimuli based on transition statistics. We demonstrate that this simple architecture can account for the major empirical properties of the MMN. These include a frequency-dependent response to rare deviants, a response to unexpected repeats in alternating sequences (ABABAA…), a lack of consideration of the global sequence context, a response to sound omission, and a sensitivity of the MMN to NMDA receptor antagonists. Novel predictions are presented, and a new magnetoencephalography experiment in healthy human subjects is presented that validates our key hypothesis: the MMN results from active cortical prediction rather than passive synaptic habituation.

Stability versus neuronal specialization for STDP: long-tail weight distributions solve the dilemma.

PubMed

Gilson, Matthieu; Fukai, Tomoki

2011-01-01

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 long-tail weight distributions, log-STDP achieves both stable dynamics for and robust competition of synapses, which are crucial for spike-based information processing.

Effect of ageing and ischemia on enzymatic activities linked to Krebs' cycle, electron transfer chain, glutamate and aminoacids metabolism of free and intrasynaptic mitochondria of cerebral cortex.

PubMed

Villa, Roberto Federico; Gorini, Antonella; Hoyer, Siegfried

2009-12-01

The effect of ageing and the relationships between the catalytic properties of enzymes linked to Krebs' cycle, electron transfer chain, glutamate and aminoacid metabolism of cerebral cortex, a functional area very sensitive to both age and ischemia, were studied on mitochondria of adult and aged rats, after complete ischemia of 15 minutes duration. The maximum rate (Vmax) of the following enzyme activities: citrate synthase, malate dehydrogenase, succinate dehydrogenase for Krebs' cycle; NADH-cytochrome c reductase as total (integrated activity of Complex I-III), rotenone sensitive (Complex I) and cytochrome oxidase (Complex IV) for electron transfer chain; glutamate dehydrogenase, glutamate-oxaloacetate-and glutamate-pyruvate transaminases for glutamate metabolism were assayed in non-synaptic, perikaryal mitochondria and in two populations of intra-synaptic mitochondria, i.e., the light and heavy mitochondrial fraction. The results indicate that in normal, steady-state cerebral cortex, the value of the same enzyme activity markedly differs according (a) to the different populations of mitochondria, i.e., non-synaptic or intra-synaptic light and heavy, (b) and respect to ageing. After 15 min of complete ischemia, the enzyme activities of mitochondria located near the nucleus (perikaryal mitochondria) and in synaptic structures (intra-synaptic mitochondria) of the cerebral tissue were substantially modified by ischemia. Non-synaptic mitochondria seem to be more affected by ischemia in adult and particularly in aged animals than the intra-synaptic light and heavy mitochondria. The observed modifications in enzyme activities reflect the metabolic state of the tissue at each specific experimental condition, as shown by comparative evaluation with respect to the content of energy-linked metabolites and substrates. The derangements in enzyme activities due to ischemia is greater in aged than in adult animals and especially the non-synaptic and the intra-synaptic light mitochondria seems to be more affected in aged animals. These data allow the hypothesis that the observed modifications of catalytic activities in non-synaptic and intra-synaptic mitochondrial enzyme systems linked to energy metabolism, amino acids and glutamate metabolism are primary responsible for the physiopathological responses of cerebral tissue to complete cerebral ischemia for 15 min duration during ageing.

Generation of dense statistical connectomes from sparse morphological data

PubMed Central

Egger, Robert; Dercksen, Vincent J.; Udvary, Daniel; Hege, Hans-Christian; Oberlaender, Marcel

2014-01-01

Sensory-evoked signal flow, at cellular and network levels, is primarily determined by the synaptic wiring of the underlying neuronal circuitry. Measurements of synaptic innervation, connection probabilities and subcellular organization of synaptic inputs are thus among the most active fields of research in contemporary neuroscience. Methods to measure these quantities range from electrophysiological recordings over reconstructions of dendrite-axon overlap at light-microscopic levels to dense circuit reconstructions of small volumes at electron-microscopic resolution. However, quantitative and complete measurements at subcellular resolution and mesoscopic scales to obtain all local and long-range synaptic in/outputs for any neuron within an entire brain region are beyond present methodological limits. Here, we present a novel concept, implemented within an interactive software environment called NeuroNet, which allows (i) integration of sparsely sampled (sub)cellular morphological data into an accurate anatomical reference frame of the brain region(s) of interest, (ii) up-scaling to generate an average dense model of the neuronal circuitry within the respective brain region(s) and (iii) statistical measurements of synaptic innervation between all neurons within the model. We illustrate our approach by generating a dense average model of the entire rat vibrissal cortex, providing the required anatomical data, and illustrate how to measure synaptic innervation statistically. Comparing our results with data from paired recordings in vitro and in vivo, as well as with reconstructions of synaptic contact sites at light- and electron-microscopic levels, we find that our in silico measurements are in line with previous results. PMID:25426033

Opposite monosynaptic scaling of BLP–vCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory

PubMed Central

Yang, Ying; Wang, Zhi-Hao; Jin, Sen; Gao, Di; Liu, Nan; Chen, Shan-Ping; Zhang, Sinan; Liu, Qing; Liu, Enjie; Wang, Xin; Liang, Xiao; Wei, Pengfei; Li, Xiaoguang; Li, Yin; Yue, Chenyu; Li, Hong-lian; Wang, Ya-Li; Wang, Qun; Ke, Dan; Xie, Qingguo; Xu, Fuqiang; Wang, Liping; Wang, Jian-Zhi

2016-01-01

Different emotional states lead to distinct behavioural consequences even when faced with the same challenging events. Emotions affect learning and memory capacities, but the underlying neurobiological mechanisms remain elusive. Here we establish models of learned helplessness (LHL) and learned hopefulness (LHF) by exposing animals to inescapable foot shocks or with anticipated avoidance trainings. The LHF animals show spatial memory potentiation with excitatory monosynaptic upscaling between posterior basolateral amygdale (BLP) and ventral hippocampal CA1 (vCA1), whereas the LHL show memory deficits with an attenuated BLP–vCA1 connection. Optogenetic disruption of BLP–vCA1 inputs abolishes the effects of LHF and impairs synaptic plasticity. By contrast, targeted BLP–vCA1 stimulation rescues the LHL-induced memory deficits and mimics the effects of LHF. BLP–vCA1 stimulation increases synaptic transmission and dendritic plasticity with the upregulation of CREB and intrasynaptic AMPA receptors in CA1. These findings indicate that opposite excitatory monosynaptic scaling of BLP–vCA1 controls LHF- and LHL-modulated spatial memory, revealing circuit-specific mechanisms linking emotions to memory. PMID:27411738

Opposite monosynaptic scaling of BLP-vCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory.

PubMed

Yang, Ying; Wang, Zhi-Hao; Jin, Sen; Gao, Di; Liu, Nan; Chen, Shan-Ping; Zhang, Sinan; Liu, Qing; Liu, Enjie; Wang, Xin; Liang, Xiao; Wei, Pengfei; Li, Xiaoguang; Li, Yin; Yue, Chenyu; Li, Hong-Lian; Wang, Ya-Li; Wang, Qun; Ke, Dan; Xie, Qingguo; Xu, Fuqiang; Wang, Liping; Wang, Jian-Zhi

2016-07-14

Different emotional states lead to distinct behavioural consequences even when faced with the same challenging events. Emotions affect learning and memory capacities, but the underlying neurobiological mechanisms remain elusive. Here we establish models of learned helplessness (LHL) and learned hopefulness (LHF) by exposing animals to inescapable foot shocks or with anticipated avoidance trainings. The LHF animals show spatial memory potentiation with excitatory monosynaptic upscaling between posterior basolateral amygdale (BLP) and ventral hippocampal CA1 (vCA1), whereas the LHL show memory deficits with an attenuated BLP-vCA1 connection. Optogenetic disruption of BLP-vCA1 inputs abolishes the effects of LHF and impairs synaptic plasticity. By contrast, targeted BLP-vCA1 stimulation rescues the LHL-induced memory deficits and mimics the effects of LHF. BLP-vCA1 stimulation increases synaptic transmission and dendritic plasticity with the upregulation of CREB and intrasynaptic AMPA receptors in CA1. These findings indicate that opposite excitatory monosynaptic scaling of BLP-vCA1 controls LHF- and LHL-modulated spatial memory, revealing circuit-specific mechanisms linking emotions to memory.

Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

PubMed

Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

2012-06-20

The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

Dendritic Na+ spikes enable cortical input to drive action potential output from hippocampal CA2 pyramidal neurons

PubMed Central

Sun, Qian; Srinivas, Kalyan V; Sotayo, Alaba; Siegelbaum, Steven A

2014-01-01

Synaptic inputs from different brain areas are often targeted to distinct regions of neuronal dendritic arbors. Inputs to proximal dendrites usually produce large somatic EPSPs that efficiently trigger action potential (AP) output, whereas inputs to distal dendrites are greatly attenuated and may largely modulate AP output. In contrast to most other cortical and hippocampal neurons, hippocampal CA2 pyramidal neurons show unusually strong excitation by their distal dendritic inputs from entorhinal cortex (EC). In this study, we demonstrate that the ability of these EC inputs to drive CA2 AP output requires the firing of local dendritic Na+ spikes. Furthermore, we find that CA2 dendritic geometry contributes to the efficient coupling of dendritic Na+ spikes to AP output. These results provide a striking example of how dendritic spikes enable direct cortical inputs to overcome unfavorable distal synaptic locale to trigger axonal AP output and thereby enable efficient cortico-hippocampal information flow. DOI: http://dx.doi.org/10.7554/eLife.04551.001 PMID:25390033

Common input to motor units of intrinsic and extrinsic hand muscles during two-digit object hold.

PubMed

Winges, Sara A; Kornatz, Kurt W; Santello, Marco

2008-03-01

Anatomical and physiological evidence suggests that common input to motor neurons of hand muscles is an important neural mechanism for hand control. To gain insight into the synaptic input underlying the coordination of hand muscles, significant effort has been devoted to describing the distribution of common input across motor units of extrinsic muscles. Much less is known, however, about the distribution of common input to motor units belonging to different intrinsic muscles and to intrinsic-extrinsic muscle pairs. To address this void in the literature, we quantified the incidence and strength of near-simultaneous discharges of motor units residing in either the same or different intrinsic hand muscles (m. first dorsal, FDI, and m. first palmar interosseus, FPI) during two-digit object hold. To extend the characterization of common input to pairs of extrinsic muscles (previous work) and pairs of intrinsic muscles (present work), we also recorded electromyographic (EMG) activity from an extrinsic thumb muscle (m. flexor pollicis longus, FPL). Motor-unit synchrony across FDI and FPI was weak (common input strength, CIS, mean +/- SE: 0.17 +/- 0.02). Similarly, motor units from extrinsic-intrinsic muscle pairs were characterized by weak synchrony (FPL-FDI: 0.25 +/- 0.02; FPL-FPI: 0.29 +/- 0.03) although stronger than FDI-FPI. Last, CIS from within FDI and FPI was more than three times stronger (0.70 +/- 0.06 and 0.66 +/- 0.06, respectively) than across these muscles. We discuss present and previous findings within the framework of muscle-pair specific distribution of common input to hand muscles based on their functional role in grasping.

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

PubMed

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.

Age-Dependent Modulation of Synaptic Plasticity and Insulin Mimetic Effect of Lipoic Acid on a Mouse Model of Alzheimer’s Disease

PubMed Central

Sancheti, Harsh; Akopian, Garnik; Yin, Fei; Brinton, Roberta D.; Walsh, John P.; Cadenas, Enrique

2013-01-01

Alzheimer’s disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer’s disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer’s disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice. PMID:23875003

Activity-induced synaptic delivery of the GluN2A-containing NMDA receptor is dependent on endoplasmic reticulum chaperone Bip and involved in fear memory

PubMed Central

Zhang, Xiao-min; Yan, Xun-yi; Zhang, Bin; Yang, Qian; Ye, Mao; Cao, Wei; Qiang, Wen-bin; Zhu, Li-jun; Du, Yong-lan; Xu, Xing-xing; Wang, Jia-sheng; Xu, Fei; Lu, Wei; Qiu, Shuang; Yang, Wei; Luo, Jian-hong

2015-01-01

The N-methyl-D-aspartate receptor (NMDAR) in adult forebrain is a heterotetramer mainly composed of two GluN1 subunits and two GluN2A and/or GluN2B subunits. The synaptic expression and relative numbers of GluN2A- and GluN2B-containing NMDARs play critical roles in controlling Ca2+-dependent signaling and synaptic plasticity. Previous studies have suggested that the synaptic trafficking of NMDAR subtypes is differentially regulated, but the precise molecular mechanism is not yet clear. In this study, we demonstrated that Bip, an endoplasmic reticulum (ER) chaperone, selectively interacted with GluN2A and mediated the neuronal activity-induced assembly and synaptic incorporation of the GluN2A-containing NMDAR from dendritic ER. Furthermore, the GluN2A-specific synaptic trafficking was effectively disrupted by peptides interrupting the interaction between Bip and GluN2A. Interestingly, fear conditioning in mice was disrupted by intraperitoneal injection of the interfering peptide before training. In summary, we have uncovered a novel mechanism for the activity-dependent supply of synaptic GluN2A-containing NMDARs, and demonstrated its relevance to memory formation. PMID:26088419

Contributions of identifiable neurons and neuron classes to lamprey vertebrate neurobiology.

PubMed

Buchanan, J T

2001-03-01

Among the advantages offered by the lamprey brainstem and spinal cord for studies of the structure and function of the nervous system is the unique identifiability of several pairs of reticulospinal neurons in the brainstem. These neurons have been exploited in investigations of the patterns of sensory input to these cells and the patterns of their outputs to spinal neurons, but no doubt these cells could be used much more effectively in exploring their roles in descending control of the spinal cord. The variability of cell positions of neurons in the spinal cord has precluded the recognition of unique spinal neurons. However, classes of nerve cells can be readily defined and characterized within the lamprey spinal cord and this has led to progress in understanding the cellular and synaptic mechanisms of locomotor activity. In addition, both the identifiable reticulospinal cells and the various spinal nerve cell classes and their known synaptic interactions have been used to demonstrate the degree and specificity of regeneration within the lamprey nervous system. The lack of uniquely identifiable cells within the lamprey spinal cord has hampered progress in these areas, especially in gaining a full understanding of the locomotor network and how neuromodulation of the network is accomplished.

PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity

PubMed Central

Madeo, G.; Schirinzi, T.; Martella, G.; Latagliata, E.C.; Puglisi, F.; Shen, J.; Valente, E.M.; Federici, M.; Mercuri, N.B.; Puglisi-Allegra, S.; Bonsi, P.; Pisani, A.

2014-01-01

Background Homozygous or compound heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene are causative of autosomal recessive, early onset PD. Single heterozygous mutations have been repeatedly detected in a subset of patients as well as in non-affected subjects, and their significance has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have shown the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. Methods In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1+/−) mice by a multidisciplinary approach. Results We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1+/−, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release. Conclusions Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies. PMID:24167038

Responses of magnocellular neurons to osmotic stimulation involves coactivation of excitatory and inhibitory input: an experimental and theoretical analysis.

PubMed

Leng, G; Brown, C H; Bull, P M; Brown, D; Scullion, S; Currie, J; Blackburn-Munro, R E; Feng, J; Onaka, T; Verbalis, J G; Russell, J A; Ludwig, M

2001-09-01

How does a neuron, challenged by an increase in synaptic input, display a response that is independent of the initial level of activity? Here we show that both oxytocin and vasopressin cells in the supraoptic nucleus of normal rats respond to intravenous infusions of hypertonic saline with gradual, linear increases in discharge rate. In hyponatremic rats, oxytocin and vasopressin cells also responded linearly to intravenous infusions of hypertonic saline but with much lower slopes. The linearity of response was surprising, given both the expected nonlinearity of neuronal behavior and the nonlinearity of the oxytocin secretory response to such infusions. We show that a simple computational model can reproduce these responses well, but only if it is assumed that hypertonic infusions coactivate excitatory and inhibitory synaptic inputs. This hypothesis was tested first by applying the GABA(A) antagonist bicuculline to the dendritic zone of the supraoptic nucleus by microdialysis. During local blockade of GABA inputs, the response of oxytocin cells to hypertonic infusion was greatly enhanced. We then went on to directly measure GABA release in the supraoptic nucleus during hypertonic infusion, confirming the predicted rise. Together, the results suggest that hypertonic infusions lead to coactivation of excitatory and inhibitory inputs and that this coactivation may confer appropriate characteristics on the output behavior of oxytocin cells. The nonlinearity of oxytocin secretion that accompanies the linear increase in oxytocin cell firing rate reflects frequency-facilitation of stimulus-secretion coupling at the neurohypophysis.

Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain.

PubMed

Hopp, Sarah C; Bihlmeyer, Nathan A; Corradi, John P; Vanderburg, Charles; Cacace, Angela M; Das, Sudeshna; Clark, Timothy W; Betensky, Rebecca A; Hyman, Bradley T; Hudry, Eloise

2018-05-28

Synaptic dysfunction and loss are core pathological features in Alzheimer disease (AD). In the vicinity of amyloid-β plaques in animal models, synaptic toxicity occurs and is associated with chronic activation of the phosphatase calcineurin (CN). Indeed, pharmacological inhibition of CN blocks amyloid-β synaptotoxicity. We therefore hypothesized that CN-mediated transcriptional changes may contribute to AD neuropathology and tested this by examining the impact of CN overexpression on neuronal gene expression in vivo. We found dramatic transcriptional downregulation, especially of synaptic mRNAs, in neurons chronically exposed to CN activation. Importantly, the transcriptional profile parallels the changes in human AD tissue. Bioinformatics analyses suggest that both nuclear factor of activated T cells (NFAT) and numerous microRNAs may all be impacted by CN, and parallel findings are observed in AD. These data and analyses support the hypothesis that at least part of the synaptic failure characterizing AD may result from aberrant CN activation leading to downregulation of synaptic genes, potentially via activation of specific transcription factors and expression of repressive microRNAs. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Synaptic Failure: Focus in an Integrative View of ALS

PubMed Central

Casas, Caty; Manzano, Raquel; Vaz, Rita; Osta, Rosario; Brites, Dora

2015-01-01

From early description by Charcot, the classification of the Amyotrophic Lateral Sclerosis (ALS) is evolving from a subtype of Motor Neuron (MN) Disease to be considered rather a multi-systemic, non-cell autonomous and complex neurodegenerative disease. In the last decade, the huge amount of knowledge acquired has shed new insights on the pathological mechanisms underlying ALS from different perspectives. However, a whole vision on the multiple dysfunctional pathways is needed with the inclusion of information often excluded in other published revisions. We propose an integrative view of ALS pathology, although centered on the synaptic failure as a converging and crucial player to the etiology of the disease. Homeostasis of input and output synaptic activity of MNs has been proved to be severely and early disrupted and to definitively contribute to microcircuitry alterations at the spinal cord. Several cells play roles in synaptic communication across the MNs network system such as interneurons, astrocytes, microglia, Schwann and skeletal muscle cells. Microglia are described as highly dynamic surveying cells of the nervous system but also as determinant contributors to the synaptic plasticity linked to neuronal activity. Several signaling axis such as TNFα/TNFR1 and CX3CR1/CX3CL1 that characterize MN-microglia cross talk contribute to synaptic scaling and maintenance, have been found altered in ALS. The presence of dystrophic and atypical microglia in late stages of ALS, with a decline in their dynamic motility and phagocytic ability, together with less synaptic and neuronal contacts disrupts the MN-microglia dialogue, decreases homeostatic regulation of neuronal activity, perturbs “on/off” signals and accelerates disease progression associated to impaired synaptic function and regeneration. Other hotspot in the ALS affected network system is the unstable neuromuscular junction (NMJ) leading to distal axonal degeneration. Reduced neuromuscular spontaneous synaptic activity in ALS mice models was also suggested to account for the selective vulnerability of MNs and decreased regenerative capability. Synaptic destabilization may as well derive from increased release of molecules by muscle cells (e.g. NogoA) and by terminal Schwann cells (e.g. semaphorin 3A) conceivably causing nerve terminal retraction and denervation, as well as inhibition of re-connection to muscle fibers. Indeed, we have overviewed the alterations on the metabolic pathways and self-regenerative capacity presented in skeletal muscle cells that contribute to muscle wasting in ALS. Finally, a detailed footpath of pathologic changes on MNs and associated dysfunctional and synaptic alterations is provided. The oriented motivation in future ALS studies as outlined in the present article will help in fruitful novel achievements on the mechanisms involved and in developing more target-driven therapies that will bring new hope in halting or delaying disease progression in ALS patients. PMID:29765840

Plasticity-Related Gene 1 Affects Mouse Barrel Cortex Function via Strengthening of Glutamatergic Thalamocortical Transmission.

