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Sample records for intracortical synaptic connections

  1. Thalamocortical Connections Drive Intracortical Activation of Functional Columns in the Mislaminated Reeler Somatosensory Cortex.

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    Wagener, Robin J; Witte, Mirko; Guy, Julien; Mingo-Moreno, Nieves; Kügler, Sebastian; Staiger, Jochen F

    2016-02-01

    Neuronal wiring is key to proper neural information processing. Tactile information from the rodent's whiskers reaches the cortex via distinct anatomical pathways. The lemniscal pathway relays whisking and touch information from the ventral posteromedial thalamic nucleus to layer IV of the primary somatosensory "barrel" cortex. The disorganized neocortex of the reeler mouse is a model system that should severely compromise the ingrowth of thalamocortical axons (TCAs) into the cortex. Moreover, it could disrupt intracortical wiring. We found that neuronal intermingling within the reeler barrel cortex substantially exceeded previous descriptions, leading to the loss of layers. However, viral tracing revealed that TCAs still specifically targeted transgenically labeled spiny layer IV neurons. Slice electrophysiology and optogenetics proved that these connections represent functional synapses. In addition, we assessed intracortical activation via immediate-early-gene expression resulting from a behavioral exploration task. The cellular composition of activated neuronal ensembles suggests extensive similarities in intracolumnar information processing in the wild-type and reeler brains. We conclude that extensive ectopic positioning of neuronal partners can be compensated for by cell-autonomous mechanisms that allow for the establishment of proper connectivity. Thus, genetic neuronal fate seems to be of greater importance for correct cortical wiring than radial neuronal position. © The Author 2015. Published by Oxford University Press.

  2. Early sensory experience influences the development of multisensory thalamocortical and intracortical connections of primary sensory cortices.

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    Henschke, Julia U; Oelschlegel, Anja M; Angenstein, Frank; Ohl, Frank W; Goldschmidt, Jürgen; Kanold, Patrick O; Budinger, Eike

    2018-04-01

    The nervous system integrates information from multiple senses. This multisensory integration already occurs in primary sensory cortices via direct thalamocortical and corticocortical connections across modalities. In humans, sensory loss from birth results in functional recruitment of the deprived cortical territory by the spared senses but the underlying circuit changes are not well known. Using tracer injections into primary auditory, somatosensory, and visual cortex within the first postnatal month of life in a rodent model (Mongolian gerbil) we show that multisensory thalamocortical connections emerge before corticocortical connections but mostly disappear during development. Early auditory, somatosensory, or visual deprivation increases multisensory connections via axonal reorganization processes mediated by non-lemniscal thalamic nuclei and the primary areas themselves. Functional single-photon emission computed tomography of regional cerebral blood flow reveals altered stimulus-induced activity and higher functional connectivity specifically between primary areas in deprived animals. Together, we show that intracortical multisensory connections are formed as a consequence of sensory-driven multisensory thalamocortical activity and that spared senses functionally recruit deprived cortical areas by an altered development of sensory thalamocortical and corticocortical connections. The functional-anatomical changes after early sensory deprivation have translational implications for the therapy of developmental hearing loss, blindness, and sensory paralysis and might also underlie developmental synesthesia.

  3. Mild hypoxia affects synaptic connectivity in cultured neuronal networks.

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    Hofmeijer, Jeannette; Mulder, Alex T B; Farinha, Ana C; van Putten, Michel J A M; le Feber, Joost

    2014-04-04

    Eighty percent of patients with chronic mild cerebral ischemia/hypoxia resulting from chronic heart failure or pulmonary disease have cognitive impairment. Overt structural neuronal damage is lacking and the precise cause of neuronal damage is unclear. As almost half of the cerebral energy consumption is used for synaptic transmission, and synaptic failure is the first abrupt consequence of acute complete anoxia, synaptic dysfunction is a candidate mechanism for the cognitive deterioration in chronic mild ischemia/hypoxia. Because measurement of synaptic functioning in patients is problematic, we use cultured networks of cortical neurons from new born rats, grown over a multi-electrode array, as a model system. These were exposed to partial hypoxia (partial oxygen pressure of 150Torr lowered to 40-50Torr) during 3 (n=14) or 6 (n=8) hours. Synaptic functioning was assessed before, during, and after hypoxia by assessment of spontaneous network activity, functional connectivity, and synaptically driven network responses to electrical stimulation. Action potential heights and shapes and non-synaptic stimulus responses were used as measures of individual neuronal integrity. During hypoxia of 3 and 6h, there was a statistically significant decrease of spontaneous network activity, functional connectivity, and synaptically driven network responses, whereas direct responses and action potentials remained unchanged. These changes were largely reversible. Our results indicate that in cultured neuronal networks, partial hypoxia during 3 or 6h causes isolated disturbances of synaptic connectivity. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Remodeling of inhibitory synaptic connections in developing ferret visual cortex

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    Dalva Matthew B

    2010-02-01

    Full Text Available Abstract Background In the visual cortex, as in many other regions of the developing brain, excitatory synaptic connections undergo substantial remodeling during development. While evidence suggests that local inhibitory synapses may behave similarly, the extent and mechanisms that mediate remodeling of inhibitory connections are not well understood. Results Using scanning laser photostimulation in slices of developing ferret visual cortex, we assessed the overall patterns of developing inhibitory and excitatory synaptic connections converging onto individual neurons. Inhibitory synaptic inputs onto pyramidal neurons in cortical layers 2 and 3 were already present as early as postnatal day 20, well before eye opening, and originated from regions close to the recorded neurons. During the ensuing 2 weeks, the numbers of synaptic inputs increased, with the numbers of inhibitory (and excitatory synaptic inputs peaking near the time of eye opening. The pattern of inhibitory inputs refined rapidly prior to the refinement of excitatory inputs. By uncaging the neurotransmtter GABA in brain slices from animals of different ages, we find that this rapid refinement correlated with a loss of excitatory activity by GABA. Conclusion Inhibitory synapses, like excitatory synapses, undergo significant postnatal remodeling. The time course of the remodeling of inhibitory connections correlates with the emergence of orientation tuning in the visual cortex, implicating these rearrangements in the genesis of adult cortical response properties.

  5. Activity-dependent modulation of neural circuit synaptic connectivity

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    Charles R Tessier

    2009-07-01

    Full Text Available In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; 1 early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and 2 subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circuits are “hard-wired” in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

  6. Synaptic Scaling in Combination with Many Generic Plasticity Mechanisms Stabilizes Circuit Connectivity

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    Tetzlaff, Christian; Kolodziejski, Christoph; Timme, Marc; Wörgötter, Florentin

    2011-01-01

    Synaptic scaling is a slow process that modifies synapses, keeping the firing rate of neural circuits in specific regimes. Together with other processes, such as conventional synaptic plasticity in the form of long term depression and potentiation, synaptic scaling changes the synaptic patterns in a network, ensuring diverse, functionally relevant, stable, and input-dependent connectivity. How synaptic patterns are generated and stabilized, however, is largely unknown. Here we formally describe and analyze synaptic scaling based on results from experimental studies and demonstrate that the combination of different conventional plasticity mechanisms and synaptic scaling provides a powerful general framework for regulating network connectivity. In addition, we design several simple models that reproduce experimentally observed synaptic distributions as well as the observed synaptic modifications during sustained activity changes. These models predict that the combination of plasticity with scaling generates globally stable, input-controlled synaptic patterns, also in recurrent networks. Thus, in combination with other forms of plasticity, synaptic scaling can robustly yield neuronal circuits with high synaptic diversity, which potentially enables robust dynamic storage of complex activation patterns. This mechanism is even more pronounced when considering networks with a realistic degree of inhibition. Synaptic scaling combined with plasticity could thus be the basis for learning structured behavior even in initially random networks. PMID:22203799

  7. The Formation of Multi-synaptic Connections by the Interaction of Synaptic and Structural Plasticity and Their Functional Consequences

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    Fauth, Michael; Wörgötter, Florentin; Tetzlaff, Christian

    2015-01-01

    Cortical connectivity emerges from the permanent interaction between neuronal activity and synaptic as well as structural plasticity. An important experimentally observed feature of this connectivity is the distribution of the number of synapses from one neuron to another, which has been measured in several cortical layers. All of these distributions are bimodal with one peak at zero and a second one at a small number (3–8) of synapses. In this study, using a probabilistic model of structural plasticity, which depends on the synaptic weights, we explore how these distributions can emerge and which functional consequences they have. We find that bimodal distributions arise generically from the interaction of structural plasticity with synaptic plasticity rules that fulfill the following biological realistic constraints: First, the synaptic weights have to grow with the postsynaptic activity. Second, this growth curve and/or the input-output relation of the postsynaptic neuron have to change sub-linearly (negative curvature). As most neurons show such input-output-relations, these constraints can be fulfilled by many biological reasonable systems. Given such a system, we show that the different activities, which can explain the layer-specific distributions, correspond to experimentally observed activities. Considering these activities as working point of the system and varying the pre- or postsynaptic stimulation reveals a hysteresis in the number of synapses. As a consequence of this, the connectivity between two neurons can be controlled by activity but is also safeguarded against overly fast changes. These results indicate that the complex dynamics between activity and plasticity will, already between a pair of neurons, induce a variety of possible stable synaptic distributions, which could support memory mechanisms. PMID:25590330

  8. Directional Trans-Synaptic Labeling of Specific Neuronal Connections in Live Animals.

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    Desbois, Muriel; Cook, Steven J; Emmons, Scott W; Bülow, Hannes E

    2015-07-01

    Understanding animal behavior and development requires visualization and analysis of their synaptic connectivity, but existing methods are laborious or may not depend on trans-synaptic interactions. Here we describe a transgenic approach for in vivo labeling of specific connections in Caenorhabditis elegans, which we term iBLINC. The method is based on BLINC (Biotin Labeling of INtercellular Contacts) and involves trans-synaptic enzymatic transfer of biotin by the Escherichia coli biotin ligase BirA onto an acceptor peptide. A BirA fusion with the presynaptic cell adhesion molecule NRX-1/neurexin is expressed presynaptically, whereas a fusion between the acceptor peptide and the postsynaptic protein NLG-1/neuroligin is expressed postsynaptically. The biotinylated acceptor peptide::NLG-1/neuroligin fusion is detected by a monomeric streptavidin::fluorescent protein fusion transgenically secreted into the extracellular space. Physical contact between neurons is insufficient to create a fluorescent signal, suggesting that synapse formation is required. The labeling approach appears to capture the directionality of synaptic connections, and quantitative analyses of synapse patterns display excellent concordance with electron micrograph reconstructions. Experiments using photoconvertible fluorescent proteins suggest that the method can be utilized for studies of protein dynamics at the synapse. Applying this technique, we find connectivity patterns of defined connections to vary across a population of wild-type animals. In aging animals, specific segments of synaptic connections are more susceptible to decline than others, consistent with dedicated mechanisms of synaptic maintenance. Collectively, we have developed an enzyme-based, trans-synaptic labeling method that allows high-resolution analyses of synaptic connectivity as well as protein dynamics at specific synapses of live animals. Copyright © 2015 by the Genetics Society of America.

  9. Synaptic transmission and plasticity in an active cortical network.

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    Ramon Reig

    Full Text Available BACKGROUND: The cerebral cortex is permanently active during both awake and sleep states. This ongoing cortical activity has an impact on synaptic transmission and short-term plasticity. An activity pattern generated by the cortical network is a slow rhythmic activity that alternates up (active and down (silent states, a pattern occurring during slow wave sleep, anesthesia and even in vitro. Here we have studied 1 how network activity affects short term synaptic plasticity and, 2 how synaptic transmission varies in up versus down states. METHODOLOGY/PRINCIPAL FINDINGS: Intracellular recordings obtained from cortex in vitro and in vivo were used to record synaptic potentials, while presynaptic activation was achieved either with electrical or natural stimulation. Repetitive activation of layer 4 to layer 2/3 synaptic connections from ferret visual cortex slices displayed synaptic augmentation that was larger and longer lasting in active than in silent slices. Paired-pulse facilitation was also significantly larger in an active network and it persisted for longer intervals (up to 200 ms than in silent slices. Intracortical synaptic potentials occurring during up states in vitro increased their amplitude while paired-pulse facilitation disappeared. Both intracortical and thalamocortical synaptic potentials were also significantly larger in up than in down states in the cat visual cortex in vivo. These enhanced synaptic potentials did not further facilitate when pairs of stimuli were given, thus paired-pulse facilitation during up states in vivo was virtually absent. Visually induced synaptic responses displayed larger amplitudes when occurring during up versus down states. This was further tested in rat barrel cortex, where a sensory activated synaptic potential was also larger in up states. CONCLUSIONS/SIGNIFICANCE: These results imply that synaptic transmission in an active cortical network is more secure and efficient due to larger amplitude of

  10. Axon and dendrite geography predict the specificity of synaptic connections in a functioning spinal cord network

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    Borisyuk Roman

    2007-09-01

    Full Text Available Abstract Background How specific are the synaptic connections formed as neuronal networks develop and can simple rules account for the formation of functioning circuits? These questions are assessed in the spinal circuits controlling swimming in hatchling frog tadpoles. This is possible because detailed information is now available on the identity and synaptic connections of the main types of neuron. Results The probabilities of synapses between 7 types of identified spinal neuron were measured directly by making electrical recordings from 500 pairs of neurons. For the same neuron types, the dorso-ventral distributions of axons and dendrites were measured and then used to calculate the probabilities that axons would encounter particular dendrites and so potentially form synaptic connections. Surprisingly, synapses were found between all types of neuron but contact probabilities could be predicted simply by the anatomical overlap of their axons and dendrites. These results suggested that synapse formation may not require axons to recognise specific, correct dendrites. To test the plausibility of simpler hypotheses, we first made computational models that were able to generate longitudinal axon growth paths and reproduce the axon distribution patterns and synaptic contact probabilities found in the spinal cord. To test if probabilistic rules could produce functioning spinal networks, we then made realistic computational models of spinal cord neurons, giving them established cell-specific properties and connecting them into networks using the contact probabilities we had determined. A majority of these networks produced robust swimming activity. Conclusion Simple factors such as morphogen gradients controlling dorso-ventral soma, dendrite and axon positions may sufficiently constrain the synaptic connections made between different types of neuron as the spinal cord first develops and allow functional networks to form. Our analysis implies that

  11. Synaptic dynamics and neuronal network connectivity are reflected in the distribution of times in Up states.

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    Dao Duc, Khanh; Parutto, Pierre; Chen, Xiaowei; Epsztein, Jérôme; Konnerth, Arthur; Holcman, David

    2015-01-01

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

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

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    Khanh eDao Duc

    2015-07-01

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

  13. Neurobiology of stress, depression, and rapid acting antidepressants: remodeling synaptic connections.

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    Duman, Ronald S

    2014-04-01

    Stress and depression are associated with atrophy and loss of neurons in limbic and cortical brain regions that could contribute to the symptoms of depression. Typical monoamine reuptake inhibitor antidepressants have only modest efficacy and require long-term treatment, and are only weakly effective in blocking or reversing these structural changes caused by stress. Recent findings demonstrate that ketamine, an NMDA receptor antagonist, produces rapid antidepressant actions in difficult to treat depressed patients. In addition, preclinical studies demonstrate that ketamine rapidly increases synaptic connections in the prefrontal cortex by increasing glutamate signaling and activation of pathways that control the synthesis of synaptic proteins. Moreover, ketamine rapidly reverses the synaptic deficits caused by exposure to chronic stress in rodent models. Studies of the signaling mechanisms underlying the actions of ketamine have provided novel approaches and targets for new rapid acting antidepressants with decreased side effects, as well as a better understanding of the neurobiology of stress, depression, and treatment response. © 2014 Wiley Periodicals, Inc.

  14. The effects of transcranial direct current stimulation on short-interval intracortical inhibition and intracortical facilitation: a systematic review and meta-analysis.

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    Biabani, Mana; Aminitehrani, Maryam; Zoghi, Maryam; Farrell, Michael; Egan, Gary; Jaberzadeh, Shapour

    2018-01-26

    Transcranial direct current stimulation (tDCS) is increasingly being used to affect the neurological conditions with deficient intracortical synaptic activities (i.e. Parkinson's disease and epilepsy). In addition, it is suggested that the lasting effects of tDCS on corticospinal excitability (CSE) have intracortical origin. This systematic review and meta-analysis aimed to examine whether tDCS has any effect on intracortical circuits. Eleven electronic databases were searched for the studies investigating intracortical changes induced by anodal (a) and cathodal (c) tDCS, in healthy individuals, using two paired-pulse transcranial magnetic stimulation (TMS) paradigms: short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Additionally, motor-evoked potential (MEP) size alterations, assessed by single-pulse TMS, were extracted from these studies to investigate the probable intracortical origin of tDCS effects on CSE. The methodological quality of included studies was examined using Physiotherapy Evidence Database (PEDro) and Downs and Black's (D&B) assessment tools. Thirteen research papers, including 24 experiments, were included in this study scoring good and medium quality in PEDro and D&B scales, respectively. Immediately following anodal tDCS (a-tDCS) applications, we found significant decreases in SICI, but increases in ICF and MEP size. However, ICF and MEP size significantly decreased, and SICI increased immediately following cathodal tDCS (c-tDCS). The results of this systematic review and meta-analysis reveal that a-tDCS changes intracortical activities (SICI and ICF) toward facilitation, whereas c-tDCS alters them toward inhibition. It can also be concluded that increases and decreases in CSE after tDCS application are associated with corresponding changes in intracortical activities. The results suggest that tDCS can be clinically useful to modulate intracortical circuits.

  15. Visual Deprivation Causes Refinement of Intracortical Circuits in the Auditory Cortex

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    Xiangying Meng

    2015-08-01

    Full Text Available Loss of a sensory modality can lead to functional enhancement of the remaining senses. For example, short-term visual deprivations, or dark exposure (DE, can enhance neuronal responses in the auditory cortex to sounds. These enhancements encompass increased spiking rates and frequency selectivity as well as increased spiking reliability. Although we previously demonstrated enhanced thalamocortical transmission after DE, increased synaptic strength cannot account for increased frequency selectivity or reliability. We thus investigated whether other changes in the underlying circuitry contributed to improved neuronal responses. We show that DE can lead to refinement of intra- and inter-laminar connections in the mouse auditory cortex. Moreover, we use a computational model to show that the combination of increased transmission and circuit refinement can lead to increased firing reliability. Thus cross-modal influences can alter the spectral and temporal processing of sensory stimuli by refinement of thalamocortical and intracortical circuits.

  16. Recombinant Fluorescent Rabies Virus Vectors for Tracing Neurons and Synaptic Connections.

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    Hagendorf, Nadin; Conzelmann, Karl-Klaus

    2015-12-02

    Recombinant rabies virus (RV) vectors expressing fluorescent proteins allow staining of neurons from many mammalian species and enable the study of neuron morphology. Because viral spread occurs only between neurons that have synaptic connections, these vectors also permit transsynaptic tracing. A recently established system for restriction of transsynaptic tracing to a single transsynaptic jump, dubbed monosynaptic tracing, uses glycoprotein gene-defective, pseudotyped RV. This allows infection of defined cells and transient complementation with the glycoprotein in situ to support a single step of transsynaptic crossing to presynaptic cells. Here, we introduce protocols describing the production of RV vectors, including the recovery of recombinant RV from complementary DNA (cDNA) and virus pseudotyping in vitro. This allows retrograde staining of neurons projecting to the inoculation site. © 2015 Cold Spring Harbor Laboratory Press.

  17. Human-Specific Cortical Synaptic Connections and Their Plasticity: Is That What Makes Us Human?

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    Joana Lourenço

    2017-01-01

    Full Text Available One outstanding difference between Homo sapiens and other mammals is the ability to perform highly complex cognitive tasks and behaviors, such as language, abstract thinking, and cultural diversity. How is this accomplished? According to one prominent theory, cognitive complexity is proportional to the repetition of specific computational modules over a large surface expansion of the cerebral cortex (neocortex. However, the human neocortex was shown to also possess unique features at the cellular and synaptic levels, raising the possibility that expanding the computational module is not the only mechanism underlying complex thinking. In a study published in PLOS Biology, Szegedi and colleagues analyzed a specific cortical circuit from live postoperative human tissue, showing that human-specific, very powerful excitatory connections between principal pyramidal neurons and inhibitory neurons are highly plastic. This suggests that exclusive plasticity of specific microcircuits might be considered among the mechanisms endowing the human neocortex with the ability to perform highly complex cognitive tasks.

  18. Spike-Triggered Regression for Synaptic Connectivity Reconstruction in Neuronal Networks.

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    Zhang, Yaoyu; Xiao, Yanyang; Zhou, Douglas; Cai, David

    2017-01-01

    How neurons are connected in the brain to perform computation is a key issue in neuroscience. Recently, the development of calcium imaging and multi-electrode array techniques have greatly enhanced our ability to measure the firing activities of neuronal populations at single cell level. Meanwhile, the intracellular recording technique is able to measure subthreshold voltage dynamics of a neuron. Our work addresses the issue of how to combine these measurements to reveal the underlying network structure. We propose the spike-triggered regression (STR) method, which employs both the voltage trace and firing activity of the neuronal population to reconstruct the underlying synaptic connectivity. Our numerical study of the conductance-based integrate-and-fire neuronal network shows that only short data of 20 ~ 100 s is required for an accurate recovery of network topology as well as the corresponding coupling strength. Our method can yield an accurate reconstruction of a large neuronal network even in the case of dense connectivity and nearly synchronous dynamics, which many other network reconstruction methods cannot successfully handle. In addition, we point out that, for sparse networks, the STR method can infer coupling strength between each pair of neurons with high accuracy in the absence of the global information of all other neurons.

  19. Synaptic Cell Adhesion

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    Missler, Markus; Südhof, Thomas C.; Biederer, Thomas

    2012-01-01

    Chemical synapses are asymmetric intercellular junctions that mediate synaptic transmission. Synaptic junctions are organized by trans-synaptic cell adhesion molecules bridging the synaptic cleft. Synaptic cell adhesion molecules not only connect pre- and postsynaptic compartments, but also mediate trans-synaptic recognition and signaling processes that are essential for the establishment, specification, and plasticity of synapses. A growing number of synaptic cell adhesion molecules that inc...

  20. Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich gene expression hubs.

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    Hegyi, Hedi

    2017-04-06

    Combining genome-wide mapping of SNP-rich regions in schizophrenics and gene expression data in all brain compartments across the human life span revealed that genes with promoters most frequently mutated in schizophrenia are expression hubs interacting with far more genes than the rest of the genome. We summed up the differentially methylated "expression neighbors" of genes that fall into one of 108 distinct schizophrenia-associated loci with high number of SNPs. Surprisingly, the number of expression neighbors of the genes in these loci were 35 times higher for the positively correlating genes (32 times higher for the negatively correlating ones) than for the rest of the ~16000 genes. While the genes in the 108 loci have little known impact in schizophrenia, we identified many more known schizophrenia-related important genes with a high degree of connectedness (e.g. MOBP, SYNGR1 and DGCR6), validating our approach. Both the most connected positive and negative hubs affected synapse-related genes the most, supporting the synaptic origin of schizophrenia. At least half of the top genes in both the correlating and anti-correlating categories are cancer-related, including oncogenes (RRAS and ALDOA), providing further insight into the observed inverse relationship between the two diseases.

  1. Developmental signature, synaptic connectivity and neurotransmission are conserved between vertebrate hair cells and tunicate coronal cells.

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    Rigon, Francesca; Gasparini, Fabio; Shimeld, Sebastian M; Candiani, Simona; Manni, Lucia

    2018-04-15

    In tunicates, the coronal organ represents a sentinel checking particle entrance into the pharynx. The organ differentiates from an anterior embryonic area considered a proto-placode. For their embryonic origin, morphological features and function, coronal sensory cells have been hypothesized to be homologues to vertebrate hair cells. However, vertebrate hair cells derive from a posterior placode. This contradicts one of the principle historical criteria for homology, similarity of position, which could be taken as evidence against coronal cells/hair cells homology. In the tunicates Ciona intestinalis and C. robusta, we found that the coronal organ expresses genes (Atoh, Notch, Delta-like, Hairy-b, and Musashi) characterizing vertebrate neural and hair cell development. Moreover, coronal cells exhibit a complex synaptic connectivity pattern, and express neurotransmitters (Glu, ACh, GABA, 5-HT, and catecholamines), or enzymes for their synthetic machinery, involved in hair cell activity. Lastly, coronal cells express the Trpa gene, which encodes an ion channel expressed in hair cells. These data lead us to hypothesize a model in which competence to make secondary mechanoreceptors was initially broadly distributed through placode territories, but has become confined to different placodes during the evolution of the vertebrate and tunicate lineages. © 2017 Wiley Periodicals, Inc.

  2. Stimulus number, duration and intensity encoding in randomly connected attractor networks with synaptic depression

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    Paul eMiller

    2013-05-01

    Full Text Available Randomly connected recurrent networks of excitatory groups of neurons can possess a multitude of attractor states. When the internal excitatory synapses of these networks are depressing, the attractor states can be destabilized with increasing input. This leads to an itinerancy, where with either repeated transient stimuli, or increasing duration of a single stimulus, the network activity advances through sequences of attractor states. We find that the resulting network state, which persists beyond stimulus offset, can encode the number of stimuli presented via a distributed representation of neural activity with non-monotonic tuning curves for most neurons. Increased duration of a single stimulus is encoded via different distributed representations, so unlike an integrator, the network distinguishes separate successive presentations of a short stimulus from a single presentation of a longer stimulus with equal total duration. Moreover, different amplitudes of stimulus cause new, distinct activity patterns, such that changes in stimulus number, duration and amplitude can be distinguished from each other. These properties of the network depend on dynamic depressing synapses, as they disappear if synapses are static. Thus short-term synaptic depression allows a network to store separately the different dynamic properties of a spatially constant stimulus.

  3. All-optical functional synaptic connectivity mapping in acute brain slices using the calcium integrator CaMPARI.

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    Zolnik, Timothy A; Sha, Fern; Johenning, Friedrich W; Schreiter, Eric R; Looger, Loren L; Larkum, Matthew E; Sachdev, Robert N S

    2017-03-01

    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. 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 Ca

  4. Pharmacological characterization of cultivated neuronal networks: relevance to synaptogenesis and synaptic connectivity.

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    Verstraelen, Peter; Pintelon, Isabel; Nuydens, Rony; Cornelissen, Frans; Meert, Theo; Timmermans, Jean-Pierre

    2014-07-01

    Mental disorders, such as schizophrenia or Alzheimer's disease, are associated with impaired synaptogenesis and/or synaptic communication. During development, neurons assemble into neuronal networks, the primary supracellular mediators of information processing. In addition to the orchestrated activation of genetic programs, spontaneous electrical activity and associated calcium signaling have been shown to be critically involved in the maturation of such neuronal networks. We established an in vitro model that recapitulates the maturation of neuronal networks, including spontaneous electrical activity. Upon plating, mouse primary hippocampal neurons grow neurites and interconnect via synapses to form a dish-wide neuronal network. Via live cell calcium imaging, we identified a limited period of time in which the spontaneous activity synchronizes across neurons, indicative of the formation of a functional network. After establishment of network activity, the neurons grow dendritic spines, the density of which was used as a morphological readout for neuronal maturity and connectivity. Hence, quantification of neurite outgrowth, synapse density, spontaneous neuronal activity, and dendritic spine density allowed to study neuronal network maturation from the day of plating until the presence of mature neuronal networks. Via acute pharmacological intervention, we show that synchronized network activity is mediated by the NMDA-R. The balance between kynurenic and quinolinic acid, both neuro-active intermediates in the tryptophan/kynurenine pathway, was shown to be decisive for the maintenance of network activity. Chronic modulation of the neurotrophic support influenced the network formation and revealed the extreme sensitivity of calcium imaging to detect subtle alterations in neuronal physiology. Given the reproducible cultivation in a 96-well setup in combination with fully automated analysis of the calcium recordings, this approach can be used to build a high

  5. Learning to discriminate through long-term changes of dynamical synaptic transmission.

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    Leibold, Christian; Bendels, Michael H K

    2009-12-01

    Short-term synaptic plasticity is modulated by long-term synaptic changes. There is, however, no general agreement on the computational role of this interaction. Here, we derive a learning rule for the release probability and the maximal synaptic conductance in a circuit model with combined recurrent and feedforward connections that allows learning to discriminate among natural inputs. Short-term synaptic plasticity thereby provides a nonlinear expansion of the input space of a linear classifier, whereas the random recurrent network serves to decorrelate the expanded input space. Computer simulations reveal that the twofold increase in the number of input dimensions through short-term synaptic plasticity improves the performance of a standard perceptron up to 100%. The distributions of release probabilities and maximal synaptic conductances at the capacity limit strongly depend on the balance between excitation and inhibition. The model also suggests a new computational interpretation of spikes evoked by stimuli outside the classical receptive field. These neuronal activities may reflect decorrelation of the expanded stimulus space by intracortical synaptic connections.

  6. A multicenter study of the early detection of synaptic dysfunction in Mild Cognitive Impairment using Magnetoencephalography-derived functional connectivity

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    Fernando Maestú, PhD

    2015-01-01

    Full Text Available Synaptic disruption is an early pathological sign of the neurodegeneration of Dementia of the Alzheimer's type (DAT. The changes in network synchronization are evident in patients with Mild Cognitive Impairment (MCI at the group level, but there are very few Magnetoencephalography (MEG studies regarding discrimination at the individual level. In an international multicenter study, we used MEG and functional connectivity metrics to discriminate MCI from normal aging at the individual person level. A labeled sample of features (links that distinguished MCI patients from controls in a training dataset was used to classify MCI subjects in two testing datasets from four other MEG centers. We identified a pattern of neuronal hypersynchronization in MCI, in which the features that best discriminated MCI were fronto-parietal and interhemispheric links. The hypersynchronization pattern found in the MCI patients was stable across the five different centers, and may be considered an early sign of synaptic disruption and a possible preclinical biomarker for MCI/DAT.

  7. TRANSGENIC STRATEGY FOR IDENTIFYING SYNAPTIC CONNECTIONS IN MICE BY FLUORESCENCE COMPLEMENTATION (GRASP

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    Masahito eYamagata

    2012-02-01

    Full Text Available In the "GFP reconstitution across synaptic partners" (GRASP method, non-fluorescent fragments of GFP are expressed in two different neurons; the fragments self-assemble at synapses between the two to form a fluorophore. GRASP has proven useful for light microscopic identification of synapses in two invertebrate species, Caenorhabditis elegans and Drosophila melanogaster, but has not yet been applied to vertebrates. Here, we describe GRASP constructs that function in mammalian cells and implement a transgenic strategy in which a Cre-dependent gene switch leads to expression of the two fragments in mutually exclusive neuronal subsets in mice. Using a transgenic line that expresses Cre selectively in rod photoreceptors, we demonstrate labeling of synapses in the outer plexiform layer of the retina. Labeling is specific, in that synapses made by rods remain labeled for at least 6 months whereas nearby synapses made by intercalated cone photoreceptors on many of the same interneurons remain unlabeled. We also generated antisera that label reconstituted GFP but neither fragment in order to amplify the GRASP signal and thereby increase the sensitivity of the method.

  8. A realistic neural mass model of the cortex with laminar-specific connections and synaptic plasticity - evaluation with auditory habituation.

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    Peng Wang

    Full Text Available In this work we propose a biologically realistic local cortical circuit model (LCCM, based on neural masses, that incorporates important aspects of the functional organization of the brain that have not been covered by previous models: (1 activity dependent plasticity of excitatory synaptic couplings via depleting and recycling of neurotransmitters and (2 realistic inter-laminar dynamics via laminar-specific distribution of and connections between neural populations. The potential of the LCCM was demonstrated by accounting for the process of auditory habituation. The model parameters were specified using Bayesian inference. It was found that: (1 besides the major serial excitatory information pathway (layer 4 to layer 2/3 to layer 5/6, there exists a parallel "short-cut" pathway (layer 4 to layer 5/6, (2 the excitatory signal flow from the pyramidal cells to the inhibitory interneurons seems to be more intra-laminar while, in contrast, the inhibitory signal flow from inhibitory interneurons to the pyramidal cells seems to be both intra- and inter-laminar, and (3 the habituation rates of the connections are unsymmetrical: forward connections (from layer 4 to layer 2/3 are more strongly habituated than backward connections (from Layer 5/6 to layer 4. Our evaluation demonstrates that the novel features of the LCCM are of crucial importance for mechanistic explanations of brain function. The incorporation of these features into a mass model makes them applicable to modeling based on macroscopic data (like EEG or MEG, which are usually available in human experiments. Our LCCM is therefore a valuable building block for future realistic models of human cognitive function.

  9. Peripheral control of the gain of a central synaptic connection between antagonistic motor neurones in the locust

    Science.gov (United States)

    Jellema; Heitler

    1996-01-01

    The metathoracic fast extensor tibiae (FETi) motor neurone of locusts is unusual amongst insect motor neurones because it makes output connections within the central nervous system as well as in the periphery. It makes excitatory chemical synaptic connections to most if not all of the antagonist flexor tibiae motor neurones. The gain of the FETi-flexor connection is dependent on the peripheral conditions at the time of the FETi spike. This dependency has two aspects. First, sensory input resulting from the extensor muscle contraction can sum with the central excitatory postsynaptic potential (EPSP) to augment its falling phase if the tibia is restrained in the flexed position (initiating a tension-dependent reflex) or is free to extend (initiating a movement-dependent resistance reflex). This effect is thus due to simple postsynaptic summation of the central EPSP with peripheral sensory input. Second, the static tibial position at the time of the FETi spike can change the amplitude of the central EPSP, in the absence of any extensor muscle contraction. The EPSP can be up to 30 % greater in amplitude if FETi spikes with the tibia held flexed rather than extended. The primary sense organ mediating this effect is the femoral chordotonal organ. Evidence is presented suggesting that the mechanism underlying this change in gain may be specifically localised to the FETi-flexor connection, rather than being due to general position-dependent sensory feedback summing with the EPSP. The change in the amplitude of the central EPSP is probably not caused by general postsynaptic summation with tonic sensory input, since a diminution in the amplitude of the central EPSP caused by tibial extension is often accompanied by overall tonic excitation of the flexor motor neurone. Small but significant changes in the peak amplitude of the FETi spike have a positive correlation with changes in the EPSP amplitude, suggesting a likely presynaptic component to the mechanism of gain control

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

    Science.gov (United States)

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

    2015-01-01

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

  11. Enhanced Synaptic Connectivity in the Dentate Gyrus during Epileptiform Activity: Network Simulation

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    Keite Lira de Almeida França

    2013-01-01

    Full Text Available Structural rearrangement of the dentate gyrus has been described as the underlying cause of many types of epilepsies, particularly temporal lobe epilepsy. It is said to occur when aberrant connections are established in the damaged hippocampus, as described in human epilepsy and experimental models. Computer modelling of the dentate gyrus circuitry and the corresponding structural changes has been used to understand how abnormal mossy fibre sprouting can subserve seizure generation observed in experimental models when epileptogenesis is induced by status epilepticus. The model follows the McCulloch-Pitts formalism including the representation of the nonsynaptic mechanisms. The neuronal network comprised granule cells, mossy cells, and interneurons. The compensation theory and the Hebbian and anti-Hebbian rules were used to describe the structural rearrangement including the effects of the nonsynaptic mechanisms on the neuronal activity. The simulations were based on neuroanatomic data and on the connectivity pattern between the cells represented. The results suggest that there is a joint action of the compensation theory and Hebbian rules during the inflammatory process that accompanies the status epilepticus. The structural rearrangement simulated for the dentate gyrus circuitry promotes speculation about the formation of the abnormal mossy fiber sprouting and its role in epileptic seizures.

  12. Nociception-induced spatial and temporal plasticity of synaptic connection and function in the hippocampal formation of rats: a multi-electrode array recording

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    Zhang Fu-Kang

    2009-09-01

    Full Text Available Abstract Background Pain is known to be processed by a complex neural network (neuromatrix in the brain. It is hypothesized that under pathological state, persistent or chronic pain can affect various higher brain functions through ascending pathways, leading to co-morbidities or mental disability of pain. However, so far the influences of pathological pain on the higher brain functions are less clear and this may hinder the advances in pain therapy. In the current study, we studied spatiotemporal plasticity of synaptic connection and function in the hippocampal formation (HF in response to persistent nociception. Results On the hippocampal slices of rats which had suffered from persistent nociception for 2 h by receiving subcutaneous bee venom (BV or formalin injection into one hand paw, multisite recordings were performed by an 8 × 8 multi-electrode array probe. The waveform of the field excitatory postsynaptic potential (fEPSP, induced by perforant path electrical stimulation and pharmacologically identified as being activity-dependent and mediated by ionotropic glutamate receptors, was consistently positive-going in the dentate gyrus (DG, while that in the CA1 was negative-going in shape in naïve and saline control groups. For the spatial characteristics of synaptic plasticity, BV- or formalin-induced persistent pain significantly increased the number of detectable fEPSP in both DG and CA1 area, implicating enlargement of the synaptic connection size by the injury or acute inflammation. Moreover, the input-output function of synaptic efficacy was shown to be distinctly enhanced by the injury with the stimulus-response curve being moved leftward compared to the control. For the temporal plasticity, long-term potentiation produced by theta burst stimulation (TBS conditioning was also remarkably enhanced by pain. Moreover, it is strikingly noted that the shape of fEPSP waveform was drastically deformed or split by a TBS conditioning under the

  13. Intracortical neural interface for prosthetic applications.

    Science.gov (United States)

    Ortmann, Valerij; Baziyan, Boris Kh

    2007-01-01

    New design of intracortical penetrating electrodes with integrated electronic front end is presented. The main advantage of the presented manufacturing technology is a simple customization of the electrode lengths and arrangement, according to the brain geometry of the specific patient. The neural interface may be used for the stimulation of the inner cortical layers and for recording of evoked potentials. Experimental investigations on several cats have shown the higher effectiveness of the intracortical stimulation of the primary visual cortex in comparison to surface electrodes.

  14. The delayed strengthening of synaptic connectivity in the amygdala depends on NMDA receptor activation during acute stress.

    Science.gov (United States)

    Yasmin, Farhana; Saxena, Kapil; McEwen, Bruce S; Chattarji, Sumantra

    2016-10-01

    There is growing evidence that stress leads to contrasting patterns of structural plasticity in the hippocampus and amygdala, two brain areas implicated in the cognitive and affective symptoms of stress-related psychiatric disorders. Acute stress has been shown to trigger a delayed increase in the density of dendritic spines in the basolateral amygdala (BLA) of rodents. However, the physiological correlates of this delayed spinogenesis in the BLA remain unexplored. Furthermore, NMDA receptors (NMDARs) have been known to underlie chronic stress-induced structural plasticity in the hippocampus, but nothing is known about the role of these receptors in the delayed spinogenesis, and its physiological consequences, in the BLA following acute stress. Here, using whole-cell recordings in rat brain slices, we find that a single exposure to 2-h immobilization stress enhances the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs) recorded from principal neurons in the BLA 10 days later. This was also accompanied by faster use-dependent block of NMDA receptor currents during repeated stimulation of thalamic inputs to the BLA, which is indicative of higher presynaptic release probability at these inputs 10 days later. Furthermore, targeted in vivo infusion of the NMDAR-antagonist APV into the BLA during the acute stress prevents the increase in mEPSC frequency and spine density 10 days later. Together, these results identify a role for NMDARs during acute stress in both the physiological and morphological strengthening of synaptic connectivity in the BLA in a delayed fashion. These findings also raise the possibility that activation of NMDA receptors during stress may serve as a common molecular mechanism despite the divergent patterns of plasticity that eventually emerge after stress in the amygdala and hippocampus. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological

  15. Intracortical osteoblastic osteosarcoma with oncogenic rickets

    International Nuclear Information System (INIS)

    Hasegawa, T.; Hirohashi, Setsuo; Shimoda, Tadakazu; Yokoyama, Ryohei; Beppu, Yasuo; Maeda, Shotaro

    1999-01-01

    Intracortical osteosarcoma is the rarest variant of osteosarcoma, occurring within, and usually confined to, the cortical bone. Oncogenic osteomalacia, or rickets, is an unusual clinicopathologic entity in which vitamin D-resistant osteomalacia, or rickets, occurs in association with some tumors of soft tissue or bone. We present a case of oncogenic rickets associated with intracortical osteosarcoma of the tibia in a 9-year-old boy, whose roentgenographic abnormalities of rickets disappeared and pertinent laboratory data except for serum alkaline phosphatase became normal after surgical resection of the tumor. Histologically, the tumor was an osteosarcoma with a prominent osteoblastic pattern. An unusual microscopic feature was the presence of matrix mineralization showing rounded calcified structures (calcified spherules). Benign osteoblastic tumors, such as osteoid osteoma and osteoblastoma, must be considered in the differential diagnosis because of the relatively low cellular atypia and mitotic activity of this tumor. The infiltrating pattern with destruction or engulfment of normal bone is a major clue to the correct diagnosis of intracortical osteosarcoma. The co-existing radiographic changes of rickets were due to the intracortical osteosarcoma. (orig.)

  16. Intracortical osteoblastic osteosarcoma with oncogenic rickets

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa, T.; Hirohashi, Setsuo [Pathology Division, National Cancer Center Research Institute, Tokyo (Japan); Shimoda, Tadakazu [Clinical Laboratory Division, National Cancer Center Hospital, Tokyo (Japan); Yokoyama, Ryohei; Beppu, Yasuo [Orthopedic Division, National Cancer Center Hospital, Tokyo (Japan); Maeda, Shotaro [Department of Pathology, Nippon Medical School Hospital, Tokyo (Japan)

    1999-01-01

    Intracortical osteosarcoma is the rarest variant of osteosarcoma, occurring within, and usually confined to, the cortical bone. Oncogenic osteomalacia, or rickets, is an unusual clinicopathologic entity in which vitamin D-resistant osteomalacia, or rickets, occurs in association with some tumors of soft tissue or bone. We present a case of oncogenic rickets associated with intracortical osteosarcoma of the tibia in a 9-year-old boy, whose roentgenographic abnormalities of rickets disappeared and pertinent laboratory data except for serum alkaline phosphatase became normal after surgical resection of the tumor. Histologically, the tumor was an osteosarcoma with a prominent osteoblastic pattern. An unusual microscopic feature was the presence of matrix mineralization showing rounded calcified structures (calcified spherules). Benign osteoblastic tumors, such as osteoid osteoma and osteoblastoma, must be considered in the differential diagnosis because of the relatively low cellular atypia and mitotic activity of this tumor. The infiltrating pattern with destruction or engulfment of normal bone is a major clue to the correct diagnosis of intracortical osteosarcoma. The co-existing radiographic changes of rickets were due to the intracortical osteosarcoma. (orig.) With 8 figs., 25 refs.

  17. ON Bipolar Cells in Macaque Retina: Type-Specific Synaptic Connectivity with Special Reference to OFF Counterparts

    Science.gov (United States)

    Tsukamoto, Yoshihiko; Omi, Naoko

    2016-01-01

    -step synaptic connections largely narrowed down the S-cone component to SBG and some OFF MG cells. The other OFF MG cells, ON MG cells, and ON and OFF PG cells constructed M/L-cone dominant pathways. PMID:27833534

  18. Intracortical cartography in an agranular area.

    Science.gov (United States)

    Shepherd, Gordon M G

    2009-01-01

    A well-defined granular layer 4 is a defining cytoarchitectonic feature associated with sensory areas of mammalian cerebral cortex, and one with hodological significance: the local axons ascending from cells in thalamorecipient layer 4 and connecting to layer 2/3 pyramidal neurons form a major feedforward excitatory interlaminar projection. Conversely, agranular cortical areas, lacking a distinct layer 4, pose a hodological conundrum: without a laminar basis for the canonical layer 4-->2/3 pathway, what is the basic circuit organization? This review highlights current challenges and prospects for local-circuit electroanatomy and electrophysiology in agranular cortex, focusing on the mouse. Different lines of evidence, drawn primarily from studies of motor areas in frontal cortex in rodents, support the view that synaptic circuits in agranular cortex are organized around prominent descending excitatory layer 2/3-->5 pathways targeting multiple classes of projection neurons.

  19. Reorganization of Synaptic Connections and Perineuronal Nets in the Deep Cerebellar Nuclei of Purkinje Cell Degeneration Mutant Mice.

    Science.gov (United States)

    Blosa, M; Bursch, C; Weigel, S; Holzer, M; Jäger, C; Janke, C; Matthews, R T; Arendt, T; Morawski, M

    2016-01-01

    The perineuronal net (PN) is a subtype of extracellular matrix appearing as a net-like structure around distinct neurons throughout the whole CNS. PNs surround the soma, proximal dendrites, and the axonal initial segment embedding synaptic terminals on the neuronal surface. Different functions of the PNs are suggested which include support of synaptic stabilization, inhibition of axonal sprouting, and control of neuronal plasticity. A number of studies provide evidence that removing PNs or PN-components results in renewed neurite growth and synaptogenesis. In a mouse model for Purkinje cell degeneration, we examined the effect of deafferentation on synaptic remodeling and modulation of PNs in the deep cerebellar nuclei. We found reduced GABAergic, enhanced glutamatergic innervations at PN-associated neurons, and altered expression of the PN-components brevican and hapln4. These data refer to a direct interaction between ECM and synapses. The altered brevican expression induced by activated astrocytes could be required for an adequate regeneration by promoting neurite growth and synaptogenesis.

  20. EDITORIAL: Synaptic electronics Synaptic electronics

    Science.gov (United States)

    Demming, Anna; Gimzewski, James K.; Vuillaume, Dominique

    2013-09-01

    Conventional computers excel in logic and accurate scientific calculations but make hard work of open ended problems that human brains handle easily. Even von Neumann—the mathematician and polymath who first developed the programming architecture that forms the basis of today's computers—was already looking to the brain for future developments before his death in 1957 [1]. Neuromorphic computing uses approaches that better mimic the working of the human brain. Recent developments in nanotechnology are now providing structures with very accommodating properties for neuromorphic approaches. This special issue, with guest editors James K Gimzewski and Dominique Vuillaume, is devoted to research at the serendipitous interface between the two disciplines. 'Synaptic electronics', looks at artificial devices with connections that demonstrate behaviour similar to synapses in the nervous system allowing a new and more powerful approach to computing. Synapses and connecting neurons respond differently to incident signals depending on the history of signals previously experienced, ultimately leading to short term and long term memory behaviour. The basic characteristics of a synapse can be replicated with around ten simple transistors. However with the human brain having around 1011 neurons and 1015 synapses, artificial neurons and synapses from basic transistors are unlikely to accommodate the scalability required. The discovery of nanoscale elements that function as 'memristors' has provided a key tool for the implementation of synaptic connections [2]. Leon Chua first developed the concept of the 'The memristor—the missing circuit element' in 1971 [3]. In this special issue he presents a tutorial describing how memristor research has fed into our understanding of synaptic behaviour and how they can be applied in information processing [4]. He also describes, 'The new principle of local activity, which uncovers a minuscule life-enabling "Goldilocks zone", dubbed the

  1. Impaired synaptic plasticity in RASopathies: a mini-review.

    Science.gov (United States)

    Mainberger, Florian; Langer, Susanne; Mall, Volker; Jung, Nikolai H

    2016-10-01

    Synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) is considered to be the neurophysiological correlate of learning and memory. Impairments are discussed to be one of the underlying pathophysiological mechanisms of developmental disorders. In so-called RASopathies [e.g., neurofibromatosis 1 (NF1)], neurocognitive impairments are frequent and are affected by components of the RAS pathway which lead to impairments in synaptic plasticity. Transcranial magnetic stimulation (TMS) provides a non-invasive method to investigate synaptic plasticity in humans. Here, we review studies using TMS to evaluate synaptic plasticity in patients with RASopathies. Patients with NF1 and Noonan syndrome (NS) showed reduced cortical LTP-like synaptic plasticity. In contrast, increased LTP-like synaptic plasticity has been shown in Costello syndrome. Notably, lovastatin normalized impaired LTP-like plasticity and increased intracortical inhibition in patients with NF1. TMS has been shown to be a safe and efficient method to investigate synaptic plasticity and intracortical inhibition in patients with RASopathies. Deeper insights in impairments of synaptic plasticity in RASopathies could help to develop new options for the therapy of learning deficits in these patients.

  2. Qualitative and quantitative estimation of comprehensive synaptic connectivity in short- and long-term cultured rat hippocampal neurons with new analytical methods inspired by Scatchard and Hill plots

    Energy Technology Data Exchange (ETDEWEB)

    Tanamoto, Ryo; Shindo, Yutaka; Niwano, Mariko [Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University (Japan); Matsumoto, Yoshinori [Department of Applied Physics and Physico-Informatics, Faculty of Science and Technology, Keio University (Japan); Miki, Norihisa [Department of Mechanical Engineering, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522 (Japan); Hotta, Kohji [Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University (Japan); Oka, Kotaro, E-mail: oka@bio.keio.ac.jp [Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University (Japan)

    2016-03-18

    To investigate comprehensive synaptic connectivity, we examined Ca{sup 2+} responses with quantitative electric current stimulation by indium-tin-oxide (ITO) glass electrode with transparent and high electro-conductivity. The number of neurons with Ca{sup 2+} responses was low during the application of stepwise increase of electric current in short-term cultured neurons (less than 17 days in-vitro (DIV)). The neurons cultured over 17 DIV showed two-type responses: S-shaped (sigmoid) and monotonous saturated responses, and Scatchard plots well illustrated the difference of these two responses. Furthermore, sigmoid like neural network responses over 17 DIV were altered to the monotonous saturated ones by the application of the mixture of AP5 and CNQX, specific blockers of NMDA and AMPA receptors, respectively. This alternation was also characterized by the change of Hill coefficients. These findings indicate that the neural network with sigmoid-like responses has strong synergetic or cooperative synaptic connectivity via excitatory glutamate synapses. - Highlights: • We succeed to evaluate the maturation of neural network by Scathard and Hill Plots. • Long-term cultured neurons showed two-type responses: sigmoid and monotonous. • The sigmoid-like increase indicates the cooperatevity of neural networks. • Excitatory glutamate synapses cause the cooperatevity of neural networks.

  3. Qualitative and quantitative estimation of comprehensive synaptic connectivity in short- and long-term cultured rat hippocampal neurons with new analytical methods inspired by Scatchard and Hill plots

    International Nuclear Information System (INIS)

    Tanamoto, Ryo; Shindo, Yutaka; Niwano, Mariko; Matsumoto, Yoshinori; Miki, Norihisa; Hotta, Kohji; Oka, Kotaro

    2016-01-01

    To investigate comprehensive synaptic connectivity, we examined Ca 2+ responses with quantitative electric current stimulation by indium-tin-oxide (ITO) glass electrode with transparent and high electro-conductivity. The number of neurons with Ca 2+ responses was low during the application of stepwise increase of electric current in short-term cultured neurons (less than 17 days in-vitro (DIV)). The neurons cultured over 17 DIV showed two-type responses: S-shaped (sigmoid) and monotonous saturated responses, and Scatchard plots well illustrated the difference of these two responses. Furthermore, sigmoid like neural network responses over 17 DIV were altered to the monotonous saturated ones by the application of the mixture of AP5 and CNQX, specific blockers of NMDA and AMPA receptors, respectively. This alternation was also characterized by the change of Hill coefficients. These findings indicate that the neural network with sigmoid-like responses has strong synergetic or cooperative synaptic connectivity via excitatory glutamate synapses. - Highlights: • We succeed to evaluate the maturation of neural network by Scathard and Hill Plots. • Long-term cultured neurons showed two-type responses: sigmoid and monotonous. • The sigmoid-like increase indicates the cooperatevity of neural networks. • Excitatory glutamate synapses cause the cooperatevity of neural networks.

  4. Intracortical inhibitory and excitatory circuits in subjects with minimal hepatic encephalopathy: a TMS study.

    Science.gov (United States)

    Nardone, Raffaele; De Blasi, Pierpaolo; Höller, Yvonne; Brigo, Francesco; Golaszewski, Stefan; Frey, Vanessa N; Orioli, Andrea; Trinka, Eugen

    2016-10-01

    Minimal hepatic encephalopathy (MHE) is the earliest form of hepatic encephalopathy (HE) and affects up to 80 % of patients with liver cirrhosis. By definition, MHE is characterized by psychomotor slowing and subtle cognitive deficits,  but obvious clinical manifestations are lacking. Given its covert nature, MHE is often underdiagnosed. This study was aimed at detecting neurophysiological changes, as assessed by means of transcranial magnetic stimulation (TMS), involved in the early pathogenesis of the HE. We investigated motor cortex excitability in 15 patients with MHE and in 15 age-matched age-matched cirrhotic patients without MHE; the resting motor threshold, the short-interval intracortical inhibition (SICI) and the intracortical facilitation (ICF) were examined. Paired-pulse TMS revealed significant increased SICI and reduced ICF in the patients with MHE. These findings may reflect abnormalities in intrinsic brain activity and altered organization of functional connectivity networks. In particular, the results suggest a shift in the balance between intracortical inhibitory and excitatory mechanisms towards a net increase of inhibitory neurotransmission. Together with other neurophysiological (in particular EEG) and neuroimaging techniques, TMS may thus provide early markers of cerebral dysfunction in cirrhotic patients with MHE.

  5. Effect of Ovariectomy on Stimulating Intracortical Remodeling in Rats

    Directory of Open Access Journals (Sweden)

    Chun Lei Li

    2014-01-01

    Full Text Available Objective. Technically primates and dogs represent ideal models to investigate diseases characterized by abnormal intracortical remodeling. High expenses and ethical issues, however, restrict the use of those animals in research. Rodent models have been used as alternatives instead, but their value is limited, if none, because these animals lack intracortical bone remodeling. This study aimed at investigating the effect of ovariectomy onto the stimulation of intracortical remodeling in rat mandibles. Materials and Methods. Sixteen 12-week-old Spraque-Dawly (SD female rats were randomly assigned into two groups, receiving either ovariectomy or sham operation. All the rats were sacrificed 18 weeks postoperatively. The entire mandibles were harvested for microcomputed tomography (micro-CT and histomorphometric assessments. Results. Micro-CT examination showed significantly decreased bone mineral density (0.95 ± 0.01 versus 1.01 ± 0.02 g/cm3, P<0.001 and bone volume (65.78 ± 5.45 versus 87.41 ± 4.12%, P<0.001 in ovariectomy group. Histomorphometric assessment detected a sixfold increased intracortical bone remodeling as well as an increased bone modeling in mandibles of ovariectomized rats. Conclusion. For the first time, to the authors’ knowledge, it was detected that ovariectomy stimulates intracortical remodeling in rat mandibles. This animal model might be of use to study various bone diseases associated with an abnormal intracortical remodeling process.

  6. Theoretical analysis of intracortical microelectrode recordings

    Science.gov (United States)

    Lempka, Scott F.; Johnson, Matthew D.; Moffitt, Michael A.; Otto, Kevin J.; Kipke, Daryl R.; McIntyre, Cameron C.

    2011-08-01

    Advanced fabrication techniques have now made it possible to produce microelectrode arrays for recording the electrical activity of a large number of neurons in the intact brain for both clinical and basic science applications. However, the long-term recording performance desired for these applications is hindered by a number of factors that lead to device failure or a poor signal-to-noise ratio (SNR). The goal of this study was to identify factors that can affect recording quality using theoretical analysis of intracortical microelectrode recordings of single-unit activity. Extracellular microelectrode recordings were simulated with a detailed multi-compartment cable model of a pyramidal neuron coupled to a finite-element volume conductor head model containing an implanted recording microelectrode. Recording noise sources were also incorporated into the overall modeling infrastructure. The analyses of this study would be very difficult to perform experimentally; however, our model-based approach enabled a systematic investigation of the effects of a large number of variables on recording quality. Our results demonstrate that recording amplitude and noise are relatively independent of microelectrode size, but instead are primarily affected by the selected recording bandwidth, impedance of the electrode-tissue interface and the density and firing rates of neurons surrounding the recording electrode. This study provides the theoretical groundwork that allows for the design of the microelectrode and recording electronics such that the SNR is maximized. Such advances could help enable the long-term functionality required for chronic neural recording applications.

  7. Synaptic connections between endomorphin 2-immunoreactive terminals and μ-opioid receptor-expressing neurons in the sacral parasympathetic nucleus of the rat.

    Directory of Open Access Journals (Sweden)

    Xiao Liang Dou

    Full Text Available The urinary bladder is innervated by parasympathetic preganglionic neurons (PPNs that express μ-opioid receptors (MOR in the sacral parasympathetic nucleus (SPN at lumbosacral segments L6-S1. The SPN also contains endomorphin 2 (EM2-immunoreactive (IR fibers and terminals. EM2 is the endogenous ligand of MOR. In the present study, retrograde tract-tracing with cholera toxin subunit b (CTb or wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP via the pelvic nerve combined with immunohistochemical staining for EM2 and MOR to identify PPNs within the SPN as well as synaptic connections between the EM2-IR terminals and MOR-expressing PPNs in the SPN of the rat. After CTb was injected into the pelvic nerve, CTb retrogradely labeled neurons were almost exclusively located in the lateral part of the intermediolateral gray matter at L6-S1 of the lumbosacral spinal cord. All of the them also expressed MOR. EM2-IR terminals formed symmetric synapses with MOR-IR, WGA-HRP-labeled and WGA-HRP/MOR double-labeled neuronal cell bodies and dendrites within the SPN. These results provided morphological evidence that EM2-containing axon terminals formed symmetric synapses with MOR-expressing PPNs in the SPN. The present results also show that EM2 and MOR might be involved in both the homeostatic control and information transmission of micturition.

  8. Intracortical circuits amplify sound-evoked activity in primary auditory cortex following systemic injection of salicylate in the rat

    Science.gov (United States)

    Chrostowski, Michael; Salvi, Richard J.; Allman, Brian L.

    2012-01-01

    A high dose of sodium salicylate temporarily induces tinnitus, mild hearing loss, and possibly hyperacusis in humans and other animals. Salicylate has well-established effects on cochlear function, primarily resulting in the moderate reduction of auditory input to the brain. Despite decreased peripheral sensitivity and output, salicylate induces a paradoxical enhancement of the sound-evoked field potential at the level of the primary auditory cortex (A1). Previous electrophysiologic studies have begun to characterize changes in thalamorecipient layers of A1; however, A1 is a complex neural circuit with recurrent intracortical connections. To describe the effects of acute systemic salicylate treatment on both thalamic and intracortical sound-driven activity across layers of A1, we applied current-source density (CSD) analysis to field potentials sampled across cortical layers in the anesthetized rat. CSD maps were normally characterized by a large, short-latency, monosynaptic, thalamically driven sink in granular layers followed by a lower amplitude, longer latency, polysynaptic, intracortically driven sink in supragranular layers. Following systemic administration of salicylate, there was a near doubling of both granular and supragranular sink amplitudes at higher sound levels. The supragranular sink amplitude input/output function changed from becoming asymptotic at approximately 50 dB to sharply nonasymptotic, often dominating the granular sink amplitude at higher sound levels. The supragranular sink also exhibited a significant decrease in peak latency, reflecting an acceleration of intracortical processing of the sound-evoked response. Additionally, multiunit (MU) activity was altered by salicylate; the normally onset/sustained MU response type was transformed into a primarily onset response type in granular and infragranular layers. The results from CSD analysis indicate that salicylate significantly enhances sound-driven response via intracortical circuits

  9. Network response synchronization enhanced by synaptic plasticity

    Science.gov (United States)

    Lobov, S.; Simonov, A.; Kastalskiy, I.; Kazantsev, V.

    2016-02-01

    Synchronization of neural network response on spatially localized periodic stimulation was studied. The network consisted of synaptically coupled spiking neurons with spike-timing-dependent synaptic plasticity (STDP). Network connectivity was defined by time evolving matrix of synaptic weights. We found that the steady-state spatial pattern of the weights could be rearranged due to locally applied external periodic stimulation. A method for visualization of synaptic weights as vector field was introduced to monitor the evolving connectivity matrix. We demonstrated that changes in the vector field and associated weight rearrangements underlay an enhancement of synchronization range.

  10. Generation of Stimulus Triggering from Intracortical Spike Activity for Brain-Machine-Body Interfaces (BMBIs).

    Science.gov (United States)

    Shahdoost, Shahab; Nudo, Randolph; Mohseni, Pedram

    2016-10-05

    Brain-machine-body interfaces (BMBIs) aim to create an artificial connection in the nervous system by converting neural activity recorded from one cortical region to electrical stimuli delivered to another cortical region, spinal cord, or muscles in real-time. In particular, conditioning-mode BMBIs utilize such activity-dependent stimulation strategies to induce functional re-organization in the nervous system and promote functional recovery after injury by exploiting mechanisms underlying neuroplasticity. This paper reports on reconfigurable, field-programmable gate array (FPGA)-based implementation of a translation algorithm to extract multichannel stimulus trigger signals from intracortical neural spike activity. The approach features digital spike discrimination based on user-set thresholding and time-amplitude windowing, decision making to support different triggering patterns for various stimulation scenarios, as well as trigger-pattern-dependent blanking schemes for robust operation in the presence of stimulus artifacts. Readily lending itself to low-power, low-area implementation for future integration, the algorithm has been synthesized on a Cyclone II FPGA using Altera's Quartus II design software and validated experimentally with prerecorded intracortical neural spike activity from an anesthetized laboratory rat.

