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Sample records for modeling neuronal activity

  1. Models of the stochastic activity of neurones

    CERN Document Server

    Holden, Arun Vivian

    1976-01-01

    These notes have grown from a series of seminars given at Leeds between 1972 and 1975. They represent an attempt to gather together the different kinds of model which have been proposed to account for the stochastic activity of neurones, and to provide an introduction to this area of mathematical biology. A striking feature of the electrical activity of the nervous system is that it appears stochastic: this is apparent at all levels of recording, ranging from intracellular recordings to the electroencephalogram. The chapters start with fluctuations in membrane potential, proceed through single unit and synaptic activity and end with the behaviour of large aggregates of neurones: L have chgaen this seque~~e\\/~~';uggest that the interesting behaviourr~f :the nervous system - its individuality, variability and dynamic forms - may in part result from the stochastic behaviour of its components. I would like to thank Dr. Julio Rubio for reading and commenting on the drafts, Mrs. Doris Beighton for producing the fin...

  2. Linking Memories across Time via Neuronal and Dendritic Overlaps in Model Neurons with Active Dendrites

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    George Kastellakis

    2016-11-01

    Full Text Available Memories are believed to be stored in distributed neuronal assemblies through activity-induced changes in synaptic and intrinsic properties. However, the specific mechanisms by which different memories become associated or linked remain a mystery. Here, we develop a simplified, biophysically inspired network model that incorporates multiple plasticity processes and explains linking of information at three different levels: (1 learning of a single associative memory, (2 rescuing of a weak memory when paired with a strong one, and (3 linking of multiple memories across time. By dissecting synaptic from intrinsic plasticity and neuron-wide from dendritically restricted protein capture, the model reveals a simple, unifying principle: linked memories share synaptic clusters within the dendrites of overlapping populations of neurons. The model generates numerous experimentally testable predictions regarding the cellular and sub-cellular properties of memory engrams as well as their spatiotemporal interactions.

  3. A neuron model with trainable activation function (TAF) and its MFNN supervised learning

    Institute of Scientific and Technical Information of China (English)

    吴佑寿; 赵明生

    2001-01-01

    This paper addresses a new kind of neuron model, which has trainable activation function (TAF) in addition to only trainable weights in the conventional M-P model. The final neuron activation function can be derived from a primitive neuron activation function by training. The BP like learning algorithm has been presented for MFNN constructed by neurons of TAF model. Several simulation examples are given to show the network capacity and performance advantages of the new MFNN in comparison with that of conventional sigmoid MFNN.

  4. Predictive features of persistent activity emergence in regular spiking and intrinsic bursting model neurons.

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    Sidiropoulou, Kyriaki; Poirazi, Panayiota

    2012-01-01

    Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC), which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS) and an intrinsic bursting (IB) model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli, in both model cells. In addition, the action potential (AP) latency and the first few inter-spike-intervals of the neuronal response can be used to reliably detect inducing vs. non-inducing inputs, suggesting a potential mechanism by which downstream neurons can rapidly decode the upcoming emergence of persistent activity. While the two model neurons did not differ in the coding features of persistent activity emergence, the properties of persistent activity, such as the firing pattern and the duration of temporally-restricted persistent activity were distinct. Collectively, our results pinpoint to specific features of the neuronal response to a given stimulus that code

  5. Predictive features of persistent activity emergence in regular spiking and intrinsic bursting model neurons.

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    Kyriaki Sidiropoulou

    Full Text Available Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC, which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS and an intrinsic bursting (IB model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli, in both model cells. In addition, the action potential (AP latency and the first few inter-spike-intervals of the neuronal response can be used to reliably detect inducing vs. non-inducing inputs, suggesting a potential mechanism by which downstream neurons can rapidly decode the upcoming emergence of persistent activity. While the two model neurons did not differ in the coding features of persistent activity emergence, the properties of persistent activity, such as the firing pattern and the duration of temporally-restricted persistent activity were distinct. Collectively, our results pinpoint to specific features of the neuronal response to a given

  6. Immunohistochemical visualization of hippocampal neuron activity after spatial learning in a mouse model of neurodevelopmental disorders.

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    Provenzano, Giovanni; Pangrazzi, Luca; Poli, Andrea; Berardi, Nicoletta; Bozzi, Yuri

    2015-05-12

    Induction of phosphorylated extracellular-regulated kinase (pERK) is a reliable molecular readout of learning-dependent neuronal activation. Here, we describe a pERK immunohistochemistry protocol to study the profile of hippocampal neuron activation following exposure to a spatial learning task in a mouse model characterized by cognitive deficits of neurodevelopmental origin. Specifically, we used pERK immunostaining to study neuronal activation following Morris water maze (MWM, a classical hippocampal-dependent learning task) in Engrailed-2 knockout (En2(-/-)) mice, a model of autism spectrum disorders (ASD). As compared to wild-type (WT) controls, En2(-/-) mice showed significant spatial learning deficits in the MWM. After MWM, significant differences in the number of pERK-positive neurons were detected in specific hippocampal subfields of En2(-/-) mice, as compared to WT animals. Thus, our protocol can robustly detect differences in pERK-positive neurons associated to hippocampal-dependent learning impairment in a mouse model of ASD. More generally, our protocol can be applied to investigate the profile of hippocampal neuron activation in both genetic or pharmacological mouse models characterized by cognitive deficits.