PubMed

Unichenko, Petr; Kirischuk, Sergei; Yang, Jenq-Wei; Baumgart, Jan; Roskoden, Thomas; Schneider, Patrick; Sommer, Angela; Horta, Guilherme; Radyushkin, Konstantin; Nitsch, Robert; Vogt, Johannes; Luhmann, Heiko J

2016-07-01

Plasticity-related gene-1 (PRG-1) is a brain-specific protein that modulates glutamatergic synaptic transmission. Here we investigated the functional role of PRG-1 in adolescent and adult mouse barrel cortex both in vitro and in vivo. Compared with wild-type (WT) animals, PRG-1-deficient (KO) mice showed specific behavioral deficits in tests assessing sensorimotor integration and whisker-based sensory discrimination as shown in the beam balance/walking test and sandpaper tactile discrimination test, respectively. At P25-31, spontaneous network activity in the barrel cortex in vivo was higher in KO mice compared with WT littermates, but not at P16-19. At P16-19, sensory evoked cortical responses in vivo elicited by single whisker stimulation were comparable in KO and WT mice. In contrast, at P25-31 evoked responses were smaller in amplitude and longer in duration in WT animals, whereas KO mice revealed no such developmental changes. In thalamocortical slices from KO mice, spontaneous activity was increased already at P16-19, and glutamatergic thalamocortical inputs to Layer 4 spiny stellate neurons were potentiated. We conclude that genetic ablation of PRG-1 modulates already at P16-19 spontaneous and evoked excitability of the barrel cortex, including enhancement of thalamocortical glutamatergic inputs to Layer 4, which distorts sensory processing in adulthood. © The Author 2016. Published by Oxford University Press.

Plasticity-Related Gene 1 Affects Mouse Barrel Cortex Function via Strengthening of Glutamatergic Thalamocortical Transmission

PubMed Central

Unichenko, Petr; Kirischuk, Sergei; Yang, Jenq-Wei; Baumgart, Jan; Roskoden, Thomas; Schneider, Patrick; Sommer, Angela; Horta, Guilherme; Radyushkin, Konstantin; Nitsch, Robert; Vogt, Johannes; Luhmann, Heiko J.

2016-01-01

Plasticity-related gene-1 (PRG-1) is a brain-specific protein that modulates glutamatergic synaptic transmission. Here we investigated the functional role of PRG-1 in adolescent and adult mouse barrel cortex both in vitro and in vivo. Compared with wild-type (WT) animals, PRG-1-deficient (KO) mice showed specific behavioral deficits in tests assessing sensorimotor integration and whisker-based sensory discrimination as shown in the beam balance/walking test and sandpaper tactile discrimination test, respectively. At P25-31, spontaneous network activity in the barrel cortex in vivo was higher in KO mice compared with WT littermates, but not at P16-19. At P16-19, sensory evoked cortical responses in vivo elicited by single whisker stimulation were comparable in KO and WT mice. In contrast, at P25-31 evoked responses were smaller in amplitude and longer in duration in WT animals, whereas KO mice revealed no such developmental changes. In thalamocortical slices from KO mice, spontaneous activity was increased already at P16-19, and glutamatergic thalamocortical inputs to Layer 4 spiny stellate neurons were potentiated. We conclude that genetic ablation of PRG-1 modulates already at P16-19 spontaneous and evoked excitability of the barrel cortex, including enhancement of thalamocortical glutamatergic inputs to Layer 4, which distorts sensory processing in adulthood. PMID:26980613

Amplitude Normalization of Dendritic EPSPs at the Soma of Binaural Coincidence Detector Neurons of the Medial Superior Olive.

PubMed

Winters, Bradley D; Jin, Shan-Xue; Ledford, Kenneth R; Golding, Nace L

2017-03-22

The principal neurons of the medial superior olive (MSO) encode cues for horizontal sound localization through comparisons of the relative timing of EPSPs. To understand how the timing and amplitude of EPSPs are maintained during propagation in the dendrites, we made dendritic and somatic whole-cell recordings from MSO principal neurons in brain slices from Mongolian gerbils. In somatic recordings, EPSP amplitudes were largely uniform following minimal stimulation of excitatory synapses at visualized locations along the dendrites. Similar results were obtained when excitatory synaptic transmission was eliminated in a low calcium solution and then restored at specific dendritic sites by pairing input stimulation and focal application of a higher calcium solution. We performed dual dendritic and somatic whole-cell recordings to measure spontaneous EPSPs using a dual-channel template-matching algorithm to separate out those events initiated at or distal to the dendritic recording location. Local dendritic spontaneous EPSP amplitudes increased sharply in the dendrite with distance from the soma (length constant, 53.6 μm), but their attenuation during propagation resulted in a uniform amplitude of ∼0.2 mV at the soma. The amplitude gradient of dendritic EPSPs was also apparent in responses to injections of identical simulated excitatory synaptic currents in the dendrites. Compartmental models support the view that these results extensively reflect the influence of dendritic cable properties. With relatively few excitatory axons innervating MSO neurons, the normalization of dendritic EPSPs at the soma would increase the importance of input timing versus location during the processing of interaural time difference cues in vivo SIGNIFICANCE STATEMENT The neurons of the medial superior olive analyze cues for sound localization by detecting the coincidence of binaural excitatory synaptic inputs distributed along the dendrites. Previous studies have shown that dendritic voltages undergo severe attenuation as they propagate to the soma, potentially reducing the influence of distal inputs. However, using dendritic and somatic patch recordings, we found that dendritic EPSP amplitude increased with distance from the soma, compensating for dendritic attenuation and normalizing EPSP amplitude at the soma. Much of this normalization reflected the influence of dendritic morphology. As different combinations of presynaptic axons may be active during consecutive cycles of sound stimuli, somatic EPSP normalization renders spike initiation more sensitive to synapse timing than dendritic location. Copyright © 2017 the authors 0270-6474/17/373138-12$15.00/0.

Organization of the central control of muscles of facial expression in man

PubMed Central

Root, A A; Stephens, J A

2003-01-01

Surface EMGs were recorded simultaneously from ipsilateral pairs of facial muscles while subjects made three different common facial expressions: the smile, a sad expression and an expression of horror, and three contrived facial expressions. Central peaks were found in the cross-correlograms of EMG activity recorded from the orbicularis oculi and zygomaticus major during smiling, the corrugator and depressor anguli oris during the sad look and the frontalis and mentalis during the horror look. The size of the central peak was significantly greater between the orbicularis oculi and zygomaticus major during smiling. It is concluded that co-contraction of facial muscles during some facial expressions are accompanied by the presence of common synaptic drive to the motoneurones supplying the muscles involved. Central peaks were found in the cross-correlograms of EMG activity recorded from the frontalis and depressor anguli oris during a contrived expression. However, no central peaks were found in the cross-correlograms of EMG activity recorded from the frontalis and orbicularis oculi or from the frontalis and zygomaticus major during the other two contrived expressions. It is concluded that a common synaptic drive is not present between all possible facial muscle pairs and suggests a functional role for the synergy. The origin of the common drive is discussed. It is concluded that activity in branches of common stem last-order presynaptic input fibres to motoneurones innervating the different facial muscles and presynaptic synchronization of input activity to the different motoneurone pools is involved. The former probably contributes more to the drive to the orbicularis oculi and zygomaticus major during smiling, while the latter is probably more prevalent in the corrugator and depressor anguli oris during the sad look, the frontalis and mentalis during the horror look and the frontalis and depressor anguli oris during one of the contrived expressions. The strength of common synaptic drive is inversely related to the degree of separate control that can be exhibited by the facial muscles involved. PMID:12692176

Influence of Synaptic Depression on Memory Storage Capacity

NASA Astrophysics Data System (ADS)

Otsubo, Yosuke; Nagata, Kenji; Oizumi, Masafumi; Okada, Masato

2011-08-01

Synaptic efficacy between neurons is known to change within a short time scale dynamically. Neurophysiological experiments show that high-frequency presynaptic inputs decrease synaptic efficacy between neurons. This phenomenon is called synaptic depression, a short term synaptic plasticity. Many researchers have investigated how the synaptic depression affects the memory storage capacity. However, the noise has not been taken into consideration in their analysis. By introducing ``temperature'', which controls the level of the noise, into an update rule of neurons, we investigate the effects of synaptic depression on the memory storage capacity in the presence of the noise. We analytically compute the storage capacity by using a statistical mechanics technique called Self Consistent Signal to Noise Analysis (SCSNA). We find that the synaptic depression decreases the storage capacity in the case of finite temperature in contrast to the case of the low temperature limit, where the storage capacity does not change.

Neurite-specific Ca2+ dynamics underlying sound processing in an auditory interneurone.

PubMed

Baden, T; Hedwig, B

2007-01-01

Concepts on neuronal signal processing and integration at a cellular and subcellular level are driven by recording techniques and model systems available. The cricket CNS with the omega-1-neurone (ON1) provides a model system for auditory pattern recognition and directional processing. Exploiting ON1's planar structure we simultaneously imaged free intracellular Ca(2+) at both input and output neurites and recorded the membrane potential in vivo during acoustic stimulation. In response to a single sound pulse the rate of Ca(2+) rise followed the onset spike rate of ON1, while the final Ca(2+) level depended on the mean spike rate. Ca(2+) rapidly increased in both dendritic and axonal arborizations and only gradually in the axon and the cell body. Ca(2+) levels were particularly high at the spike-generating zone. Through the activation of a Ca(2+)-sensitive K(+) current this may exhibit a specific control over the cell's electrical response properties. In all cellular compartments presentation of species-specific calling song caused distinct oscillations of the Ca(2+) level in the chirp rhythm, but not the faster syllable rhythm. The Ca(2+)-mediated hyperpolarization of ON1 suppressed background spike activity between chirps, acting as a noise filter. During directional auditory processing, the functional interaction of Ca(2+)-mediated inhibition and contralateral synaptic inhibition was demonstrated. Upon stimulation with different sound frequencies, the dendrites, but not the axonal arborizations, demonstrated a tonotopic response profile. This mirrored the dominance of the species-specific carrier frequency and resulted in spatial filtering of high frequency auditory inputs. (c) 2006 Wiley Periodicals, Inc.

Retinal input to efferent target amacrine cells in the avian retina

PubMed Central

Lindstrom, Sarah H.; Azizi, Nason; Weller, Cynthia; Wilson, Martin

2012-01-01

The bird visual system includes a substantial projection, of unknown function, from a midbrain nucleus to the contralateral retina. Every centrifugal, or efferent, neuron originating in the midbrain nucleus makes synaptic contact with the soma of a single, unique amacrine cell, the target cell (TC). By labeling efferent neurons in the midbrain we have been able to identify their terminals in retinal slices and make patch clamp recordings from TCs. TCs generate Na+ based action potentials triggered by spontaneous EPSPs originating from multiple classes of presynaptic neurons. Exogenously applied glutamate elicited inward currents having the mixed pharmacology of NMDA, kainate and inward rectifying AMPA receptors. Exogenously applied GABA elicited currents entirely suppressed by GABAzine, and therefore mediated by GABAA receptors. Immunohistochemistry showed the vesicular glutamate transporter, vGluT2, to be present in the characteristic synaptic boutons of efferent terminals, whereas the GABA synthetic enzyme, GAD, was present in much smaller processes of intrinsic retinal neurons. Extracellular recording showed that exogenously applied GABA was directly excitatory to TCs and, consistent with this, NKCC, the Cl− transporter often associated with excitatory GABAergic synapses, was identified in TCs by antibody staining. The presence of excitatory retinal input to TCs implies that TCs are not merely slaves to their midbrain input; instead, their output reflects local retinal activity and descending input from the midbrain. PMID:20650017

Astrocytes refine cortical connectivity at dendritic spines

PubMed Central

Risher, W Christopher; Patel, Sagar; Kim, Il Hwan; Uezu, Akiyoshi; Bhagat, Srishti; Wilton, Daniel K; Pilaz, Louis-Jan; Singh Alvarado, Jonnathan; Calhan, Osman Y; Silver, Debra L; Stevens, Beth; Calakos, Nicole; Soderling, Scott H; Eroglu, Cagla

2014-01-01

During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines. DOI: http://dx.doi.org/10.7554/eLife.04047.001 PMID:25517933

The optimal neural strategy for a stable motor task requires a compromise between level of muscle cocontraction and synaptic gain of afferent feedback

PubMed Central

Dideriksen, Jakob L.; Negro, Francesco

2015-01-01

Increasing joint stiffness by cocontraction of antagonist muscles and compensatory reflexes are neural strategies to minimize the impact of unexpected perturbations on movement. Combining these strategies, however, may compromise steadiness, as elements of the afferent input to motor pools innervating antagonist muscles are inherently negatively correlated. Consequently, a high afferent gain and active contractions of both muscles may imply negatively correlated neural drives to the muscles and thus an unstable limb position. This hypothesis was systematically explored with a novel computational model of the peripheral nervous system and the mechanics of one limb. Two populations of motor neurons received synaptic input from descending drive, spinal interneurons, and afferent feedback. Muscle force, simulated based on motor unit activity, determined limb movement that gave rise to afferent feedback from muscle spindles and Golgi tendon organs. The results indicated that optimal steadiness was achieved with low synaptic gain of the afferent feedback. High afferent gains during cocontraction implied increased levels of common drive in the motor neuron outputs, which were negatively correlated across the two populations, constraining instability of the limb. Increasing the force acting on the joint and the afferent gain both effectively minimized the impact of an external perturbation, and suboptimal adjustment of the afferent gain could be compensated by muscle cocontraction. These observations show that selection of the strategy for a given contraction implies a compromise between steadiness and effectiveness of compensations to perturbations. This indicates that a task-dependent selection of neural strategy for steadiness is necessary when acting in different environments. PMID:26203102

Physiological and morphological characterization of organotypic cocultures of the chick forebrain area MNH and its main input area DMA/DMP.

PubMed

Endepols, H; Jungnickel, J; Braun, K

2001-01-01

Cocultures of the learning-relevant forebrain region mediorostral neostriatum and hyperstriatum ventrale (MNH) and its main glutamatergic input area nucleus dorsomedialis anterior thalami/posterior thalami were morphologically and physiologically characterized. Synaptic contacts of thalamic fibers were light- and electron-microscopically detected on MNH neurons by applying the fluorescence tracer DiI-C18(3) into the thalamus part of the coculture. Most thalamic synapses on MNH neurons were symmetric and located on dendritic shafts, but no correlation between Gray-type ultrastructure and dendritic localization was found. Using intracellular current clamp recordings, we found that the electrophysiological properties, such as input resistance, time constant, action potential threshold, amplitude, and duration of MNH neurons, remain stable for over 30 days in vitro. Pharmacological blockade experiments revealed glutamate as the main neurotransmitter of thalamic synapses on MNH neurons, which were also found on inhibitory neurons. High frequency stimulation of thalamic inputs evoked synaptic potentiation in 22% of MNH neurons. The results indicate that DMA/DMP-MNH cocultures, which can be maintained under stable conditions for at least 4 weeks, provide an attractive in vitro model for investigating synaptic plasticity in the avian brain.

Physiological and Morphological Characterization of Organotypic Cocultures of the Chick Forebrain Area MNH and its Main Input Area DMA/DMP

PubMed Central

Endepols, Heike; Jungnickel, Julia; Braun, Katharina

2001-01-01

Cocultures of the learning-relevant forebrain region mediorostrai neostriatum and hyperstriatum ventrale (MNH) and its main glutamatergic input area nucleus dorsomedialis anterior thalami/posterior thalami were morphologically and physiologically characterized. Synaptic contacts of thalamic fibers were lightand electron-microscopically detected on MNH neurons by applying the fluorescence tracer DiI-C18(3) into the thalamus part of the coculture. Most thalamic synapses on MNH neurons were symmetric and located on dendritic shafts, but no correlation between Gray-type ultrastructure and dendritic localization was found. Using intraceilular current clamp recordings, we found that the electrophysiological properties, such as input resistance, time constant, action potential threshold, amplitude, and duration of MNH neurons, remain stable for over 30 days in vitro. Pharmacological blockade experiments revealed glutamate as the main neurotransmitter of thalamic synapses on MNH neurons, which were also found on inhibitory neurons. High frequency stimulation of thalamic inputs evoked synaptic potentiation in 22% of MNH neurons. The results indicate that DMA/DMP-MNH cocultures, which can be maintained under stable conditions for at least 4 weeks, provide an attractive in vitro model for investigating synaptic plasticity in the avian brain. PMID:12018771

A Novel Form of Compensation in the Tg2576 Amyloid Mouse Model of Alzheimer’s Disease

PubMed Central

Somogyi, Attila; Katonai, Zoltán; Alpár, Alán; Wolf, Ervin

2016-01-01

One century after its first description, pathology of Alzheimer’s disease (AD) is still poorly understood. Amyloid-related dendritic atrophy and membrane alterations of susceptible brain neurons in AD, and in animal models of AD are widely recognized. However, little effort has been made to study the potential effects of combined morphological and membrane alterations on signal transfer and synaptic integration in neurons that build up affected neural networks in AD. In this study spatial reconstructions and electrophysiological measurements of layer II/III pyramidal neurons of the somatosensory cortex from wild-type (WT) and transgenic (TG) human amyloid precursor protein (hAPP) overexpressing Tg2576 mice were used to build faithful segmental cable models of these neurons. Local synaptic activities were simulated in various points of the dendritic arbors and properties of subthreshold dendritic impulse propagation and predictors of synaptic input pattern recognition ability were quantified and compared in modeled WT and TG neurons. Despite the widespread dendritic degeneration and membrane alterations in mutant mouse neurons, surprisingly little, or no change was detected in steady-state and 50 Hz sinusoidal voltage transfers, current transfers, and local and propagation delays of PSPs traveling along dendrites of TG neurons. Synaptic input pattern recognition ability was also predicted to be unaltered in TG neurons in two different soma-dendritic membrane models investigated. Our simulations predict the way how subthreshold dendritic signaling and pattern recognition are preserved in TG neurons: amyloid-related membrane alterations compensate for the pathological effects that dendritic atrophy has on subthreshold dendritic signal transfer and integration in layer II/III somatosensory neurons of this hAPP mouse model for AD. Since neither propagation of single PSPs nor integration of multiple PSPs (pattern recognition) changes in TG neurons, we conclude that AD-related neuronal hyperexcitability cannot be accounted for by altered subthreshold dendritic signaling in these neurons but hyperexcitability is related to changes in active membrane properties and network connectivity. PMID:27378850

A Novel Form of Compensation in the Tg2576 Amyloid Mouse Model of Alzheimer's Disease.

PubMed

Somogyi, Attila; Katonai, Zoltán; Alpár, Alán; Wolf, Ervin

2016-01-01

One century after its first description, pathology of Alzheimer's disease (AD) is still poorly understood. Amyloid-related dendritic atrophy and membrane alterations of susceptible brain neurons in AD, and in animal models of AD are widely recognized. However, little effort has been made to study the potential effects of combined morphological and membrane alterations on signal transfer and synaptic integration in neurons that build up affected neural networks in AD. In this study spatial reconstructions and electrophysiological measurements of layer II/III pyramidal neurons of the somatosensory cortex from wild-type (WT) and transgenic (TG) human amyloid precursor protein (hAPP) overexpressing Tg2576 mice were used to build faithful segmental cable models of these neurons. Local synaptic activities were simulated in various points of the dendritic arbors and properties of subthreshold dendritic impulse propagation and predictors of synaptic input pattern recognition ability were quantified and compared in modeled WT and TG neurons. Despite the widespread dendritic degeneration and membrane alterations in mutant mouse neurons, surprisingly little, or no change was detected in steady-state and 50 Hz sinusoidal voltage transfers, current transfers, and local and propagation delays of PSPs traveling along dendrites of TG neurons. Synaptic input pattern recognition ability was also predicted to be unaltered in TG neurons in two different soma-dendritic membrane models investigated. Our simulations predict the way how subthreshold dendritic signaling and pattern recognition are preserved in TG neurons: amyloid-related membrane alterations compensate for the pathological effects that dendritic atrophy has on subthreshold dendritic signal transfer and integration in layer II/III somatosensory neurons of this hAPP mouse model for AD. Since neither propagation of single PSPs nor integration of multiple PSPs (pattern recognition) changes in TG neurons, we conclude that AD-related neuronal hyperexcitability cannot be accounted for by altered subthreshold dendritic signaling in these neurons but hyperexcitability is related to changes in active membrane properties and network connectivity.

Tonotopic tuning in a sound localization circuit.