  11. Emergent spatial synaptic structure from diffusive plasticity.

    Science.gov (United States)

    Sweeney, Yann; Clopath, Claudia

    2017-04-01

    Some neurotransmitters can diffuse freely across cell membranes, influencing neighbouring neurons regardless of their synaptic coupling. This provides a means of neural communication, alternative to synaptic transmission, which can influence the way in which neural networks process information. Here, we ask whether diffusive neurotransmission can also influence the structure of synaptic connectivity in a network undergoing plasticity. We propose a form of Hebbian synaptic plasticity which is mediated by a diffusive neurotransmitter. Whenever a synapse is modified at an individual neuron through our proposed mechanism, similar but smaller modifications occur in synapses connecting to neighbouring neurons. The effects of this diffusive plasticity are explored in networks of rate-based neurons. This leads to the emergence of spatial structure in the synaptic connectivity of the network. We show that this spatial structure can coexist with other forms of structure in the synaptic connectivity, such as with groups of strongly interconnected neurons that form in response to correlated external drive. Finally, we explore diffusive plasticity in a simple feedforward network model of receptive field development. We show that, as widely observed across sensory cortex, the preferred stimulus identity of neurons in our network become spatially correlated due to diffusion. Our proposed mechanism of diffusive plasticity provides an efficient mechanism for generating these spatial correlations in stimulus preference which can flexibly interact with other forms of synaptic organisation. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  12. Synaptic Determinants of Rett Syndrome

    Science.gov (United States)

    Boggio, Elena M.; Lonetti, Giuseppina; Pizzorusso, Tommaso; Giustetto, Maurizio

    2010-01-01

    There is mounting evidence showing that the structural and molecular organization of synaptic connections is affected both in human patients and in animal models of neurological and psychiatric diseases. As a consequence of these experimental observations, it has been introduced the concept of synapsopathies, a notion describing brain disorders of synaptic function and plasticity. A close correlation between neurological diseases and synaptic abnormalities is especially relevant for those syndromes including also mental retardation in their symptomatology, such as Rett syndrome (RS). RS (MIM312750) is an X-linked dominant neurological disorder that is caused in the majority of cases by mutations in methyl-CpG-binding protein 2 (MeCP2). This review will focus on the current knowledge of the synaptic alterations produced by mutations of the gene MeCP2 in mouse models of RS and will highlight prospects experimental therapies currently in use. Different experimental approaches have revealed that RS could be the consequence of an impairment in the homeostasis of synaptic transmission in specific brain regions. Indeed, several forms of experience-induced neuronal plasticity are impaired in the absence of MeCP2. Based on the results presented in this review, it is reasonable to propose that understanding how the brain is affected by diseases such as RS is at reach. This effort will bring us closer to identify the neurobiological bases of human cognition. PMID:21423514

  13. Synaptic determinants of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Elena M B Boggio

    2010-08-01

    Full Text Available There is mounting evidence showing that the structural and molecular organization of synaptic connections are affected both in human patients and in animal models of neurological and psychiatric diseases. As a consequence of these experimental observations, it has been introduced the concept of synapsopathies, a notion describing brain disorders of synaptic function and plasticity. A close correlation between neurological diseases and synaptic abnormalities is especially relevant for those syndromes including also mental retardation in their symptomatology, such as Rett Syndrome (RS. RS (MIM312750 is an X-linked dominant neurological disorder that is caused, in the majority of cases by mutations in methyl-CpG-binding protein 2 (MeCP2. This review will focus on the current knowledge of the synaptic alterations produced by mutations of the gene MeCP2 in mouse models of RS and will highlight prospects experimental therapies currently in use. Different experimental approaches have revealed that RS could be the consequence of an impairment in the homeostasis of synaptic transmission in specific brain regions. Indeed, several forms of experience-induced neuronal plasticity are impaired in the absence of MeCP2. Based on the results presented in this review, it is reasonable to propose that understanding how the brain is affected by diseases such as RS is at reach. This effort will bring us closer to identify the neurobiological bases of human cognition.

  14. Assessment of capacitor electrodes for intracortical neural stimulation.

    Science.gov (United States)

    Rose, T L; Kelliher, E M; Robblee, L S

    1985-01-01

    Capacitor electrodes offer the potential for the safest method of stimulation of neural tissue because they operate without any faradaic process occurring at the electrode-electrolyte interface. Their use eliminates problems associated with metal dissolution or water electrolysis which may occur with electrodes of noble metals. This paper reviews recent work aimed at increasing the charge storage density of capacitor electrodes to allow their application with the small areas of 10(-4) mm2 required for intracortical stimulation of single neurons. Increased charge storage with electrodes using anodic films such as TiO2 and Ta2O5 has been obtained by increasing the real surface area of microelectrodes. Experiments have also been done with BaTiO3 films which have a much higher dielectric constant than the anodic film dielectrics. State-of-the-art electrodes made with these materials, however, have a charge storage density which at best is comparable to that obtained with Pt and is considerably lower than electrochemically safe charge densities that have been reported for activated Ir. It is concluded that for very small intracortical electrodes, capacitor electrodes will not be competitive with electrodes which operate using surface localized faradaic reactions.

  15. PTH treatment activates intracortical bone remodeling in patients with hypoparathyroidism

    DEFF Research Database (Denmark)

    Sikjær, Tanja Tvistholm; Rejnmark, Lars; Thomsen, Jesper Skovhus

    2017-01-01

    Hypoparathyroidism (hypoPT) is characterized by a state of low bone turnover and high BMD. We have previously shown that hypoPT patients treated with PTH(1-84) for six months have highly increased bone turnover markers and a decrease in aBMD at the hip and spine(1). The present study aims...... to investigate the effect of PTH(1-84) on cortical bone and intracortical bone remodeling in hypoPT. The study was conducted on 20 transiliac bone biopsies from hypoPT patients after six months of treatment with either PTH(1-84) 100 µg s.c./day N=10 or placebo N=10. The groups were age- (±6 years) and gender......-matched. Age, duration of disease, and etiology of hypoPT did not differ between groups. A comprehensive analysis of the cortical bone was performed including estimates of cortical porosity, and pore density (# of pores/mm2). The remodeling stage of all intracortical pores was evaluated, and pore area...

  16. Attempt of correlative observation of morphological synaptic connectivity by combining confocal laser-scanning microscope and FIB-SEM for immunohistochemical staining technique.

    Science.gov (United States)

    Sonomura, Takahiro; Furuta, Takahiro; Nakatani, Ikuko; Yamamoto, Yo; Honma, Satoru; Kaneko, Takeshi

    2014-11-01

    Ten years have passed since a serial block-face scanning electron microscopy (SBF-SEM) method was developed [1]. In this innovative method, samples were automatically sectioned with an ultramicrotome placed inside a scanning electron microscope column, and the block surfaces were imaged one after another by SEM to capture back-scattered electrons. The contrast-inverted images obtained by the SBF-SEM were very similar to those acquired using conventional TEM. SFB-SEM has made easy to acquire image stacks of the transmission electron microscopy (TEM) in the mesoscale, which is taken with the confocal laser-scanning microcopy(CF-LSM).Furthermore, serial-section SEM has been combined with the focused ion beam (FIB) milling method [2]. FIB-incorporated SEM (FIB-SEM) has enabled the acquisition of three-dimensional images with a higher z-axis resolution com- pared to ultramicrotome-equipped SEM.We tried immunocytochemistry for FIB-SEM and correlated this immunoreactivity with that in CF-LSM. Dendrites of neurons in the rat neostriatum were visualized using a recombinant viral vector. Moreover, the thalamostriatal afferent terminals were immunolabeled with Cy5 fluorescence for vesicular glutamate transporter 2 (VGluT2). After detection of the sites of terminals apposed to the dendrites by using CF-LSM, GFP and VGluT2 immunoreactivities were further developed for EM by using immunogold/silver enhancement and immunoperoxidase/diaminobenzidine (DAB) methods, respectively.We showed that conventional immuno-cytochemical staining for TEM was applicable to FIB-SEM. Furthermore, several synaptic contacts, which were thought to exist on the basis of CF-LSM findings, were confirmed with FIB-SEM, revealing the usefulness of the combined method of CF-LSM and FIB-SEM. © The Author 2014. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. A brain-machine interface instructed by direct intracortical microstimulation

    Directory of Open Access Journals (Sweden)

    Joseph E O'Doherty

    2009-09-01

    Full Text Available Brain-machine interfaces (BMIs establish direct communications between the brain and artificial actuators. As such, they hold considerable promise for restoring mobility and communication in patients suffering from severe body paralysis. To achieve this end, future BMIs must also provide a means for delivering sensory signals from the actuators back to the brain. Prosthetic sensation is needed so that neuroprostheses can be better perceived and controlled. Here we show that a direct intracortical input can be added to a BMI to instruct rhesus monkeys in choosing the direction of reaching movements generated by the BMI. Somatosensory instructions were provided to two monkeys operating the BMI using either: (a vibrotactile stimulation of the monkey’s hands or (b multi-channel intracortical microstimulation (ICMS delivered to the primary somatosensory cortex (S1 in one monkey and posterior parietal cortex (PP in the other. Stimulus delivery was contingent on the position of the computer cursor: the monkey placed it in the center of the screen to receive machine-brain recursive input. After two weeks of training, the same level of proficiency in utilizing somatosensory information was achieved with ICMS of S1 as with the stimulus delivered to the hand skin. ICMS of PP was not effective. These results indicate that direct, bi-directional communication between the brain and neuroprosthetic devices can be achieved through the combination of chronic multi-electrode recording and microstimulation of S1. We propose that in the future, bidirectional BMIs incorporating ICMS may become an effective paradigm for sensorizing neuroprosthetic devices.

  18. Intracortical inhibition is modulated by phase of prosthetic rehabilitation in transtibial amputees

    Directory of Open Access Journals (Sweden)

    Brenton eHordacre

    2015-05-01

    Full Text Available Reorganisation of primary motor cortex (M1 is well described in long-term lower limb amputees. In contrast cortical reorganisation during the rehabilitation period after amputation is poorly understood. Thirteen transtibial amputees and thirteen gender matched control participants of similar age were recruited. Transcranial magnetic stimulation was used to assess corticomotor and intracortical excitability of M1 bilaterally. Neurophysiological assessments were conducted at admission, prosthetic casting, first walk and discharge. Gait variability at discharge was assessed as a functional measure. Compared to controls, amputees had reduced short-latency intracortical inhibition for the ipsilateral M1 at admission (p=0.01. Analysis across rehabilitation revealed short-latency intracortical inhibition was reduced for the contralateral M1 at first walk compared to discharge (p=0.003. For the ipsilateral M1 both short and long-latency intracortical inhibition were reduced at admission (p<0.05 and prosthetic casting (p<0.02. Analysis of the neurophysiology and gait function revealed several interesting relationships. For the contralateral M1, reduced inhibition at admission (p=0.04 and first walk (p=0.05 was associated with better gait function. For the ipsilateral M1, reduced inhibition at discharge (p=0.05 was associated with poor gait function. This study characterised intracortical excitability in rehabilitating amputees. A dichotomous relationship between reduced intracortical inhibition for each M1 and gait function was observed at different times. Intracortical inhibition may be an appropriate cortical biomarker of gait function in lower limb amputees during rehabilitation, but requires further investigation. Understanding M1 intracortical excitability of amputees undertaking prosthetic rehabilitation provides insight into brain reorganisation in the sub-acute post amputation period and may guide future studies seeking to improve rehabilitation

  19. Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance

    Science.gov (United States)

    Cohen, Laurie D.; Zuchman, Rina; Sorokina, Oksana; Müller, Anke; Dieterich, Daniela C.; Armstrong, J. Douglas; Ziv, Tamar; Ziv, Noam E.

    2013-01-01

    Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non–Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2–5 days. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. The relatively low turnover rates measured here (∼0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load

  20. Intracortical inhibition is modulated by phase of prosthetic rehabilitation in transtibial amputees

    Science.gov (United States)

    Hordacre, Brenton; Bradnam, Lynley V.; Barr, Christopher; Patritti, Benjamin L.; Crotty, Maria

    2015-01-01

    Reorganization of primary motor cortex (M1) is well-described in long-term lower limb amputees. In contrast cortical reorganization during the rehabilitation period after amputation is poorly understood. Thirteen transtibial amputees and 13 gender matched control participants of similar age were recruited. Transcranial magnetic stimulation was used to assess corticomotor and intracortical excitability of M1 bilaterally. Neurophysiological assessments were conducted at admission, prosthetic casting, first walk and discharge. Gait variability at discharge was assessed as a functional measure. Compared to controls, amputees had reduced short-latency intracortical inhibition (SICI) for the ipsilateral M1 at admission (p = 0.01). Analysis across rehabilitation revealed SICI was reduced for the contralateral M1 at first walk compared to discharge (p = 0.003). For the ipsilateral M1 both short and long-latency intracortical inhibition were reduced at admission (p rehabilitating amputees. A dichotomous relationship between reduced intracortical inhibition for each M1 and gait function was observed at different times. Intracortical inhibition may be an appropriate cortical biomarker of gait function in lower limb amputees during rehabilitation, but requires further investigation. Understanding M1 intracortical excitability of amputees undertaking prosthetic rehabilitation provides insight into brain reorganization in the sub-acute post-amputation period and may guide future studies seeking to improve rehabilitation outcomes. PMID:26042015

  1. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

    Science.gov (United States)

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

  2. Intracortical chondroblastoma mimicking intra-articular osteoid osteoma

    Energy Technology Data Exchange (ETDEWEB)

    Ishida, Tsuyoshi; Mukai, Kiyoshi [First Department of Pathology, Tokyo Medical University, Shinjuku 6-1-1, Shinjuku-ku, Tokyo 160-8402 (Japan); Goto, Takahiro [Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo (Japan); Motoi, Noriko [Department of Pathology, Toranomon Hospital, Tokyo (Japan)

    2002-10-01

    We report a case of intra-articular intracortical chondroblastoma of the femoral condyle which radiologically appeared to be osteoid osteoma. A 19-year-old woman presented with a 3-year history of gradually increasing pain in the right knee and had been on nonsteroidal anti-inflammatory drugs for pain relief. Laboratory data were within normal limits. Radiographs showed a well-demarcated lucent lesion in the medial condyle of the right femur. A nidus-like lesion with calcifications and a sclerotic rim located in the cortex was imaged by computed tomography scan. Magnetic resonance imaging revealed bone marrow edema and soft tissue swelling around the lesion, with low signal intensity of the nidus-like lesion on both T1- and T2-weighted images. The lesion was excised en bloc and the histological diagnosis of chondroblastoma was made. A mild inflammatory reaction was observed in the bone marrow and synovium around the tumor. The chondroblastoma cells were shown to express cyclooxygenase-2 with immunohistochemistry. (orig.)

  3. A computational model that predicts behavioral sensitivity to intracortical microstimulation

    Science.gov (United States)

    Kim, Sungshin; Callier, Thierri; Bensmaia, Sliman J.

    2017-02-01

    Objective. Intracortical microstimulation (ICMS) is a powerful tool to investigate the neural mechanisms of perception and can be used to restore sensation for patients who have lost it. While sensitivity to ICMS has previously been characterized, no systematic framework has been developed to summarize the detectability of individual ICMS pulse trains or the discriminability of pairs of pulse trains. Approach. We develop a simple simulation that describes the responses of a population of neurons to a train of electrical pulses delivered through a microelectrode. We then perform an ideal observer analysis on the simulated population responses to predict the behavioral performance of non-human primates in ICMS detection and discrimination tasks. Main results. Our computational model can predict behavioral performance across a wide range of stimulation conditions with high accuracy (R 2 = 0.97) and generalizes to novel ICMS pulse trains that were not used to fit its parameters. Furthermore, the model provides a theoretical basis for the finding that amplitude discrimination based on ICMS violates Weber’s law. Significance. The model can be used to characterize the sensitivity to ICMS across the range of perceptible and safe stimulation regimes. As such, it will be a useful tool for both neuroscience and neuroprosthetics.

  4. Discriminability of Single and Multichannel Intracortical Microstimulation within Somatosensory Cortex

    Directory of Open Access Journals (Sweden)

    Cynthia Kay Overstreet

    2016-12-01

    Full Text Available The addition of tactile and proprioceptive feedback to neuroprosthetic limbs is expected to significantly improve the control of these devices. Intracortical microstimulation (ICMS of somatosensory cortex is a promising method of delivering this sensory feedback. To date, the main focus of somatosensory ICMS studies has been to deliver discriminable signals, corresponding to varying intensity, to a single location in cortex. However, multiple independent and simultaneous streams of sensory information will need to be encoded by ICMS to provide functionally relevant feedback for a neuroprosthetic limb (e.g. encoding contact events and pressure on multiple digits.In this study, we evaluated the ability of an awake, behaving non-human primate (Macaca mulatta to discriminate ICMS stimuli delivered on multiple electrodes spaced within somatosensory cortex. We delivered serial stimulation on single electrodes to evaluate the discriminability of sensations corresponding to ICMS of distinct cortical locations. Additionally, we delivered trains of multichannel stimulation, derived from a tactile sensor, synchronously across multiple electrodes. Our results indicate that discrimination of multiple ICMS stimuli is a challenging task, but that discriminable sensory percepts can be elicited by both single and multichannel ICMS on electrodes spaced within somatosensory cortex.

  5. Statistical mechanics of attractor neural network models with synaptic depression

    International Nuclear Information System (INIS)

    Igarashi, Yasuhiko; Oizumi, Masafumi; Otsubo, Yosuke; Nagata, Kenji; Okada, Masato

    2009-01-01

    Synaptic depression is known to control gain for presynaptic inputs. Since cortical neurons receive thousands of presynaptic inputs, and their outputs are fed into thousands of other neurons, the synaptic depression should influence macroscopic properties of neural networks. We employ simple neural network models to explore the macroscopic effects of synaptic depression. Systems with the synaptic depression cannot be analyzed due to asymmetry of connections with the conventional equilibrium statistical-mechanical approach. Thus, we first propose a microscopic dynamical mean field theory. Next, we derive macroscopic steady state equations and discuss the stabilities of steady states for various types of neural network models.

  6. Lateral regulation of synaptic transmission by astrocytes.

    Science.gov (United States)

    Covelo, A; Araque, A

    2016-05-26

    Fifteen years ago the concept of the "tripartite synapse" was proposed to conceptualize the functional view that astrocytes are integral elements of synapses. The signaling exchange between astrocytes and neurons within the tripartite synapse results in the synaptic regulation of synaptic transmission and plasticity through an autocrine form of communication. However, recent evidence indicates that the astrocyte synaptic regulation is not restricted to the active tripartite synapse but can be manifested through astrocyte signaling at synapses relatively distant from active synapses, a process termed lateral astrocyte synaptic regulation. This phenomenon resembles the classical heterosynaptic modulation but is mechanistically different because it involves astrocytes and its properties critically depend on the morphological and functional features of astrocytes. Therefore, the functional concept of the tripartite synapse as a fundamental unit must be expanded to include the interaction between tripartite synapses. Through lateral synaptic regulation, astrocytes serve as an active processing bridge for synaptic interaction and crosstalk between synapses with no direct neuronal connectivity, supporting the idea that neural network function results from the coordinated activity of astrocytes and neurons. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Input significance analysis: feature selection through synaptic ...

    African Journals Online (AJOL)

    This work is interested in ISA methods that can manipulate synaptic weights namely. Connection Weights (CW) and Garson's Algorithm (GA) and the classifier selected is. Evolving Fuzzy Neural Networks (EFuNNs). Firstly, it test FS method on a dataset selected from the UCI Machine Learning Repository and executed in an ...

  8. Learning and Memory, Part II: Molecular Mechanisms of Synaptic Plasticity

    Science.gov (United States)

    Lombroso, Paul; Ogren, Marilee

    2009-01-01

    The molecular events that are responsible for strengthening synaptic connections and how these are linked to memory and learning are discussed. The laboratory preparations that allow the investigation of these events are also described.

  9. Black bears with longer disuse (hibernation) periods have lower femoral osteon population density and greater mineralization and intracortical porosity.

    Science.gov (United States)

    Wojda, Samantha J; Weyland, David R; Gray, Sarah K; McGee-Lawrence, Meghan E; Drummer, Thomas D; Donahue, Seth W

    2013-08-01

    Intracortical bone remodeling is persistent throughout life, leading to age related increases in osteon population density (OPD). Intracortical porosity also increases with age in many mammals including humans, contributing to bone fragility and fracture risk. Unbalanced bone resorption and formation during disuse (e.g., physical inactivity) also increases intracortical porosity. In contrast, hibernating bears are a naturally occurring model for the prevention of both age-related and disuse osteoporoses. Intracortical bone remodeling is decreased during hibernation, but resorption and formation remain balanced. Black bears spend 0.25-7 months in hibernation annually depending on climate and food availability. We found longer hibernating bears demonstrate lower OPD and higher cortical bone mineralization than bears with shorter hibernation durations, but we surprisingly found longer hibernating bears had higher intracortical porosity. However, bears from three different latitudes showed age-related decreases in intracortical porosity, indicating that regardless of hibernation duration, black bears do not show the disuse- or age-related increases in intracortical porosity which is typical of other animals. This ability to prevent increases in intracortical porosity likely contributes to their ability to maintain bone strength during prolonged periods of physical inactivity and throughout life. Improving our understanding of the unique bone metabolism in hibernating bears will potentially increase our ability to develop treatments for age- and disuse-related osteoporoses in humans. Copyright © 2013 Wiley Periodicals, Inc.

  10. Oxide-based synaptic transistors gated by solution-processed gelatin electrolytes

    Science.gov (United States)

    He, Yinke; Sun, Jia; Qian, Chuan; Kong, Ling-An; Gou, Guangyang; Li, Hongjian

    2017-04-01

    In human brain, a large number of neurons are connected via synapses. Simulation of the synaptic behaviors using electronic devices is the most important step for neuromorphic systems. In this paper, proton conducting gelatin electrolyte-gated oxide field-effect transistors (FETs) were used for emulating synaptic functions, in which the gate electrode is regarded as pre-synaptic neuron and the channel layer as the post-synaptic neuron. In analogy to the biological synapse, a potential spike can be applied at the gate electrode and trigger ionic motion in the gelatin electrolyte, which in turn generates excitatory post-synaptic current (EPSC) in the channel layer. Basic synaptic behaviors including spike time-dependent EPSC, paired-pulse facilitation (PPF), self-adaptation, and frequency-dependent synaptic transmission were successfully mimicked. Such ionic/electronic hybrid devices are beneficial for synaptic electronics and brain-inspired neuromorphic systems.

  11. Depressed intracortical inhibition after long trains of subthreshold repetitive magnetic stimuli at low frequency.

    Science.gov (United States)

    Modugno, Nicola; Currà, Antonio; Conte, Antonella; Inghilleri, Maurizio; Fofi, Luisa; Agostino, Rocco; Manfredi, Mario; Berardelli, Alfredo

    2003-12-01

    Repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability. These effects outlast the rTMS train, and range from inhibition to facilitation according to the variables used for rTMS. Several studies have demonstrated short and long-term effects on motor evoked potential (MEP) size, whereas the effects on intracortical inhibition (ICI) and facilitation (ICF) are still unclear. We investigated short- (1-15 min), intermediate- (16-30 min), and long-term (6 h) effects on intracortical excitability. Fourteen healthy subjects were stimulated with rTMS trains of 900 pulses (1 Hz, 90% resting motor threshold (rMTh)), delivered over the primary motor cortex and the occipital area. MTh, MEP size, silent period, intracortical inhibition at short (ICI) and long inter-stimulus intervals, and ICF were tested before and after rTMS. ICI was reduced 16-30 min after 1 Hz rTMS trains over the primary motor area, whereas the other response variables remained unchanged. The ICI reduction at 16-30 min was reproducible on different days in the same subjects; it was absent at 6 h and after stimulation of the occipital area. Subthreshold 1 Hz rTMS decreases ICI by reducing the excitability of intracortical inhibitory interneurones or by altering the electrical properties of the facilitatory chain of neurons responsible for the I waves.

  12. Soft-bound synaptic plasticity increases storage capacity.

    Directory of Open Access Journals (Sweden)

    Mark C W van Rossum

    Full Text Available Accurate models of synaptic plasticity are essential to understand the adaptive properties of the nervous system and for realistic models of learning and memory. Experiments have shown that synaptic plasticity depends not only on pre- and post-synaptic activity patterns, but also on the strength of the connection itself. Namely, weaker synapses are more easily strengthened than already strong ones. This so called soft-bound plasticity automatically constrains the synaptic strengths. It is known that this has important consequences for the dynamics of plasticity and the synaptic weight distribution, but its impact on information storage is unknown. In this modeling study we introduce an information theoretic framework to analyse memory storage in an online learning setting. We show that soft-bound plasticity increases a variety of performance criteria by about 18% over hard-bound plasticity, and likely maximizes the storage capacity of synapses.

  13. Lateral spread of orientation selectivity in V1 is controlled by intracortical cooperativity

    Directory of Open Access Journals (Sweden)

    Frédéric eChavane

    2011-02-01

    Full Text Available Neurons in the primary visual cortex receive subliminal information originating from the periphery of their receptive fields through a variety of cortical connections. In the cat primary visual cortex, long-range horizontal axons have been reported to preferentially bind to distant columns of similar orientation preferences, whereas feedback connections from higher visual areas provide a more diverse functional input. To understand the role of these lateral interactions, it is crucial to characterize their effective functional connectivity and tuning properties. However, the overall functional impact of cortical lateral connections, whatever their anatomical origin, is unknown since it has never been directly characterized. Using direct measurements of postsynaptic integration in cat areas 17/18, we performed multi-scale assessments of the functional impact of visually driven lateral networks. Voltage-sensitive dye imaging showed that local oriented stimuli evoke an orientation-selective activity that remains confined to the cortical feedforward imprint of the stimulus. Beyond a distance of one hypercolumn, the lateral spread of cortical activity gradually lost its orientation preference approximated as an exponential with a space constant of about 1mm. Intracellular recordings showed that this loss of orientation selectivity arises from the diversity of converging synaptic input patterns originating from outside the classical receptive field. In contrast, when the stimulus size was increased, we observed orientation-selective spread of activation beyond the feedforward imprint. We conclude that stimulus-induced cooperativity enhances the long-range orientation-selective spread.

  14. Spike Pattern Structure Influences Synaptic Efficacy Variability under STDP and Synaptic Homeostasis. I: Spike Generating Models on Converging Motifs

    OpenAIRE

    Bi, Zedong; Zhou, Changsong

    2016-01-01

    In neural systems, synaptic plasticity is usually driven by spike trains. Due to the inherent noises of neurons and synapses as well as the randomness of connection details, spike trains typically exhibit variability such as spatial randomness and temporal stochasticity, resulting in variability of synaptic changes under plasticity, which we call efficacy variability. How the variability of spike trains influences the efficacy variability of synapses remains unclear. In this paper, we try to...

  15. Leucine-rich repeat-containing synaptic adhesion molecules as organizers of synaptic specificity and diversity.

    Science.gov (United States)

    Schroeder, Anna; de Wit, Joris

    2018-04-09

    The brain harbors billions of neurons that form distinct neural circuits with exquisite specificity. Specific patterns of connectivity between distinct neuronal cell types permit the transfer and computation of information. The molecular correlates that give rise to synaptic specificity are incompletely understood. Recent studies indicate that cell-surface molecules are important determinants of cell type identity and suggest that these are essential players in the specification of synaptic connectivity. Leucine-rich repeat (LRR)-containing adhesion molecules in particular have emerged as key organizers of excitatory and inhibitory synapses. Here, we discuss emerging evidence that LRR proteins regulate the assembly of specific connectivity patterns across neural circuits, and contribute to the diverse structural and functional properties of synapses, two key features that are critical for the proper formation and function of neural circuits.

  16. Emergence of Functional Specificity in Balanced Networks with Synaptic Plasticity.

    Directory of Open Access Journals (Sweden)

    Sadra Sadeh

    2015-06-01

    Full Text Available In rodent visual cortex, synaptic connections between orientation-selective neurons are unspecific at the time of eye opening, and become to some degree functionally specific only later during development. An explanation for this two-stage process was proposed in terms of Hebbian plasticity based on visual experience that would eventually enhance connections between neurons with similar response features. For this to work, however, two conditions must be satisfied: First, orientation selective neuronal responses must exist before specific recurrent synaptic connections can be established. Second, Hebbian learning must be compatible with the recurrent network dynamics contributing to orientation selectivity, and the resulting specific connectivity must remain stable for unspecific background activity. Previous studies have mainly focused on very simple models, where the receptive fields of neurons were essentially determined by feedforward mechanisms, and where the recurrent network was small, lacking the complex recurrent dynamics of large-scale networks of excitatory and inhibitory neurons. Here we studied the emergence of functionally specific connectivity in large-scale recurrent networks with synaptic plasticity. Our results show that balanced random networks, which already exhibit highly selective responses at eye opening, can develop feature-specific connectivity if appropriate rules of synaptic plasticity are invoked within and between excitatory and inhibitory populations. If these conditions are met, the initial orientation selectivity guides the process of Hebbian learning and, as a result, functionally specific and a surplus of bidirectional connections emerge. Our results thus demonstrate the cooperation of synaptic plasticity and recurrent dynamics in large-scale functional networks with realistic receptive fields, highlight the role of inhibition as a critical element in this process, and paves the road for further computational

  17. Hebbian Wiring Plasticity Generates Efficient Network Structures for Robust Inference with Synaptic Weight Plasticity

    Science.gov (United States)

    Hiratani, Naoki; Fukai, Tomoki

    2016-01-01

    In the adult mammalian cortex, a small fraction of spines are created and eliminated every day, and the resultant synaptic connection structure is highly nonrandom, even in local circuits. However, it remains unknown whether a particular synaptic connection structure is functionally advantageous in local circuits, and why creation and elimination of synaptic connections is necessary in addition to rich synaptic weight plasticity. To answer these questions, we studied an inference task model through theoretical and numerical analyses. We demonstrate that a robustly beneficial network structure naturally emerges by combining Hebbian-type synaptic weight plasticity and wiring plasticity. Especially in a sparsely connected network, wiring plasticity achieves reliable computation by enabling efficient information transmission. Furthermore, the proposed rule reproduces experimental observed correlation between spine dynamics and task performance. PMID:27303271

  18. Hebbian Wiring Plasticity Generates Efficient Network Structures for Robust Inference with Synaptic Weight Plasticity.

    Science.gov (United States)

    Hiratani, Naoki; Fukai, Tomoki

    2016-01-01

    In the adult mammalian cortex, a small fraction of spines are created and eliminated every day, and the resultant synaptic connection structure is highly nonrandom, even in local circuits. However, it remains unknown whether a particular synaptic connection structure is functionally advantageous in local circuits, and why creation and elimination of synaptic connections is necessary in addition to rich synaptic weight plasticity. To answer these questions, we studied an inference task model through theoretical and numerical analyses. We demonstrate that a robustly beneficial network structure naturally emerges by combining Hebbian-type synaptic weight plasticity and wiring plasticity. Especially in a sparsely connected network, wiring plasticity achieves reliable computation by enabling efficient information transmission. Furthermore, the proposed rule reproduces experimental observed correlation between spine dynamics and task performance.

  19. Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

    Directory of Open Access Journals (Sweden)

    Wilfredo Blanco

    2015-05-01

    Full Text Available Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS followed by a rebound during rapid-eye-movement sleep (REM. The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes

  20. Intra-cortical excitability in healthy human subjects after tongue training

    DEFF Research Database (Denmark)

    Baad-Hansen, Lene; Blicher, Jakob; Lapitskaya, Natallia

    2009-01-01

    ) and intra-cortical facilitatory (ICF) networks. This study examined changes in SICI and ICF in tongue motor cortex after tongue training in 11 healthy volunteers using ppTMS. Paired pulse TMS was applied to the 'hot-spot' for the tongue motor cortex and motor-evoked potentials (MEPs) were recorded from...... tongue muscles. In tongue motor cortex, bilateral SICI (P 0.063). The success rate improved during training (P ... to changes in single MEP amplitude (P 0.113). This first study of SICI/ICF after tongue training showed no training-related changes in intra-cortical inhibitory or facilitatory networks. However, there was an association between task performance and changes in corticomotor...

  1. The Effect of the Elimination of Micromotion and Tissue Strain on Intracortical Device Performance

    Science.gov (United States)

    2017-10-01

    would exhibit an improved tissue response and enhanced device performance, there have been no definitive studies that definitively test this...hypothesis. We are developing intracortical probes using shape memory polymers (SMPs): materials which have the capacity to transition from stiff to soft upon...Does probe softening improve the surrounding tissue response and recording performance of the device? The short term impact will be on the scientific

  2. The Effect of the Elimination of Micromotion and Tissue Strain on Intracortical Device Performance

    Science.gov (United States)

    2016-10-01

    Loctite Hysol Medical grade device epoxy. Our first test devices were composed of SMP 7, the fully softening polymer . Close examination of our initial...studies that definitively test this hypothesis. We are developing intracortical probes using shape memory polymers (SMPs): materials which have the...capacity to transition from stiff to soft upon implantation. We will tune the degree of stiffness such that we can definitively address a fundamental

  3. Comparative pathogenesis of radium-induced intracortical bone lesions in humans and beagles

    International Nuclear Information System (INIS)

    Pool, R.R.; Morgan, J.P.; Parks, N.J.; Farnham, J.E.; Littman, M.S.

    1982-01-01

    An interlaboratory research team from our Laboratory and the Center for Human Radiobiology at Argonne National Laboratory has performed an initial comparison of intracortical lesions in the long bones of dog and man following chronic radium deposition in the skeleton. The sequential radiographic appearance and morphology of radiation osteodystrophy is discussed. The role of osteodystrohy in the evaluation of bone tumors in the dog is examined

  4. Augmenting intracortical brain-machine interface with neurally driven error detectors

    Science.gov (United States)

    Even-Chen, Nir; Stavisky, Sergey D.; Kao, Jonathan C.; Ryu, Stephen I.; Shenoy, Krishna V.

    2017-12-01

    Objective. Making mistakes is inevitable, but identifying them allows us to correct or adapt our behavior to improve future performance. Current brain-machine interfaces (BMIs) make errors that need to be explicitly corrected by the user, thereby consuming time and thus hindering performance. We hypothesized that neural correlates of the user perceiving the mistake could be used by the BMI to automatically correct errors. However, it was unknown whether intracortical outcome error signals were present in the premotor and primary motor cortices, brain regions successfully used for intracortical BMIs. Approach. We report here for the first time a putative outcome error signal in spiking activity within these cortices when rhesus macaques performed an intracortical BMI computer cursor task. Main results. We decoded BMI trial outcomes shortly after and even before a trial ended with 96% and 84% accuracy, respectively. This led us to develop and implement in real-time a first-of-its-kind intracortical BMI error ‘detect-and-act’ system that attempts to automatically ‘undo’ or ‘prevent’ mistakes. The detect-and-act system works independently and in parallel to a kinematic BMI decoder. In a challenging task that resulted in substantial errors, this approach improved the performance of a BMI employing two variants of the ubiquitous Kalman velocity filter, including a state-of-the-art decoder (ReFIT-KF). Significance. Detecting errors in real-time from the same brain regions that are commonly used to control BMIs should improve the clinical viability of BMIs aimed at restoring motor function to people with paralysis.

  5. Impaired intracortical transmission in G2019S leucine rich-repeat kinase Parkinson patients.

    Science.gov (United States)

    Ponzo, Viviana; Di Lorenzo, Francesco; Brusa, Livia; Schirinzi, Tommaso; Battistini, Stefania; Ricci, Claudia; Sambucci, Manolo; Caltagirone, Carlo; Koch, Giacomo

    2017-05-01

    A mutation in leucine-rich repeat kinase 2 is the most common cause of hereditary Parkinson's disease (PD), yet the neural mechanisms and the circuitry potentially involved are poorly understood. We used different transcranial magnetic stimulation protocols to explore in the primary motor cortex the activity of intracortical circuits and cortical plasticity (long-term potentiation) in patients with the G2019S leucine-rich repeat kinase 2 gene mutation when compared with idiopathic PD patients and age-matched healthy subjects. Paired pulse transcranial magnetic stimulation was used to investigate short intracortical inhibition and facilitation and short afferent inhibition. Intermittent theta burst stimulation, a form of repetitive transcranial magnetic stimulation, was used to test long-term potentiation-like cortical plasticity. Leucine-rich repeat kinase 2 and idiopathic PD were tested both in ON and in OFF l-dopa therapy. When compared with idiopathic PD and healthy subjects, leucine-rich repeat kinase 2 PD patients showed a remarkable reduction of short intracortical inhibition in both ON and in OFF l-dopa therapy. This reduction was paralleled by an increase of intracortical facilitation in OFF l-dopa therapy. Leucine-rich repeat kinase 2 PD showed abnormal long-term potentiation-like cortical plasticity in ON l-dopa therapy. The motor cortex in leucine-rich repeat kinase 2 mutated PD patients is strongly disinhibited and hyperexcitable. These abnormalities could be a result of an impairment of inhibitory (gamma-Aminobutyric acid) transmission eventually related to altered neurotransmitter release. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  6. Cerebellar Synaptic Plasticity and the Credit Assignment Problem.

    Science.gov (United States)

    Jörntell, Henrik

    2016-04-01

    The mechanism by which a learnt synaptic weight change can contribute to learning or adaptation of brain function is a type of credit assignment problem, which is a key issue for many parts of the brain. In the cerebellum, detailed knowledge not only of the local circuitry connectivity but also of the topography of different sources of afferent/external information makes this problem particularly tractable. In addition, multiple forms of synaptic plasticity and their general rules of induction have been identified. In this review, we will discuss the possible roles of synaptic and cellular plasticity at specific locations in contributing to behavioral changes. Focus will be on the parts of the cerebellum that are devoted to limb control, which constitute a large proportion of the cortex and where the knowledge of the external connectivity is particularly well known. From this perspective, a number of sites of synaptic plasticity appear to primarily have the function of balancing the overall level of activity in the cerebellar circuitry, whereas the locations at which synaptic plasticity leads to functional changes in terms of limb control are more limited. Specifically, the postsynaptic forms of long-term potentiation (LTP) and long-term depression (LTD) at the parallel fiber synapses made on interneurons and Purkinje cells, respectively, are the types of plasticity that mediate the widest associative capacity and the tightest link between the synaptic change and the external functions that are to be controlled.

  7. Synaptic Mechanisms of Memory Consolidation during Sleep Slow Oscillations.

    Science.gov (United States)

    Wei, Yina; Krishnan, Giri P; Bazhenov, Maxim

    2016-04-13

    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. 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. Copyright © 2016 the authors 0270-6474/16/364231-17$15.00/0.

  8. Integrated neuron circuit for implementing neuromorphic system with synaptic device

    Science.gov (United States)

    Lee, Jeong-Jun; Park, Jungjin; Kwon, Min-Woo; Hwang, Sungmin; Kim, Hyungjin; Park, Byung-Gook

    2018-02-01

    In this paper, we propose and fabricate Integrate & Fire neuron circuit for implementing neuromorphic system. Overall operation of the circuit is verified by measuring discrete devices and the output characteristics of the circuit. Since the neuron circuit shows asymmetric output characteristic that can drive synaptic device with Spike-Timing-Dependent-Plasticity (STDP) characteristic, the autonomous weight update process is also verified by connecting the synaptic device and the neuron circuit. The timing difference of the pre-neuron and the post-neuron induce autonomous weight change of the synaptic device. Unlike 2-terminal devices, which is frequently used to implement neuromorphic system, proposed scheme of the system enables autonomous weight update and simple configuration by using 4-terminal synapse device and appropriate neuron circuit. Weight update process in the multi-layer neuron-synapse connection ensures implementation of the hardware-based artificial intelligence, based on Spiking-Neural- Network (SNN).

  9. Synaptic Plasticity and Translation Initiation

    Science.gov (United States)

    Klann, Eric; Antion, Marcia D.; Banko, Jessica L.; Hou, Lingfei

    2004-01-01

    It is widely accepted that protein synthesis, including local protein synthesis at synapses, is required for several forms of synaptic plasticity. Local protein synthesis enables synapses to control synaptic strength independent of the cell body via rapid protein production from pre-existing mRNA. Therefore, regulation of translation initiation is…

  10. Abnormal interhemispheric connectivity in male psychopathic offenders.

    Science.gov (United States)

    Hoppenbrouwers, Sylco S; De Jesus, Danilo R; Sun, Yinming; Stirpe, Tania; Hofman, Dennis; McMaster, Jeff; Hughes, Ginny; Daskalakis, Zafiris J; Schutter, Dennis J L G

    2014-01-01

    Psychopathic offenders inevitably violate interpersonal norms and frequently resort to aggressive and criminal behaviour. The affective and cognitive deficits underlying these behaviours have been linked to abnormalities in functional interhemispheric connectivity. However, direct neurophysiological evidence for dysfunctional connectivity in psychopathic offenders is lacking. We used transcranial magnetic stimulation combined with electroencephalography to examine interhemispheric connectivity in the dorsolateral and motor cortex in a sample of psychopathic offenders and healthy controls. We also measured intracortical inhibition and facilitation over the left and right motor cortex to investigate the effects of local cortical processes on interhemispheric connectivity. We enrolled 17 psychopathic offenders and 14 controls in our study. Global abnormalities in right to left functional connectivity were observed in psychopathic offenders compared with controls. Furthermore, in contrast to controls, psychopathic offenders showed increased intracortical inhibition in the right, but not the left, hemisphere. The relatively small sample size limited the sensitivity to show that the abnormalities in interhemispheric connectivity were specifically related to the dorsolateral prefrontal cortex in psychopathic offenders. To our knowledge, this study provides the first neurophysiological evidence for abnormal interhemispheric connectivity in psychopathic offenders and may further our understanding of the disruptive antisocial behaviour of these offenders.

  11. Decoder calibration with ultra small current sample set for intracortical brain-machine interface.

    Science.gov (United States)

    Zhang, Peng; Ma, Xuan; Chen, Luyao; Zhou, Jin; Wang, Changyong; Li, Wei; He, Jiping

    2018-04-01

    Intracortical brain-machine interfaces (iBMIs) aim to restore efficient communication and movement ability for paralyzed patients. However, frequent recalibration is required for consistency and reliability, and every recalibration will require relatively large most current sample set. The aim in this study is to develop an effective decoder calibration method that can achieve good performance while minimizing recalibration time. Two rhesus macaques implanted with intracortical microelectrode arrays were trained separately on movement and sensory paradigm. Neural signals were recorded to decode reaching positions or grasping postures. A novel principal component analysis-based domain adaptation (PDA) method was proposed to recalibrate the decoder with only ultra small current sample set by taking advantage of large historical data, and the decoding performance was compared with other three calibration methods for evaluation. The PDA method closed the gap between historical and current data effectively, and made it possible to take advantage of large historical data for decoder recalibration in current data decoding. Using only ultra small current sample set (five trials of each category), the decoder calibrated using the PDA method could achieve much better and more robust performance in all sessions than using other three calibration methods in both monkeys. (1) By this study, transfer learning theory was brought into iBMIs decoder calibration for the first time. (2) Different from most transfer learning studies, the target data in this study were ultra small sample set and were transferred to the source data. (3) By taking advantage of historical data, the PDA method was demonstrated to be effective in reducing recalibration time for both movement paradigm and sensory paradigm, indicating a viable generalization. By reducing the demand for large current training data, this new method may facilitate the application of intracortical brain-machine interfaces in

  12. Decoder calibration with ultra small current sample set for intracortical brain-machine interface

    Science.gov (United States)

    Zhang, Peng; Ma, Xuan; Chen, Luyao; Zhou, Jin; Wang, Changyong; Li, Wei; He, Jiping

    2018-04-01

    Objective. Intracortical brain-machine interfaces (iBMIs) aim to restore efficient communication and movement ability for paralyzed patients. However, frequent recalibration is required for consistency and reliability, and every recalibration will require relatively large most current sample set. The aim in this study is to develop an effective decoder calibration method that can achieve good performance while minimizing recalibration time. Approach. Two rhesus macaques implanted with intracortical microelectrode arrays were trained separately on movement and sensory paradigm. Neural signals were recorded to decode reaching positions or grasping postures. A novel principal component analysis-based domain adaptation (PDA) method was proposed to recalibrate the decoder with only ultra small current sample set by taking advantage of large historical data, and the decoding performance was compared with other three calibration methods for evaluation. Main results. The PDA method closed the gap between historical and current data effectively, and made it possible to take advantage of large historical data for decoder recalibration in current data decoding. Using only ultra small current sample set (five trials of each category), the decoder calibrated using the PDA method could achieve much better and more robust performance in all sessions than using other three calibration methods in both monkeys. Significance. (1) By this study, transfer learning theory was brought into iBMIs decoder calibration for the first time. (2) Different from most transfer learning studies, the target data in this study were ultra small sample set and were transferred to the source data. (3) By taking advantage of historical data, the PDA method was demonstrated to be effective in reducing recalibration time for both movement paradigm and sensory paradigm, indicating a viable generalization. By reducing the demand for large current training data, this new method may facilitate the application

  13. Synaptic electronics: materials, devices and applications.

    Science.gov (United States)

    Kuzum, Duygu; Yu, Shimeng; Wong, H-S Philip

    2013-09-27

    In this paper, the recent progress of synaptic electronics is reviewed. The basics of biological synaptic plasticity and learning are described. The material properties and electrical switching characteristics of a variety of synaptic devices are discussed, with a focus on the use of synaptic devices for neuromorphic or brain-inspired computing. Performance metrics desirable for large-scale implementations of synaptic devices are illustrated. A review of recent work on targeted computing applications with synaptic devices is presented.

  14. Control of synaptic plasticity in deep cortical networks

    NARCIS (Netherlands)

    Roelfsema, Pieter R; Holtmaat, Anthony

    2018-01-01

    Humans and many other animals have an enormous capacity to learn about sensory stimuli and to master new skills. However, many of the mechanisms that enable us to learn remain to be understood. One of the greatest challenges of systems neuroscience is to explain how synaptic connections change to

  15. Spontaneous Activity Drives Local Synaptic Plasticity In Vivo

    NARCIS (Netherlands)

    Winnubst, Johan; Cheyne, Juliette E; Niculescu, Dragos; Lohmann, C.

    2015-01-01

    Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in

  16. Distinct Subunit Domains Govern Synaptic Stability and Specificity of the Kainate Receptor

    Directory of Open Access Journals (Sweden)

    Christoph Straub

    2016-07-01

    Full Text Available Synaptic communication between neurons requires the precise localization of neurotransmitter receptors to the correct synapse type. Kainate-type glutamate receptors restrict synaptic localization that is determined by the afferent presynaptic connection. The mechanisms that govern this input-specific synaptic localization remain unclear. Here, we examine how subunit composition and specific subunit domains contribute to synaptic localization of kainate receptors. The cytoplasmic domain of the GluK2 low-affinity subunit stabilizes kainate receptors at synapses. In contrast, the extracellular domain of the GluK4/5 high-affinity subunit synergistically controls the synaptic specificity of kainate receptors through interaction with C1q-like proteins. Thus, the input-specific synaptic localization of the native kainate receptor complex involves two mechanisms that underlie specificity and stabilization of the receptor at synapses.

  17. Virtual typing by people with tetraplegia using a self-calibrating intracortical brain-computer interface.

    Science.gov (United States)

    Jarosiewicz, Beata; Sarma, Anish A; Bacher, Daniel; Masse, Nicolas Y; Simeral, John D; Sorice, Brittany; Oakley, Erin M; Blabe, Christine; Pandarinath, Chethan; Gilja, Vikash; Cash, Sydney S; Eskandar, Emad N; Friehs, Gerhard; Henderson, Jaimie M; Shenoy, Krishna V; Donoghue, John P; Hochberg, Leigh R

    2015-11-11

    Brain-computer interfaces (BCIs) promise to restore independence for people with severe motor disabilities by translating decoded neural activity directly into the control of a computer. However, recorded neural signals are not stationary (that is, can change over time), degrading the quality of decoding. Requiring users to pause what they are doing whenever signals change to perform decoder recalibration routines is time-consuming and impractical for everyday use of BCIs. We demonstrate that signal nonstationarity in an intracortical BCI can be mitigated automatically in software, enabling long periods (hours to days) of self-paced point-and-click typing by people with tetraplegia, without degradation in neural control. Three key innovations were included in our approach: tracking the statistics of the neural activity during self-timed pauses in neural control, velocity bias correction during neural control, and periodically recalibrating the decoder using data acquired during typing by mapping neural activity to movement intentions that are inferred retrospectively based on the user's self-selected targets. These methods, which can be extended to a variety of neurally controlled applications, advance the potential for intracortical BCIs to help restore independent communication and assistive device control for people with paralysis. Copyright © 2015, American Association for the Advancement of Science.

  18. Patients in a vegetative state following traumatic brain injury display a reduced intracortical modulation.

    Science.gov (United States)

    Bagnato, Sergio; Boccagni, Cristina; Sant'Angelo, Antonino; Prestandrea, Caterina; Rizzo, Silvia; Galardi, Giuseppe

    2012-10-01

    Patients in coma who fail to wake develop a condition known as a vegetative state (VS). While we know that some cortical activities exist in patients in VS, it remains unclear whether interneuronal modulation can be abnormal in the cerebral cortex of these patients. The aim of the study was to evaluate the inhibitory and excitatory interneuronal circuits in patients in VS following a traumatic brain injury. Cortical excitability was studied in 5 VS patients and in 10 healthy subjects using paired pulses transcranial magnetic stimulation (TMS). Resting motor threshold and intracortical inhibition and facilitation at short intervals (2 and 10 ms, respectively) were evaluated. Two patients were studied again after their level of consciousness transitioned into a minimally conscious state (MCS). Both intracortical inhibition and facilitation were significantly reduced in patients compared to healthy subjects (p<0.05). In addition, these results did not significantly change in the 2 patients who evolved into a MCS. This is the first report showing an abnormal cortical excitability in patients in VS. Our findings suggest a pathophysiological base for future work aiming to restore the lack of interneuronal transmission in patients in VS. Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  19. Muscle Relaxation of the Foot Reduces Corticospinal Excitability of Hand Muscles and Enhances Intracortical Inhibition

    Science.gov (United States)

    Kato, Kouki; Muraoka, Tetsuro; Mizuguchi, Nobuaki; Nakagawa, Kento; Nakata, Hiroki; Kanosue, Kazuyuki

    2016-01-01

    The object of this study was to clarify the effects of foot muscle relaxation on activity in the primary motor cortex (M1) of the hand area. Subjects were asked to volitionally relax the right foot from sustained contraction of either the dorsiflexor (tibialis anterior; TA relaxation) or plantarflexor (soleus; SOL relaxation) in response to an auditory stimulus. Single- and paired-pulse transcranial magnetic stimulation (TMS) was delivered to the hand area of the left M1 at different time intervals before and after the onset of TA or SOL relaxation. Motor evoked potentials (MEPs) were recorded from the right extensor carpi radialis (ECR) and flexor carpi radialis (FCR). MEP amplitudes of ECR and FCR caused by single-pulse TMS temporarily decreased after TA and SOL relaxation onset, respectively, as compared with those of the resting control. Furthermore, short-interval intracortical inhibition (SICI) of ECR evaluated with paired-pulse TMS temporarily increased after TA relaxation onset. Our findings indicate that muscle relaxation of the dorsiflexor reduced corticospinal excitability of the ipsilateral hand muscles. This is most likely caused by an increase in intracortical inhibition. PMID:27242482

  20. Intracortical myelination in musicians with absolute pitch: Quantitative morphometry using 7‐T MRI

    Science.gov (United States)

    Knösche, Thomas R.

    2016-01-01

    Abstract Absolute pitch (AP) is known as the ability to recognize and label the pitch chroma of a given tone without external reference. Known brain structures and functions related to AP are mainly of macroscopic aspects. To shed light on the underlying neural mechanism of AP, we investigated the intracortical myeloarchitecture in musicians with and without AP using the quantitative mapping of the longitudinal relaxation rates with ultra‐high‐field magnetic resonance imaging at 7 T. We found greater intracortical myelination for AP musicians in the anterior region of the supratemporal plane, particularly the medial region of the right planum polare (PP). In the same region of the right PP, we also found a positive correlation with a behavioral index of AP performance. In addition, we found a positive correlation with a frequency discrimination threshold in the anterolateral Heschl's gyrus in the right hemisphere, demonstrating distinctive neural processes of absolute recognition and relative discrimination of pitch. Regarding possible effects of local myelination in the cortex and the known importance of the anterior superior temporal gyrus/sulcus for the identification of auditory objects, we argue that pitch chroma may be processed as an identifiable object property in AP musicians. Hum Brain Mapp 37:3486–3501, 2016. © 2016 Wiley Periodicals, Inc. PMID:27160707

  1. Intracortical myelination in musicians with absolute pitch: Quantitative morphometry using 7-T MRI.

    Science.gov (United States)

    Kim, Seung-Goo; Knösche, Thomas R

    2016-10-01

    Absolute pitch (AP) is known as the ability to recognize and label the pitch chroma of a given tone without external reference. Known brain structures and functions related to AP are mainly of macroscopic aspects. To shed light on the underlying neural mechanism of AP, we investigated the intracortical myeloarchitecture in musicians with and without AP using the quantitative mapping of the longitudinal relaxation rates with ultra-high-field magnetic resonance imaging at 7 T. We found greater intracortical myelination for AP musicians in the anterior region of the supratemporal plane, particularly the medial region of the right planum polare (PP). In the same region of the right PP, we also found a positive correlation with a behavioral index of AP performance. In addition, we found a positive correlation with a frequency discrimination threshold in the anterolateral Heschl's gyrus in the right hemisphere, demonstrating distinctive neural processes of absolute recognition and relative discrimination of pitch. Regarding possible effects of local myelination in the cortex and the known importance of the anterior superior temporal gyrus/sulcus for the identification of auditory objects, we argue that pitch chroma may be processed as an identifiable object property in AP musicians. Hum Brain Mapp 37:3486-3501, 2016. © 2016 Wiley Periodicals, Inc. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

  2. Muscle relaxation of the foot reduces corticospinal excitability of hand muscles and enhances intracortical inhibition

    Directory of Open Access Journals (Sweden)

    Kouki eKato

    2016-05-01

    Full Text Available The object of this study was to clarify the effects of foot muscle relaxation on activity in the primary motor cortex of the hand area. Subjects were asked to volitionally relax the right foot from sustained contraction of either the dorsiflexor (tibialis anterior; TA relaxation or plantarflexor (soleus; SOL relaxation in response to an auditory stimulus. Single- and paired-pulse transcranial magnetic stimulation (TMS was delivered to the hand area of the left primary motor cortex at different time intervals before and after the onset of TA or SOL relaxation. Motor evoked potentials (MEPs were recorded from the right extensor carpi radialis (ECR and flexor carpi radialis (FCR. MEP amplitudes of ECR and FCR caused by single-pulse TMS temporarily decreased after TA and SOL relaxation onset, respectively, as compared with those of the resting control. Furthermore, short-interval intracortical inhibition (SICI of ECR evaluated with paired-pulse TMS temporarily increased after TA relaxation onset. Our findings indicate that muscle relaxation of the dorsiflexor reduced corticospinal excitability of the ipsilateral hand muscles. This is most likely caused by an increase in intracortical inhibition.

  3. Circadian Regulation of Synaptic Plasticity

    Directory of Open Access Journals (Sweden)

    Marcos G. Frank

    2016-07-01

    Full Text Available Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity.

  4. Isolation of Synaptosomes, Synaptic Plasma Membranes, and Synaptic Junctional Complexes.

    Science.gov (United States)

    Michaelis, Mary L; Jiang, Lei; Michaelis, Elias K

    2017-01-01

    Isolation of synaptic nerve terminals or synaptosomes provides an opportunity to study the process of neurotransmission at many levels and with a variety of approaches. For example, structural features of the synaptic terminals and the organelles within them, such as synaptic vesicles and mitochondria, have been elucidated with electron microscopy. The postsynaptic membranes are joined to the presynaptic "active zone" of transmitter release through cell adhesion molecules and remain attached throughout the isolation of synaptosomes. These "post synaptic densities" or "PSDs" contain the receptors for the transmitters released from the nerve terminals and can easily be seen with electron microscopy. Biochemical and cell biological studies with synaptosomes have revealed which proteins and lipids are most actively involved in synaptic release of neurotransmitters. The functional properties of the nerve terminals, such as responses to depolarization and the uptake or release of signaling molecules, have also been characterized through the use of fluorescent dyes, tagged transmitters, and transporter substrates. In addition, isolated synaptosomes can serve as the starting material for the isolation of relatively pure synaptic plasma membranes (SPMs) that are devoid of organelles from the internal environment of the nerve terminal, such as mitochondria and synaptic vesicles. The isolated SPMs can reseal and form vesicular structures in which transport of ions such as sodium and calcium, as well as solutes such as neurotransmitters can be studied. The PSDs also remain associated with the presynaptic membranes during isolation of SPM fractions, making it possible to isolate the synaptic junctional complexes (SJCs) devoid of the rest of the plasma membranes of the nerve terminals and postsynaptic membrane components. Isolated SJCs can be used to identify the proteins that constitute this highly specialized region of neurons. In this chapter, we describe the steps involved

  5. Endocannabinoid signaling and synaptic function

    Science.gov (United States)

    Castillo, Pablo E.; Younts, Thomas J.; Chávez, Andrés E.; Hashimotodani, Yuki

    2012-01-01

    Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a non-retrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. Synaptic endocannabinoid signaling is thus mechanistically more complex and diverse than originally thought. In this review, we focus on new advances in endocannabinoid signaling and highlight their role as potent regulators of synaptic function in the mammalian brain. PMID:23040807

  6. Relative contributions of intracortical and thalamo-cortical processes in the generation of alpha rhythms, revealed by partial coherence analysis

    NARCIS (Netherlands)

    Lopes da Silva, F.H.; Vos, J.E.; Mooibroek, J.; Rotterdam, A. van

    1980-01-01

    The thalamo-cortical relationships of alpha rhythms have been analysed in dogs using partial coherence function analysis. The objective was to clarify how far the large intracortical coherence commonly recorded between different cortical sites could depend on a common thalamic site. It was found

  7. Intracortical inhibition in the soleus muscle is reduced during the control of upright standing in both young and old adults

    NARCIS (Netherlands)

    Papegaaij, Selma; Baudry, Stéphane; Négyesi, János; Taube, Wolfgang; Hortobagyi, Tibor

    Purpose In a previous study, we reported that a short-interval intracortical inhibition (SICI) decreases in old but not in young adults when standing on foam vs. a rigid surface. Here, we examined if such an age by task difficulty interaction in motor cortical excitability also occurs in easier

  8. The EEG microstate topography is predominantly determined by intracortical sources in the alpha band.

    Science.gov (United States)

    Milz, P; Pascual-Marqui, R D; Achermann, P; Kochi, K; Faber, P L

    2017-11-15

    Human brain electric activity can be measured at high temporal and fairly good spatial resolution via electroencephalography (EEG). The EEG microstate analysis is an increasingly popular method used to investigate this activity at a millisecond resolution by segmenting it into quasi-stable states of approximately 100 ms duration. These so-called EEG microstates were postulated to represent atoms of thoughts and emotions and can be classified into four classes of topographies A through D, which explain up to 90% of the variance of continuous EEG. The present study investigated whether these topographies are primarily driven by alpha activity originating from the posterior cingulate cortex (all topographies), left and right posterior cortices, and the anterior cingulate cortex (topographies A, B, and C, respectively). We analyzed two 64-channel resting state EEG datasets (N = 61 and N = 78) of healthy participants. Sources of head-surface signals were determined via exact low resolution electromagnetic tomography (eLORETA). The Hilbert transformation was applied to identify instantaneous source strength of four EEG frequency bands (delta through beta). These source strength values were averaged for each participant across time periods belonging to a particular microstate. For each dataset, these averages of the different microstate classes were compared for each voxel. Consistent differences across datasets were identified via a conjunction analysis. The intracortical strength and spatial distribution of alpha band activity mainly determined whether a head-surface topography of EEG microstate class A, B, C, or D was induced. EEG microstate class C was characterized by stronger alpha activity compared to all other classes in large portions of the cortex. Class A was associated with stronger left posterior alpha activity than classes B and D, and class B was associated with stronger right posterior alpha activity than A and D. Previous results indicated that EEG

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

    Science.gov (United States)

    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.

  10. Influence of position and stimulation parameters on intracortical inhibition and facilitation in human tongue motor cortex

    DEFF Research Database (Denmark)

    Kothari, Mohit; Svensson, Peter; Nielsen, Jørgen Feldbæk

    Paired-pulse transcranial magnetic stimulation (ppTMS) can be used to assess short-interval intracortical inhibitory (SICI) and facilitatory (ICF) networks. The aim of the study was to examine the influence of body positions (recline and supine), inter-stimulus intervals (ISI) between the test...... stimulus (TS) and conditioning stimulus (CS) and intensities of the TS and CS on the degree of SICI and ICF. In study 1 and 2, fourteen and seventeen healthy volunteers participated respectively. ppTMS was applied over the “hot-spot” of the tongue motor cortex and motor evoked potentials (MEPs) were.......042) in study 1. In study 2, there was a significant effect of ISI (PICF in the tongue motor cortex....

  11. Optogenetic Examination of Prefrontal-Amygdala Synaptic Development.

    Science.gov (United States)

    Arruda-Carvalho, Maithe; Wu, Wan-Chen; Cummings, Kirstie A; Clem, Roger L

    2017-03-15

    A brain network comprising the medial prefrontal cortex (mPFC) and amygdala plays important roles in developmentally regulated cognitive and emotional processes. However, very little is known about the maturation of mPFC-amygdala circuitry. We conducted anatomical tracing of mPFC projections and optogenetic interrogation of their synaptic connections with neurons in the basolateral amygdala (BLA) at neonatal to adult developmental stages in mice. Results indicate that mPFC-BLA projections exhibit delayed emergence relative to other mPFC pathways and establish synaptic transmission with BLA excitatory and inhibitory neurons in late infancy, events that coincide with a massive increase in overall synaptic drive. During subsequent adolescence, mPFC-BLA circuits are further modified by excitatory synaptic strengthening as well as a transient surge in feedforward inhibition. The latter was correlated with increased spontaneous inhibitory currents in excitatory neurons, suggesting that mPFC-BLA circuit maturation culminates in a period of exuberant GABAergic transmission. These findings establish a time course for the onset and refinement of mPFC-BLA transmission and point to potential sensitive periods in the development of this critical network. SIGNIFICANCE STATEMENT Human mPFC-amygdala functional connectivity is developmentally regulated and figures prominently in numerous psychiatric disorders with a high incidence of adolescent onset. However, it remains unclear when synaptic connections between these structures emerge or how their properties change with age. Our work establishes developmental windows and cellular substrates for synapse maturation in this pathway involving both excitatory and inhibitory circuits. The engagement of these substrates by early life experience may support the ontogeny of fundamental behaviors but could also lead to inappropriate circuit refinement and psychopathology in adverse situations. Copyright © 2017 the authors 0270-6474/17/372976-10$15.00/0.