  7. A new kind of neuron model with a tunable activation function and its applications

    Institute of Scientific and Technical Information of China (English)

    吴佑寿; 赵明生; 丁晓青

    1997-01-01

    A new neuron model with a tunable activation function, denoted by the TAF model, and its application are addressed. The activation function as well as the connection weights of the neuron model can be adjusted in the training process The two-spiral problem was used as an example to show how to deduce the adjustable activation function required, and how to construct and train the network by the use of the a priori knowledge of the problem. Due to the incorporation of constraints known a priori into the activation function, many novel aspects are revealed, such as small network size, fast learning and good performances. It is believed that the introduction of the new neuron model will pave a new way in ANN studies.

  8. Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency.

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    Tricarico, Paola Maura; Piscianz, Elisa; Monasta, Lorenzo; Kleiner, Giulio; Crovella, Sergio; Marcuzzi, Annalisa

    2015-08-01

    Mevalonate kinase deficiency is a rare disease whose worst manifestation, characterised by severe neurologic impairment, is called mevalonic aciduria. The progressive neuronal loss associated to cell death can be studied in vitro with a simplified model based on a biochemical block of the mevalonate pathway and a subsequent inflammatory trigger. The aim of this study was to evaluate the effect of the mevalonate blocking on glial cells (BV-2) and the following effects on neuronal cells (SH-SY5Y) when the two populations were cultured together. To better understand the cross-talk between glial and neuronal cells, as it happens in vivo, BV-2 and SH-SY5Y were co-cultured in different experimental settings (alone, transwell, direct contact); the effect of mevalonate pathway biochemical block by Lovastatin, followed by LPS inflammatory trigger, were evaluated by analysing programmed cell death and mitochondrial membrane potential, cytokines' release and cells' morphology modifications. In this experimental condition, glial cells underwent an evident activation, confirmed by elevated pro-inflammatory cytokines release, typical of these disorders, and a modification in morphology. Moreover, the activation induced an increase in apoptosis. When glial cells were co-cultured with neurons, their activation caused an increase of programmed cell death also in neuronal cells, but only if the two populations were cultured in direct contact. Our findings, being aware of the limitations related to the cell models used, represent a preliminary step towards understanding the pathological and neuroinflammatory mechanisms occurring in mevalonate kinase diseases. Contact co-culture between neuronal and microglial cells seems to be a good model to study mevalonic aciduria in vitro, and to contribute to the identification of potential drugs able to block microglial activation for this orphan disease. In fact, in such a pathological condition, we demonstrated that microglial cells are

  9. Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy

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    Nakhaei-Rad, Saeideh; Montenegro-Venegas, Carolina; Pina-Fernández, Eneko; Marini, Claudia; Santos, Monica; Ahmadian, Mohammad R.; Stork, Oliver; Zenker, Martin

    2017-01-01

    Noonan syndrome (NS) is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain. Unlike mice with a global expression of this mutation, this strain is viable and without severe systemic phenotype, but shows lower exploratory activity and reduced memory specificity, which is in line with a causal role of disturbed neuronal Ptpn11 signaling in the development of NS-linked cognitive deficits. To explore the underlying mechanisms we investigated the neuronal activity-regulated Ras signaling in brains and neuronal cultures derived from this model. We observed an altered surface expression and trafficking of synaptic glutamate receptors, which are crucial for hippocampal neuronal plasticity. Furthermore, we show that the neuronal activity-induced ERK signaling, as well as the consecutive regulation of gene expression are strongly perturbed. Microarray-based hippocampal gene expression profiling revealed profound differences in the basal state and upon stimulation of neuronal activity. The neuronal activity-dependent gene regulation was strongly attenuated in Ptpn11D61Y neurons. In silico analysis of functional networks revealed changes in the cellular signaling beyond the dysregulation of Ras/MAPK signaling that is nearly exclusively discussed in the context of NS at present. Importantly, changes in PI3K/AKT/mTOR and JAK/STAT signaling were experimentally confirmed. In summary, this study uncovers aberrant neuronal activity-induced signaling and regulation

  10. Stochastic neuron models

    CERN Document Server

    Greenwood, Priscilla E

    2016-01-01

    This book describes a large number of open problems in the theory of stochastic neural systems, with the aim of enticing probabilists to work on them. This includes problems arising from stochastic models of individual neurons as well as those arising from stochastic models of the activities of small and large networks of interconnected neurons. The necessary neuroscience background to these problems is outlined within the text, so readers can grasp the context in which they arise. This book will be useful for graduate students and instructors providing material and references for applying probability to stochastic neuron modeling. Methods and results are presented, but the emphasis is on questions where additional stochastic analysis may contribute neuroscience insight. An extensive bibliography is included. Dr. Priscilla E. Greenwood is a Professor Emerita in the Department of Mathematics at the University of British Columbia. Dr. Lawrence M. Ward is a Professor in the Department of Psychology and the Brain...

  11. Whole-brain mapping of neuronal activity in the learned helplessness model of depression

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    Yongsoo eKim

    2016-02-01

    Full Text Available Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial two-photon tomography to detect expression of c-FosGFP – a marker of neuronal activation – in c-fosGFP transgenic mice subjected to the learned helplessness (LH procedure, a widely used model of stress-induced depression-like phenotype in laboratory animals. We found that mice showing helpless behavior had an overall brain-wide reduction in the level of neuronal activation compared with mice showing resilient behavior, with the exception of a few brain areas, including the locus coeruleus, that were more activated in the helpless mice. In addition, the helpless mice showed a strong trend of having higher similarity in whole brain activity profile among individuals, suggesting that helplessness is represented by a more stereotypic brain-wide activation pattern. This latter effect was confirmed in rats subjected to the LH procedure, using 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography to assess neural activity. Our findings reveal distinct brain activity markings that correlate with adaptive and maladaptive behavioral responses to stress, and provide a framework for further studies investigating the contribution of specific brain regions to maladaptive stress responses.