PubMed

Slee, Sean J; Higgs, Matthew H; Fairhall, Adrienne L; Spain, William J

2010-05-01

Nucleus laminaris (NL) neurons encode interaural time difference (ITD), the cue used to localize low-frequency sounds. A physiologically based model of NL input suggests that ITD information is contained in narrow frequency bands around harmonics of the sound frequency. This suggested a theory, which predicts that, for each tone frequency, there is an optimal time course for synaptic inputs to NL that will elicit the largest modulation of NL firing rate as a function of ITD. The theory also suggested that neurons in different tonotopic regions of NL require specialized tuning to take advantage of the input gradient. Tonotopic tuning in NL was investigated in brain slices by separating the nucleus into three regions based on its anatomical tonotopic map. Patch-clamp recordings in each region were used to measure both the synaptic and the intrinsic electrical properties. The data revealed a tonotopic gradient of synaptic time course that closely matched the theoretical predictions. We also found postsynaptic band-pass filtering. Analysis of the combined synaptic and postsynaptic filters revealed a frequency-dependent gradient of gain for the transformation of tone amplitude to NL firing rate modulation. Models constructed from the experimental data for each tonotopic region demonstrate that the tonotopic tuning measured in NL can improve ITD encoding across sound frequencies.

Involvement of Mossy Cells in Sharp Wave-Ripple Activity In Vitro.

PubMed

Swaminathan, Aarti; Wichert, Ines; Schmitz, Dietmar; Maier, Nikolaus

2018-05-29

The role of mossy cells (MCs) of the hippocampal dentate area has long remained mysterious. Recent research has begun to unveil their significance in spatial computation of the hippocampus. Here, we used an in vitro model of sharp wave-ripple complexes (SWRs), which contribute to hippocampal memory formation, to investigate MC involvement in this fundamental population activity. We find that a significant fraction of MCs (∼47%) is recruited into the active neuronal network during SWRs in the CA3 area. Moreover, MCs receive pronounced, ripple-coherent, excitatory and inhibitory synaptic input. Finally, we find evidence for SWR-related synaptic activity in granule cells that is mediated by MCs. Given the widespread connectivity of MCs within and between hippocampi, our data suggest a role for MCs as a hub functionally coupling the CA3 and the DG during ripple-associated computations. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Functional Evaluation of Biological Neurotoxins in Networked Cultures of Stem Cell-derived Central Nervous System Neurons

PubMed Central

Hubbard, Kyle; Beske, Phillip; Lyman, Megan; McNutt, Patrick

2015-01-01

Therapeutic and mechanistic studies of the presynaptically targeted clostridial neurotoxins (CNTs) have been limited by the need for a scalable, cell-based model that produces functioning synapses and undergoes physiological responses to intoxication. Here we describe a simple and robust method to efficiently differentiate murine embryonic stem cells (ESCs) into defined lineages of synaptically active, networked neurons. Following an 8 day differentiation protocol, mouse embryonic stem cell-derived neurons (ESNs) rapidly express and compartmentalize neurotypic proteins, form neuronal morphologies and develop intrinsic electrical responses. By 18 days after differentiation (DIV 18), ESNs exhibit active glutamatergic and γ-aminobutyric acid (GABA)ergic synapses and emergent network behaviors characterized by an excitatory:inhibitory balance. To determine whether intoxication with CNTs functionally antagonizes synaptic neurotransmission, thereby replicating the in vivo pathophysiology that is responsible for clinical manifestations of botulism or tetanus, whole-cell patch clamp electrophysiology was used to quantify spontaneous miniature excitatory post-synaptic currents (mEPSCs) in ESNs exposed to tetanus neurotoxin (TeNT) or botulinum neurotoxin (BoNT) serotypes /A-/G. In all cases, ESNs exhibited near-complete loss of synaptic activity within 20 hr. Intoxicated neurons remained viable, as demonstrated by unchanged resting membrane potentials and intrinsic electrical responses. To further characterize the sensitivity of this approach, dose-dependent effects of intoxication on synaptic activity were measured 20 hr after addition of BoNT/A. Intoxication with 0.005 pM BoNT/A resulted in a significant decrement in mEPSCs, with a median inhibitory concentration (IC50) of 0.013 pM. Comparisons of median doses indicate that functional measurements of synaptic inhibition are faster, more specific and more sensitive than SNARE cleavage assays or the mouse lethality assay. These data validate the use of synaptically coupled, stem cell-derived neurons for the highly specific and sensitive detection of CNTs. PMID:25742030

Congenital Anophthalmia and Binocular Neonatal Enucleation Differently Affect the Proteome of Primary and Secondary Visual Cortices in Mice.

PubMed

Laramée, Marie-Eve; Smolders, Katrien; Hu, Tjing-Tjing; Bronchti, Gilles; Boire, Denis; Arckens, Lutgarde

2016-01-01

In blind individuals, visually deprived occipital areas are activated by non-visual stimuli. The extent of this cross-modal activation depends on the age at onset of blindness. Cross-modal inputs have access to several anatomical pathways to reactivate deprived visual areas. Ectopic cross-modal subcortical connections have been shown in anophthalmic animals but not in animals deprived of sight at a later age. Direct and indirect cross-modal cortical connections toward visual areas could also be involved, yet the number of neurons implicated is similar between blind mice and sighted controls. Changes at the axon terminal, dendritic spine or synaptic level are therefore expected upon loss of visual inputs. Here, the proteome of V1, V2M and V2L from P0-enucleated, anophthalmic and sighted mice, sharing a common genetic background (C57BL/6J x ZRDCT/An), was investigated by 2-D DIGE and Western analyses to identify molecular adaptations to enucleation and/or anophthalmia. Few proteins were differentially expressed in enucleated or anophthalmic mice in comparison to sighted mice. The loss of sight affected three pathways: metabolism, synaptic transmission and morphogenesis. Most changes were detected in V1, followed by V2M. Overall, cross-modal adaptations could be promoted in both models of early blindness but not through the exact same molecular strategy. A lower metabolic activity observed in visual areas of blind mice suggests that even if cross-modal inputs reactivate visual areas, they could remain suboptimally processed.

Congenital Anophthalmia and Binocular Neonatal Enucleation Differently Affect the Proteome of Primary and Secondary Visual Cortices in Mice

PubMed Central

Smolders, Katrien; Hu, Tjing-Tjing; Bronchti, Gilles; Boire, Denis; Arckens, Lutgarde

2016-01-01

In blind individuals, visually deprived occipital areas are activated by non-visual stimuli. The extent of this cross-modal activation depends on the age at onset of blindness. Cross-modal inputs have access to several anatomical pathways to reactivate deprived visual areas. Ectopic cross-modal subcortical connections have been shown in anophthalmic animals but not in animals deprived of sight at a later age. Direct and indirect cross-modal cortical connections toward visual areas could also be involved, yet the number of neurons implicated is similar between blind mice and sighted controls. Changes at the axon terminal, dendritic spine or synaptic level are therefore expected upon loss of visual inputs. Here, the proteome of V1, V2M and V2L from P0-enucleated, anophthalmic and sighted mice, sharing a common genetic background (C57BL/6J x ZRDCT/An), was investigated by 2-D DIGE and Western analyses to identify molecular adaptations to enucleation and/or anophthalmia. Few proteins were differentially expressed in enucleated or anophthalmic mice in comparison to sighted mice. The loss of sight affected three pathways: metabolism, synaptic transmission and morphogenesis. Most changes were detected in V1, followed by V2M. Overall, cross-modal adaptations could be promoted in both models of early blindness but not through the exact same molecular strategy. A lower metabolic activity observed in visual areas of blind mice suggests that even if cross-modal inputs reactivate visual areas, they could remain suboptimally processed. PMID:27410964

Synaptic vesicle exocytosis in hippocampal synaptosomes correlates directly with total mitochondrial volume

PubMed Central

Ivannikov, Maxim V.; Sugimori, Mutsuyuki; Llinás, Rodolfo R.

2012-01-01

Synaptic plasticity in many regions of the central nervous system leads to the continuous adjustment of synaptic strength, which is essential for learning and memory. In this study, we show by visualizing synaptic vesicle release in mouse hippocampal synaptosomes that presynaptic mitochondria and specifically, their capacities for ATP production are essential determinants of synaptic vesicle exocytosis and its magnitude. Total internal reflection microscopy of FM1-43 loaded hippocampal synaptosomes showed that inhibition of mitochondrial oxidative phosphorylation reduces evoked synaptic release. This reduction was accompanied by a substantial drop in synaptosomal ATP levels. However, cytosolic calcium influx was not affected. Structural characterization of stimulated hippocampal synaptosomes revealed that higher total presynaptic mitochondrial volumes were consistently associated with higher levels of exocytosis. Thus, synaptic vesicle release is linked to the presynaptic ability to regenerate ATP, which itself is a utility of mitochondrial density and activity. PMID:22772899

CPG2 Recruits Endophilin B2 to the Cytoskeleton for Activity-Dependent Endocytosis of Synaptic Glutamate Receptors.

PubMed

Loebrich, Sven; Benoit, Marc Robert; Konopka, Jaclyn Aleksandra; Cottrell, Jeffrey Richard; Gibson, Joanne; Nedivi, Elly

2016-02-08

Internalization of glutamate receptors at the postsynaptic membrane via clathrin-mediated endocytosis (CME) is a key mechanism for regulating synaptic strength. A role for the F-actin cytoskeleton in CME is well established, and recently, PKA-dependent association of candidate plasticity gene 2 (CPG2) with the spine-cytoskeleton has been shown to mediate synaptic glutamate receptor internalization. Yet, how the endocytic machinery is physically coupled to the actin cytoskeleton to facilitate glutamate receptor internalization has not been demonstrated. Moreover, there has been no distinction of endocytic-machinery components that are specific to activity-dependent versus constitutive glutamate receptor internalization. Here, we show that CPG2, through a direct physical interaction, recruits endophilin B2 (EndoB2) to F-actin, thus anchoring the endocytic machinery to the spine cytoskeleton and facilitating glutamate receptor internalization. Regulation of CPG2 binding to the actin cytoskeleton by protein kinase A directly impacts recruitment of EndoB2 and clathrin. Specific disruption of EndoB2 or the CPG2-EndoB2 interaction impairs activity-dependent, but not constitutive, internalization of both NMDA- and AMPA-type glutamate receptors. These results demonstrate that, through direct interactions with F-actin and EndoB2, CPG2 physically bridges the spine cytoskeleton and the endocytic machinery, and this tripartite association is critical specifically for activity-dependent CME of synaptic glutamate receptors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacological activation of CB1 receptor modulates long term potentiation by interfering with protein synthesis.

PubMed

Navakkode, Sheeja; Korte, Martin

2014-04-01

Cognitive impairment is one of the most important side effects associated with cannabis drug abuse, as well as the serious issue concerning the therapeutic use of cannabinoids. Cognitive impairments and neuropsychiatric symptoms are caused by early synaptic dysfunctions, such as loss of synaptic connections in different brain structures including the hippocampus, a region that is believed to play an important role in certain forms of learning and memory. We report here that metaplastic priming of synapses with a cannabinoid type 1 receptor (CB1 receptor) agonist, WIN55,212-2 (WIN55), significantly impaired long-term potentiation in the apical dendrites of CA1 pyramidal neurons. Interestingly, the CB1 receptor exerts its effect by altering the balance of protein synthesis machinery towards higher protein production. Therefore the activation of CB1 receptor, prior to strong tetanization, increased the propensity to produce new proteins. In addition, WIN55 priming resulted in the expression of late-LTP in a synaptic input that would have normally expressed early-LTP, thus confirming that WIN55 priming of LTP induces new synthesis of plasticity-related proteins. Furthermore, in addition to the effects on protein translation, WIN55 also induced synaptic deficits due to the ability of CB1 receptors to inhibit the release of acetylcholine, mediated by both muscarinic and nicotinic acetylcholine receptors. Taken together this supports the notion that the modulation of cholinergic activity by CB1 receptor activation is one mechanism that regulates the synthesis of plasticity-related proteins. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hunger States Control the Directions of Synaptic Plasticity via Switching Cell Type-Specific Subunits of NMDA Receptors.

PubMed

Qi, Yong; Yang, Yunlei

2015-09-23

It remains largely unknown whether and how hunger states control activity-dependent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). We here report that both LTP and LTD of excitatory synaptic strength within the appetite control circuits residing in hypothalamic arcuate nucleus (ARC) behave in a manner of hunger states dependence and cell type specificity. For instance, we find that tetanic stimulation induces LTP at orexigenic agouti-related protein (AgRP) neurons in ad libitum fed mice, whereas it induces LTD in food-deprived mice. In an opposite direction, the same induction protocol induces LTD at anorexigenic pro-opiomelanocortin (POMC) neurons in fed mice but weak LTP in deprived mice. Mechanistically, we also find that food deprivation increases the expressions of NR2C/NR2D/NR3-containing NMDA receptors (NMDARs) at AgRP neurons that contribute to the inductions of LTD, whereas it decreases their expressions at POMC neurons. Collectively, our data reveal that hunger states control the directions of activity-dependent synaptic plasticity by switching NMDA receptor subpopulations in a cell type-specific manner, providing insights into NMDAR-mediated interactions between energy states and associative memory. Significance statement: Based on the experiments performed in this study, we demonstrate that activity-dependent synaptic plasticity is also under the control of energy states by regulating NMDAR subpopulations in a cell type-specific manner. We thus propose a reversible memory configuration constructed from energy states-dependent cell type-specific bidirectional conversions of LTP and LTD. Together with the distinct functional roles played by NMDAR signaling in the control of food intake and energy states, these findings reveal a new reciprocal interaction between energy states and associative memory, one that might serve as a target for therapeutic treatments of the energy-related memory disorders or vice versa. Copyright © 2015 the authors 0270-6474/15/3513171-12$15.00/0.

Joint statistics of strongly correlated neurons via dimensionality reduction

NASA Astrophysics Data System (ADS)

Deniz, Taşkın; Rotter, Stefan

2017-06-01

The relative timing of action potentials in neurons recorded from local cortical networks often shows a non-trivial dependence, which is then quantified by cross-correlation functions. Theoretical models emphasize that such spike train correlations are an inevitable consequence of two neurons being part of the same network and sharing some synaptic input. For non-linear neuron models, however, explicit correlation functions are difficult to compute analytically, and perturbative methods work only for weak shared input. In order to treat strong correlations, we suggest here an alternative non-perturbative method. Specifically, we study the case of two leaky integrate-and-fire neurons with strong shared input. Correlation functions derived from simulated spike trains fit our theoretical predictions very accurately. Using our method, we computed the non-linear correlation transfer as well as correlation functions that are asymmetric due to inhomogeneous intrinsic parameters or unequal input.

Early-life seizures alter synaptic calcium-permeable AMPA receptor function and plasticity

PubMed Central

Lippman-Bell, Jocelyn J.; Zhou, Chengwen; Sun, Hongyu; Feske, Joel S.; Jensen, Frances E.

2016-01-01

Calcium (Ca2+)-mediated1 signaling pathways are critical to synaptic plasticity. In adults, the NMDA glutamate receptor (NMDAR) represents a major route for activity-dependent synaptic Ca2+ entry. However, during neonatal development, when synaptic plasticity is high, many AMPA glutamate receptors (AMPARs) are also permeable to Ca2+ (CP-AMPAR) due to low GluA2 subunit expression, providing an additional route for activity- and glutamate-dependent Ca2+ influx and subsequent signaling. Therefore, altered hippocampal Ca2+ signaling may represent an age-specific pathogenic mechanism. We thus aimed to assess Ca2+ responses 48 hours after hypoxia-induced neonatal seizures (HS) in postnatal day (P)10 rats, a post-seizure time point at which we previously reported LTP attenuation. We found that Ca2+ responses were higher in brain slices from post-HS rats than in controls and this increase was CP-AMPAR-dependent. To determine whether synaptic CP-AMPAR expression was also altered post-HS, we assessed the expression of GluA2 at hippocampal synapses and the expression of long-term depression (LTD), which has been linked to the presence of synaptic GluA2. Here we report a decrease 48 hours after HS in synaptic GluA2 expression at synapses and LTD in hippocampal CA1. Given the potentially critical role of AMPAR trafficking in disease progression, we aimed to establish whether post-seizure in vivo AMPAR antagonist treatment prevented the enhanced Ca2+ responses, changes in GluA2 synaptic expression, and diminished LTD. We found that NBQX treatment prevents all three of these post-seizure consequences, further supporting a critical role for AMPARs as an age-specific therapeutic target. PMID:27521497

A Neural Model for Temporal Order Judgments and Their Active Recalibration: A Common Mechanism for Space and Time?

PubMed Central

Cai, Mingbo; Stetson, Chess; Eagleman, David M.

2012-01-01

When observers experience a constant delay between their motor actions and sensory feedback, their perception of the temporal order between actions and sensations adapt (Stetson et al., 2006). We present here a novel neural model that can explain temporal order judgments (TOJs) and their recalibration. Our model employs three ubiquitous features of neural systems: (1) information pooling, (2) opponent processing, and (3) synaptic scaling. Specifically, the model proposes that different populations of neurons encode different delays between motor-sensory events, the outputs of these populations feed into rivaling neural populations (encoding “before” and “after”), and the activity difference between these populations determines the perceptual judgment. As a consequence of synaptic scaling of input weights, motor acts which are consistently followed by delayed sensory feedback will cause the network to recalibrate its point of subjective simultaneity. The structure of our model raises the possibility that recalibration of TOJs is a temporal analog to the motion aftereffect (MAE). In other words, identical neural mechanisms may be used to make perceptual determinations about both space and time. Our model captures behavioral recalibration results for different numbers of adapting trials and different adapting delays. In line with predictions of the model, we additionally demonstrate that temporal recalibration can last through time, in analogy to storage of the MAE. PMID:23130010

Neuromodulation to the Rescue: Compensation of Temperature-Induced Breakdown of Rhythmic Motor Patterns via Extrinsic Neuromodulatory Input

PubMed Central

Städele, Carola; Heigele, Stefanie; Stein, Wolfgang

2015-01-01

Stable rhythmic neural activity depends on the well-coordinated interplay of synaptic and cell-intrinsic conductances. Since all biophysical processes are temperature dependent, this interplay is challenged during temperature fluctuations. How the nervous system remains functional during temperature perturbations remains mostly unknown. We present a hitherto unknown mechanism of how temperature-induced changes in neural networks are compensated by changing their neuromodulatory state: activation of neuromodulatory pathways establishes a dynamic coregulation of synaptic and intrinsic conductances with opposing effects on neuronal activity when temperature changes, hence rescuing neuronal activity. Using the well-studied gastric mill pattern generator of the crab, we show that modest temperature increase can abolish rhythmic activity in isolated neural circuits due to increased leak currents in rhythm-generating neurons. Dynamic clamp-mediated addition of leak currents was sufficient to stop neuronal oscillations at low temperatures, and subtraction of additional leak currents at elevated temperatures was sufficient to rescue the rhythm. Despite the apparent sensitivity of the isolated nervous system to temperature fluctuations, the rhythm could be stabilized by activating extrinsic neuromodulatory inputs from descending projection neurons, a strategy that we indeed found to be implemented in intact animals. In the isolated nervous system, temperature compensation was achieved by stronger extrinsic neuromodulatory input from projection neurons or by augmenting projection neuron influence via bath application of the peptide cotransmitter Cancer borealis tachykinin-related peptide Ia (CabTRP Ia). CabTRP Ia activates the modulator-induced current IMI (a nonlinear voltage-gated inward current) that effectively acted as a negative leak current and counterbalanced the temperature-induced leak to rescue neuronal oscillations. Computational modelling revealed the ability of IMI to reduce detrimental leak-current influences on neuronal networks over a broad conductance range and indicated that leak and IMI are closely coregulated in the biological system to enable stable motor patterns. In conclusion, these results show that temperature compensation does not need to be implemented within the network itself but can be conditionally provided by extrinsic neuromodulatory input that counterbalances temperature-induced modifications of circuit-intrinsic properties. PMID:26417944

Enhanced Sensitivity to Hyperpolarizing Inhibition in Mesoaccumbal Relative to Nigrostriatal Dopamine Neuron Subpopulations

PubMed Central

2017-01-01

Midbrain dopamine neurons recorded in vivo pause their firing in response to reward omission and aversive stimuli. While the initiation of pauses typically involves synaptic or modulatory input, intrinsic membrane properties may also enhance or limit hyperpolarization, raising the question of how intrinsic conductances shape pauses in dopamine neurons. Using retrograde labeling and electrophysiological techniques combined with computational modeling, we examined the intrinsic conductances that shape pauses evoked by current injections and synaptic stimulation in subpopulations of dopamine neurons grouped according to their axonal projections to the nucleus accumbens or dorsal striatum in mice. Testing across a range of conditions and pulse durations, we found that mesoaccumbal and nigrostriatal neurons differ substantially in rebound properties with mesoaccumbal neurons displaying significantly longer delays to spiking following hyperpolarization. The underlying mechanism involves an inactivating potassium (IA) current with decay time constants of up to 225 ms, and small-amplitude hyperpolarization-activated currents (IH), characteristics that were most often observed in mesoaccumbal neurons. Pharmacological block of IA completely abolished rebound delays and, importantly, shortened synaptically evoked inhibitory pauses, thereby demonstrating the involvement of A-type potassium channels in prolonging pauses evoked by GABAergic inhibition. Therefore, these results show that mesoaccumbal and nigrostriatal neurons display differential responses to hyperpolarizing inhibitory stimuli that favors a higher sensitivity to inhibition in mesoaccumbal neurons. These findings may explain, in part, observations from in vivo experiments that ventral tegmental area neurons tend to exhibit longer aversive pauses relative to SNc neurons. SIGNIFICANCE STATEMENT Our study examines rebound, postburst, and synaptically evoked inhibitory pauses in subpopulations of midbrain dopamine neurons. We show that pauses in dopamine neuron firing, evoked by either stimulation of GABAergic inputs or hyperpolarizing current injections, are enhanced by a subclass of potassium conductances that are recruited at voltages below spike threshold. Importantly, A-type potassium currents recorded in mesoaccumbal neurons displayed substantially slower inactivation kinetics, which, combined with weaker expression of hyperpolarization-activated currents, lengthened hyperpolarization-induced delays in spiking relative to nigrostriatal neurons. These results suggest that input integration differs among dopamine neurons favoring higher sensitivity to inhibition in mesoaccumbal neurons and may partially explain in vivo observations that ventral tegmental area neurons exhibit longer aversive pauses relative to SNc neurons. PMID:28219982

Spectrotemporal dynamics of auditory cortical synaptic receptive field plasticity.