  12. Advantages of closed-loop calibration in intracortical brain-computer interfaces for people with tetraplegia

    Science.gov (United States)

    Jarosiewicz, Beata; Masse, Nicolas Y.; Bacher, Daniel; Cash, Sydney S.; Eskandar, Emad; Friehs, Gerhard; Donoghue, John P.; Hochberg, Leigh R.

    2013-08-01

    Objective. Brain-computer interfaces (BCIs) aim to provide a means for people with severe motor disabilities to control their environment directly with neural activity. In intracortical BCIs for people with tetraplegia, the decoder that maps neural activity to desired movements has typically been calibrated using ‘open-loop’ (OL) imagination of control while a cursor automatically moves to targets on a computer screen. However, because neural activity can vary across contexts, a decoder calibrated using OL data may not be optimal for ‘closed-loop’ (CL) neural control. Here, we tested whether CL calibration creates a better decoder than OL calibration even when all other factors that might influence performance are held constant, including the amount of data used for calibration and the amount of elapsed time between calibration and testing. Approach. Two people with tetraplegia enrolled in the BrainGate2 pilot clinical trial performed a center-out-back task using an intracortical BCI, switching between decoders that had been calibrated on OL versus CL data. Main results. Even when all other variables were held constant, CL calibration improved neural control as well as the accuracy and strength of the tuning model. Updating the CL decoder using additional and more recent data resulted in further improvements. Significance. Differences in neural activity between OL and CL contexts contribute to the superiority of CL decoders, even prior to their additional ‘adaptive’ advantage. In the near future, CL decoder calibration may enable robust neural control without needing to pause ongoing, practical use of BCIs, an important step toward clinical utility.

  13. Neural control of finger movement via intracortical brain-machine interface.

    Science.gov (United States)

    Irwin, Z T; Schroeder, K E; Vu, P P; Bullard, A J; Tat, D M; Nu, C S; Vaskov, A; Nason, S R; Thompson, D E; Bentley, J N; Patil, P G; Chestek, C A

    2017-12-01

    Intracortical brain-machine interfaces (BMIs) are a promising source of prosthesis control signals for individuals with severe motor disabilities. Previous BMI studies have primarily focused on predicting and controlling whole-arm movements; precise control of hand kinematics, however, has not been fully demonstrated. Here, we investigate the continuous decoding of precise finger movements in rhesus macaques. In order to elicit precise and repeatable finger movements, we have developed a novel behavioral task paradigm which requires the subject to acquire virtual fingertip position targets. In the physical control condition, four rhesus macaques performed this task by moving all four fingers together in order to acquire a single target. This movement was equivalent to controlling the aperture of a power grasp. During this task performance, we recorded neural spikes from intracortical electrode arrays in primary motor cortex. Using a standard Kalman filter, we could reconstruct continuous finger movement offline with an average correlation of ρ  =  0.78 between actual and predicted position across four rhesus macaques. For two of the monkeys, this movement prediction was performed in real-time to enable direct brain control of the virtual hand. Compared to physical control, neural control performance was slightly degraded; however, the monkeys were still able to successfully perform the task with an average target acquisition rate of 83.1%. The monkeys' ability to arbitrarily specify fingertip position was also quantified using an information throughput metric. During brain control task performance, the monkeys achieved an average 1.01 bits s -1 throughput, similar to that achieved in previous studies which decoded upper-arm movements to control computer cursors using a standard Kalman filter. This is, to our knowledge, the first demonstration of brain control of finger-level fine motor skills. We believe that these results represent an important step

  14. Neural control of finger movement via intracortical brain-machine interface

    Science.gov (United States)

    Irwin, Z. T.; Schroeder, K. E.; Vu, P. P.; Bullard, A. J.; Tat, D. M.; Nu, C. S.; Vaskov, A.; Nason, S. R.; Thompson, D. E.; Bentley, J. N.; Patil, P. G.; Chestek, C. A.

    2017-12-01

    Objective. Intracortical brain-machine interfaces (BMIs) are a promising source of prosthesis control signals for individuals with severe motor disabilities. Previous BMI studies have primarily focused on predicting and controlling whole-arm movements; precise control of hand kinematics, however, has not been fully demonstrated. Here, we investigate the continuous decoding of precise finger movements in rhesus macaques. Approach. In order to elicit precise and repeatable finger movements, we have developed a novel behavioral task paradigm which requires the subject to acquire virtual fingertip position targets. In the physical control condition, four rhesus macaques performed this task by moving all four fingers together in order to acquire a single target. This movement was equivalent to controlling the aperture of a power grasp. During this task performance, we recorded neural spikes from intracortical electrode arrays in primary motor cortex. Main results. Using a standard Kalman filter, we could reconstruct continuous finger movement offline with an average correlation of ρ  =  0.78 between actual and predicted position across four rhesus macaques. For two of the monkeys, this movement prediction was performed in real-time to enable direct brain control of the virtual hand. Compared to physical control, neural control performance was slightly degraded; however, the monkeys were still able to successfully perform the task with an average target acquisition rate of 83.1%. The monkeys’ ability to arbitrarily specify fingertip position was also quantified using an information throughput metric. During brain control task performance, the monkeys achieved an average 1.01 bits s-1 throughput, similar to that achieved in previous studies which decoded upper-arm movements to control computer cursors using a standard Kalman filter. Significance. This is, to our knowledge, the first demonstration of brain control of finger-level fine motor skills. We believe

  15. Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders.

    Science.gov (United States)

    Neniskyte, Urte; Gross, Cornelius T

    2017-11-01

    The final stage of brain development is associated with the generation and maturation of neuronal synapses. However, the same period is also associated with a peak in synapse elimination - a process known as synaptic pruning - that has been proposed to be crucial for the maturation of remaining synaptic connections. Recent studies have pointed to a key role for glial cells in synaptic pruning in various parts of the nervous system and have identified a set of critical signalling pathways between glia and neurons. At the same time, brain imaging and post-mortem anatomical studies suggest that insufficient or excessive synaptic pruning may underlie several neurodevelopmental disorders, including autism, schizophrenia and epilepsy. Here, we review current data on the cellular, physiological and molecular mechanisms of glial-cell-dependent synaptic pruning and outline their potential contribution to neurodevelopmental disorders.

  16. Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

    Science.gov (United States)

    Krystal, John H.; Abdallah, Chadi G.; Averill, Lynette A.; Kelmendi, Benjamin; Harpaz-Rotem, Ilan; Sanacora, Gerard; Southwick, Steven M.; Duman, Ronald S.

    2018-01-01

    Purpose of Review Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity. Recent Findings Here, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Summary Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics. PMID:28844076

  17. Tumor necrosis factor alpha maintains denervation-induced homeostatic synaptic plasticity of mouse dentate granule cells

    Directory of Open Access Journals (Sweden)

    Denise eBecker

    2013-12-01

    Full Text Available Neurons which lose part of their input respond with a compensatory increase in excitatory synaptic strength. This observation is of particular interest in the context of neurological diseases, which are accompanied by the loss of neurons and subsequent denervation of connected brain regions. However, while the cellular and molecular mechanisms of pharmacologically induced homeostatic synaptic plasticity have been identified to a certain degree, denervation-induced homeostatic synaptic plasticity remains not well understood. Here, we employed the entorhinal denervation in vitro model to study the role of tumor necrosis factor alpha (TNFα on changes in excitatory synaptic strength of mouse dentate granule cells following partial deafferentation. Our experiments disclose that TNFα is required for the maintenance of a compensatory increase in excitatory synaptic strength at 3/4 days postlesion (dpl, but not for the induction of synaptic scaling at 1 - 2 dpl. Furthermore, laser capture microdissection (LMD combined with quantitative PCR (qPCR demonstrates an increase in TNFα-mRNA levels in the denervated zone, which is consistent with our previous finding on a local, i.e., layer-specific increase in excitatory synaptic strength at 3 - 4 dpl. Immunostainings for the glial fibrillary acidic protein (GFAP and TNFα suggest that astrocytes are a source of TNFα in our experimental setting. We conclude that TNFα-signaling is a major regulatory system that aims at maintaining the homeostatic synaptic response of denervated neurons.

  18. Synaptic ultrastructure changes in trigeminocervical complex posttrigeminal nerve injury.

    Science.gov (United States)

    Park, John; Trinh, Van Nancy; Sears-Kraxberger, Ilse; Li, Kang-Wu; Steward, Oswald; Luo, Z David

    2016-02-01

    Trigeminal nerves collecting sensory information from the orofacial area synapse on second-order neurons in the dorsal horn of subnucleus caudalis and cervical C1/C2 spinal cord (Vc/C2, or trigeminocervical complex), which is critical for sensory information processing. Injury to the trigeminal nerves may cause maladaptive changes in synaptic connectivity that plays an important role in chronic pain development. Here we examined whether injury to the infraorbital nerve, a branch of the trigeminal nerves, led to synaptic ultrastructural changes when the injured animals have developed neuropathic pain states. Transmission electron microscopy was used to examine synaptic profiles in Vc/C2 at 3 weeks postinjury, corresponding to the time of peak behavioral hypersensitivity following chronic constriction injury to the infraorbital nerve (CCI-ION). Using established criteria, synaptic profiles were classified as associated with excitatory (R-), inhibitory (F-), and primary afferent (C-) terminals. Each type was counted within the superficial dorsal horn of the Vc/C2 and the means from each rat were compared between sham and injured animals; synaptic contact length was also measured. The overall analysis indicates that rats with orofacial pain states had increased numbers and decreased mean synaptic length of R-profiles within the Vc/C2 superficial dorsal horn (lamina I) 3 weeks post-CCI-ION. Increases in the number of excitatory synapses in the superficial dorsal horn of Vc/C2 could lead to enhanced activation of nociceptive pathways, contributing to the development of orofacial pain states. © 2015 Wiley Periodicals, Inc.

  19. Identifying and tracking simulated synaptic inputs from neuronal firing: insights from in vitro experiments.

    Directory of Open Access Journals (Sweden)

    Maxim Volgushev

    2015-03-01

    Full Text Available Accurately describing synaptic interactions between neurons and how interactions change over time are key challenges for systems neuroscience. Although intracellular electrophysiology is a powerful tool for studying synaptic integration and plasticity, it is limited by the small number of neurons that can be recorded simultaneously in vitro and by the technical difficulty of intracellular recording in vivo. One way around these difficulties may be to use large-scale extracellular recording of spike trains and apply statistical methods to model and infer functional connections between neurons. These techniques have the potential to reveal large-scale connectivity structure based on the spike timing alone. However, the interpretation of functional connectivity is often approximate, since only a small fraction of presynaptic inputs are typically observed. Here we use in vitro current injection in layer 2/3 pyramidal neurons to validate methods for inferring functional connectivity in a setting where input to the neuron is controlled. In experiments with partially-defined input, we inject a single simulated input with known amplitude on a background of fluctuating noise. In a fully-defined input paradigm, we then control the synaptic weights and timing of many simulated presynaptic neurons. By analyzing the firing of neurons in response to these artificial inputs, we ask 1 How does functional connectivity inferred from spikes relate to simulated synaptic input? and 2 What are the limitations of connectivity inference? We find that individual current-based synaptic inputs are detectable over a broad range of amplitudes and conditions. Detectability depends on input amplitude and output firing rate, and excitatory inputs are detected more readily than inhibitory. Moreover, as we model increasing numbers of presynaptic inputs, we are able to estimate connection strengths more accurately and detect the presence of connections more quickly. These results

  20. Spike Pattern Structure Influences Synaptic Efficacy Variability Under STDP and Synaptic Homeostasis. I: Spike Generating Models on Converging Motifs

    Directory of Open Access Journals (Sweden)

    Zedong eBi

    2016-02-01

    Full Text Available In neural systems, synaptic plasticity is usually driven by spike trains. Due to the inherent noises of neurons and synapses as well as the randomness of connection details, spike trains typically exhibit variability such as spatial randomness and temporal stochasticity, resulting in variability of synaptic changes under plasticity, which we call efficacy variability. How the variability of spike trains influences the efficacy variability of synapses remains unclear. In this paper, we try to understand this influence under pair-wise additive spike-timing dependent plasticity (STDP when the mean strength of plastic synapses into a neuron is bounded (synaptic homeostasis. Specifically, we systematically study, analytically and numerically, how four aspects of statistical features, i.e. synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations, as well as their interactions influence the efficacy variability in converging motifs (simple networks in which one neuron receives from many other neurons. Neurons (including the post-synaptic neuron in a converging motif generate spikes according to statistical models with tunable parameters. In this way, we can explicitly control the statistics of the spike patterns, and investigate their influence onto the efficacy variability, without worrying about the feedback from synaptic changes onto the dynamics of the post-synaptic neuron. We separate efficacy variability into two parts: the drift part (DriftV induced by the heterogeneity of change rates of different synapses, and the diffusion part (DiffV induced by weight diffusion caused by stochasticity of spike trains. Our main findings are: (1 synchronous firing and burstiness tend to increase DiffV, (2 heterogeneity of rates induces DriftV when potentiation and depression in STDP are not balanced, and (3 heterogeneity of cross-correlations induces DriftV together with heterogeneity of rates. We anticipate our

  1. Association of intracortical inhibition with social cognition deficits in schizophrenia: Findings from a transcranial magnetic stimulation study.

    Science.gov (United States)

    Mehta, Urvakhsh Meherwan; Thirthalli, Jagadisha; Basavaraju, Rakshathi; Gangadhar, Bangalore N

    2014-09-01

    Abnormal cortical-inhibition has been hypothesized to underlie social-cognition deficits in schizophrenia. Studies using transcranial magnetic stimulation (TMS) as a neurophysiological probe have demonstrated cortical-inhibition deficits in this group. We compared TMS-measured short- and long-interval intracortical-inhibition (SICI & LICI) in antipsychotic-naïve (n=33) and medicated (n=21) schizophrenia patients and in healthy comparison subjects (n=45). We also studied the association between cortical-inhibition and social-cognition deficits in the patients. Antipsychotic-naïve patients had significant deficits in SICI (i.e., less inhibitory response). In this group, SICI had significant inverse correlations with emotion processing and a global social-cognition score. Impaired intracortical-inhibition may thus contribute to social-cognition deficits in schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Optogenetic analysis of synaptic function

    NARCIS (Netherlands)

    Liewald, Jana F.; Brauner, Martin; Stephens, Greg J.; Bouhours, Magali; Schultheis, Christian; Zhen, Mei; Gottschalk, Alexander

    2008-01-01

    We introduce optogenetic investigation of neurotransmission (OptIoN) for time-resolved and quantitative assessment of synaptic function via behavioral and electrophysiological analyses. We photo-triggered release of acetylcholine or γ-aminobutyric acid at Caenorhabditis elegans neuromuscular

  3. Synaptic AMPA receptor plasticity and behavior

    NARCIS (Netherlands)

    Kessels, Helmut W.; Malinow, Roberto

    2009-01-01

    The ability to change behavior likely depends on the selective strengthening and weakening of brain synapses. The cellular models of synaptic plasticity, long-term potentiation (LTP) and depression (LTD) of synaptic strength, can be expressed by the synaptic insertion or removal of AMPA receptors

  4. Failure mode analysis of silicon-based intracortical microelectrode arrays in non-human primates

    Science.gov (United States)

    Barrese, James C.; Rao, Naveen; Paroo, Kaivon; Triebwasser, Corey; Vargas-Irwin, Carlos; Franquemont, Lachlan; Donoghue, John P.

    2013-12-01

    Objective. Brain-computer interfaces (BCIs) using chronically implanted intracortical microelectrode arrays (MEAs) have the potential to restore lost function to people with disabilities if they work reliably for years. Current sensors fail to provide reliably useful signals over extended periods of time for reasons that are not clear. This study reports a comprehensive retrospective analysis from a large set of implants of a single type of intracortical MEA in a single species, with a common set of measures in order to evaluate failure modes. Approach. Since 1996, 78 silicon MEAs were implanted in 27 monkeys (Macaca mulatta). We used two approaches to find reasons for sensor failure. First, we classified the time course leading up to complete recording failure as acute (abrupt) or chronic (progressive). Second, we evaluated the quality of electrode recordings over time based on signal features and electrode impedance. Failure modes were divided into four categories: biological, material, mechanical, and unknown. Main results. Recording duration ranged from 0 to 2104 days (5.75 years), with a mean of 387 days and a median of 182 days (n = 78). Sixty-two arrays failed completely with a mean time to failure of 332 days (median = 133 days) while nine array experiments were electively terminated for experimental reasons (mean = 486 days). Seven remained active at the close of this study (mean = 753 days). Most failures (56%) occurred within a year of implantation, with acute mechanical failures the most common class (48%), largely because of connector issues (83%). Among grossly observable biological failures (24%), a progressive meningeal reaction that separated the array from the parenchyma was most prevalent (14.5%). In the absence of acute interruptions, electrode recordings showed a slow progressive decline in spike amplitude, noise amplitude, and number of viable channels that predicts complete signal loss by about eight years. Impedance measurements showed

  5. Irregular persistent activity induced by synaptic excitatory feedback

    Directory of Open Access Journals (Sweden)

    Francesca Barbieri

    2007-11-01

    Full Text Available Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV of interspike intervals (ISI of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i the post-spike reset is close enough to threshold , (ii synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between presynaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD. First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

  6. Differential regulation of spontaneous and evoked inhibitory synaptic transmission in somatosensory cortex by retinoic acid.

    Science.gov (United States)

    Yee, Ada X; Chen, Lu

    2016-11-01

    Retinoic acid (RA), a developmental morphogen, has emerged in recent studies as a novel synaptic signaling molecule that acts in mature hippocampal neurons to modulate excitatory and inhibitory synaptic transmission in the context of homeostatic synaptic plasticity. However, it is unclear whether RA is capable of modulating neural circuits outside of the hippocampus, and if so, whether the mode of RA's action at synapses is similar to that within the hippocampal network. Here we explore for the first time RA's synaptic function outside the hippocampus and uncover a novel function of all-trans retinoic acid at inhibitory synapses. Acute RA treatment increases spontaneous inhibitory synaptic transmission in L2/3 pyramidal neurons of the somatosensory cortex, and this effect requires expression of RA's receptor RARα both pre- and post-synaptically. Intriguingly, RA does not seem to affect evoked inhibitory transmission assayed with either extracellular stimulation or direct activation of action potentials in presynaptic interneurons at connected pairs of interneurons and pyramidal neurons. Taken together, these results suggest that RA's action at synapses is not monotonous, but is diverse depending on the type of synaptic connection (excitatory versus inhibitory) and circuit (hippocampal versus cortical). Thus, synaptic signaling of RA may mediate multi-faceted regulation of synaptic plasticity. In addition to its classic roles in brain development, retinoic acid (RA) has recently been shown to regulate excitatory and inhibitory transmission in the adult brain. Here, the authors show that in layer 2/3 (L2/3) of the somatosensory cortex (S1), acute RA induces increases in spontaneous but not action-potential evoked transmission, and that this requires retinoic acid receptor (RARα) both in presynaptic PV-positive interneurons and postsynaptic pyramidal (PN) neurons. © 2016 Wiley Periodicals, Inc.

  7. On the estimation of population-specific synaptic currents from laminar multielectrode recordings

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    Sergey L Gratiy

    2011-12-01

    Full Text Available Multielectrode array recordings of extracellular electrical field potentials along the depth axis of the cerebral cortex is an up-and-coming approach for investigating activity of cortical neuronal circuits. The low-frequency band of extracellular potential, i.e., the local field potential (LFP, is assumed to reflect the synaptic activity and can be used to extract the current source density (CSD profile. However, physiological interpretation of CSD profiles is uncertain because the analysis does not disambiguate synaptic inputs from passive return currents. Here we present a novel mathematical framework for identifying excited neuronal populations and for separating synaptic input currents from return currents based on LFP recordings. This involves a combination of the linear forward model, which predicts population-specific laminar LFP in response to sinusoidal synaptic inputs applied at different locations along the population cells having realistic morphologies and the linear inverse model, which reconstructs laminar profiles of synaptic inputs from the Fourier spectrum of the laminar LFP data based on the forward prediction. The model allows reconstruction of synaptic input profiles on a spatial scale comparable to known anatomical organization of synaptic projections within a cortical column. Assuming spatial correlation of synaptic inputs within individual populations, the model decomposes the columnar LFP into population-specific contributions. Constraining the solution with a priori knowledge of the spatial distribution of synaptic connectivity further allows prediction of active projections from the composite LFP profile. This modeling framework successfully delineates the main relationships between the synaptic input currents and the evoked LFP and can serve as a foundation for modeling more realistic processing of active dendritic conductances.

  8. Long-term stability of sensitivity to intracortical microstimulation of somatosensory cortex

    Science.gov (United States)

    Callier, Thierri; Schluter, Erik W.; Tabot, Gregg A.; Miller, Lee E.; Tenore, Francesco V.; Bensmaia, Sliman J.

    2015-10-01

    Objective. The dexterous manipulation of objects depends heavily on somatosensory signals from the limb. The development of anthropomorphic robotic arms and of algorithms to decode intended movements from neuronal signals has stimulated the need to restore somatosensation for use in upper-limb neuroprostheses. Without touch and proprioception, patients have difficulty controlling prosthetic limbs to a level that justifies the required invasive surgery. Intracortical microstimulation (ICMS) through chronically implanted electrode arrays has the potential to provide rich and intuitive sensory feedback. This approach to sensory restoration requires, however, that the evoked sensations remain stable over time. Approach. To investigate the stability of ICMS-evoked sensations, we measured the ability of non-human primates to detect ICMS over experimental sessions that spanned years. Main results. We found that the performance of the animals remained highly stable over time, even when they were tested with electrodes that had experienced extensive stimulation. Significance. Given the stability of the sensations that it evokes, ICMS may thus be a viable approach for sensory restoration.

  9. Time course of corticospinal excitability and intracortical inhibition just before muscle relaxation

    Directory of Open Access Journals (Sweden)

    Tomotaka eSuzuki

    2016-01-01

    Full Text Available Using transcranial magnetic stimulation (TMS, we investigated how short-interval intracortical inhibition (SICI was involved with transient motor cortex excitability changes observed just before the transition from muscle contraction to muscle relaxation. Ten healthy participants performed a simultaneous relaxation task of the ipsilateral finger and foot, relaxing from 10% of their maximal voluntary contraction force after the go signal. In the simple reaction time paradigm, single or paired TMS pulses were randomly delivered after the go signal, and motor evoked potentials were recorded from the right first dorsal interosseous muscle. We analyzed the time course prior to the estimated relaxation reaction time, defined here as the onset of voluntary relaxation. SICI decreased in the 80–100 ms before relaxation reaction time, and motor evoked potentials were significantly greater in amplitude in the 60–80 ms period before relaxation reaction time than in the other intervals in single-pulse trials. TMS pulses did not effectively increase relaxation reaction time. These results show that cortical excitability in the early stage, before muscle relaxation, plays an important role in muscle relaxation control. SICI circuits may vary between decreased and increased activation to continuously maintain muscle relaxation during or after a relaxation response. With regard to motor cortex excitability dynamics, we suggest that SICI also dynamically changes throughout the muscle relaxation process.

  10. Brain computer interface learning for systems based on electrocorticography and intracortical microelectrode arrays.

    Science.gov (United States)

    Hiremath, Shivayogi V; Chen, Weidong; Wang, Wei; Foldes, Stephen; Yang, Ying; Tyler-Kabara, Elizabeth C; Collinger, Jennifer L; Boninger, Michael L

    2015-01-01

    A brain-computer interface (BCI) system transforms neural activity into control signals for external devices in real time. A BCI user needs to learn to generate specific cortical activity patterns to control external devices effectively. We call this process BCI learning, and it often requires significant effort and time. Therefore, it is important to study this process and develop novel and efficient approaches to accelerate BCI learning. This article reviews major approaches that have been used for BCI learning, including computer-assisted learning, co-adaptive learning, operant conditioning, and sensory feedback. We focus on BCIs based on electrocorticography and intracortical microelectrode arrays for restoring motor function. This article also explores the possibility of brain modulation techniques in promoting BCI learning, such as electrical cortical stimulation, transcranial magnetic stimulation, and optogenetics. Furthermore, as proposed by recent BCI studies, we suggest that BCI learning is in many ways analogous to motor and cognitive skill learning, and therefore skill learning should be a useful metaphor to model BCI learning.

  11. Brain Computer Interface Learning for Systems Based on Electrocorticography and Intracortical Microelectrode Arrays

    Directory of Open Access Journals (Sweden)

    Shivayogi V Hiremath

    2015-06-01

    Full Text Available A brain-computer interface (BCI system transforms neural activity into control signals for external devices in real time. A BCI user needs to learn to generate specific cortical activity patterns to control external devices effectively. We call this process BCI learning, and it often requires significant effort and time. Therefore, it is important to study this process and develop novel and efficient approaches to accelerate BCI learning. This article reviews major approaches that have been used for BCI learning, including computer-assisted learning, co-adaptive learning, operant conditioning, and sensory feedback. We focus on BCIs based on electrocorticography and intracortical microelectrode arrays for restoring motor function. This article also explores the possibility of brain modulation techniques in promoting BCI learning, such as electrical cortical stimulation, transcranial magnetic stimulation, and optogenetics. Furthermore, as proposed by recent BCI studies, we suggest that BCI learning is in many ways analogous to motor and cognitive skill learning, and therefore skill learning should be a useful metaphor to model BCI learning.

  12. Delayed grip relaxation and altered modulation of intracortical inhibition with aging

    Science.gov (United States)

    Motawar, Binal; Stinear, James W.; Lauer, Abigail W.; Ramakrishnan, V. Viswanathan; Seo, Na Jin

    2015-01-01

    Grip relaxation is a voluntary action that requires an increase in short-interval intracortical inhibition (SICI) in healthy young adults, rather than a simple termination of excitatory drive. The way aging affects this voluntary inhibitory action and timing of grip relaxation is currently unknown. The objective of this study was to examine aging-related delays in grip relaxation and SICI modulation for the flexor digitorum superficialis (FDS) muscle during grip relaxation. The main finding was that young adults increased SICI to relax their grips, whereas older adults did not increase SICI with a prolonged grip relaxation time (prelaxation time). A secondary experiment showed that both young and older adults did not change H reflex excitability during grip relaxation. Our data suggest that grip relaxation is mediated by increased cortical inhibitory output in young adults, and aging-related impairment in increasing cortical inhibitory output may hamper timely cessation of muscle activity. Our data also suggest a lesser role of the spinal circuits in grip muscle relaxation. This knowledge may contribute to understanding of aging-related movement deterioration and development of interventions for improving modulation of SICI to improve muscle relaxation and movement coordination. PMID:26686531

  13. Molecular Recognition within Synaptic Scaffolds

    DEFF Research Database (Denmark)

    Erlendsson, Simon

    -length structural model of the PICK1 dimer in-solution. We found the PICK1 BAR dimer to resemble an elongated crescent-shaped structure, spanning ~160 Å, with the PICK1 PDZ domains loosely attached to the BAR domain. This finding is in contrast to previous findings for other BAR domain proteins, where adjacent......Scaffolding proteins are abundant participants and regulators of the extensive intracellular framework required for maintaining cellular functions such as cellular adhesion and signal transduction cascades. In excitatory neuronal synapses these scaffolding proteins often contain one or more PDZ...... domains, responsible for tethering their respective synaptic protein ligands. Therefore, understanding the specificity and binding mechanisms of PDZ domain proteins is essential to understand regulation of synaptic plasticity. PICK1 is a PDZ domain-containing scaffolding protein predominantly expressed...

  14. Rewiring of neuronal networks during synaptic silencing.

    Science.gov (United States)

    Wrosch, Jana Katharina; Einem, Vicky von; Breininger, Katharina; Dahlmanns, Marc; Maier, Andreas; Kornhuber, Johannes; Groemer, Teja Wolfgang

    2017-09-15

    Analyzing the connectivity of neuronal networks, based on functional brain imaging data, has yielded new insight into brain circuitry, bringing functional and effective networks into the focus of interest for understanding complex neurological and psychiatric disorders. However, the analysis of network changes, based on the activity of individual neurons, is hindered by the lack of suitable meaningful and reproducible methodologies. Here, we used calcium imaging, statistical spike time analysis and a powerful classification model to reconstruct effective networks of primary rat hippocampal neurons in vitro. This method enables the calculation of network parameters, such as propagation probability, path length, and clustering behavior through the measurement of synaptic activity at the single-cell level, thus providing a fuller understanding of how changes at single synapses translate to an entire population of neurons. We demonstrate that our methodology can detect the known effects of drug-induced neuronal inactivity and can be used to investigate the extensive rewiring processes affecting population-wide connectivity patterns after periods of induced neuronal inactivity.

  15. Binocular Rivalry in a Competitive Neural Network with Synaptic Depression

    KAUST Repository

    Kilpatrick, Zachary P.

    2010-01-01

    We study binocular rivalry in a competitive neural network with synaptic depression. In particular, we consider two coupled hypercolums within primary visual cortex (V1), representing orientation selective cells responding to either left or right eye inputs. Coupling between hypercolumns is dominated by inhibition, especially for neurons with dissimilar orientation preferences. Within hypercolumns, recurrent connectivity is excitatory for similar orientations and inhibitory for different orientations. All synaptic connections are modifiable by local synaptic depression. When the hypercolumns are driven by orthogonal oriented stimuli, it is possible to induce oscillations that are representative of binocular rivalry. We first analyze the occurrence of oscillations in a space-clamped version of the model using a fast-slow analys is, taking advantage of the fact that depression evolves much slower than population activity. We th en analyze the onset of oscillations in the full spatially extended system by carrying out a piecewise smooth stability analysis of single (winner-take-all) and double (fusion) bumps within the network. Although our stability analysis takes into account only instabilities associated with real eigenvalues, it identifies points of instability that are consistent with what is found numerically. In particular, we show that, in regions of parameter space where double bumps are unstable and no single bumps exist, binocular rivalry can arise as a slow alternation between either population supporting a bump. © 2010 Society for Industrial and Applied Mathematics.

  16. Experience-Dependent Equilibration of AMPAR-Mediated Synaptic Transmission during the Critical Period

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    Kyung-Seok Han

    2017-01-01

    Full Text Available Experience-dependent synapse refinement is essential for functional optimization of neural circuits. However, how sensory experience sculpts excitatory synaptic transmission is poorly understood. Here, we show that despite substantial remodeling of synaptic connectivity, AMPAR-mediated synaptic transmission remains at equilibrium during the critical period in the mouse primary visual cortex. The maintenance of this equilibrium requires neurogranin (Ng, a postsynaptic calmodulin-binding protein important for synaptic plasticity. With normal visual experience, loss of Ng decreased AMPAR-positive synapse numbers, prevented AMPAR-silent synapse maturation, and increased spine elimination. Importantly, visual deprivation halted synapse loss caused by loss of Ng, revealing that Ng coordinates experience-dependent AMPAR-silent synapse conversion to AMPAR-active synapses and synapse elimination. Loss of Ng also led to sensitized long-term synaptic depression (LTD and impaired visually guided behavior. Our synaptic interrogation reveals that experience-dependent coordination of AMPAR-silent synapse conversion and synapse elimination hinges upon Ng-dependent mechanisms for constructive synaptic refinement during the critical period.

  17. Addictive nicotine alters local circuit inhibition during the induction of in vivo hippocampal synaptic potentiation.

    Science.gov (United States)

    Zhang, Tao A; Tang, Jianrong; Pidoplichko, Volodymyr I; Dani, John A

    2010-05-05

    The drug addiction process shares many commonalities with normal learning and memory. Addictive drugs subvert normal synaptic plasticity mechanisms, and the consequent synaptic changes underlie long-lasting modifications in behavior that accrue during the progression from drug use to addiction. Supporting this hypothesis, it was recently shown that nicotine administered to freely moving mice induces long-term synaptic potentiation of the perforant path connection to granule cells of the dentate gyrus. The perforant path carries place and spatial information that links the environment to drug taking. An example of that association is the nicotine-induced synaptic potentiation of the perforant path that was found to underlie nicotine-conditioned place preference. The present study examines the influence of nicotine over local GABAergic inhibition within the dentate gyrus during the drug-induced synaptic potentiation. In vivo recordings from freely moving mice suggested that both feedforward and feedback inhibition onto granules cells were diminished by nicotine during the induction of synaptic potentiation. In vitro brain slice studies indicated that nicotine altered local circuit inhibition within the dentate gyrus leading to disinhibition of granule cells. These changes in local inhibition contributed to nicotine-induced in vivo synaptic potentiation, thus, likely contributed to drug-associated memories. Through this learning process, environmental features become cues that motivate conditioned drug-seeking and drug-taking behaviors.

  18. Synaptic dysfunction in amygdala in intellectual disorder models.

    Science.gov (United States)

    Aincy, Marianne; Meziane, Hamid; Herault, Yann; Humeau, Yann

    2018-06-08

    The amygdala is a part of the limbic circuit that has been extensively studied in terms of synaptic connectivity, plasticity and cellular organization since decades (Ehrlich et al., 2009; Ledoux, 2000; Maren, 2001). Amygdala sub-nuclei, including lateral, basolateral and central amygdala appear now as "hubs" providing in parallel and in series neuronal processing enabling the animal to elicit freezing or escaping behavior in response to external threats. In rodents, these behaviors are easily observed and quantified following associative fear conditioning. Thus, studies on amygdala circuit in association with threat/fear behavior became very popular in laboratories and are often used among other behavioral tests to evaluate learning abilities of mouse models for various neuropsychiatric conditions including genetically encoded intellectual disabilities (ID). Yet, more than 100 human X-linked genes - and several hundreds of autosomal genes - have been associated with ID in humans. These mutations introduced in mice can generate social deficits, anxiety dysregulations and fear learning impairments (McNaughton et al., 2008; Houbaert et al., 2013; Jayachandran et al., 2014; Zhang et al., 2015). Noteworthy, a significant proportion of the coded ID gene products are synaptic proteins. It is postulated that the loss of function of these proteins could destabilize neuronal circuits by global changes of the balance between inhibitory and excitatory drives onto neurons. However, whereas amygdala related behavioral deficits are commonly observed in ID models, the role of most of these ID-genes in synaptic function and plasticity in the amygdala are only sparsely studied. We will here discuss some of the concepts that emerged from amygdala-targeted studies examining the role of syndromic and non-syndromic ID genes in fear-related behaviors and/or synaptic function. Along describing these cases, we will discuss how synaptic deficits observed in amygdala circuits could impact

  19. Late onset deficits in synaptic plasticity in the valproic acid rat model of autism

    Directory of Open Access Journals (Sweden)

    Henry Giles Stratten Martin

    2014-01-01

    Full Text Available Valproic acid (VPA is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP due to an up-regulation of NMDA receptor (NMDAR expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDA receptors during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.

  20. Ataxias and cerebellar dysfunction: involvement of synaptic plasticity deficits?

    Science.gov (United States)

    Rinaldo, Lorenzo; Hansel, Christian

    2011-01-01

    Summary Adaptive processes within cerebellar circuits, such as long-term depression and long-term potentiation at parallel fiber-Purkinje cell synapses, have long been seen as important to cerebellar motor learning, and yet little attention has been given to any possible significance of these processes for cerebellar dysfunction and disease. Several forms of ataxia are caused by mutations in genes encoding for ion channels located at key junctures in pathways that lead to the induction of synaptic plasticity, suggesting that there might be an association between deficits in plasticity and the ataxic phenotype. Herein we explore this possibility and examine the available evidence linking the two together, highlighting specifically the role of P/Q-type calcium channels and their downstream effector small-conductance calcium-sensitive (SK2) potassium channels in the regulation of synaptic gain and intrinsic excitability, and reviewing their connections to ataxia. PMID:21232209

  1. Cerebro-cerebellar connectivity is increased in primary lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Avner Meoded

    2015-01-01

    Full Text Available Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS, a long-lived motor neuron disease. Connectivity matrices were constructed from resting state fMRI in 16 PLS patients to identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used to examine structural connections between regions of differing connectivity. PLS patients had 12 regions with increased functional connectivity compared to controls, with a predominance of cerebro-cerebellar connections. Increased functional connectivity was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber tracking detected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact.

  2. Cerebro-cerebellar connectivity is increased in primary lateral sclerosis.

    Science.gov (United States)

    Meoded, Avner; Morrissette, Arthur E; Katipally, Rohan; Schanz, Olivia; Gotts, Stephen J; Floeter, Mary Kay

    2015-01-01

    Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS), a long-lived motor neuron disease. Connectivity matrices were constructed from resting state fMRI in 16 PLS patients to identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used to examine structural connections between regions of differing connectivity. PLS patients had 12 regions with increased functional connectivity compared to controls, with a predominance of cerebro-cerebellar connections. Increased functional connectivity was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber tracking detected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact.

  3. Comparison of spike sorting and thresholding of voltage waveforms for intracortical brain-machine interface performance

    Science.gov (United States)

    Christie, Breanne P.; Tat, Derek M.; Irwin, Zachary T.; Gilja, Vikash; Nuyujukian, Paul; Foster, Justin D.; Ryu, Stephen I.; Shenoy, Krishna V.; Thompson, David E.; Chestek, Cynthia A.

    2015-02-01

    Objective. For intracortical brain-machine interfaces (BMIs), action potential voltage waveforms are often sorted to separate out individual neurons. If these neurons contain independent tuning information, this process could increase BMI performance. However, the sorting of action potentials (‘spikes’) requires high sampling rates and is computationally expensive. To explicitly define the difference between spike sorting and alternative methods, we quantified BMI decoder performance when using threshold-crossing events versus sorted action potentials. Approach. We used data sets from 58 experimental sessions from two rhesus macaques implanted with Utah arrays. Data were recorded while the animals performed a center-out reaching task with seven different angles. For spike sorting, neural signals were sorted into individual units by using a mixture of Gaussians to cluster the first four principal components of the waveforms. For thresholding events, spikes that simply crossed a set threshold were retained. We decoded the data offline using both a Naïve Bayes classifier for reaching direction and a linear regression to evaluate hand position. Main results. We found the highest performance for thresholding when placing a threshold between -3 and -4.5 × Vrms. Spike sorted data outperformed thresholded data for one animal but not the other. The mean Naïve Bayes classification accuracy for sorted data was 88.5% and changed by 5% on average when data were thresholded. The mean correlation coefficient for sorted data was 0.92, and changed by 0.015 on average when thresholded. Significance. For prosthetics applications, these results imply that when thresholding is used instead of spike sorting, only a small amount of performance may be lost. The utilization of threshold-crossing events may significantly extend the lifetime of a device because these events are often still detectable once single neurons are no longer isolated.

  4. Behavioral detection of intra-cortical microstimulation in the primary and secondary auditory cortex of cats

    Directory of Open Access Journals (Sweden)

    Zhenling eZhao

    2015-04-01

    Full Text Available Although neural responses to sound stimuli have been thoroughly investigated in various areas of the auditory cortex, the results electrophysiological recordings cannot establish a causal link between neural activation and brain function. Electrical microstimulation, which can selectively perturb neural activity in specific parts of the nervous system, is an important tool for exploring the organization and function of brain circuitry. To date, the studies describing the behavioral effects of electrical stimulation have largely been conducted in the primary auditory cortex. In this study, to investigate the potential differences in the effects of electrical stimulation on different cortical areas, we measured the behavioral performance of cats in detecting intra-cortical microstimulation (ICMS delivered in the primary and secondary auditory fields (A1 and A2, respectively. After being trained to perform a Go/No-Go task cued by sounds, we found that cats could also learn to perform the task cued by ICMS; furthermore, the detection of the ICMS was similarly sensitive in A1 and A2. Presenting wideband noise together with ICMS substantially decreased the performance of cats in detecting ICMS in A1 and A2, consistent with a noise masking effect on the sensation elicited by the ICMS. In contrast, presenting ICMS with pure-tones in the spectral receptive field of the electrode-implanted cortical site reduced ICMS detection performance in A1 but not A2. Therefore, activation of A1 and A2 neurons may produce different qualities of sensation. Overall, our study revealed that ICMS-induced neural activity could be easily integrated into an animal’s behavioral decision process and had an implication for the development of cortical auditory prosthetics.

  5. High performance communication by people with paralysis using an intracortical brain-computer interface.

    Science.gov (United States)

    Pandarinath, Chethan; Nuyujukian, Paul; Blabe, Christine H; Sorice, Brittany L; Saab, Jad; Willett, Francis R; Hochberg, Leigh R; Shenoy, Krishna V; Henderson, Jaimie M

    2017-02-21

    Brain-computer interfaces (BCIs) have the potential to restore communication for people with tetraplegia and anarthria by translating neural activity into control signals for assistive communication devices. While previous pre-clinical and clinical studies have demonstrated promising proofs-of-concept (Serruya et al., 2002; Simeral et al., 2011; Bacher et al., 2015; Nuyujukian et al., 2015; Aflalo et al., 2015; Gilja et al., 2015; Jarosiewicz et al., 2015; Wolpaw et al., 1998; Hwang et al., 2012; Spüler et al., 2012; Leuthardt et al., 2004; Taylor et al., 2002; Schalk et al., 2008; Moran, 2010; Brunner et al., 2011; Wang et al., 2013; Townsend and Platsko, 2016; Vansteensel et al., 2016; Nuyujukian et al., 2016; Carmena et al., 2003; Musallam et al., 2004; Santhanam et al., 2006; Hochberg et al., 2006; Ganguly et al., 2011; O'Doherty et al., 2011; Gilja et al., 2012), the performance of human clinical BCI systems is not yet high enough to support widespread adoption by people with physical limitations of speech. Here we report a high-performance intracortical BCI (iBCI) for communication, which was tested by three clinical trial participants with paralysis. The system leveraged advances in decoder design developed in prior pre-clinical and clinical studies (Gilja et al., 2015; Kao et al., 2016; Gilja et al., 2012). For all three participants, performance exceeded previous iBCIs (Bacher et al., 2015; Jarosiewicz et al., 2015) as measured by typing rate (by a factor of 1.4-4.2) and information throughput (by a factor of 2.2-4.0). This high level of performance demonstrates the potential utility of iBCIs as powerful assistive communication devices for people with limited motor function.Clinical Trial No: NCT00912041.

  6. The effect of chronic intracortical microstimulation on the electrode-tissue interface

    Science.gov (United States)

    Chen, Kevin H.; Dammann, John F.; Boback, Jessica L.; Tenore, Francesco V.; Otto, Kevin J.; Gaunt, Robert A.; Bensmaia, Sliman J.

    2014-04-01

    Objective. Somatosensation is critical for effective object manipulation, but current upper limb prostheses do not provide such feedback to the user. For individuals who require use of prosthetic limbs, this lack of feedback transforms a mundane task into one that requires extreme concentration and effort. Although vibrotactile motors and sensory substitution devices can be used to convey gross sensations, a direct neural interface is required to provide detailed and intuitive sensory feedback. The viability of intracortical microstimulation (ICMS) as a method to deliver feedback depends in part on the long-term reliability of implanted electrodes used to deliver the stimulation. The objective of the present study is to investigate the effects of chronic ICMS on the electrode-tissue interface. Approach. We stimulate the primary somatosensory cortex of three Rhesus macaques through chronically implanted electrodes for 4 h per day over a period of six months, with different electrodes subjected to different regimes of stimulation. We measure the impedance and voltage excursion as a function of time and of ICMS parameters. We also test the sensorimotor consequences of chronic ICMS by having animals grasp and manipulate small treats. Main results. We show that impedance and voltage excursion both decay with time but stabilize after 10-12 weeks. The magnitude of this decay is dependent on the amplitude of the ICMS and, to a lesser degree, the duration of individual pulse trains. Furthermore, chronic ICMS does not produce any deficits in fine motor control. Significance. The results suggest that chronic ICMS has only a minor effect on the electrode-tissue interface and may thus be a viable means to convey sensory feedback in neuroprosthetics.

  7. A fast intracortical brain-machine interface with patterned optogenetic feedback.

    Science.gov (United States)

    Abbasi, Aamir; Goueytes, Dorian; Shulz, Daniel E; Ego-Stengel, Valerie; Estebanez, Luc

    2018-04-04

    The development of brain-machine interfaces (BMIs) brings a new perspective to patients with a loss of autonomy. By combining online recordings of brain activity with a decoding algorithm, patients can learn to control a robotic arm in order to perform simple actions. However, in contrast to the vast amounts of somatosensory information channeled by limbs to the brain, current BMIs are devoid of touch and force sensors. Patients must therefore rely solely on vision and audition, which are maladapted to the control of a prosthesis. In contrast, in a healthy limb, somatosensory inputs alone can efficiently guide the handling of a fragile object, or ensure a smooth trajectory. We have developed a BMI in the mouse that includes a rich artificial somatosensory-like cortical feedback. Our setup includes online recordings of the activity of multiple neurons in the whisker primary motor cortex (vM1), and delivers feedback simultaneously via a low-latency, high-refresh rate and spatially structured photo-stimulation of the whisker primary somatosensory cortex (vS1), based on a mapping obtained by intrinsic imaging. We demonstrate the operation of the loop and show that mice can detect the neuronal spiking in vS1 triggered by the photo-stimulations. Finally, we show that the mice can learn a behavioral task relying only on the artificial inputs and outputs of the closed-loop BMI. This is the first motor BMI that includes a short-latency, intracortical, somatosensory-like feedback. It will be a useful platform to discover efficient cortical feedback schemes towards future human BMI applications. Creative Commons Attribution license.

  8. Computational modeling of direct neuronal recruitment during intracortical microstimulation in somatosensory cortex

    Science.gov (United States)

    Overstreet, C. K.; Klein, J. D.; Helms Tillery, S. I.

    2013-12-01

    Objective. Electrical stimulation of cortical tissue could be used to deliver sensory information as part of a neuroprosthetic device, but current control of the location, resolution, quality, and intensity of sensations elicited by intracortical microstimulation (ICMS) remains inadequate for this purpose. One major obstacle to resolving this problem is the poor understanding of the neural activity induced by ICMS. Even with new imaging methods, quantifying the activity of many individual neurons within cortex is difficult. Approach. We used computational modeling to examine the response of somatosensory cortex to ICMS. We modeled the axonal arbors of eight distinct morphologies of interneurons and seven types of pyramidal neurons found in somatosensory cortex and identified their responses to extracellular stimulation. We then combined these axonal elements to form a multi-layered slab of simulated cortex and investigated the patterns of neural activity directly induced by ICMS. Specifically we estimated the number, location, and variety of neurons directly recruited by stimulation on a single penetrating microelectrode. Main results. The population of neurons activated by ICMS was dependent on both stimulation strength and the depth of the electrode within cortex. Strikingly, stimulation recruited interneurons and pyramidal neurons in very different patterns. Interneurons are primarily recruited within a dense, continuous region around the electrode, while pyramidal neurons were recruited in a sparse fashion both near the electrode and up to several millimeters away. Thus ICMS can lead to an unexpectedly complex spatial distribution of firing neurons. Significance. These results lend new insights to the complexity and range of neural activity that can be induced by ICMS. This work also suggests mechanisms potentially responsible for the inconsistency and unnatural quality of sensations initiated by ICMS. Understanding these mechanisms will aid in the design of

  9. Psychophysical correspondence between vibrotactile intensity and intracortical microstimulation for tactile neuroprostheses in rats

    Science.gov (United States)

    Devecioğlu, İsmail; Güçlü, Burak

    2017-02-01

    Objective. Recent studies showed that intracortical microstimulation (ICMS) generates artificial sensations which can be utilized as somatosensory feedback in cortical neuroprostheses. To mimic the natural psychophysical response, ICMS parameters are modulated according to psychometric equivalence functions (PEFs). PEFs match the intensity levels of ICMS and mechanical stimuli, which elicit equal detection probabilities, but they typically do not include the frequency as a control variable. We aimed to establish frequency-dependent PEFs for vibrotactile stimulation of the glabrous skin and ICMS in the primary somatosensory cortex of awake freely behaving rats. Approach. We collected psychometric data for vibrotactile and ICMS detection at three stimulation frequencies (40, 60 and 80 Hz). The psychometric data were fitted with a model equation of two independent variables (stimulus intensity and frequency) and four subject-dependent parameters. For each rat, we constructed a separate PEF which was used to estimate the ICMS current amplitude for a given displacement amplitude and frequency. The ICMS frequency was set equal to the vibrotactile frequency. We validated the PEFs in a modified task which included randomly selected probe trials presented either with a vibrotactile or an ICMS stimulus, and also at frequencies and intensity levels not tested before. Main results. The PEFs were generally successful in estimating the ICMS current intensities (no significant differences between vibrotactile and ICMS trials in Kolmogorov-Smirnov tests). Specifically, hit rates from both trial conditions were significantly correlated in 86% of the cases, and 52% of all data had perfect match in linear regression. Significance. The psychometric correspondence model presented in this study was constructed based on surface functions which define psychophysical detection probability as a function of stimulus intensity and frequency. Therefore, it may be used for the real

  10. Linear distributed source modeling of local field potentials recorded with intra-cortical electrode arrays.

    Directory of Open Access Journals (Sweden)

    Rikkert Hindriks

    Full Text Available Planar intra-cortical electrode (Utah arrays provide a unique window into the spatial organization of cortical activity. Reconstruction of the current source density (CSD underlying such recordings, however, requires "inverting" Poisson's equation. For inter-laminar recordings, this is commonly done by the CSD method, which consists in taking the second-order spatial derivative of the recorded local field potentials (LFPs. Although the CSD method has been tremendously successful in mapping the current generators underlying inter-laminar LFPs, its application to planar recordings is more challenging. While for inter-laminar recordings the CSD method seems reasonably robust against violations of its assumptions, is it unclear as to what extent this holds for planar recordings. One of the objectives of this study is to characterize the conditions under which the CSD method can be successfully applied to Utah array data. Using forward modeling, we find that for spatially coherent CSDs, the CSD method yields inaccurate reconstructions due to volume-conducted contamination from currents in deeper cortical layers. An alternative approach is to "invert" a constructed forward model. The advantage of this approach is that any a priori knowledge about the geometrical and electrical properties of the tissue can be taken into account. Although several inverse methods have been proposed for LFP data, the applicability of existing electroencephalographic (EEG and magnetoencephalographic (MEG inverse methods to LFP data is largely unexplored. Another objective of our study therefore, is to assess the applicability of the most commonly used EEG/MEG inverse methods to Utah array data. Our main conclusion is that these inverse methods provide more accurate CSD reconstructions than the CSD method. We illustrate the inverse methods using event-related potentials recorded from primary visual cortex of a macaque monkey during a motion discrimination task.

  11. Proactive modulation of long-interval intracortical inhibition during response inhibition

    Science.gov (United States)

    Cowie, Matthew J.; MacDonald, Hayley J.; Cirillo, John

    2016-01-01

    Daily activities often require sudden cancellation of preplanned movement, termed response inhibition. When only a subcomponent of a whole response must be suppressed (required here on Partial trials), the ensuing component is markedly delayed. The neural mechanisms underlying partial response inhibition remain unclear. We hypothesized that Partial trials would be associated with nonselective corticomotor suppression and that GABAB receptor-mediated inhibition within primary motor cortex might be responsible for the nonselective corticomotor suppression contributing to Partial trial response delays. Sixteen right-handed participants performed a bimanual anticipatory response inhibition task while single- and paired-pulse transcranial magnetic stimulation was delivered to elicit motor evoked potentials in the left first dorsal interosseous muscle. Lift times, amplitude of motor evoked potentials, and long-interval intracortical inhibition were examined across the different trial types (Go, Stop-Left, Stop-Right, Stop-Both). Go trials produced a tight distribution of lift times around the target, whereas those during Partial trials (Stop-Left and Stop-Right) were substantially delayed. The modulation of motor evoked potential amplitude during Stop-Right trials reflected anticipation, suppression, and subsequent reinitiation of movement. Importantly, suppression was present across all Stop trial types, indicative of a “default” nonselective inhibitory process. Compared with blocks containing only Go trials, inhibition increased when Stop trials were introduced but did not differ between trial types. The amount of inhibition was positively correlated with lift times during Stop-Right trials. Tonic levels of inhibition appear to be proactively modulated by task context and influence the speed at which unimanual responses occur after a nonselective “brake” is applied. PMID:27281744

  12. Fast State-Space Methods for Inferring Dendritic Synaptic Connectivity

    Science.gov (United States)

    2013-08-08

    2.23) which we can sample from using Markov Chain Monte Carlo ( MCMC ) methods. In particular we use a Gibbs sampler that cyclically samples a, τ2 and (W...computationally more intensive than the LARS method, not only due to the computational cost of the MCMC sampling , but because we need to pre-compute the full M... sampling from the posterior (2.23), but it is known that heavy- tailed distributions, such as log-Normal, are a more realistic choice (Song et al

  13. Natural Firing Patterns Imply Low Sensitivity of Synaptic Plasticity to Spike Timing Compared with Firing Rate.

    Science.gov (United States)

    Graupner, Michael; Wallisch, Pascal; Ostojic, Srdjan

    2016-11-02

    Synaptic plasticity is sensitive to the rate and the timing of presynaptic and postsynaptic action potentials. In experimental protocols inducing plasticity, the imposed spike trains are typically regular and the relative timing between every presynaptic and postsynaptic spike is fixed. This is at odds with firing patterns observed in the cortex of intact animals, where cells fire irregularly and the timing between presynaptic and postsynaptic spikes varies. To investigate synaptic changes elicited by in vivo-like firing, we used numerical simulations and mathematical analysis of synaptic plasticity models. We found that the influence of spike timing on plasticity is weaker than expected from regular stimulation protocols. Moreover, when neurons fire irregularly, synaptic changes induced by precise spike timing can be equivalently induced by a modest firing rate variation. Our findings bridge the gap between existing results on synaptic plasticity and plasticity occurring in vivo, and challenge the dominant role of spike timing in plasticity. Synaptic plasticity, the change in efficacy of connections between neurons, is thought to underlie learning and memory. The dominant paradigm posits that the precise timing of neural action potentials (APs) is central for plasticity induction. This concept is based on experiments using highly regular and stereotyped patterns of APs, in stark contrast with natural neuronal activity. Using synaptic plasticity models, we investigated how irregular, in vivo-like activity shapes synaptic plasticity. We found that synaptic changes induced by precise timing of APs are much weaker than suggested by regular stimulation protocols, and can be equivalently induced by modest variations of the AP rate alone. Our results call into question the dominant role of precise AP timing for plasticity in natural conditions. Copyright © 2016 Graupner et al.

  14. Characterization of emergent synaptic topologies in noisy neural networks

    Science.gov (United States)

    Miller, Aaron James

    Learned behaviors are one of the key contributors to an animal's ultimate survival. It is widely believed that the brain's microcircuitry undergoes structural changes when a new behavior is learned. In particular, motor learning, during which an animal learns a sequence of muscular movements, often requires precisely-timed coordination between muscles and becomes very natural once ingrained. Experiments show that neurons in the motor cortex exhibit precisely-timed spike activity when performing a learned motor behavior, and constituent stereotypical elements of the behavior can last several hundred milliseconds. The subject of this manuscript concerns how organized synaptic structures that produce stereotypical spike sequences emerge from random, dynamical networks. After a brief introduction in Chapter 1, we begin Chapter 2 by introducing a spike-timing-dependent plasticity (STDP) rule that defines how the activity of the network drives changes in network topology. The rule is then applied to idealized networks of leaky integrate-and-fire neurons (LIF). These neurons are not subjected to the variability that typically characterize neurons in vivo. In noiseless networks, synapses develop closed loops of strong connectivity that reproduce stereotypical, precisely-timed spike patterns from an initially random network. We demonstrate the characteristics of the asymptotic synaptic configuration are dependent on the statistics of the initial random network. The spike timings of the neurons simulated in Chapter 2 are generated exactly by a computationally economical, nonlinear mapping which is extended to LIF neurons injected with fluctuating current in Chapter 3. Development of an economical mapping that incorporates noise provides a practical solution to the long simulation times required to produce asymptotic synaptic topologies in networks with STDP in the presence of realistic neuronal variability. The mapping relies on generating numerical solutions to the dynamics

  15. Changes in intracortical microporosities induced by pharmaceutical treatment of osteoporosis as detected by high resolution micro-CT

    Energy Technology Data Exchange (ETDEWEB)

    Tommasini S. M.; Miller L.; Trinward, A.; Acerbo, A.S.; De Carlo F. and Judex, S.

    2011-12-28

    Bone's microporosities play important biologic and mechanical roles. Here, we quantified 3D changes in cortical osteocyte-lacunae and other small porosities induced by estrogen withdrawal and two different osteoporosistreatments. Unlike 2D measurements, these data collected via synchrotron radiation-based {mu}CT describe the size and 3D spatial distribution of a large number of porous structures. Six-month old female Sprague-Dawley rats were separated into four groups of age-matched controls, untreated OVX, OVX treated with PTH, and OVX treated with Alendronate (ALN). Intracortical microporosity of the medial quadrant of the femoral diaphysis was quantified at endosteal, intracortical, and periosteal regions of the samples, allowing the quantification of osteocyte lacunae that were formed primarily before versus after the start of treatment. Across the overall thickness of the medial cortex, lacunar volume fraction (Lc.V/TV) was significantly lower in ALN treated rats compared to PTH. In the endosteal region, average osteocyte lacunar volume (< Lc.V >) of untreated OVX rats was significantly lower than in age-matched controls, indicating a decrease in osteocyte lacunar size in bone formed on the endosteal surface after estrogen withdrawal. The effect of treatment (OVX, ALN, PTH) on the number of lacunae per tissue volume (Lc.N/TV) was dependent on the specific location within the cortex (endosteal, intracortical, periosteal). In both the endosteal and intracortical regions, Lc.N/TV was significantly lower in ALN than in untreated OVX, suggesting a site-specific effect in osteocyte lacuna density with ALN treatment. There also were a significantly greater number of small pores (5-100 {micro}m{sup 3} in volume) in the endosteal region for PTH compared to ALN. The mechanical impact of this altered microporosity structure is unknown, but might serve to enhance, rather than deteriorate bone strength with PTH treatment, as smaller osteocyte lacunae may be better

  16. Synaptic Plasticity and Memory Formation

    Science.gov (United States)

    1993-06-30

    suspected of being the substrate of several forms of memory encoded by synapses in the forebrain of humans and other mammals. Work in the past year...of LTP will enhance the encoding of memory . Aniracetam , as noted, prolongs the open time of the AMPA receptor and in this way facilitates excitatory...121 t Iffw,,a" S. FUNO4NG mUMSERS Synaptic Plasticity and Memory Formation F 49620-92-0307 C (ci) b.q F Gary Lynch 7. Pf(RfO*INN ORGAMIZAMNIO NMMW(S

  17. Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Amin Mottahedin

    2017-07-01

    Full Text Available The brain is a plastic organ where both the intrinsic CNS milieu and extrinsic cues play important roles in shaping and wiring neural connections. The perinatal period constitutes a critical time in central nervous system development with extensive refinement of neural connections, which are highly sensitive to fetal and neonatal compromise, such as inflammatory challenges. Emerging evidence suggests that inflammatory cells in the brain such as microglia and astrocytes are pivotal in regulating synaptic structure and function. In this article, we will review the role of glia cells in synaptic physiology and pathophysiology, including microglia-mediated elimination of synapses. We propose that activation of the immune system dynamically affects synaptic organization and function in the developing brain. We will discuss the role of neuroinflammation in altered synaptic plasticity following perinatal inflammatory challenges and potential implications for neurodevelopmental and neurodegenerative disorders.

  18. Klotho regulates CA1 hippocampal synaptic plasticity.

    Science.gov (United States)

    Li, Qin; Vo, Hai T; Wang, Jing; Fox-Quick, Stephanie; Dobrunz, Lynn E; King, Gwendalyn D

    2017-04-07

    Global klotho overexpression extends lifespan while global klotho-deficiency shortens it. As well, klotho protein manipulations inversely regulate cognitive function. Mice without klotho develop rapid onset cognitive impairment before they are 2months old. Meanwhile, adult mice overexpressing klotho show enhanced cognitive function, particularly in hippocampal-dependent tasks. The cognitive enhancing effects of klotho extend to humans with a klotho polymorphism that increases circulating klotho and executive function. To affect cognitive function, klotho could act in or on the synapse to modulate synaptic transmission or plasticity. However, it is not yet known if klotho is located at synapses, and little is known about its effects on synaptic function. To test this, we fractionated hippocampi and detected klotho expression in both pre and post-synaptic compartments. We find that loss of klotho enhances both pre and post-synaptic measures of CA1 hippocampal synaptic plasticity at 5weeks of age. However, a rapid loss of synaptic enhancement occurs such that by 7weeks, when mice are cognitively impaired, there is no difference from wild-type controls. Klotho overexpressing mice show no early life effects on synaptic plasticity, but decreased CA1 hippocampal long-term potentiation was measured at 6months of age. Together these data suggest that klotho affects cognition, at least in part, by regulating hippocampal synaptic plasticity. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. The developmental stages of synaptic plasticity

    NARCIS (Netherlands)

    Lohmann, Christian; Kessels, Helmut W.

    2014-01-01

    The brain is programmed to drive behaviour by precisely wiring the appropriate neuronal circuits. Wiring and rewiring of neuronal circuits largely depends on the orchestrated changes in the strengths of synaptic contacts. Here, we review how the rules of synaptic plasticity change during development

  20. Reduced diaphyseal strength associated with high intracortical vascular porosity within long bones of children with osteogenesis imperfecta.