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

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    Sebastien Naze

    2015-05-01

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

  13. Effect of spontaneous activity on stimulus detection in a simple neuronal model.

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    Levakova, Marie

    2016-06-01

    It is studied what level of a continuous-valued signal is optimally estimable on the basis of first-spike latency neuronal data. When a spontaneous neuronal activity is present, the first spike after the stimulus onset may be caused either by the stimulus itself, or it may be a result of the prevailing spontaneous activity. Under certain regularity conditions, Fisher information is the inverse of the variance of the best estimator. It can be considered as a function of the signal intensity and then indicates accuracy of the estimation for each signal level. The Fisher information is normalized with respect to the time needed to obtain an observation. The accuracy of signal level estimation is investigated in basic discharge patterns modelled by a Poisson and a renewal process and the impact of the complex interaction between spontaneous activity and a delay of the response is shown.

  14. Ongoing spontaneous activity controls access to consciousness: a neuronal model for inattentional blindness.

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    Stanislas Dehaene

    2005-05-01

    Full Text Available Even in the absence of sensory inputs, cortical and thalamic neurons can show structured patterns of ongoing spontaneous activity, whose origins and functional significance are not well understood. We use computer simulations to explore the conditions under which spontaneous activity emerges from a simplified model of multiple interconnected thalamocortical columns linked by long-range, top-down excitatory axons, and to examine its interactions with stimulus-induced activation. Simulations help characterize two main states of activity. First, spontaneous gamma-band oscillations emerge at a precise threshold controlled by ascending neuromodulator systems. Second, within a spontaneously active network, we observe the sudden "ignition" of one out of many possible coherent states of high-level activity amidst cortical neurons with long-distance projections. During such an ignited state, spontaneous activity can block external sensory processing. We relate those properties to experimental observations on the neural bases of endogenous states of consciousness, and particularly the blocking of access to consciousness that occurs in the psychophysical phenomenon of "inattentional blindness," in which normal subjects intensely engaged in mental activity fail to notice salient but irrelevant sensory stimuli. Although highly simplified, the generic properties of a minimal network may help clarify some of the basic cerebral phenomena underlying the autonomy of consciousness.

  15. Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

    KAUST Repository

    Jolivet, Renaud

    2015-02-26

    Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.

  16. An ultra-low-voltage electronic implementation of inertial neuron model with nonmonotonous Liao's activation function.

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    Kant, Nasir Ali; Dar, Mohamad Rafiq; Khanday, Farooq Ahmad

    2015-01-01

    The output of every neuron in neural network is specified by the employed activation function (AF) and therefore forms the heart of neural networks. As far as the design of artificial neural networks (ANNs) is concerned, hardware approach is preferred over software one because it promises the full utilization of the application potential of ANNs. Therefore, besides some arithmetic blocks, designing AF in hardware is the most important for designing ANN. While attempting to design the AF in hardware, the designs should be compatible with the modern Very Large Scale Integration (VLSI) design techniques. In this regard, the implemented designs should: only be in Metal Oxide Semiconductor (MOS) technology in order to be compatible with the digital designs, provide electronic tunability feature, and be able to operate at ultra-low voltage. Companding is one of the promising circuit design techniques for achieving these goals. In this paper, 0.5 V design of Liao's AF using sinh-domain technique is introduced. Furthermore, the function is tested by implementing inertial neuron model. The performance of the AF and inertial neuron model have been evaluated through simulation results, using the PSPICE software with the MOS transistor models provided by the 0.18-μm Taiwan Semiconductor Manufacturer Complementary Metal Oxide Semiconductor (TSM CMOS) process.

  17. Ordering Dynamics in Neuron Activity Pattern Model: An Insight to Brain Functionality.

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    Gundh, Jasleen; Singh, Awaneesh; Singh, R K Brojen

    2015-01-01

    We study the domain ordering kinetics in d = 2 ferromagnets which corresponds to populated neuron activities with both long-ranged interactions, V(r) ∼ r-n and short-ranged interactions. We present the results from comprehensive Monte Carlo (MC) simulations for the nonconserved Ising model with n ≥ 2, interaction range considering near and far neighbors. Our model results could represent the long-ranged neuron kinetics (n ≤ 4) in consistent with the same dynamical behaviour of short-ranged case (n ≥ 4) at far below and near criticality. We found that emergence of fast and slow kinetics of long and short ranged case could imitate the formation of connections among near and distant neurons. The calculated characteristic length scale in long-ranged interaction is found to be n independent (L(t) ∼ t1/(n-2)), whereas short-ranged interaction follows L(t) ∼ t1/2 law and approximately preserve universality in domain kinetics. Further, we did the comparative study of phase ordering near the critical temperature which follows different behaviours of domain ordering near and far critical temperature but follows universal scaling law.

  18. Reduced synaptic activity in neuronal networks derived from embryonic stem cells of murine Rett syndrome model.

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    Barth, Lydia; Sütterlin, Rosmarie; Nenniger, Markus; Vogt, Kaspar E

    2014-01-01

    Neurodevelopmental diseases such as the Rett syndrome (RTT) have received renewed attention, since the mechanisms involved may underlie a broad range of neuropsychiatric disorders such as schizophrenia and autism. In vertebrates early stages in the functional development of neurons and neuronal networks are difficult to study. Embryonic stem cell-derived neurons provide an easily accessible tool to investigate neuronal differentiation and early network formation. We used in vitro cultures of neurons derived from murine embryonic stem cells missing the methyl-CpG-binding protein 2 (MECP2) gene (MeCP2-/y) and from wild type cells of the corresponding background. Cultures were assessed using whole-cell patch-clamp electrophysiology and immunofluorescence. We studied the functional maturation of developing neurons and the activity of the synaptic connections they formed. Neurons exhibited minor differences in the developmental patterns for their intrinsic parameters, such as resting membrane potential and excitability; with the MeCP2-/y cells showing a slightly accelerated development, with shorter action potential half-widths at early stages. There was no difference in the early phase of synapse development, but as the cultures matured, significant deficits became apparent, particularly for inhibitory synaptic activity. MeCP2-/y embryonic stem cell-derived neuronal cultures show clear developmental deficits that match phenotypes observed in slice preparations and thus provide a compelling tool to further investigate the mechanisms behind RTT pathophysiology.