PubMed

Froemke, Robert C; Martins, Ana Raquel O

2011-09-01

The nervous system must dynamically represent sensory information in order for animals to perceive and operate within a complex, changing environment. Receptive field plasticity in the auditory cortex allows cortical networks to organize around salient features of the sensory environment during postnatal development, and then subsequently refine these representations depending on behavioral context later in life. Here we review the major features of auditory cortical receptive field plasticity in young and adult animals, focusing on modifications to frequency tuning of synaptic inputs. Alteration in the patterns of acoustic input, including sensory deprivation and tonal exposure, leads to rapid adjustments of excitatory and inhibitory strengths that collectively determine the suprathreshold tuning curves of cortical neurons. Long-term cortical plasticity also requires co-activation of subcortical neuromodulatory control nuclei such as the cholinergic nucleus basalis, particularly in adults. Regardless of developmental stage, regulation of inhibition seems to be a general mechanism by which changes in sensory experience and neuromodulatory state can remodel cortical receptive fields. We discuss recent findings suggesting that the microdynamics of synaptic receptive field plasticity unfold as a multi-phase set of distinct phenomena, initiated by disrupting the balance between excitation and inhibition, and eventually leading to wide-scale changes to many synapses throughout the cortex. These changes are coordinated to enhance the representations of newly-significant stimuli, possibly for improved signal processing and language learning in humans. Copyright © 2011 Elsevier B.V. All rights reserved.

Spectrotemporal Dynamics of Auditory Cortical Synaptic Receptive Field Plasticity

PubMed Central

Froemke, Robert C.; Martins, Ana Raquel O.

2011-01-01

The nervous system must dynamically represent sensory information in order for animals to perceive and operate within a complex, changing environment. Receptive field plasticity in the auditory cortex allows cortical networks to organize around salient features of the sensory environment during postnatal development, and then subsequently refine these representations depending on behavioral context later in life. Here we review the major features of auditory cortical receptive field plasticity in young and adult animals, focusing on modifications to frequency tuning of synaptic inputs. Alteration in the patterns of acoustic input, including sensory deprivation and tonal exposure, leads to rapid adjustments of excitatory and inhibitory strengths that collectively determine the suprathreshold tuning curves of cortical neurons. Long-term cortical plasticity also requires co-activation of subcortical neuromodulatory control nuclei such as the cholinergic nucleus basalis, particularly in adults. Regardless of developmental stage, regulation of inhibition seems to be a general mechanism by which changes in sensory experience and neuromodulatory state can remodel cortical receptive fields. We discuss recent findings suggesting that the microdynamics of synaptic receptive field plasticity unfold as a multi-phase set of distinct phenomena, initiated by disrupting the balance between excitation and inhibition, and eventually leading to wide-scale changes to many synapses throughout the cortex. These changes are coordinated to enhance the representations of newly-significant stimuli, possibly for improved signal processing and language learning in humans. PMID:21426927

Mover Is a Homomeric Phospho-Protein Present on Synaptic Vesicles

PubMed Central

Kremer, Thomas; Hoeber, Jan; Kiran Akula, Asha; Urlaub, Henning; Islinger, Markus; Kirsch, Joachim; Dean, Camin; Dresbach, Thomas

2013-01-01

With remarkably few exceptions, the molecules mediating synaptic vesicle exocytosis at active zones are structurally and functionally conserved between vertebrates and invertebrates. Mover was found in a yeast-2-hybrid assay using the vertebrate-specific active zone scaffolding protein bassoon as a bait. Peptides of Mover have been reported in proteomics screens for self-interacting proteins, phosphorylated proteins, and synaptic vesicle proteins, respectively. Here, we tested the predictions arising from these screens. Using flotation assays, carbonate stripping of peripheral membrane proteins, mass spectrometry, immunogold labelling of purified synaptic vesicles, and immuno-organelle isolation, we found that Mover is indeed a peripheral synaptic vesicle membrane protein. In addition, by generating an antibody against phosphorylated Mover and Western blot analysis of fractionated rat brain, we found that Mover is a bona fide phospho-protein. The localization of Mover to synaptic vesicles is phosphorylation dependent; treatment with a phosphatase caused Mover to dissociate from synaptic vesicles. A yeast-2-hybrid screen, co-immunoprecipitation and cell-based optical assays of homomerization revealed that Mover undergoes homophilic interaction, and regions within both the N- and C- terminus of the protein are required for this interaction. Deleting a region required for homomeric interaction abolished presynaptic targeting of recombinant Mover in cultured neurons. Together, these data prove that Mover is associated with synaptic vesicles, and implicate phosphorylation and multimerization in targeting of Mover to synaptic vesicles and presynaptic sites. PMID:23723986

Cell-Autonomous Regulation of Dendritic Spine Density by PirB.

PubMed

Vidal, George S; Djurisic, Maja; Brown, Kiana; Sapp, Richard W; Shatz, Carla J

2016-01-01

Synapse density on cortical pyramidal neurons is modulated by experience. This process is highest during developmental critical periods, when mechanisms of synaptic plasticity are fully engaged. In mouse visual cortex, the critical period for ocular dominance (OD) plasticity coincides with the developmental pruning of synapses. At this time, mice lacking paired Ig-like receptor B (PirB) have excess numbers of dendritic spines on L5 neurons; these spines persist and are thought to underlie the juvenile-like OD plasticity observed in adulthood. Here we examine whether PirB is required specifically in excitatory neurons to exert its effect on dendritic spine and synapse density during the critical period. In mice with a conditional allele of PirB (PirB fl/fl ), PirB was deleted only from L2/3 cortical pyramidal neurons in vivo by timed in utero electroporation of Cre recombinase. Sparse mosaic expression of Cre produced neurons lacking PirB in a sea of wild-type neurons and glia. These neurons had significantly elevated dendritic spine density, as well as increased frequency of miniature EPSCs, suggesting that they receive a greater number of synaptic inputs relative to Cre - neighbors. The effect of cell-specific PirB deletion on dendritic spine density was not accompanied by changes in dendritic branching complexity or axonal bouton density. Together, results imply a neuron-specific, cell-autonomous action of PirB on synaptic density in L2/3 pyramidal cells of visual cortex. Moreover, they are consistent with the idea that PirB functions normally to corepress spine density and synaptic plasticity, thereby maintaining headroom for cells to encode ongoing experience-dependent structural change throughout life.

Control of Excitation/Inhibition Balance in a Hippocampal Circuit by Calcium Sensor Protein Regulation of Presynaptic Calcium Channels.

PubMed

Nanou, Evanthia; Lee, Amy; Catterall, William A

2018-05-02

Activity-dependent regulation controls the balance of synaptic excitation to inhibition in neural circuits, and disruption of this regulation impairs learning and memory and causes many neurological disorders. The molecular mechanisms underlying short-term synaptic plasticity are incompletely understood, and their role in inhibitory synapses remains uncertain. Here we show that regulation of voltage-gated calcium (Ca 2+ ) channel type 2.1 (Ca V 2.1) by neuronal Ca 2+ sensor (CaS) proteins controls synaptic plasticity and excitation/inhibition balance in a hippocampal circuit. Prevention of CaS protein regulation by introducing the IM-AA mutation in Ca V 2.1 channels in male and female mice impairs short-term synaptic facilitation at excitatory synapses of CA3 pyramidal neurons onto parvalbumin (PV)-expressing basket cells. In sharp contrast, the IM-AA mutation abolishes rapid synaptic depression in the inhibitory synapses of PV basket cells onto CA1 pyramidal neurons. These results show that CaS protein regulation of facilitation and inactivation of Ca V 2.1 channels controls the direction of short-term plasticity at these two synapses. Deletion of the CaS protein CaBP1/caldendrin also blocks rapid depression at PV-CA1 synapses, implicating its upregulation of inactivation of Ca V 2.1 channels in control of short-term synaptic plasticity at this inhibitory synapse. Studies of local-circuit function revealed reduced inhibition of CA1 pyramidal neurons by the disynaptic pathway from CA3 pyramidal cells via PV basket cells and greatly increased excitation/inhibition ratio of the direct excitatory input versus indirect inhibitory input from CA3 pyramidal neurons to CA1 pyramidal neurons. This striking defect in local-circuit function may contribute to the dramatic impairment of spatial learning and memory in IM-AA mice. SIGNIFICANCE STATEMENT Many forms of short-term synaptic plasticity in neuronal circuits rely on regulation of presynaptic voltage-gated Ca 2+ (Ca V ) channels. Regulation of Ca V 2.1 channels by neuronal calcium sensor (CaS) proteins controls short-term synaptic plasticity. Here we demonstrate a direct link between regulation of Ca V 2.1 channels and short-term synaptic plasticity in native hippocampal excitatory and inhibitory synapses. We also identify CaBP1/caldendrin as the calcium sensor interacting with Ca V 2.1 channels to mediate rapid synaptic depression in the inhibitory hippocampal synapses of parvalbumin-expressing basket cells to CA1 pyramidal cells. Disruption of this regulation causes altered short-term plasticity and impaired balance of hippocampal excitatory to inhibitory circuits. Copyright © 2018 the authors 0270-6474/18/384430-11$15.00/0.

Encoding of Spatio-Temporal Input Characteristics by a CA1 Pyramidal Neuron Model

PubMed Central

Pissadaki, Eleftheria Kyriaki; Sidiropoulou, Kyriaki; Reczko, Martin; Poirazi, Panayiota

2010-01-01

The in vivo activity of CA1 pyramidal neurons alternates between regular spiking and bursting, but how these changes affect information processing remains unclear. Using a detailed CA1 pyramidal neuron model, we investigate how timing and spatial arrangement variations in synaptic inputs to the distal and proximal dendritic layers influence the information content of model responses. We find that the temporal delay between activation of the two layers acts as a switch between excitability modes: short delays induce bursting while long delays decrease firing. For long delays, the average firing frequency of the model response discriminates spatially clustered from diffused inputs to the distal dendritic tree. For short delays, the onset latency and inter-spike-interval succession of model responses can accurately classify input signals as temporally close or distant and spatially clustered or diffused across different stimulation protocols. These findings suggest that a CA1 pyramidal neuron may be capable of encoding and transmitting presynaptic spatiotemporal information about the activity of the entorhinal cortex-hippocampal network to higher brain regions via the selective use of either a temporal or a rate code. PMID:21187899

Muscles innervated by a single motor neuron exhibit divergent synaptic properties on multiple time scales.

PubMed

Blitz, Dawn M; Pritchard, Amy E; Latimer, John K; Wakefield, Andrew T

2017-04-01

Adaptive changes in the output of neural circuits underlying rhythmic behaviors are relayed to muscles via motor neuron activity. Presynaptic and postsynaptic properties of neuromuscular junctions can impact the transformation from motor neuron activity to muscle response. Further, synaptic plasticity occurring on the time scale of inter-spike intervals can differ between multiple muscles innervated by the same motor neuron. In rhythmic behaviors, motor neuron bursts can elicit additional synaptic plasticity. However, it is unknown whether plasticity regulated by the longer time scale of inter-burst intervals also differs between synapses from the same neuron, and whether any such distinctions occur across a physiological activity range. To address these issues, we measured electrical responses in muscles innervated by a chewing circuit neuron, the lateral gastric (LG) motor neuron, in a well-characterized small motor system, the stomatogastric nervous system (STNS) of the Jonah crab, Cancer borealis In vitro and in vivo , sensory, hormonal and modulatory inputs elicit LG bursting consisting of inter-spike intervals of 50-250 ms and inter-burst intervals of 2-24 s. Muscles expressed similar facilitation measured with paired stimuli except at the shortest inter-spike interval. However, distinct decay time constants resulted in differences in temporal summation. In response to bursting activity, augmentation occurred to different extents and saturated at different inter-burst intervals. Further, augmentation interacted with facilitation, resulting in distinct intra-burst facilitation between muscles. Thus, responses of multiple target muscles diverge across a physiological activity range as a result of distinct synaptic properties sensitive to multiple time scales. © 2017. Published by The Company of Biologists Ltd.

Short-Term Plasticity in a Computational Model of the Tail-Withdrawal Circuit in Aplysia

PubMed Central

Baxter, Douglas A.; Byrne, John H.

2007-01-01

The tail-withdrawal circuit of Aplysia provides a useful model system for investigating synaptic dynamics. Sensory neurons within the circuit manifest several forms of synaptic plasticity. Here, we developed a model of the circuit and investigated the ways in which depression (DEP) and potentiation (POT) contributed to information processing. DEP limited the amount of motor neuron activity that could be elicited by the monosynaptic pathway alone. POT within the monosynaptic pathway did not compensate for DEP. There was, however, a synergistic interaction between POT and the polysynaptic pathway. This synergism extended the dynamic range of the network, and the interplay between DEP and POT made the circuit responded preferentially to long-duration, low-frequency inputs. PMID:17957237

Temperature manipulation of neuronal dynamics in a forebrain motor control nucleus

PubMed Central

Mindlin, Gabriel B.

2017-01-01

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 is based on intrinsic neuronal characteristics, may help to understand emergent behavioral changes. PMID:28829769

Activity-Dependence of Synaptic Vesicle Dynamics

PubMed Central

Forte, Luca A.

2017-01-01

The proper function of synapses relies on efficient recycling of synaptic vesicles. The small size of synaptic boutons has hampered efforts to define the dynamical states of vesicles during recycling. Moreover, whether vesicle motion during recycling is regulated by neural activity remains largely unknown. We combined nanoscale-resolution tracking of individual synaptic vesicles in cultured hippocampal neurons from rats of both sexes with advanced motion analyses to demonstrate that the majority of recently endocytosed vesicles undergo sequences of transient dynamical states including epochs of directed, diffusional, and stalled motion. We observed that vesicle motion is modulated in an activity-dependent manner, with dynamical changes apparent in ∼20% of observed boutons. Within this subpopulation of boutons, 35% of observed vesicles exhibited acceleration and 65% exhibited deceleration, accompanied by corresponding changes in directed motion. Individual vesicles observed in the remaining ∼80% of boutons did not exhibit apparent dynamical changes in response to stimulation. More quantitative transient motion analyses revealed that the overall reduction of vesicle mobility, and specifically of the directed motion component, is the predominant activity-evoked change across the entire bouton population. Activity-dependent modulation of vesicle mobility may represent an important mechanism controlling vesicle availability and neurotransmitter release. SIGNIFICANCE STATEMENT Mechanisms governing synaptic vesicle dynamics during recycling remain poorly understood. Using nanoscale resolution tracking of individual synaptic vesicles in hippocampal synapses and advanced motion analysis tools we demonstrate that synaptic vesicles undergo complex sets of dynamical states that include epochs of directed, diffusive, and stalled motion. Most importantly, our analyses revealed that vesicle motion is modulated in an activity-dependent manner apparent as the reduction in overall vesicle mobility in response to stimulation. These results define the vesicle dynamical states during recycling and reveal their activity-dependent modulation. Our study thus provides fundamental new insights into the principles governing synaptic function. PMID:28954868

A family of photoswitchable NMDA receptors

PubMed Central

Berlin, Shai; Szobota, Stephanie; Reiner, Andreas; Carroll, Elizabeth C; Kienzler, Michael A; Guyon, Alice; Xiao, Tong; Trauner, Dirk; Isacoff, Ehud Y

2016-01-01

NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo-antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino-tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity. DOI: http://dx.doi.org/10.7554/eLife.12040.001 PMID:26929991

Temporal sequence learning in winner-take-all networks of spiking neurons demonstrated in a brain-based device.

PubMed

McKinstry, Jeffrey L; Edelman, Gerald M

2013-01-01

Animal behavior often involves a temporally ordered sequence of actions learned from experience. Here we describe simulations of interconnected networks of spiking neurons that learn to generate patterns of activity in correct temporal order. The simulation consists of large-scale networks of thousands of excitatory and inhibitory neurons that exhibit short-term synaptic plasticity and spike-timing dependent synaptic plasticity. The neural architecture within each area is arranged to evoke winner-take-all (WTA) patterns of neural activity that persist for tens of milliseconds. In order to generate and switch between consecutive firing patterns in correct temporal order, a reentrant exchange of signals between these areas was necessary. To demonstrate the capacity of this arrangement, we used the simulation to train a brain-based device responding to visual input by autonomously generating temporal sequences of motor actions.

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

PubMed

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.

Orientation Selectivity of Synaptic Input to Neurons in Mouse and Cat Primary Visual Cortex

PubMed Central

Tan (陈勇毅), Andrew Y. Y.; Brown, Brandon D.; Scholl, Benjamin; Mohanty, Deepankar; Priebe, Nicholas J.

2011-01-01

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. PMID:21865476

Spike Timing and Reliability in Cortical Pyramidal Neurons: Effects of EPSC Kinetics, Input Synchronization and Background Noise on Spike Timing

PubMed Central

Rodriguez-Molina, Victor M.; Aertsen, Ad; Heck, Detlef H.

2007-01-01

In vivo studies have shown that neurons in the neocortex can generate action potentials at high temporal precision. The mechanisms controlling timing and reliability of action potential generation in neocortical neurons, however, are still poorly understood. Here we investigated the temporal precision and reliability of spike firing in cortical layer V pyramidal cells at near-threshold membrane potentials. Timing and reliability of spike responses were a function of EPSC kinetics, temporal jitter of population excitatory inputs, and of background synaptic noise. We used somatic current injection to mimic population synaptic input events and measured spike probability and spike time precision (STP), the latter defined as the time window (Δt) holding 80% of response spikes. EPSC rise and decay times were varied over the known physiological spectrum. At spike threshold level, EPSC decay time had a stronger influence on STP than rise time. Generally, STP was highest (≤2.45 ms) in response to synchronous compounds of EPSCs with fast rise and decay kinetics. Compounds with slow EPSC kinetics (decay time constants>6 ms) triggered spikes at lower temporal precision (≥6.58 ms). We found an overall linear relationship between STP and spike delay. The difference in STP between fast and slow compound EPSCs could be reduced by incrementing the amplitude of slow compound EPSCs. The introduction of a temporal jitter to compound EPSCs had a comparatively small effect on STP, with a tenfold increase in jitter resulting in only a five fold decrease in STP. In the presence of simulated synaptic background activity, precisely timed spikes could still be induced by fast EPSCs, but not by slow EPSCs. PMID:17389910

Detection of zinc translocation into apical dendrite of CA1 pyramidal neuron after electrical stimulation.