    Science.gov (United States)

    Albert, Carolyne; Jameson, John; Smith, Peter; Harris, Gerald

    2014-09-01

    Osteogenesis imperfecta is a genetic disorder resulting in bone fragility. The mechanisms behind this fragility are not well understood. In addition to characteristic bone mass deficiencies, research suggests that bone material properties are compromised in individuals with this disorder. However, little data exists regarding bone properties beyond the microstructural scale in individuals with this disorder. Specimens were obtained from long bone diaphyses of nine children with osteogenesis imperfecta during routine osteotomy procedures. Small rectangular beams, oriented longitudinally and transversely to the diaphyseal axis, were machined from these specimens and elastic modulus, yield strength, and maximum strength were measured in three-point bending. Intracortical vascular porosity, bone volume fraction, osteocyte lacuna density, and volumetric tissue mineral density were determined by synchrotron micro-computed tomography, and relationships among these mechanical properties and structural parameters were explored. Modulus and strength were on average 64-68% lower in the transverse vs. longitudinal beams (Posteogenesis imperfecta. Results confirm that these properties are anisotropic. Elevated vascular porosity was observed in most specimens, and this parameter was associated with reduced bone material strength. These results offer insight toward understanding bone fragility and the role of intracortical porosity on the strength of bone tissue in children with osteogenesis imperfecta. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Short- and long-term modulation of synaptic inputs to brain reward areas by nicotine

    NARCIS (Netherlands)

    Fagen, Z.M.; Mansvelder, H.D.; Keath, R.; McGehee, D.S.

    2003-01-01

    Dopamine signaling in brain reward areas is a key element in the development of drug abuse and dependence. Recent anatomical and electrophysiological research has begun to elucidate both complexity and specificity In synaptic connections between ventral tegmental neurons and their inputs.

  2. Pushing synaptic vesicles over the RIM.

    Science.gov (United States)

    Kaeser, Pascal S

    2011-05-01

    In a presynaptic nerve terminal, neurotransmitter release is largely restricted to specialized sites called active zones. Active zones consist of a complex protein network, and they organize fusion of synaptic vesicles with the presynaptic plasma membrane in response to action potentials. Rab3-interacting molecules (RIMs) are central components of active zones. In a recent series of experiments, we have systematically dissected the molecular mechanisms by which RIMs operate in synaptic vesicle release. We found that RIMs execute two critical functions of active zones by virtue of independent protein domains. They tether presyanptic Ca(2+) channels to the active zone, and they activate priming of synaptic vesicles by monomerizing homodimeric, constitutively inactive Munc13. These data indicate that RIMs orchestrate synaptic vesicle release into a coherent process. In conjunction with previous studies, they suggest that RIMs form a molecular platform on which plasticity of synaptic vesicle release can operate.

  3. Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development.

    Science.gov (United States)

    Forcelli, Patrick A; Janssen, Megan J; Vicini, Stefano; Gale, Karen

    2012-09-01

    Drug exposure during critical periods of brain development may adversely affect nervous system function, posing a challenge for treating infants. This is of particular concern for treating neonatal seizures, as early life exposure to drugs such as phenobarbital is associated with adverse neurological outcomes in patients and induction of neuronal apoptosis in animal models. The functional significance of the preclinical neurotoxicity has been questioned due to the absence of evidence for functional impairment associated with drug-induced developmental apoptosis. We used patch-clamp recordings to examine functional synaptic maturation in striatal medium spiny neurons from neonatal rats exposed to antiepileptic drugs with proapoptotic action (phenobarbital, phenytoin, lamotrigine) and without proapoptotic action (levetiracetam). Phenobarbital-exposed rats were also assessed for reversal learning at weaning. Recordings from control animals revealed increased inhibitory and excitatory synaptic connectivity between postnatal day (P)10 and P18. This maturation was absent in rats exposed at P7 to a single dose of phenobarbital, phenytoin, or lamotrigine. Additionally, phenobarbital exposure impaired striatal-mediated behavior on P25. Neuroprotective pretreatment with melatonin, which prevents drug-induced neurodevelopmental apoptosis, prevented the drug-induced disruption in maturation. Levetiracetam was found not to disrupt synaptic development. Our results provide the first evidence that exposure to antiepileptic drugs during a sensitive postnatal period impairs physiological maturation of synapses in neurons that survive the initial drug insult. These findings suggest a mechanism by which early life exposure to antiepileptic drugs can impact cognitive and behavioral outcomes, underscoring the need to identify therapies that control seizures without compromising synaptic maturation. Copyright © 2012 American Neurological Association.

  4. Visual Stimulation Activates ERK in Synaptic and Somatic Compartments of Rat Cortical Neurons with Parallel Kinetics

    Science.gov (United States)

    Boggio, Elena M.; Putignano, Elena; Sassoè-Pognetto, Marco; Pizzorusso, Tommaso; Giustetto, Maurizio

    2007-01-01

    Background Extracellular signal-regulated kinase (ERK) signalling pathway plays a crucial role in regulating diverse neuronal processes, such as cell proliferation and differentiation, and long-term synaptic plasticity. However, a detailed understanding of the action of ERK in neurons is made difficult by the lack of knowledge about its subcellular localization in response to physiological stimuli. To address this issue, we have studied the effect of visual stimulation in vivo of dark-reared rats on the spatial-temporal dynamics of ERK activation in pyramidal neurons of the visual cortex. Methodology/Principal Findings Using immunogold electron microscopy, we show that phosphorylated ERK (pERK) is present in dendritic spines, both at synaptic and non-synaptic plasma membrane domains. Moreover, pERK is also detected in presynaptic axonal boutons forming connections with dendritic spines. Visual stimulation after dark rearing during the critical period causes a rapid increase in the number of pERK-labelled synapses in cortical layers I–II/III. This visually-induced activation of ERK at synaptic sites occurs in pre- and post-synaptic compartments and its temporal profile is identical to that of ERK activation in neuronal cell bodies. Conclusions/Significance Visual stimulation in vivo increases pERK expression at pre- and post-synaptic sites of axo-spinous junctions, suggesting that ERK plays an important role in the local modulation of synaptic function. The data presented here support a model in which pERK can have early and late actions both centrally in the cell nucleus and peripherally at synaptic contacts. PMID:17622349

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

    Science.gov (United States)

    Jia, Yan; Parker, David

    2016-01-01

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

  6. Activity-dependent synaptic plasticity modulates the critical phase of brain development.

    Science.gov (United States)

    Chaudhury, Sraboni; Sharma, Vikram; Kumar, Vivek; Nag, Tapas C; Wadhwa, Shashi

    2016-04-01

    Plasticity or neuronal plasticity is a unique and adaptive feature of nervous system which allows neurons to reorganize their interactions in response to an intrinsic or extrinsic stimulation and shapes the formation and maintenance of a functional neuronal circuit. Synaptic plasticity is the most important form of neural plasticity and plays critical role during the development allowing the formation of precise neural connectivity via the process of pruning. In the sensory systems-auditory and visual, this process is heavily dependent on the external cues perceived during the development. Environmental enrichment paradigms in an activity-dependent manner result in early maturation of the synapses and more efficient trans-synaptic signaling or communication flow. This has been extensively observed in the avian auditory system. On the other hand, stimuli results in negative effect can cause alterations in the synaptic connectivity and strength resulting in various developmental brain disorders including autism, fragile X syndrome and rett syndrome. In this review we discuss the role of different forms of activity (spontaneous or environmental) during the development of the nervous system in modifying synaptic plasticity necessary for shaping the adult brain. Also, we try to explore various factors (molecular, genetic and epigenetic) involved in altering the synaptic plasticity in positive and negative way. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  7. Synaptic and Cellular Organization of Layer 1 of the Developing Rat Somatosensory Cortex

    Directory of Open Access Journals (Sweden)

    Shruti eMuralidhar

    2014-01-01

    Full Text Available We have performed a systematic and quantitative study of the neuronal and synaptic organisation of neocortical layer 1 in the somatosensory cortex in juvenile rats (P13 – P16 using multi-neuron patch-clamp and 3D morphology reconstructions. We used both subjective expert based and objective classification to establish distinct morphological groups. According to expert based subjective classification, the neurons were classified into six morphological types: (1 the dense axon neurogliaform cell (NGC-DA and (2 a sparse axon neurogliaform cell (NGC-SA, (3 the horizontal axon cell (HAC and (4 those with descending axonal colaterals (DAC, (5 the large axon cell (LAC and (6 the small axon cell (SAC. We also used objective supervised and unsupervised analyses that confirmed 4 out of the 6 expert proposed groups, namely, DAC, HAC, LAC and a combined NGC. The cells were also classified into 5 electrophysiological types based on the Petilla convention; classical non-adapting (cNAC, burst non-adapting (bNAC, classical adapting (cAC, classical stuttering (cSTUT and classical irregular spiking (cIR. The most common electrophysiological type was the cNAC type (40% and the most commonly encountered morpho-electrical type of neuron was the NGC-DA - cNAC. Layer 1 cells are connected by GABAergic inhibitory synaptic connections with a 7.9% connection probability, as well gap junctions with 5.2% connection probability. Most synaptic connections were mediated by both GABAA and GABAB receptors (62.6%, as observed from the response characteristics to single pulse and train stimulations. A smaller fraction of synaptic connections were mediated exclusively by GABAA (15.4% or GABAB (21.8% receptors. Based on the morphological reconstructions, we found multi-synapse connections with an average of 9 putative synapses per connection. These putative touches were widely distributed with 39% on somata and 61% on dendrites.

  8. Models of Short-Term Synaptic Plasticity.

    Science.gov (United States)

    Barroso-Flores, Janet; Herrera-Valdez, Marco A; Galarraga, Elvira; Bargas, José

    2017-01-01

    We focus on dynamical descriptions of short-term synaptic plasticity. Instead of focusing on the molecular machinery that has been reviewed recently by several authors, we concentrate on the dynamics and functional significance of synaptic plasticity, and review some mathematical models that reproduce different properties of the dynamics of short term synaptic plasticity that have been observed experimentally. The complexity and shortcomings of these models point to the need of simple, yet physiologically meaningful models. We propose a simplified model to be tested in synapses displaying different types of short-term plasticity.

  9. Molecular mechanisms of synaptic remodeling in alcoholism.

    Science.gov (United States)

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-05

    Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal. Alcohol exerts a potent effect on synaptic plasticity and dendritic spine formation in specific brain regions, providing a neuroanatomical substrate for the pathophysiology of alcoholism. Epigenetics has recently emerged as a critical regulator of gene expression and synaptic plasticity-related events in the brain. Alcohol exposure and withdrawal induce changes in crucial epigenetic processes in the emotional brain circuitry (amygdala) that may be relevant to the negative affective state defined as the "dark side" of addiction. Here, we review the literature concerning synaptic plasticity and epigenetics, with a particular focus on molecular events related to dendritic remodeling during alcohol abuse and alcoholism. Targeting epigenetic processes that modulate synaptic plasticity may yield novel treatments for alcoholism. Published by Elsevier Ireland Ltd.

  10. Quantitative Proteomics of Synaptic and Nonsynaptic Mitochondria: Insights for Synaptic Mitochondrial Vulnerability

    Science.gov (United States)

    2015-01-01

    Synaptic mitochondria are essential for maintaining calcium homeostasis and producing ATP, processes vital for neuronal integrity and synaptic transmission. Synaptic mitochondria exhibit increased oxidative damage during aging and are more vulnerable to calcium insult than nonsynaptic mitochondria. Why synaptic mitochondria are specifically more susceptible to cumulative damage remains to be determined. In this study, the generation of a super-SILAC mix that served as an appropriate internal standard for mouse brain mitochondria mass spectrometry based analysis allowed for the quantification of the proteomic differences between synaptic and nonsynaptic mitochondria isolated from 10-month-old mice. We identified a total of 2260 common proteins between synaptic and nonsynaptic mitochondria of which 1629 were annotated as mitochondrial. Quantitative proteomic analysis of the proteins common between synaptic and nonsynaptic mitochondria revealed significant differential expression of 522 proteins involved in several pathways including oxidative phosphorylation, mitochondrial fission/fusion, calcium transport, and mitochondrial DNA replication and maintenance. In comparison to nonsynaptic mitochondria, synaptic mitochondria exhibited increased age-associated mitochondrial DNA deletions and decreased bioenergetic function. These findings provide insights into synaptic mitochondrial susceptibility to damage. PMID:24708184

  11. Inter-Synaptic Lateral Diffusion of GABAA Receptors Shapes Inhibitory Synaptic Currents.

    Science.gov (United States)

    de Luca, Emanuela; Ravasenga, Tiziana; Petrini, Enrica Maria; Polenghi, Alice; Nieus, Thierry; Guazzi, Stefania; Barberis, Andrea

    2017-07-05

    The lateral mobility of neurotransmitter receptors has been shown to tune synaptic signals. Here we report that GABAA receptors (GABAARs) can diffuse between adjacent dendritic GABAergic synapses in long-living desensitized states, thus laterally spreading "activation memories" between inhibitory synapses. Glutamatergic activity limits this inter-synaptic diffusion by trapping GABAARs at excitatory synapses. This novel form of activity-dependent hetero-synaptic interplay is likely to modulate dendritic synaptic signaling. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. Microanatomy of dendritic spines: emerging principles of synaptic pathology in psychiatric and neurological disease.

    Science.gov (United States)

    Blanpied, Thomas A; Ehlers, Michael D

    2004-06-15

    Psychiatric and neurologic disorders ranging from mental retardation to addiction are accompanied by structural and functional alterations of synaptic connections in the brain. Such alterations include abnormal density and morphology of dendritic spines, synapse loss, and aberrant synaptic signaling and plasticity. Recent work is revealing an unexpectedly complex biochemical and subcellular organization of dendritic spines. In this review, we highlight the molecular interplay between functional domains of the spine, including the postsynaptic density, the actin cytoskeleton, and membrane trafficking domains. This research points to an emerging level of analysis--a microanatomical understanding of synaptic physiology--that will be critical for discerning how synapses operate in normal physiologic states and for identifying and reversing microscopic changes in psychiatric and neurologic disease. Copyright 2004 Society of Biological Psychiatry

  13. Mapping sensory circuits by anterograde trans-synaptic transfer of recombinant rabies virus

    Science.gov (United States)

    Zampieri, Niccolò; Jessell, Thomas M.; Murray, Andrew J.

    2014-01-01

    Summary Primary sensory neurons convey information from the external world to relay circuits within the central nervous system (CNS), but the identity and organization of the neurons that process incoming sensory information remains sketchy. Within the CNS viral tracing techniques that rely on retrograde trans-synaptic transfer provide a powerful tool for delineating circuit organization. Viral tracing of the circuits engaged by primary sensory neurons has, however, been hampered by the absence of a genetically tractable anterograde transfer system. In this study we demonstrate that rabies virus can infect sensory neurons in the somatosensory system, is subject to anterograde trans-synaptic transfer from primary sensory to spinal target neurons, and can delineate output connectivity with third-order neurons. Anterograde trans-synaptic transfer is a feature shared by other classes of primary sensory neurons, permitting the identification and potentially the manipulation of neural circuits processing sensory feedback within the mammalian CNS. PMID:24486087

  14. Synaptic molecular imaging in spared and deprived columns of mouse barrel cortex with array tomography.

    Science.gov (United States)

    Weiler, Nicholas C; Collman, Forrest; Vogelstein, Joshua T; Burns, Randal; Smith, Stephen J

    2014-01-01

    A major question in neuroscience is how diverse subsets of synaptic connections in neural circuits are affected by experience dependent plasticity to form the basis for behavioral learning and memory. Differences in protein expression patterns at individual synapses could constitute a key to understanding both synaptic diversity and the effects of plasticity at different synapse populations. Our approach to this question leverages the immunohistochemical multiplexing capability of array tomography (ATomo) and the columnar organization of mouse barrel cortex to create a dataset comprising high resolution volumetric images of spared and deprived cortical whisker barrels stained for over a dozen synaptic molecules each. These dataset has been made available through the Open Connectome Project for interactive online viewing, and may also be downloaded for offline analysis using web, Matlab, and other interfaces.

  15. Motor unit recruitment strategies and muscle properties determine the influence of synaptic noise on force steadiness

    Science.gov (United States)

    Dideriksen, Jakob L.; Negro, Francesco; Enoka, Roger M.

    2012-01-01

    Motoneurons receive synaptic inputs from tens of thousands of connections that cause membrane potential to fluctuate continuously (synaptic noise), which introduces variability in discharge times of action potentials. We hypothesized that the influence of synaptic noise on force steadiness during voluntary contractions is limited to low muscle forces. The hypothesis was examined with an analytical description of transduction of motor unit spike trains into muscle force, a computational model of motor unit recruitment and rate coding, and experimental analysis of interspike interval variability during steady contractions with the abductor digiti minimi muscle. Simulations varied contraction force, level of synaptic noise, size of motor unit population, recruitment range, twitch contraction times, and level of motor unit short-term synchronization. Consistent with the analytical derivations, simulations and experimental data showed that force variability at target forces above a threshold was primarily due to low-frequency oscillations in neural drive, whereas the influence of synaptic noise was almost completely attenuated by two low-pass filters, one related to convolution of motoneuron spike trains with motor unit twitches (temporal summation) and the other attributable to summation of single motor unit forces (spatial summation). The threshold force above which synaptic noise ceased to influence force steadiness depended on recruitment range, size of motor unit population, and muscle contractile properties. This threshold was low (motor unit recruitment and muscle properties of a typical muscle are tuned to limit the influence of synaptic noise on force steadiness to low forces and that the inability to produce a constant force during stronger contractions is mainly attributable to the common low-frequency oscillations in motoneuron discharge rates. PMID:22423000

  16. Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders

    DEFF Research Database (Denmark)

    Mottahedin, Amin; Ardalan, Maryam; Chumak, Tetyana

    2017-01-01

    The brain is a plastic organ where both the intrinsic CNS milieu and extrinsic cues play important roles in shaping and wiring neural connections. The perinatal period constitutes a critical time in central nervous system development with extensive refinement of neural connections, which are highly...... physiology and pathophysiology, including microglia-mediated elimination of synapses. We propose that activation of the immune system dynamically affects synaptic organization and function in the developing brain. We will discuss the role of neuroinflammation in altered synaptic plasticity following...

  17. Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer's Disease.

    Science.gov (United States)

    Beckelman, Brenna C; Day, Stephen; Zhou, Xueyan; Donohue, Maggie; Gouras, Gunnar K; Klann, Eric; Keene, C Dirk; Ma, Tao

    2016-09-06

    Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer's disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets.

  18. Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity

    Science.gov (United States)

    Shin, Hyewon; van Riesen, Christoph; Whitcomb, Daniel; Warburton, Julia M.; Jo, Jihoon; Kim, Doyoun; Kim, Sun Gyun; Um, Seung Min; Kwon, Seok-kyu; Kim, Myoung-Hwan; Roh, Junyeop Daniel; Woo, Jooyeon; Jun, Heejung; Lee, Dongmin; Mah, Won; Kim, Hyun; Kaang, Bong-Kiun; Cho, Kwangwook; Rhee, Jeong-Seop; Choquet, Daniel; Kim, Eunjoon

    2016-01-01

    Summary Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms including trans-synaptic adhesion and recruitment of diverse synaptic proteins. We report here that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule preferentially expressed in the brain, is a novel and dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPAR glutamate receptors (AMPARs). IgSF11 requires PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilizes synaptic AMPARs, as shown by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high-throughput, single-molecule tracking. IgSF11 deletion in mice leads to suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long-term potentiation in the CA1 region of the hippocampus. IgSF11 does not regulate the functional characteristics of AMPARs, including desensitization, deactivation, or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs. PMID:26595655

  19. Functional connectivity for somatosensory and motor cortex in spastic diplegia.

    Science.gov (United States)

    Burton, Harold; Dixit, Sachin; Litkowski, Patricia; Wingert, Jason R

    2009-12-01

    Functional connectivity (fcMRI) was analyzed in individuals with spastic diplegia and age-matched controls. Pearson correlations (r-values) were computed between resting state spontaneous activity in selected seed regions (sROI) and each voxel throughout the brain. Seed ROI were centered on foci activated by tactile stimulation of the second fingertip in somatosensory and parietal dorsal attention regions. The group with diplegia showed significantly expanded networks for the somatomotor but not dorsal attention areas. These expanded networks overran nearly all topological representations in somatosensory and motor areas despite a sROI in a fingertip focus. A possible underlying cause for altered fcMRI in the group with dipegia, and generally sensorimotor deficits in spastic diplegia, is that prenatal third trimester white-matter injury leads to localized damage to subplate neurons. We hypothesize that intracortical connections become dominant in spastic diplegia through successful competition with diminished or absent thalamocortical inputs. Similar to the effects of subplate ablations on ocular dominance columns (Kanold and Shatz, Neuron 2006;51:627-638), a spike timing-dependent plasticity model is proposed to explain a shift towards intracortical inputs.

  20. Plasticity-Driven Self-Organization under Topological Constraints Accounts for Non-random Features of Cortical Synaptic Wiring.

    Science.gov (United States)

    Miner, Daniel; Triesch, Jochen

    2016-02-01

    Understanding the structure and dynamics of cortical connectivity is vital to understanding cortical function. Experimental data strongly suggest that local recurrent connectivity in the cortex is significantly non-random, exhibiting, for example, above-chance bidirectionality and an overrepresentation of certain triangular motifs. Additional evidence suggests a significant distance dependency to connectivity over a local scale of a few hundred microns, and particular patterns of synaptic turnover dynamics, including a heavy-tailed distribution of synaptic efficacies, a power law distribution of synaptic lifetimes, and a tendency for stronger synapses to be more stable over time. Understanding how many of these non-random features simultaneously arise would provide valuable insights into the development and function of the cortex. While previous work has modeled some of the individual features of local cortical wiring, there is no model that begins to comprehensively account for all of them. We present a spiking network model of a rodent Layer 5 cortical slice which, via the interactions of a few simple biologically motivated intrinsic, synaptic, and structural plasticity mechanisms, qualitatively reproduces these non-random effects when combined with simple topological constraints. Our model suggests that mechanisms of self-organization arising from a small number of plasticity rules provide a parsimonious explanation for numerous experimentally observed non-random features of recurrent cortical wiring. Interestingly, similar mechanisms have been shown to endow recurrent networks with powerful learning abilities, suggesting that these mechanism are central to understanding both structure and function of cortical synaptic wiring.

  1. Robust network oscillations during mammalian respiratory rhythm generation driven by synaptic dynamics

    Science.gov (United States)

    Guerrier, Claire; Hayes, John A.; Fortin, Gilles; Holcman, David

    2015-01-01

    How might synaptic dynamics generate synchronous oscillations in neuronal networks? We address this question in the preBötzinger complex (preBötC), a brainstem neural network that paces robust, yet labile, inspiration in mammals. The preBötC is composed of a few hundred neurons that alternate bursting activity with silent periods, but the mechanism underlying this vital rhythm remains elusive. Using a computational approach to model a randomly connected neuronal network that relies on short-term synaptic facilitation (SF) and depression (SD), we show that synaptic fluctuations can initiate population activities through recurrent excitation. We also show that a two-step SD process allows activity in the network to synchronize (bursts) and generate a population refractory period (silence). The model was validated against an array of experimental conditions, which recapitulate several processes the preBötC may experience. Consistent with the modeling assumptions, we reveal, by electrophysiological recordings, that SF/SD can occur at preBötC synapses on timescales that influence rhythmic population activity. We conclude that nondeterministic neuronal spiking and dynamic synaptic strengths in a randomly connected network are sufficient to give rise to regular respiratory-like rhythmic network activity and lability, which may play an important role in generating the rhythm for breathing and other coordinated motor activities in mammals. PMID:26195782

  2. Altered gene regulation and synaptic morphology in Drosophila learning and memory mutants

    Science.gov (United States)

    Guan, Zhuo; Buhl, Lauren K.; Quinn, William G.; Littleton, J. Troy

    2011-01-01

    Genetic studies in Drosophila have revealed two separable long-term memory pathways defined as anesthesia-resistant memory (ARM) and long-lasting long-term memory (LLTM). ARM is disrupted in radish (rsh) mutants, whereas LLTM requires CREB-dependent protein synthesis. Although the downstream effectors of ARM and LLTM are distinct, pathways leading to these forms of memory may share the cAMP cascade critical for associative learning. Dunce, which encodes a cAMP-specific phosphodiesterase, and rutabaga, which encodes an adenylyl cyclase, both disrupt short-term memory. Amnesiac encodes a pituitary adenylyl cyclase-activating peptide homolog and is required for middle-term memory. Here, we demonstrate that the Radish protein localizes to the cytoplasm and nucleus and is a PKA phosphorylation target in vitro. To characterize how these plasticity pathways may manifest at the synaptic level, we assayed synaptic connectivity and performed an expression analysis to detect altered transcriptional networks in rutabaga, dunce, amnesiac, and radish mutants. All four mutants disrupt specific aspects of synaptic connectivity at larval neuromuscular junctions (NMJs). Genome-wide DNA microarray analysis revealed ∼375 transcripts that are altered in these mutants, suggesting defects in multiple neuronal signaling pathways. In particular, the transcriptional target Lapsyn, which encodes a leucine-rich repeat cell adhesion protein, localizes to synapses and regulates synaptic growth. This analysis provides insights into the Radish-dependent ARM pathway and novel transcriptional targets that may contribute to memory processing in Drosophila. PMID:21422168

  3. Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels

    Directory of Open Access Journals (Sweden)

    Caixia Lv

    2016-06-01

    Full Text Available Synaptic ribbons are structures made largely of the protein Ribeye that hold synaptic vesicles near release sites in non-spiking cells in some sensory systems. Here, we introduce frameshift mutations in the two zebrafish genes encoding for Ribeye and thus remove Ribeye protein from neuromast hair cells. Despite Ribeye depletion, vesicles collect around ribbon-like structures that lack electron density, which we term “ghost ribbons.” Ghost ribbons are smaller in size but possess a similar number of smaller vesicles and are poorly localized to synapses and calcium channels. These hair cells exhibit enhanced exocytosis, as measured by capacitance, and recordings from afferent neurons post-synaptic to hair cells show no significant difference in spike rates. Our results suggest that Ribeye makes up most of the synaptic ribbon density in neuromast hair cells and is necessary for proper localization of calcium channels and synaptic ribbons.

  4. Ca2+-permeable AMPA receptors in homeostatic synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Hey-Kyoung eLee

    2012-02-01

    Full Text Available Neurons possess diverse mechanisms of homeostatic adaptation to overall changes in neural and synaptic activity, which are critical for proper brain functions. Homeostatic regulation of excitatory synapses has been studied in the context of synaptic scaling, which allows neurons to adjust their excitatory synaptic gain to maintain their activity within a dynamic range. Recent evidence suggests that one of the main mechanisms underlying synaptic scaling is by altering the function of postsynaptic AMPA receptors (AMPARs, including synaptic expression of Ca2+-permeable (CP- AMPARs. CP-AMPARs endow synapses with unique properties, which may benefit adaptation of neurons to periods of inactivity as would occur when a major input is lost. This review will summarize how synaptic expression of CP-AMPARs is regulated during homeostatic synaptic plasticity in the context of synaptic scaling, and will address the potential functional consequences of altering synaptic CP-AMPAR content.

  5. Diacylglycerol Kinases in the Coordination of Synaptic Plasticity.

    Science.gov (United States)

    Lee, Dongwon; Kim, Eunjoon; Tanaka-Yamamoto, Keiko

    2016-01-01

    Synaptic plasticity is activity-dependent modification of the efficacy of synaptic transmission. Although, detailed mechanisms underlying synaptic plasticity are diverse and vary at different types of synapses, diacylglycerol (DAG)-associated signaling has been considered as an important regulator of many forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Recent evidences indicate that DAG kinases (DGKs), which phosphorylate DAG to phosphatidic acid to terminate DAG signaling, are important regulators of LTP and LTD, as supported by the results from mice lacking specific DGK isoforms. This review will summarize these studies and discuss how specific DGK isoforms distinctly regulate different forms of synaptic plasticity at pre- and postsynaptic sites. In addition, we propose a general role of DGKs as coordinators of synaptic plasticity that make local synaptic environments more permissive for synaptic plasticity by regulating DAG concentration and interacting with other synaptic proteins.

  6. Synaptic Correlates of Working Memory Capacity.

    Science.gov (United States)

    Mi, Yuanyuan; Katkov, Mikhail; Tsodyks, Misha

    2017-01-18

    Psychological studies indicate that human ability to keep information in readily accessible working memory is limited to four items for most people. This extremely low capacity severely limits execution of many cognitive tasks, but its neuronal underpinnings remain unclear. Here we show that in the framework of synaptic theory of working memory, capacity can be analytically estimated to scale with characteristic time of short-term synaptic depression relative to synaptic current time constant. The number of items in working memory can be regulated by external excitation, enabling the system to be tuned to the desired load and to clear the working memory of currently held items to make room for new ones. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Astrocytes optimize the synaptic transmission of information.

    Directory of Open Access Journals (Sweden)

    Suhita Nadkarni

    2008-05-01

    Full Text Available Chemical synapses transmit information via the release of neurotransmitter-filled vesicles from the presynaptic terminal. Using computational modeling, we predict that the limited availability of neurotransmitter resources in combination with the spontaneous release of vesicles limits the maximum degree of enhancement of synaptic transmission. This gives rise to an optimal tuning that depends on the number of active zones. There is strong experimental evidence that astrocytes that enwrap synapses can modulate the probabilities of vesicle release through bidirectional signaling and hence regulate synaptic transmission. For low-fidelity hippocampal synapses, which typically have only one or two active zones, the predicted optimal values lie close to those determined by experimentally measured astrocytic feedback, suggesting that astrocytes optimize synaptic transmission of information.

  8. Heterosynaptic Plasticity Prevents Runaway Synaptic Dynamics

    Science.gov (United States)

    Chen, Jen-Yung; Lonjers, Peter; Lee, Christopher; Chistiakova, Marina; Volgushev, Maxim

    2013-01-01

    Spike timing-dependent plasticity (STDP) and other conventional Hebbian-type plasticity rules are prone to produce runaway dynamics of synaptic weights. Once potentiated, a synapse would have higher probability to lead to spikes and thus to be further potentiated, but once depressed, a synapse would tend to be further depressed. The runaway synaptic dynamics can be prevented by precisely balancing STDP rules for potentiation and depression; however, experimental evidence shows a great variety of potentiation and depression windows and magnitudes. Here we show that modifications of synapses to layer 2/3 pyramidal neurons from rat visual and auditory cortices in slices can be induced by intracellular tetanization: bursts of postsynaptic spikes without presynaptic stimulation. Induction of these heterosynaptic changes depended on the rise of intracellular calcium, and their direction and magnitude correlated with initial state of release mechanisms. We suggest that this type of plasticity serves as a mechanism that stabilizes the distribution of synaptic weights and prevents their runaway dynamics. To test this hypothesis, we develop a cortical neuron model implementing both homosynaptic (STDP) and heterosynaptic plasticity with properties matching the experimental data. We find that heterosynaptic plasticity effectively prevented runaway dynamics for the tested range of STDP and input parameters. Synaptic weights, although shifted from the original, remained normally distributed and nonsaturated. Our study presents a biophysically constrained model of how the interaction of different forms of plasticity—Hebbian and heterosynaptic—may prevent runaway synaptic dynamics and keep synaptic weights unsaturated and thus capable of further plastic changes and formation of new memories. PMID:24089497

  9. Paired-Pulse TMS and Fine-Wire Recordings Reveal Short-Interval Intracortical Inhibition and Facilitation of Deep Multifidus Muscle Fascicles.

    Directory of Open Access Journals (Sweden)

    Hugo Massé-Alarie

    Full Text Available Paired-pulse transcranial magnetic stimulation (ppTMS is used to probe inhibitory and excitatory networks within the primary motor cortex (M1. These mechanisms are identified for limb muscles but it is unclear whether they share properties with trunk muscles. The aim was to determine whether it was possible to test the intracortical inhibition and facilitation of the deep multifidus muscle fascicles (DM and at which inter-stimulus intervals (ISI.In ten pain-free individuals, TMS was applied over M1 and motor evoked potentials (MEP were recorded using fine-wire electrodes in DM. MEPs were conditioned with subthreshold stimuli at ISIs of 1 to 12 ms to test short-interval intracortical inhibition (SICI and at 15 ms for long-interval intracortical facilitation. Short-interval facilitation (SICF was tested using 1-ms ISI.SICI of DM was consistently obtained with ISI of 1-, 3-, 4- and 12-ms. Facilitation of DM MEP was only identified using SICF paradigm.A similar pattern of MEP modulation with ISI changes for deep trunk and limb muscles implies that M1 networks share some functional properties.The ppTMS paradigm presents a potential to determine how M1 inhibitory and excitatory mechanisms participate in brain re-organization in back pain that affects control of trunk muscles.

  10. Disruption of an Evolutionarily Novel Synaptic Expression Pattern in Autism.

    Directory of Open Access Journals (Sweden)

    Xiling Liu

    2016-09-01

    Full Text Available Cognitive defects in autism spectrum disorder (ASD include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans.

  11. Disruption of an Evolutionarily Novel Synaptic Expression Pattern in Autism

    Science.gov (United States)

    Jiang, Xi; Hu, Haiyang; Guijarro, Patricia; Mitchell, Amanda; Ely, John J.; Sherwood, Chet C.; Hof, Patrick R.; Qiu, Zilong; Pääbo, Svante; Akbarian, Schahram; Khaitovich, Philipp

    2016-01-01

    Cognitive defects in autism spectrum disorder (ASD) include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR) transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans. PMID:27685936

  12. Extracellular ATP hydrolysis inhibits synaptic transmission by increasing ph buffering in the synaptic cleft.

    Directory of Open Access Journals (Sweden)

    Rozan Vroman

    2014-05-01

    Full Text Available Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms, highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca²⁺ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form

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

    Directory of Open Access Journals (Sweden)

    Frédéric eLavigne

    2014-08-01

    Full Text Available 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.

  14. "The seven sins" of the Hebbian synapse: can the hypothesis of synaptic plasticity explain long-term memory consolidation?

    Science.gov (United States)

    Arshavsky, Yuri I

    2006-10-01

    Memorizing new facts and events means that entering information produces specific physical changes within the brain. According to the commonly accepted view, traces of memory are stored through the structural modifications of synaptic connections, which result in changes of synaptic efficiency and, therefore, in formations of new patterns of neural activity (the hypothesis of synaptic plasticity). Most of the current knowledge on learning and initial stages of memory consolidation ("synaptic consolidation") is based on this hypothesis. However, the hypothesis of synaptic plasticity faces a number of conceptual and experimental difficulties when it deals with potentially permanent consolidation of declarative memory ("system consolidation"). These difficulties are rooted in the major intrinsic self-contradiction of the hypothesis: stable declarative memory is unlikely to be based on such a non-stable foundation as synaptic plasticity. Memory that can last throughout an entire lifespan should be "etched in stone." The only "stone-like" molecules within living cells are DNA molecules. Therefore, I advocate an alternative, genomic hypothesis of memory, which suggests that acquired information is persistently stored within individual neurons through modifications of DNA, and that these modifications serve as the carriers of elementary memory traces.

  15. The role of sleep in regulating structural plasticity and synaptic strength: Implications for memory and cognitive function.

    Science.gov (United States)

    Raven, Frank; Van der Zee, Eddy A; Meerlo, Peter; Havekes, Robbert

    2017-05-18

    Dendritic spines are the major sites of synaptic transmission in the central nervous system. Alterations in the strength of synaptic connections directly affect the neuronal communication, which is crucial for brain function as well as the processing and storage of information. Sleep and sleep loss bidirectionally alter structural plasticity, by affecting spine numbers and morphology, which ultimately can affect the functional output of the brain in terms of alertness, cognition, and mood. Experimental data from studies in rodents suggest that sleep deprivation may impact structural plasticity in different ways. One of the current views, referred to as the synaptic homeostasis hypothesis, suggests that wake promotes synaptic potentiation whereas sleep facilitates synaptic downscaling. On the other hand, several studies have now shown that sleep deprivation can reduce spine density and attenuate synaptic efficacy in the hippocampus. These data are the basis for the view that sleep promotes hippocampal structural plasticity critical for memory formation. Altogether, the impact of sleep and sleep loss may vary between regions of the brain. A better understanding of the role that sleep plays in regulating structural plasticity may ultimately lead to novel therapeutic approaches for brain disorders that are accompanied by sleep disturbances and sleep loss. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Attenuation of inhibitory synaptic transmission by glial dysfunction in rat thalamus

    OpenAIRE

    Yang, Sunggu; Cox, Charles L.

    2011-01-01

    The thalamus serves as the obligatory gateway to the neocortex for sensory processing, and also serves as a pathway for corticocortical communication. In addition, the reciprocal synaptic connectivity between the thalamic reticular nucleus (TRN) and adjacent thalamic relay nuclei generates rhythmic activities similar to that observed during different arousal states and certain neurological conditions such as absence epilepsy. Epileptiform activity can arise from a variety of neural mechanisms...

  17. The Less Things Change, the More They Are Different: Contributions of Long-Term Synaptic Plasticity and Homeostasis to Memory

    Science.gov (United States)

    Schacher, Samuel; Hu, Jiang-Yuan

    2014-01-01

    An important cellular mechanism contributing to the strength and duration of memories is activity-dependent alterations in the strength of synaptic connections within the neural circuit encoding the memory. Reversal of the memory is typically correlated with a reversal of the cellular changes to levels expressed prior to the stimulation. Thus, for…

  18. Flexible Proton-Gated Oxide Synaptic Transistors on Si Membrane.

    Science.gov (United States)

    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.

  19. Rapid neural circuit switching mediated by synaptic plasticity during neural morphallactic regeneration.

    Science.gov (United States)

    Lybrand, Zane R; Zoran, Mark J

    2012-09-01

    The aquatic oligochaete, Lumbriculus variegatus (Lumbriculidae), undergoes a rapid regenerative transformation of its neural circuits following body fragmentation. This type of nervous system plasticity, called neural morphallaxis, involves the remodeling of the giant fiber pathways that mediate rapid head and tail withdrawal behaviors. Extra- and intracellular electrophysiological recordings demonstrated that changes in cellular properties and synaptic connections underlie neurobehavioral plasticity during morphallaxis. Sensory-to-giant interneuron connections, undetectable prior to body injury, emerged within hours of segment amputation. The appearance of functional synaptic transmission was followed by interneuron activation, coupling of giant fiber spiking to motor outputs and overt segmental shortening. The onset of morphallactic plasticity varied along the body axis and emerged more rapidly in segments closer to regions of sensory field overlap between the two giant fiber pathways. The medial and lateral giant fibers were simultaneously activated during a transient phase of network remodeling. Thus, synaptic plasticity at sensory-to-giant interneuron connections mediates escape circuit morphallaxis in this regenerating annelid worm. Copyright © 2011 Wiley Periodicals, Inc.

  20. Enhancement of signal sensitivity in a heterogeneous neural network refined from synaptic plasticity

    Energy Technology Data Exchange (ETDEWEB)

    Li Xiumin; Small, Michael, E-mail: ensmall@polyu.edu.h, E-mail: 07901216r@eie.polyu.edu.h [Department of Electronic and Information Engineering, Hong Kong Polytechnic University, Hung Hom, Kowloon (Hong Kong)

    2010-08-15

    Long-term synaptic plasticity induced by neural activity is of great importance in informing the formation of neural connectivity and the development of the nervous system. It is reasonable to consider self-organized neural networks instead of prior imposition of a specific topology. In this paper, we propose a novel network evolved from two stages of the learning process, which are respectively guided by two experimentally observed synaptic plasticity rules, i.e. the spike-timing-dependent plasticity (STDP) mechanism and the burst-timing-dependent plasticity (BTDP) mechanism. Due to the existence of heterogeneity in neurons that exhibit different degrees of excitability, a two-level hierarchical structure is obtained after the synaptic refinement. This self-organized network shows higher sensitivity to afferent current injection compared with alternative archetypal networks with different neural connectivity. Statistical analysis also demonstrates that it has the small-world properties of small shortest path length and high clustering coefficients. Thus the selectively refined connectivity enhances the ability of neuronal communications and improves the efficiency of signal transmission in the network.

  1. Changes in corticomotor excitability and intracortical inhibition of the primary motor cortex forearm area induced by anodal tDCS.

    Directory of Open Access Journals (Sweden)

    Xue Zhang

    Full Text Available OBJECTIVE: Previous studies have investigated how tDCS over the primary motor cortex modulates excitability in the intrinsic hand muscles. Here, we tested if tDCS changes corticomotor excitability and/or cortical inhibition when measured in the extensor carpi radialis (ECR and if these aftereffects can be successfully assessed during controlled muscle contraction. METHODS: We implemented a double blind cross-over design in which participants (n = 16 completed two sessions where the aftereffects of 20 min of 1 mA (0.04 mA/cm2 anodal vs sham tDCS were tested in a resting muscle, and two more sessions where the aftereffects of anodal vs sham tDCS were tested in an active muscle. RESULTS: Anodal tDCS increased corticomotor excitability in ECR when aftereffects were measured with a low-level controlled muscle contraction. Furthermore, anodal tDCS decreased short interval intracortical inhibition but only when measured at rest and after non-responders (n = 2 were removed. We found no changes in the cortical silent period. CONCLUSION: These findings suggest that targeting more proximal muscles in the upper limb with anodal tDCS is achievable and corticomotor excitability can be assessed in the presence of a low-level controlled contraction of the target muscle.

  2. Synaptic plasticity and the warburg effect

    KAUST Repository

    Magistretti, Pierre J.

    2014-01-01

    Functional brain imaging studies show that in certain brain regions glucose utilization exceeds oxygen consumption, indicating the predominance of aerobic glycolysis. In this issue, Goyal et al. (2014) report that this metabolic profile is associated with an enrichment in the expression of genes involved in synaptic plasticity and remodeling processes. © 2014 Elsevier Inc.

  3. P2X Receptors and Synaptic Plasticity

    Czech Academy of Sciences Publication Activity Database

    Pankratov, Y.; Lalo, U.; Krishtal, A.; Verkhratsky, Alexei

    2009-01-01

    Roč. 158, č. 1 (2009), s. 137-148 ISSN 0306-4522 Institutional research plan: CEZ:AV0Z50390512 Keywords : ATP * P2X receptors * synaptic plasticity Subject RIV: FH - Neurology Impact factor: 3.292, year: 2009

  4. Neuronal cytoskeleton in synaptic plasticity and regeneration.

    Science.gov (United States)

    Gordon-Weeks, Phillip R; Fournier, Alyson E

    2014-04-01

    During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo-dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre- and post-synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system. © 2013 International Society for Neurochemistry.

  5. Connected Traveler

    Energy Technology Data Exchange (ETDEWEB)

    Schroeder, Alex

    2015-11-01

    The Connected Traveler project is a multi-disciplinary undertaking that seeks to validate potential for transformative transportation system energy savings by incentivizing efficient traveler behavior. This poster outlines various aspects of the Connected Traveler project, including market opportunity, understanding traveler behavior and decision-making, automation and connectivity, and a projected timeline for Connected Traveler's key milestones.

  6. Basic mechanisms for recognition and transport of synaptic cargos

    NARCIS (Netherlands)

    M.A. Schlager (Max); C.C. Hoogenraad (Casper)

    2009-01-01

    textabstractSynaptic cargo trafficking is essential for synapse formation, function and plasticity. In order to transport synaptic cargo, such as synaptic vesicle precursors, mitochondria, neurotransmitter receptors and signaling proteins to their site of action, neurons make use of molecular motor

  7. Bilinearity in spatiotemporal integration of synaptic inputs.

    Directory of Open Access Journals (Sweden)

    Songting Li

    2014-12-01

    Full Text Available 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 [Formula: see text]. 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 [Formula: see text] 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.

  8. Differential regulation of synaptic AP-2/clathrin vesicle uncoating in synaptic plasticity.

    Science.gov (United States)

    Candiello, Ermes; Mishra, Ratnakar; Schmidt, Bernhard; Jahn, Olaf; Schu, Peter

    2017-11-17

    AP-1/σ1B-deficiency causes X-linked intellectual disability. AP-1/σ1B -/- mice have impaired synaptic vesicle recycling, fewer synaptic vesicles and enhanced endosome maturation mediated by AP-1/σ1A. Despite defects in synaptic vesicle recycling synapses contain two times more endocytic AP-2 clathrin-coated vesicles. We demonstrate increased formation of two classes of AP-2/clathrin coated vesicles. One which uncoats readily and a second with a stabilised clathrin coat. Coat stabilisation is mediated by three molecular mechanisms: reduced recruitment of Hsc70 and synaptojanin1 and enhanced μ2/AP-2 phosphorylation and activation. Stabilised AP-2 vesicles are enriched in the structural active zone proteins Git1 and stonin2 and synapses contain more Git1. Endocytosis of the synaptic vesicle exocytosis regulating Munc13 isoforms are differentially effected. Regulation of synaptic protein endocytosis by the differential stability of AP-2/clathrin coats is a novel molecular mechanism of synaptic plasticity.

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

    Science.gov (United States)

    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

  10. Brain-like associative learning using a nanoscale non-volatile phase change synaptic device array

    Directory of Open Access Journals (Sweden)

    Sukru Burc Eryilmaz

    2014-07-01

    Full Text Available Recent advances in neuroscience together with nanoscale electronic device technology have resulted in huge interests in realizing brain-like computing hardwares using emerging nanoscale memory devices as synaptic elements. Although there has been experimental work that demonstrated the operation of nanoscale synaptic element at the single device level, network level studies have been limited to simulations. In this work, we demonstrate, using experiments, array level associative learning using phase change synaptic devices connected in a grid like configuration similar to the organization of the biological brain. Implementing Hebbian learning with phase change memory cells, the synaptic grid was able to store presented patterns and recall missing patterns in an associative brain-like fashion. We found that the system is robust to device variations, and large variations in cell resistance states can be accommodated by increasing the number of training epochs. We illustrated the tradeoff between variation tolerance of the network and the overall energy consumption, and found that energy consumption is decreased significantly for lower variation tolerance.

  11. The Roles of Protein Expression in Synaptic Plasticity and Memory Consolidation

    Directory of Open Access Journals (Sweden)

    Tali eRosenberg

    2014-11-01

    Full Text Available The amount and availability of proteins are regulated by their synthesis, degradation, and transport. These processes can specifically, locally, and temporally regulate a protein or a population of proteins, thus affecting numerous biological processes in health and disease states. Accordingly, malfunction in the processes of protein turnover and localization underlies different neuronal diseases. However, as early as a century ago, it was recognized that there is a specific need for normal macromolecular synthesis in a specific fragment of the learning process, memory consolidation, which takes place minutes to hours following acquisition. Memory consolidation is the process by which fragile short-term memory is converted into stable long-term memory. It is accepted today that synaptic plasticity is a cellular mechanism of learning and memory processes. Interestingly, similar molecular mechanisms subserve both memory and synaptic plasticity consolidation. In this review, we survey the current view on the connection between memory consolidation processes and proteostasis, i.e., maintaining the protein contents at the neuron and the synapse. In addition, we describe the technical obstacles and possible new methods to determine neuronal proteostasis of synaptic function and better explain the process of memory and synaptic plasticity consolidation.

  12. Complement emerges as a masterful regulator of CNS homeostasis, neural synaptic plasticity and cognitive function.

    Science.gov (United States)

    Mastellos, Dimitrios C

    2014-11-01

    Growing evidence points to a previously elusive role of complement-modulated pathways in CNS development, neurogenesis and synaptic plasticity. Distinct complement effectors appear to play a multifaceted role in brain homeostasis by regulating synaptic pruning in the retinogeniculate system and sculpting functional neural circuits both in the developing and adult mammalian brain. A recent study by Perez-Alcazar et al. (2014) provides novel insights into this intricate interplay between complement and the dynamically regulated brain synaptic circuitry, by reporting that mice deficient in C3 exhibit enhanced hippocampus-dependent spatial learning and cognitive performance. This behavioral pattern is associated with an impact of C3 on the functional capacity of glutamatergic synapses, supporting a crucial role for complement in excitatory synapse elimination in the hippocampus. These findings add a fresh twist to this rapidly evolving research field, suggesting that discrete complement components may differentially modulate synaptic connectivity by wiring up with diverse neural effectors in different regions of the brain. The emerging role of complement in synaptogenesis and neural network plasticity opens new conceptual avenues for considering complement interception as a potential therapeutic modality for ameliorating progressive cognitive impairment in age-related, debilitating brain diseases with a prominent inflammatory signature. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Predicting seizure by modeling synaptic plasticity based on EEG signals - a case study of inherited epilepsy

    Science.gov (United States)

    Zhang, Honghui; Su, Jianzhong; Wang, Qingyun; Liu, Yueming; Good, Levi; Pascual, Juan M.

    2018-03-01

    This paper explores the internal dynamical mechanisms of epileptic seizures through quantitative modeling based on full brain electroencephalogram (EEG) signals. Our goal is to provide seizure prediction and facilitate treatment for epileptic patients. Motivated by an earlier mathematical model with incorporated synaptic plasticity, we studied the nonlinear dynamics of inherited seizures through a differential equation model. First, driven by a set of clinical inherited electroencephalogram data recorded from a patient with diagnosed Glucose Transporter Deficiency, we developed a dynamic seizure model on a system of ordinary differential equations. The model was reduced in complexity after considering and removing redundancy of each EEG channel. Then we verified that the proposed model produces qualitatively relevant behavior which matches the basic experimental observations of inherited seizure, including synchronization index and frequency. Meanwhile, the rationality of the connectivity structure hypothesis in the modeling process was verified. Further, through varying the threshold condition and excitation strength of synaptic plasticity, we elucidated the effect of synaptic plasticity to our seizure model. Results suggest that synaptic plasticity has great effect on the duration of seizure activities, which support the plausibility of therapeutic interventions for seizure control.

  14. Age-related synaptic loss of the medial olivocochlear efferent innervation

    Directory of Open Access Journals (Sweden)

    Schrader Angela

    2010-11-01

    Full Text Available Abstract Age-related functional decline of the nervous system is consistently observed, though cellular and molecular events responsible for this decline remain largely unknown. One of the most prevalent age-related functional declines is age-related hearing loss (presbycusis, a major cause of which is the loss of outer hair cells (OHCs and spiral ganglion neurons. Previous studies have also identified an age-related functional decline in the medial olivocochlear (MOC efferent system prior to age-related loss of OHCs. The present study evaluated the hypothesis that this functional decline of the MOC efferent system is due to age-related synaptic loss of the efferent innervation of the OHCs. To this end, we used a recently-identified transgenic mouse line in which the expression of yellow fluorescent protein (YFP, under the control of neuron-specific elements from the thy1 gene, permits the visualization of the synaptic connections between MOC efferent fibers and OHCs. In this model, there was a dramatic synaptic loss between the MOC efferent fibers and the OHCs in older mice. However, age-related loss of efferent synapses was independent of OHC status. These data demonstrate for the first time that age-related loss of efferent synapses may contribute to the functional decline of the MOC efferent system and that this synaptic loss is not necessary for age-related loss of OHCs.

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

    Directory of Open Access Journals (Sweden)

    Christian Keck

    Full Text Available 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.

  16. Predicting seizure by modeling synaptic plasticity based on EEG signals - a case study of inherited epilepsy.

    Science.gov (United States)

    Zhang, Honghui; Su, Jianzhong; Wang, Qingyun; Liu, Yueming; Good, Levi; Pascual, Juan

    2018-03-01

    This paper explores the internal dynamical mechanisms of epileptic seizures through quantitative modeling based on full brain electroencephalogram (EEG) signals. Our goal is to provide seizure prediction and facilitate treatment for epileptic patients. Motivated by an earlier mathematical model with incorporated synaptic plasticity, we studied the nonlinear dynamics of inherited seizures through a differential equation model. First, driven by a set of clinical inherited electroencephalogram data recorded from a patient with diagnosed Glucose Transporter Deficiency, we developed a dynamic seizure model on a system of ordinary differential equations. The model was reduced in complexity after considering and removing redundancy of each EEG channel. Then we verified that the proposed model produces qualitatively relevant behavior which matches the basic experimental observations of inherited seizure, including synchronization index and frequency. Meanwhile, the rationality of the connectivity structure hypothesis in the modeling process was verified. Further, through varying the threshold condition and excitation strength of synaptic plasticity, we elucidated the effect of synaptic plasticity to our seizure model. Results suggest that synaptic plasticity has great effect on the duration of seizure activities, which support the plausibility of therapeutic interventions for seizure control.

  17. Stochastic single-molecule dynamics of synaptic membrane protein domains

    Science.gov (United States)

    Kahraman, Osman; Li, Yiwei; Haselwandter, Christoph A.

    2016-09-01

    Motivated by single-molecule experiments on synaptic membrane protein domains, we use a stochastic lattice model to study protein reaction and diffusion processes in crowded membranes. We find that the stochastic reaction-diffusion dynamics of synaptic proteins provide a simple physical mechanism for collective fluctuations in synaptic domains, the molecular turnover observed at synaptic domains, key features of the single-molecule trajectories observed for synaptic proteins, and spatially inhomogeneous protein lifetimes at the cell membrane. Our results suggest that central aspects of the single-molecule and collective dynamics observed for membrane protein domains can be understood in terms of stochastic reaction-diffusion processes at the cell membrane.

  18. Estimating short-term synaptic plasticity from pre- and postsynaptic spiking

    Science.gov (United States)

    Malyshev, Aleksey; Stevenson, Ian H.

    2017-01-01

    Short-term synaptic plasticity (STP) critically affects the processing of information in neuronal circuits by reversibly changing the effective strength of connections between neurons on time scales from milliseconds to a few seconds. STP is traditionally studied using intracellular recordings of postsynaptic potentials or currents evoked by presynaptic spikes. However, STP also affects the statistics of postsynaptic spikes. Here we present two model-based approaches for estimating synaptic weights and short-term plasticity from pre- and postsynaptic spike observations alone. We extend a generalized linear model (GLM) that predicts postsynaptic spiking as a function of the observed pre- and postsynaptic spikes and allow the connection strength (coupling term in the GLM) to vary as a function of time based on the history of presynaptic spikes. Our first model assumes that STP follows a Tsodyks-Markram description of vesicle depletion and recovery. In a second model, we introduce a functional description of STP where we estimate the coupling term as a biophysically unrestrained function of the presynaptic inter-spike intervals. To validate the models, we test the accuracy of STP estimation using the spiking of pre- and postsynaptic neurons with known synaptic dynamics. We first test our models using the responses of layer 2/3 pyramidal neurons to simulated presynaptic input with different types of STP, and then use simulated spike trains to examine the effects of spike-frequency adaptation, stochastic vesicle release, spike sorting errors, and common input. We find that, using only spike observations, both model-based methods can accurately reconstruct the time-varying synaptic weights of presynaptic inputs for different types of STP. Our models also capture the differences in postsynaptic spike responses to presynaptic spikes following short vs long inter-spike intervals, similar to results reported for thalamocortical connections. These models may thus be useful

  19. Mitochondria are critical for BDNF-mediated Synaptic and Vascular plasticity of Hippocampus following Repeated Electroconvulsive Seizures

    DEFF Research Database (Denmark)

    Chen, Fenghua; Ardalan, Maryam; Elfving, Betina

    2017-01-01

    Background: Electroconvulsive therapy (ECT) is a fast acting and efficient treatment of depression used in the clinic. The underlying mechanism of its therapeutic effect is still unclear. However, recovery of synaptic connections and synaptic remodeling is thought to play a critical role...... electroconvulsive seizures (ECS), an animal model of ECT. Methods: ECS or sham treatment was given daily for 10 days to rats displaying a genetically driven phenotype modelling clinical depression: the Flinders Sensitive and Resistant Line (FSL/FRL) rats. Stereological principles were employed to quantify numbers...

  20. Influence of Synaptic Depression on Memory Storage Capacity

    Science.gov (United States)

    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.

  1. Carbon Nanotube Synaptic Transistor Network for Pattern Recognition.

    Science.gov (United States)

    Kim, Sungho; Yoon, Jinsu; Kim, Hee-Dong; Choi, Sung-Jin

    2015-11-18

    Inspired by the human brain, a neuromorphic system combining complementary metal-oxide semiconductor (CMOS) and adjustable synaptic devices may offer new computing paradigms by enabling massive neural-network parallelism. In particular, synaptic devices, which are capable of emulating the functions of biological synapses, are used as the essential building blocks for an information storage and processing system. However, previous synaptic devices based on two-terminal resistive devices remain challenging because of their variability and specific physical mechanisms of resistance change, which lead to a bottleneck in the implementation of a high-density synaptic device network. Here we report that a three-terminal synaptic transistor based on carbon nanotubes can provide reliable synaptic functions that encode relative timing and regulate weight change. In addition, using system-level simulations, the developed synaptic transistor network associated with CMOS circuits can perform unsupervised learning for pattern recognition using a simplified spike-timing-dependent plasticity scheme.

  2. Tripartite synapses: astrocytes process and control synaptic information.

    Science.gov (United States)

    Perea, Gertrudis; Navarrete, Marta; Araque, Alfonso

    2009-08-01

    The term 'tripartite synapse' refers to a concept in synaptic physiology based on the demonstration of the existence of bidirectional communication between astrocytes and neurons. Consistent with this concept, in addition to the classic 'bipartite' information flow between the pre- and postsynaptic neurons, astrocytes exchange information with the synaptic neuronal elements, responding to synaptic activity and, in turn, regulating synaptic transmission. Because recent evidence has demonstrated that astrocytes integrate and process synaptic information and control synaptic transmission and plasticity, astrocytes, being active partners in synaptic function, are cellular elements involved in the processing, transfer and storage of information by the nervous system. Consequently, in contrast to the classically accepted paradigm that brain function results exclusively from neuronal activity, there is an emerging view, which we review herein, in which brain function actually arises from the coordinated activity of a network comprising both neurons and glia.

  3. The Duration of Motor Responses Evoked with Intracortical Microstimulation in Rats Is Primarily Modulated by Stimulus Amplitude and Train Duration.

    Directory of Open Access Journals (Sweden)

    Meghan Watson

    Full Text Available Microstimulation of brain tissue plays a key role in a variety of sensory prosthetics, clinical therapies and research applications, however the effects of stimulation parameters on the responses they evoke remain widely unknown. In particular, the effects of parameters when delivered in the form of a stimulus train as opposed to a single pulse are not well understood despite the prevalence of stimulus train use. We aimed to investigate the contribution of each parameter of a stimulus train to the duration of the motor responses they evoke in forelimb muscles. We used constant-current, biphasic, square wave pulse trains in acute terminal experiments under ketamine anaesthesia. Stimulation parameters were systematically tested in a pair-wise fashion in the caudal forelimb region of the motor cortex in 7 Sprague-Dawley rats while motor evoked potential (MEP recordings from the forelimb were used to quantify the influence of each parameter in the train. Stimulus amplitude and train duration were shown to be the dominant parameters responsible for increasing the total duration of the MEP, while interphase interval had no effect. Increasing stimulus frequency from 100-200 Hz or pulse duration from 0.18-0.34 ms were also effective methods of extending response durations. Response duration was strongly correlated with peak time and amplitude. Our findings suggest that motor cortex intracortical microstimulations are often conducted at a higher frequency rate and longer train duration than necessary to evoke maximal response duration. We demonstrated that the temporal properties of the evoked response can be both predicted by certain response metrics and modulated via alterations to the stimulation signal parameters.

  4. Age-related mapping of intracortical myelin from late adolescence to middle adulthood using T1-weighted MRI.

    Science.gov (United States)

    Rowley, Christopher D; Sehmbi, Manpreet; Bazin, Pierre-Louis; Tardif, Christine L; Minuzzi, Luciano; Frey, Benicio N; Bock, Nicholas A

    2017-04-30

    Magnetic resonance imaging (MRI) studies in humans have reported that the T 1 -weighted signal in the cerebral cortex follows an inverted "U" trajectory over the lifespan. Here, we investigated the T 1 -weighted signal trajectory from late adolescence to middle adulthood in humans to characterize the age range when mental illnesses tend to present, and efficacy of treatments are evaluated. We compared linear to quadratic predictors of age on signal in 67 healthy individuals, 17-45 years old. We investigated ¼, ½, and ¾ depths in the cortex representing intracortical myelin (ICM), in the superficial white matter (SWM), and in a reference deep white matter tract. We found that the quadratic fit was superior in all regions of the cortex, while signal in the SWM and deep white matter showed no global dependence on age over this range. The signal trajectory in any region followed a similar shape regardless of cortical depth. The quadratic fit was analyzed in 70 cortical regions to obtain the age of maximum signal intensity. We found that visual, cingulate, and left ventromedial prefrontal cortices peak first around 34 years old, whereas motor and premotor areas peak latest at ∼38 years. Our analysis suggests that ICM trajectories over this range can be modeled well in small cohorts of subjects using quadratic functions, which are amenable to statistical analysis, thus suitable for investigating regional changes in ICM with disease. This study highlights a novel approach to map ICM trajectories using an age range that coincides with the onset of many mental illnesses. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  5. The Duration of Motor Responses Evoked with Intracortical Microstimulation in Rats Is Primarily Modulated by Stimulus Amplitude and Train Duration.

    Science.gov (United States)

    Watson, Meghan; Sawan, Mohamad; Dancause, Numa

    2016-01-01

    Microstimulation of brain tissue plays a key role in a variety of sensory prosthetics, clinical therapies and research applications, however the effects of stimulation parameters on the responses they evoke remain widely unknown. In particular, the effects of parameters when delivered in the form of a stimulus train as opposed to a single pulse are not well understood despite the prevalence of stimulus train use. We aimed to investigate the contribution of each parameter of a stimulus train to the duration of the motor responses they evoke in forelimb muscles. We used constant-current, biphasic, square wave pulse trains in acute terminal experiments under ketamine anaesthesia. Stimulation parameters were systematically tested in a pair-wise fashion in the caudal forelimb region of the motor cortex in 7 Sprague-Dawley rats while motor evoked potential (MEP) recordings from the forelimb were used to quantify the influence of each parameter in the train. Stimulus amplitude and train duration were shown to be the dominant parameters responsible for increasing the total duration of the MEP, while interphase interval had no effect. Increasing stimulus frequency from 100-200 Hz or pulse duration from 0.18-0.34 ms were also effective methods of extending response durations. Response duration was strongly correlated with peak time and amplitude. Our findings suggest that motor cortex intracortical microstimulations are often conducted at a higher frequency rate and longer train duration than necessary to evoke maximal response duration. We demonstrated that the temporal properties of the evoked response can be both predicted by certain response metrics and modulated via alterations to the stimulation signal parameters.