  19. Knockdown of GAD67 protein levels normalizes neuronal activity in a rat model of Parkinson's disease

    DEFF Research Database (Denmark)

    Horvath, Lazlo; van Marion, Ingrid; Taï, Khalid

    2011-01-01

    Dopamine depletion of the striatum is one of the hallmarks of Parkinson's disease. The loss of dopamine upregulates GAD67 expression in the striatal projection neurons and causes other changes in the activity of the basal ganglia circuit.......Dopamine depletion of the striatum is one of the hallmarks of Parkinson's disease. The loss of dopamine upregulates GAD67 expression in the striatal projection neurons and causes other changes in the activity of the basal ganglia circuit....

  20. Shaping Neuronal Network Activity by Presynaptic Mechanisms.

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    Ayal Lavi

    2015-09-01

    Full Text Available Neuronal microcircuits generate oscillatory activity, which has been linked to basic functions such as sleep, learning and sensorimotor gating. Although synaptic release processes are well known for their ability to shape the interaction between neurons in microcircuits, most computational models do not simulate the synaptic transmission process directly and hence cannot explain how changes in synaptic parameters alter neuronal network activity. In this paper, we present a novel neuronal network model that incorporates presynaptic release mechanisms, such as vesicle pool dynamics and calcium-dependent release probability, to model the spontaneous activity of neuronal networks. The model, which is based on modified leaky integrate-and-fire neurons, generates spontaneous network activity patterns, which are similar to experimental data and robust under changes in the model's primary gain parameters such as excitatory postsynaptic potential and connectivity ratio. Furthermore, it reliably recreates experimental findings and provides mechanistic explanations for data obtained from microelectrode array recordings, such as network burst termination and the effects of pharmacological and genetic manipulations. The model demonstrates how elevated asynchronous release, but not spontaneous release, synchronizes neuronal network activity and reveals that asynchronous release enhances utilization of the recycling vesicle pool to induce the network effect. The model further predicts a positive correlation between vesicle priming at the single-neuron level and burst frequency at the network level; this prediction is supported by experimental findings. Thus, the model is utilized to reveal how synaptic release processes at the neuronal level govern activity patterns and synchronization at the network level.

  1. Increased white matter neuron density in a rat model of maternal immune activation - Implications for schizophrenia.

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    Duchatel, Ryan J; Jobling, Phillip; Graham, Brett A; Harms, Lauren R; Michie, Patricia T; Hodgson, Deborah M; Tooney, Paul A

    2016-02-01

    Interstitial neurons are located among white matter tracts of the human and rodent brain. Post-mortem studies have identified increased interstitial white matter neuron (IWMN) density in the fibre tracts below the cortex in people with schizophrenia. The current study assesses IWMN pathology in a model of maternal immune activation (MIA); a risk factor for schizophrenia. Experimental MIA was produced by an injection of polyinosinic:polycytidylic acid (PolyI:C) into pregnant rats on gestational day (GD) 10 or GD19. A separate control group received saline injections. The density of neuronal nuclear antigen (NeuN(+)) and somatostatin (SST(+)) IWMNs was determined in the white matter of the corpus callosum in two rostrocaudally adjacent areas in the 12week old offspring of GD10 (n=10) or GD19 polyI:C dams (n=18) compared to controls (n=20). NeuN(+) IWMN density trended to be higher in offspring from dams exposed to polyI:C at GD19, but not GD10. A subpopulation of these NeuN(+) IWMNs was shown to express SST. PolyI:C treatment of dams induced a significant increase in the density of SST(+) IWMNs in the offspring when delivered at both gestational stages with more regionally widespread effects observed at GD19. A positive correlation was observed between NeuN(+) and SST(+) IWMN density in animals exposed to polyI:C at GD19, but not controls. This is the first study to show that MIA increases IWMN density in adult offspring in a similar manner to that seen in the brain in schizophrenia. This suggests the MIA model will be useful in future studies aimed at probing the relationship between IWMNs and schizophrenia.

  2. The statistics of repeating patterns of cortical activity can be reproduced by a model network of stochastic binary neurons.

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    Roxin, Alex; Hakim, Vincent; Brunel, Nicolas

    2008-10-15

    Calcium imaging of the spontaneous activity in cortical slices has revealed repeating spatiotemporal patterns of transitions between so-called down states and up states (Ikegaya et al., 2004). Here we fit a model network of stochastic binary neurons to data from these experiments, and in doing so reproduce the distributions of such patterns. We use two versions of this model: (1) an unconnected network in which neurons are activated as independent Poisson processes; and (2) a network with an interaction matrix, estimated from the data, representing effective interactions between the neurons. The unconnected model (model 1) is sufficient to account for the statistics of repeating patterns in 11 of the 15 datasets studied. Model 2, with interactions between neurons, is required to account for pattern statistics of the remaining four. Three of these four datasets are the ones that contain the largest number of transitions, suggesting that long datasets are in general necessary to render interactions statistically visible. We then study the topology of the matrix of interactions estimated for these four datasets. For three of the four datasets, we find sparse matrices with long-tailed degree distributions and an overrepresentation of certain network motifs. The remaining dataset exhibits a strongly interconnected, spatially localized subgroup of neurons. In all cases, we find that interactions between neurons facilitate the generation of long patterns that do not repeat exactly.