PubMed

Suh, Sang Won

2009-02-15

Translocation of the endogenous cation zinc from presynaptic terminals to postsynaptic neurons after brain insult has been implicated as a potential neurotoxic event. Several studies have previously demonstrated that a brief electrical stimulation is sufficient to induce the translocation of zinc from presynaptic vesicles into the cytoplasm (soma) of postsynaptic neurons. In the present work I have extended those findings in three ways: (i) providing evidence that zinc translocation occurs into apical dendrites, (ii) presenting data that there is an apparent translocation into apical dendrites when only a zinc-containing synaptic input is stimulated, and (iii) presenting data that there is no zinc translocation into apical dendrite of ZnT3 KO mice following electrical stimulation. Hippocampal slices were preloaded with the "trappable" zinc fluorescent probe, Newport Green. After washout, a single apical dendrite in the stratum radiatum of hippocampal CA1 area was selected and focused on. Burst stimulation (100Hz, 500microA, 0.2ms, monopolar) was delivered to either the adjacent Schaffer-collateral inputs (zinc-containing) or to the adjacent temporo-ammonic inputs (zinc-free) to the CA1 dendrites. Stimulation of the Schaffer collaterals increased the dendritic fluorescence, which was blocked by TTX, low-Ca medium, or the extracellular zinc chelator, CaEDTA. Stimulation of the temporo-ammonic pathway caused no significant rise in the fluorescence. Genetic depletion of vesicular zinc by ZnT3 KO showed no stimulation-induced apical dendrite zinc rise. The present study provides evidence that synaptically released zinc translocates into postsynaptic neurons through the apical dendrites of CA1 pyramidal neurons during physiological synaptic activity.

Control of glycinergic input to spinal dorsal horn neurons by distinct muscarinic receptor subtypes revealed using knockout mice.

PubMed

Zhang, Hong-Mei; Zhou, Hong-Yi; Chen, Shao-Rui; Gautam, Dinesh; Wess, Jürgen; Pan, Hui-Lin

2007-12-01

Muscarinic acetylcholine receptors (mAChRs) play an important role in the tonic regulation of nociceptive transmission in the spinal cord. However, how mAChR subtypes contribute to the regulation of synaptic glycine release is unknown. To determine their role, glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in lamina II neurons by using whole-cell recordings in spinal cord slices of wild-type (WT) and mAChR subtype knockout (KO) mice. In WT mice, the mAChR agonist oxotremorine-M dose-dependently decreased the frequency of sIPSCs in most neurons, but it had variable effects in other neurons. In contrast, in M3-KO mice, oxotremorine-M consistently decreased the glycinergic sIPSC frequency in all neurons tested, and in M2/M4 double-KO mice, it always increased the sIPSC frequency. In M2/M4 double-KO mice, the potentiating effect of oxotremorine-M was attenuated by higher concentrations in some neurons through activation of GABA(B) receptors. In pertussis toxin-treated WT mice, oxotremorine-M also consistently increased the sIPSC frequency. In M2-KO and M4-KO mice, the effect of oxotremorine-M on sIPSCs was divergent because of the opposing functions of the M3 subtype and the M2 and M4 subtypes. This study demonstrates that stimulation of the M2 and M4 subtypes inhibits glycinergic inputs to spinal dorsal horn neurons of mice, whereas stimulation of the M3 subtype potentiates synaptic glycine release. Furthermore, GABA(B) receptors are involved in the feedback regulation of glycinergic synaptic transmission in the spinal cord. This study revealed distinct functions of mAChR subtypes in controlling glycinergic input to spinal dorsal horn neurons.

A Three-Threshold Learning Rule Approaches the Maximal Capacity of Recurrent Neural Networks

PubMed Central

Alemi, Alireza; Baldassi, Carlo; Brunel, Nicolas; Zecchina, Riccardo

2015-01-01

Understanding the theoretical foundations of how memories are encoded and retrieved in neural populations is a central challenge in neuroscience. A popular theoretical scenario for modeling memory function is the attractor neural network scenario, whose prototype is the Hopfield model. The model simplicity and the locality of the synaptic update rules come at the cost of a poor storage capacity, compared with the capacity achieved with perceptron learning algorithms. Here, by transforming the perceptron learning rule, we present an online learning rule for a recurrent neural network that achieves near-maximal storage capacity without an explicit supervisory error signal, relying only upon locally accessible information. The fully-connected network consists of excitatory binary neurons with plastic recurrent connections and non-plastic inhibitory feedback stabilizing the network dynamics; the memory patterns to be memorized are presented online as strong afferent currents, producing a bimodal distribution for the neuron synaptic inputs. Synapses corresponding to active inputs are modified as a function of the value of the local fields with respect to three thresholds. Above the highest threshold, and below the lowest threshold, no plasticity occurs. In between these two thresholds, potentiation/depression occurs when the local field is above/below an intermediate threshold. We simulated and analyzed a network of binary neurons implementing this rule and measured its storage capacity for different sizes of the basins of attraction. The storage capacity obtained through numerical simulations is shown to be close to the value predicted by analytical calculations. We also measured the dependence of capacity on the strength of external inputs. Finally, we quantified the statistics of the resulting synaptic connectivity matrix, and found that both the fraction of zero weight synapses and the degree of symmetry of the weight matrix increase with the number of stored patterns. PMID:26291608

A Three-Threshold Learning Rule Approaches the Maximal Capacity of Recurrent Neural Networks.

PubMed

Alemi, Alireza; Baldassi, Carlo; Brunel, Nicolas; Zecchina, Riccardo

2015-08-01

Understanding the theoretical foundations of how memories are encoded and retrieved in neural populations is a central challenge in neuroscience. A popular theoretical scenario for modeling memory function is the attractor neural network scenario, whose prototype is the Hopfield model. The model simplicity and the locality of the synaptic update rules come at the cost of a poor storage capacity, compared with the capacity achieved with perceptron learning algorithms. Here, by transforming the perceptron learning rule, we present an online learning rule for a recurrent neural network that achieves near-maximal storage capacity without an explicit supervisory error signal, relying only upon locally accessible information. The fully-connected network consists of excitatory binary neurons with plastic recurrent connections and non-plastic inhibitory feedback stabilizing the network dynamics; the memory patterns to be memorized are presented online as strong afferent currents, producing a bimodal distribution for the neuron synaptic inputs. Synapses corresponding to active inputs are modified as a function of the value of the local fields with respect to three thresholds. Above the highest threshold, and below the lowest threshold, no plasticity occurs. In between these two thresholds, potentiation/depression occurs when the local field is above/below an intermediate threshold. We simulated and analyzed a network of binary neurons implementing this rule and measured its storage capacity for different sizes of the basins of attraction. The storage capacity obtained through numerical simulations is shown to be close to the value predicted by analytical calculations. We also measured the dependence of capacity on the strength of external inputs. Finally, we quantified the statistics of the resulting synaptic connectivity matrix, and found that both the fraction of zero weight synapses and the degree of symmetry of the weight matrix increase with the number of stored patterns.

Interplay between population firing stability and single neuron dynamics in hippocampal networks

PubMed Central

Slomowitz, Edden; Styr, Boaz; Vertkin, Irena; Milshtein-Parush, Hila; Nelken, Israel; Slutsky, Michael; Slutsky, Inna

2015-01-01

Neuronal circuits' ability to maintain the delicate balance between stability and flexibility in changing environments is critical for normal neuronal functioning. However, to what extent individual neurons and neuronal populations maintain internal firing properties remains largely unknown. In this study, we show that distributions of spontaneous population firing rates and synchrony are subject to accurate homeostatic control following increase of synaptic inhibition in cultured hippocampal networks. Reduction in firing rate triggered synaptic and intrinsic adaptive responses operating as global homeostatic mechanisms to maintain firing macro-stability, without achieving local homeostasis at the single-neuron level. Adaptive mechanisms, while stabilizing population firing properties, reduced short-term facilitation essential for synaptic discrimination of input patterns. Thus, invariant ongoing population dynamics emerge from intrinsically unstable activity patterns of individual neurons and synapses. The observed differences in the precision of homeostatic control at different spatial scales challenge cell-autonomous theory of network homeostasis and suggest the existence of network-wide regulation rules. DOI: http://dx.doi.org/10.7554/eLife.04378.001 PMID:25556699

Differences in the Electrophysiological Properties of Mouse Somatosensory Layer 2/3 Neurons In Vivo and Slice Stem from Intrinsic Sources Rather than a Network-Generated High Conductance State

PubMed Central

2018-01-01

Abstract Synaptic activity in vivo can potentially alter the integration properties of neurons. Using recordings in awake mice, we targeted somatosensory layer 2/3 pyramidal neurons and compared neuronal properties with those from slices. Pyramidal cells in vivo had lower resistance and gain values, as well as broader spikes and increased spike frequency adaptation compared to the same cells in slices. Increasing conductance in neurons using dynamic clamp to levels observed in vivo, however, did not lessen the differences between in vivo and slice conditions. Further, local application of tetrodotoxin (TTX) in vivo blocked synaptic-mediated membrane voltage fluctuations but had little impact on pyramidal cell membrane input resistance and time constant values. Differences in electrophysiological properties of layer 2/3 neurons in mouse somatosensory cortex, therefore, stem from intrinsic sources separate from synaptic-mediated membrane voltage fluctuations. PMID:29662946

CROSS-DISCIPLINARY PHYSICS AND RELATED AREAS OF SCIENCE AND TECHNOLOGY: Mechanism for propagation of rate signals through a 10-layer feedforward neuronal network

NASA Astrophysics Data System (ADS)

Li, Jie; Yu, Wan-Qing; Xu, Ding; Liu, Feng; Wang, Wei

2009-12-01

Using numerical simulations, we explore the mechanism for propagation of rate signals through a 10-layer feedforward network composed of Hodgkin-Huxley (HH) neurons with sparse connectivity. When white noise is afferent to the input layer, neuronal firing becomes progressively more synchronous in successive layers and synchrony is well developed in deeper layers owing to the feedforward connections between neighboring layers. The synchrony ensures the successful propagation of rate signals through the network when the synaptic conductance is weak. As the synaptic time constant τsyn varies, coherence resonance is observed in the network activity due to the intrinsic property of HH neurons. This makes the output firing rate single-peaked as a function of τsyn, suggesting that the signal propagation can be modulated by the synaptic time constant. These results are consistent with experimental results and advance our understanding of how information is processed in feedforward networks.

Excitatory and inhibitory synaptic connectivity to layer V fast-spiking interneurons in the freeze lesion model of cortical microgyria

PubMed Central

Jin, Xiaoming; Jiang, Kewen

2014-01-01

A variety of major developmental cortical malformations are closely associated with clinically intractable epilepsy. Pathophysiological aspects of one such disorder, human polymicrogyria, can be modeled by making neocortical freeze lesions (FL) in neonatal rodents, resulting in the formation of microgyri. Previous studies showed enhanced excitatory and inhibitory synaptic transmission and connectivity in cortical layer V pyramidal neurons in the paramicrogyral cortex. In young adult transgenic mice that express green fluorescent protein (GFP) specifically in parvalbumin positive fast-spiking (FS) interneurons, we used laser scanning photostimulation (LSPS) of caged glutamate to map excitatory and inhibitory synaptic connectivity onto FS interneurons in layer V of paramicrogyral cortex in control and FL groups. The proportion of uncaging sites from which excitatory postsynaptic currents (EPSCs) could be evoked (hotspot ratio) increased slightly but significantly in FS cells of the FL vs. control cortex, while the mean amplitude of LSPS-evoked EPSCs at hotspots did not change. In contrast, the hotspot ratio of inhibitory postsynaptic currents (IPSCs) was significantly decreased in FS neurons of the FL cortex. These alterations in synaptic inputs onto FS interneurons may result in an enhanced inhibitory output. We conclude that alterations in synaptic connectivity to cortical layer V FS interneurons do not contribute to hyperexcitability of the FL model. Instead, the enhanced inhibitory output from these neurons may partially offset an earlier demonstrated increase in synaptic excitation of pyramidal cells and thereby maintain a relative balance between excitation and inhibition in the affected cortical circuitry. PMID:24990567

Metal Toxicity at the Synapse: Presynaptic, Postsynaptic, and Long-Term Effects

PubMed Central

Sadiq, Sanah; Ghazala, Zena; Chowdhury, Arnab; Büsselberg, Dietrich

2012-01-01

Metal neurotoxicity is a global health concern. This paper summarizes the evidence for metal interactions with synaptic transmission and synaptic plasticity. Presynaptically metal ions modulate neurotransmitter release through their interaction with synaptic vesicles, ion channels, and the metabolism of neurotransmitters (NT). Many metals (e.g., Pb 2+, Cd 2+, and Hg +) also interact with intracellular signaling pathways. Postsynaptically, processes associated with the binding of NT to their receptors, activation of channels, and degradation of NT are altered by metals. Zn 2+, Pb 2+, Cu 2+, Cd 2+, Ni 2+, Co 2+, Li 3+, Hg +, and methylmercury modulate NMDA, AMPA/kainate, and/or GABA receptors activity. Al 3+, Pb 2+, Cd 2+, and As 2 O 3 also impair synaptic plasticity by targeting molecules such as CaM, PKC, and NOS as well as the transcription machinery involved in the maintenance of synaptic plasticity. The multiple effects of metals might occur simultaneously and are based on the specific metal species, metal concentrations, and the types of neurons involved. PMID:22287959

Modulation of neuronal signal transduction and memory formation by synaptic zinc.

PubMed

Sindreu, Carlos; Storm, Daniel R

2011-01-01

The physiological role of synaptic zinc has remained largely enigmatic since its initial detection in hippocampal mossy fibers over 50 years ago. The past few years have witnessed a number of studies highlighting the ability of zinc ions to regulate ion channels and intracellular signaling pathways implicated in neuroplasticity, and others that shed some light on the elusive role of synaptic zinc in learning and memory. Recent behavioral studies using knock-out mice for the synapse-specific zinc transporter ZnT-3 indicate that vesicular zinc is required for the formation of memories dependent on the hippocampus and the amygdala, two brain centers that are prominently innervated by zinc-rich fibers. A common theme emerging from this research is the activity-dependent regulation of the Erk1/2 mitogen-activated-protein kinase pathway by synaptic zinc through diverse mechanisms in neurons. Here we discuss current knowledge on how synaptic zinc may play a role in cognition through its impact on neuronal signaling.

Modulation of Neuronal Signal Transduction and Memory Formation by Synaptic Zinc

PubMed Central

Sindreu, Carlos; Storm, Daniel R.

2011-01-01

The physiological role of synaptic zinc has remained largely enigmatic since its initial detection in hippocampal mossy fibers over 50 years ago. The past few years have witnessed a number of studies highlighting the ability of zinc ions to regulate ion channels and intracellular signaling pathways implicated in neuroplasticity, and others that shed some light on the elusive role of synaptic zinc in learning and memory. Recent behavioral studies using knock-out mice for the synapse-specific zinc transporter ZnT-3 indicate that vesicular zinc is required for the formation of memories dependent on the hippocampus and the amygdala, two brain centers that are prominently innervated by zinc-rich fibers. A common theme emerging from this research is the activity-dependent regulation of the Erk1/2 mitogen-activated-protein kinase pathway by synaptic zinc through diverse mechanisms in neurons. Here we discuss current knowledge on how synaptic zinc may play a role in cognition through its impact on neuronal signaling. PMID:22084630

Enhanced excitatory input to melanin concentrating hormone neurons during developmental period of high food intake is mediated by GABA.

PubMed

Li, Ying; van den Pol, Anthony N

2009-12-02

In contrast to the local axons of GABA neurons of the cortex and hippocampus, lateral hypothalamic neurons containing melanin concentrating hormone (MCH) and GABA send long axons throughout the brain and play key roles in energy homeostasis and mental status. In adults, MCH neurons maintain a hyperpolarized membrane potential and most of the synaptic input is inhibitory. In contrast, we found that developing MCH neurons received substantially more excitatory synaptic input. Based on gramicidin-perforated patch recordings in hypothalamic slices from MCH-green fluorescent protein transgenic mice, we found that GABA was the primary excitatory synaptic transmitter in embryonic and neonatal ages up to postnatal day 10. Surprisingly, glutamate assumed only a minor excitatory role, if any. GABA plays a complex role in developing MCH neurons, with its actions conditionally dependent on a number of factors. GABA depolarization could lead to an increase in spikes either independently or in summation with other depolarizing stimuli, or alternately, depending on the relative timing of other depolarizing events, could lead to shunting inhibition. The developmental shift from depolarizing to hyperpolarizing occurred later in the dendrites than in the cell body. Early GABA depolarization was based on a Cl(-)-dependent inward current. An interesting secondary depolarization in mature neurons that followed an initial hyperpolarization was based on a bicarbonate mechanism. Thus during the early developmental period when food consumption is high, MCH neurons are more depolarized than in the adult, and an increased level of excitatory synaptic input to these orexigenic cells is mediated by GABA.

Enhanced excitatory input to MCH neurons during developmental period of high food intake is mediated by GABA

PubMed Central

Li, Ying; van den Pol, Anthony N.

2010-01-01

In contrast to the local axons of GABA neurons of the cortex and hippocampus, lateral hypothalamic neurons containing melanin concentrating hormone (MCH) and GABA send long axons throughout the brain and play key roles in energy homeostasis and mental status. In adults, MCH neurons maintain a hyperpolarized membrane potential and most of the synaptic input is inhibitory. In contrast, we found that developing MCH neurons received substantially more excitatory synaptic input. Based on gramicidicin-perforated patch recordings in hypothalamic slices from MCH-GFP transgenic mice, we found that GABA was the primary excitatory synaptic transmitter in embryonic and neonatal ages up to postnatal day 10. Surprisingly, glutamate assumed only a minor excitatory role, if any. GABA plays a complex role in developing MCH neurons, with its actions conditionally dependent on a number of factors. GABA depolarization could lead to an increase in spikes either independently or in summation with other depolarizing stimuli, or alternately, depending on the relative timing of other depolarizing events, could lead to shunting inhibition. The developmental shift from depolarizing to hyperpolarizing occurred later in the dendrites than in the cell body. Early GABA depolarization was based on a Cl− dependent inward current. An interesting secondary depolarization in mature neurons that followed an initial hyperpolarization was based on a bicarbonate mechanism. Thus during the early developmental period when food consumption is high, MCH neurons are more depolarized than in the adult, and an increased level of excitatory synaptic input to these orexigenic cells is mediated by GABA. PMID:19955372

Pharmacological Analysis of Ionotropic Glutamate Receptor Function in Neuronal Circuits of the Zebrafish Olfactory Bulb

PubMed Central

Tabor, Rico; Friedrich, Rainer W.

2008-01-01

Although synaptic functions of ionotropic glutamate receptors in the olfactory bulb have been studied in vitro, their roles in pattern processing in the intact system remain controversial. We therefore examined the functions of ionotropic glutamate receptors during odor processing in the intact olfactory bulb of zebrafish using pharmacological manipulations. Odor responses of mitral cells and interneurons were recorded by electrophysiology and 2-photon Ca2+ imaging. The combined blockade of AMPA/kainate and NMDA receptors abolished odor-evoked excitation of mitral cells. The blockade of AMPA/kainate receptors alone, in contrast, increased the mean response of mitral cells and decreased the mean response of interneurons. The blockade of NMDA receptors caused little or no change in the mean responses of mitral cells and interneurons. However, antagonists of both receptor types had diverse effects on the magnitude and time course of individual mitral cell and interneuron responses and, thus, changed spatio-temporal activity patterns across neuronal populations. Oscillatory synchronization was abolished or reduced by AMPA/kainate and NMDA receptor antagonists, respectively. These results indicate that (1) interneuron responses depend mainly on AMPA/kainate receptor input during an odor response, (2) interactions among mitral cells and interneurons regulate the total olfactory bulb output activity, (3) AMPA/kainate receptors participate in the synchronization of odor-dependent neuronal ensembles, and (4) ionotropic glutamate receptor-containing synaptic circuits shape odor-specific patterns of olfactory bulb output activity. These mechanisms are likely to be important for the processing of odor-encoding activity patterns in the olfactory bulb. PMID:18183297

Glucose Rapidly Induces Different Forms of Excitatory Synaptic Plasticity in Hypothalamic POMC Neurons

PubMed Central

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

A fast BK-type KCa current acts as a postsynaptic modulator of temporal selectivity for communication signals.

PubMed

Kohashi, Tsunehiko; Carlson, Bruce A

2014-01-01

Temporal patterns of spiking often convey behaviorally relevant information. Various synaptic mechanisms and intrinsic membrane properties can influence neuronal selectivity to temporal patterns of input. However, little is known about how synaptic mechanisms and intrinsic properties together determine the temporal selectivity of neuronal output. We tackled this question by recording from midbrain electrosensory neurons in mormyrid fish, in which the processing of temporal intervals between communication signals can be studied in a reduced in vitro preparation. Mormyrids communicate by varying interpulse intervals (IPIs) between electric pulses. Within the midbrain posterior exterolateral nucleus (ELp), the temporal patterns of afferent spike trains are filtered to establish single-neuron IPI tuning. We performed whole-cell recording from ELp neurons in a whole-brain preparation and examined the relationship between intrinsic excitability and IPI tuning. We found that spike frequency adaptation of ELp neurons was highly variable. Postsynaptic potentials (PSPs) of strongly adapting (phasic) neurons were more sharply tuned to IPIs than weakly adapting (tonic) neurons. Further, the synaptic filtering of IPIs by tonic neurons was more faithfully converted into variation in spiking output, particularly at short IPIs. Pharmacological manipulation under current- and voltage-clamp revealed that tonic firing is mediated by a fast, large-conductance Ca(2+)-activated K(+) (KCa) current (BK) that speeds up action potential repolarization. These results suggest that BK currents can shape the temporal filtering of sensory inputs by modifying both synaptic responses and PSP-to-spike conversion. Slow SK-type KCa currents have previously been implicated in temporal processing. Thus, both fast and slow KCa currents can fine-tune temporal selectivity.