  6. Ultrafast Synaptic Events in a Chalcogenide Memristor

    Science.gov (United States)

    Li, Yi; Zhong, Yingpeng; Xu, Lei; Zhang, Jinjian; Xu, Xiaohua; Sun, Huajun; Miao, Xiangshui

    2013-04-01

    Compact and power-efficient plastic electronic synapses are of fundamental importance to overcoming the bottlenecks of developing a neuromorphic chip. Memristor is a strong contender among the various electronic synapses in existence today. However, the speeds of synaptic events are relatively slow in most attempts at emulating synapses due to the material-related mechanism. Here we revealed the intrinsic memristance of stoichiometric crystalline Ge2Sb2Te5 that originates from the charge trapping and releasing by the defects. The device resistance states, representing synaptic weights, were precisely modulated by 30 ns potentiating/depressing electrical pulses. We demonstrated four spike-timing-dependent plasticity (STDP) forms by applying programmed pre- and postsynaptic spiking pulse pairs in different time windows ranging from 50 ms down to 500 ns, the latter of which is 105 times faster than the speed of STDP in human brain. This study provides new opportunities for building ultrafast neuromorphic computing systems and surpassing Von Neumann architecture.

  7. Molecular Signatures Underlying Synaptic Vesicle Cargo Retrieval

    Science.gov (United States)

    Mori, Yasunori; Takamori, Shigeo

    2018-01-01

    Efficient retrieval of the synaptic vesicle (SV) membrane from the presynaptic plasma membrane, a process called endocytosis, is crucial for the fidelity of neurotransmission, particularly during sustained neural activity. Although multiple modes of endocytosis have been identified, it is clear that the efficient retrieval of the major SV cargos into newly formed SVs during any of these modes is fundamental for synaptic transmission. It is currently believed that SVs are eventually reformed via a clathrin-dependent pathway. Various adaptor proteins recognize SV cargos and link them to clathrin, ensuring the efficient retrieval of the cargos into newly formed SVs. Here, we summarize our current knowledge of the molecular signatures within individual SV cargos that underlie efficient retrieval into SV membranes, as well as discuss possible contributions of the mechanisms under physiological conditions. PMID:29379416

  8. Synaptic devices based on purely electronic memristors

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Ruobing [Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China); Institute of Materials Science, School of Materials Science and Engineering, Shanghai University, Shanghai 200072 (China); Li, Jun; Zhuge, Fei, E-mail: zhugefei@nimte.ac.cn, E-mail: h-cao@nimte.ac.cn; Zhu, Liqiang; Liang, Lingyan; Zhang, Hongliang; Gao, Junhua; Cao, Hongtao, E-mail: zhugefei@nimte.ac.cn, E-mail: h-cao@nimte.ac.cn; Fu, Bing; Li, Kang [Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China)

    2016-01-04

    Memristive devices have been widely employed to emulate biological synaptic behavior. In these cases, the memristive switching generally originates from electrical field induced ion migration or Joule heating induced phase change. In this letter, the Ti/ZnO/Pt structure was found to show memristive switching ascribed to a carrier trapping/detrapping of the trap sites (e.g., oxygen vacancies or zinc interstitials) in ZnO. The carrier trapping/detrapping level can be controllably adjusted by regulating the current compliance level or voltage amplitude. Multi-level conductance states can, therefore, be realized in such memristive device. The spike-timing-dependent plasticity, an important Hebbian learning rule, has been implemented in this type of synaptic device. Compared with filamentary-type memristive devices, purely electronic memristors have potential to reduce their energy consumption and work more stably and reliably, since no structural distortion occurs.

  9. Hippocampal synaptic plasticity, spatial memory and anxiety

    OpenAIRE

    Bannerman, David M.; Sprengel, Rolf; Sanderson, David J.; McHugh, Stephen B.; Rawlins, J. Nicholas P.; Monyer, Hannah; Seeburg, Peter H.

    2014-01-01

    Recent studies using transgenic mice lacking NMDA receptors in the hippocampus challenge the long-standing hypothesis that hippocampal long-term potentiation-like mechanisms underlie the encoding and storage of associative long-term spatial memories. However, it may not be the synaptic plasticity-dependent memory hypothesis that is wrong; instead, it may be the role of the hippocampus that needs to be re-examined. We present an account of hippocampal function that explains its role in both me...

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

    Science.gov (United States)

    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.

  11. Layer-Dependent Short-Term Synaptic Plasticity Between Excitatory Neurons in the C2 Barrel Column of Mouse Primary Somatosensory Cortex.

    Science.gov (United States)

    Lefort, Sandrine; Petersen, Carl C H

    2017-07-01

    Neurons process information through spatiotemporal integration of synaptic input. Synaptic transmission between any given pair of neurons is typically a dynamic process with presynaptic action potentials (APs) evoking depressing or facilitating postsynaptic potentials when presynaptic APs occur within hundreds of milliseconds of each other. In order to understand neocortical function, it is therefore important to investigate such short-term synaptic plasticity at synapses between different types of neocortical neurons. Here, we examine short-term synaptic dynamics between excitatory neurons in different layers of the mouse C2 barrel column through in vitro whole-cell recordings. We find layer-dependent short-term plasticity, with depression being dominant at many synaptic connections. Interestingly, however, presynaptic layer 2 neurons predominantly give rise to facilitating excitatory synaptic output at short interspike intervals of 10 and 30 ms. Previous studies have found prominent burst firing of excitatory neurons in supragranular layers of awake mice. The facilitation we observed in the synaptic output of layer 2 may, therefore, be functionally relevant, possibly serving to enhance the postsynaptic impact of burst firing. © The Author 2017. Published by Oxford University Press.

  12. Synaptic theory of Replicator-like melioration

    Directory of Open Access Journals (Sweden)

    Yonatan Loewenstein

    2010-06-01

    Full Text Available According to the theory of Melioration, organisms in repeated choice settings shift their choice preference in favor of the alternative that provides the highest return. The goal of this paper is to explain how this learning behavior can emerge from microscopic changes in the efficacies of synapses, in the context of two-alternative repeated-choice experiment. I consider a large family of synaptic plasticity rules in which changes in synaptic efficacies are driven by the covariance between reward and neural activity. I construct a general framework that predicts the learning dynamics of any decision-making neural network that implements this synaptic plasticity rule and show that melioration naturally emerges in such networks. Moreover, the resultant learning dynamics follows the Replicator equation which is commonly used to phenomenologically describe changes in behavior in operant conditioning experiments. Several examples demonstrate how the learning rate of the network is affected by its properties and by the specifics of the plasticity rule. These results help bridge the gap between cellular physiology and learning behavior.

  13. Characterization and extraction of the synaptic apposition surface for synaptic geometry analysis

    Science.gov (United States)

    Morales, Juan; Rodríguez, Angel; Rodríguez, José-Rodrigo; DeFelipe, Javier; Merchán-Pérez, Angel

    2013-01-01

    Geometrical features of chemical synapses are relevant to their function. Two critical components of the synaptic junction are the active zone (AZ) and the postsynaptic density (PSD), as they are related to the probability of synaptic release and the number of postsynaptic receptors, respectively. Morphological studies of these structures are greatly facilitated by the use of recent electron microscopy techniques, such as combined focused ion beam milling and scanning electron microscopy (FIB/SEM), and software tools that permit reconstruction of large numbers of synapses in three dimensions. Since the AZ and the PSD are in close apposition and have a similar surface area, they can be represented by a single surface—the synaptic apposition surface (SAS). We have developed an efficient computational technique to automatically extract this surface from synaptic junctions that have previously been three-dimensionally reconstructed from actual tissue samples imaged by automated FIB/SEM. Given its relationship with the release probability and the number of postsynaptic receptors, the surface area of the SAS is a functionally relevant measure of the size of a synapse that can complement other geometrical features like the volume of the reconstructed synaptic junction, the equivalent ellipsoid size and the Feret's diameter. PMID:23847474

  14. Dynamic Control of Synaptic Adhesion and Organizing Molecules in Synaptic Plasticity

    Energy Technology Data Exchange (ETDEWEB)

    Rudenko, Gabby (Texas-MED)

    2017-01-01

    Synapses play a critical role in establishing and maintaining neural circuits, permitting targeted information transfer throughout the brain. A large portfolio of synaptic adhesion/organizing molecules (SAMs) exists in the mammalian brain involved in synapse development and maintenance. SAMs bind protein partners, formingtrans-complexes spanning the synaptic cleft orcis-complexes attached to the same synaptic membrane. SAMs play key roles in cell adhesion and in organizing protein interaction networks; they can also provide mechanisms of recognition, generate scaffolds onto which partners can dock, and likely take part in signaling processes as well. SAMs are regulated through a portfolio of different mechanisms that affect their protein levels, precise localization, stability, and the availability of their partners at synapses. Interaction of SAMs with their partners can further be strengthened or weakened through alternative splicing, competing protein partners, ectodomain shedding, or astrocytically secreted factors. Given that numerous SAMs appear altered by synaptic activity, in vivo, these molecules may be used to dynamically scale up or scale down synaptic communication. Many SAMs, including neurexins, neuroligins, cadherins, and contactins, are now implicated in neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorder, schizophrenia, and bipolar disorder and studying their molecular mechanisms holds promise for developing novel therapeutics.

  15. Characterization and extraction of the synaptic apposition surface for synaptic geometry analysis.

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    Juan eMorales

    2013-07-01

    Full Text Available Geometrical features of chemical synapses are relevant to their function. Two critical components of the synaptic junction are the active zone and the postsynaptic density, as they are related to the probability of synaptic release and the number of postsynaptic receptors, respectively. Morphological studies of these structures are greatly facilitated by the use of recent electron microscopy techniques, such as combined focused ion beam milling and scanning electron microscopy (FIB/SEM, and software tools that permit reconstruction of large numbers of synapses in three dimensions. Since the active zone and the postsynaptic density are in close apposition and have a similar surface area, they can be represented by a single surface — the synaptic apposition surface (SAS. We have developed an efficient computational technique to automatically extract this surface from synaptic junctions that have previously been three-dimensionally reconstructed from actual tissue samples imaged by automated FIB/SEM. Given its relationship with the release probability and the number of postsynaptic receptors, the surface area of the SAS is a functionally relevant measure of the size of a synapse that can complement other geometrical features like the volume of the reconstructed synaptic junction, the equivalent ellipsoid size and the Feret’s diameter.

  16. Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases

    Science.gov (United States)

    Lin, Chi-Ying; Wang, Jie; Sims, Peter A.; Pan, Ming-Kai; Liou, Jyun-you; Lee, Danielle; Tate, William J.; Kelly, Geoffrey C.; Louis, Elan D.; Faust, Phyllis L.

    2017-01-01

    Changes in climbing fiber-Purkinje cell (CF-PC) synaptic connections have been found in the essential tremor (ET) cerebellum, and these changes are correlated with tremor severity. Whether these postmortem changes are specific to ET remains to be investigated. We assessed CF-PC synaptic pathology in the postmortem cerebellum across a range of degenerative movement disorders [10 Parkinson’s disease (PD) cases, 10 multiple system atrophy (MSA) cases, 10 spinocerebellar ataxia type 1 (SCA1) cases, and 20 ET cases] and 25 controls. We observed differences in terms of CF pathological features across these disorders. Specifically, PD cases and ET cases both had more CFs extending into the parallel fiber (PF) territory, but ET cases had more complex branching and increased length of CFs in the PF territory along with decreased CF synaptic density compared to PD cases. MSA cases and SCA1 cases had the most severely reduced CF synaptic density and a marked paucity of CFs extending into the PF territory. Furthermore, CFs in a subset of MSA cases formed collateral branches parallel to the PC layer, a feature not seen in other diagnostic groups. Using unsupervised cluster analysis, the cases and controls could all be categorized into four clusters based on the CF pathology and features of PC pathology, including counts of PCs and their axonal torpedoes. ET cases and PD cases co-segregated into two clusters, whereas SCA1 cases and MSA cases formed another cluster, separate from the control cluster. Interestingly, the presence of resting tremor seemed to be the clinical feature that separated the cases into the two ET-PD clusters. In conclusion, our study demonstrates that these degenerative movement disorders seem to differ with respect to the pattern of CF synaptic pathology they exhibit. It remains to be determined how these differences contribute to the clinical presentations of these diseases. PMID:27704282

  17. Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination.

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    van Wijk, Nick; Broersen, Laus M; de Wilde, Martijn C; Hageman, Robert J J; Groenendijk, Martine; Sijben, John W C; Kamphuis, Patrick J G H

    2014-01-01

    Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models.

  18. Synaptic Homeostasis and Its Immunological Disturbance in Neuromuscular Junction Disorders

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    Masaharu Takamori

    2017-04-01

    Full Text Available In the neuromuscular junction, postsynaptic nicotinic acetylcholine receptor (nAChR clustering, trans-synaptic communication and synaptic stabilization are modulated by the molecular mechanisms underlying synaptic plasticity. The synaptic functions are based presynaptically on the active zone architecture, synaptic vesicle proteins, Ca2+ channels and synaptic vesicle recycling. Postsynaptically, they are based on rapsyn-anchored nAChR clusters, localized sensitivity to ACh, and synaptic stabilization via linkage to the extracellular matrix so as to be precisely opposed to the nerve terminal. Focusing on neural agrin, Wnts, muscle-specific tyrosine kinase (a mediator of agrin and Wnts signalings and regulator of trans-synaptic communication, low-density lipoprotein receptor-related protein 4 (the receptor of agrin and Wnts and participant in retrograde signaling, laminin-network (including muscle-derived agrin, extracellular matrix proteins (participating in the synaptic stabilization and presynaptic receptors (including muscarinic and adenosine receptors, we review the functional structures of the synapse by making reference to immunological pathogenecities in postsynaptic disease, myasthenia gravis. The synapse-related proteins including cortactin, coronin-6, caveolin-3, doublecortin, R-spondin 2, amyloid precursor family proteins, glia cell-derived neurotrophic factor and neurexins are also discussed in terms of their possible contribution to efficient synaptic transmission at the neuromuscular junction.

  19. Symmetric synaptic patterns between starburst amacrine cells and direction selective ganglion cells in the rabbit retina.

    Science.gov (United States)

    Chen, Yung-Cheng; Chiao, Chuan-Chin

    2008-05-01

    Inputs from starburst amacrine cells (SACs) to ON-OFF direction selective ganglion cells (DSGCs) in the rabbit retina are themselves directional. However, the synaptic asymmetry between SACs and DSGCs required for generating direction selectivity has been controversial. We investigated dendritic contacts and distribution of inhibitory synapses between SACs and their overlapped DSGCs. Double injection of SAC/DSGC pairs and quantitative analysis revealed no obvious asymmetry of dendritic contacts between SACs and DSGCs. Furthermore, examination of the inhibitory input pattern on the dendrites of DSGCs using antibodies against GABA(A) receptors also suggested an isotropic arrangement with the overlapping SACs in both the preferred and the null directions. Therefore, the presynaptic mechanism of direction selectivity upon DSGCs may not result from a simple asymmetric arrangement with overlapping SACs. Multiple layer interactions and sophisticated synaptic connections between SACs and DSGCs are necessary. (c) 2008 Wiley-Liss, Inc.

  20. Diverse synaptic plasticity mechanisms orchestrated to form and retrieve memories in spiking neural networks.

    Science.gov (United States)

    Zenke, Friedemann; Agnes, Everton J; Gerstner, Wulfram

    2015-04-21

    Synaptic plasticity, the putative basis of learning and memory formation, manifests in various forms and across different timescales. Here we show that the interaction of Hebbian homosynaptic plasticity with rapid non-Hebbian heterosynaptic plasticity is, when complemented with slower homeostatic changes and consolidation, sufficient for assembly formation and memory recall in a spiking recurrent network model of excitatory and inhibitory neurons. In the model, assemblies were formed during repeated sensory stimulation and characterized by strong recurrent excitatory connections. Even days after formation, and despite ongoing network activity and synaptic plasticity, memories could be recalled through selective delay activity following the brief stimulation of a subset of assembly neurons. Blocking any component of plasticity prevented stable functioning as a memory network. Our modelling results suggest that the diversity of plasticity phenomena in the brain is orchestrated towards achieving common functional goals.

  1. Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis.

    Science.gov (United States)

    Arendt, Kristin L; Zhang, Zhenjie; Ganesan, Subhashree; Hintze, Maik; Shin, Maggie M; Tang, Yitai; Cho, Ahryon; Graef, Isabella A; Chen, Lu

    2015-10-20

    Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca(2+) levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca(2+)-levels to RA synthesis remains unknown. Here we identify the Ca(2+)-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca(2+)-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.

  2. Syncrip/hnRNP Q influences synaptic transmission and regulates BMP signaling at the Drosophila neuromuscular synapse

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    James M. Halstead

    2014-08-01

    Full Text Available Synaptic plasticity involves the modulation of synaptic connections in response to neuronal activity via multiple pathways. One mechanism modulates synaptic transmission by retrograde signals from the post-synapse that influence the probability of vesicle release in the pre-synapse. Despite its importance, very few factors required for the expression of retrograde signals, and proper synaptic transmission, have been identified. Here, we identify the conserved RNA binding protein Syncrip as a new factor that modulates the efficiency of vesicle release from the motoneuron and is required for correct synapse structure. We show that syncrip is required genetically and its protein product is detected only in the muscle and not in the motoneuron itself. This unexpected non-autonomy is at least partly explained by the fact that Syncrip modulates retrograde BMP signals from the muscle back to the motoneuron. We show that Syncrip influences the levels of the Bone Morphogenic Protein ligand Glass Bottom Boat from the post-synapse and regulates the pre-synapse. Our results highlight the RNA-binding protein Syncrip as a novel regulator of synaptic output. Given its known role in regulating translation, we propose that Syncrip is important for maintaining a balance between the strength of presynaptic vesicle release and postsynaptic translation.

  3. Optimal synaptic signaling connectome for locomotory behavior in Caenorhabditis elegans: Design minimizing energy cost.

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    Franciszek Rakowski

    2017-11-01

    Full Text Available The detailed knowledge of C. elegans connectome for 3 decades has not contributed dramatically to our understanding of worm's behavior. One of main reasons for this situation has been the lack of data on the type of synaptic signaling between particular neurons in the worm's connectome. The aim of this study was to determine synaptic polarities for each connection in a small pre-motor circuit controlling locomotion. Even in this compact network of just 7 neurons the space of all possible patterns of connection types (excitation vs. inhibition is huge. To deal effectively with this combinatorial problem we devised a novel and relatively fast technique based on genetic algorithms and large-scale parallel computations, which we combined with detailed neurophysiological modeling of interneuron dynamics and compared the theory to the available behavioral data. As a result of these massive computations, we found that the optimal connectivity pattern that matches the best locomotory data is the one in which all interneuron connections are inhibitory, even those terminating on motor neurons. This finding is consistent with recent experimental data on cholinergic signaling in C. elegans, and it suggests that the system controlling locomotion is designed to save metabolic energy. Moreover, this result provides a solid basis for a more realistic modeling of neural control in these worms, and our novel powerful computational technique can in principle be applied (possibly with some modifications to other small-scale functional circuits in C. elegans.

  4. Mechanisms of glycine release, which build up synaptic and extrasynaptic glycine levels: the role of synaptic and non-synaptic glycine transporters.

    Science.gov (United States)

    Harsing, Laszlo G; Matyus, Peter

    2013-04-01

    Glycine is an amino acid neurotransmitter that is involved in both inhibitory and excitatory neurochemical transmission in the central nervous system. The role of glycine in excitatory neurotransmission is related to its coagonist action at glutamatergic N-methyl-D-aspartate receptors. The glycine levels in the synaptic cleft rise many times higher during synaptic activation assuring that glycine spills over into the extrasynaptic space. Another possible origin of extrasynaptic glycine is the efflux of glycine occurring from astrocytes associated with glutamatergic synapses. The release of glycine from neuronal or glial origins exhibits several differences compared to that of biogenic amines or other amino acid neurotransmitters. These differences appear in an external Ca(2+)- and temperature-dependent manner, conferring unique characteristics on glycine as a neurotransmitter. Glycine transporter type-1 at synapses may exhibit neural and glial forms and plays a role in controlling synaptic glycine levels and the spill over rate of glycine from the synaptic cleft into the extrasynaptic biophase. Non-synaptic glycine transporter type-1 regulates extrasynaptic glycine concentrations, either increasing or decreasing them depending on the reverse or normal mode operation of the carrier molecule. While we can, at best, only estimate synaptic glycine levels at rest and during synaptic activation, glycine concentrations are readily measurable via brain microdialysis technique applied in the extrasynaptic space. The non-synaptic N-methyl-D-aspartate receptor may obtain glycine for activation following its spill over from highly active synapses or from its release mediated by the reverse operation of non-synaptic glycine transporter-1. The sensitivity of non-synaptic N-methyl-D-aspartate receptors to glutamate and glycine is many times higher than that of synaptic N-methyl-D-aspartate receptors making the former type of receptor the primary target for drug action. Synaptic

  5. Effects of decreased inhibition on synaptic plasticity and dendritic morphology in the juvenile prefrontal cortex

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    Xanthippi Konstantoudaki

    2014-03-01

    , we tested whether synaptic plasticity properties of intra-cortical layer II synapses are affected. In adult control mice, tetanic stimulation results in long-term potentiation that lasts at least 50 min (Konstantoudaki et al, 2013. In control mice of the age tested in this study (PD 20-30, LTP could not be induced with the same stimulation. However, we find that Rac1 KO mice do express long-term potentiation. We next studied the dendritic morphology of layer II neurons in the prefrontal cortex, in an effort to identify the mechanism by which Rac1 KO mice exhibit LTP, while the control mice of the same age do not. For this, we stained mouse brains of Rac1 KO and Rac1 heterozygous mice with the Golgi-Cox method. We analyzed the number of secondary apical dendrites, their thickness, as well as the number of spines. We find that the dendrites of pyramidal neurons of Rac1 KO mice have decreased thickness and increased number of spines compared to pyramidal neurons from Rac1 heterozygous mice. These findings could also provide a mechanistic explanation for the presence of LTP in Rac1 KO mice. In conclusion, we find that decreased inhibition during development alters the morphological and functional characteristics of pyramidal neurons in layer II prefrontal cortex of mice. These alterations could provide a cellular substrate for emotional and cognitive dysfunctions present in these mice (Konstantoudaki et al, 2012.

  6. LTD-like molecular pathways in developmental synaptic pruning

    Science.gov (United States)

    Piochon, Claire; Kano, Masanobu; Hansel, Christian

    2016-01-01

    In long-term depression (LTD) at synapses in the adult brain, synaptic strength is reduced in an experience-dependent manner. LTD thus provides a cellular mechanism for information storage in some forms of learning. A similar activity-dependent reduction in synaptic strength also occurs in the developing brain and there provides an essential step in synaptic pruning and the postnatal development of neural circuits. Here we review evidence suggesting that LTD and synaptic pruning share components of their underlying molecular machinery and may thus represent two developmental stages of the same type of synaptic modulation that serve different, but related, functions in neural circuit plasticity. We also assess the relationship between LTD and synaptic pruning in the context of recent findings of LTD dysregulation in several mouse models of autism spectrum disorder (ASD) and discuss whether LTD deficits can indicate impaired pruning processes that are required for proper brain development. PMID:27669991

  7. Potentiation of electrical and chemical synaptic transmission mediated by endocannabinoids

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    Cachope, Roger; Mackie, Ken; Triller, Antoine; O’Brien, John; Pereda, Alberto E.

    2009-01-01

    SUMMARY Endocannabinoids are well established as inhibitors of chemical synaptic transmission via presynaptic activation of the cannabinoid type 1 receptor (CB1R). Contrasting this notion, we show that dendritic release of endocannabinoids mediates potentiation of synaptic transmission at mixed (electrical and chemical) synaptic contacts on the goldfish Mauthner cell. Remarkably, the observed enhancement was not restricted to the glutamatergic component of the synaptic response but also included a parallel increase in electrical transmission. This novel effect involved the activation of CB1 receptors and was indirectly mediated via the release of dopamine from nearby varicosities, which in turn led to potentiation of the synaptic response via a cAMP-dependent protein kinase-mediated postsynaptic mechanism. Thus, endocannabinoid release can potentiate synaptic transmission and its functional roles include the regulation of gap junction-mediated electrical synapses. Similar interactions between endocannabinoid and dopaminergic systems may be widespread and potentially relevant for the motor and rewarding effects of cannabis derivatives. PMID:18093525

  8. Electrophysiological Techniques for Studying Synaptic Activity In Vivo.

    Science.gov (United States)

    Jeggo, Ross; Zhao, Fei-Yue; Spanswick, David

    2014-03-03

    Understanding the physiology, pharmacology, and plasticity associated with synaptic function is a key goal of neuroscience research and is fundamental to identifying the processes involved in the development and manifestation of neurological disease. A diverse range of electrophysiological methodologies are used to study synaptic function. Described in this unit is a technique for recording electrical activity from a single component of the central nervous system that is used to investigate pre- and post-synaptic elements of synaptic function. A strength of this technique is that it can be used on live animals, although the effect of anesthesia must be taken into consideration when interpreting the results. This methodology can be employed not only in naïve animals for studying normal physiological synaptic function, but also in a variety of disease models, including transgenic animals, to examine dysfunctional synaptic plasticity associated with neurological pathologies. Copyright © 2013 John Wiley & Sons, Inc. All rights reserved.

  9. [Astrocytes and microglia: active players in synaptic plasticity].

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    Ronzano, Rémi

    2017-12-01

    Synaptic plasticity consists in a change in structure and composition of presynaptic and postsynaptic compartments. For a long time, synaptic plasticity had been thought as a neuronal mechanism only under the control of neural network activity. However, recently, with the growing knowledge about glial physiology, plasticity has been reviewed as a mechanism influenced by the synaptic environment. Thus, it appears that astrocytes and microglia modulate these mechanisms modifying neural environment by clearance of neurotransmitters, releasing essential factors and modulating inflammation. Moreover, glia can change its own activity and the expression pattern of many factors that modulate synaptic plasticity according to the environment. Hence, these populations of "non-neuronal" cells in the central nervous system seem to be active players in synaptic plasticity. This review discusses how glia modulates synaptic plasticity focusing on long-term potentiation and depression, and questions the role of the signaling processes between astrocytes and microglia in these mechanisms. © 2017 médecine/sciences – Inserm.

  10. Astrocytes and synaptic plasticity in health and disease.

    Science.gov (United States)

    Singh, A; Abraham, Wickliffe C

    2017-06-01

    Activity-dependent synaptic plasticity phenomena such as long-term potentiation and long-term depression are candidate mechanisms for storing information in the brain. Regulation of synaptic plasticity is critical for healthy cognition and learning and this is provided in part by metaplasticity, which can act to maintain synaptic transmission within a dynamic range and potentially prevent excitotoxicity. Metaplasticity mechanisms also allow neurons to integrate plasticity-associated signals over time. Interestingly, astrocytes appear to be critical for certain forms of synaptic plasticity and metaplasticity mechanisms. Synaptic dysfunction is increasingly viewed as an early feature of AD that is correlated with the severity of cognitive decline, and the development of these pathologies is correlated with a rise in reactive astrocytes. This review focuses on the contributions of astrocytes to synaptic plasticity and metaplasticity in normal tissue, and addresses whether astroglial pathology may lead to aberrant engagement of these mechanisms in neurological diseases such as Alzheimer's disease.

  11. Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants

    OpenAIRE

    Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.

    2010-01-01

    Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) β subunit genes. These mutants exhibit a loss of glycinergic synaptic ...

  12. A pivotal role of GSK-3 in synaptic plasticity

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    Clarrisa A Bradley

    2012-02-01

    Full Text Available Glycogen synthase kinase-3 (GSK-3 has many cellular functions. Recent evidence suggests that it plays a key role in certain types of synaptic plasticity, in particular a form of long-term depression (LTD that is induced by the synaptic activation of N-methyl-D-aspartate (NMDA receptors. In the present article we summarise what is currently known concerning the roles of GSK-3 in synaptic plasticity at both glutamatergic and GABAergic synapses. We summarise its role in cognition and speculate on how alterations in the synaptic functioning of GSK-3 may be a major factor in certain neurodegenerative disorders.

  13. A pivotal role of GSK-3 in synaptic plasticity

    Science.gov (United States)

    Bradley, Clarrisa A.; Peineau, Stéphane; Taghibiglou, Changiz; Nicolas, Celine S.; Whitcomb, Daniel J.; Bortolotto, Zuner A.; Kaang, Bong-Kiun; Cho, Kwangwook; Wang, Yu Tian; Collingridge, Graham L.

    2012-01-01

    Glycogen synthase kinase-3 (GSK-3) has many cellular functions. Recent evidence suggests that it plays a key role in certain types of synaptic plasticity, in particular a form of long-term depression (LTD) that is induced by the synaptic activation of N-methyl-D-aspartate receptors (NMDARs). In the present article we summarize what is currently known concerning the roles of GSK-3 in synaptic plasticity at both glutamatergic and GABAergic synapses. We summarize its role in cognition and speculate on how alterations in the synaptic functioning of GSK-3 may be a major factor in certain neurodegenerative disorders. PMID:22363262

  14. Autophagy mediates the degradation of synaptic vesicles: A potential mechanism of synaptic plasticity injury induced by microwave exposure in rats.

    Science.gov (United States)

    Hao, Yanhui; Li, Wenchao; Wang, Hui; Zhang, Jing; Yu, Chao; Tan, Shengzhi; Wang, Haoyu; Xu, Xinping; Dong, Ji; Yao, Binwei; Zhou, Hongmei; Zhao, Li; Peng, Ruiyun

    2018-02-03

    To explore how autophagy changes and whether autophagy is involved in the pathophysiological process of synaptic plasticity injury caused by microwave radiation, we established a 30 mW/cm 2 microwave-exposure in vivo model, which caused reversible injuries in rat neurons. Microwave radiation induced cognitive impairment in rats and synaptic plasticity injury in rat hippocampal neurons. Autophagy in rat hippocampal neurons was activated following microwave exposure. Additionally, we observed that synaptic vesicles were encapsulated by autophagosomes, a phenomenon more evident in the microwave-exposed group. Colocation of autophagosomes and synaptic vesicles in rat hippocampal neurons increased following microwave exposure. microwave exposure led to the activation of autophagy in rat hippocampal neurons, and excessive activation of autophagy might damage synaptic plasticity by mediating synaptic vesicle degradation. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Radix Puerariae modulates glutamatergic synaptic architecture and potentiates functional synaptic plasticity in primary hippocampal neurons.

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    Bhuiyan, Mohammad Maqueshudul Haque; Haque, Md Nazmul; Mohibbullah, Md; Kim, Yung Kyu; Moon, Il Soo

    2017-09-14

    Neurologic disorders are frequently characterized by synaptic pathology, including abnormal density and morphology of dendritic spines, synapse loss, and aberrant synaptic signaling and plasticity. Therefore, to promote and/or protect synapses by the use of natural molecules capable of modulating neurodevelopmental events, such as, spinogenesis and synaptic plasticity, could offer a preventive and curative strategy for nervous disorders associated with synaptic pathology. Radix Puerariae, the root of Pueraria monatana var. lobata (Willd.) Sanjappa&Pradeep, is a Chinese ethnomedicine, traditionally used for the treatment of memory-related nervous disorders including Alzheimer's disease. In the previous study, we showed that the ethanolic extracts of Radix Puerariae (RPE) and its prime constituent, puerarin induced neuritogenesis and synapse formation in cultured hippocampal neurons, and thus could improve memory functions. In the present study, we specifically investigated the abilities of RPE and puerarin to improve memory-related brain disorders through modulating synaptic maturation and functional potentiation. Rat embryonic (E19) brain neurons were cultured in the absence or presence of RPE or puerarin. At predetermined times, cells were live-stained with DiO or fixed and immunostained to visualize neuronal morphologies, or lysed for protein harvesting. Morphometric analyses of dendritic spines and synaptogenesis were performed using Image J software. Functional pre- and postsynaptic plasticity was measured by FM1-43 staining and whole-cell patch clamping, respectively. RPE or puerarin-mediated changes in actin-related protein 2 were assessed by Western blotting. Neuronal survivals were measured using propidium iodide exclusion assay. RPE and puerarin both: (1) promoted a significant increase in the numbers, and maturation, of dendritic spines; (2) modulated the formation of glutamatergic synapses; (3) potentiated synaptic transmission by increasing the sizes of

  16. Synaptic Democracy and Vesicular Transport in Axons

    Science.gov (United States)

    Bressloff, Paul C.; Levien, Ethan

    2015-04-01

    Synaptic democracy concerns the general problem of how regions of an axon or dendrite far from the cell body (soma) of a neuron can play an effective role in neuronal function. For example, stimulated synapses far from the soma are unlikely to influence the firing of a neuron unless some sort of active dendritic processing occurs. Analogously, the motor-driven transport of newly synthesized proteins from the soma to presynaptic targets along the axon tends to favor the delivery of resources to proximal synapses. Both of these phenomena reflect fundamental limitations of transport processes based on a localized source. In this Letter, we show that a more democratic distribution of proteins along an axon can be achieved by making the transport process less efficient. This involves two components: bidirectional or "stop-and-go" motor transport (which can be modeled in terms of advection-diffusion), and reversible interactions between motor-cargo complexes and synaptic targets. Both of these features have recently been observed experimentally. Our model suggests that, just as in human societies, there needs to be a balance between "efficiency" and "equality".

  17. Structural homeostasis: compensatory adjustments of dendritic arbor geometry in response to variations of synaptic input.

    Directory of Open Access Journals (Sweden)

    Marco Tripodi

    2008-10-01

    Full Text Available As the nervous system develops, there is an inherent variability in the connections formed between differentiating neurons. Despite this variability, neural circuits form that are functional and remarkably robust. One way in which neurons deal with variability in their inputs is through compensatory, homeostatic changes in their electrical properties. Here, we show that neurons also make compensatory adjustments to their structure. We analysed the development of dendrites on an identified central neuron (aCC in the late Drosophila embryo at the stage when it receives its first connections and first becomes electrically active. At the same time, we charted the distribution of presynaptic sites on the developing postsynaptic arbor. Genetic manipulations of the presynaptic partners demonstrate that the postsynaptic dendritic arbor adjusts its growth to compensate for changes in the activity and density of synaptic sites. Blocking the synthesis or evoked release of presynaptic neurotransmitter results in greater dendritic extension. Conversely, an increase in the density of presynaptic release sites induces a reduction in the extent of the dendritic arbor. These growth adjustments occur locally in the arbor and are the result of the promotion or inhibition of growth of neurites in the proximity of presynaptic sites. We provide evidence that suggest a role for the postsynaptic activity state of protein kinase A in mediating this structural adjustment, which modifies dendritic growth in response to synaptic activity. These findings suggest that the dendritic arbor, at least during early stages of connectivity, behaves as a homeostatic device that adjusts its size and geometry to the level and the distribution of input received. The growing arbor thus counterbalances naturally occurring variations in synaptic density and activity so as to ensure that an appropriate level of input is achieved.

  18. About Connections

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    Kathleen S Rockland

    2015-05-01

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

  19. Spike timing analysis in neural networks with unsupervised synaptic plasticity

    Science.gov (United States)

    Mizusaki, B. E. P.; Agnes, E. J.; Brunnet, L. G.; Erichsen, R., Jr.

    2013-01-01

    The synaptic plasticity rules that sculpt a neural network architecture are key elements to understand cortical processing, as they may explain the emergence of stable, functional activity, while avoiding runaway excitation. For an associative memory framework, they should be built in a way as to enable the network to reproduce a robust spatio-temporal trajectory in response to an external stimulus. Still, how these rules may be implemented in recurrent networks and the way they relate to their capacity of pattern recognition remains unclear. We studied the effects of three phenomenological unsupervised rules in sparsely connected recurrent networks for associative memory: spike-timing-dependent-plasticity, short-term-plasticity and an homeostatic scaling. The system stability is monitored during the learning process of the network, as the mean firing rate converges to a value determined by the homeostatic scaling. Afterwards, it is possible to measure the recovery efficiency of the activity following each initial stimulus. This is evaluated by a measure of the correlation between spike fire timings, and we analysed the full memory separation capacity and limitations of this system.

  20. Synaptic Plasticity and Spike Synchronisation in Neuronal Networks

    Science.gov (United States)

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

    2017-12-01

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

  1. Synaptic plasticity enables adaptive self-tuning critical networks.

    Directory of Open Access Journals (Sweden)

    Nigel Stepp

    2015-01-01

    Full Text Available During rest, the mammalian cortex displays spontaneous neural activity. Spiking of single neurons during rest has been described as irregular and asynchronous. In contrast, recent in vivo and in vitro population measures of spontaneous activity, using the LFP, EEG, MEG or fMRI suggest that the default state of the cortex is critical, manifested by spontaneous, scale-invariant, cascades of activity known as neuronal avalanches. Criticality keeps a network poised for optimal information processing, but this view seems to be difficult to reconcile with apparently irregular single neuron spiking. Here, we simulate a 10,000 neuron, deterministic, plastic network of spiking neurons. We show that a combination of short- and long-term synaptic plasticity enables these networks to exhibit criticality in the face of intrinsic, i.e. self-sustained, asynchronous spiking. Brief external perturbations lead to adaptive, long-term modification of intrinsic network connectivity through long-term excitatory plasticity, whereas long-term inhibitory plasticity enables rapid self-tuning of the network back to a critical state. The critical state is characterized by a branching parameter oscillating around unity, a critical exponent close to -3/2 and a long tail distribution of a self-similarity parameter between 0.5 and 1.

  2. A distance constrained synaptic plasticity model of C. elegans neuronal network

    Science.gov (United States)

    Badhwar, Rahul; Bagler, Ganesh

    2017-03-01

    Brain research has been driven by enquiry for principles of brain structure organization and its control mechanisms. The neuronal wiring map of C. elegans, the only complete connectome available till date, presents an incredible opportunity to learn basic governing principles that drive structure and function of its neuronal architecture. Despite its apparently simple nervous system, C. elegans is known to possess complex functions. The nervous system forms an important underlying framework which specifies phenotypic features associated to sensation, movement, conditioning and memory. In this study, with the help of graph theoretical models, we investigated the C. elegans neuronal network to identify network features that are critical for its control. The 'driver neurons' are associated with important biological functions such as reproduction, signalling processes and anatomical structural development. We created 1D and 2D network models of C. elegans neuronal system to probe the role of features that confer controllability and small world nature. The simple 1D ring model is critically poised for the number of feed forward motifs, neuronal clustering and characteristic path-length in response to synaptic rewiring, indicating optimal rewiring. Using empirically observed distance constraint in the neuronal network as a guiding principle, we created a distance constrained synaptic plasticity model that simultaneously explains small world nature, saturation of feed forward motifs as well as observed number of driver neurons. The distance constrained model suggests optimum long distance synaptic connections as a key feature specifying control of the network.

  3. Attenuation of inhibitory synaptic transmission by glial dysfunction in rat thalamus.

    Science.gov (United States)

    Yang, Sunggu; Cox, Charles L

    2011-12-01

    The thalamus serves as the obligatory gateway to the neocortex for sensory processing, and also serves as a pathway for corticocortical communication. In addition, the reciprocal synaptic connectivity between the thalamic reticular nucleus (TRN) and adjacent thalamic relay nuclei generates rhythmic activities similar to that observed during different arousal states and certain neurological conditions such as absence epilepsy. Epileptiform activity can arise from a variety of neural mechanisms, but in addition glia are thought to have an important role in such activities as well. Glia serve a central role in glutamine synthesis, a precursor for glutamate or GABA in nerve terminals. While alterations in glutamine shuttling from glia to neurons can influence GABA and glutamate neurotransmission; the consequences of such action on synaptic transmission and subsequent network activities within thalamic circuits is less understood. We investigated the consequences of altering glutamine transport on inhibitory transmission and intrathalamic activities using the in vitro thalamic slice preparation. Disruption of the glutamine shuttling by the neuronal glutamine transporter (system A transporter) antagonist, α-(methylamino)isobutyric acid (MeAIB), or the selective gliotoxic drug, fluorocitric acid (Fc) dramatically decreased intrathalamic rhythmic activities. At the single cell level, MeAIB and Fc significantly attenuated electrically evoked inhibitory postsynaptic currents (eIPSCs) in thalamic relay neurons; however, miniature IPSCs were unaffected. These data indicate that glutamate-glutamine shuttle is critical for sustaining thalamic synaptic transmission, and thereby alterations in this shuttle can influence intrathalamic rhythmic activities associated with absence epilepsy. Copyright © 2011 Wiley-Liss, Inc.

  4. Synaptic abnormalities in a Drosophila model of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Siddhita D. Mhatre

    2014-03-01

    Full Text Available Alzheimer’s disease (AD is an age-related neurodegenerative disease characterized by memory loss and decreased synaptic function. Advances in transgenic animal models of AD have facilitated our understanding of this disorder, and have aided in the development, speed and efficiency of testing potential therapeutics. Recently, we have described the characterization of a novel model of AD in the fruit fly, Drosophila melanogaster, where we expressed the human AD-associated proteins APP and BACE in the central nervous system of the fly. Here we describe synaptic defects in the larval neuromuscular junction (NMJ in this model. Our results indicate that expression of human APP and BACE at the larval NMJ leads to defective larval locomotion behavior, decreased presynaptic connections, altered mitochondrial localization in presynaptic motor neurons and decreased postsynaptic protein levels. Treating larvae expressing APP and BACE with the γ-secretase inhibitor L-685,458 suppresses the behavioral defects as well as the pre- and postsynaptic defects. We suggest that this model will be useful to assess and model the synaptic dysfunction normally associated with AD, and will also serve as a powerful in vivo tool for rapid testing of potential therapeutics for AD.

  5. Ubiquitination-dependent mechanisms regulate synaptic growth and function.

    Science.gov (United States)

    DiAntonio, A; Haghighi, A P; Portman, S L; Lee, J D; Amaranto, A M; Goodman, C S

    2001-07-26

    The covalent attachment of ubiquitin to cellular proteins is a powerful mechanism for controlling protein activity and localization. Ubiquitination is a reversible modification promoted by ubiquitin ligases and antagonized by deubiquitinating proteases. Ubiquitin-dependent mechanisms regulate many important processes including cell-cycle progression, apoptosis and transcriptional regulation. Here we show that ubiquitin-dependent mechanisms regulate synaptic development at the Drosophila neuromuscular junction (NMJ). Neuronal overexpression of the deubiquitinating protease fat facets leads to a profound disruption of synaptic growth control; there is a large increase in the number of synaptic boutons, an elaboration of the synaptic branching pattern, and a disruption of synaptic function. Antagonizing the ubiquitination pathway in neurons by expression of the yeast deubiquitinating protease UBP2 (ref. 5) also produces synaptic overgrowth and dysfunction. Genetic interactions between fat facets and highwire, a negative regulator of synaptic growth that has structural homology to a family of ubiquitin ligases, suggest that synaptic development may be controlled by the balance between positive and negative regulators of ubiquitination.

  6. Synaptic Tagging, Evaluation of Memories, and the Distal Reward Problem

    Science.gov (United States)

    Papper, Marc; Kempter, Richard; Leibold, Christian

    2011-01-01

    Long-term synaptic plasticity exhibits distinct phases. The synaptic tagging hypothesis suggests an early phase in which synapses are prepared, or "tagged," for protein capture, and a late phase in which those proteins are integrated into the synapses to achieve memory consolidation. The synapse specificity of the tags is consistent with…

  7. A presynaptic role for PKA in synaptic tagging and memory.

    Science.gov (United States)

    Park, Alan Jung; Havekes, Robbert; Choi, Jennifer Hk; Luczak, Vince; Nie, Ting; Huang, Ted; Abel, Ted

    2014-10-01

    Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and memory because PKA also regulates presynaptic transmitter release. Here, we examine this issue using genetic and pharmacological application of Ht31, a PKA anchoring disrupting peptide. At the hippocampal Schaffer collateral CA3-CA1 synapse, Ht31 treatment elicits a rapid decay of synaptic responses to repetitive stimuli, indicating a fast depletion of the readily releasable pool of synaptic vesicles. The interaction between PKA and proteins involved in producing this pool of synaptic vesicles is supported by biochemical assays showing that synaptic vesicle protein 2 (SV2), Rim1, and SNAP25 are components of a complex that interacts with cAMP. Moreover, acute treatment with Ht31 reduces the levels of SV2. Finally, experiments with transgenic mouse lines, which express Ht31 in excitatory neurons at the Schaffer collateral CA3-CA1 synapse, highlight a requirement for presynaptically anchored PKA in pathway-specific synaptic tagging and long-term contextual fear memory. These results suggest that a presynaptically compartmentalized PKA is critical for synaptic plasticity and memory by regulating the readily releasable pool of synaptic vesicles. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. The discovery of GluA3-dependent synaptic plasticity

    NARCIS (Netherlands)

    Renner, M.C.

    2016-01-01

    AMPA receptors (AMPARs) are responsible for fast excitatory synaptic transmission. GluA1-containing AMPARs have been extensively studied and play a key role in several forms of synaptic plasticity and memory. In contrast, GluA3-containing AMPARs have historically been ignored because they have

  9. Role of MicroRNA in Governing Synaptic Plasticity.

    Science.gov (United States)

    Ye, Yuqin; Xu, Hongyu; Su, Xinhong; He, Xiaosheng

    2016-01-01

    Although synaptic plasticity in neural circuits is orchestrated by an ocean of genes, molecules, and proteins, the underlying mechanisms remain poorly understood. Recently, it is well acknowledged that miRNA exerts widespread regulation over the translation and degradation of target gene in nervous system. Increasing evidence suggests that quite a few specific miRNAs play important roles in various respects of synaptic plasticity including synaptogenesis, synaptic morphology alteration, and synaptic function modification. More importantly, the miRNA-mediated regulation of synaptic plasticity is not only responsible for synapse development and function but also involved in the pathophysiology of plasticity-related diseases. A review is made here on the function of miRNAs in governing synaptic plasticity, emphasizing the emerging regulatory role of individual miRNAs in synaptic morphological and functional plasticity, as well as their implications in neurological disorders. Understanding of the way in which miRNAs contribute to synaptic plasticity provides rational clues in establishing the novel therapeutic strategy for plasticity-related diseases.

  10. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

    Science.gov (United States)

    van Huijstee, Aile N.; Mansvelder, Huibert D.

    2015-01-01

    Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behavior, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA). This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC), with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioral symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drug-associated cues. Remodeling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction. PMID:25653591

  11. Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus.

    Directory of Open Access Journals (Sweden)

    Yiu Chung Tse

    Full Text Available Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs, which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP and long-term depression (LTD within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1-2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation.

  12. Testing Brain Overgrowth and Synaptic Models of Autism Using NPC’s and Neurons from Patient-Derived IPS Cells

    Science.gov (United States)

    2014-10-01

    Zikopoulos, B. & Barbas, H. Altered neural connectivity in excitatory and inhibitory cortical circuits in autism . Frontiers in human neuroscience 7, 609, doi:10.3389/fnhum.2013.00609 (2013). 11. APPENDICES: Nothing to report ...Models of Autism Using NPC’s and Neurons from Patient- Derived IPS Cells PRINCIPAL INVESTIGATOR: Fred H. Gage, Ph.D...SUBTITLE Testing Brain Overgrowth and Synaptic Models of Autism Using NPC’s and Neurons from Patient- Derived IPS Cells 5a. CONTRACT

  13. HR Connect

    Data.gov (United States)

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

  14. Internet Connectivity

    Indian Academy of Sciences (India)

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

  15. MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity

    International Nuclear Information System (INIS)

    Zhu Guoqi; Chen Ying; Huang Yuying; Li Qinglin; Behnisch, Thomas

    2011-01-01

    Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. - Highlights: → I.p. MPTP-injection mediates death of dopaminergic neurons. → I.p. MPTP-injection depletes DA and DOPAC in striatum and hippocampus. → I.p. MPTP-injection does not alter basal synaptic transmission. → Reduction of LTP and enhancement of LTD after i.p. MPTP-injection. → Attenuation of NMDA-receptors mediated

  16. Nicotinic mechanisms influencing synaptic plasticity in the hippocampus

    Science.gov (United States)

    Placzek, Andon Nicholas; Zhang, Tao A; Dani, John Anthony

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the hippocampus, and nicotinic signaling plays an important role in neuronal function. In the context of learning and memory related behaviors associated with hippocampal function, a potentially significant feature of nAChR activity is the impact it has on synaptic plasticity. Synaptic plasticity in hippocampal neurons has long been considered a contributing cellular mechanism of learning and memory. These same kinds of cellular mechanisms are a factor in the development of nicotine addiction. Nicotinic signaling has been demonstrated by in vitro studies to affect synaptic plasticity in hippocampal neurons via multiple steps, and the signaling has also been shown to evoke synaptic plasticity in vivo. This review focuses on the nAChRs subtypes that contribute to hippocampal synaptic plasticity at the cellular and circuit level. It also considers nicotinic influences over long-term changes in the hippocampus that may contribute to addiction. PMID:19434057

  17. [Involvement of aquaporin-4 in synaptic plasticity, learning and memory].

    Science.gov (United States)

    Wu, Xin; Gao, Jian-Feng

    2017-06-25

    Aquaporin-4 (AQP-4) is the predominant water channel in the central nervous system (CNS) and primarily expressed in astrocytes. Astrocytes have been generally believed to play important roles in regulating synaptic plasticity and information processing. However, the role of AQP-4 in regulating synaptic plasticity, learning and memory, cognitive function is only beginning to be investigated. It is well known that synaptic plasticity is the prime candidate for mediating of learning and memory. Long term potentiation (LTP) and long term depression (LTD) are two forms of synaptic plasticity, and they share some but not all the properties and mechanisms. Hippocampus is a part of limbic system that is particularly important in regulation of learning and memory. This article is to review some research progresses of the function of AQP-4 in synaptic plasticity, learning and memory, and propose the possible role of AQP-4 as a new target in the treatment of cognitive dysfunction.

  18. Synaptic Plasticity onto Dopamine Neurons Shapes Fear Learning.

    Science.gov (United States)

    Pignatelli, Marco; Umanah, George Kwabena Essien; Ribeiro, Sissi Palma; Chen, Rong; Karuppagounder, Senthilkumar Senthil; Yau, Hau-Jie; Eacker, Stephen; Dawson, Valina Lynn; Dawson, Ted Murray; Bonci, Antonello

    2017-01-18

    Fear learning is a fundamental behavioral process that requires dopamine (DA) release. Experience-dependent synaptic plasticity occurs on DA neurons while an organism is engaged in aversive experiences. However, whether synaptic plasticity onto DA neurons is causally involved in aversion learning is unknown. Here, we show that a stress priming procedure enhances fear learning by engaging VTA synaptic plasticity. Moreover, we took advantage of the ability of the ATPase Thorase to regulate the internalization of AMPA receptors (AMPARs) in order to selectively manipulate glutamatergic synaptic plasticity on DA neurons. Genetic ablation of Thorase in DAT + neurons produced increased AMPAR surface expression and function that lead to impaired induction of both long-term depression (LTD) and long-term potentiation (LTP). Strikingly, animals lacking Thorase in DAT + neurons expressed greater associative learning in a fear conditioning paradigm. In conclusion, our data provide a novel, causal link between synaptic plasticity onto DA neurons and fear learning. Published by Elsevier Inc.

  19. Stochastic lattice model of synaptic membrane protein domains

    Science.gov (United States)

    Li, Yiwei; Kahraman, Osman; Haselwandter, Christoph A.

    2017-05-01

    Neurotransmitter receptor molecules, concentrated in synaptic membrane domains along with scaffolds and other kinds of proteins, are crucial for signal transmission across chemical synapses. In common with other membrane protein domains, synaptic domains are characterized by low protein copy numbers and protein crowding, with rapid stochastic turnover of individual molecules. We study here in detail a stochastic lattice model of the receptor-scaffold reaction-diffusion dynamics at synaptic domains that was found previously to capture, at the mean-field level, the self-assembly, stability, and characteristic size of synaptic domains observed in experiments. We show that our stochastic lattice model yields quantitative agreement with mean-field models of nonlinear diffusion in crowded membranes. Through a combination of analytic and numerical solutions of the master equation governing the reaction dynamics at synaptic domains, together with kinetic Monte Carlo simulations, we find substantial discrepancies between mean-field and stochastic models for the reaction dynamics at synaptic domains. Based on the reaction and diffusion properties of synaptic receptors and scaffolds suggested by previous experiments and mean-field calculations, we show that the stochastic reaction-diffusion dynamics of synaptic receptors and scaffolds provide a simple physical mechanism for collective fluctuations in synaptic domains, the molecular turnover observed at synaptic domains, key features of the observed single-molecule trajectories, and spatial heterogeneity in the effective rates at which receptors and scaffolds are recycled at the cell membrane. Our work sheds light on the physical mechanisms and principles linking the collective properties of membrane protein domains to the stochastic dynamics that rule their molecular components.

  20. Stochastic lattice model of synaptic membrane protein domains.

    Science.gov (United States)

    Li, Yiwei; Kahraman, Osman; Haselwandter, Christoph A

    2017-05-01

    Neurotransmitter receptor molecules, concentrated in synaptic membrane domains along with scaffolds and other kinds of proteins, are crucial for signal transmission across chemical synapses. In common with other membrane protein domains, synaptic domains are characterized by low protein copy numbers and protein crowding, with rapid stochastic turnover of individual molecules. We study here in detail a stochastic lattice model of the receptor-scaffold reaction-diffusion dynamics at synaptic domains that was found previously to capture, at the mean-field level, the self-assembly, stability, and characteristic size of synaptic domains observed in experiments. We show that our stochastic lattice model yields quantitative agreement with mean-field models of nonlinear diffusion in crowded membranes. Through a combination of analytic and numerical solutions of the master equation governing the reaction dynamics at synaptic domains, together with kinetic Monte Carlo simulations, we find substantial discrepancies between mean-field and stochastic models for the reaction dynamics at synaptic domains. Based on the reaction and diffusion properties of synaptic receptors and scaffolds suggested by previous experiments and mean-field calculations, we show that the stochastic reaction-diffusion dynamics of synaptic receptors and scaffolds provide a simple physical mechanism for collective fluctuations in synaptic domains, the molecular turnover observed at synaptic domains, key features of the observed single-molecule trajectories, and spatial heterogeneity in the effective rates at which receptors and scaffolds are recycled at the cell membrane. Our work sheds light on the physical mechanisms and principles linking the collective properties of membrane protein domains to the stochastic dynamics that rule their molecular components.

  1. Effect of prenatal auditory stimulation on numerical synaptic density and mean synaptic height in the posthatch Day 1 chick hippocampus.

    Science.gov (United States)

    Chaudhury, Sraboni; Nag, Tapas Chandra; Wadhwa, Shashi

    2009-02-01

    Previous studies on prenatal auditory stimulation by species-specific sound or sitar music showed enhanced morphological and biochemical changes in chick hippocampus, which plays an important role in learning and memory. Changes in the efficiency of synapses, synaptic morphology and de novo synapse formation affects learning and memory. Therefore, in the present study, we set out to investigate the mean synaptic density and mean synaptic height at posthatch Day 1 in dorsal and ventral part of chick hippocampus following prenatal auditory stimulation. Fertilized 0 day eggs of domestic chick incubated under normal conditions were exposed to patterned sounds of species-specific and sitar music at 65 dB levels for 15 min/h round the clock (frequency range: 100-6300 Hz) from embryonic Day 10 till hatching. The synapses identified under transmission electron microscope were estimated for their numerical density by physical disector method and also the mean synaptic height calculated. Our results demonstrate a significant increase in mean synaptic density with no alterations in the mean synaptic height following both types of auditory stimulation in the dorsal as well as ventral part of the hippocampus. The observed increase in mean synaptic density suggests enhanced synaptic substrate to strengthen hippocampal function. 2008 Wiley-Liss, Inc.

  2. Epigenetic mechanisms in memory and synaptic function

    Science.gov (United States)

    Sultan, Faraz A; Day, Jeremy J

    2011-01-01

    Although the term ‘epigenetics’ was coined nearly seventy years ago, its critical function in memory processing by the adult CNS has only recently been appreciated. The hypothesis that epigenetic mechanisms regulate memory and behavior was motivated by the need for stable molecular processes that evade turnover of the neuronal proteome. In this article, we discuss evidence that supports a role for neural epigenetic modifications in the formation, consolidation and storage of memory. In addition, we will review the evidence that epigenetic mechanisms regulate synaptic plasticity, a cellular correlate of memory. We will also examine how the concerted action of multiple epigenetic mechanisms with varying spatiotemporal profiles influence selective gene expression in response to behavioral experience. Finally, we will suggest key areas for future research that will help elucidate the complex, vital and still mysterious, role of epigenetic mechanisms in neural function and behavior. PMID:22122279

  3. Alzheimer's disease: synaptic dysfunction and Abeta

    LENUS (Irish Health Repository)

    Shankar, Ganesh M

    2009-11-23

    Abstract Synapse loss is an early and invariant feature of Alzheimer\\'s disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid β-protein (Aβ) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Aβ are mediators of synaptic compromise. We also discuss the possible mechanisms of Aβ synaptotoxicity and potential targets for therapeutic intervention.

  4. Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders.

    Science.gov (United States)

    Sala, Carlo; Vicidomini, Cinzia; Bigi, Ilaria; Mossa, Adele; Verpelli, Chiara

    2015-12-01

    Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia. Thus, the term 'Shankopathies' identifies a number of neuronal diseases caused by alteration of Shank protein expression leading to abnormal synaptic development. With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations and also patients affected by other neurodevelopmental and neuropsychiatric disorders. Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia (SCZ). With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations. © 2015 International Society for Neurochemistry.

  5. Resistive and reactive changes to the impedance of intracortical microelectrodes can be mitigated with polyethylene glycol under acute in vitro and in vivo settings

    Directory of Open Access Journals (Sweden)

    Salah eSommakia

    2014-08-01

    Full Text Available The reactive response of brain tissue to implantable intracortical microelectrodes is thought to negatively affect their recordable signal quality and impedance, resulting in unreliable longitudinal performance. The relationship between the progression of the reactive tissue into a glial scar and the decline in device performance is unclear. We show that exposure to a model protein solution in vitro and acute implantation result in both resistive and capacitive changes to electrode impedance, rather than purely resistive changes. We also show that applying 4000 MW polyethylene glycol (PEG prevents impedance increases in vitro, and reduces the percent change in impedance in vivo following implantation. Our results highlight the importance of considering the contributions of non-cellular components to the decline in neural microelectrode performance, and present a proof of concept for using a simple dip-coated PEG film to modulate changes in microelectrode impedance.

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

    Science.gov (United States)

    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

  7. TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.

    Science.gov (United States)

    Liu, Yong; Zhou, Li-Jun; Wang, Jun; Li, Dai; Ren, Wen-Jie; Peng, Jiyun; Wei, Xiao; Xu, Ting; Xin, Wen-Jun; Pang, Rui-Ping; Li, Yong-Yong; Qin, Zhi-Hai; Murugan, Madhuvika; Mattson, Mark P; Wu, Long-Jun; Liu, Xian-Guo

    2017-01-25

    Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-α) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-α in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-α and microglial activation and may underlie chronic pain and memory deficits. Chronic pain is often accompanied by memory deficits. Previous studies have shown that peripheral nerve injury produces both neuropathic pain and memory deficits and induces long

  8. Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer's disease.

    Science.gov (United States)

    Garcia, Pierre; Youssef, Ihsen; Utvik, Jo K; Florent-Béchard, Sabrina; Barthélémy, Vanassa; Malaplate-Armand, Catherine; Kriem, Badreddine; Stenger, Christophe; Koziel, Violette; Olivier, Jean-Luc; Escanye, Marie-Christine; Hanse, Marine; Allouche, Ahmad; Desbène, Cédric; Yen, Frances T; Bjerkvig, Rolf; Oster, Thierry; Niclou, Simone P; Pillot, Thierry

    2010-06-02

    The development of novel therapeutic strategies for Alzheimer's disease (AD) represents one of the biggest unmet medical needs today. Application of neurotrophic factors able to modulate neuronal survival and synaptic connectivity is a promising therapeutic approach for AD. We aimed to determine whether the loco-regional delivery of ciliary neurotrophic factor (CNTF) could prevent amyloid-beta (Abeta) oligomer-induced synaptic damages and associated cognitive impairments that typify AD. To ensure long-term administration of CNTF in the brain, we used recombinant cells secreting CNTF encapsulated in alginate polymers. The implantation of these bioreactors in the brain of Abeta oligomer-infused mice led to a continuous secretion of recombinant CNTF and was associated with the robust improvement of cognitive performances. Most importantly, CNTF led to full recovery of cognitive functions associated with the stabilization of synaptic protein levels in the Tg2576 AD mouse model. In vitro as well as in vivo, CNTF activated a Janus kinase/signal transducer and activator of transcription-mediated survival pathway that prevented synaptic and neuronal degeneration. These preclinical studies suggest that CNTF and/or CNTF receptor-associated pathways may have AD-modifying activity through protection against progressive Abeta-related memory deficits. Our data also encourage additional exploration of ex vivo gene transfer for the prevention and/or treatment of AD.

  9. Gendered Connections

    DEFF Research Database (Denmark)

    Jensen, Steffen Bo

    2009-01-01

    This article explores the gendered nature of urban politics in Cape Town by focusing on a group of female, township politicians. Employing the Deleuzian concept of `wild connectivity', it argues that these politically entrepreneurial women were able to negotiate a highly volatile urban landscape...... space also drew on quite traditional notions of female respectability. Furthermore, the article argues, the form of wild connectivity to an extent was a function of the political transition, which destabilized formal structures of gendered authority. It remains a question whether this form...

  10. Connected Traveler

    Energy Technology Data Exchange (ETDEWEB)

    2016-06-01

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

  11. Connecting Grammaticalisation

    DEFF Research Database (Denmark)

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

    This monograph presents a view on grammaticalisation radically different from standard views centering around the cline of grammaticality. Grammar is seen as a complex sign system, and, as a consequence, grammatical change always comprises semantic change. What unites morphology, topology (word...... morphological, topological and constructional paradigms often connect to form complex paradigms. The book introduces the concept of connecting grammaticalisation to describe the formation, restructuring and dismantling of such complex paradigms. Drawing primarily on data from Germanic, Romance and Slavic...... languages, the book offers both a broad general discussion of theoretical issues (part one) and three case studies (part two)....