  3. Recombinant-activated factor Ⅶ and neuronal apoptosis in a rat model of intracerebral hemorrhage

    Institute of Scientific and Technical Information of China (English)

    Qiang Li; Wei Li; Suju Ding; Jianping Tang; Jing Fang; Benqiang Deng; Tao Wu

    2009-01-01

    BACKGROUND:Activated clotting factor Ⅶ has been demonstrated to exhibit obvious anti-apoptosis effects.OBJECTIVE:To observe the effect of activated clotting factor Ⅶ on neuronal apoptosis at different time points following rat intracerebral hemorrhage (ICH).DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at the Neurobiological Laboratory of Second Military Medical University from October 2005 to April 2006.MATERIALS:Recombinant-activated clotting factor Vlla (rFⅧa) was purchased from Danish Novo Nordisk,Denmark.In situ cell death detection kit-POD kit was purchased from Roche,Switzerland.Caspase-3 activity determination kit from Biovision,USA.METHODS:A total of 72 healthy,male,Sprague Dawley rats,aged 5-8 months,were randomly assigned to three groups (n=24):sham-operated,ICH model,and rFⅧa.In the ICH model and rFⅧa groups,80.0 μL autologous non-clotting blood from rat tails was injected into the right caudate putamen to establish the ICH.The empty microinjector was inserted into the caudate putamen in the sham-operated group.The ICH model and rFⅧa groups were subdivided into four subsets separately:6,24,72 hours and 7 clays following ICH.The rats in the rFⅧa group were injected with 160 μg/kg rFⅧa via the dorsal vein of the penis.MAIN OUTCOME MEASURES:Apoptotic cells were detected in the right caudate putamen by TUNEL;caspase-3 activity by spectrophotometry;and rat neurological function was evaluated by neurological functional impairment scales.RESULTS:Rat neurological function was deteriorated at 24,72 hours,and 7 days following ICH.The TUNEL-positive cells and caspase-3 activity in the right caudate putamen was significantly increased in the ICH rats (P<0.05);rFVlla treatment reduced the number of TUNEL-positive cells and caspase-3 activity in the right caudate putamen (P<0.05),and neurological function was significantly improved (P<0.05).CONCLUSION:rFⅧa was applied within 72 hours after ICH,which reduced

  4. Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease

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    Mariani, M. M.; Malm, T.; Lamb, R.; Jay, T. R.; Neilson, L.; Casali, B.; Medarametla, L.; Landreth, G. E.

    2017-01-01

    Alzheimer’s disease (AD) is characterized by extensive neuron loss that accompanies profound impairments in memory and cognition. We examined the neuronally directed effects of the retinoid X receptor agonist bexarotene in an aggressive model of AD. We report that a two week treatment of 3.5 month old 5XFAD mice with bexarotene resulted in the clearance of intraneuronal amyloid deposits. Importantly, neuronal loss was attenuated by 44% in the subiculum in mice 4 months of age and 18% in layer V of the cortex in mice 8 months of age. Moreover, bexarotene treatment improved remote memory stabilization in fear conditioned mice and improved olfactory cross habituation. These improvements in neuron viability and function were correlated with significant increases in the levels of post-synaptic marker PSD95 and the pre-synaptic marker synaptophysin. Moreover, bexarotene pretreatment improved neuron survival in primary 5XFAD neurons in vitro in response to glutamate-induced excitotoxicity. The salutary effects of bexarotene were accompanied by reduced plaque burden, decreased astrogliosis, and suppression of inflammatory gene expression. Collectively, these data provide evidence that bexarotene treatment reduced neuron loss, elevated levels of markers of synaptic integrity that was linked to improved cognition and in an aggressive model of AD. PMID:28205585

  5. Exploring neuronal activity with photons

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    Bourdieu, Laurent; Léger, Jean-François

    2015-10-01

    The following sections are included: * Introduction * Information coding * Optical recordings of neuronal activity * Functional organization of the cortex at the level of a cortical column * Microarchitecture of a cortical column * Dynamics of neuronal populations * Outlook * Bibliography

  6. A synaptic input portal for a mapped clock oscillator model of neuronal electrical rhythmic activity

    Science.gov (United States)

    Zariffa, José; Ebden, Mark; Bardakjian, Berj L.

    2004-09-01

    Neuronal electrical oscillations play a central role in a variety of situations, such as epilepsy and learning. The mapped clock oscillator (MCO) model is a general model of transmembrane voltage oscillations in excitable cells. In order to be able to investigate the behaviour of neuronal oscillator populations, we present a neuronal version of the model. The neuronal MCO includes an extra input portal, the synaptic portal, which can reflect the biological relationships in a chemical synapse between the frequency of the presynaptic action potentials and the postsynaptic resting level, which in turn affects the frequency of the postsynaptic potentials. We propose that the synaptic input-output relationship must include a power function in order to be able to reproduce physiological behaviour such as resting level saturation. One linear and two power functions (Butterworth and sigmoidal) are investigated, using the case of an inhibitory synapse. The linear relation was not able to produce physiologically plausible behaviour, whereas both the power function examples were appropriate. The resulting neuronal MCO model can be tailored to a variety of neuronal cell types, and can be used to investigate complex population behaviour, such as the influence of network topology and stochastic resonance.