Discharge regularity in the turtle posterior crista: comparisons between experiment and theory.

PubMed

Goldberg, Jay M; Holt, Joseph C

2013-12-01

Intra-axonal recordings were made from bouton fibers near their termination in the turtle posterior crista. Spike discharge, miniature excitatory postsynaptic potentials (mEPSPs), and afterhyperpolarizations (AHPs) were monitored during resting activity in both regularly and irregularly discharging units. Quantal size (qsize) and quantal rate (qrate) were estimated by shot-noise theory. Theoretically, the ratio, σV/(dμV/dt), between synaptic noise (σV) and the slope of the mean voltage trajectory (dμV/dt) near threshold crossing should determine discharge regularity. AHPs are deeper and more prolonged in regular units; as a result, dμV/dt is larger, the more regular the discharge. The qsize is larger and qrate smaller in irregular units; these oppositely directed trends lead to little variation in σV with discharge regularity. Of the two variables, dμV/dt is much more influential than the nearly constant σV in determining regularity. Sinusoidal canal-duct indentations at 0.3 Hz led to modulations in spike discharge and synaptic voltage. Gain, the ratio between the amplitudes of the two modulations, and phase leads re indentation of both modulations are larger in irregular units. Gain variations parallel the sensitivity of the postsynaptic spike encoder, the set of conductances that converts synaptic input into spike discharge. Phase variations reflect both synaptic inputs to the encoder and postsynaptic processes. Experimental data were interpreted using a stochastic integrate-and-fire model. Advantages of an irregular discharge include an enhanced encoder gain and the prevention of nonlinear phase locking. Regular and irregular units are more efficient, respectively, in the encoding of low- and high-frequency head rotations, respectively.

Discharge regularity in the turtle posterior crista: comparisons between experiment and theory

PubMed Central

Holt, Joseph C.

2013-01-01

Intra-axonal recordings were made from bouton fibers near their termination in the turtle posterior crista. Spike discharge, miniature excitatory postsynaptic potentials (mEPSPs), and afterhyperpolarizations (AHPs) were monitored during resting activity in both regularly and irregularly discharging units. Quantal size (qsize) and quantal rate (qrate) were estimated by shot-noise theory. Theoretically, the ratio, σV/(dμV/dt), between synaptic noise (σV) and the slope of the mean voltage trajectory (dμV/dt) near threshold crossing should determine discharge regularity. AHPs are deeper and more prolonged in regular units; as a result, dμV/dt is larger, the more regular the discharge. The qsize is larger and qrate smaller in irregular units; these oppositely directed trends lead to little variation in σV with discharge regularity. Of the two variables, dμV/dt is much more influential than the nearly constant σV in determining regularity. Sinusoidal canal-duct indentations at 0.3 Hz led to modulations in spike discharge and synaptic voltage. Gain, the ratio between the amplitudes of the two modulations, and phase leads re indentation of both modulations are larger in irregular units. Gain variations parallel the sensitivity of the postsynaptic spike encoder, the set of conductances that converts synaptic input into spike discharge. Phase variations reflect both synaptic inputs to the encoder and postsynaptic processes. Experimental data were interpreted using a stochastic integrate-and-fire model. Advantages of an irregular discharge include an enhanced encoder gain and the prevention of nonlinear phase locking. Regular and irregular units are more efficient, respectively, in the encoding of low- and high-frequency head rotations, respectively. PMID:24004525

Asynchronous inputs alter excitability, spike timing, and topography in primary auditory cortex

PubMed Central

Pandya, Pritesh K.; Moucha, Raluca; Engineer, Navzer D.; Rathbun, Daniel L.; Vazquez, Jessica; Kilgard, Michael P.

2010-01-01

Correlation-based synaptic plasticity provides a potential cellular mechanism for learning and memory. Studies in the visual and somatosensory systems have shown that behavioral and surgical manipulation of sensory inputs leads to changes in cortical organization that are consistent with the operation of these learning rules. In this study, we examine how the organization of primary auditory cortex (A1) is altered by tones designed to decrease the average input correlation across the frequency map. After one month of separately pairing nucleus basalis stimulation with 2 and 14 kHz tones, a greater proportion of A1 neurons responded to frequencies below 2 kHz and above 14 kHz. Despite the expanded representation of these tones, cortical excitability was specifically reduced in the high and low frequency regions of A1, as evidenced by increased neural thresholds and decreased response strength. In contrast, in the frequency region between the two paired tones, driven rates were unaffected and spontaneous firing rate was increased. Neural response latencies were increased across the frequency map when nucleus basalis stimulation was associated with asynchronous activation of the high and low frequency regions of A1. This set of changes did not occur when pulsed noise bursts were paired with nucleus basalis stimulation. These results are consistent with earlier observations that sensory input statistics can shape cortical map organization and spike timing. PMID:15855025

Caspase-like activity is essential for long-term synaptic plasticity in the terrestrial snail Helix.

PubMed

Bravarenko, N I; Onufriev, M V; Stepanichev, M Yu; Ierusalimsky, V N; Balaban, P M; Gulyaeva, N V

2006-01-01

Although caspase activity in the nervous system of mollusks has not been described before, we suggested that these cysteine proteases might be involved in the phenomena of neuroplasticity in mollusks. We directly measured caspase-3 (DEVDase) activity in the Helix lucorum central nervous system (CNS) using a fluorometrical approach and showed that the caspase-3-like immunoreactivity is present in the central neurons of Helix. Western blots revealed the presence of caspase-3-immunoreactive proteins with a molecular mass of 29 kDa. Staurosporin application, routinely used to induce apoptosis in mammalian neurons through the activating cleavage of caspase-3, did not result in the appearance of a smaller subunit corresponding to the active caspase in the snail. However, it did increase the enzyme activity in the snail CNS. This suggests differences in the regulation of caspase-3 activity in mammals and snails. In the snail CNS, the caspase homolog seems to possess an active center without activating cleavage typical for mammals. In electrophysiological experiments with identified snail neurons, selective blockade of the caspase-3 with the irreversible and cell-permeable inhibitor of caspase-3 N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp-(OMe)-fluoro-methylketone prevented development of the long-term stage of synaptic input sensitization, suggesting that caspase is necessary for normal synaptic plasticity in snails. The results of our study give the first direct evidence that the caspase-3-like activity is essential for long-term plasticity in the invertebrate neurons. This activity is presumably involved in removing inhibitory constraints on the storage of long-term memory.

Exploring the retinal connectome

PubMed Central

Anderson, James R.; Jones, Bryan W.; Watt, Carl B.; Shaw, Margaret V.; Yang, Jia-Hui; DeMill, David; Lauritzen, James S.; Lin, Yanhua; Rapp, Kevin D.; Mastronarde, David; Koshevoy, Pavel; Grimm, Bradley; Tasdizen, Tolga; Whitaker, Ross

2011-01-01

Purpose A connectome is a comprehensive description of synaptic connectivity for a neural domain. Our goal was to produce a connectome data set for the inner plexiform layer of the mammalian retina. This paper describes our first retinal connectome, validates the method, and provides key initial findings. Methods We acquired and assembled a 16.5 terabyte connectome data set RC1 for the rabbit retina at ≈2 nm resolution using automated transmission electron microscope imaging, automated mosaicking, and automated volume registration. RC1 represents a column of tissue 0.25 mm in diameter, spanning the inner nuclear, inner plexiform, and ganglion cell layers. To enhance ultrastructural tracing, we included molecular markers for 4-aminobutyrate (GABA), glutamate, glycine, taurine, glutamine, and the in vivo activity marker, 1-amino-4-guanidobutane. This enabled us to distinguish GABAergic and glycinergic amacrine cells; to identify ON bipolar cells coupled to glycinergic cells; and to discriminate different kinds of bipolar, amacrine, and ganglion cells based on their molecular signatures and activity. The data set was explored and annotated with Viking, our multiuser navigation tool. Annotations were exported to additional applications to render cells, visualize network graphs, and query the database. Results Exploration of RC1 showed that the 2 nm resolution readily recapitulated well known connections and revealed several new features of retinal organization: (1) The well known AII amacrine cell pathway displayed more complexity than previously reported, with no less than 17 distinct signaling modes, including ribbon synapse inputs from OFF bipolar cells, wide-field ON cone bipolar cells and rod bipolar cells, and extensive input from cone-pathway amacrine cells. (2) The axons of most cone bipolar cells formed a distinct signal integration compartment, with ON cone bipolar cell axonal synapses targeting diverse cell types. Both ON and OFF bipolar cells receive axonal veto synapses. (3) Chains of conventional synapses were very common, with intercalated glycinergic-GABAergic chains and very long chains associated with starburst amacrine cells. Glycinergic amacrine cells clearly play a major role in ON-OFF crossover inhibition. (4) Molecular and excitation mapping clearly segregates ultrastructurally defined bipolar cell groups into different response clusters. (5) Finally, low-resolution electron or optical imaging cannot reliably map synaptic connections by process geometry, as adjacency without synaptic contact is abundant in the retina. Only direct visualization of synapses and gap junctions suffices. Conclusions Connectome assembly and analysis using conventional transmission electron microscopy is now practical for network discovery. Our surveys of volume RC1 demonstrate that previously studied systems such as the AII amacrine cell network involve more network motifs than previously known. The AII network, primarily considered a scotopic pathway, clearly derives ribbon synapse input from photopic ON and OFF cone bipolar cell networks and extensive photopic GABAergic amacrine cell inputs. Further, bipolar cells show extensive inputs and outputs along their axons, similar to multistratified nonmammalian bipolar cells. Physiologic evidence of significant ON-OFF channel crossover is strongly supported by our anatomic data, showing alternating glycine-to-GABA paths. Long chains of amacrine cell networks likely arise from homocellular GABAergic synapses between starburst amacrine cells. Deeper analysis of RC1 offers the opportunity for more complete descriptions of specific networks. PMID:21311605

Exploring the retinal connectome.

PubMed

Anderson, James R; Jones, Bryan W; Watt, Carl B; Shaw, Margaret V; Yang, Jia-Hui; Demill, David; Lauritzen, James S; Lin, Yanhua; Rapp, Kevin D; Mastronarde, David; Koshevoy, Pavel; Grimm, Bradley; Tasdizen, Tolga; Whitaker, Ross; Marc, Robert E

2011-02-03

A connectome is a comprehensive description of synaptic connectivity for a neural domain. Our goal was to produce a connectome data set for the inner plexiform layer of the mammalian retina. This paper describes our first retinal connectome, validates the method, and provides key initial findings. We acquired and assembled a 16.5 terabyte connectome data set RC1 for the rabbit retina at ≈ 2 nm resolution using automated transmission electron microscope imaging, automated mosaicking, and automated volume registration. RC1 represents a column of tissue 0.25 mm in diameter, spanning the inner nuclear, inner plexiform, and ganglion cell layers. To enhance ultrastructural tracing, we included molecular markers for 4-aminobutyrate (GABA), glutamate, glycine, taurine, glutamine, and the in vivo activity marker, 1-amino-4-guanidobutane. This enabled us to distinguish GABAergic and glycinergic amacrine cells; to identify ON bipolar cells coupled to glycinergic cells; and to discriminate different kinds of bipolar, amacrine, and ganglion cells based on their molecular signatures and activity. The data set was explored and annotated with Viking, our multiuser navigation tool. Annotations were exported to additional applications to render cells, visualize network graphs, and query the database. Exploration of RC1 showed that the 2 nm resolution readily recapitulated well known connections and revealed several new features of retinal organization: (1) The well known AII amacrine cell pathway displayed more complexity than previously reported, with no less than 17 distinct signaling modes, including ribbon synapse inputs from OFF bipolar cells, wide-field ON cone bipolar cells and rod bipolar cells, and extensive input from cone-pathway amacrine cells. (2) The axons of most cone bipolar cells formed a distinct signal integration compartment, with ON cone bipolar cell axonal synapses targeting diverse cell types. Both ON and OFF bipolar cells receive axonal veto synapses. (3) Chains of conventional synapses were very common, with intercalated glycinergic-GABAergic chains and very long chains associated with starburst amacrine cells. Glycinergic amacrine cells clearly play a major role in ON-OFF crossover inhibition. (4) Molecular and excitation mapping clearly segregates ultrastructurally defined bipolar cell groups into different response clusters. (5) Finally, low-resolution electron or optical imaging cannot reliably map synaptic connections by process geometry, as adjacency without synaptic contact is abundant in the retina. Only direct visualization of synapses and gap junctions suffices. Connectome assembly and analysis using conventional transmission electron microscopy is now practical for network discovery. Our surveys of volume RC1 demonstrate that previously studied systems such as the AII amacrine cell network involve more network motifs than previously known. The AII network, primarily considered a scotopic pathway, clearly derives ribbon synapse input from photopic ON and OFF cone bipolar cell networks and extensive photopic GABAergic amacrine cell inputs. Further, bipolar cells show extensive inputs and outputs along their axons, similar to multistratified nonmammalian bipolar cells. Physiologic evidence of significant ON-OFF channel crossover is strongly supported by our anatomic data, showing alternating glycine-to-GABA paths. Long chains of amacrine cell networks likely arise from homocellular GABAergic synapses between starburst amacrine cells. Deeper analysis of RC1 offers the opportunity for more complete descriptions of specific networks.

Pathological effect of homeostatic synaptic scaling on network dynamics in diseases of the cortex.

PubMed

Fröhlich, Flavio; Bazhenov, Maxim; Sejnowski, Terrence J

2008-02-13

Slow periodic EEG discharges are common in CNS disorders. The pathophysiology of this aberrant rhythmic activity is poorly understood. We used a computational model of a neocortical network with a dynamic homeostatic scaling rule to show that loss of input (partial deafferentation) can trigger network reorganization that results in pathological periodic discharges. The decrease in average firing rate in the network by deafferentation was compensated by homeostatic synaptic scaling of recurrent excitation among pyramidal cells. Synaptic scaling succeeded in recovering the network target firing rate for all degrees of deafferentation (fraction of deafferented cells), but there was a critical degree of deafferentation for pathological network reorganization. For deafferentation degrees below this value, homeostatic upregulation of recurrent excitation had minimal effect on the macroscopic network dynamics. For deafferentation above this threshold, however, a slow periodic oscillation appeared, patterns of activity were less sparse, and bursting occurred in individual neurons. Also, comparison of spike-triggered afferent and recurrent excitatory conductances revealed that information transmission was strongly impaired. These results suggest that homeostatic plasticity can lead to secondary functional impairment in case of cortical disorders associated with cell loss.

Synaptic integration in dendrites: exceptional need for speed

PubMed Central

Golding, Nace L; Oertel, Donata

2012-01-01

Some neurons in the mammalian auditory system are able to detect and report the coincident firing of inputs with remarkable temporal precision. A strong, low-voltage-activated potassium conductance (gKL) at the cell body and dendrites gives these neurons sensitivity to the rate of depolarization by EPSPs, allowing neurons to assess the coincidence of the rising slopes of unitary EPSPs. Two groups of neurons in the brain stem, octopus cells in the posteroventral cochlear nucleus and principal cells of the medial superior olive (MSO), extract acoustic information by assessing coincident firing of their inputs over a submillisecond timescale and convey that information at rates of up to 1000 spikes s−1. Octopus cells detect the coincident activation of groups of auditory nerve fibres by broadband transient sounds, compensating for the travelling wave delay by dendritic filtering, while MSO neurons detect coincident activation of similarly tuned neurons from each of the two ears through separate dendritic tufts. Each makes use of filtering that is introduced by the spatial distribution of inputs on dendrites. PMID:22930273

Post-Inhibitory Rebound Spikes in Rat Medial Entorhinal Layer II/III Principal Cells: In Vivo, In Vitro, and Computational Modeling Characterization

PubMed Central

Ferrante, Michele; Shay, Christopher F.; Tsuno, Yusuke; William Chapman, G.; Hasselmo, Michael E.

2017-01-01

Abstract Medial entorhinal cortex Layer-II stellate cells (mEC-LII-SCs) primarily interact via inhibitory interneurons. This suggests the presence of alternative mechanisms other than excitatory synaptic inputs for triggering action potentials (APs) in stellate cells during spatial navigation. Our intracellular recordings show that the hyperpolarization-activated cation current (Ih) allows post-inhibitory-rebound spikes (PIRS) in mEC-LII-SCs. In vivo, strong inhibitory-post-synaptic potentials immediately preceded most APs shortening their delay and enhancing excitability. In vitro experiments showed that inhibition initiated spikes more effectively than excitation and that more dorsal mEC-LII-SCs produced faster and more synchronous spikes. In contrast, PIRS in Layer-II/III pyramidal cells were harder to evoke, voltage-independent, and slower in dorsal mEC. In computational simulations, mEC-LII-SCs morphology and Ih homeostatically regulated the dorso-ventral differences in PIRS timing and most dendrites generated PIRS with a narrow range of stimulus amplitudes. These results suggest inhibitory inputs could mediate the emergence of grid cell firing in a neuronal network. PMID:26965902

The dependence of neuronal encoding efficiency on Hebbian plasticity and homeostatic regulation of neurotransmitter release

PubMed Central

Faghihi, Faramarz; Moustafa, Ahmed A.

2015-01-01

Synapses act as information filters by different molecular mechanisms including retrograde messenger that affect neuronal spiking activity. One of the well-known effects of retrograde messenger in presynaptic neurons is a change of the probability of neurotransmitter release. Hebbian learning describe a strengthening of a synapse between a presynaptic input onto a postsynaptic neuron when both pre- and postsynaptic neurons are coactive. In this work, a theory of homeostatic regulation of neurotransmitter release by retrograde messenger and Hebbian plasticity in neuronal encoding is presented. Encoding efficiency was measured for different synaptic conditions. In order to gain high encoding efficiency, the spiking pattern of a neuron should be dependent on the intensity of the input and show low levels of noise. In this work, we represent spiking trains as zeros and ones (corresponding to non-spike or spike in a time bin, respectively) as words with length equal to three. Then the frequency of each word (here eight words) is measured using spiking trains. These frequencies are used to measure neuronal efficiency in different conditions and for different parameter values. Results show that neurons that have synapses acting as band-pass filters show the highest efficiency to encode their input when both Hebbian mechanism and homeostatic regulation of neurotransmitter release exist in synapses. Specifically, the integration of homeostatic regulation of feedback inhibition with Hebbian mechanism and homeostatic regulation of neurotransmitter release in the synapses leads to even higher efficiency when high stimulus intensity is presented to the neurons. However, neurons with synapses acting as high-pass filters show no remarkable increase in encoding efficiency for all simulated synaptic plasticity mechanisms. This study demonstrates the importance of cooperation of Hebbian mechanism with regulation of neurotransmitter release induced by rapid diffused retrograde messenger in neurons with synapses as low and band-pass filters to obtain high encoding efficiency in different environmental and physiological conditions. PMID:25972786

The emergence of polychronization and feature binding in a spiking neural network model of the primate ventral visual system.

PubMed

Eguchi, Akihiro; Isbister, James B; Ahmad, Nasir; Stringer, Simon

2018-07-01

We present a hierarchical neural network model, in which subpopulations of neurons develop fixed and regularly repeating temporal chains of spikes (polychronization), which respond specifically to randomized Poisson spike trains representing the input training images. The performance is improved by including top-down and lateral synaptic connections, as well as introducing multiple synaptic contacts between each pair of pre- and postsynaptic neurons, with different synaptic contacts having different axonal delays. Spike-timing-dependent plasticity thus allows the model to select the most effective axonal transmission delay between neurons. Furthermore, neurons representing the binding relationship between low-level and high-level visual features emerge through visually guided learning. This begins to provide a way forward to solving the classic feature binding problem in visual neuroscience and leads to a new hypothesis concerning how information about visual features at every spatial scale may be projected upward through successive neuronal layers. We name this hypothetical upward projection of information the "holographic principle." (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Spike-timing-dependent plasticity in the human dorso-lateral prefrontal cortex.