  12. Pannexin 1 Regulates Bidirectional Hippocampal Synaptic Plasticity in Adult Mice

    Directory of Open Access Journals (Sweden)

    Alvaro O. Ardiles

    2014-10-01

    Full Text Available The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR composition of GluN2 subunits. Pannexin 1 (Panx1, a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP, it remains unknown whether these channels also modulate long-term depression (LTD or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory.

  13. Synapse geometry and receptor dynamics modulate synaptic strength.

    Directory of Open Access Journals (Sweden)

    Dominik Freche

    Full Text Available Synaptic transmission relies on several processes, such as the location of a released vesicle, the number and type of receptors, trafficking between the postsynaptic density (PSD and extrasynaptic compartment, as well as the synapse organization. To study the impact of these parameters on excitatory synaptic transmission, we present a computational model for the fast AMPA-receptor mediated synaptic current. We show that in addition to the vesicular release probability, due to variations in their release locations and the AMPAR distribution, the postsynaptic current amplitude has a large variance, making a synapse an intrinsic unreliable device. We use our model to examine our experimental data recorded from CA1 mice hippocampal slices to study the differences between mEPSC and evoked EPSC variance. The synaptic current but not the coefficient of variation is maximal when the active zone where vesicles are released is apposed to the PSD. Moreover, we find that for certain type of synapses, receptor trafficking can affect the magnitude of synaptic depression. Finally, we demonstrate that perisynaptic microdomains located outside the PSD impacts synaptic transmission by regulating the number of desensitized receptors and their trafficking to the PSD. We conclude that geometrical modifications, reorganization of the PSD or perisynaptic microdomains modulate synaptic strength, as the mechanisms underlying long-term plasticity.

  14. Arc protein: a flexible hub for synaptic plasticity and cognition.

    Science.gov (United States)

    Nikolaienko, Oleksii; Patil, Sudarshan; Eriksen, Maria Steene; Bramham, Clive R

    2017-09-07

    Mammalian excitatory synapses express diverse types of synaptic plasticity. A major challenge in neuroscience is to understand how a neuron utilizes different types of plasticity to sculpt brain development, function, and behavior. Neuronal activity-induced expression of the immediate early protein, Arc, is critical for long-term potentiation and depression of synaptic transmission, homeostatic synaptic scaling, and adaptive functions such as long-term memory formation. However, the molecular basis of Arc protein function as a regulator of synaptic plasticity and cognition remains a puzzle. Recent work on the biophysical and structural properties of Arc, its protein-protein interactions and post-translational modifications have shed light on the issue. Here, we present Arc protein as a flexible, multifunctional and interactive hub. Arc interacts with specific effector proteins in neuronal compartments (dendritic spines, nuclear domains) to bidirectionally regulate synaptic strength by distinct molecular mechanisms. Arc stability, subcellular localization, and interactions are dictated by synaptic activity and post-translational modification of Arc. This functional versatility and context-dependent signaling supports a view of Arc as a highly specialized master organizer of long-term synaptic plasticity, critical for information storage and cognition. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice.

    Science.gov (United States)

    Ardiles, Alvaro O; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M; Palacios, Adrian G; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C; Martínez, Agustín D

    2014-01-01

    The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca(2+) concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory.

  16. Dynamic effective connectivity in resting state fMRI.

    Science.gov (United States)

    Park, Hae-Jeong; Friston, Karl J; Pae, Chongwon; Park, Bumhee; Razi, Adeel

    2017-11-20

    Context-sensitive and activity-dependent fluctuations in connectivity underlie functional integration in the brain and have been studied widely in terms of synaptic plasticity, learning and condition-specific (e.g., attentional) modulations of synaptic efficacy. This dynamic aspect of brain connectivity has recently attracted a lot of attention in the resting state fMRI community. To explain dynamic functional connectivity in terms of directed effective connectivity among brain regions, we introduce a novel method to identify dynamic effective connectivity using spectral dynamic causal modelling (spDCM). We used parametric empirical Bayes (PEB) to model fluctuations in directed coupling over consecutive windows of resting state fMRI time series. Hierarchical PEB can model random effects on connectivity parameters at the second (between-window) level given connectivity estimates from the first (within-window) level. In this work, we used a discrete cosine transform basis set or eigenvariates (i.e., expression of principal components) to model fluctuations in effective connectivity over windows. We evaluated the ensuing dynamic effective connectivity in terms of the consistency of baseline connectivity within default mode network (DMN), using the resting state fMRI from Human Connectome Project (HCP). To model group-level baseline and dynamic effective connectivity for DMN, we extended the PEB approach by conducting a multilevel PEB analysis of between-session and between-subject group effects. Model comparison clearly spoke to dynamic fluctuations in effective connectivity - and the dynamic functional connectivity these changes explain. Furthermore, baseline effective connectivity was consistent across independent sessions - and notably more consistent than estimates based upon conventional models. This work illustrates the advantage of hierarchical modelling with spDCM, in characterizing the dynamics of effective connectivity. Copyright © 2017 The Authors

  17. A Voltage Mode Memristor Bridge Synaptic Circuit with Memristor Emulators

    Directory of Open Access Journals (Sweden)

    Leon Chua

    2012-03-01

    Full Text Available A memristor bridge neural circuit which is able to perform signed synaptic weighting was proposed in our previous study, where the synaptic operation was verified via software simulation of the mathematical model of the HP memristor. This study is an extension of the previous work advancing toward the circuit implementation where the architecture of the memristor bridge synapse is built with memristor emulator circuits. In addition, a simple neural network which performs both synaptic weighting and summation is built by combining memristor emulators-based synapses and differential amplifier circuits. The feasibility of the memristor bridge neural circuit is verified via SPICE simulations.

  18. Get Connected

    Science.gov (United States)

    Horton, Jessica; Hagevik, Rita; Adkinson, Bennett; Parmly, Jilynn

    2013-01-01

    Technology can be both a blessing and a curse in the classroom. Although technology can provide greater access to information and increase student engagement, if screen time replaces time spent outside, then students stand to lose awareness and connectivity to the surrounding natural environment. This article describes how Google Earth can foster…

  19. Getting Connected

    Science.gov (United States)

    Larkin, Patrick

    2011-01-01

    That the world outside schools is changing faster than ever is old news. Unfortunately, that the world "inside" schools is changing at a glacial pace is even older news. As school leaders, principals have an important choice to make as they move into the second decade of the 21st century. School leaders have a moral obligation to connect and…

  20. Making connections

    NARCIS (Netherlands)

    Marion Duimel

    2007-01-01

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

  1. Creating Connections

    Science.gov (United States)

    Ellison, Ann

    2009-01-01

    In this article, the author talks about the Connections Camp, an innovative therapeutic social skill development program designed to meet the unique needs of youth with autism spectrum disorders (ASD). For six weeks each summer, youth ages 5-18 have fun while developing skills that lead to improved communication, better coping strategies, and…

  2. CMS Connect

    Science.gov (United States)

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

    2017-10-01

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

  3. Places Connected:

    DEFF Research Database (Denmark)

    Hansen, Annette Skovsted

    experiences of place, however, when it is often the same people who experience many different places? Along with many other so-called donors in the 1950s, Denmark and Japan chose to invest in the education of own and other nationals involved in development and thereby financed personal connections between...

  4. Activity Regulates the Incidence of Heteronymous Sensory-Motor Connections

    Science.gov (United States)

    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

  5. Synaptic signal streams generated by ex vivo neuronal networks contain non-random, complex patterns.

    Science.gov (United States)

    Lee, Sangmook; Zemianek, Jill M; Shultz, Abraham; Vo, Anh; Maron, Ben Y; Therrien, Mikaela; Courtright, Christina; Guaraldi, Mary; Yanco, Holly A; Shea, Thomas B

    2014-11-01

    Cultured embryonic neurons develop functional networks that transmit synaptic signals over multiple sequentially connected neurons as revealed by multi-electrode arrays (MEAs) embedded within the culture dish. Signal streams of ex vivo networks contain spikes and bursts of varying amplitude and duration. Despite the random interactions inherent in dissociated cultures, neurons are capable of establishing functional ex vivo networks that transmit signals among synaptically connected neurons, undergo developmental maturation, and respond to exogenous stimulation by alterations in signal patterns. These characteristics indicate that a considerable degree of organization is an inherent property of neurons. We demonstrate herein that (1) certain signal types occur more frequently than others, (2) the predominant signal types change during and following maturation, (3) signal predominance is dependent upon inhibitory activity, and (4) certain signals preferentially follow others in a non-reciprocal manner. These findings indicate that the elaboration of complex signal streams comprised of a non-random distribution of signal patterns is an emergent property of ex vivo neuronal networks. Copyright © 2014. Published by Elsevier Ltd.

  6. Synaptic remodeling generates synchronous oscillations in the degenerated outer mouse retina

    Science.gov (United States)

    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

  7. Autaptic self-inhibition of cortical GABAergic neurons: synaptic narcissism or useful introspection?

    Science.gov (United States)

    Deleuze, Charlotte; Pazienti, Antonio; Bacci, Alberto

    2014-06-01

    Fast synaptic inhibition sculpts all forms of cortical activity by means of a specialized connectivity pattern between highly heterogeneous inhibitory interneurons and principal excitatory cells. Importantly, inhibitory neurons connect also to each other extensively, following a detailed blueprint, and, indeed, specific forms of disinhibition affect important behavioral functions. Here we discuss a peculiar form of cortical disinhibition: the massive autaptic self-inhibition of parvalbumin-(PV) positive basket cells. Despite being described long ago, autaptic inhibition onto PV basket cells is rarely included in cortical circuit diagrams, perhaps because of its still elusive function. We propose here a potential dual role of autaptic feedback inhibition in temporally coordinating PV basket cells during cortical network activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Dendritic Branch Intersections Are Structurally Regulated Targets for Efficient Axonal Wiring and Synaptic Clustering

    Science.gov (United States)

    Pinchas, Monika; Baranes, Danny

    2013-01-01

    Synaptic clustering on dendritic branches enhances plasticity, input integration and neuronal firing. However, the mechanisms guiding axons to cluster synapses at appropriate sites along dendritic branches are poorly understood. We searched for such a mechanism by investigating the structural overlap between dendritic branches and axons in a simplified model of neuronal networks - the hippocampal cell culture. Using newly developed software, we converted images of meshes of overlapping axonal and dendrites into topological maps of intersections, enabling quantitative study of overlapping neuritic geometry at the resolution of single dendritic branch-to-branch and axon-to-branch crossings. Among dendro-dendritic crossing configurations, it was revealed that the orientations through which dendritic branches cross is a regulated attribute. While crossing angle distribution among branches thinner than 1 µm appeared to be random, dendritic branches 1 µm or wider showed a preference for crossing each other at angle ranges of either 50°–70° or 80°–90°. It was then found that the dendro-dendritic crossings themselves, as well as their selective angles, both affected the path of axonal growth. Axons displayed 4 fold stronger tendency to traverse within 2 µm of dendro-dendritic intersections than at farther distances, probably to minimize wiring length. Moreover, almost 70% of the 50°–70° dendro-denritic crossings were traversed by axons from the obtuse angle’s zone, whereas only 15% traversed through the acute angle’s zone. By contrast, axons showed no orientation restriction when traversing 80°–90° crossings. When such traverse behavior was repeated by many axons, they converged in the vicinity of dendro-dendritic intersections, thereby clustering their synaptic connections. Thus, the vicinity of dendritic branch-to-branch crossings appears to be a regulated structure used by axons as a target for efficient wiring and as a preferred site for synaptic

  9. Ribbon Synaptic Plasticity in Gravity Sensors of Rats Flown on Neurolab

    Science.gov (United States)

    Ross, Muriel D.; Varelas, Joseph

    2003-01-01

    Previous spaceflight experiments (Space Life Sciences-1 and -2 (SLS-1 and SLS-2)) first demonstrated the extraordinary ability of gravity sensor hair cells to change the number, kind, and distribution of connections (synapses) they make to other cells while in weightlessness. The number of synapses in hair cells in one part of the inner ear (the utricle) was markedly elevated on flight day 13 (FD13) of SLS-2. Unanswered questions, however, were whether these increases in synapses occur rapidly and whether they remain stable in weightlessness. The answers have implications for long-duration human space travel. If gravity sensors can adapt quickly, crews may be able to move easily between different gravity levels, since the sensors will adapt rapidly to weightlessness on the spacecraft and then back to Earth's gravity when the mission ends. This ability to adapt is also important for recovery from balance disorders. To further our understanding of this adaptive potential (a property called neuronal synaptic plasticity), the present Neurolab research was undertaken. Our experiment examined whether: (a) increases in synapses would remain stable throughout the flight, (b) changes in the number of synapses were uniform across different portions of the gravity sensors (the utricle and saccule), and (c) synaptic changes were similar for the different types of hair cells (Type I and Type II). Utricular and saccular maculae (the gravity-sensing portions of the inner ear) were collected in flight from rats on FD2 and FD14. Samples were also collected from control rats on the ground. Tissues were prepared for ultrastructural study. Hair cells and their ribbon synapses were examined in a transmission electron microscope. Synapses were counted in all hair cells in 50 consecutive sections that crossed the striolar zone. Results indicate that utricular hair cell synapses initially increased significantly in number in both types of hair cells by FD2. Counts declined by FD14, but

  10. A Model of Bidirectional Synaptic Plasticity: From Signaling Network to Channel Conductance

    Science.gov (United States)

    Castellani, Gastone C.; Quinlan, Elizabeth M.; Bersani, Ferdinando; Cooper, Leon N.; Shouval, Harel Z.

    2005-01-01

    In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of…

  11. A presynaptic role for PKA in synaptic tagging and memory

    NARCIS (Netherlands)

    Park, Alan Jung; Havekes, Robbert; Choi, Jennifer H K; Luczak, Vincent; Nie, Ting; Huang, Ted; Abel, Ted

    2014-01-01

    Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and

  12. The roles of STP and LTP in synaptic encoding

    Directory of Open Access Journals (Sweden)

    Arturas Volianskis

    2013-02-01

    Full Text Available Long-term potentiation (LTP, a cellular model of learning and memory, is generally regarded as a unitary phenomenon that alters the strength of synaptic transmission by increasing the postsynaptic response to the release of a quantum of neurotransmitter. LTP, at CA3-CA1 synapses in the hippocampus, contains a stimulation-labile phase of short-term potentiation (STP, or transient LTP, t-LTP that decays into stable LTP. By studying the responses of populations of neurons to brief bursts of high-frequency afferent stimulation before and after the induction of LTP, we found that synaptic responses during bursts are potentiated equally during LTP but not during STP. We show that STP modulates the frequency response of synaptic transmission whereas LTP preserves the fidelity. Thus, STP and LTP have different functional consequences for the transfer of synaptic information.

  13. Neuro-inspired computing using resistive synaptic devices

    CERN Document Server

    2017-01-01

    This book summarizes the recent breakthroughs in hardware implementation of neuro-inspired computing using resistive synaptic devices. The authors describe how two-terminal solid-state resistive memories can emulate synaptic weights in a neural network. Readers will benefit from state-of-the-art summaries of resistive synaptic devices, from the individual cell characteristics to the large-scale array integration. This book also discusses peripheral neuron circuits design challenges and design strategies. Finally, the authors describe the impact of device non-ideal properties (e.g. noise, variation, yield) and their impact on the learning performance at the system-level, using a device-algorithm co-design methodology. • Provides single-source reference to recent breakthroughs in resistive synaptic devices, not only at individual cell-level, but also at integrated array-level; • Includes detailed discussion of the peripheral circuits and array architecture design of the neuro-crossbar system; • Focuses on...

  14. Experience-dependent homeostatic synaptic plasticity in neocortex.

    Science.gov (United States)

    Whitt, Jessica L; Petrus, Emily; Lee, Hey-Kyoung

    2014-03-01

    The organism's ability to adapt to the changing sensory environment is due in part to the ability of the nervous system to change with experience. Input and synapse specific Hebbian plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), are critical for sculpting the nervous system to wire its circuit in tune with the environment and for storing memories. However, these synaptic plasticity mechanisms are innately unstable and require another mode of plasticity that maintains homeostasis to allow neurons to function within a desired dynamic range. Several modes of homeostatic adaptation are known, some of which work at the synaptic level. This review will focus on the known mechanisms of experience-induced homeostatic synaptic plasticity in the neocortex and their potential function in sensory cortex plasticity. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Brain Regions Showing White Matter Loss in Huntington's Disease Are Enriched for Synaptic and Metabolic Genes.

    Science.gov (United States)

    McColgan, Peter; Gregory, Sarah; Seunarine, Kiran K; Razi, Adeel; Papoutsi, Marina; Johnson, Eileanoir; Durr, Alexandra; Roos, Raymund A C; Leavitt, Blair R; Holmans, Peter; Scahill, Rachael I; Clark, Chris A; Rees, Geraint; Tabrizi, Sarah J

    2018-03-01

    The earliest white matter changes in Huntington's disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability. Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington's disease relative to control participants. The baseline cohort included 72 premanifest Huntington's disease participants and 85 healthy control participants. We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntington's disease is associated with gene expression profiles enriched for synaptic genes and metabolic genes. Corticostriatal gene expression profiles are predominately associated with motor, parietal, and occipital regions, while interhemispheric expression profiles are associated with frontotemporal regions. We also show that genes with known abnormal transcription in human Huntington's disease and animal models are overrepresented in synaptic gene expression profiles, but not in metabolic gene expression profiles. These findings suggest a dual mechanism of white matter vulnerability in Huntington's disease, in which abnormal transcription of synaptic genes and metabolic disturbance not related to transcription may drive white matter loss. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  16. Synaptic Control of Secretory Trafficking in Dendrites

    Directory of Open Access Journals (Sweden)

    Cyril Hanus

    2014-06-01

    Full Text Available Localized signaling in neuronal dendrites requires tight spatial control of membrane composition. Upon initial synthesis, nascent secretory cargo in dendrites exits the endoplasmic reticulum (ER from local zones of ER complexity that are spatially coupled to post-ER compartments. Although newly synthesized membrane proteins can be processed locally, the mechanisms that control the spatial range of secretory cargo transport in dendritic segments are unknown. Here, we monitored the dynamics of nascent membrane proteins in dendritic post-ER compartments under regimes of low or increased neuronal activity. In response to activity blockade, post-ER carriers are highly mobile and are transported over long distances. Conversely, increasing synaptic activity dramatically restricts the spatial scale of post-ER trafficking along dendrites. This activity-induced confinement of secretory cargo requires site-specific phosphorylation of the kinesin motor KIF17 by Ca2+/calmodulin-dependent protein kinases (CaMK. Thus, the length scales of early secretory trafficking in dendrites are tuned by activity-dependent regulation of microtubule-dependent transport.

  17. Design principles of electrical synaptic plasticity.

    Science.gov (United States)

    O'Brien, John

    2017-09-08

    Essentially all animals with nervous systems utilize electrical synapses as a core element of communication. Electrical synapses, formed by gap junctions between neurons, provide rapid, bidirectional communication that accomplishes tasks distinct from and complementary to chemical synapses. These include coordination of neuron activity, suppression of voltage noise, establishment of electrical pathways that define circuits, and modulation of high order network behavior. In keeping with the omnipresent demand to alter neural network function in order to respond to environmental cues and perform tasks, electrical synapses exhibit extensive plasticity. In some networks, this plasticity can have dramatic effects that completely remodel circuits or remove the influence of certain cell types from networks. Electrical synaptic plasticity occurs on three distinct time scales, ranging from milliseconds to days, with different mechanisms accounting for each. This essay highlights principles that dictate the properties of electrical coupling within networks and the plasticity of the electrical synapses, drawing examples extensively from retinal networks. Copyright © 2017 The Author. Published by Elsevier B.V. All rights reserved.

  18. Development of auditory cortical synaptic receptive fields.

    Science.gov (United States)

    Froemke, Robert C; Jones, Bianca J

    2011-11-01

    The central nervous system is plastic throughout life, but is most sensitive to the statistics of the sensory environment during critical periods of early postnatal development. In the auditory cortex, various forms of acoustic experience have been found to shape the formation of receptive fields and influence the overall rate of cortical organization. The synaptic mechanisms that control cortical receptive field plasticity are beginning to be described, particularly for frequency tuning in rodent primary auditory cortex. Inhibitory circuitry plays a major role in critical period regulation, and new evidence suggests that the formation of excitatory-inhibitory balance determines the duration of critical period plasticity for auditory cortical frequency tuning. Cortical inhibition is poorly tuned in the infant brain, but becomes co-tuned with excitation in an experience-dependent manner over the first postnatal month. We discuss evidence suggesting that this may be a general feature of the developing cortex, and describe the functional implications of such transient excitatory-inhibitory imbalance. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. Inhibitory Control of Synaptic and Behavioral Plasticity by Octopaminergic Signaling

    Science.gov (United States)

    Koon, Alex C.; Budnik, Vivian

    2012-01-01

    Adrenergic receptors and their ligands are important regulators of synaptic plasticity and metaplasticity, but the exact mechanisms underlying their action are still poorly understood. Octopamine, the invertebrate homolog of mammalian adrenaline or noradrenaline, plays important roles in modulating behavior and synaptic functions. We previously uncovered an octopaminergic positive feedback mechanism to regulate structural synaptic plasticity during development and in response to starvation. Under this mechanism, activation of Octß2R autoreceptors by octopamine at octopaminergic neurons initiated a cAMP-dependent cascade that stimulated the development of new synaptic boutons at the Drosophila larval neuromuscular junction (NMJ). However, the regulatory mechanisms that served to brake such positive feedback were not known. Here, we report the presence of an alternative octopamine autoreceptor, Octß1R, with antagonistic functions on synaptic growth. Mutations in octß1r result in the overgrowth of both glutamatergic and octopaminergic NMJs suggesting that Octß1R is a negative regulator of synaptic expansion. As Octß2R, Octß1R functioned in a cell autonomous manner at presynaptic motorneurons. However, unlike Octß2R, which activated a cAMP pathway, Octß1R likely inhibited cAMP production through inhibitory Goα. Despite its inhibitory role, Octß1R was required for acute changes in synaptic structure in response to octopamine and for starvation-induced increase in locomotor speed. These results demonstrate the dual action of octopamine on synaptic growth and behavioral plasticity, and highlight the important role of inhibitory influences for normal responses to physiological stimuli. PMID:22553037

  20. Common mechanisms of synaptic plasticity in vertebrates and invertebrates

    Science.gov (United States)

    Glanzman, David L.

    2016-01-01

    Until recently, the literature on learning-related synaptic plasticity in invertebrates has been dominated by models assuming plasticity is mediated by presynaptic changes, whereas the vertebrate literature has been dominated by models assuming it is mediated by postsynaptic changes. Here I will argue that this situation does not reflect a biological reality and that, in fact, invertebrate and vertebrate nervous systems share a common set of mechanisms of synaptic plasticity. PMID:20152143

  1. Synaptic plasticity model of therapeutic sleep deprivation in major depression.

    Science.gov (United States)

    Wolf, Elias; Kuhn, Marion; Normann, Claus; Mainberger, Florian; Maier, Jonathan G; Maywald, Sarah; Bredl, Aliza; Klöppel, Stefan; Biber, Knut; van Calker, Dietrich; Riemann, Dieter; Sterr, Annette; Nissen, Christoph

    2016-12-01

    Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50-60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i.e., the neural basis of adaptive network function and behavior, represent a critical mechanism of therapeutic SD in MDD. Particularly, this article centers on two major hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, and on how they can be integrated into a novel synaptic plasticity model of therapeutic SD in MDD. As a major component, the model proposes that therapeutic SD, by homeostatically enhancing cortical synaptic strength, shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP) in patients with MDD in a more favorable window of associative plasticity. Research on the molecular effects of SD in animals and humans, including observations in the neurotrophic, adenosinergic, monoaminergic, and glutamatergic system, provides some support for the hypothesis of associative synaptic plasticity facilitation after therapeutic SD in MDD. The model proposes a novel framework for a mechanism of action of therapeutic SD that can be further tested in humans based on non-invasive indices and in animals based on direct studies of synaptic plasticity. Further determining the mechanisms of action of SD might contribute to the development of novel fast acting treatments for MDD, one of the major health problems worldwide. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. An Improved Test for Detecting Multiplicative Homeostatic Synaptic Scaling

    Science.gov (United States)

    Kim, Jimok; Tsien, Richard W.; Alger, Bradley E.

    2012-01-01

    Homeostatic scaling of synaptic strengths is essential for maintenance of network “gain”, but also poses a risk of losing the distinctions among relative synaptic weights, which are possibly cellular correlates of memory storage. Multiplicative scaling of all synapses has been proposed as a mechanism that would preserve the relative weights among them, because they would all be proportionately adjusted. It is crucial for this hypothesis that all synapses be affected identically, but whether or not this actually occurs is difficult to determine directly. Mathematical tests for multiplicative synaptic scaling are presently carried out on distributions of miniature synaptic current amplitudes, but the accuracy of the test procedure has not been fully validated. We now show that the existence of an amplitude threshold for empirical detection of miniature synaptic currents limits the use of the most common method for detecting multiplicative changes. Our new method circumvents the problem by discarding the potentially distorting subthreshold values after computational scaling. This new method should be useful in assessing the underlying neurophysiological nature of a homeostatic synaptic scaling transformation, and therefore in evaluating its functional significance. PMID:22615990

  3. BDNF-induced local protein synthesis and synaptic plasticity.

    Science.gov (United States)

    Leal, Graciano; Comprido, Diogo; Duarte, Carlos B

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and long-term potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-γ (PLC-γ) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre- and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short- and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Self-organised criticality via retro-synaptic signals

    Science.gov (United States)

    Hernandez-Urbina, Victor; Herrmann, J. Michael

    2016-12-01

    The brain is a complex system par excellence. In the last decade the observation of neuronal avalanches in neocortical circuits suggested the presence of self-organised criticality in brain networks. The occurrence of this type of dynamics implies several benefits to neural computation. However, the mechanisms that give rise to critical behaviour in these systems, and how they interact with other neuronal processes such as synaptic plasticity are not fully understood. In this paper, we present a long-term plasticity rule based on retro-synaptic signals that allows the system to reach a critical state in which clusters of activity are distributed as a power-law, among other observables. Our synaptic plasticity rule coexists with other synaptic mechanisms such as spike-timing-dependent plasticity, which implies that the resulting synaptic modulation captures not only the temporal correlations between spiking times of pre- and post-synaptic units, which has been suggested as requirement for learning and memory in neural systems, but also drives the system to a state of optimal neural information processing.

  5. NMDA-receptor inhibition restores Protease-Activated Receptor 1 (PAR1) mediated alterations in homeostatic synaptic plasticity of denervated mouse dentate granule cells.

    Science.gov (United States)

    Becker, Denise; Ikenberg, Benno; Schiener, Sabine; Maggio, Nicola; Vlachos, Andreas

    2014-11-01

    A common feature of neurological diseases is the loss of central neurons, which leads to deafferentation of connected brain regions. In turn, the remodeling of denervated neuronal networks is considered to play an important role for the postlesional recovery, but has also been linked to maladaptive plasticity resulting in disease-related complications such as memory dysfunction or epilepsy. Recent work has indicated that Protease-Activated Receptor 1 (PAR1), which can be activated by thrombin that enters the brain under pathological conditions, alters synaptic plasticity and neuronal excitability. However, the role of PAR1 in lesion-induced synaptic plasticity remains incompletely understood. Here, we used entorhinal denervation of organotypic hippocampal slice cultures to study the effects of PAR1 on denervation-induced homeostatic synaptic plasticity. Our results disclose that PAR1 activation counters the ability of denervated dentate granule cells to increase their excitatory synaptic strength in a compensatory, i.e., homeostatic manner. Furthermore, we demonstrate that this PAR1 effect is rescued by pharmacological inhibition of N-methyl-d-aspartate receptors (NMDA-R). Thus, NMDA-R inhibitors may restore the ability of denervated neurons to express homeostatic synaptic plasticity under conditions of increased PAR1-activity, which may contribute to their beneficial effects seen in the context of neurological diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Crossmodal Connections of Primary Sensory Cortices Largely Vanish During Normal Aging

    Science.gov (United States)

    Henschke, Julia U.; Ohl, Frank W.; Budinger, Eike

    2018-01-01

    During aging, human response times (RTs) to unisensory and crossmodal stimuli decrease. However, the elderly benefit more from crossmodal stimulus representations than younger people. The underlying short-latency multisensory integration process is mediated by direct crossmodal connections at the level of primary sensory cortices. We investigate the age-related changes of these connections using a rodent model (Mongolian gerbil), retrograde tracer injections into the primary auditory (A1), somatosensory (S1), and visual cortex (V1), and immunohistochemistry for markers of apoptosis (Caspase-3), axonal plasticity (Growth associated protein 43, GAP 43), and a calcium-binding protein (Parvalbumin, PV). In adult animals, primary sensory cortices receive a substantial number of direct thalamic inputs from nuclei of their matched, but also from nuclei of non-matched sensory modalities. There are also direct intracortical connections among primary sensory cortices and connections with secondary sensory cortices of other modalities. In very old animals, the crossmodal connections strongly decrease in number or vanish entirely. This is likely due to a retraction of the projection neuron axonal branches rather than ongoing programmed cell death. The loss of crossmodal connections is also accompanied by changes in anatomical correlates of inhibition and excitation in the sensory thalamus and cortex. Together, the loss and restructuring of crossmodal connections during aging suggest a shift of multisensory processing from primary cortices towards other sensory brain areas in elderly individuals. PMID:29551970

  7. Dopaminergic modulation of default mode network brain functional connectivity in attention deficit hyperactivity disorder.

    Science.gov (United States)

    Silberstein, Richard B; Pipingas, Andrew; Farrow, Maree; Levy, Florence; Stough, Con K

    2016-12-01

    Recent evidence suggests that attention deficit hyperactivity disorder (ADHD) is associated with a range of brain functional connectivity abnormalities, with one of the most prominent being reduced inhibition of the default mode network (DMN) while performing a cognitive task. In this study, we examine the effects of a methylphenidate dose on brain functional connectivity in boys diagnosed with ADHD while they performed a cognitive task. Brain functional connectivity was estimated using steady-state visual evoked potential partial coherence before and 90 min after the administration of a methylphenidate dose to 42 stimulant drug-naïve boys newly diagnosed with ADHD while they performed the A-X version of the continuous performance task (CPT A-X). Methylphenidate robustly reversed the transient functional connectivity increase in the A-X interval seen premedication to a postmedication decrease during this interval. In addition, methylphenidate-induced reductions in individual reaction time were correlated with corresponding reductions in functional connectivity. These findings suggest that methylphenidate suppresses the increased functional connectivity observed in ADHD and that such suppression is associated with improved performance. Our findings support the suggestion that the increased functional connectivity we have observed in ADHD is associated with abnormal DMN activity. In addition, we comment on the significance of specific frequency channels mediating top-down communication within the cortex and the extent to which our findings are selectively sensitive to top-down intracortical communication.

  8. Crossmodal Connections of Primary Sensory Cortices Largely Vanish During Normal Aging

    Directory of Open Access Journals (Sweden)

    Julia U. Henschke

    2018-03-01

    Full Text Available During aging, human response times (RTs to unisensory and crossmodal stimuli decrease. However, the elderly benefit more from crossmodal stimulus representations than younger people. The underlying short-latency multisensory integration process is mediated by direct crossmodal connections at the level of primary sensory cortices. We investigate the age-related changes of these connections using a rodent model (Mongolian gerbil, retrograde tracer injections into the primary auditory (A1, somatosensory (S1, and visual cortex (V1, and immunohistochemistry for markers of apoptosis (Caspase-3, axonal plasticity (Growth associated protein 43, GAP 43, and a calcium-binding protein (Parvalbumin, PV. In adult animals, primary sensory cortices receive a substantial number of direct thalamic inputs from nuclei of their matched, but also from nuclei of non-matched sensory modalities. There are also direct intracortical connections among primary sensory cortices and connections with secondary sensory cortices of other modalities. In very old animals, the crossmodal connections strongly decrease in number or vanish entirely. This is likely due to a retraction of the projection neuron axonal branches rather than ongoing programmed cell death. The loss of crossmodal connections is also accompanied by changes in anatomical correlates of inhibition and excitation in the sensory thalamus and cortex. Together, the loss and restructuring of crossmodal connections during aging suggest a shift of multisensory processing from primary cortices towards other sensory brain areas in elderly individuals.

  9. Connecting dots

    DEFF Research Database (Denmark)

    Murakami, Kyoko; Jacobs, Rachel L.

    2017-01-01

    the family history. We explore how intergenerational relationships are formed through associations with membership categories and reveal how vital information is passed onto future generations. Unlike conventional reminiscence used for therapeutic purposes, family reminiscence is a discursive practice...... of connecting the dots of recalled moments of individual family members lives and is geared towards building a family’s shared future for posterity. Lastly, we consider a wider implication of family reminiscence in terms of human development. http://www.infoagepub.com/products/Memory-Practices-and-Learning...

  10. Synaptic dimorphism in Onychophoran cephalic ganglia

    Directory of Open Access Journals (Sweden)

    Z Peña-Contreras

    2007-03-01

    Full Text Available The taxonomic location of the Onychophora has been controversial because of their phenotypic and genotypic characteristics, related to both annelids and arthropods. We analyzed the ultrastructure of the neurons and their synapses in the cephalic ganglion of a poorly known invertebrate, the velvet worm Peripatus sedgwicki, from the mountainous region of El Valle, Mérida, Venezuela. Cephalic ganglia were dissected, fixed and processed for transmission electron microscopy. The animal has a high degree of neurobiological development, as evidenced by the presence of asymmetric (excitatory and symmetric (inhibitory synapses, as well as the existence of glial cell processes in a wide neuropile zone. The postsynaptic terminals were seen to contain subsynaptic cisterns formed by membranes of smooth endoplasmic reticulum beneath the postsynaptic density, whereas the presynaptic terminal showed numerous electron transparent synaptic vesicles. From the neurophylogenetic perspectives, the ultrastructural characteristics of the central nervous tissue of the Onychophora show important evolutionary acquirements, such as the presence of both excitatory and inhibitory synapses, indicating functional synaptic transmission, and the appearance of mature glial cells. Rev. Biol . Trop. 55 (1: 261-267. Epub 2007 March. 31.Estudiamos la ultraestructura de las neuronas y sus sinapsis del ganglio cefálico de un invertebrado poco conocido del phylum Onychophora: Peripatus sedgwicki de los Andes Venezolanos, utilizando para ello la microscopía electrónica de transmisión. La localización taxonómica de los onicóforos ha sido controversial debido a sus características fenotípicas y genotípicas que los relacionan tanto con los anélidos como con los artrópodos. Para este trabajo se estudió el ganglio cefálico de P. sedgwicki de la zona montañosa de El Valle, Mérida, Venezuela. El ganglio cefálico se localiza en la región anterior del animal y fue diseccionado

  11. Neural control of cursor trajectory and click by a human with tetraplegia 1000 days after implant of an intracortical microelectrode array

    Science.gov (United States)

    Simeral, J. D.; Kim, S.-P.; Black, M. J.; Donoghue, J. P.; Hochberg, L. R.

    2011-04-01

    The ongoing pilot clinical trial of the BrainGate neural interface system aims in part to assess the feasibility of using neural activity obtained from a small-scale, chronically implanted, intracortical microelectrode array to provide control signals for a neural prosthesis system. Critical questions include how long implanted microelectrodes will record useful neural signals, how reliably those signals can be acquired and decoded, and how effectively they can be used to control various assistive technologies such as computers and robotic assistive devices, or to enable functional electrical stimulation of paralyzed muscles. Here we examined these questions by assessing neural cursor control and BrainGate system characteristics on five consecutive days 1000 days after implant of a 4 × 4 mm array of 100 microelectrodes in the motor cortex of a human with longstanding tetraplegia subsequent to a brainstem stroke. On each of five prospectively-selected days we performed time-amplitude sorting of neuronal spiking activity, trained a population-based Kalman velocity decoding filter combined with a linear discriminant click state classifier, and then assessed closed-loop point-and-click cursor control. The participant performed both an eight-target center-out task and a random target Fitts metric task which was adapted from a human-computer interaction ISO standard used to quantify performance of computer input devices. The neural interface system was further characterized by daily measurement of electrode impedances, unit waveforms and local field potentials. Across the five days, spiking signals were obtained from 41 of 96 electrodes and were successfully decoded to provide neural cursor point-and-click control with a mean task performance of 91.3% ± 0.1% (mean ± s.d.) correct target acquisition. Results across five consecutive days demonstrate that a neural interface system based on an intracortical microelectrode array can provide repeatable, accurate point

  12. Synaptic polarity of the command interneurons for Caenorhabditis Elegans directional motion

    Directory of Open Access Journals (Sweden)

    Franciszek Maria Rakowski

    2014-03-01

    Full Text Available The command interneuron circuit for Caenorhabditis Elegans locomotion has been known for a long time [1,2]. However, synaptic polarities of these interneurons, and thus, the circuit functioning is largely unknown. Additionally, nematode command neurons express both glutamate-gated chloride channels and glutamate-gated cation channels, which causes that each synapse, even when belonging to the same neuron, might be either inhibitory or excitatory. We use an experimental behavioral data set: eighteen different neural ablations were performed and times spent in the forward and reverse motions were registered. Therefore one can consider eighteen different command neuron network structures where each one as a whole, controls the behavior of the nematode, and results with one of the eighteen different behavioral patterns. In order to decipher the particular polarities of each neuron we have constructed a theoretical (interneuron network model, in which neural activities are represented by a set of differential equations and searched all possible synaptic polarity combinations in the circuit to find the best match to the timing data [3,4]. Here, we present the extension of this model, where we explicitly incorporate calcium concentration dynamics as the regulatory factor and detailed connectivity diagram based on the transmission type of each synapse. Since the parameter space spanned by the morphological and regulatory factors is huge, we have applied an evolutionary strategy for finding the parameters of the mathematical model, for which the theoretical results and the experimental data fit the best. The overall model output consists of the averaged values: neuron activities, calcium concentration levels, input signal (the upstream neurons activity pattern and of the resolved detailed connectivity diagram. The deciphered list of the types of synapses states that most of the synapses, including strongest connections, e.g. ASH ->

  13. Synaptic and functional linkages between spinal premotor interneurons and hand-muscle activity during precision grip

    Directory of Open Access Journals (Sweden)

    Tomohiko eTakei

    2013-04-01

    Full Text Available Grasping is a highly complex movement that requires the coordination of a number of hand joints and muscles. Previous studies showed that spinal premotor interneurons (PreM-INs in the primate cervical spinal cord have divergent synaptic effects on hand motoneurons and that they might contribute to hand-muscle synergies. However, the extent to which these PreM-IN synaptic connections functionally contribute to modulating hand-muscle activity is not clear. In this paper, we explored the contribution of spinal PreM-INs to hand-muscle activation by quantifying the synaptic linkage (SL and functional linkage (FL of the PreM-INs with hand-muscle activities. The activity of 23 PreM-INs was recorded from the cervical spinal cord (C6–T1, with EMG signals measured simultaneously from hand and arm muscles in two macaque monkeys performing a precision grip task. Spike-triggered averages (STAs of rectified EMGs were compiled for 456 neuron–muscle pairs; 63 pairs showed significant post-spike effects (i.e., SL. Conversely, 231 of 456 pairs showed significant cross-correlations between the IN firing rate and rectified EMG (i.e., FL. Importantly, a greater proportion of the neuron–muscle pairs with SL showed FL (43/63 pairs, 68% compared with the pairs without SL (203/393, 52%, and the presence of SL was significantly associated with that of FL. However, a significant number of pairs had SL without FL (SL∩!FL, n = 20 or FL without SL (!SL∩FL, n = 203, and the proportions of these incongruities exceeded the number expected by chance. These results suggested that spinal PreM-INs function to significantly modulate hand-muscle activity during precision grip, but the contribution of other neural structures is also needed to recruit an adequate combination of hand-muscle motoneurons.

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

    Science.gov (United States)

    Srinivasa, Narayan; Cho, Youngkwan

    2014-01-01

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

  15. Bayesian inference of synaptic quantal parameters from correlated vesicle release

    Directory of Open Access Journals (Sweden)

    Alexander D Bird

    2016-11-01

    Full Text Available Synaptic transmission is both history-dependent and stochastic, resulting in varying responses to presentations of the same presynaptic stimulus. This complicates attempts to infer synaptic parameters and has led to the proposal of a number of different strategies for their quantification. Recently Bayesian approaches have been applied to make more efficient use of the data collected in paired intracellular recordings. Methods have been developed that either provide a complete model of the distribution of amplitudes for isolated responses or approximate the amplitude distributions of a train of post-synaptic potentials, with correct short-term synaptic dynamics but neglecting correlations. In both cases the methods provided significantly improved inference of model parameters as compared to existing mean-variance fitting approaches. However, for synapses with high release probability, low vesicle number or relatively low restock rate and for data in which only one or few repeats of the same pattern are available, correlations between serial events can allow for the extraction of significantly more information from experiment: a more complete Bayesian approach would take this into account also. This has not been possible previously because of the technical difficulty in calculating the likelihood of amplitudes seen in correlated post-synaptic potential trains; however, recent theoretical advances have now rendered the likelihood calculation tractable for a broad class of synaptic dynamics models. Here we present a compact mathematical form for the likelihood in terms of a matrix product and demonstrate how marginals of the posterior provide information on covariance of parameter distributions. The associated computer code for Bayesian parameter inference for a variety of models of synaptic dynamics is provided in the supplementary material allowing for quantal and dynamical parameters to be readily inferred from experimental data sets.

  16. Synaptic vesicle dynamic changes in a model of fragile X.

    Science.gov (United States)

    Broek, Jantine A C; Lin, Zhanmin; de Gruiter, H Martijn; van 't Spijker, Heleen; Haasdijk, Elize D; Cox, David; Ozcan, Sureyya; van Cappellen, Gert W A; Houtsmuller, Adriaan B; Willemsen, Rob; de Zeeuw, Chris I; Bahn, Sabine

    2016-01-01

    Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated. Here, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MS(E)) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy. Key findings relate to altered levels of proteins involved in GABA-signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission. Our findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS.

  17. 78 FR 55684 - ConnectED Workshop

    Science.gov (United States)

    2013-09-11

    ... connecting virtually all K-12 students in the United States to next- generation broadband. This Notice...'s ConnectED initiative would bring next-generation Internet speeds to K-12 schools across the nation... schools for digital learning. The ConnectED Workshop will discuss the growing bandwidth needs of K-12...

  18. Development of neural circuitry for precise temporal sequences through spontaneous activity, axon remodeling, and synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Joseph K Jun

    2007-08-01

    Full Text Available Temporally precise sequences of neuronal spikes that span hundreds of milliseconds are observed in many brain areas, including songbird premotor nucleus, cat visual cortex, and primary motor cortex. Synfire chains-networks in which groups of neurons are connected via excitatory synapses into a unidirectional chain-are thought to underlie the generation of such sequences. It is unknown, however, how synfire chains can form in local neural circuits, especially for long chains. Here, we show through computer simulation that long synfire chains can develop through spike-time dependent synaptic plasticity and axon remodeling-the pruning of prolific weak connections that follows the emergence of a finite number of strong connections. The formation process begins with a random network. A subset of neurons, called training neurons, intermittently receive superthreshold external input. Gradually, a synfire chain emerges through a recruiting process, in which neurons within the network connect to the tail of the chain started by the training neurons. The model is robust to varying parameters, as well as natural events like neuronal turnover and massive lesions. Our model suggests that long synfire chain can form during the development through self-organization, and axon remodeling, ubiquitous in developing neural circuits, is essential in the process.

  19. Assessing direct paths of intracortical causal information flow of oscillatory activity with the isolated effective coherence (iCoh

    Directory of Open Access Journals (Sweden)

    Roberto D Pascual-Marqui

    2014-06-01

    Full Text Available Functional connectivity is of central importance in understanding brain function. For this purpose, multiple time series of electric cortical activity can be used for assessing the properties of a network: the strength, directionality, and spectral characteristics (i.e. which oscillations are preferentially transmitted of the connections. The partial directed coherence (PDC of Baccala and Sameshima (2001 is a widely used method for this problem. The three aims of this study are: (1 To show that the PDC can misrepresent the frequency response under plausible realistic conditions, thus defeating the main purpose for which the measure was developed; (2 To provide a solution to this problem, namely the isolated effective coherence (iCoh, which consists of estimating the partial coherence under a multivariate autoregressive model, followed by setting all irrelevant associations to zero, other than the particular directional association of interest; and (3 To show that adequate iCoh estimators can be obtained from non-invasively computed cortical signals based on exact low resolution electromagnetic tomography (eLORETA applied to scalp EEG recordings. To illustrate the severity of the problem with the PDC, and the solution achieved by the iCoh, three examples are given, based on: (1 Simulated time series with known dynamics; (2 Simulated cortical sources with known dynamics, used for generating EEG recordings, which are then used for estimating (with eLORETA the source signals for the final connectivity assessment; and (3 EEG recordings in rats. Lastly, real human recordings are analyzed, where the iCoh between six cortical regions of interest are calculated and compared under eyes open and closed conditions, using 61-channel EEG recordings from 109 subjects. During eyes closed, the posterior cingulate sends alpha activity to all other regions. During eyes open, the anterior cingulate sends theta-alpha activity to other frontal regions.

  20. Connecting dots

    DEFF Research Database (Denmark)

    Murakami, Kyoko; Jacobs, Rachel L.

    2017-01-01

    shall present a discursive approach, a methodology that captures the dynamics of reminiscence. We analyse collected conversational data of British family members reminiscing on their past as a joint family activity. Through such talk-in-interaction, the family members develop continuity within...... and Middleton, 1995). A reminiscence conversation is a dynamic talk-in-interaction, which can produce valuable learning experience for the participants involved. Reminiscence talk contains rich, personal, historic data that can reveal and inform family members of an unknown past. In this seminar/chapter, we...... of connecting the dots of recalled moments of individual family members lives and is geared towards building a family’s shared future for posterity. Lastly, we consider a wider implication of family reminiscence in terms of human development. http://www.infoagepub.com/products/Memory-Practices-and-Learning...

  1. Frequency of Synaptic Autoantibody Accompaniments and Neurological Manifestations of Thymoma.

    Science.gov (United States)

    Zekeridou, Anastasia; McKeon, Andrew; Lennon, Vanda A

    2016-07-01

    Thymoma is commonly recognized in association with paraneoplastic autoimmune myasthenia gravis (MG), an IgG-mediated impairment of synaptic transmission targeting the nicotinic acetylcholine receptor of muscle. Newly identified synaptic autoantibodies may expand the serological profile of thymoma. To investigate the frequency of potentially pathogenic neural synaptic autoantibodies in patients with thymoma. We retrospectively identified patients with histopathologically confirmed thymoma and serum available to test for synaptic autoantibodies (collected 1986-2014) at the Mayo Clinic Neuroimmunology Laboratory. We identified and classified 193 patients with thymoma into 4 groups: (1) lacking neurological autoimmunity (n = 43); (2) isolated MG (n = 98); (3) MG plus additional autoimmune neurological manifestations (n = 26); and (4) neurological autoimmunity other than MG (n = 26). Clinical presentation and serum profile of autoantibodies reactive with molecularly defined synaptic plasma membrane proteins of muscle, peripheral, and central nervous systems. Of the 193 patients with thymoma, mean patient age was 52 years and did not significantly differ by sex (106 women) or group. Myasthenia gravis was the most prevalent clinical manifestation (64%) followed by dysautonomia (16 patients [8%]) and encephalopathy (15 patients [8%]); 164 patients (85%) had at least 1 synaptic autoantibody, and 63 of these patients (38%) had at least 1 more. Muscle acetylcholine receptor was most frequent (78%), followed by ganglionic acetylcholine receptor (20%), voltage-gated Kv1 potassium channel-complex (13%), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (5%). Less frequent were aquaporin-4, voltage-gated Kv1 potassium channel-complex related proteins (leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2), glycine receptor, and γ-aminobutyric acid-A receptor. Synaptic autoantibodies were significantly more frequent in patients

  2. Synaptic plasticity in the auditory system: a review.

    Science.gov (United States)

    Friauf, Eckhard; Fischer, Alexander U; Fuhr, Martin F

    2015-07-01

    Synaptic transmission via chemical synapses is dynamic, i.e., the strength of postsynaptic responses may change considerably in response to repeated synaptic activation. Synaptic strength is increased during facilitation, augmentation and potentiation, whereas a decrease in synaptic strength is characteristic for depression and attenuation. This review attempts to discuss the literature on short-term and long-term synaptic plasticity in the auditory brainstem of mammals and birds. One hallmark of the auditory system, particularly the inner ear and lower brainstem stations, is information transfer through neurons that fire action potentials at very high frequency, thereby activating synapses >500 times per second. Some auditory synapses display morphological specializations of the presynaptic terminals, e.g., calyceal extensions, whereas other auditory synapses do not. The review focuses on short-term depression and short-term facilitation, i.e., plastic changes with durations in the millisecond range. Other types of short-term synaptic plasticity, e.g., posttetanic potentiation and depolarization-induced suppression of excitation, will be discussed much more briefly. The same holds true for subtypes of long-term plasticity, like prolonged depolarizations and spike-time-dependent plasticity. We also address forms of plasticity in the auditory brainstem that do not comprise synaptic plasticity in a strict sense, namely short-term suppression, paired tone facilitation, short-term adaptation, synaptic adaptation and neural adaptation. Finally, we perform a meta-analysis of 61 studies in which short-term depression (STD) in the auditory system is opposed to short-term depression at non-auditory synapses in order to compare high-frequency neurons with those that fire action potentials at a lower rate. This meta-analysis reveals considerably less STD in most auditory synapses than in non-auditory ones, enabling reliable, failure-free synaptic transmission even at

  3. Exercise-Induced Fatigue Impairs Bidirectional Corticostriatal Synaptic Plasticity.

    Science.gov (United States)

    Ma, Jing; Chen, Huimin; Liu, Xiaoli; Zhang, Lingtao; Qiao, Decai

    2018-01-01

    Exercise-induced fatigue (EF) is a ubiquitous phenomenon in sports competition and training. It can impair athletes' motor skill execution and cognition. Corticostriatal synaptic plasticity is considered to be the cellular mechanism of movement control and motor learning. However, the effect of EF on corticostriatal synaptic plasticity remains elusive. In the present study, using field excitatory postsynaptic potential recording, we found that the corticostriatal long-term potentiation (LTP) and long-term depression (LTD) were both impaired in EF mice. To further investigate the cellular mechanisms underlying the impaired synaptic plasticity in corticostriatal pathway, whole-cell patch clamp recordings were carried out on striatal medium spiny neurons (MSNs). MSNs in EF mice exhibited increased spontaneous excitatory postsynaptic current (sEPSC) frequency and decreased paired-pulse ratio (PPR), while with normal basic electrophysiological properties and normal sEPSC amplitude. Furthermore, the N-methyl-D-aspartate (NMDA)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) ratio of MSNs was reduced in EF mice. These results suggest that the enhanced presynaptic glutamate (Glu) release and downregulated postsynaptic NMDA receptor function lead to the impaired corticostriatal plasticity in EF mice. Taken together, our findings for the first time show that the bidirectional corticostriatal synaptic plasticity is impaired after EF, and suggest that the aberrant corticostriatal synaptic plasticity may be involved in the production and/or maintenance of EF.

  4. Cell-specific synaptic plasticity induced by network oscillations.

    Science.gov (United States)

    Zarnadze, Shota; Bäuerle, Peter; Santos-Torres, Julio; Böhm, Claudia; Schmitz, Dietmar; Geiger, Jörg Rp; Dugladze, Tamar; Gloveli, Tengis

    2016-05-24

    Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave-ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner.

  5. Synaptic Transmission Optimization Predicts Expression Loci of Long-Term Plasticity.

    Science.gov (United States)

    Costa, Rui Ponte; Padamsey, Zahid; D'Amour, James A; Emptage, Nigel J; Froemke, Robert C; Vogels, Tim P

    2017-09-27

    Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression-pre- or postsynaptic-is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures.

    Science.gov (United States)

    Lionel, Anath C; Vaags, Andrea K; Sato, Daisuke; Gazzellone, Matthew J; Mitchell, Elyse B; Chen, Hong Yang; Costain, Gregory; Walker, Susan; Egger, Gerald; Thiruvahindrapuram, Bhooma; Merico, Daniele; Prasad, Aparna; Anagnostou, Evdokia; Fombonne, Eric; Zwaigenbaum, Lonnie; Roberts, Wendy; Szatmari, Peter; Fernandez, Bridget A; Georgieva, Lyudmila; Brzustowicz, Linda M; Roetzer, Katharina; Kaschnitz, Wolfgang; Vincent, John B; Windpassinger, Christian; Marshall, Christian R; Trifiletti, Rosario R; Kirmani, Salman; Kirov, George; Petek, Erwin; Hodge, Jennelle C; Bassett, Anne S; Scherer, Stephen W

    2013-05-15

    The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.

  7. Cortical spreading depression modulates synaptic transmission of the rat lateral amygdala.

    Science.gov (United States)

    Dehbandi, Shahab; Speckmann, Erwin-Josef; Pape, Hans Christian; Gorji, Ali

    2008-04-01

    Clinical and pathophysiological evidence connects migraine and the amygdala. Cortical spreading depression (CSD) plays a causative role in the generation of aura symptoms. However, the role of CSD in the pathophysiology of other symptoms of migraine needs to be investigated. An in vitro brain slice technique was used to investigate CSD effects on tetanus-induced long-term potentiation (LTP) in the lateral amygdala (LA) of the combined rat amygdala-hippocampus-cortex slices. More than 75% of CSD induced in temporal cortex propagated to LA. Induction of CSD in combined amygdala-hippocampus-cortex slices in which CSD propagated from neocortex to LA significantly augmented LTP in LA. LTP was inhibited when CSD travelled only in the neocortical tissues. Separation of the amygdala from the remaining neocortical part of the slice, in which CSD propagation was limited to the neocortex, increased LTP close to the control levels. Pharmacological manipulations of the slices, in which CSD reached LA, revealed the involvement of NMDA and AMPA glutamate subreceptors as well as dopamine D2 receptors in the enhancement of LTP in LA. However, neither blocking of GABA receptors nor activation of dopamine D1 receptors affected LTP in these slices. The results indicate the disturbances of LA synaptic transmission triggered by propagation of CSD. This perturbation of LA synaptic transmission induced by CSD may relate to some symptoms occurring during migraine attacks.

  8. Propagation of Homeostatic Sleep Signals by Segregated Synaptic Microcircuits of the Drosophila Mushroom Body.

    Science.gov (United States)

    Sitaraman, Divya; Aso, Yoshinori; Jin, Xin; Chen, Nan; Felix, Mario; Rubin, Gerald M; Nitabach, Michael N

    2015-11-16

    The Drosophila mushroom body (MB) is a key associative memory center that has also been implicated in the control of sleep. However, the identity of MB neurons underlying homeostatic sleep regulation, as well as the types of sleep signals generated by specific classes of MB neurons, has remained poorly understood. We recently identified two MB output neuron (MBON) classes whose axons convey sleep control signals from the MB to converge in the same downstream target region: a cholinergic sleep-promoting MBON class and a glutamatergic wake-promoting MBON class. Here, we deploy a combination of neurogenetic, behavioral, and physiological approaches to identify and mechanistically dissect sleep-controlling circuits of the MB. Our studies reveal the existence of two segregated excitatory synaptic microcircuits that propagate homeostatic sleep information from different populations of intrinsic MB "Kenyon cells" (KCs) to specific sleep-regulating MBONs: sleep-promoting KCs increase sleep by preferentially activating the cholinergic MBONs, while wake-promoting KCs decrease sleep by preferentially activating the glutamatergic MBONs. Importantly, activity of the sleep-promoting MB microcircuit is increased by sleep deprivation and is necessary for homeostatic rebound sleep (i.e., the increased sleep that occurs after, and in compensation for, sleep lost during deprivation). These studies reveal for the first time specific functional connections between subsets of KCs and particular MBONs and establish the identity of synaptic microcircuits underlying transmission of homeostatic sleep signals in the MB. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Neural Activity during Voluntary Movements in Each Body Representation of the Intracortical Microstimulation-Derived Map in the Macaque Motor Cortex.

    Science.gov (United States)

    Higo, Noriyuki; Kunori, Nobuo; Murata, Yumi

    2016-01-01

    In order to accurately interpret experimental data using the topographic body map identified by conventional intracortical microstimulation (ICMS), it is important to know how neurons in each division of the map respond during voluntary movements. Here we systematically investigated neuronal responses in each body representation of the ICMS map during a reach-grasp-retrieval task that involves the movements of multiple body parts. The topographic body map in the primary motor cortex (M1) generally corresponds to functional divisions of voluntary movements; neurons at the recording sites in each body representation with movement thresholds of 10 μA or less were differentially activated during the task, and the timing of responses was consistent with the movements of the body part represented. Moreover, neurons in the digit representation responded differently for the different types of grasping. In addition, the present study showed that neural activity depends on the ICMS current threshold required to elicit body movements and the location of the recording on the cortical surface. In the ventral premotor cortex (PMv), no correlation was found between the response properties of neurons and the body representation in the ICMS map. Neural responses specific to forelimb movements were often observed in the rostral part of PMv, including the lateral bank of the lower arcuate limb, in which ICMS up to 100 μA evoked no detectable movement. These results indicate that the physiological significance of the ICMS-derived maps is different between, and even within, areas M1 and PMv.

  10. PRRT2: from Paroxysmal Disorders to Regulation of Synaptic Function.

    Science.gov (United States)

    Valtorta, Flavia; Benfenati, Fabio; Zara, Federico; Meldolesi, Jacopo

    2016-10-01

    In the past few years, proline-rich transmembrane protein (PRRT)2 has been identified as the causative gene for several paroxysmal neurological disorders. Recently, an important role of PRRT2 in synapse development and function has emerged. Knock down of the protein strongly impairs the formation of synaptic contacts and neurotransmitter release. At the nerve terminal, PRRT2 endows synaptic vesicle exocytosis with Ca 2+ sensitivity by interacting with proteins of the fusion complex and with the Ca 2+ sensors synaptotagmins (Syts). In the postsynaptic compartment, PRRT2 interacts with glutamate receptors. The study of PRRT2 and of its mutations may help in refining our knowledge of the process of synaptic transmission and elucidating the pathogenetic mechanisms leading to derangement of network function in paroxysmal disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Synaptic clustering within dendrites: an emerging theory of memory formation.

    Science.gov (United States)

    Kastellakis, George; Cai, Denise J; Mednick, Sara C; Silva, Alcino J; Poirazi, Panayiota

    2015-03-01

    It is generally accepted that complex memories are stored in distributed representations throughout the brain, however the mechanisms underlying these representations are not understood. Here, we review recent findings regarding the subcellular mechanisms implicated in memory formation, which provide evidence for a dendrite-centered theory of memory. Plasticity-related phenomena which affect synaptic properties, such as synaptic tagging and capture, synaptic clustering, branch strength potentiation and spinogenesis provide the foundation for a model of memory storage that relies heavily on processes operating at the dendrite level. The emerging picture suggests that clusters of functionally related synapses may serve as key computational and memory storage units in the brain. We discuss both experimental evidence and theoretical models that support this hypothesis and explore its advantages for neuronal function. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Synaptic proteins and receptors defects in autism spectrum disorders

    Directory of Open Access Journals (Sweden)

    Jianling eChen

    2014-09-01

    Full Text Available Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms have contributed to the occurrence of autism spectrum disorders (ASDs. The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95 (PSD-95, SH3 and multiple ankyrin repeat domains 3 (SHANK3, synapsin, gephyrin, cadherin (CDH and protocadherin (PCDH, thousand-and-one-amino acid 2 kinase (TAOK2, and contactin (CNTN, have been shown to play important roles in the development and function of synapses. In addition, synaptic receptors, such as gamma-aminobutyric acid (GABA receptors and glutamate receptors, have also been associated with ASDs. This review will primarily focus on the defects of synaptic proteins and receptors associated with ASDs and their roles in the pathogenesis of ASDs via synaptic pathways.

  13. Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study

    Science.gov (United States)

    De Pittà, Maurizio; Brunel, Nicolas

    2016-01-01

    Glutamatergic gliotransmission, that is, the release of glutamate from perisynaptic astrocyte processes in an activity-dependent manner, has emerged as a potentially crucial signaling pathway for regulation of synaptic plasticity, yet its modes of expression and function in vivo remain unclear. Here, we focus on two experimentally well-identified gliotransmitter pathways, (i) modulations of synaptic release and (ii) postsynaptic slow inward currents mediated by glutamate released from astrocytes, and investigate their possible functional relevance on synaptic plasticity in a biophysical model of an astrocyte-regulated synapse. Our model predicts that both pathways could profoundly affect both short- and long-term plasticity. In particular, activity-dependent glutamate release from astrocytes could dramatically change spike-timing-dependent plasticity, turning potentiation into depression (and vice versa) for the same induction protocol. PMID:27195153

  14. Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity

    Science.gov (United States)

    Beckhauser, Thiago Fernando; Francis-Oliveira, José; De Pasquale, Roberto

    2016-01-01

    In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated. PMID:27625575

  15. Synaptic connections of starburst amacrine cells and localization of acetylcholine receptors in primate retinas.

    Science.gov (United States)

    Yamada, Elizabeth S; Dmitrieva, Nina; Keyser, Kent T; Lindstrom, Jon M; Hersh, Louis B; Marshak, David W

    2003-06-16

    Starburst amacrine cells in the macaque retina were studied by electron microscopic immunohistochemistry. We found that these amacrine cells make a type of synapse not described previously; they are presynaptic to axon terminals of bipolar cells. We also confirmed that starburst amacrine cells are presynaptic to ganglion cell dendrites and amacrine cell processes. In order to determine the functions of these synapses, we localized acetylcholine receptors using a monoclonal antibody (mAb210) that recognizes human alpha3- and alpha5-containing nicotinic receptors and also antisera against the five known subtypes of muscarinic receptors. The majority of the mAb210-immunoreactive perikarya were amacrine cells and ganglion cells, but a subpopulation of bipolar cells was also labeled. A subset of bipolar cells and a subset of horizontal cells were labeled with antibodies to M3 muscarinic receptors. A subset of amacrine cells, including those that contain cholecystokinin, were labeled with antibodies to M2 receptors. Taken together, these results suggest that acetylcholine can modulate the activity of retinal ganglion cells by multiple pathways. Copyright 2003 Wiley-Liss, Inc.