  7. Store-operated calcium entry modulates neuronal network activity in a model of chronic epilepsy.

    Science.gov (United States)

    Steinbeck, Julius A; Henke, Nadine; Opatz, Jessica; Gruszczynska-Biegala, Joanna; Schneider, Lars; Theiss, Stephan; Hamacher, Nadine; Steinfarz, Barbara; Golz, Stefan; Brüstle, Oliver; Kuznicki, Jacek; Methner, Axel

    2011-12-01

    Store-operated Ca(2+) entry (SOCE) over the plasma membrane is activated by depletion of intracellular Ca(2+) stores and has only recently been shown to play a role in CNS processes like synaptic plasticity. However, the direct effect of SOCE on the excitability of neuronal networks in vitro and in vivo has never been determined. We confirmed the presence of SOCE and the expression of the calcium sensors STIM1 and STIM2, which convey information about the calcium load of the stores to channel proteins at the plasma membrane, in neurons and astrocytes. Inhibition of SOCE by pharmacological agents 2-APB and ML-9 reduced the steady-state neuronal Ca(2+) concentration, reduced network activity, and increased synchrony of primary neuronal cultures grown on multi-electrode arrays, which prompted us to elucidate the relative expression of STIM proteins in conditions of pathologic excitability. Both proteins were increased in brains of chronic epileptic rodents and strongly expressed in hippocampal specimens from medial temporal lobe epilepsy patients. Pharmacologic inhibition of SOCE in chronic epileptic hippocampal slices suppressed interictal spikes and rhythmized epileptic burst activity. Our results indicate that SOCE modulates the activity of neuronal networks in vitro and in vivo and delineates SOCE as a potential drug target. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. A codimension-2 bifurcation controlling endogenous bursting activity and pulse-triggered responses of a neuron model.

    Directory of Open Access Journals (Sweden)

    William H Barnett

    Full Text Available The dynamics of individual neurons are crucial for producing functional activity in neuronal networks. An open question is how temporal characteristics can be controlled in bursting activity and in transient neuronal responses to synaptic input. Bifurcation theory provides a framework to discover generic mechanisms addressing this question. We present a family of mechanisms organized around a global codimension-2 bifurcation. The cornerstone bifurcation is located at the intersection of the border between bursting and spiking and the border between bursting and silence. These borders correspond to the blue sky catastrophe bifurcation and the saddle-node bifurcation on an invariant circle (SNIC curves, respectively. The cornerstone bifurcation satisfies the conditions for both the blue sky catastrophe and SNIC. The burst duration and interburst interval increase as the inverse of the square root of the difference between the corresponding bifurcation parameter and its bifurcation value. For a given set of burst duration and interburst interval, one can find the parameter values supporting these temporal characteristics. The cornerstone bifurcation also determines the responses of silent and spiking neurons. In a silent neuron with parameters close to the SNIC, a pulse of current triggers a single burst. In a spiking neuron with parameters close to the blue sky catastrophe, a pulse of current temporarily silences the neuron. These responses are stereotypical: the durations of the transient intervals-the duration of the burst and the duration of latency to spiking-are governed by the inverse-square-root laws. The mechanisms described here could be used to coordinate neuromuscular control in central pattern generators. As proof of principle, we construct small networks that control metachronal-wave motor pattern exhibited in locomotion. This pattern is determined by the phase relations of bursting neurons in a simple central pattern generator

  9. Lemon Odor Reduces Stress-induced Neuronal Activation in the Emotion Expression System: An Animal Model Study

    Science.gov (United States)

    Sanada, Kazue; Sugimoto, Koji; Shutoh, Fumihiro; Hisano, Setsuji

    Perception of particular sensory stimuli from the surroundings can influence emotion in individuals. In an uncomfortable situation, humans protect themselves from some aversive stimulus by acutely evoking a stress response. Animal model studies have contributed to an understanding of neuronal mechanisms underlying the stress response in humans. To study a possible anti-stressful effect of lemon odor, an excitation of neurons secreting corticotropin-releasing hormone (CRH) as a primary factor of the hypothalamic-pituitary-adrenal axis (HPA) was analyzed in animal model experiments, in which rats are restrained in the presence or absence of the odor. The effect was evaluated by measuring expression of c-Fos (an excited neuron marker) in the hypothalamic paraventricular nucleus (PVN), a key structure of the HPA in the brain. We prepared 3 animal groups: Groups S, L and I. Groups S and L were restrained for 30 minutes while being blown by air and being exposed to the lemon odor, respectively. Group I was intact without any treatment. Two hours later of the onset of experiments, brains of all groups were sampled and processed for microscopic examination. Brain sections were processed for c-Fos immunostaining and/or in situ hybridization for CRH. In Group S but not in Group I, c-Fos expression was found in the PVN. A combined in situ hybridization-immunohistochemical dual labeling revealed that CRH mRNA-expressing neurons express c-Fos. In computer-assisted automatic counting, the incidence of c-Fos-expressing neurons in the entire PVN was statistically lower in Group L than in Group S. Detailed analysis of PVN subregions demonstrated that c-Fos-expressing neurons are fewer in Group L than in Group S in the dorsal part of the medial parvocellular subregion. These results may suggest that lemon odor attenuates the restraint stress-induced neuronal activation including CRH neurons, presumably mimicking an aspect of stress responses in humans.

  10. Licochalcone A Prevents the Loss of Dopaminergic Neurons by Inhibiting Microglial Activation in Lipopolysaccharide (LPS)-Induced Parkinson's Disease Models.