PubMed

Casula, Elias Paolo; Pellicciari, Maria Concetta; Picazio, Silvia; Caltagirone, Carlo; Koch, Giacomo

2016-12-01

Changes in the synaptic strength of neural connections are induced by repeated coupling of activity of interconnected neurons with precise timing, a phenomenon known as spike-timing-dependent plasticity (STDP). It is debated if this mechanism exists in large-scale cortical networks in humans. We combined transcranial magnetic stimulation (TMS) with concurrent electroencephalography (EEG) to directly investigate the effects of two paired associative stimulation (PAS) protocols (fronto-parietal and parieto-frontal) of pre and post-synaptic inputs within the human fronto-parietal network. We found evidence that the dorsolateral prefrontal cortex (DLPFC) has the potential to form robust STDP. Long-term potentiation/depression of TMS-evoked cortical activity is prompted after that DLPFC stimulation is followed/preceded by posterior parietal stimulation. Such bidirectional changes are paralleled by sustained increase/decrease of high-frequency oscillatory activity, likely reflecting STDP responsivity. The current findings could be important to drive plasticity of damaged cortical circuits in patients with cognitive or psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Reactivation in Working Memory: An Attractor Network Model of Free Recall

PubMed Central

Lansner, Anders; Marklund, Petter; Sikström, Sverker; Nilsson, Lars-Göran

2013-01-01

The dynamic nature of human working memory, the general-purpose system for processing continuous input, while keeping no longer externally available information active in the background, is well captured in immediate free recall of supraspan word-lists. Free recall tasks produce several benchmark memory phenomena, like the U-shaped serial position curve, reflecting enhanced memory for early and late list items. To account for empirical data, including primacy and recency as well as contiguity effects, we propose here a neurobiologically based neural network model that unifies short- and long-term forms of memory and challenges both the standard view of working memory as persistent activity and dual-store accounts of free recall. Rapidly expressed and volatile synaptic plasticity, modulated intrinsic excitability, and spike-frequency adaptation are suggested as key cellular mechanisms underlying working memory encoding, reactivation and recall. Recent findings on the synaptic and molecular mechanisms behind early LTP and on spiking activity during delayed-match-to-sample tasks support this view. PMID:24023690

Reactivation in working memory: an attractor network model of free recall.

PubMed

Lansner, Anders; Marklund, Petter; Sikström, Sverker; Nilsson, Lars-Göran

2013-01-01

The dynamic nature of human working memory, the general-purpose system for processing continuous input, while keeping no longer externally available information active in the background, is well captured in immediate free recall of supraspan word-lists. Free recall tasks produce several benchmark memory phenomena, like the U-shaped serial position curve, reflecting enhanced memory for early and late list items. To account for empirical data, including primacy and recency as well as contiguity effects, we propose here a neurobiologically based neural network model that unifies short- and long-term forms of memory and challenges both the standard view of working memory as persistent activity and dual-store accounts of free recall. Rapidly expressed and volatile synaptic plasticity, modulated intrinsic excitability, and spike-frequency adaptation are suggested as key cellular mechanisms underlying working memory encoding, reactivation and recall. Recent findings on the synaptic and molecular mechanisms behind early LTP and on spiking activity during delayed-match-to-sample tasks support this view.

The Chronotron: A Neuron That Learns to Fire Temporally Precise Spike Patterns

PubMed Central

Florian, Răzvan V.

2012-01-01

In many cases, neurons process information carried by the precise timings of spikes. Here we show how neurons can learn to generate specific temporally precise output spikes in response to input patterns of spikes having precise timings, thus processing and memorizing information that is entirely temporally coded, both as input and as output. We introduce two new supervised learning rules for spiking neurons with temporal coding of information (chronotrons), one that provides high memory capacity (E-learning), and one that has a higher biological plausibility (I-learning). With I-learning, the neuron learns to fire the target spike trains through synaptic changes that are proportional to the synaptic currents at the timings of real and target output spikes. We study these learning rules in computer simulations where we train integrate-and-fire neurons. Both learning rules allow neurons to fire at the desired timings, with sub-millisecond precision. We show how chronotrons can learn to classify their inputs, by firing identical, temporally precise spike trains for different inputs belonging to the same class. When the input is noisy, the classification also leads to noise reduction. We compute lower bounds for the memory capacity of chronotrons and explore the influence of various parameters on chronotrons' performance. The chronotrons can model neurons that encode information in the time of the first spike relative to the onset of salient stimuli or neurons in oscillatory networks that encode information in the phases of spikes relative to the background oscillation. Our results show that firing one spike per cycle optimizes memory capacity in neurons encoding information in the phase of firing relative to a background rhythm. PMID:22879876

Expression of TRPV1 channels by Cajal-Retzius cells and layer-specific modulation of synaptic transmission by capsaicin in the mouse hippocampus.

PubMed

Anstötz, Max; Lee, Sun Kyong; Maccaferri, Gianmaria

2018-05-28

By taking advantage of calcium imaging and electrophysiology, we provide direct pharmacological evidence for the functional expression of TRPV1 channels in hippocampal Cajal-Retzius cells. Application of the TRPV1 activator capsaicin powerfully enhances spontaneous synaptic transmission in the hippocampal layers that are innervated by the axons of Cajal-Retzius cells. Capsaicin-triggered calcium responses and membrane currents in Cajal-Retzius cells, as well as layer-specific modulation of spontaneous synaptic transmission, are absent when the drug is applied to slices prepared from TRPV1 - / - animals. We discuss the implications of the functional expression of TRPV1 channels in Cajal-Retzius cells and of the observed TRPV1-dependent layer-specific modulation of synaptic transmission for physiological and pathological network processing. The vanilloid receptor TRPV1 forms complex polymodal channels that are expressed by sensory neurons and play a critical role in nociception. Their distribution pattern and functions in cortical circuits are, however, much less understood. Although TRPV1 reporter mice have suggested that, in the hippocampus, TRPV1 is predominantly expressed by Cajal-Retzius cells (CRs), direct functional evidence is missing. As CRs powerfully excite GABAergic interneurons of the molecular layers, TRPV1 could play important roles in the regulation of layer-specific processing. Here, we have taken advantage of calcium imaging with the genetically encoded indicator GCaMP6s and patch-clamp techniques to study the responses of hippocampal CRs to the activation of TRPV1 by capsaicin, and have compared the effect of TRPV1 stimulation on synaptic transmission in layers innervated or non-innervated by CRs. Capsaicin induced both calcium responses and membrane currents in ∼50% of the cell tested. Neither increases of intracellular calcium nor whole-cell currents were observed in the presence of the TRPV1 antagonists capsazepine/Ruthenium Red or in slices prepared from TRPV1 knockout mice. We also report a powerful TRPV1-dependent enhancement of spontaneous synaptic transmission onto interneurons with dendritic trees confined to the layers innervated by CRs. In conclusion, our work establishes that functional TRPV1 is expressed by a significant fraction of CRs and we propose that TRPV1 activity may regulate layer-specific synaptic transmission in the hippocampus. Lastly, as CR density decreases during postnatal development, we also propose that functional TRPV1 receptors may be related to mechanisms involved in CR progressive reduction by calcium-dependent toxicity/apoptosis. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Synaptic remodeling generates synchronous oscillations in the degenerated outer mouse retina

PubMed Central

Haq, Wadood; Arango-Gonzalez, Blanca; Zrenner, Eberhart; Euler, Thomas; Schubert, Timm

2014-01-01

During neuronal degenerative diseases, neuronal microcircuits undergo severe structural alterations, leading to remodeling of synaptic connectivity. The functional consequences of such remodeling are mostly unknown. For instance, in mutant rd1 mouse retina, a common model for Retinitis Pigmentosa, rod bipolar cells (RBCs) establish contacts with remnant cone photoreceptors (cones) as a consequence of rod photoreceptor cell death and the resulting lack of presynaptic input. To assess the functional connectivity in the remodeled, light-insensitive outer rd1 retina, we recorded spontaneous population activity in retinal wholemounts using Ca2+ imaging and identified the participating cell types. Focusing on cones, RBCs and horizontal cells (HCs), we found that these cell types display spontaneous oscillatory activity and form synchronously active clusters. Overall activity was modulated by GABAergic inhibition from interneurons such as HCs and/or possibly interplexiform cells. Many of the activity clusters comprised both cones and RBCs. Opposite to what is expected from the intact (wild-type) cone-ON bipolar cell pathway, cone and RBC activity was positively correlated and, at least partially, mediated by glutamate transporters expressed on RBCs. Deletion of gap junctional coupling between cones reduced the number of clusters, indicating that electrical cone coupling plays a crucial role for generating the observed synchronized oscillations. In conclusion, degeneration-induced synaptic remodeling of the rd1 retina results in a complex self-sustained outer retinal oscillatory network, that complements (and potentially modulates) the recently described inner retinal oscillatory network consisting of amacrine, bipolar and ganglion cells. PMID:25249942

Hexamethonium sensitivity of the swim musculature of the pteropod mollusc, Clione limacina.

PubMed

Satterlie, Richard A; Courtney, Christopher

2008-12-01

Swimming in reduced electrophysiological preparations of the pteropod mollusc, Clione limacina, was blocked by bath application of hexamethonium even though pattern generator activity continued with this treatment. Neuromuscular recordings indicated that hexamethonium blocked synaptic input from Pd-3 and Pd-4 motoneurons to slow-twitch muscle cells, while connections from Pd-1A and Pd-2A motoneurons to fast-twitch muscle cells were variable in their response to hexamethonium-synaptic inputs were suppressed in most cases and occasionally blocked, but the latter only with high concentrations and long incubations. Acutely dissociated wing muscle cells showed a concentration-dependency in the percentage of contracted cells with bath application of acetylcholine, and this contractile activity was blocked in preparations that were first bathed in hexamethonium. Intracellular recordings from dissociated slow-twitch muscle cells showed conductance-increase depolarizations of approximately 20 mV following 1 s pressure ejections of 10(-4) M acetylcholine from micropipettes placed immediately adjacent to the muscle cells. These responses were blocked when hexamethonium was bath applied prior to the pressure-applied acetylcholine. The results suggest the Pd-3/Pd-4 motoneuron to slow-twitch muscle cell junctions are cholinergic with nicotinic-like receptors, while the Pd-1A/Pd-2A to fast-twitch muscle cell connections are likely cholinergic, but with a different receptor type.

Unc-51 controls active zone density and protein composition by downregulating ERK signaling.

PubMed

Wairkar, Yogesh P; Toda, Hirofumi; Mochizuki, Hiroaki; Furukubo-Tokunaga, Katsuo; Tomoda, Toshifumi; Diantonio, Aaron

2009-01-14

Efficient synaptic transmission requires the apposition of neurotransmitter release sites opposite clusters of postsynaptic neurotransmitter receptors. Transmitter is released at active zones, which are composed of a large complex of proteins necessary for synaptic development and function. Many active zone proteins have been identified, but little is known of the mechanisms that ensure that each active zone receives the proper complement of proteins. Here we use a genetic analysis in Drosophila to demonstrate that the serine threonine kinase Unc-51 acts in the presynaptic motoneuron to regulate the localization of the active zone protein Bruchpilot opposite to glutamate receptors at each synapse. In the absence of Unc-51, many glutamate receptor clusters are unapposed to Bruchpilot, and ultrastructural analysis demonstrates that fewer active zones contain dense body T-bars. In addition to the presence of these aberrant synapses, there is also a decrease in the density of all synapses. This decrease in synaptic density and abnormal active zone composition is associated with impaired evoked transmitter release. Mechanistically, Unc-51 inhibits the activity of the MAP kinase ERK to promote synaptic development. In the unc-51 mutant, increased ERK activity leads to the decrease in synaptic density and the absence of Bruchpilot from many synapses. Hence, activated ERK negatively regulates synapse formation, resulting in either the absence of active zones or the formation of active zones without their proper complement of proteins. The Unc-51-dependent inhibition of ERK activity provides a potential mechanism for synapse-specific control of active zone protein composition and release probability.

A Million-Plus Neuron Model of the Hippocampal Dentate Gyrus: Critical Role for Topography in Determining Spatiotemporal Network Dynamics.

PubMed

Hendrickson, Phillip J; Yu, Gene J; Song, Dong; Berger, Theodore W

2016-01-01

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. Information contained within previously published maps of this major hippocampal afferent were systematically converted to scales that allowed the topographical distribution and relative synaptic densities of perforant path inputs to be quantitatively estimated for inclusion in the current model. 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 nonrandom pattern of spiking best described as a 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 spatiotemporal 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" or "channels" that organize the processing of entorhinal signals. This modeling study also reveals for the first time how a global signal processing feature of a neural network can evolve from one of its underlying structural characteristics.

A Million-Plus Neuron Model of the Hippocampal Dentate Gyrus: Critical Role for Topography in Determining Spatio-Temporal Network Dynamics

PubMed Central

Hendrickson, Phillip J.; Yu, Gene J.; Song, Dong; Berger, Theodore W.

2016-01-01

Goal This manuscript 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. Methods 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. Information contained within previously published maps of this major hippocampal afferent were systematically converted to scales that allowed the topographical distribution and relative synaptic densities of perforant path inputs to be quantitatively estimated for inclusion in the current model. Results 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 spatio-temporal “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. Conclusion 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” or “channels” that organize the processing of entorhinal signals. This modeling study also reveals for the first time how a global signal processing feature of a neural network can evolve from one of its underlying structural characteristics. PMID:26087482

Phosphorylation of Synaptojanin Differentially Regulates Endocytosis of Functionally Distinct Synaptic Vesicle Pools.

PubMed

Geng, Junhua; Wang, Liping; Lee, Joo Yeun; Chen, Chun-Kan; Chang, Karen T

2016-08-24

The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood. Here we identify that Mnb phosphorylates Synj at S1029 in Drosophila We find that phosphorylation of Synj at S1029 enhances Synj phosphatase activity, alters interaction between Synj and endophilin, and promotes efficient endocytosis of the active cycling vesicle pool (also referred to as exo-endo cycling pool) at the expense of reserve pool vesicle endocytosis. Dephosphorylated Synj, on the other hand, is deficient in the endocytosis of the active recycling pool vesicles but maintains reserve pool vesicle endocytosis to restore total vesicle pool size and sustain synaptic transmission. Together, our findings reveal a novel role for Synj in modulating reserve pool vesicle endocytosis and further indicate that dynamic phosphorylation and dephosphorylation of Synj differentially maintain endocytosis of distinct functional synaptic vesicle pools. Synaptic vesicle endocytosis sustains communication between neurons during a wide range of neuronal activities by recycling used vesicle membrane and protein components. Here we identify that Synaptojanin, a protein with a known role in synaptic vesicle endocytosis, is phosphorylated at S1029 in vivo by the Minibrain kinase. We further demonstrate that the phosphorylation status of Synaptojanin at S1029 differentially regulates its participation in the recycling of distinct synaptic vesicle pools. Our results reveal a new role for Synaptojanin in maintaining synaptic vesicle pool size and in reserve vesicle endocytosis. As Synaptojanin and Minibrain perturbations are associated with various neurological disorders, such as Parkinson's, autism, and Down syndrome, understanding mechanisms modulating Synaptojanin function provides valuable insights into processes affecting neuronal communication. Copyright © 2016 the authors 0270-6474/16/368882-13$15.00/0.

Phosphorylation of Synaptojanin Differentially Regulates Endocytosis of Functionally Distinct Synaptic Vesicle Pools

PubMed Central

Geng, Junhua; Wang, Liping; Lee, Joo Yeun; Chen, Chun-Kan

2016-01-01

The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood. Here we identify that Mnb phosphorylates Synj at S1029 in Drosophila. We find that phosphorylation of Synj at S1029 enhances Synj phosphatase activity, alters interaction between Synj and endophilin, and promotes efficient endocytosis of the active cycling vesicle pool (also referred to as exo-endo cycling pool) at the expense of reserve pool vesicle endocytosis. Dephosphorylated Synj, on the other hand, is deficient in the endocytosis of the active recycling pool vesicles but maintains reserve pool vesicle endocytosis to restore total vesicle pool size and sustain synaptic transmission. Together, our findings reveal a novel role for Synj in modulating reserve pool vesicle endocytosis and further indicate that dynamic phosphorylation and dephosphorylation of Synj differentially maintain endocytosis of distinct functional synaptic vesicle pools. SIGNIFICANCE STATEMENT Synaptic vesicle endocytosis sustains communication between neurons during a wide range of neuronal activities by recycling used vesicle membrane and protein components. Here we identify that Synaptojanin, a protein with a known role in synaptic vesicle endocytosis, is phosphorylated at S1029 in vivo by the Minibrain kinase. We further demonstrate that the phosphorylation status of Synaptojanin at S1029 differentially regulates its participation in the recycling of distinct synaptic vesicle pools. Our results reveal a new role for Synaptojanin in maintaining synaptic vesicle pool size and in reserve vesicle endocytosis. As Synaptojanin and Minibrain perturbations are associated with various neurological disorders, such as Parkinson's, autism, and Down syndrome, understanding mechanisms modulating Synaptojanin function provides valuable insights into processes affecting neuronal communication. PMID:27559170

Effect of gap junctions on the firing patterns and synchrony for different external inputs in the striatal fast-spiking neuron network.

PubMed

Zhang, Mingming; Zhao, Zongya; He, Ping; Wang, Jue

2014-01-01

Gap junctions are the mechanism for striatal fast-spiking interneurons (FSIs) to interconnect with each other and play an important role in determining the physiological functioning of the FSIs. To investigate the effect of gap junctions on the firing activities and synchronization of the network for different external inputs, a simple network with least connections and a Newman-Watts small-world network were constructed. Our research shows that both properties of neural networks are related to the conductance of the gap junctions, as well as the frequency and correlation of the external inputs. The effect of gap junctions on the synchronization of network is different for inputs with different frequencies and correlations. The addition of gap junctions can promote the network synchrony in some conditions but suppress it in others, and they can inhibit the firing activities in most cases. Both the firing rate and synchronization of the network increase along with the increase of the electrical coupling strength for inputs with low frequency and high correlation. Thus, the network of coupled FSIs can act as a detector for synchronous synaptic input from cortex and thalamus.

Long-term potentiation of synaptic response and intrinsic excitability in neurons of the rat medial vestibular nuclei.

PubMed

Pettorossi, V E; Dieni, C V; Scarduzio, M; Grassi, S

2011-07-28

Using intracellular recordings, we investigated the effects of high frequency stimulation (HFS) of the primary vestibular afferents on the evoked excitatory postsynaptic potential (EPSP) and intrinsic excitability (IE) of type-A and type-B neurons of the medial vestibular nucleus (MVN), in male rat brainstem slices. HFS induces long-term potentiation (LTP) of both EPSP and IE, which may occur in combination or separately. Synaptic LTP is characterized by an increase in the amplitude, slope and decay time constant of EPSP and IE-LTP through enhancements of spontaneous and evoked neuron firing and of input resistance (Rin). Moreover, IE-LTP is associated with a decrease in action potential afterhyperpolarization (AHP) amplitude and an increase in interspike slope steepness (ISS). The more frequent effects of HFS are EPSP-LTP in type-B neurons and IE-LTP in type-A neurons. In addition, the development of EPSP-LTP is fast in type-B neurons but slow in type-A, whereas IE-LTP develops slowly in both types. We have demonstrated that activation of N-methyl-d aspartate receptors (NMDARs) is only required for EPSP-LTP induction, whereas metabotropic glutamate receptors type-1 (mGluR1) are necessary for IE-LTP induction as well as the full development and maintenance of EPSP-LTP. Taken together, these findings demonstrate that brief and intense activation of vestibular afferent input to the MVN neurons may provoke synaptic LTP and/or IE-LTP that, induced in combination or separately, may assure the different selectivity of the MVN neuron response enhancement to the afferent signals. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Computing the Local Field Potential (LFP) from Integrate-and-Fire Network Models.

PubMed

Mazzoni, Alberto; Lindén, Henrik; Cuntz, Hermann; Lansner, Anders; Panzeri, Stefano; Einevoll, Gaute T

2015-12-01

Leaky integrate-and-fire (LIF) network models are commonly used to study how the spiking dynamics of neural networks changes with stimuli, tasks or dynamic network states. However, neurophysiological studies in vivo often rather measure the mass activity of neuronal microcircuits with the local field potential (LFP). Given that LFPs are generated by spatially separated currents across the neuronal membrane, they cannot be computed directly from quantities defined in models of point-like LIF neurons. Here, we explore the best approximation for predicting the LFP based on standard output from point-neuron LIF networks. To search for this best "LFP proxy", we compared LFP predictions from candidate proxies based on LIF network output (e.g, firing rates, membrane potentials, synaptic currents) with "ground-truth" LFP obtained when the LIF network synaptic input currents were injected into an analogous three-dimensional (3D) network model of multi-compartmental neurons with realistic morphology, spatial distributions of somata and synapses. We found that a specific fixed linear combination of the LIF synaptic currents provided an accurate LFP proxy, accounting for most of the variance of the LFP time course observed in the 3D network for all recording locations. This proxy performed well over a broad set of conditions, including substantial variations of the neuronal morphologies. Our results provide a simple formula for estimating the time course of the LFP from LIF network simulations in cases where a single pyramidal population dominates the LFP generation, and thereby facilitate quantitative comparison between computational models and experimental LFP recordings in vivo.