  16. Neuromodulated Synaptic Plasticity on the SpiNNaker Neuromorphic System

    Directory of Open Access Journals (Sweden)

    Mantas Mikaitis

    2018-02-01

    Full Text Available SpiNNaker is a digital neuromorphic architecture, designed specifically for the low power simulation of large-scale spiking neural networks at speeds close to biological real-time. Unlike other neuromorphic systems, SpiNNaker allows users to develop their own neuron and synapse models as well as specify arbitrary connectivity. As a result SpiNNaker has proved to be a powerful tool for studying different neuron models as well as synaptic plasticity—believed to be one of the main mechanisms behind learning and memory in the brain. A number of Spike-Timing-Dependent-Plasticity(STDP rules have already been implemented on SpiNNaker and have been shown to be capable of solving various learning tasks in real-time. However, while STDP is an important biological theory of learning, it is a form of Hebbian or unsupervised learning and therefore does not explain behaviors that depend on feedback from the environment. Instead, learning rules based on neuromodulated STDP (three-factor learning rules have been shown to be capable of solving reinforcement learning tasks in a biologically plausible manner. In this paper we demonstrate for the first time how a model of three-factor STDP, with the third-factor representing spikes from dopaminergic neurons, can be implemented on the SpiNNaker neuromorphic system. Using this learning rule we first show how reward and punishment signals can be delivered to a single synapse before going on to demonstrate it in a larger network which solves the credit assignment problem in a Pavlovian conditioning experiment. Because of its extra complexity, we find that our three-factor learning rule requires approximately 2× as much processing time as the existing SpiNNaker STDP learning rules. However, we show that it is still possible to run our Pavlovian conditioning model with up to 1 × 104 neurons in real-time, opening up new research opportunities for modeling behavioral learning on SpiNNaker.

  17. Selectivity and sparseness in randomly connected balanced networks.

    Directory of Open Access Journals (Sweden)

    Cengiz Pehlevan

    Full Text Available Neurons in sensory cortex show stimulus selectivity and sparse population response, even in cases where no strong functionally specific structure in connectivity can be detected. This raises the question whether selectivity and sparseness can be generated and maintained in randomly connected networks. We consider a recurrent network of excitatory and inhibitory spiking neurons with random connectivity, driven by random projections from an input layer of stimulus selective neurons. In this architecture, the stimulus-to-stimulus and neuron-to-neuron modulation of total synaptic input is weak compared to the mean input. Surprisingly, we show that in the balanced state the network can still support high stimulus selectivity and sparse population response. In the balanced state, strong synapses amplify the variation in synaptic input and recurrent inhibition cancels the mean. Functional specificity in connectivity emerges due to the inhomogeneity caused by the generative statistical rule used to build the network. We further elucidate the mechanism behind and evaluate the effects of model parameters on population sparseness and stimulus selectivity. Network response to mixtures of stimuli is investigated. It is shown that a balanced state with unselective inhibition can be achieved with densely connected input to inhibitory population. Balanced networks exhibit the "paradoxical" effect: an increase in excitatory drive to inhibition leads to decreased inhibitory population firing rate. We compare and contrast selectivity and sparseness generated by the balanced network to randomly connected unbalanced networks. Finally, we discuss our results in light of experiments.

  18. Precise synaptic efficacy alignment suggests potentiation dominated learning

    Directory of Open Access Journals (Sweden)

    Christoph eHartmann

    2016-01-01

    Full Text Available Recent evidence suggests that parallel synapses from the same axonal branch onto the same dendritic branch have almost identical strength. It has been proposed that this alignment is only possible through learning rules that integrate activity over long time spans. However, learning mechanisms such as spike-timing-dependent plasticity (STDP are commonly assumed to be temporally local. Here, we propose that the combination of temporally local STDP and a multiplicative synaptic normalization mechanism is sufficient to explain the alignment of parallel synapses.To address this issue, we introduce three increasingly complex models: First, we model the idealized interaction of STDP and synaptic normalization in a single neuron as a simple stochastic process and derive analytically that the alignment effect can be described by a so-called Kesten process. From this we can derive that synaptic efficacy alignment requires potentiation-dominated learning regimes. We verify these conditions in a single-neuron model with independent spiking activities but more realistic synapses. As expected, we only observe synaptic efficacy alignment for long-term potentiation-biased STDP. Finally, we explore how well the findings transfer to recurrent neural networks where the learning mechanisms interact with the correlated activity of the network. We find that due to the self-reinforcing correlations in recurrent circuits under STDP, alignment occurs for both long-term potentiation- and depression-biased STDP, because the learning will be potentiation dominated in both cases due to the potentiating events induced by correlated activity. This is in line with recent results demonstrating a dominance of potentiation over depression during waking and normalization during sleep. This leads us to predict that individual spine pairs will be more similar in the morning than they are after sleep depriviation.In conclusion, we show that synaptic normalization in conjunction with

  19. Defective glycinergic synaptic transmission in zebrafish motility mutants

    Directory of Open Access Journals (Sweden)

    Hiromi Hirata

    2010-01-01

    Full Text Available Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR β subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch once’ mutants, including beo and sho, and report the identification of a new α2 subunit that revises the phylogeny of zebrafish GlyRs.

  20. Depression as a Glial-Based Synaptic Dysfunction

    Science.gov (United States)

    Rial, Daniel; Lemos, Cristina; Pinheiro, Helena; Duarte, Joana M.; Gonçalves, Francisco Q.; Real, Joana I.; Prediger, Rui D.; Gonçalves, Nélio; Gomes, Catarina A.; Canas, Paula M.; Agostinho, Paula; Cunha, Rodrigo A.

    2016-01-01

    Recent studies combining pharmacological, behavioral, electrophysiological and molecular approaches indicate that depression results from maladaptive neuroplastic processes occurring in defined frontolimbic circuits responsible for emotional processing such as the prefrontal cortex, hippocampus, amygdala and ventral striatum. However, the exact mechanisms controlling synaptic plasticity that are disrupted to trigger depressive conditions have not been elucidated. Since glial cells (astrocytes and microglia) tightly and dynamically interact with synapses, engaging a bi-directional communication critical for the processing of synaptic information, we now revisit the role of glial cells in the etiology of depression focusing on a dysfunction of the “quad-partite” synapse. This interest is supported by the observations that depressive-like conditions are associated with a decreased density and hypofunction of astrocytes and with an increased microglia “activation” in frontolimbic regions, which is expected to contribute for the synaptic dysfunction present in depression. Furthermore, the traditional culprits of depression (glucocorticoids, biogenic amines, brain-derived neurotrophic factor, BDNF) affect glia functioning, whereas antidepressant treatments (serotonin-selective reuptake inhibitors, SSRIs, electroshocks, deep brain stimulation) recover glia functioning. In this context of a quad-partite synapse, systems modulating glia-synapse bidirectional communication—such as the purinergic neuromodulation system operated by adenosine 5′-triphosphate (ATP) and adenosine—emerge as promising candidates to “re-normalize” synaptic function by combining direct synaptic effects with an ability to also control astrocyte and microglia function. This proposed triple action of purines to control aberrant synaptic function illustrates the rationale to consider the interference with glia dysfunction as a mechanism of action driving the design of future

  1. Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants

    Science.gov (United States)

    Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.

    2009-01-01

    Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) β subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho) mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch-once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch-once’ mutants, including beo and sho, and report the identification of a new α2 subunit that revises the phylogeny of zebrafish GlyRs. PMID:20161699

  2. Depression as a Glial-Based Synaptic Dysfunction

    Directory of Open Access Journals (Sweden)

    Daniel eRial

    2016-01-01

    Full Text Available Recent studies combining pharmacological, behavioral, electrophysiological and molecular approaches indicate that depression results from maladaptive neuroplastic processing occurring in defined frontolimbic circuits responsible for emotional processing such as the prefrontal cortex, hippocampus, amygdala and ventral striatum. However, the exact mechanisms controlling synaptic plasticity that are disrupted to trigger depressive conditions have not been elucidated. Since glial cells (astrocytes and microglia tightly and dynamically interact with synapses, engaging a bi-directional communication critical for the processing of synaptic information, we now revisit the role of glial cells in the etiology of depression focusing on a dysfunction of the ‘quad-partite’ synapse. This interest is supported by the observations that depressive-like conditions are associated with a decreased density and hypofunction of astrocytes and with an increase microglia ‘activation’ in frontolimbic regions, which is expected to contribute for the synaptic dysfunction present in depression. Furthermore, the traditional culprits of depression (glucocorticoids, biogenic amines, BDNF affect glia functioning, whereas antidepressant treatments (SSRIs, electroshock, deep brain stimulation recover glia functioning. In this context of a quad-partite synapse, systems modulating glia-synapse bidirectional communication - such as the purinergic neuromodulation system operated by ATP and adenosine - emerge as promising candidates to re-normalize synaptic function by combining direct synaptic effects with an ability to also control astrocyte and microglia function. This proposed triple action of purines to control aberrant synaptic function illustrates the rationale to consider the interference with glia dysfunction as a mechanism of action driving the design of future pharmacological tools to manage depression.

  3. Neuron-wide RNA transport combines with netrin-mediated local translation to spatially regulate the synaptic proteome.

    Science.gov (United States)

    Kim, Sangmok; Martin, Kelsey C

    2015-01-08

    The persistence of experience-dependent changes in brain connectivity requires RNA localization and protein synthesis. Previous studies have demonstrated a role for local translation in altering the structure and function of synapses during synapse formation and experience-dependent synaptic plasticity. In this study, we ask whether in addition to promoting local translation, local stimulation also triggers directed trafficking of RNAs from nucleus to stimulated synapses. Imaging of RNA localization and translation in cultured Aplysia sensory-motor neurons revealed that RNAs were delivered throughout the arbor of the sensory neuron, but that translation was enriched only at sites of synaptic contact and/or synaptic stimulation. Investigation of the mechanisms that trigger local translation revealed a role for calcium-dependent retrograde netrin-1/DCC receptor signaling. Spatially restricting gene expression by regulating local translation rather than by directing the delivery of mRNAs from nucleus to stimulated synapses maximizes the readiness of the entire neuronal arbor to respond to local cues.

  4. Mid-life environmental enrichment increases synaptic density in CA1 in a mouse model of Aβ-associated pathology and positively influences synaptic and cognitive health in healthy ageing.

    Science.gov (United States)

    Stuart, Kimberley E; King, Anna E; Fernandez-Martos, Carmen M; Dittmann, Justin; Summers, Mathew J; Vickers, James C

    2017-06-01

    Early-life cognitive enrichment may reduce the risk of experiencing cognitive deterioration and dementia in later-life. However, an intervention to prevent or delay dementia is likely to be taken up in mid to later-life. Hence, we investigated the effects of environmental enrichment in wildtype mice and in a mouse model of Aβ neuropathology (APP SWE /PS1 dE9 ) from 6 months of age. After 6 months of housing in standard laboratory cages, APP SWE /PS1 dE9 (n = 27) and healthy wildtype (n = 21) mice were randomly assigned to either enriched or standard housing. At 12 months of age, wildtype mice showed altered synaptic protein levels and relatively superior cognitive performance afforded by environmental enrichment. Environmental enrichment was not associated with alterations to Aβ plaque pathology in the neocortex or hippocampus of APP SWE /PS1 dE9 mice. However, a significant increase in synaptophysin immunolabeled puncta in the hippocampal subregion, CA1, in APP SWE /PS1 dE9 mice was detected, with no significant synaptic density changes observed in CA3, or the Fr2 region of the prefrontal cortex. Moreover, a significant increase in hippocampal BDNF was detected in APP SWE /PS1 dE9 mice exposed to EE, however, no changes were detected in neocortex or between Wt animals. These results demonstrate that mid to later-life cognitive enrichment has the potential to promote synaptic and cognitive health in ageing, and to enhance compensatory capacity for synaptic connectivity in pathological ageing associated with Aβ deposition. © 2017 Wiley Periodicals, Inc.

  5. Histamine H3 Heteroreceptors Suppress Glutamatergic and GABAergic Synaptic Transmission in the Rat Insular Cortex

    Directory of Open Access Journals (Sweden)

    Hiroki Takei

    2017-11-01

    Full Text Available Histamine H3 receptors are autoreceptors that regulate histamine release from histaminergic neuronal terminals. The cerebral cortex, including the insular cortex (IC, expresses abundant H3 receptors; however, the functions and mechanisms of H3 receptors remain unknown. The aim of this study was to elucidate the functional roles of H3 in synaptic transmission in layer V of the rat IC. Unitary excitatory and inhibitory postsynaptic currents (uEPSCs and uIPSCs were obtained through paired whole-cell patch-clamp recording in cerebrocortical slice preparations. The H3 receptor agonist, R-α-methylhistamine (RAMH, reduced the uEPSC amplitude obtained from pyramidal cell to pyramidal cell or GABAergic interneuron connections. Similarly, RAMH reduced the uIPSC amplitude in GABAergic interneuron to pyramidal cell connections. RAMH-induced decreases in both the uEPSC and uIPSC amplitudes were accompanied by increases in the failure rate and paired-pulse ratio. JNJ 5207852 dihydrochloride or thioperamide, H3 receptor antagonists, inhibited RAMH-induced suppression of uEPSCs and uIPSCs. Unexpectedly, thioperamide alone increased the uIPSC amplitude, suggesting that thioperamide was likely to act as an inverse agonist. Miniature EPSC or IPSC recordings support the hypothesis that the activation of H3 receptors suppresses the release of glutamate and GABA from presynaptic terminals. The colocalization of H3 receptors and glutamate decarboxylase or vesicular glutamate transport protein 1 in presynaptic axon terminals was confirmed through double pre-embedding microscopy, using a combination of pre-embedding immunogold and immunoperoxidase techniques. The suppressive regulation of H3 heteroreceptors on synaptic transmission might mediate the regulation of sensory information processes, such as gustation and visceral sensation, in the IC.

  6. Fragile X Syndrome: Keys to the Molecular Genetics of Synaptic Plasticity

    Science.gov (United States)

    Lombroso, Paul J.; Ogren, Marilee P.

    2008-01-01

    Fragile X syndrome, the most common form of inherited mental retardation is discussed. The relationship between specific impairments in synaptic plasticity and Fragile X syndrome is investigated as it strengthens synaptic contacts between neurons.

  7. Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain

    Directory of Open Access Journals (Sweden)

    Sarah L. DeVos

    2018-04-01

    pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.

  8. Sleep and protein synthesis-dependent synaptic plasticity: impacts of sleep loss and stress

    Science.gov (United States)

    Grønli, Janne; Soulé, Jonathan; Bramham, Clive R.

    2014-01-01

    Sleep has been ascribed a critical role in cognitive functioning. Several lines of evidence implicate sleep in the consolidation of synaptic plasticity and long-term memory. Stress disrupts sleep while impairing synaptic plasticity and cognitive performance. Here, we discuss evidence linking sleep to mechanisms of protein synthesis-dependent synaptic plasticity and synaptic scaling. We then consider how disruption of sleep by acute and chronic stress may impair these mechanisms and degrade sleep function. PMID:24478645

  9. Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1

    NARCIS (Netherlands)

    Havekes, Robbert; Park, Alan J; Tudor, Jennifer C; Luczak, Vincent G; Hansen, Rolf T; Ferri, Sarah L; Bruinenberg, Vibeke M; Poplawski, Shane G; Day, Jonathan P; Aton, Sara J; Radwańska, Kasia; Meerlo, Peter; Houslay, Miles D; Baillie, George S; Abel, Ted

    2016-01-01

    Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we

  10. How do astrocytes shape synaptic transmission? Insights from electrophysiology

    Directory of Open Access Journals (Sweden)

    Glenn eDallérac

    2013-10-01

    Full Text Available A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy.

  11. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction.

    NARCIS (Netherlands)

    van Huijstee, A.N.; Mansvelder, H.D.

    2015-01-01

    Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review

  12. Intense synaptic activity enhances temporal resolution in spinal motoneurons.

    Directory of Open Access Journals (Sweden)

    Rune W Berg

    Full Text Available In neurons, spike timing is determined by integration of synaptic potentials in delicate concert with intrinsic properties. Although the integration time is functionally crucial, it remains elusive during network activity. While mechanisms of rapid processing are well documented in sensory systems, agility in motor systems has received little attention. Here we analyze how intense synaptic activity affects integration time in spinal motoneurons during functional motor activity and report a 10-fold decrease. As a result, action potentials can only be predicted from the membrane potential within 10 ms of their occurrence and detected for less than 10 ms after their occurrence. Being shorter than the average inter-spike interval, the AHP has little effect on integration time and spike timing, which instead is entirely determined by fluctuations in membrane potential caused by the barrage of inhibitory and excitatory synaptic activity. By shortening the effective integration time, this intense synaptic input may serve to facilitate the generation of rapid changes in movements.

  13. Inhibition of hippocampal synaptic transmission by impairment of Ral function

    DEFF Research Database (Denmark)

    Owe-Larsson, Björn; Chaves-Olarte, Esteban; Chauhan, Ashok

    2005-01-01

    Large clostridial cytotoxins and protein overexpression were used to probe for involvement of Ras-related GTPases (guanosine triphosphate) in synaptic transmission in cultured rat hippocampal neurons. The toxins TcdA-10463 (inactivates Rho, Rac, Cdc42, Rap) and TcsL-1522 (inactivates Ral, Rac, Ra...

  14. Polymer-electrolyte-gated nanowire synaptic transistors for neuromorphic applications

    Science.gov (United States)

    Zou, Can; Sun, Jia; Gou, Guangyang; Kong, Ling-An; Qian, Chuan; Dai, Guozhang; Yang, Junliang; Guo, Guang-hua

    2017-09-01

    Polymer-electrolytes are formed by dissolving a salt in polymer instead of water, the conducting mechanism involves the segmental motion-assisted diffusion of ion in the polymer matrix. Here, we report on the fabrication of tin oxide (SnO2) nanowire synaptic transistors using polymer-electrolyte gating. A thin layer of poly(ethylene oxide) and lithium perchlorate (PEO/LiClO4) was deposited on top of the devices, which was used to boost device performances. A voltage spike applied on the in-plane gate attracts ions toward the polymer-electrolyte/SnO2 nanowire interface and the ions are gradually returned after the pulse is removed, which can induce a dynamic excitatory postsynaptic current in the nanowire channel. The SnO2 synaptic transistors exhibit the behavior of short-term plasticity like the paired-pulse facilitation and self-adaptation, which is related to the electric double-effect regulation. In addition, the synaptic logic functions and the logical function transformation are also discussed. Such single SnO2 nanowire-based synaptic transistors are of great importance for future neuromorphic devices.

  15. Amino Acid Neurotransmitters; Mechanisms of Their Uptake into Synaptic Vesicles

    Science.gov (United States)

    1991-08-01

    phenylhydrazone (CCCP), ouabain. L-glutamate (disodium gan and Whittaker, 1966: Rassin , 1972; Kontro et al., salt), D-aspartate, diaminobutyric acid (DABA... Rassin D. K. 1 972) Amino acids as putative transmitters: failure to endings Isynaptosomes) in different regions of brain: effect of bind synaptic

  16. Synaptic mRNAs are modulated by learning.

    Science.gov (United States)

    Ferrara, Eugenia; Cefaliello, Carolina; Eyman, Maria; De Stefano, Rosanna; Giuditta, Antonio; Crispino, Marianna

    2009-07-01

    We have recently demonstrated that brain plastic events significantly modify synaptic protein synthesis measured by the incorporation of [(35)S]methionine in brain synaptosomal proteins. Notably, in rats learning a two-way active avoidance task, the local synthesis of two synaptic proteins was selectively enhanced. Because this effect may be attributed to transcriptional modulation, we used reverse transcriptase-polymerase chain reaction methods to determine the content of discrete synaptosomal mRNAs in rats exposed to the same training protocol. Correlative analyses between behavioral responses and synaptosomal mRNA content showed that GAT-1 mRNA (a prevalent presynaptic component) correlates with avoidances and escapes in rat cerebellum, while glial fibrillary acid protein mRNA (an astrocytic component) correlates with freezings in cerebellum and cerebral cortex. These observations support the hypothesis that synaptic protein synthesis may be transcriptionally regulated. The cellular origin of synaptic transcripts is briefly discussed, with special regard to those present at large distances from neuron somas. (c) 2009 Wiley-Liss, Inc.

  17. Synaptically evoked glutamate transporter currents in Spinal Dorsal Horn Astrocytes

    Directory of Open Access Journals (Sweden)

    Dougherty Patrick M

    2009-07-01

    Full Text Available Abstract Background Removing and sequestering synaptically released glutamate from the extracellular space is carried out by specific plasma membrane transporters that are primarily located in astrocytes. Glial glutamate transporter function can be monitored by recording the currents that are produced by co-transportation of Na+ ions with the uptake of glutamate. The goal of this study was to characterize glutamate transporter function in astrocytes of the spinal cord dorsal horn in real time by recording synaptically evoked glutamate transporter currents. Results Whole-cell patch clamp recordings were obtained from astrocytes in the spinal substantia gelatinosa (SG area in spinal slices of young adult rats. Glutamate transporter currents were evoked in these cells by electrical stimulation at the spinal dorsal root entry zone in the presence of bicuculline, strychnine, DNQX and D-AP5. Transporter currents were abolished when synaptic transmission was blocked by TTX or Cd2+. Pharmacological studies identified two subtypes of glutamate transporters in spinal astrocytes, GLAST and GLT-1. Glutamate transporter currents were graded with stimulus intensity, reaching peak responses at 4 to 5 times activation threshold, but were reduced following low-frequency (0.1 – 1 Hz repetitive stimulation. Conclusion These results suggest that glutamate transporters of spinal astrocytes could be activated by synaptic activation, and recording glutamate transporter currents may provide a means of examining the real time physiological responses of glial cells in spinal sensory processing, sensitization, hyperalgesia and chronic pain.

  18. Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Robert Nisticò

    Full Text Available Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS and its mouse model, experimental autoimmune encephalomyelitis (EAE. In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP induction was favored over long-term depression (LTD in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS.

  19. Modulation of synaptic potentials and cell excitability by dendritic

    Indian Academy of Sciences (India)

    Its major cellular substrates, the medium spiny (MS) neurons, possess a wide variety of dendritic active conductances that may modulate the excitatory post synaptic potentials (EPSPs) and cell excitability. We examine this issue using a biophysically detailed 189-compartment stylized model of the NAc MS neuron, ...

  20. Learning may need only a few bits of synaptic precision

    Science.gov (United States)

    Baldassi, Carlo; Gerace, Federica; Lucibello, Carlo; Saglietti, Luca; Zecchina, Riccardo

    2016-05-01

    Learning in neural networks poses peculiar challenges when using discretized rather then continuous synaptic states. The choice of discrete synapses is motivated by biological reasoning and experiments, and possibly by hardware implementation considerations as well. In this paper we extend a previous large deviations analysis which unveiled the existence of peculiar dense regions in the space of synaptic states which accounts for the possibility of learning efficiently in networks with binary synapses. We extend the analysis to synapses with multiple states and generally more plausible biological features. The results clearly indicate that the overall qualitative picture is unchanged with respect to the binary case, and very robust to variation of the details of the model. We also provide quantitative results which suggest that the advantages of increasing the synaptic precision (i.e., the number of internal synaptic states) rapidly vanish after the first few bits, and therefore that, for practical applications, only few bits may be needed for near-optimal performance, consistent with recent biological findings. Finally, we demonstrate how the theoretical analysis can be exploited to design efficient algorithmic search strategies.

  1. Synaptic activity regulates AMPA receptor trafficking through different recycling pathways

    Science.gov (United States)

    Zheng, Ning; Jeyifous, Okunola; Munro, Charlotte; Montgomery, Johanna M; Green, William N

    2015-01-01

    Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites. DOI: http://dx.doi.org/10.7554/eLife.06878.001 PMID:25970033

  2. Cdk5 is essential for synaptic vesicle endocytosis

    DEFF Research Database (Denmark)

    Tan, Timothy C; Valova, Valentina A; Malladi, Chandra S

    2003-01-01

    Synaptic vesicle endocytosis (SVE) is triggered by calcineurin-mediated dephosphorylation of the dephosphin proteins. SVE is maintained by the subsequent rephosphorylation of the dephosphins by unidentified protein kinases. Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin...

  3. Modulation of synaptic potentials and cell excitability by dendritic ...

    Indian Academy of Sciences (India)

    Modulation of synaptic potentials and cell excitability by dendritic. KIR and KAs channels in nucleus accumbens medium spiny neurons: A computational study. JESSY JOHN* and ROHIT MANCHANDA. Biomedical Engineering group, Department of Biosciences and Bioengineering, Indian Institute of Technology. Bombay ...

  4. Emerging Link between Alzheimer's Disease and Homeostatic Synaptic Plasticity

    Science.gov (United States)

    Jang, Sung-Soo; Chung, Hee Jung

    2016-01-01

    Alzheimer's disease (AD) is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β (Aβ) peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβ oligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβ levels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets. PMID:27019755

  5. Isoform Specificity of Protein Kinase Cs in Synaptic Plasticity

    Science.gov (United States)

    Sossin, Wayne S.

    2007-01-01

    Protein kinase Cs (PKCs) are implicated in many forms of synaptic plasticity. However, the specific isoform(s) of PKC that underlie(s) these events are often not known. We have used "Aplysia" as a model system in order to investigate the isoform specificity of PKC actions due to the presence of fewer isoforms and a large number of documented…

  6. Corticosterone alters AMPAR mobility and facilitates bidirectional synaptic plasticity

    NARCIS (Netherlands)

    Martin, S.; Henley, J.M.; Holman, D.; Zhou, M.; Wiegert, O.; van Spronsen, M.; Joëls, M.; Hoogenraad, C.C.; Krugers, H.J.

    2009-01-01

    Background: The stress hormone corticosterone has the ability both to enhance and suppress synaptic plasticity and learning and memory processes. However, until today there is very little known about the molecular mechanism that underlies the bidirectional effects of stress and corticosteroid

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

    Science.gov (United States)

    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…

  8. The Role of Proteases in Hippocampal Synaptic Plasticity: Putting Together Small Pieces of a Complex Puzzle.

    Science.gov (United States)

    Salazar, Ivan L; Caldeira, Margarida V; Curcio, Michele; Duarte, Carlos B

    2016-02-01

    Long-term synaptic plasticity in the hippocampus is thought to underlie the formation of certain forms of memory, including spatial memory. The early phase of long-term synaptic potentiation and synaptic depression depends on post-translational modifications of synaptic proteins, while protein synthesis is also required for the late-phase of both forms of synaptic plasticity (L-LTP and L-LTD). Numerous pieces of evidence show a role for different types of proteases in synaptic plasticity, further increasing the diversity of mechanisms involved in the regulation of the intracellular and extracellular protein content. The cleavage of extracellular proteins is coupled to changes in postsynaptic intracellular mechanisms, and additional alterations in this compartment result from the protease-mediated targeting of intracellular proteins. Both mechanisms contribute to initiate signaling cascades that drive downstream pathways coupled to synaptic plasticity. In this review we summarize the evidence pointing to a role for extracellular and intracellular proteases, with distinct specificities, in synaptic plasticity. Where in the cells the proteases are located, and how they are regulated is also discussed. The combined actions of proteases and translation mechanisms contribute to a tight control of the synaptic proteome relevant for long-term synaptic potentiation and synaptic depression in the hippocampus. Additional studies are required to elucidate the mechanisms whereby these changes in the synaptic proteome are related with plasticity phenomena.

  9. Conditional reduction of adult neurogenesis impairs bidirectional hippocampal synaptic plasticity

    Science.gov (United States)

    Massa, Federico; Koehl, Muriel; Wiesner, Theresa; Grosjean, Noelle; Revest, Jean-Michel; Piazza, Pier-Vincenzo; Abrous, Djoher Nora; Oliet, Stéphane H. R.

    2011-01-01

    Adult neurogenesis is a process by which the brain produces new neurons once development has ceased. Adult hippocampal neurogenesis has been linked to the relational processing of spatial information, a role attributed to the contribution of newborn neurons to long-term potentiation (LTP). However, whether newborn neurons also influence long-term depression (LTD), and how synaptic transmission and plasticity are affected as they incorporate their network, remain to be determined. To address these issues, we took advantage of a genetic model in which a majority of adult-born neurons can be selectively ablated in the dentate gyrus (DG) and, most importantly, in which neurogenesis can be restored on demand. Using electrophysiological recordings, we show that selective reduction of adult-born neurons impairs synaptic transmission at medial perforant pathway synapses onto DG granule cells. Furthermore, LTP and LTD are largely compromised at these synapses, probably as a result of an increased induction threshold. Whereas the deficits in synaptic transmission and plasticity are completely rescued by restoring neurogenesis, these synapses regain their ability to express LTP much faster than their ability to express LTD. These results demonstrate that both LTP and LTD are influenced by adult neurogenesis. They also indicate that as newborn neurons integrate their network, the ability to express bidirectional synaptic plasticity is largely improved at these synapses. These findings establish that adult neurogenesis is an important process for synaptic transmission and bidirectional plasticity in the DG, accounting for its role in efficiently integrating novel incoming information and in forming new memories. PMID:21464314

  10. Neural ECM molecules in axonal and synaptic homeostatic plasticity.

    Science.gov (United States)

    Frischknecht, Renato; Chang, Kae-Jiun; Rasband, Matthew N; Seidenbecher, Constanze I

    2014-01-01

    Neural circuits can express different forms of plasticity. So far, Hebbian synaptic plasticity was considered the most important plastic phenomenon, but over the last decade, homeostatic mechanisms gained more interest because they can explain how a neuronal network maintains stable baseline function despite multiple plastic challenges, like developmental plasticity, learning, or lesion. Such destabilizing influences can be counterbalanced by the mechanisms of homeostatic plasticity, which restore the stability of neuronal circuits. Synaptic scaling is a mechanism in which neurons can detect changes in their own firing rates through a set of molecular sensors that then regulate receptor trafficking to scale the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms allow local changes in synaptic activation to generate local synaptic adaptations and network-wide changes in activity, which lead to adjustments in the balance between excitation and inhibition. The molecular pathways underlying these forms of homeostatic plasticity are currently under intense investigation, and it becomes clear that the extracellular matrix (ECM) of the brain, which surrounds individual neurons and integrates them into the tissue, is an important element in these processes. As a highly dynamic structure, which can be remodeled and degraded in an activity-dependent manner and in concerted action of neurons and glial cells, it can on one hand promote structural and functional plasticity and on the other hand stabilize neural microcircuits. This chapter highlights the composition of brain ECM with particular emphasis on perisynaptic and axonal matrix formations and its involvement in plastic and adaptive processes of the central nervous system.

  11. Odor-Specific Habituation Arises from Interaction of Afferent Synaptic Adaptation and Intrinsic Synaptic Potentiation in Olfactory Cortex

    Science.gov (United States)

    Linster, Christiane; Menon, Alka V.; Singh, Christopher Y.; Wilson, Donald A.

    2009-01-01

    Segmentation of target odorants from background odorants is a fundamental computational requirement for the olfactory system and is thought to be behaviorally mediated by olfactory habituation memory. Data from our laboratory have shown that odor-specific adaptation in piriform neurons, mediated at least partially by synaptic adaptation between…

  12. A calcium-dependent plasticity rule for HCN channels maintains activity homeostasis and stable synaptic learning.

    Science.gov (United States)

    Honnuraiah, Suraj; Narayanan, Rishikesh

    2013-01-01

    Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM)-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific physiological roles

  13. A calcium-dependent plasticity rule for HCN channels maintains activity homeostasis and stable synaptic learning.

    Directory of Open Access Journals (Sweden)

    Suraj Honnuraiah

    Full Text Available Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific

  14. A Calcium-Dependent Plasticity Rule for HCN Channels Maintains Activity Homeostasis and Stable Synaptic Learning

    Science.gov (United States)

    Honnuraiah, Suraj; Narayanan, Rishikesh

    2013-01-01

    Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM)-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific physiological roles

  15. Attribute-space connectivity and connected filters

    NARCIS (Netherlands)

    Wilkinson, Michael H.F.

    2007-01-01

    In this paper connected operators from mathematical morphology are extended to a wider class of operators, which are based on connectivities in higher dimensional spaces, similar to scale spaces, which will be called attribute-spaces. Though some properties of connected filters are lost,

  16. Agrin and synaptic laminin are required to maintain adult neuromuscular junctions.

    Directory of Open Access Journals (Sweden)

    Melanie A Samuel

    Full Text Available As synapses form and mature the synaptic partners produce organizing molecules that regulate each other's differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ, these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-α4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.

  17. Just-in-time connectivity for large spiking networks.

    Science.gov (United States)

    Lytton, William W; Omurtag, Ahmet; Neymotin, Samuel A; Hines, Michael L

    2008-11-01

    The scale of large neuronal network simulations is memory limited due to the need to store connectivity information: connectivity storage grows as the square of neuron number up to anatomically relevant limits. Using the NEURON simulator as a discrete-event simulator (no integration), we explored the consequences of avoiding the space costs of connectivity through regenerating connectivity parameters when needed: just in time after a presynaptic cell fires. We explored various strategies for automated generation of one or more of the basic static connectivity parameters: delays, postsynaptic cell identities, and weights, as well as run-time connectivity state: the event queue. Comparison of the JitCon implementation to NEURON's standard NetCon connectivity method showed substantial space savings, with associated run-time penalty. Although JitCon saved space by eliminating connectivity parameters, larger simulations were still memory limited due to growth of the synaptic event queue. We therefore designed a JitEvent algorithm that added items to the queue only when required: instead of alerting multiple postsynaptic cells, a spiking presynaptic cell posted a callback event at the shortest synaptic delay time. At the time of the callback, this same presynaptic cell directly notified the first postsynaptic cell and generated another self-callback for the next delay time. The JitEvent implementation yielded substantial additional time and space savings. We conclude that just-in-time strategies are necessary for very large network simulations but that a variety of alternative strategies should be considered whose optimality will depend on the characteristics of the simulation to be run.

  18. Short-term synaptic plasticity and heterogeneity in neural systems

    Science.gov (United States)

    Mejias, J. F.; Kappen, H. J.; Longtin, A.; Torres, J. J.

    2013-01-01

    We review some recent results on neural dynamics and information processing which arise when considering several biophysical factors of interest, in particular, short-term synaptic plasticity and neural heterogeneity. The inclusion of short-term synaptic plasticity leads to enhanced long-term memory capacities, a higher robustness of memory to noise, and irregularity in the duration of the so-called up cortical states. On the other hand, considering some level of neural heterogeneity in neuron models allows neural systems to optimize information transmission in rate coding and temporal coding, two strategies commonly used by neurons to codify information in many brain areas. In all these studies, analytical approximations can be made to explain the underlying dynamics of these neural systems.

  19. Emulating short-term synaptic dynamics with memristive devices

    Science.gov (United States)

    Berdan, Radu; Vasilaki, Eleni; Khiat, Ali; Indiveri, Giacomo; Serb, Alexandru; Prodromakis, Themistoklis

    2016-01-01

    Neuromorphic architectures offer great promise for achieving computation capacities beyond conventional Von Neumann machines. The essential elements for achieving this vision are highly scalable synaptic mimics that do not undermine biological fidelity. Here we demonstrate that single solid-state TiO2 memristors can exhibit non-associative plasticity phenomena observed in biological synapses, supported by their metastable memory state transition properties. We show that, contrary to conventional uses of solid-state memory, the existence of rate-limiting volatility is a key feature for capturing short-term synaptic dynamics. We also show how the temporal dynamics of our prototypes can be exploited to implement spatio-temporal computation, demonstrating the memristors full potential for building biophysically realistic neural processing systems.

  20. Characterization of auditory synaptic inputs to gerbil perirhinal cortex

    Directory of Open Access Journals (Sweden)

    Vibhakar C Kotak

    2015-08-01

    Full Text Available The representation of acoustic cues involves regions downstream from the auditory cortex (ACx. One such area, the perirhinal cortex (PRh, processes sensory signals containing mnemonic information. Therefore, our goal was to assess whether PRh receives auditory inputs from the auditory thalamus (MG and ACx in an auditory thalamocortical brain slice preparation and characterize these afferent-driven synaptic properties. When the MG or ACx was electrically stimulated, synaptic responses were recorded from the PRh neurons. Blockade of GABA-A receptors dramatically increased the amplitude of evoked excitatory potentials. Stimulation of the MG or ACx also evoked calcium transients in most PRh neurons. Separately, when fluoro ruby was injected in ACx in vivo, anterogradely labeled axons and terminals were observed in the PRh. Collectively, these data show that the PRh integrates auditory information from the MG and ACx and that auditory driven inhibition dominates the postsynaptic responses in a non-sensory cortical region downstream from the auditory cortex.

  1. Stochastic Learning in Oxide Binary Synaptic Device for Neuromorphic Computing

    Directory of Open Access Journals (Sweden)

    Shimeng eYu

    2013-10-01

    Full Text Available Hardware implementation of neuromorphic computing is attractive as a computing paradigm beyond the conventional digital computing. In this work, we show that the SET (off-to-on transition of metal oxide resistance switching memory becomes probabilistic under a weak programming condition. The switching variability of the binary synaptic device implements a stochastic learning rule. Such stochastic SET transition was statistically measured and modeled for a simulation of a winner-take-all network for competitive learning. The simulation illustrates that with such stochastic learning, the orientation classification function of input patterns can be effectively realized. The system performance metrics were compared between the conventional approach using the analog synapse and the approach in this work that employs the binary synapse utilizing the stochastic learning. The feasibility of using binary synapse in the neurormorphic computing may relax the constraints to engineer continuous multilevel intermediate states and widens the material choice for the synaptic device design.

  2. Synaptic plasticity in sleep: learning, homeostasis, and disease

    Science.gov (United States)

    Wang, Gordon; Grone, Brian; Colas, Damien; Appelbaum, Lior; Mourrain, Philippe

    2012-01-01

    Sleep is a fundamental and evolutionarily conserved aspect of animal life. Recent studies have shed light on the role of sleep in synaptic plasticity. Demonstrations of memory replay and synapse homeostasis suggest that one essential role of sleep is in the consolidation and optimization of synaptic circuits to retain salient memory traces despite the noise of daily experience. Here, we review this recent evidence, and suggest that sleep creates a heightened state of plasticity, which may be essential for this optimization. Furthermore, we discuss how sleep deficits seen in diseases such as Alzheimer’s disease and autism spectrum disorders might not just reflect underlying circuit malfunction, but could also play a direct role in the progression of those disorders. PMID:21840068

  3. Synaptic Bistability Due to Nucleation and Evaporation of Receptor Clusters

    KAUST Repository

    Burlakov, V. M.

    2012-01-10

    We introduce a bistability mechanism for long-term synaptic plasticity based on switching between two metastable states that contain significantly different numbers of synaptic receptors. One state is characterized by a two-dimensional gas of mobile interacting receptors and is stabilized against clustering by a high nucleation barrier. The other state contains a receptor gas in equilibrium with a large cluster of immobile receptors, which is stabilized by the turnover rate of receptors into and out of the synapse. Transitions between the two states can be initiated by either an increase (potentiation) or a decrease (depotentiation) of the net receptor flux into the synapse. This changes the saturation level of the receptor gas and triggers nucleation or evaporation of receptor clusters. © 2012 American Physical Society.

  4. Stochastic learning in oxide binary synaptic device for neuromorphic computing.

    Science.gov (United States)

    Yu, Shimeng; Gao, Bin; Fang, Zheng; Yu, Hongyu; Kang, Jinfeng; Wong, H-S Philip

    2013-01-01

    Hardware implementation of neuromorphic computing is attractive as a computing paradigm beyond the conventional digital computing. In this work, we show that the SET (off-to-on) transition of metal oxide resistive switching memory becomes probabilistic under a weak programming condition. The switching variability of the binary synaptic device implements a stochastic learning rule. Such stochastic SET transition was statistically measured and modeled for a simulation of a winner-take-all network for competitive learning. The simulation illustrates that with such stochastic learning, the orientation classification function of input patterns can be effectively realized. The system performance metrics were compared between the conventional approach using the analog synapse and the approach in this work that employs the binary synapse utilizing the stochastic learning. The feasibility of using binary synapse in the neurormorphic computing may relax the constraints to engineer continuous multilevel intermediate states and widens the material choice for the synaptic device design.

  5. Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina.

    Science.gov (United States)

    Wang, Xu; Zhao, Lian; Zhang, Jun; Fariss, Robert N; Ma, Wenxin; Kretschmer, Friedrich; Wang, Minhua; Qian, Hao Hua; Badea, Tudor C; Diamond, Jeffrey S; Gan, Wen-Biao; Roger, Jerome E; Wong, Wai T

    2016-03-02

    Microglia, the principal resident immune cell of the CNS, exert significant influence on neurons during development and in pathological situations. However, if and how microglia contribute to normal neuronal function in the mature uninjured CNS is not well understood. We used the model of the adult mouse retina, a part of the CNS amenable to structural and functional analysis, to investigate the constitutive role of microglia by depleting microglia from the retina in a sustained manner using genetic methods. We discovered that microglia are not acutely required for the maintenance of adult retinal architecture, the survival of retinal neurons, or the laminar organization of their dendritic and axonal compartments. However, sustained microglial depletion results in the degeneration of photoreceptor synapses in the outer plexiform layer, leading to a progressive functional deterioration in retinal light responses. Our results demonstrate that microglia are constitutively required for the maintenance of synaptic structure in the adult retina and for synaptic transmission underlying normal visual function. Our findings on constitutive microglial function are relevant in understanding microglial contributions to pathology and in the consideration of therapeutic interventions that reduce or perturb constitutive microglial function. Microglia, the principal resident immune cell population in the CNS, has been implicated in diseases in the brain and retina. However, how they contribute to the everyday function of the CNS is unclear. Using the model of the adult mouse retina, we examined the constitutive role of microglia by depleting microglia from the retina. We found that in the absence of microglia, retinal neurons did not undergo overt cell death or become structurally disorganized in their processes. However, connections between neurons called synapses begin to break down, leading to a decreased ability of the retina to transmit light responses. Our results indicate

  6. A Unifying Framework of Synaptic and Intrinsic Plasticity in Neural Populations.

    Science.gov (United States)

    Leugering, Johannes; Pipa, Gordon

    2018-01-17

    A neuronal population is a computational unit that receives a multivariate, time-varying input signal and creates a related multivariate output. These neural signals are modeled as stochastic processes that transmit information in real time, subject to stochastic noise. In a stationary environment, where the input signals can be characterized by constant statistical properties, the systematic relationship between its input and output processes determines the computation carried out by a population. When these statistical characteristics unexpectedly change, the population needs to adapt to its new environment if it is to maintain stable operation. Based on the general concept of homeostatic plasticity, we propose a simple compositional model of adaptive networks that achieve invariance with regard to undesired changes in the statistical properties of their input signals and maintain outputs with well-defined joint statistics. To achieve such invariance, the network model combines two functionally distinct types of plasticity. An abstract stochastic process neuron model implements a generalized form of intrinsic plasticity that adapts marginal statistics, relying only on mechanisms locally confined within each neuron and operating continuously in time, while a simple form of Hebbian synaptic plasticity operates on synaptic connections, thus shaping the interrelation between neurons as captured by a copula function. The combined effect of both mechanisms allows a neuron population to discover invariant representations of its inputs that remain stable under a wide range of transformations (e.g., shifting, scaling and (affine linear) mixing). The probabilistic model of homeostatic adaptation on a population level as presented here allows us to isolate and study the individual and the interaction dynamics of both mechanisms of plasticity and could guide the future search for computationally beneficial types of adaptation.

  7. Reduced synaptic facilitation between pyramidal neurons in the piriform cortex after odor learning.

    Science.gov (United States)

    Saar, D; Grossman, Y; Barkai, E

    1999-10-01

    Learning-related cellular modifications were studied in the rat piriform cortex after operand conditioning. Rats were trained to discriminate positive cues in pairs of odors. In one experimental paradigm, rats were trained to memorize 35-50 pairs of odors ("extensive training"). In another paradigm, training was continued only until rats acquired the rule of the task, usually after learning the first two pairs of odors ("short training"). "Pseudotrained" and "naive" rats served as controls. We have previously shown that "rule learning" of this task was accompanied by reduced spike afterhyperpolarization in pyramidal neurons in brain slices of the piriform cortex. In the present study, synaptic inputs to the same cells were examined. Pairs of electrical stimuli applied to the intrinsic fibers that interconnect layer II pyramidal neurons revealed significant reduction in paired-pulse facilitation (PPF) in this pathway even after short training. PPF in shortly trained rats was reduced to the same extent as in extensively trained rats. PPF reduction did not result from modification of membrane properties in the postsynaptic cells, change in postsynaptic inhibition, or impairment of the facilitation mechanism. Extracellular field potential recordings showed enhanced synaptic transmission in these synapses. The reduction in PPF became apparent only 3 d after task acquisition and returned to control value 5 d later. PPF evoked by stimulating the afferent fibers to the same neurons was increased 1 d after training for 2 d. We suggest that the transient enhancement in connectivity in the intrinsic pathway is related to the enhanced learning capability and not to memory for specific odors, which lasts for weeks.

  8. A robust and scalable neuromorphic communication system by combining synaptic time multiplexing and MIMO-OFDM.

    Science.gov (United States)

    Srinivasa, Narayan; Zhang, Deying; Grigorian, Beayna

    2014-03-01

    This paper describes a novel architecture for enabling robust and efficient neuromorphic communication. The architecture combines two concepts: 1) synaptic time multiplexing (STM) that trades space for speed of processing to create an intragroup communication approach that is firing rate independent and offers more flexibility in connectivity than cross-bar architectures and 2) a wired multiple input multiple output (MIMO) communication with orthogonal frequency division multiplexing (OFDM) techniques to enable a robust and efficient intergroup communication for neuromorphic systems. The MIMO-OFDM concept for the proposed architecture was analyzed by simulating large-scale spiking neural network architecture. Analysis shows that the neuromorphic system with MIMO-OFDM exhibits robust and efficient communication while operating in real time with a high bit rate. Through combining STM with MIMO-OFDM techniques, the resulting system offers a flexible and scalable connectivity as well as a power and area efficient solution for the implementation of very large-scale spiking neural architectures in hardware.

  9. Intermodal Passenger Connectivity Database -

    Data.gov (United States)

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

  10. Role of standardized grape polyphenol preparation as a novel treatment to improve synaptic plasticity through attenuation of features of metabolic syndrome in a mouse model.

    Science.gov (United States)

    Wang, Jun; Tang, Cheuk; Ferruzzi, Mario G; Gong, Bing; Song, Brian J; Janle, Elsa M; Chen, Tzu-Ying; Cooper, Bruce; Varghese, Merina; Cheng, Alice; Freire, Daniel; Bilski, Amanda; Roman, Jessica; Nguyen, Tuyen; Ho, Lap; Talcott, Stephen T; Simon, James E; Wu, Qingli; Pasinetti, Giulio M

    2013-12-01

    Metabolic syndrome has become an epidemic and poses tremendous burden on the health system. People with metabolic syndrome are more likely to experience cognitive decline. As obesity and sedentary lifestyles become more common, the development of early prevention strategies is critical. In this study, we explore the potential beneficial effects of a combinatory polyphenol preparation composed of grape seed extract, Concord purple grape juice extract, and resveratrol, referred to as standardized grape polyphenol preparation (SGP), on peripheral as well as brain dysfunction induced by metabolic syndrome. We found dietary fat content had minimal effect on absorption of metabolites of major polyphenols derived from SGP. Using a diet-induced animal model of metabolic syndrome (DIM), we found that brain functional connectivity and synaptic plasticity are compromised in the DIM mice. Treatment with SGP not only prevented peripheral metabolic abnormality but also improved brain synaptic plasticity. Our study demonstrated that SGP, comprised of multiple bioavailable and bioactive components targeting a wide range of metabolic syndrome related pathological features, provides greater global protection against peripheral and central nervous system dysfunctions and can be potentially developed as a novel prevention/treatment for improving brain connectivity and synaptic plasticity important for learning and memory. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Short term synaptic depression improves information transfer in perceptual multistability

    OpenAIRE

    Kilpatrick, Zachary P.

    2013-01-01

    Competitive neural networks are often used to model the dynamics of perceptual bistability. Switching between percepts can occur through fluctuations and/or a slow adaptive process. Here, we analyze switching statistics in competitive networks with short term synaptic depression and noise. We start by analyzing a ring model that yields spatially structured solutions and complement this with a study of a space-free network whose populations are coupled with mutual inhibition. Dominance times a...

  12. Cholinergic synaptic vesicle heterogeneity: evidence for regulation of acetylcholine transport

    International Nuclear Information System (INIS)

    Gracz, L.M.; Wang, W.; Parsons, S.M.

    1988-01-01

    Crude cholinergic synaptic vesicles from a homogenate of the electric organ of Torpedo californica were centrifuged to equilibrium in an isosmotic sucrose density gradient. The classical VP 1 synaptic vesicles banding at 1.055 g/mL actively transported [ 3 H]acetylcholine (AcCh). An organelle banding at about 1.071 g/mL transported even more [ 3 H]AcCh. Transport by both organelles was inhibited by the known AcCh storage blockers trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol, formerly AH5183) and nigericin. Relative to VP 1 vesicles the denser organelle was slightly smaller as shown by size-exclusion chromatography. It is concluded that the denser organelle corresponds to the recycling VP 2 synaptic vesicle originally described in intact Torpedo marmorata electric organ. The properties of the receptor for vesamicol were studied by measuring binding of [ 3 H]vesamicol, and the amount of SV2 antigen characteristic of secretory vesicles was assayed with a monoclonal antibody directed against it. Relative to VP 1 vesicles the VP 2 vesicles had a ratio of [ 3 H]AcCh transport activity to vesamicol receptor concentration that typically was 4-7-fold higher, whereas the ratio of SV2 antigen concentration to vesamicol receptor concentration was about 2-fold higher. The Hill coefficients α/sub H/ and equilibrium dissociation constants K for vesamicol binding to VP 1 and VP 2 vesicles were essentially the same. The positive Hill coefficient suggests that the vesamicol receptor exists as a homotropic oligomeric complex. The results demonstrate that VP 1 and VP 2 synaptic vesicles exhibit functional differences in the AcCh transport system, presumably as a result of regulatory phenomena

  13. Synaptic metaplasticity underlies tetanic potentiation in Lymnaea: a novel paradigm.

    Directory of Open Access Journals (Sweden)

    Anita Mehta

    Full Text Available We present a mathematical model that explains and interprets a novel form of short-term potentiation, which was found to be use-, but not time-dependent, in experiments done on Lymnaea neurons. The high degree of potentiation is explained using a model of synaptic metaplasticity, while the use-dependence (which is critically reliant on the presence of kinase in the experiment is explained using a model of a stochastic and bistable biological switch.

  14. Presynaptic Active Zone Density during Development and Synaptic Plasticity.

    Science.gov (United States)

    Clarke, Gwenaëlle L; Chen, Jie; Nishimune, Hiroshi

    2012-01-01

    Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density) during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs), the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS), active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and β-adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated.

  15. Dynamic learning and memory, synaptic plasticity and neurogenesis: an update

    Czech Academy of Sciences Publication Activity Database

    Stuchlík, Aleš

    2014-01-01

    Roč. 8, APR 1 (2014), s. 106 ISSN 1662-5153 R&D Projects: GA ČR(CZ) GA14-03627S Grant - others:Rada Programu interní podpory projektů mezinárodní spolupráce AV ČR(CZ) M200111204 Institutional support: RVO:67985823 Keywords : learning * memory * synaptic plasticity * neurogenesis Subject RIV: FH - Neurology Impact factor: 3.270, year: 2014

  16. Presynaptic active zone density during development and synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Gwenaëlle L Clarke

    2012-02-01

    Full Text Available Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs, the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS, active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and β-adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated.

  17. Torsin A Localization in the Mouse Cerebellar Synaptic Circuitry.

    Directory of Open Access Journals (Sweden)

    Francesca Puglisi

    Full Text Available Torsin A (TA is a ubiquitous protein belonging to the superfamily of proteins called "ATPases associated with a variety of cellular activities" (AAA(+ ATPase. To date, a great deal of attention has been focused on neuronal TA since its mutant form causes early-onset (DYT1 torsion dystonia, an inherited movement disorder characterized by sustained muscle contractions and abnormal postures. Interestingly, it has been proposed that TA, by interacting with the cytoskeletal network, may contribute to the control of neurite outgrowth and/or by acting as a chaperone at synapses could affect synaptic vesicle turnover and neurotransmitter release. Accordingly, both its peculiar developmental expression in striatum and cerebellum and evidence from DYT1 knock-in mice suggest that TA may influence dendritic arborization and synaptogenesis in the brain. Therefore, to better understand TA function a detailed description of its localization at synaptic level is required. Here, we characterized by means of rigorous quantitative confocal analysis TA distribution in the mouse cerebellum at postnatal day 14 (P14, when both cerebellar synaptogenesis and TA expression peak. We observed that the protein is broadly distributed both in cerebellar cortex and in the deep cerebellar nuclei (DCN. Of note, Purkinje cells (PC express high levels of TA also in the spines and axonal terminals. In addition, abundant expression of the protein was found in the main GABA-ergic and glutamatergic inputs of the cerebellar cortex. Finally, TA was observed also in glial cells, a cellular population little explored so far. These results extend our knowledge on TA synaptic localization providing a clue to its potential role in synaptic development.

  18. The computational power of astrocyte mediated synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Rogier eMin

    2012-11-01

    Full Text Available Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte-mediated signaling processes described in the literature today, the current challenge is to identify which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways.

  19. Evolution of the aging brain transcriptome and synaptic regulation.

    Directory of Open Access Journals (Sweden)

    Patrick M Loerch

    Full Text Available Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4. However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

  20. Control of synaptic function by endocannabinoid-mediated retrograde signaling

    Science.gov (United States)

    KANO, Masanobu

    2014-01-01

    Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca2+ elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation. PMID:25169670

  1. A versatile optical tool for studying synaptic GABAA receptor trafficking.

    Science.gov (United States)

    Lorenz-Guertin, Joshua M; Wilcox, Madeleine R; Zhang, Ming; Larsen, Mads B; Pilli, Jyotsna; Schmidt, Brigitte F; Bruchez, Marcel P; Johnson, Jon W; Waggoner, Alan S; Watkins, Simon C; Jacob, Tija C

    2017-11-15

    Live-cell imaging methods can provide critical real-time receptor trafficking measurements. Here, we describe an optical tool to study synaptic γ-aminobutyric acid (GABA) type A receptor (GABA A R) dynamics through adaptable fluorescent-tracking capabilities. A fluorogen-activating peptide (FAP) was genetically inserted into a GABA A R γ2 subunit tagged with pH-sensitive green fluorescent protein (γ2 pH FAP). The FAP selectively binds and activates Malachite Green (MG) dyes that are otherwise non-fluorescent in solution. γ2 pH FAP GABA A Rs are expressed at the cell surface in transfected cortical neurons, form synaptic clusters and do not perturb neuronal development. Electrophysiological studies show γ2 pH FAP GABA A Rs respond to GABA and exhibit positive modulation upon stimulation with the benzodiazepine diazepam. Imaging studies using γ2 pH FAP-transfected neurons and MG dyes show time-dependent receptor accumulation into intracellular vesicles, revealing constitutive endosomal and lysosomal trafficking. Simultaneous analysis of synaptic, surface and lysosomal receptors using the γ2 pH FAP-MG dye approach reveals enhanced GABA A R turnover following a bicucculine-induced seizure paradigm, a finding not detected by standard surface receptor measurements. To our knowledge, this is the first application of the FAP-MG dye system in neurons, demonstrating the versatility to study nearly all phases of GABA A R trafficking. © 2017. Published by The Company of Biologists Ltd.

  2. STDP with adaptive synaptic delay for robot navigation control

    Science.gov (United States)

    Arena, Paolo; Patané, Luca; Distefano, Francesco; Bucolo, Sebastiano; Aiello, Orazio

    2007-05-01

    In this work a biologically inspired network of spiking neurons is used for robot navigation control. The two tasks taken into account are obstacle avoidance and landmark-based navigation. The system learns the correlation among unconditioned stimuli (pre-wired sensors) and conditioned stimuli (high level sensors) through Spike Timing Dependent Plasticity (STDP). In order to improve the robot behaviours not only the synaptic weight but also the synaptic delay is subject to learning. Modulating the synaptic delay the robot is able to store the landmark position, like in a short time memory, and to use this information to smooth the turning actions prolonging the landmark effects also when it is no more visible. Simulations are carried out in a dynamic simulation environment and the robotic system considered is a cockroach-inspired hexapod robot. The locomotion signals are generated by a Central Pattern Generator and the spiking network is devoted to control the heading of the robot acting on the amplitude of the leg steps. Several scenarios have been proposed, for instance a T-shaped labyrinth, used in laboratory experiments with mice to demonstrate classical and operant conditioning, has been considered. Finally the proposed adaptive navigation control structure can be extended in a modular way to include other features detected by new sensors included in the correlation-based learning process.

  3. Robust Short-Term Memory without Synaptic Learning

    Science.gov (United States)

    Johnson, Samuel; Marro, J.; Torres, Joaquín J.

    2013-01-01

    Short-term memory in the brain cannot in general be explained the way long-term memory can – as a gradual modification of synaptic weights – since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds). The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings. PMID:23349664

  4. Functional consequences of pre- and postsynaptic expression of synaptic plasticity.

    Science.gov (United States)

    Costa, Rui Ponte; Mizusaki, Beatriz E P; Sjöström, P Jesper; van Rossum, Mark C W

    2017-03-05

    Growing experimental evidence shows that both homeostatic and Hebbian synaptic plasticity can be expressed presynaptically as well as postsynaptically. In this review, we start by discussing this evidence and methods used to determine expression loci. Next, we discuss the functional consequences of this diversity in pre- and postsynaptic expression of both homeostatic and Hebbian synaptic plasticity. In particular, we explore the functional consequences of a biologically tuned model of pre- and postsynaptically expressed spike-timing-dependent plasticity complemented with postsynaptic homeostatic control. The pre- and postsynaptic expression in this model predicts (i) more reliable receptive fields and sensory perception, (ii) rapid recovery of forgotten information (memory savings), and (iii) reduced response latencies, compared with a model with postsynaptic expression only. Finally, we discuss open questions that will require a considerable research effort to better elucidate how the specific locus of expression of homeostatic and Hebbian plasticity alters synaptic and network computations.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. © 2017 The Authors.

  5. Structural Components of Synaptic Plasticity and Memory Consolidation

    Science.gov (United States)

    Bailey, Craig H.; Kandel, Eric R.; Harris, Kristen M.

    2015-01-01

    Consolidation of implicit memory in the invertebrate Aplysia and explicit memory in the mammalian hippocampus are associated with remodeling and growth of preexisting synapses and the formation of new synapses. Here, we compare and contrast structural components of the synaptic plasticity that underlies these two distinct forms of memory. In both cases, the structural changes involve time-dependent processes. Thus, some modifications are transient and may contribute to early formative stages of long-term memory, whereas others are more stable, longer lasting, and likely to confer persistence to memory storage. In addition, we explore the possibility that trans-synaptic signaling mechanisms governing de novo synapse formation during development can be reused in the adult for the purposes of structural synaptic plasticity and memory storage. Finally, we discuss how these mechanisms set in motion structural rearrangements that prepare a synapse to strengthen the same memory and, perhaps, to allow it to take part in other memories as a basis for understanding how their anatomical representation results in the enhanced expression and storage of memories in the brain. PMID:26134321

  6. High pressure and [Ca2+] produce an inverse modulation of synaptic input strength, network excitability and frequency response in the rat dentate gyrus

    Directory of Open Access Journals (Sweden)

    Thomas I Talpalar

    2016-09-01

    Full Text Available Hyperbaric environments induce the high pressure neurological syndrome (HPNS characterized by hyperexcitability of the central nervous system and memory impairment. Human divers and other animals experience the HPNS at pressures beyond 1.1 MPa. High pressure depresses synaptic transmission and alters its dynamics in various animal models. Medial perforant path (MPP synapses connecting the medial entorhinal cortex with the hippocampal formation are suppressed by 50% at 10.1MPa. Reduction of synaptic inputs is paradoxically associated with enhanced ability of dentate gyrus’ granule cells to generate spikes at high pressure. This mechanism allows MPP inputs to elicit standard granule cell outputs at 0.1 -25 Hz frequencies under hyperbaric conditions. An increased postsynaptic gain of MPP inputs probably allows diving animals to perform in hyperbaric environments, but makes them vulnerable to high intensity/frequency stimuli producing hyperexcitability. Increasing extracellular Ca2+ (Ca2+o partially reverted pressure-mediated depression of MPP inputs and increased MPP’s low-pass filter properties. We postulated that raising Ca2+o in addition to increase synaptic inputs may reduce network excitability in the dentate gyrus potentially improving its function and reducing sensitivity to high intensity and pathologic stimuli. For this matter, we activated the MPP with single and 50 Hz frequency stimuli that simulated physiologic and deleterious conditions, while assessing the granule cell’s output under various conditions of pressure and Ca2+o. Our results reveal that pressure and Ca2+o produce an inverse modulation on synaptic input strength and network excitability. These coincident phenomena suggest a potential general mechanism of networks that adjusts gain as an inverse function of synaptic inputs’ strength. Such mechanism may serve for adaptation to variable pressure and other physiological and pathological conditions and may explain the

  7. Minimum cost connection networks

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Tvede, Mich

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

  8. Effective Mechanism for Synthesis of Neurotransmitter Glutamate and its Loading into Synaptic Vesicles.

    Science.gov (United States)

    Takeda, Kouji; Ueda, Tetsufumi

    2017-01-01

    Glutamate accumulation into synaptic vesicles is a pivotal step in glutamate transmission. This process is achieved by a vesicular glutamate transporter (VGLUT) coupled to v-type proton ATPase. Normal synaptic transmission, in particular during intensive neuronal firing, would demand rapid transmitter re-filling of emptied synaptic vesicles. We have previously shown that isolated synaptic vesicles are capable of synthesizing glutamate from α-ketoglutarate (not from glutamine) by vesicle-bound aspartate aminotransferase for immediate uptake, in addition to ATP required for uptake by vesicle-bound glycolytic enzymes. This suggests that local synthesis of these substances, essential for glutamate transmission, could occur at the synaptic vesicle. Here we provide evidence that synaptosomes (pinched-off nerve terminals) also accumulate α-ketoglutarate-derived glutamate into synaptic vesicles within, at the expense of ATP generated through glycolysis. Glutamine-derived glutamate is also accumulated into synaptic vesicles in synaptosomes. The underlying mechanism is discussed. It is suggested that local synthesis of both glutamate and ATP at the presynaptic synaptic vesicle would represent an efficient mechanism for swift glutamate loading into synaptic vesicles, supporting maintenance of normal synaptic transmission.