    Science.gov (United States)

    Huang, Bingxu; Liu, Juxiong; Ju, Chen; Yang, Dongxue; Chen, Guangxin; Xu, Shiyao; Zeng, Yalong; Yan, Xuan; Wang, Wei; Liu, Dianfeng; Fu, Shoupeng

    2017-09-22

    The neuroprotective effects of Licochalcone A (Lico.A), a flavonoid isolated from the herb licorice, in Parkinson's disease (PD) have not been elucidated. The prominent pathological feature of PD is the loss of dopaminergic neurons. The crucial role of neuroinflammation induced by activated microglia in dopaminergic neurodegeneration has been validated. In this study, we explore the therapeutic effects of Lico.A in lipopolysaccharide (LPS)-induced PD models in vivo and in vitro. We find that Lico.A significantly inhibits LPS-stimulated production of pro-inflammatory mediators and microglial activation by blocking the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and nuclear factor κB (NF-κB) p65 in BV-2 cells. In addition, through cultured primary mesencephalic neuron-glia cell experiments, we illustrate that Lico.A attenuates the decrease in [³H] dopamine (DA) uptake and the loss of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in LPS-induced PD models in vitro. Furthermore, LPS intoxication in rats results in microglial activation, dopaminergic neurodegeneration and significant behavioral deficits in vivo. Lico.A treatment prevents microglial activation and reduction of dopaminergic neuron and ameliorates PD-like behavioral impairments. Thus, these results demonstrate for the first time that the neuroprotective effects of Lico.A are associated with microglia and anti-inflammatory effects in PD models.

  11. Novel model of neuronal bioenergetics

    DEFF Research Database (Denmark)

    Bak, Lasse Kristoffer; Obel, Linea Lykke Frimodt; Walls, Anne B

    2012-01-01

    matrix thus activating the tricarboxylic acid cycle dehydrogenases. This will lead to a lower activity of the MASH (malate-aspartate shuttle), which in turn will result in anaerobic glycolysis and lactate production rather than lactate utilization. In the present work, we have investigated the effect......We have previously investigated the relative roles of extracellular glucose and lactate as fuels for glutamatergic neurons during synaptic activity. The conclusion from these studies was that cultured glutamatergic neurons utilize glucose rather than lactate during NMDA (N......-methyl-d-aspartate)-induced synaptic activity and that lactate alone is not able to support neurotransmitter glutamate homoeostasis. Subsequently, a model was proposed to explain these results at the cellular level. In brief, the intermittent rises in intracellular Ca2+ during activation cause influx of Ca2+ into the mitochondrial...

  12. Simulation study on dynamics transition in neuronal activity during sleep cycle by using asynchronous and symmetry neural network model.

    Science.gov (United States)

    Nakao, M; Takahashi, T; Mizutani, Y; Yamamoto, M

    1990-01-01

    We have found that single neuronal activities in different regions in the brain commonly exhibit the distinct dynamics transition during sleep-waking cycle in cats. Especially, power spectral densities of single neuronal activities change their profiles from the white to the 1/f along with sleep cycle from slow wave sleep (SWS) to paradoxical sleep (PS). Each region has different neural network structure and physiological function. This suggests a globally working mechanism may be underlying the dynamics transition we concern. Pharmacological studies have shown that a change in a wide-spread serotonergic input to these regions possibly causes the neuronal dynamics transition during sleep cycle. In this paper, based on these experimental results, an asynchronous and symmetry neural network model including inhibitory input, which represents the role of the serotonergic system, is utilized to examine the reality of our idea that the inhibitory input level varying during sleep cycle induce that transition. Simulation results show that the globally applied inhibitory input can control the dynamics of single neuronal state evolution in the artificial neural network: 1/f-like power spectral density profiles result under weak inhibition, which possibly corresponds to PS, and white profiles under strong inhibition, which possibly corresponds to SWS. An asynchronous neural network is known to change its state according to its energy function. The geometrical structure of network energy function is thought to vary along with the change in inhibitory level, which is expected to cause the dynamics transition of neuronal state evolution in the network model. These simulation results support the possibility that the serotonergic system is essential for the dynamics transition of single neuronal activities during sleep cycle.

  13. Sloppiness in spontaneously active neuronal networks.

    Science.gov (United States)

    Panas, Dagmara; Amin, Hayder; Maccione, Alessandro; Muthmann, Oliver; van Rossum, Mark; Berdondini, Luca; Hennig, Matthias H

    2015-06-01

    Various plasticity mechanisms, including experience-dependent, spontaneous, as well as homeostatic ones, continuously remodel neural circuits. Yet, despite fluctuations in the properties of single neurons and synapses, the behavior and function of neuronal assemblies are generally found to be very stable over time. This raises the important question of how plasticity is coordinated across the network. To address this, we investigated the stability of network activity in cultured rat hippocampal neurons recorded with high-density multielectrode arrays over several days. We used parametric models to characterize multineuron activity patterns and analyzed their sensitivity to changes. We found that the models exhibited sloppiness, a property where the model behavior is insensitive to changes in many parameter combinations, but very sensitive to a few. The activity of neurons with sloppy parameters showed faster and larger fluctuations than the activity of a small subset of neurons associated with sensitive parameters. Furthermore, parameter sensitivity was highly correlated with firing rates. Finally, we tested our observations from cell cultures on an in vivo recording from monkey visual cortex and we confirm that spontaneous cortical activity also shows hallmarks of sloppy behavior and firing rate dependence. Our findings suggest that a small subnetwork of highly active and stable neurons supports group stability, and that this endows neuronal networks with the flexibility to continuously remodel without compromising stability and function.