Computing the Local Field Potential (LFP) from Integrate-and-Fire Network Models

PubMed Central

Cuntz, Hermann; Lansner, Anders; Panzeri, Stefano; Einevoll, Gaute T.

2015-01-01

Leaky integrate-and-fire (LIF) network models are commonly used to study how the spiking dynamics of neural networks changes with stimuli, tasks or dynamic network states. However, neurophysiological studies in vivo often rather measure the mass activity of neuronal microcircuits with the local field potential (LFP). Given that LFPs are generated by spatially separated currents across the neuronal membrane, they cannot be computed directly from quantities defined in models of point-like LIF neurons. Here, we explore the best approximation for predicting the LFP based on standard output from point-neuron LIF networks. To search for this best “LFP proxy”, we compared LFP predictions from candidate proxies based on LIF network output (e.g, firing rates, membrane potentials, synaptic currents) with “ground-truth” LFP obtained when the LIF network synaptic input currents were injected into an analogous three-dimensional (3D) network model of multi-compartmental neurons with realistic morphology, spatial distributions of somata and synapses. We found that a specific fixed linear combination of the LIF synaptic currents provided an accurate LFP proxy, accounting for most of the variance of the LFP time course observed in the 3D network for all recording locations. This proxy performed well over a broad set of conditions, including substantial variations of the neuronal morphologies. Our results provide a simple formula for estimating the time course of the LFP from LIF network simulations in cases where a single pyramidal population dominates the LFP generation, and thereby facilitate quantitative comparison between computational models and experimental LFP recordings in vivo. PMID:26657024

Modeling the impact of common noise inputs on the network activity of retinal ganglion cells

PubMed Central

Ahmadian, Yashar; Shlens, Jonathon; Pillow, Jonathan W.; Kulkarni, Jayant; Litke, Alan M.; Chichilnisky, E. J.; Simoncelli, Eero; Paninski, Liam

2013-01-01

Synchronized spontaneous firing among retinal ganglion cells (RGCs), on timescales faster than visual responses, has been reported in many studies. Two candidate mechanisms of synchronized firing include direct coupling and shared noisy inputs. In neighboring parasol cells of primate retina, which exhibit rapid synchronized firing that has been studied extensively, recent experimental work indicates that direct electrical or synaptic coupling is weak, but shared synaptic input in the absence of modulated stimuli is strong. However, previous modeling efforts have not accounted for this aspect of firing in the parasol cell population. Here we develop a new model that incorporates the effects of common noise, and apply it to analyze the light responses and synchronized firing of a large, densely-sampled network of over 250 simultaneously recorded parasol cells. We use a generalized linear model in which the spike rate in each cell is determined by the linear combination of the spatio-temporally filtered visual input, the temporally filtered prior spikes of that cell, and unobserved sources representing common noise. The model accurately captures the statistical structure of the spike trains and the encoding of the visual stimulus, without the direct coupling assumption present in previous modeling work. Finally, we examined the problem of decoding the visual stimulus from the spike train given the estimated parameters. The common-noise model produces Bayesian decoding performance as accurate as that of a model with direct coupling, but with significantly more robustness to spike timing perturbations. PMID:22203465

Cornering the fear engram: long-term synaptic changes in the lateral nucleus of the amygdala after fear conditioning.

PubMed

Kwon, Jeong-Tae; Choi, June-Seek

2009-08-05

Use-dependent synaptic modifications in the lateral nucleus of the amygdala (LA) have been suggested to be the cellular analog of memory trace after pavlovian fear conditioning. However, whether neurophysiological changes in the LA are produced as a direct consequence of associative learning awaits additional proof. Using microstimulation of the medial geniculate nucleus of the thalamus as the conditioned stimulus (CS), we demonstrated that contingent pairings of the brain-stimulation CS and a footshock unconditioned stimulus lead to enhanced synaptic efficacy in the thalamic input to the LA, supporting the hypothesis that localized synaptic alterations underlie fear memory formation.

Non-synaptic signaling from cerebellar climbing fibers modulates Golgi cell activity.

PubMed

Nietz, Angela K; Vaden, Jada H; Coddington, Luke T; Overstreet-Wadiche, Linda; Wadiche, Jacques I

2017-10-13

Golgi cells are the principal inhibitory neurons at the input stage of the cerebellum, providing feedforward and feedback inhibition through mossy fiber and parallel fiber synapses. In vivo studies have shown that Golgi cell activity is regulated by climbing fiber stimulation, yet there is little functional or anatomical evidence for synapses between climbing fibers and Golgi cells. Here, we show that glutamate released from climbing fibers activates ionotropic and metabotropic receptors on Golgi cells through spillover-mediated transmission. The interplay of excitatory and inhibitory conductances provides flexible control over Golgi cell spiking, allowing either excitation or a biphasic sequence of excitation and inhibition following single climbing fiber stimulation. Together with prior studies of spillover transmission to molecular layer interneurons, these results reveal that climbing fibers exert control over inhibition at both the input and output layers of the cerebellar cortex.

Long-term potentiation and long-term depression: a clinical perspective

PubMed Central

Bliss, Timothy V.P.; Cooke, Sam F

2011-01-01

Long-term potentiation and long-term depression are enduring changes in synaptic strength, induced by specific patterns of synaptic activity, that have received much attention as cellular models of information storage in the central nervous system. Work in a number of brain regions, from the spinal cord to the cerebral cortex, and in many animal species, ranging from invertebrates to humans, has demonstrated a reliable capacity for chemical synapses to undergo lasting changes in efficacy in response to a variety of induction protocols. In addition to their physiological relevance, long-term potentiation and depression may have important clinical applications. A growing insight into the molecular mechanisms underlying these processes, and technological advances in non-invasive manipulation of brain activity, now puts us at the threshold of harnessing long-term potentiation and depression and other forms of synaptic, cellular and circuit plasticity to manipulate synaptic strength in the human nervous system. Drugs may be used to erase or treat pathological synaptic states and non-invasive stimulation devices may be used to artificially induce synaptic plasticity to ameliorate conditions arising from disrupted synaptic drive. These approaches hold promise for the treatment of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus and stroke. PMID:21779718

A thalamic input to the nucleus accumbens mediates opiate dependence.

PubMed

Zhu, Yingjie; Wienecke, Carl F R; Nachtrab, Gregory; Chen, Xiaoke

2016-02-11

Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.

Cellular and Network Mechanisms Underlying Information Processing in a Simple Sensory System

NASA Technical Reports Server (NTRS)

Jacobs, Gwen; Henze, Chris; Biegel, Bryan (Technical Monitor)

2002-01-01

Realistic, biophysically-based compartmental models were constructed of several primary sensory interneurons in the cricket cercal sensory system. A dynamic atlas of the afferent input to these cells was used to set spatio-temporal parameters for the simulated stimulus-dependent synaptic inputs. We examined the roles of dendritic morphology, passive membrane properties, and active conductances on the frequency tuning of the neurons. The sensitivity of narrow-band low pass interneurons could be explained entirely by the electronic structure of the dendritic arbors and the dynamic sensitivity of the SIZ. The dynamic characteristics of interneurons with higher frequency sensitivity required models with voltage-dependent dendritic conductances.

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

PubMed

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

2018-05-01

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.

The influences of metabotropic receptor activation on cellular signaling and synaptic function in amacrine cells.

PubMed

Gleason, Evanna

2012-01-01

Amacrine cells receive glutamatergic input from bipolar cells and GABAergic, glycinergic, cholinergic, and dopaminergic input from other amacrine cells. Glutamate, GABA, glycine, and acetylcholine (ACh) interact with ionotropic receptors and it is these interactions that form much of the functional circuitry in the inner retina. However, glutamate, GABA, ACh, and dopamine also activate metabotropic receptors linked to second messenger pathways that have the potential to modify the function of individual cells as well as retinal circuitry. Here, the physiological effects of activating dopamine receptors, metabotropic glutamate receptors, GABAB receptors, and muscarinic ACh receptors on amacrine cells will be discussed. The retina also expresses metabotropic receptors and the biochemical machinery associated with the synthesis and degradation of endocannabinoids and sphingosine-1-phosphate (S1P). The effects of activating cannabinoid receptors and S1P receptors on amacrine cell function will also be addressed. Copyright © Cambridge University Press, 2012

A Cre Mouse Line for Probing Irradiance- and Direction-Encoding Retinal Networks

PubMed Central

Sabbah, Shai

2017-01-01

Abstract Cell type-specific Cre driver lines have revolutionized the analysis of retinal cell types and circuits. We show that the transgenic mouse Rbp4-Cre selectively labels several retinal neuronal types relevant to the encoding of absolute light intensity (irradiance) and visual motion. In the ganglion cell layer (GCL), most marked cells are wide-field spiking polyaxonal amacrine cells (ACs) with sustained irradiance-encoding ON responses that persist during chemical synaptic blockade. Their arbors spread about 1 mm across the retina and are restricted to the inner half of the ON sublamina of the inner plexiform layer (IPL). There, they costratify with dendrites of M2 intrinsically photosensitive retinal ganglion cells (ipRGCs), to which they are tracer coupled. We propose that synaptically driven and intrinsic photocurrents of M2 cells pass through gap junctions to drive AC light responses. Also marked in this mouse are two types of RGCs. R-cells have a bistratified dendritic arbor, weak directional tuning, and irradiance-encoding ON responses. However, they also receive excitatory OFF input, revealed during ON-channel blockade. Serial blockface electron microscopic (SBEM) reconstruction confirms OFF bipolar input, and reveals that some OFF input derives from a novel type of OFF bipolar cell (BC). R-cells innervate specific layers of the dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC). The other marked RGC type (RDS) is bistratified, transient, and ON-OFF direction selective (DS). It apparently innervates the nucleus of the optic tract (NOT). The Rbp4-Cre mouse will be valuable for targeting these cell types for further study and for selectively manipulating them for circuit analysis. PMID:28466070

A gustatory second-order neuron that connects sucrose-sensitive primary neurons and a distinct region of the gnathal ganglion in the Drosophila brain

PubMed Central

Miyazaki, Takaaki; Lin, Tzu-Yang; Ito, Kei; Lee, Chi-Hon; Stopfer, Mark

2016-01-01

Although the gustatory system provides animals with sensory cues important for food choice and other critical behaviors, little is known about neural circuitry immediately following gustatory sensory neurons (GSNs). Here, we identify and characterize a bilateral pair of gustatory second-order neurons in Drosophila. Previous studies identified GSNs that relay taste information to distinct subregions of the primary gustatory center (PGC) in the gnathal ganglia (GNG). To identify candidate gustatory second-order neurons (G2Ns) we screened ~5,000 GAL4 driver strains for lines that label neural fibers innervating the PGC. We then combined GRASP (GFP reconstitution across synaptic partners) with presynaptic labeling to visualize potential synaptic contacts between the dendrites of the candidate G2Ns and the axonal terminals of Gr5a-expressing GSNs, which are known to respond to sucrose. Results of the GRASP analysis, followed by a single cell analysis by FLPout recombination, revealed a pair of neurons that contact Gr5a axon terminals in both brain hemispheres, and send axonal arborizations to a distinct region outside the PGC but within the GNG. To characterize the input and output branches, respectively, we expressed fluorescence-tagged acetylcholine receptor subunit (Dα7) and active-zone marker (Brp) in the G2Ns. We found that G2N input sites overlaid GRASP-labeled synaptic contacts to Gr5a neurons, while presynaptic sites were broadly distributed throughout the neurons’ arborizations. GRASP analysis and further tests with the Syb-GRASP method suggested that the identified G2Ns receive synaptic inputs from Gr5a-expressing GSNs, but not Gr66a-expressing GSNs, which respond to caffeine. The identified G2Ns relay information from Gr5a-expressing GSNs to distinct regions in the GNG, and are distinct from other, recently identified gustatory projection neurons, which relay information about sugars to a brain region called the antennal mechanosensory and motor center (AMMC). Our findings suggest unexpected complexity for taste information processing in the first relay of the gustatory system. PMID:26004543

Neuronal modelling of baroreflex response to orthostatic stress

NASA Astrophysics Data System (ADS)

Samin, Azfar

The accelerations experienced in aerial combat can cause pilot loss of consciousness (GLOC) due to a critical reduction in cerebral blood circulation. The development of smart protective equipment requires understanding of how the brain processes blood pressure (BP) information in response to acceleration. We present a biologically plausible model of the Baroreflex to investigate the neural correlates of short-term BP control under acceleration or orthostatic stress. The neuronal network model, which employs an integrate-and-fire representation of a biological neuron, comprises the sensory, motor, and the central neural processing areas that form the Baroreflex. Our modelling strategy is to test hypotheses relating to the encoding mechanisms of multiple sensory inputs to the nucleus tractus solitarius (NTS), the site of central neural processing. The goal is to run simulations and reproduce model responses that are consistent with the variety of available experimental data. Model construction and connectivity are inspired by the available anatomical and neurophysiological evidence that points to a barotopic organization in the NTS, and the presence of frequency-dependent synaptic depression, which provides a mechanism for generating non-linear local responses in NTS neurons that result in quantifiable dynamic global baroreflex responses. The entire physiological range of BP and rate of change of BP variables is encoded in a palisade of NTS neurons in that the spike responses approximate Gaussian 'tuning' curves. An adapting weighted-average decoding scheme computes the motor responses and a compensatory signal regulates the heart rate (HR). Model simulations suggest that: (1) the NTS neurons can encode the hydrostatic pressure difference between two vertically separated sensory receptor regions at +Gz, and use changes in that difference for the regulation of HR; (2) even though NTS neurons do not fire with a cardiac rhythm seen in the afferents, pulse-rhythmic activity is regained downstream provided the input phase information in preserved centrally; (3) frequency-dependent synaptic depression, which causes temporal variations in synaptic strength due to changes in input frequency, is a possible mechanism of non-linear dynamic baroreflex gain control. Synaptic depression enables the NTS neuron to encode dBP/dt but to lose information about the steady state firing of the afferents.

A gustatory second-order neuron that connects sucrose-sensitive primary neurons and a distinct region of the gnathal ganglion in the Drosophila brain.

PubMed

Miyazaki, Takaaki; Lin, Tzu-Yang; Ito, Kei; Lee, Chi-Hon; Stopfer, Mark

2015-01-01

Although the gustatory system provides animals with sensory cues important for food choice and other critical behaviors, little is known about neural circuitry immediately following gustatory sensory neurons (GSNs). Here, we identify and characterize a bilateral pair of gustatory second-order neurons (G2Ns) in Drosophila. Previous studies identified GSNs that relay taste information to distinct subregions of the primary gustatory center (PGC) in the gnathal ganglia (GNG). To identify candidate G2Ns, we screened ∼5,000 GAL4 driver strains for lines that label neural fibers innervating the PGC. We then combined GRASP (GFP reconstitution across synaptic partners) with presynaptic labeling to visualize potential synaptic contacts between the dendrites of the candidate G2Ns and the axonal terminals of Gr5a-expressing GSNs, which are known to respond to sucrose. Results of the GRASP analysis, followed by a single-cell analysis by FLP-out recombination, revealed a pair of neurons that contact Gr5a axon terminals in both brain hemispheres and send axonal arborizations to a distinct region outside the PGC but within the GNG. To characterize the input and output branches, respectively, we expressed fluorescence-tagged acetylcholine receptor subunit (Dα7) and active-zone marker (Brp) in the G2Ns. We found that G2N input sites overlaid GRASP-labeled synaptic contacts to Gr5a neurons, while presynaptic sites were broadly distributed throughout the neurons' arborizations. GRASP analysis and further tests with the Syb-GRASP method suggested that the identified G2Ns receive synaptic inputs from Gr5a-expressing GSNs, but not Gr66a-expressing GSNs, which respond to caffeine. The identified G2Ns relay information from Gr5a-expressing GSNs to distinct regions in the GNG, and are distinct from other, recently identified gustatory projection neurons, which relay information about sugars to a brain region called the antennal mechanosensory and motor center (AMMC). Our findings suggest unexpected complexity for taste information processing in the first relay of the gustatory system.

Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment.

PubMed

Vizi, E S; Fekete, A; Karoly, R; Mike, A

2010-06-01

Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the 'what' of brain function, the 'how' of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the 'how' that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic-extrasynaptic receptor trafficking, neuron-glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them.

Synaptic Plasticity in the Bed Nucleus of the Stria Terminalis: Underlying Mechanisms and Potential Ramifications for Reinstatement of Drug- and Alcohol-Seeking Behaviors.

PubMed

Harris, Nicholas A; Winder, Danny G

2018-06-13

The bed nucleus of the stria terminalis (BNST) is a component of the extended amygdala that shows significant changes in activity and plasticity through chronic exposure to drugs and stress. The region is critical for stress- and cue-induced reinstatement of drug-seeking behaviors and is thus a candidate region for the plastic changes that occur in abstinence that prime addicted patients for reinstatement behaviors. Here, we discuss the various forms of long-term potentiation (LTP) and long-term depression (LTD) in the rodent BNST and highlight the way that these changes in excitatory transmission interact with exposure to alcohol and other drugs of abuse, as well as other stressors. In addition, we highlight potential areas for future research in this area, including investigating input- and cell-specific bidirectional changes in activity. As we continue to accrue foundational knowledge in the mechanisms and effects of plasticity in the BNST, molecular targets and treatment strategies that are relevant to reinstatement behaviors will also begin to emerge. Here, we briefly discuss the effects of catecholamine receptor modulators on synaptic plasticity in the BNST due to the role of norepinephrine in LTD and dopamine on the short-term component of LTP as well as the role that signaling at these receptors plays in reinstatement of drug- and alcohol-seeking behaviors. We hope that insights gained on the specific changes in plasticity that occur within the BNST during abstinence from alcohol and other drugs of abuse will provide insight into the biological underpinnings of relapse behavior in human addicts and inform future treatment modalities for addiction that tackle this complex biological problem.

Effect of Heterogeneity on Decorrelation Mechanisms in Spiking Neural Networks: A Neuromorphic-Hardware Study

NASA Astrophysics Data System (ADS)

Pfeil, Thomas; Jordan, Jakob; Tetzlaff, Tom; Grübl, Andreas; Schemmel, Johannes; Diesmann, Markus; Meier, Karlheinz

2016-04-01

High-level brain function, such as memory, classification, or reasoning, can be realized by means of recurrent networks of simplified model neurons. Analog neuromorphic hardware constitutes a fast and energy-efficient substrate for the implementation of such neural computing architectures in technical applications and neuroscientific research. The functional performance of neural networks is often critically dependent on the level of correlations in the neural activity. In finite networks, correlations are typically inevitable due to shared presynaptic input. Recent theoretical studies have shown that inhibitory feedback, abundant in biological neural networks, can actively suppress these shared-input correlations and thereby enable neurons to fire nearly independently. For networks of spiking neurons, the decorrelating effect of inhibitory feedback has so far been explicitly demonstrated only for homogeneous networks of neurons with linear subthreshold dynamics. Theory, however, suggests that the effect is a general phenomenon, present in any system with sufficient inhibitory feedback, irrespective of the details of the network structure or the neuronal and synaptic properties. Here, we investigate the effect of network heterogeneity on correlations in sparse, random networks of inhibitory neurons with nonlinear, conductance-based synapses. Emulations of these networks on the analog neuromorphic-hardware system Spikey allow us to test the efficiency of decorrelation by inhibitory feedback in the presence of hardware-specific heterogeneities. The configurability of the hardware substrate enables us to modulate the extent of heterogeneity in a systematic manner. We selectively study the effects of shared input and recurrent connections on correlations in membrane potentials and spike trains. Our results confirm that shared-input correlations are actively suppressed by inhibitory feedback also in highly heterogeneous networks exhibiting broad, heavy-tailed firing-rate distributions. In line with former studies, cell heterogeneities reduce shared-input correlations. Overall, however, correlations in the recurrent system can increase with the level of heterogeneity as a consequence of diminished effective negative feedback.

Voluntary Running Depreciates the Requirement of Ca[superscript 2+]-Stimulated cAMP Signaling in Synaptic Potentiation and Memory Formation

ERIC Educational Resources Information Center

Zheng, Fei; Zhang, Ming; Ding, Qi; Sethna, Ferzin; Yan, Lily; Moon, Changjong; Yang, Miyoung; Wang, Hongbing

2016-01-01

Mental health and cognitive functions are influenced by both genetic and environmental factors. Although having active lifestyle with physical exercise improves learning and memory, how it interacts with the specific key molecular regulators of synaptic plasticity is largely unknown. Here, we examined the effects of voluntary running on long-term…