  9. Differentiated effect of ageing on the enzymes of Krebs' cycle, electron transfer complexes and glutamate metabolism of non-synaptic and intra-synaptic mitochondria from cerebral cortex.

    Science.gov (United States)

    Villa, R F; Gorini, A; Hoyer, S

    2006-11-01

    The effect of ageing on the activity of enzymes linked to Krebs' cycle, electron transfer chain and glutamate metabolism was studied in three different types of mitochondria of cerebral cortex of 1-year old and 2-year old male Wistar rats. We assessed the maximum rate (V(max)) of the mitochondrial enzyme activities in non-synaptic perikaryal mitochondria, and in two populations of intra-synaptic mitochondria. The results indicated that: (i) in normal, steady-state cerebral cortex the values of the catalytic activities of the enzymes markedly differed in the various populations of mitochondria; (ii) in intra-synaptic mitochondria, ageing affected the catalytic properties of the enzymes linked to Krebs' cycle, electron transfer chain and glutamate metabolism; (iii) these changes were more evident in intra-synaptic "heavy" than "light" mitochondria. These results indicate a different age-related vulnerability of subpopulations of mitochondria in vivo located into synapses than non-synaptic ones.

  10. Spike Pattern Structure Influences Synaptic Efficacy Variability under STDP and Synaptic Homeostasis. II: Spike Shuffling Methods on LIF Networks

    Science.gov (United States)

    Bi, Zedong; Zhou, Changsong

    2016-01-01

    Synapses may undergo variable changes during plasticity because of the variability of spike patterns such as temporal stochasticity and spatial randomness. Here, we call the variability of synaptic weight changes during plasticity to be efficacy variability. In this paper, we investigate how four aspects of spike pattern statistics (i.e., synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations) influence the efficacy variability under pair-wise additive spike-timing dependent plasticity (STDP) and synaptic homeostasis (the mean strength of plastic synapses into a neuron is bounded), by implementing spike shuffling methods onto spike patterns self-organized by a network of excitatory and inhibitory leaky integrate-and-fire (LIF) neurons. With the increase of the decay time scale of the inhibitory synaptic currents, the LIF network undergoes a transition from asynchronous state to weak synchronous state and then to synchronous bursting state. We first shuffle these spike patterns using a variety of methods, each designed to evidently change a specific pattern statistics; and then investigate the change of efficacy variability of the synapses under STDP and synaptic homeostasis, when the neurons in the network fire according to the spike patterns before and after being treated by a shuffling method. In this way, we can understand how the change of pattern statistics may cause the change of efficacy variability. Our results are consistent with those of our previous study which implements spike-generating models on converging motifs. We also find that burstiness/regularity is important to determine the efficacy variability under asynchronous states, while heterogeneity of cross-correlations is the main factor to cause efficacy variability when the network moves into synchronous bursting states (the states observed in epilepsy). PMID:27555816

  11. Spike Pattern Structure Influences Synaptic Efficacy Variability Under STDP and Synaptic Homeostasis. II: Spike Shuffling Methods on LIF Networks

    Directory of Open Access Journals (Sweden)

    Zedong Bi

    2016-08-01

    Full Text Available Synapses may undergo variable changes during plasticity because of the variability of spike patterns such as temporal stochasticity and spatial randomness. Here, we call the variability of synaptic weight changes during plasticity to be efficacy variability. In this paper, we investigate how four aspects of spike pattern statistics (i.e., synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations influence the efficacy variability under pair-wise additive spike-timing dependent plasticity (STDP and synaptic homeostasis (the mean strength of plastic synapses into a neuron is bounded, by implementing spike shuffling methods onto spike patterns self-organized by a network of excitatory and inhibitory leaky integrate-and-fire (LIF neurons. With the increase of the decay time scale of the inhibitory synaptic currents, the LIF network undergoes a transition from asynchronous state to weak synchronous state and then to synchronous bursting state. We first shuffle these spike patterns using a variety of methods, each designed to evidently change a specific pattern statistics; and then investigate the change of efficacy variability of the synapses under STDP and synaptic homeostasis, when the neurons in the network fire according to the spike patterns before and after being treated by a shuffling method. In this way, we can understand how the change of pattern statistics may cause the change of efficacy variability. Our results are consistent with those of our previous study which implements spike-generating models on converging motifs. We also find that burstiness/regularity is important to determine the efficacy variability under asynchronous states, while heterogeneity of cross-correlations is the main factor to cause efficacy variability when the network moves into synchronous bursting states (the states observed in epilepsy.

  12. Spike Pattern Structure Influences Synaptic Efficacy Variability under STDP and Synaptic Homeostasis. II: Spike Shuffling Methods on LIF Networks

    OpenAIRE

    Bi, Zedong; Zhou, Changsong

    2016-01-01

    Synapses may undergo variable changes during plasticity because of the variability of spike patterns such as temporal stochasticity and spatial randomness. Here, we call the variability of synaptic weight changes during plasticity to be efficacy variability. In this paper, we investigate how four aspects of spike pattern statistics (i.e., synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations) influence the efficacy variability under pair-wis...

  13. Electroencephalography Source Functional Connectivity Reveals Abnormal High-Frequency Communication Among Large-Scale Functional Networks in Depression.

    Science.gov (United States)

    Whitton, Alexis E; Deccy, Stephanie; Ironside, Manon L; Kumar, Poornima; Beltzer, Miranda; Pizzagalli, Diego A

    2018-01-01

    Functional magnetic resonance imaging studies of resting-state functional connectivity have shown that major depressive disorder (MDD) is characterized by increased connectivity within the default mode network (DMN) and between the DMN and the frontoparietal network (FPN). However, much remains unknown about abnormalities in higher frequency (>1 Hz) synchronization. Findings of abnormal synchronization in specific frequencies would contribute to a better understanding of the potential neurophysiological origins of disrupted functional connectivity in MDD. We used the high temporal resolution of electroencephalography to compare the spectral properties of resting-state functional connectivity in individuals with MDD (n = 65) with healthy control subjects (n = 79) and examined the extent to which connectivity disturbances were evident in a third sample of individuals in remission from depression (n = 30). Exact low resolution electromagnetic tomography was used to compute intracortical activity from regions within the DMN and FPN, and functional connectivity was computed using lagged phase synchronization. Compared to control subjects, the MDD group showed greater within-DMN beta 2 band (18.5-21 Hz) connectivity and greater beta 1 band (12.5-18 Hz) connectivity between the DMN and FPN. This hyperconnectivity was not observed in the remitted MDD group. However, greater beta 1 band DMN-FPN connectivity was associated with more frequent depressive episodes since first depression onset, even after controlling for current symptom severity. These findings extend our understanding of the neurophysiological basis of abnormal resting-state functional connectivity in MDD and indicate that elevations in high-frequency DMN-FPN connectivity may be a neural marker linked to a more recurrent illness course. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  14. Synaptic and non-synaptic mitochondria in hippocampus of adult rats differ in their sensitivity to hypothyroidism.

    Science.gov (United States)

    Zhuravliova, E; Barbakadze, T; Jojua, N; Zaalishvili, E; Shanshiashvili, L; Natsvlishvili, N; Kalandadze, I; Narmania, N; Chogovadze, I; Mikeladze, D

    2012-11-01

    Hypothyroidism in humans provokes various neuropsychiatric disorders, movement, and cognitive abnormalities that may greatly depend on the mitochondrial energy metabolism. Brain cells contain at least two major populations of mitochondria that include the non-synaptic mitochondria, which originate from neuronal and glial cell bodies (CM), and the synaptic (SM) mitochondria, which primarily originate from the nerve terminals. Several parameters of oxidative stress and other parameters in SM and CM fractions of hippocampus of adult rats were compared among euthyroid (control), hypothyroid (methimazol-treated), and thyroxine (T4)-treated hypothyroid states. nNOS translocation to CM was observed with concomitant increase of mtNOS's activity in hypothyroid rats. In parallel, oxidation of cytochrome c oxidase and production of peroxides with substrates of complex I (glutamate + malate) were enhanced in CM, whereas the activity of aconitase and mitochondrial membrane potential (ΔΨm) were decreased. Furthermore, the elevation of mitochondrial hexokinase activity in CM was also found. No differences in these parameters between control and hypothyroid animals were observed in SM. However, in contrast to CM, hypothyroidism increases the level of pro-apoptotic K-Ras and Bad in SM. Our results suggest that hypothyroidism induces moderate and reversible oxidative/nitrosative stress in hippocampal CM, leading to the compensatory elevation of hexokinase activity and aerobic glycolysis. Such adaptive activation in glycolytic metabolism does not occur in SM, suggesting that synaptic mitochondria differ in their sensitivity to the energetic disturbance in hypothyroid conditions.

  15. Development of Connectivity in a Motoneuronal Network in Drosophila Larvae

    Science.gov (United States)

    Couton, Louise; Mauss, Alex S.; Yunusov, Temur; Diegelmann, Soeren; Evers, Jan Felix; Landgraf, Matthias

    2015-01-01

    Summary Background Much of our understanding of how neural networks develop is based on studies of sensory systems, revealing often highly stereotyped patterns of connections, particularly as these diverge from the presynaptic terminals of sensory neurons. We know considerably less about the wiring strategies of motor networks, where connections converge onto the dendrites of motoneurons. Here, we investigated patterns of synaptic connections between identified motoneurons with sensory neurons and interneurons in the motor network of the Drosophila larva and how these change as it develops. Results We find that as animals grow, motoneurons increase the number of synapses with existing presynaptic partners. Different motoneurons form characteristic cell-type-specific patterns of connections. At the same time, there is considerable variability in the number of synapses formed on motoneuron dendrites, which contrasts with the stereotypy reported for presynaptic terminals of sensory neurons. Where two motoneurons of the same cell type contact a common interneuron partner, each postsynaptic cell can arrive at a different connectivity outcome. Experimentally changing the positioning of motoneuron dendrites shows that the geography of dendritic arbors in relation to presynaptic partner terminals is an important determinant in shaping patterns of connectivity. Conclusions In the Drosophila larval motor network, the sets of connections that form between identified neurons manifest an unexpected level of variability. Synapse number and the likelihood of forming connections appear to be regulated on a cell-by-cell basis, determined primarily by the postsynaptic dendrites of motoneuron terminals. PMID:25702582

  16. A comparison between uni- and bilateral tDCS effects on functional connectivity of the human motor cortex

    Directory of Open Access Journals (Sweden)

    Bernhard eSehm

    2013-05-01

    Full Text Available tDCS over the primary motor cortex (M1 has been shown to induce changes in motor performance and learning. Recent studies indicate that tDCS is capable of modulating widespread neural network properties within the brain. However the temporal evolution of online- and after- effects of tDCS on functional connectivity within and across the stimulated motor cortices (M1 still remain elusive. In the present study, two different tDCS setups were investigated: (i unilateral M1 tDCS (anode over right M1, cathode over the contralateral supraorbital region and (ii bilateral M1 tDCS (anode over right M1, cathode over left M1. In a randomized single-blinded crossover design, 12 healthy subjects underwent resting-state functional magnetic resonance imaging at rest (rs-fMRI before, during and after 20 min of either bi-, unilateral or sham M1 tDCS. Seed-based functional connectivity analysis (FC was used to investigate tDCS-induced changes across and within M1. We found that bilateral M1 tDCS induced (a a decrease in interhemispheric FC during stimulation and (b an increase in intracortical FC within right M1 after termination of the intervention. While unilateral M1 tDCS also resulted in similar effects during stimulation, no such changes could be observed after termination of tDCS. Our results provide evidence that depending on the electrode montage, tDCS acts upon a modulation of either intracortical and/or interhemispheric processing of M1.

  17. Cooperative stochastic binding and unbinding explain synaptic size dynamics and statistics.

    Science.gov (United States)

    Shomar, Aseel; Geyrhofer, Lukas; Ziv, Noam E; Brenner, Naama

    2017-07-01

    Synapses are dynamic molecular assemblies whose sizes fluctuate significantly over time-scales of hours and days. In the current study, we examined the possibility that the spontaneous microscopic dynamics exhibited by synaptic molecules can explain the macroscopic size fluctuations of individual synapses and the statistical properties of synaptic populations. We present a mesoscopic model, which ties the two levels. Its basic premise is that synaptic size fluctuations reflect cooperative assimilation and removal of molecules at a patch of postsynaptic membrane. The introduction of cooperativity to both assimilation and removal in a stochastic biophysical model of these processes, gives rise to features qualitatively similar to those measured experimentally: nanoclusters of synaptic scaffolds, fluctuations in synaptic sizes, skewed, stable size distributions and their scaling in response to perturbations. Our model thus points to the potentially fundamental role of cooperativity in dictating synaptic remodeling dynamics and offers a conceptual understanding of these dynamics in terms of central microscopic features and processes.

  18. Cooperative stochastic binding and unbinding explain synaptic size dynamics and statistics.

    Directory of Open Access Journals (Sweden)

    Aseel Shomar

    2017-07-01

    Full Text Available Synapses are dynamic molecular assemblies whose sizes fluctuate significantly over time-scales of hours and days. In the current study, we examined the possibility that the spontaneous microscopic dynamics exhibited by synaptic molecules can explain the macroscopic size fluctuations of individual synapses and the statistical properties of synaptic populations. We present a mesoscopic model, which ties the two levels. Its basic premise is that synaptic size fluctuations reflect cooperative assimilation and removal of molecules at a patch of postsynaptic membrane. The introduction of cooperativity to both assimilation and removal in a stochastic biophysical model of these processes, gives rise to features qualitatively similar to those measured experimentally: nanoclusters of synaptic scaffolds, fluctuations in synaptic sizes, skewed, stable size distributions and their scaling in response to perturbations. Our model thus points to the potentially fundamental role of cooperativity in dictating synaptic remodeling dynamics and offers a conceptual understanding of these dynamics in terms of central microscopic features and processes.

  19. Opposing Effects of Intrinsic Conductance and Correlated Synaptic Input on V-Fluctuations during Network Activity

    DEFF Research Database (Denmark)

    Kolind, Jens; Hounsgaard, Jørn Dybkjær; Berg, Rune W

    2012-01-01

    Neurons often receive massive concurrent bombardment of synaptic inhibition and excitation during functional network activity. This increases membrane conductance and causes fluctuations in membrane potential (V(m)) and spike timing. The conductance increase is commonly attributed to synaptic...... conductance, but also includes the intrinsic conductances recruited during network activity. These two sources of conductance have contrasting dynamic properties at sub-threshold membrane potentials. Synaptic transmitter gated conductance changes abruptly and briefly with each presynaptic action potential...... input we find that the magnitude of the membrane fluctuations uniquely determines the relative contribution of synaptic and intrinsic conductance. We also quantify how V(m)-fluctuations vary with synaptic correlations for fixed ratios of synaptic and intrinsic conductance. Interestingly, the levels of V...

  20. Electronic imitation of behavioral and psychological synaptic activities using TiOx/Al2O3-based memristor devices.

    Science.gov (United States)

    Banerjee, Writam; Liu, Qi; Lv, Hangbing; Long, Shibing; Liu, Ming

    2017-10-05

    Seeking an effective electronic synapse to emulate biological synaptic behavior is fundamental for building brain-inspired computers. An emerging two-terminal memristor, in which the conductance can be gradually modulated by external electrical stimuli, is widely considered as the strongest competitor of the electronic synapse. Here, we show the capability of TiO x /Al 2 O 3 -based memristor devices to imitate synaptic behaviors. Along with analog resistive switching performances, the devices replicate the bio-synapse behaviors of potentiation/depression, short-term-plasticity, and long-term-potentiation, which show that TiO x /Al 2 O 3 -based memristors may be useful as electronic synapses. The essential memorizing capabilities of the brain are dependent on the connection strength between neurons, and the memory types change from short-term memory to long-term memory. In the TiO x /Al 2 O 3 -based electronic synaptic junction, the memorizing levels can change their state via a standard rehearsal process and also via newly introduced process called "impact of event" i.e. the impact of pulse amplitude, and the width of the input pulse. The devices show a short-term to long-term memory effect with the introduction of intermediate mezzanine memory. The experimental achievements using the TiO x /Al 2 O 3 electronic synapses are finally psychologically modeled by considering the mezzanine level. It is highly recommended that similar phenomena should be investigated for other memristor systems to check the authenticity of this model.

  1. Dynamic effective connectivity of inter-areal brain circuits.

    Directory of Open Access Journals (Sweden)

    Demian Battaglia

    Full Text Available Anatomic connections between brain areas affect information flow between neuronal circuits and the synchronization of neuronal activity. However, such structural connectivity does not coincide with effective connectivity (or, more precisely, causal connectivity, related to the elusive question "Which areas cause the present activity of which others?". Effective connectivity is directed and depends flexibly on contexts and tasks. Here we show that dynamic effective connectivity can emerge from transitions in the collective organization of coherent neural activity. Integrating simulation and semi-analytic approaches, we study mesoscale network motifs of interacting cortical areas, modeled as large random networks of spiking neurons or as simple rate units. Through a causal analysis of time-series of model neural activity, we show that different dynamical states generated by a same structural connectivity motif correspond to distinct effective connectivity motifs. Such effective motifs can display a dominant directionality, due to spontaneous symmetry breaking and effective entrainment between local brain rhythms, although all connections in the considered structural motifs are reciprocal. We show then that transitions between effective connectivity configurations (like, for instance, reversal in the direction of inter-areal interactions can be triggered reliably by brief perturbation inputs, properly timed with respect to an ongoing local oscillation, without the need for plastic synaptic changes. Finally, we analyze how the information encoded in spiking patterns of a local neuronal population is propagated across a fixed structural connectivity motif, demonstrating that changes in the active effective connectivity regulate both the efficiency and the directionality of information transfer. Previous studies stressed the role played by coherent oscillations in establishing efficient communication between distant areas. Going beyond these early

  2. PSD-95 and PSD-93 Play Critical but Distinct Roles in Synaptic Scaling Up and Down

    Science.gov (United States)

    Sun, Qian; Turrigiano, Gina G.

    2011-01-01

    Synaptic scaling stabilizes neuronal firing through the homeostatic regulation of postsynaptic strength, but the mechanisms by which chronic changes in activity lead to bidirectional adjustments in synaptic AMPAR abundance are incompletely understood. Further, it remains unclear to what extent scaling up and scaling down utilize distinct molecular machinery. PSD-95 is a scaffold protein proposed to serve as a binding “slot” that determines synaptic AMPAR content, and synaptic PSD-95 abundance is regulated by activity, raising the possibility that activity-dependent changes in the synaptic abundance of PSD-95 or other MAGUKs drives the bidirectional changes in AMPAR accumulation during synaptic scaling. We found that synaptic PSD-95 and SAP102 (but not PSD-93) abundance were bidirectionally regulated by activity, but these changes were not sufficient to drive homeostatic changes in synaptic strength. Although not sufficient, the PSD-95-MAGUKs were necessary for synaptic scaling, but scaling up and down were differentially dependent on PSD-95 and PSD-93. Scaling down was completely blocked by reduced or enhanced PSD-95, through a mechanism that depended on the PDZ1/2 domains. In contrast scaling up could be supported by either PSD-95 or PSD-93 in a manner that depended on neuronal age, and was unaffected by a superabundance of PSD-95. Taken together, our data suggest that scaling up and down of quantal amplitude is not driven by changes in synaptic abundance of PSD-95-MAGUKs, but rather that the PSD-95 MAGUKs serve as critical synaptic organizers that utilize distinct protein-protein interactions to mediate homeostatic accumulation and loss of synaptic AMPAR. PMID:21543610

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

    OpenAIRE

    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 tempo...

  4. Linking Network Activity to Synaptic Plasticity during Sleep: Hypotheses and Recent Data.

    Science.gov (United States)

    Puentes-Mestril, Carlos; Aton, Sara J

    2017-01-01

    Research findings over the past two decades have supported a link between sleep states and synaptic plasticity. Numerous mechanistic hypotheses have been put forth to explain this relationship. For example, multiple studies have shown structural alterations to synapses (including changes in synaptic volume, spine density, and receptor composition) indicative of synaptic weakening after a period of sleep. Direct measures of neuronal activity and synaptic strength support the idea that a period of sleep can reduce synaptic strength. This has led to the synaptic homeostasis hypothesis (SHY), which asserts that during slow wave sleep, synapses are downscaled throughout the brain to counteract net strengthening of network synapses during waking experience (e.g., during learning). However, neither the cellular mechanisms mediating these synaptic changes, nor the sleep-dependent activity changes driving those cellular events are well-defined. Here we discuss potential cellular and network dynamic mechanisms which could underlie reductions in synaptic strength during sleep. We also discuss recent findings demonstrating circuit-specific synaptic strengthening (rather than weakening) during sleep. Based on these data, we explore the hypothetical role of sleep-associated network activity patterns in driving synaptic strengthening. We propose an alternative to SHY-namely that depending on experience during prior wake, a variety of plasticity mechanisms may operate in the brain during sleep. We conclude that either synaptic strengthening or synaptic weakening can occur across sleep, depending on changes to specific neural circuits (such as gene expression and protein translation) induced by experiences in wake. Clarifying the mechanisms underlying these different forms of sleep-dependent plasticity will significantly advance our understanding of how sleep benefits various cognitive functions.

  5. Minimum cost connection networks

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Tvede, Mich

    2015-01-01

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

  6. Synaptic proteome changes in the hypothalamus of mother rats.

    Science.gov (United States)

    Udvari, Edina Brigitta; Völgyi, Katalin; Gulyássy, Péter; Dimén, Diána; Kis, Viktor; Barna, János; Szabó, Éva Rebeka; Lubec, Gert; Juhász, Gábor; Kékesi, Katalin Adrienna; Dobolyi, Árpád

    2017-04-21

    To establish synaptic proteome changes associated with motherhood, we isolated synaptosome fractions from the hypothalamus of mother rats and non-maternal control females at the 11th postpartum day. Proteomic analysis by two-dimensional differential gel electrophoresis combined with mass spectrometric protein identification established 26 significant proteins, 7 increasing and 19 decreasing protein levels in the dams. The altered proteins are mainly involved in energy homeostasis, protein folding, and metabolic processes suggesting the involvement of these cellular processes in maternal adaptations. The decrease in a significantly altered protein, complement component 1q subcomponent-binding protein (C1qbp) was validated with Western blotting. Furthermore, immunohistochemistry showed its presence in hypothalamic fibers and terminals in agreement with its presence in synaptosomes. We also found the expression of C1qbp in different hypothalamic nuclei including the preoptic area and the paraventricular hypothalamic nucleus at the protein and at the mRNA level using immunohistochemistry and in situ hybridization histochemistry, respectively. Bioinformatical network analysis revealed that cytokines, growth factors, and protein kinases are common regulators, which indicates a complex regulation of the proteome change in mothers. The results suggest that maternal responsiveness is associated with synaptic proteins level changes in the hypothalamus, and that growth factors and cytokines may govern these alterations. The period of motherhood is accompanied with several behavioral, neuroendocrine, emotional and metabolic adaptations in the brain. Although it is established that various hypothalamic networks participate in the maternal adaptations of the rodent brain, our knowledge on the molecular background of these alterations remains seriously limited. In the present study, we first determined that the functional alterations of the maternal brain can be detected at the

  7. Addiction-like Synaptic Impairments in Diet-Induced Obesity.

    Science.gov (United States)

    Brown, Robyn Mary; Kupchik, Yonatan Michael; Spencer, Sade; Garcia-Keller, Constanza; Spanswick, David C; Lawrence, Andrew John; Simonds, Stephanie Elise; Schwartz, Danielle Joy; Jordan, Kelsey Ann; Jhou, Thomas Clayton; Kalivas, Peter William

    2017-05-01

    There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core considered hallmarks of addiction. Sprague Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed ratio 1, 3, and 5 and progressive ratio schedules. Subsequently, nucleus accumbens brain slices were prepared, and we tested for changes in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate currents and the ability to exhibit long-term depression. We found that propensity to develop DIO is linked to deficits in the ability to induce long-term depression in the nucleus accumbens, as well as increased potentiation at these synapses as measured by AMPA/N-methyl-D-aspartate currents. Consistent with these impairments, we observed addictive-like behavior in DIO-prone rats, including 1) heightened motivation for palatable food; 2) excessive intake; and 3) increased food seeking when food was unavailable. Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction. Copyright © 2016 Society of Biological Psychiatry. All rights reserved.

  8. Remodeling Functional Connectivity in Multiple Sclerosis: A Challenging Therapeutic Approach

    Directory of Open Access Journals (Sweden)

    Mario Stampanoni Bassi

    2017-12-01

    Full Text Available Neurons in the central nervous system are organized in functional units interconnected to form complex networks. Acute and chronic brain damage disrupts brain connectivity producing neurological signs and/or symptoms. In several neurological diseases, particularly in Multiple Sclerosis (MS, structural imaging studies cannot always demonstrate a clear association between lesion site and clinical disability, originating the “clinico-radiological paradox.” The discrepancy between structural damage and disability can be explained by a complex network perspective. Both brain networks architecture and synaptic plasticity may play important roles in modulating brain networks efficiency after brain damage. In particular, long-term potentiation (LTP may occur in surviving neurons to compensate network disconnection. In MS, inflammatory cytokines dramatically interfere with synaptic transmission and plasticity. Importantly, in addition to acute and chronic structural damage, inflammation could contribute to reduce brain networks efficiency in MS leading to worse clinical recovery after a relapse and worse disease progression. These evidence suggest that removing inflammation should represent the main therapeutic target in MS; moreover, as synaptic plasticity is particularly altered by inflammation, specific strategies aimed at promoting LTP mechanisms could be effective for enhancing clinical recovery. Modulation of plasticity with different non-invasive brain stimulation (NIBS techniques has been used to promote recovery of MS symptoms. Better knowledge of features inducing brain disconnection in MS is crucial to design specific strategies to promote recovery and use NIBS with an increasingly tailored approach.

  9. Chronic murine toxoplasmosis is defined by subtle changes in neuronal connectivity

    Directory of Open Access Journals (Sweden)

    Alexandru Parlog

    2014-04-01

    Full Text Available Recent studies correlate chronic Toxoplasma gondii (T. gondii infection with behavioral changes in rodents; additionally, seropositivity in humans is reported to be associated with behavioral and neuropsychiatric diseases. In this study we investigated whether the described behavioral changes in a murine model of chronic toxoplasmosis are associated with changes in synaptic plasticity and brain neuronal circuitry. In mice chronically infected with T. gondii, magnetic resonance imaging (MRI data analysis displayed the presence of heterogeneous lesions scattered throughout all brain areas. However, a higher density of lesions was observed within specific regions such as the somatosensory cortex (SSC. Further histopathological examination of these brain areas indicated the presence of activated resident glia and recruited immune cells accompanied by limited alterations of neuronal viability. In vivo diffusion-tensor MRI analysis of neuronal fiber density within the infected regions revealed connectivity abnormalities in the SSC. Altered fiber density was confirmed by morphological analysis of individual, pyramidal and granule neurons, showing a reduction in dendritic arbor and spine density within the SSC, as well as in the hippocampus. Evaluation of synapse efficacy revealed diminished levels of two key synaptic proteins, PSD95 and synaptophysin, within the same brain areas, indicating deficits in functionality of the synaptic neurotransmission in infected mice. Our results demonstrate that persistent T. gondii infection in a murine model results in synaptic deficits within brain structures leading to disturbances in the morphology of noninfected neurons and modified brain connectivity, suggesting a potential explanation for the behavioral and neuropsychiatric alterations.

  10. Two aspects of ASIC function: Synaptic plasticity and neuronal injury.

    Science.gov (United States)

    Huang, Yan; Jiang, Nan; Li, Jun; Ji, Yong-Hua; Xiong, Zhi-Gang; Zha, Xiang-ming

    2015-07-01

    Extracellular brain pH fluctuates in both physiological and disease conditions. The main postsynaptic proton receptor is the acid-sensing ion channels (ASICs). During the past decade, much progress has been made on protons, ASICs, and neurological disease. This review summarizes the recent progress on synaptic role of protons and our current understanding of how ASICs contribute to various types of neuronal injury in the brain. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Colocalization of synapsin and actin during synaptic vesicle recycling

    DEFF Research Database (Denmark)

    Bloom, Ona; Evergren, Emma; Tomilin, Nikolay

    2003-01-01

    activity, however, synapsin was detected in the pool of vesicles proximal to the active zone. In addition, actin and synapsin were found colocalized in a dynamic filamentous cytomatrix at the sites of synaptic vesicle recycling, endocytic zones. Synapsin immunolabeling was not associated with clathrin......-coated intermediates but was found on vesicles that appeared to be recycling back to the cluster. Disruption of synapsin function by microinjection of antisynapsin antibodies resulted in a prominent reduction of the cytomatrix at endocytic zones of active synapses. Our data suggest that in addition to its known...

  12. Synaptic plasticity in health and disease: introduction and overview

    Science.gov (United States)

    Bliss, T. V. P.; Collingridge, G. L.; Morris, R. G. M.

    2014-01-01

    We summarize the reviews and research papers submitted by speakers at a discussion meeting on Synaptic Plasticity in Health and Disease held at the Royal Society, London on 2–3 December 2013, and a subsequent satellite meeting convened at the Royal Society/Kavli Centre at Chicheley Hall on 4–5 December 2013. Together, these contributions give an overview of current research and controversies in a vibrant branch of neuroscience with important implications for the understanding of many forms of learning and memory, and a wide spectrum of neurological and cognitive disorders. PMID:24298133

  13. Plasticity and mTOR: Towards Restoration of Impaired Synaptic Plasticity in mTOR-Related Neurogenetic Disorders

    Directory of Open Access Journals (Sweden)

    Tanjala T. Gipson

    2012-01-01

    Full Text Available Objective. To review the recent literature on the clinical features, genetic mutations, neurobiology associated with dysregulation of mTOR (mammalian target of rapamycin, and clinical trials for tuberous sclerosis complex (TSC, neurofibromatosis-1 (NF1 and fragile X syndrome (FXS, and phosphatase and tensin homolog hamartoma syndromes (PTHS, which are neurogenetic disorders associated with abnormalities in synaptic plasticity and mTOR signaling. Methods. Pubmed and Clinicaltrials.gov were searched using specific search strategies. Results/Conclusions. Although traditionally thought of as irreversible disorders, significant scientific progress has been made in both humans and preclinical models to understand how pathologic features of these neurogenetic disorders can be reduced or reversed. This paper revealed significant similarities among the conditions. Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features—autism, intellectual disability, cutaneous lesions, and tumors. Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well.

  14. BDNF genotype modulates resting functional connectivity in children

    Directory of Open Access Journals (Sweden)

    Moriah E Thomason

    2009-11-01

    Full Text Available A specific polymorphism of the brain-derived neurotrophic factor (BDNF gene is associated with alterations in brain anatomy and memory; its relevance to the functional connectivity of brain networks, however, is unclear. Given that altered hippocampal function and structure has been found in adults who carry the methionine (met allele of the BDNF gene and the molecular studies elucidating the role of BDNF in neurogenesis and synapse formation, we examined in the association between BDNF gene variants and neural resting connectivity in children and adolescents. We observed a reduction in hippocampal and parahippocampal to cortical connectivity in met-allele carriers within each of three resting networks: the default-mode, executive, and paralimbic networks. In contrast, we observed increased connectivity to amygdala, insula and striatal regions in met-carriers, within the paralimbic network. Because the BDNF met-allele has been linked to increased susceptibility to neuropsychiatric disorders, this latter finding of greater connectivity in circuits important for emotion processing may indicate a new neural mechanism through which these gene-related psychiatric differences are manifest. Here we show that the BDNF gene, known to regulate synaptic plasticity and connectivity in the brain, affects functional connectivity at the neural systems level. Additionally, we provide the first demonstration that the spatial topography of multiple high-level resting state networks in healthy children and adolescents is similar to that observed in adults.

  15. Connected vehicle standards.

    Science.gov (United States)

    2016-01-01

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

  16. Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex

    Science.gov (United States)

    Pinto, Joshua G. A.; Jones, David G.; Murphy, Kathryn M.

    2013-01-01

    Two theories have influenced our understanding of cortical development: the integrated network theory, where synaptic development is coordinated across areas; and the cascade theory, where the cortex develops in a wave-like manner from sensory to non-sensory areas. These different views on cortical development raise challenges for current studies aimed at comparing detailed maturation of the connectome among cortical areas. We have taken a different approach to compare synaptic development in rat visual, somatosensory, and frontal cortex by measuring expression of pre-synaptic (synapsin and synaptophysin) proteins that regulate vesicle cycling, and post-synaptic density (PSD-95 and Gephyrin) proteins that anchor excitatory or inhibitory (E-I) receptors. We also compared development of the balances between the pairs of pre- or post-synaptic proteins, and the overall pre- to post-synaptic balance, to address functional maturation and emergence of the E-I balance. We found that development of the individual proteins and the post-synaptic index overlapped among the three cortical areas, but the pre-synaptic index matured later in frontal cortex. Finally, we applied a neuroinformatics approach using principal component analysis and found that three components captured development of the synaptic proteins. The first component accounted for 64% of the variance in protein expression and reflected total protein expression, which overlapped among the three cortical areas. The second component was gephyrin and the E-I balance, it emerged as sequential waves starting in somatosensory, then frontal, and finally visual cortex. The third component was the balance between pre- and post-synaptic proteins, and this followed a different developmental trajectory in somatosensory cortex. Together, these results give the most support to an integrated network of synaptic development, but also highlight more complex patterns of development that vary in timing and end point among the

  17. Role of DHA in aging-related changes in mouse brain synaptic plasma membrane proteome.

    Science.gov (United States)

    Sidhu, Vishaldeep K; Huang, Bill X; Desai, Abhishek; Kevala, Karl; Kim, Hee-Yong

    2016-05-01

    Aging has been related to diminished cognitive function, which could be a result of ineffective synaptic function. We have previously shown that synaptic plasma membrane proteins supporting synaptic integrity and neurotransmission were downregulated in docosahexaenoic acid (DHA)-deprived brains, suggesting an important role of DHA in synaptic function. In this study, we demonstrate aging-induced synaptic proteome changes and DHA-dependent mitigation of such changes using mass spectrometry-based protein quantitation combined with western blot or messenger RNA analysis. We found significant reduction of 15 synaptic plasma membrane proteins in aging brains including fodrin-α, synaptopodin, postsynaptic density protein 95, synaptic vesicle glycoprotein 2B, synaptosomal-associated protein 25, synaptosomal-associated protein-α, N-methyl-D-aspartate receptor subunit epsilon-2 precursor, AMPA2, AP2, VGluT1, munc18-1, dynamin-1, vesicle-associated membrane protein 2, rab3A, and EAAT1, most of which are involved in synaptic transmission. Notably, the first 9 proteins were further reduced when brain DHA was depleted by diet, indicating that DHA plays an important role in sustaining these synaptic proteins downregulated during aging. Reduction of 2 of these proteins was reversed by raising the brain DHA level by supplementing aged animals with an omega-3 fatty acid sufficient diet for 2 months. The recognition memory compromised in DHA-depleted animals was also improved. Our results suggest a potential role of DHA in alleviating aging-associated cognitive decline by offsetting the loss of neurotransmission-regulating synaptic proteins involved in synaptic function. Published by Elsevier Inc.

  18. Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex.

    Science.gov (United States)

    Pinto, Joshua G A; Jones, David G; Murphy, Kathryn M

    2013-01-01

    Two theories have influenced our understanding of cortical development: the integrated network theory, where synaptic development is coordinated across areas; and the cascade theory, where the cortex develops in a wave-like manner from sensory to non-sensory areas. These different views on cortical development raise challenges for current studies aimed at comparing detailed maturation of the connectome among cortical areas. We have taken a different approach to compare synaptic development in rat visual, somatosensory, and frontal cortex by measuring expression of pre-synaptic (synapsin and synaptophysin) proteins that regulate vesicle cycling, and post-synaptic density (PSD-95 and Gephyrin) proteins that anchor excitatory or inhibitory (E-I) receptors. We also compared development of the balances between the pairs of pre- or post-synaptic proteins, and the overall pre- to post-synaptic balance, to address functional maturation and emergence of the E-I balance. We found that development of the individual proteins and the post-synaptic index overlapped among the three cortical areas, but the pre-synaptic index matured later in frontal cortex. Finally, we applied a neuroinformatics approach using principal component analysis and found that three components captured development of the synaptic proteins. The first component accounted for 64% of the variance in protein expression and reflected total protein expression, which overlapped among the three cortical areas. The second component was gephyrin and the E-I balance, it emerged as sequential waves starting in somatosensory, then frontal, and finally visual cortex. The third component was the balance between pre- and post-synaptic proteins, and this followed a different developmental trajectory in somatosensory cortex. Together, these results give the most support to an integrated network of synaptic development, but also highlight more complex patterns of development that vary in timing and end point among the

  19. F42. CHONDROTIN-6 SULFATE CLUSTERS: ASSOCIATION OF SYNAPTIC DOMAINS AND REGULATION OF SYNAPTIC PLASTICITY DURING FEAR LEARNING

    Science.gov (United States)

    Chelini, Gabriele; Berciu, Cristina; Pilobello, Kanoelani; Peter, Durning; Rachel, Jenkins; Kahn, Moazzzam; Ramikie, Teniel; Subramanian, Siva; Ressler, Kerry; Pantazopoulos, Charalampos; Berretta, Sabina

    2018-01-01

    Abstract Background Emerging evidence from our group and others has brought the brain extracellular matrix (ECM) to the forefront of investigations on brain disorders. Our group has shown that organized perisynaptic ECM aggregates, i.e. perineuronal nets (PNNs) are decreased in several brain regions in people with schizophrenia (SZ) and bipolar disorder (BD). PNNs were detected by their expression of specific chondroitin sulfate proteoglycans (CSPGs), main components of the ECM, thought to play a key role in synaptic regulation during development and adulthood. Our studies have also shown that glial cells expressing CSPGs are altered in these disorders, suggesting a link between glial cell and PNN abnormalities. Finally, we have recently shown that novel CSPG structures, bearing a distinct CS-6 sulfation pattern and named CS-6 glial clusters, are decreased in the amygdala of people with SZ and BD. The morphology and function of CS-6 glial clusters is not currently known, but evidence from rodents and on the role of CSPGs in regulating synaptic functions strongly suggest that they may affect synaptic plasticity. We tested this hypothesis using a combination of human postmortem and rodent brain studies. Methods High Resolution electron microscopy was used to investigate the ultrastructural organization of CS-6 glia clusters. A transgenic mouse model expressing green fluorescent protein in a subset of excitatory pyramidal neurons was used to investigate dendritic spines association with CS-6 glia clusters. Mice were exposed to a single session of auditory fear conditioning for a total of 15 minutes. Animals were euthanized 4 hours after behavioral test. Multiplex immunocytochemistry was used to visualize CS-6 clusters. Results In human tissue, we show that CS-6 glia clusters are widespread in several brain regions, including the amygdala, entorhinal cortex, thalamus and hippocampus. Ultrastructural results show that CS-6 glia clusters are formed by CS-6 accumulations

  20. Connecting to Everyday Practices

    DEFF Research Database (Denmark)

    Iversen, Ole Sejer; Smith, Rachel Charlotte

    2012-01-01

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

  1. Exaggerated translation causes synaptic and behavioural aberrations associated with autism.

    Science.gov (United States)

    Santini, Emanuela; Huynh, Thu N; MacAskill, Andrew F; Carter, Adam G; Pierre, Philippe; Ruggero, Davide; Kaphzan, Hanoch; Klann, Eric

    2013-01-17

    Autism spectrum disorders (ASDs) are an early onset, heterogeneous group of heritable neuropsychiatric disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and ritualistic-like repetitive behaviours. One of the hypotheses for a common molecular mechanism underlying ASDs is altered translational control resulting in exaggerated protein synthesis. Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with autism. Importantly, a rare single nucleotide polymorphism has been identified in autism that is associated with increased promoter activity in the EIF4E gene. Here we show that genetically increasing the levels of eukaryotic translation initiation factor 4E (eIF4E) in mice results in exaggerated cap-dependent translation and aberrant behaviours reminiscent of autism, including repetitive and perseverative behaviours and social interaction deficits. Moreover, these autistic-like behaviours are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum and hippocampus. The autistic-like behaviours displayed by the eIF4E-transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Our findings demonstrate a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction and aberrant behaviours associated with autism.

  2. Emerging Links between Homeostatic Synaptic Plasticity and Neurological Disease

    Directory of Open Access Journals (Sweden)

    Dion eDickman

    2013-11-01

    Full Text Available Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.

  3. Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease.

    Science.gov (United States)

    Tönnies, Eric; Trushina, Eugenia

    2017-01-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.

  4. Finite post synaptic potentials cause a fast neuronal response

    Directory of Open Access Journals (Sweden)

    Moritz eHelias

    2011-02-01

    Full Text Available A generic property of the communication between neurons is the exchange of pulsesat discrete time points, the action potentials. However, the prevalenttheory of spiking neuronal networks of integrate-and-fire model neuronsrelies on two assumptions: the superposition of many afferent synapticimpulses is approximated by Gaussian white noise, equivalent to avanishing magnitude of the synaptic impulses, and the transfer oftime varying signals by neurons is assessable by linearization. Goingbeyond both approximations, we find that in the presence of synapticimpulses the response to transient inputs differs qualitatively fromprevious predictions. It is instantaneous rather than exhibiting low-passcharacteristics, depends non-linearly on the amplitude of the impulse,is asymmetric for excitation and inhibition and is promoted by a characteristiclevel of synaptic background noise. These findings resolve contradictionsbetween the earlier theory and experimental observations. Here wereview the recent theoretical progress that enabled these insights.We explain why the membrane potential near threshold is sensitiveto properties of the afferent noise and show how this shapes the neuralresponse. A further extension of the theory to time evolution in discretesteps quantifies simulation artifacts and yields improved methodsto cross check results.

  5. Synaptic Wnt/GSK3β Signaling Hub in Autism

    Science.gov (United States)

    Caracci, Mario O.; Ávila, Miguel E.; De Ferrari, Giancarlo V.

    2016-01-01

    Hundreds of genes have been associated with autism spectrum disorders (ASDs) and the interaction of weak and de novo variants derive from distinct autistic phenotypes thus making up the “spectrum.” The convergence of these variants in networks of genes associated with synaptic function warrants the study of cell signaling pathways involved in the regulation of the synapse. The Wnt/β-catenin signaling pathway plays a central role in the development and regulation of the central nervous system and several genes belonging to the cascade have been genetically associated with ASDs. In the present paper, we review basic information regarding the role of Wnt/β-catenin signaling in excitatory/inhibitory balance (E/I balance) through the regulation of pre- and postsynaptic compartments. Furthermore, we integrate information supporting the role of the glycogen synthase kinase 3β (GSK3β) in the onset/development of ASDs through direct modulation of Wnt/β-catenin signaling. Finally, given GSK3β activity as key modulator of synaptic plasticity, we explore the potential of this kinase as a therapeutic target for ASD. PMID:26881141

  6. Local Order within Global Disorder: Synaptic Architecture of Visual Space.

    Science.gov (United States)

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

    2017-12-06

    Substantial evidence at the subcellular level indicates that the spatial arrangement of synaptic inputs onto dendrites could play a significant role in cortical computations, but how synapses of functionally defined cortical networks are arranged within the dendrites of individual neurons remains unclear. Here we assessed one-dimensional spatial receptive fields of individual dendritic spines within individual layer 2/3 neuron dendrites. Spatial receptive field properties of dendritic spines were strikingly diverse, with no evidence of large-scale topographic organization. At a fine scale, organization was evident: neighboring spines separated by less than 10 μm shared similar spatial receptive field properties and exhibited a distance-dependent correlation in sensory-driven and spontaneous activity patterns. Fine-scale dendritic organization was supported by the fact that functional groups of spines defined by dimensionality reduction of receptive field properties exhibited non-random dendritic clustering. Our results demonstrate that functional synaptic clustering is a robust feature existing at a local spatial scale. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Role of connectivity in immune and neural network models: memory development and aging.

    Science.gov (United States)

    Remondini, Daniel; Bazzani, Armando; Franceschi, Claudio; Bersani, Ferdinando; Verondini, Ettore; Castellani, Gastone

    2003-01-01

    In this paper we analyzed how connectivity (defined as number of connections between network elements) can affect the memory capacity of a network-based model of the Immune System (IS) and of a model of the Nervous System (NS) synaptic plasticity (BCM model). The key point is the concept of competition between the characteristic variables that represent the response of such systems to environmental stimuli: the clonal concentrations for the IS, and the neuron responses for the BCM model. The memory states of both systems are characterized by a high selectivity to specific input patterns, reflecting a similar behaviour of their development rules. This selectivity property of memory states can be controlled by changing the degree of the internal connectivity in each system. We can explain the changes occurring in IS memory states during lifespan as due to a reshaping of its internal connectivity. This assumption is in agreement with experimental observations, reporting an increase of IS memory cells during lifespan. The change of connectivity in the BCM model leads to the introduction of quasilocal variables governing the plasticity of groups of synaptic junctions. This could be interpreted as the result of a refinement of neuron internal mechanisms during development, or it could be seen as a different learning rule deriving from the original BCM theory. We argue that connectivity seems to play an important role in a large class of biological systems controlled by competition mechanisms. Moreover, changes in connectivity may lead to changes in memory properties during development and aging.

  8. Two Wnts Instruct Topographic Synaptic Innervation in C. elegans

    Directory of Open Access Journals (Sweden)

    Kota Mizumoto

    2013-10-01

    Full Text Available Gradients of topographic cues play essential roles in the organization of sensory systems by guiding axonal growth cones. Little is known about whether there are additional mechanisms for precise topographic mapping of synaptic connections. Whereas the C. elegans DA8 and DA9 neurons have similar axonal trajectories, their synapses are positioned in distinct but adjacent domains in the anterior-posterior axis. We found that two Wnts, LIN-44 and EGL-20, are responsible for this spatial organization of synapses. Both Wnts form putative posterior-high, anterior-low gradients. The posteriorly expressed LIN-44 inhibits synapse formation in both DA9 and DA8, and creates a synapse-free domain on both axons via LIN-17 /Frizzled. EGL-20, a more anteriorly expressed Wnt, inhibits synapse formation through MIG-1/Frizzled, which is expressed in DA8 but not in DA9. The Wnt-Frizzled specificity and selective Frizzled expression dictate the stereotyped, topographic positioning of synapses between these two neurons.

  9. Synaptic and network consequences of monosynaptic nociceptive inputs of parabrachial nucleus origin in the central amygdala

    Science.gov (United States)

    Sugimura, Yae K.; Takahashi, Yukari; Watabe, Ayako M.

    2016-01-01

    A large majority of neurons in the superficial layer of the dorsal horn projects to the lateral parabrachial nucleus (LPB). LPB neurons then project to the capsular part of the central amygdala (CeA; CeC), a key structure underlying the nociception-emotion link. LPB-CeC synaptic transmission is enhanced in various pain models by using electrical stimulation of putative fibers of LPB origin in brain slices. However, this approach has limitations for examining direct monosynaptic connections devoid of directly stimulating fibers from other structures and local GABAergic neurons. To overcome these limitations, we infected the LPB of rats with an adeno-associated virus vector expressing channelrhodopsin-2 and prepared coronal and horizontal brain slices containing the amygdala. We found that blue light stimulation resulted in monosynaptic excitatory postsynaptic currents (EPSCs), with very small latency fluctuations, followed by a large polysynaptic inhibitory postsynaptic current in CeC neurons, regardless of the firing pattern type. Intraplantar formalin injection at 24 h before slice preparation significantly increased EPSC amplitude in late firing-type CeC neurons. These results indicate that direct monosynaptic glutamatergic inputs from the LPB not only excite CeC neurons but also regulate CeA network signaling through robust feed-forward inhibition, which is under plastic modulation in response to persistent inflammatory pain. PMID:26888105

  10. How attention can create synaptic tags for the learning of working memories in sequential tasks.

    Directory of Open Access Journals (Sweden)

    Jaldert O Rombouts

    2015-03-01

    Full Text Available Intelligence is our ability to learn appropriate responses to new stimuli and situations. Neurons in association cortex are thought to be essential for this ability. During learning these neurons become tuned to relevant features and start to represent them with persistent activity during memory delays. This learning process is not well understood. Here we develop a biologically plausible learning scheme that explains how trial-and-error learning induces neuronal selectivity and working memory representations for task-relevant information. We propose that the response selection stage sends attentional feedback signals to earlier processing levels, forming synaptic tags at those connections responsible for the stimulus-response mapping. Globally released neuromodulators then interact with tagged synapses to determine their plasticity. The resulting learning rule endows neural networks with the capacity to create new working memory representations of task relevant information as persistent activity. It is remarkably generic: it explains how association neurons learn to store task-relevant information for linear as well as non-linear stimulus-response mappings, how they become tuned to category boundaries or analog variables, depending on the task demands, and how they learn to integrate probabilistic evidence for perceptual decisions.

  11. GABA type a receptor trafficking and the architecture of synaptic inhibition.

    Science.gov (United States)

    Lorenz-Guertin, Joshua M; Jacob, Tija C

    2018-03-01

    Ubiquitous expression of GABA type A receptors (GABA A R) in the central nervous system establishes their central role in coordinating most aspects of neural function and development. Dysregulation of GABAergic neurotransmission manifests in a number of human health disorders and conditions that in certain cases can be alleviated by drugs targeting these receptors. Precise changes in the quantity or activity of GABA A Rs localized at the cell surface and at GABAergic postsynaptic sites directly impact the strength of inhibition. The molecular mechanisms constituting receptor trafficking to and from these compartments therefore dictate the efficacy of GABA A R function. Here we review the current understanding of how GABA A Rs traffic through biogenesis, plasma membrane transport, and degradation. Emphasis is placed on discussing novel GABAergic synaptic proteins, receptor and scaffolding post-translational modifications, activity-dependent changes in GABA A R confinement, and neuropeptide and neurosteroid mediated changes. We further highlight modern techniques currently advancing the knowledge of GABA A R trafficking and clinically relevant neurodevelopmental diseases connected to GABAergic dysfunction. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 238-270, 2018. © 2017 Wiley Periodicals, Inc.

  12. Synaptic Plasticity and Excitation-Inhibition Balance in the Dentate Gyrus: Insights from In Vivo Recordings in Neuroligin-1, Neuroligin-2, and Collybistin Knockouts

    Directory of Open Access Journals (Sweden)

    Peter Jedlicka

    2018-01-01

    Full Text Available The hippocampal dentate gyrus plays a role in spatial learning and memory and is thought to encode differences between similar environments. The integrity of excitatory and inhibitory transmission and a fine balance between them is essential for efficient processing of information. Therefore, identification and functional characterization of crucial molecular players at excitatory and inhibitory inputs is critical for understanding the dentate gyrus function. In this minireview, we discuss recent studies unraveling molecular mechanisms of excitatory/inhibitory synaptic transmission, long-term synaptic plasticity, and dentate granule cell excitability in the hippocampus of live animals. We focus on the role of three major postsynaptic proteins localized at excitatory (neuroligin-1 and inhibitory synapses (neuroligin-2 and collybistin. In vivo recordings of field potentials have the advantage of characterizing the effects of the loss of these proteins on the input-output function of granule cells embedded in a network with intact connectivity. The lack of neuroligin-1 leads to deficient synaptic plasticity and reduced excitation but normal granule cell output, suggesting unaltered excitation-inhibition ratio. In contrast, the lack of neuroligin-2 and collybistin reduces inhibition resulting in a shift towards excitation of the dentate circuitry.

  13. Synaptic Plasticity and Excitation-Inhibition Balance in the Dentate Gyrus: Insights from In Vivo Recordings in Neuroligin-1, Neuroligin-2, and Collybistin Knockouts.

    Science.gov (United States)

    Jedlicka, Peter; Muellerleile, Julia; Schwarzacher, Stephan W

    2018-01-01

    The hippocampal dentate gyrus plays a role in spatial learning and memory and is thought to encode differences between similar environments. The integrity of excitatory and inhibitory transmission and a fine balance between them is essential for efficient processing of information. Therefore, identification and functional characterization of crucial molecular players at excitatory and inhibitory inputs is critical for understanding the dentate gyrus function. In this minireview, we discuss recent studies unraveling molecular mechanisms of excitatory/inhibitory synaptic transmission, long-term synaptic plasticity, and dentate granule cell excitability in the hippocampus of live animals. We focus on the role of three major postsynaptic proteins localized at excitatory (neuroligin-1) and inhibitory synapses (neuroligin-2 and collybistin). In vivo recordings of field potentials have the advantage of characterizing the effects of the loss of these proteins on the input-output function of granule cells embedded in a network with intact connectivity. The lack of neuroligin-1 leads to deficient synaptic plasticity and reduced excitation but normal granule cell output, suggesting unaltered excitation-inhibition ratio. In contrast, the lack of neuroligin-2 and collybistin reduces inhibition resulting in a shift towards excitation of the dentate circuitry.

  14. A light-stimulated synaptic transistor with synaptic plasticity and memory functions based on InGaZnOx–Al2O3 thin film structure

    International Nuclear Information System (INIS)

    Li, H. K.; Chen, T. P.; Liu, P.; Zhang, Q.; Hu, S. G.; Liu, Y.; Lee, P. S.

    2016-01-01

    In this work, a synaptic transistor based on the indium gallium zinc oxide (IGZO)–aluminum oxide (Al 2 O 3 ) thin film structure, which uses ultraviolet (UV) light pulses as the pre-synaptic stimulus, has been demonstrated. The synaptic transistor exhibits the behavior of synaptic plasticity like the paired-pulse facilitation. In addition, it also shows the brain's memory behaviors including the transition from short-term memory to long-term memory and the Ebbinghaus forgetting curve. The synapse-like behavior and memory behaviors of the transistor are due to the trapping and detrapping processes of the holes, which are generated by the UV pulses, at the IGZO/Al 2 O 3 interface and/or in the Al 2 O 3 layer.

  15. A light-stimulated synaptic transistor with synaptic plasticity and memory functions based on InGaZnOx-Al2O3 thin film structure

    Science.gov (United States)

    Li, H. K.; Chen, T. P.; Liu, P.; Hu, S. G.; Liu, Y.; Zhang, Q.; Lee, P. S.

    2016-06-01

    In this work, a synaptic transistor based on the indium gallium zinc oxide (IGZO)-aluminum oxide (Al2O3) thin film structure, which uses ultraviolet (UV) light pulses as the pre-synaptic stimulus, has been demonstrated. The synaptic transistor exhibits the behavior of synaptic plasticity like the paired-pulse facilitation. In addition, it also shows the brain's memory behaviors including the transition from short-term memory to long-term memory and the Ebbinghaus forgetting curve. The synapse-like behavior and memory behaviors of the transistor are due to the trapping and detrapping processes of the holes, which are generated by the UV pulses, at the IGZO/Al2O3 interface and/or in the Al2O3 layer.

  16. On the Basis of Synaptic Integration Constancy during Growth of a Neuronal Circuit

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    Adriana De-La-Rosa Tovar

    2016-08-01

    Full Text Available We studied how a neuronal circuit composed of two neuron types connected by chemical and electrical synapses maintains constant its integrative capacities as neurons grow. For this we combined electrophysiological experiments with mathematical modeling in pairs of electrically-coupled Retzius neurons from postnatal to adult leeches. The electrically-coupled dendrites of both Retzius neurons receive a common chemical input, which produces excitatory postsynaptic potentials (EPSPs with varying amplitudes. Each EPSP spreads to the soma, but also crosses the electrical synapse to arrive at the soma of the coupled neuron. The leak of synaptic current across the electrical synapse reduces the amplitude of the EPSPs in proportion to the coupling ratio. In addition, summation of EPSPs generated in both neurons generates the baseline action potentials of these serotonergic neurons. To study how integration is adjusted as neurons grow, we first studied the characteristics of the chemical and electrical connections onto the coupled dendrites of neuron pairs with soma diameters ranging from 21 to 75 μm. Then by feeding a mathematical model with the neuronal voltage responses to pseudorandom noise currents we obtained the values of the coupling ratio, the membrane resistance of the soma (rm and dendrites (rdend, the space constant (λ and the characteristic dendritic length (L = l/λ. We found that the EPSPs recorded from the somata were similar regardless on the neuron size. However, the amplitude of the EPSPs and the firing frequency of the neurons were inversely proportional to the coupling ratio of the neuron pair, which also was independent from the neuronal size. This data indicated that the integrative constancy relied on the passive membrane properties. We show that the growth of Retzius neurons was compensated by increasing the membrane resistance of the dendrites and therefore the λ value. By solely increasing the dendrite resistance this circuit

  17. Synaptic plasticity in a recurrent neural network for versatile and adaptive behaviors of a walking robot

    Directory of Open Access Journals (Sweden)

    Eduard eGrinke

    2015-10-01

    Full Text Available Walking animals, like insects, with little neural computing can effectively perform complex behaviors. They can walk around their environment, escape from corners/deadlocks, and avoid or climb over obstacles. While performing all these behaviors, they can also adapt their movements to deal with an unknown situation. As a consequence, they successfully navigate through their complex environment. The versatile and adaptive abilities are the result of an integration of several ingredients embedded in their sensorimotor loop. Biological studies reveal that the ingredients include neural dynamics, plasticity, sensory feedback, and biomechanics. Generating such versatile and adaptive behaviors for a walking robot is a challenging task. In this study, we present a bio-inspired approach to solve this task. Specifically, the approach combines neural mechanisms with plasticity, sensory feedback, and biomechanics. The neural mechanisms consist of adaptive neural sensory processing and modular neural locomotion control. The sensory processing is based on a small recurrent network consisting of two fully connected neurons. Online correlation-based learning with synaptic scaling is applied to adequately change the connections of the network. By doing so, we can effectively exploit neural dynamics (i.e., hysteresis effects and single attractors in the network to generate different turning angles with short-term memory for a biomechanical walking robot. The turning information is transmitted as descending steering signals to the locomotion control which translates the signals into motor actions. As a result, the robot can walk around and adapt its turning angle for avoiding obstacles in different situations as well as escaping from sharp corners or deadlocks. Using backbone joint control embedded in the locomotion control allows the robot to climb over small obstacles. Consequently, it can successfully explore and navigate in complex environments.

  18. A multi-component model of the developing retinocollicular pathway incorporating axonal and synaptic growth.

    Directory of Open Access Journals (Sweden)

    Keith B Godfrey

    2009-12-01

    Full Text Available During development, neurons extend axons to different brain areas and produce stereotypical patterns of connections. The mechanisms underlying this process have been intensively studied in the visual system, where retinal neurons form retinotopic maps in the thalamus and superior colliculus. The mechanisms active in map formation include molecular guidance cues, trophic factor release, spontaneous neural activity, spike-timing dependent plasticity (STDP, synapse creation and retraction, and axon growth, branching and retraction. To investigate how these mechanisms interact, a multi-component model of the developing retinocollicular pathway was produced based on phenomenological approximations of each of these mechanisms. Core assumptions of the model were that the probabilities of axonal branching and synaptic growth are highest where the combined influences of chemoaffinity and trophic factor cues are highest, and that activity-dependent release of trophic factors acts to stabilize synapses. Based on these behaviors, model axons produced morphologically realistic growth patterns and projected to retinotopically correct locations in the colliculus. Findings of the model include that STDP, gradient detection by axonal growth cones and lateral connectivity among collicular neurons were not necessary for refinement, and that the instructive cues for axonal growth appear to be mediated first by molecular guidance and then by neural activity. Although complex, the model appears to be insensitive to variations in how the component developmental mechanisms are implemented. Activity, molecular guidance and the growth and retraction of axons and synapses are common features of neural development, and the findings of this study may have relevance beyond organization in the retinocollicular pathway.

  19. SynProt: A Database for Proteins of Detergent-Resistant Synaptic Protein Preparations

    Science.gov (United States)

    Pielot, Rainer; Smalla, Karl-Heinz; Müller, Anke; Landgraf, Peter; Lehmann, Anne-Christin; Eisenschmidt, Elke; Haus, Utz-Uwe; Weismantel, Robert; Gundelfinger, Eckart D.; Dieterich, Daniela C.

    2012-01-01

    Chemical synapses are highly specialized cell–cell contacts for communication between neurons in the CNS characterized by complex and dynamic protein networks at both synaptic membranes. The cytomatrix at the active zone (CAZ) organizes the apparatus for the regulated release of transmitters from the presynapse. At the postsynaptic side, the postsynaptic density constitutes the machinery for detection, integration, and transduction of the transmitter signal. Both pre- and postsynaptic protein networks represent the molecular substrates for synaptic plasticity. Their function can be altered both by regulating their composition and by post-translational modification of their components. For a comprehensive understanding of synaptic networks the entire ensemble of synaptic proteins has to be considered. To support this, we established a comprehensive database for synaptic junction proteins (SynProt database) primarily based on proteomics data obtained from biochemical preparations of detergent-resistant synaptic junctions. The database currently contains 2,788 non-redundant entries of rat, mouse, and some human proteins, which mainly have been manually extracted from 12 proteomic studies and annotated for synaptic subcellular localization. Each dataset is completed with manually added information including protein classifiers as well as automatically retrieved and updated information from public databases (UniProt and PubMed). We intend that the database will be used to support modeling of synaptic protein networks and rational experimental design. PMID:22737123