  14. Self-sustaining non-repetitive activity in a large scale neuronal-level model of the hippocampal circuit.

    Science.gov (United States)

    Scorcioni, Ruggero; Hamilton, David J; Ascoli, Giorgio A

    2008-10-01

    The mammalian hippocampus is involved in spatial representation and memory storage and retrieval, and much research is ongoing to elucidate the cellular and system-level mechanisms underlying these cognitive functions. Modeling may be useful to link network-level activity patterns to the relevant features of hippocampal anatomy and electrophysiology. Investigating the effects of circuit connectivity requires simulations of a number of neurons close to real scale. To this end, we construct a model of the hippocampus with 16 distinct neuronal classes (including both local and projection cells) and 200,000 individual neurons. The number of neurons in each class and their interconnectivity are drawn from rat anatomy. Here we analyze the emergent network activity and how it is affected by reducing either the size or the connectivity diversity of the model. When the model is run with a simple variation of the McCulloch-Pitts formalism, self-sustaining non-repetitive activity patterns consistently emerge. Specific firing threshold values are narrowly constrained for each cell class upon multiple runs with different stochastic wiring and initial conditions, yet these values do not directly affect network stability. Analysis of the model at different network sizes demonstrates that a scale reduction of one order of magnitude drastically alters network dynamics, including the variability of the output range, the distribution of firing frequencies, and the duration of self-sustained activity. Moreover, comparing the model to a control condition with an equivalent number of (excitatory/inhibitory balanced) synapses, but removing all class-specific information (i.e. collapsing the network to homogeneous random connectivity) has surprisingly similar effects to downsizing the total number of neurons. The reduced-scale model is also compared directly with integrate-and-fire simulations, which capture considerably more physiological detail at the single-cell level, but still fail

  15. A model of calcium-mediated coupling between membrane activity and clock gene expression in neurons of the suprachiasmatic nucleus

    CERN Document Server

    Casado, J M

    2015-01-01

    Rhythms in electrical activity in the membrane of cells in the suprachiasmatic nucleus (SCN) are crucial for the function of the circadian timing system, which is characterized by the expression of the so-called clock genes. Intracellular Ca$^{2+}$ ions seem to connect, at least in part, the electrical activity of SCN neurons with the expression of clock genes. In this paper, we introduce a simple mathematical model describing the linking of membrane activity to the transcription of one gene by means of a feedback mechanism based on the dynamics of intracellular calcium ions.

  16. Schwann cells are activated by ATP released from neurons in an in vitro cellular model of Miller Fisher syndrome

    Directory of Open Access Journals (Sweden)

    Umberto Rodella

    2017-05-01

    Full Text Available The neuromuscular junction is exposed to different types of insult, including mechanical trauma, toxins and autoimmune antibodies and, accordingly, has retained through evolution a remarkable ability to regenerate. Regeneration is driven by multiple signals that are exchanged among the cellular components of the junction. These signals are largely unknown. Miller Fisher syndrome is a variant of Guillain–Barré syndrome caused by autoimmune antibodies specific for epitopes of peripheral axon terminals. Using an animal model of Miller Fisher syndrome, we recently reported that a monoclonal anti-polysialoganglioside GQ1b antibody plus complement damages nerve terminals with production of mitochondrial hydrogen peroxide, which activates Schwann cells. Several additional signaling molecules are likely to be involved in the activation of the regeneration program in these cells. Using an in vitro cellular model consisting of co-cultured primary neurons and Schwann cells, we found that ATP is released by neurons injured by the anti-GQ1b antibody plus complement. Neuron-derived ATP acts as an alarm messenger for Schwann cells, where it induces the activation of intracellular pathways, including calcium signaling, cAMP and CREB, which, in turn, produce signals that promote nerve regeneration. These results contribute to defining the cross-talk taking place at the neuromuscular junction when it is attacked by anti-gangliosides autoantibodies plus complement, which is crucial for nerve regeneration and is also likely to be important in other peripheral neuropathies.

  17. Activation of vasopressin neurons leads to phenotype progression in a mouse model for familial neurohypophysial diabetes insipidus.

    Science.gov (United States)

    Hiroi, Maiko; Morishita, Yoshiaki; Hayashi, Masayuki; Ozaki, Nobuaki; Sugimura, Yoshihisa; Nagasaki, Hiroshi; Shiota, Akira; Oiso, Yutaka; Arima, Hiroshi

    2010-02-01

    Familial neurohypophysial diabetes insipidus (FNDI) is a rare disease that is inherited in an autosomal dominant manner. In a previous study, we made a mouse model for FNDI, which showed progressive polyuria accompanied by inclusion bodies in the arginine vasopressin (AVP) neurons formed by aggregates in the endoplasmic reticulum. The present study was conducted to determine whether the activities of AVP neurons are related to the phenotype progression in the FNDI model. In the first experiment, female heterozygous mice were administered either desmopressin (dDAVP) or a vehicle (control) subcutaneously with osmotic minipumps for 30 days. The dDAVP treatment significantly decreased the urine volume, AVP mRNA expression, and inclusion bodies in the AVP neurons. Urine volume in the dDAVP group remained significantly less than the control for 14 days even after the minipumps were removed. In the second experiment, the males were fed either a 0.2% Na or 2.0% Na diet for 6 mo. Urine AVP excretion was significantly increased in the 2.0% Na group compared with the 0.2% Na group for the first 2 mo but gradually decreased thereafter. Throughout the experiments, urine volume increased progressively in the 2.0% Na group but not in the 0.2% Na group. Immunohistochemical analyses revealed that inclusion bodies in the AVP cells had significantly increased in the 2.0% Na compared with the 0.2% Na group. These data demonstrated that activation of AVP neurons could accelerate the aggregate formation as well as the progression of the polyuria in the FNDI model mice.

  18. Aberrant Axonal Arborization of PDF Neurons Induced by Aβ42-Mediated JNK Activation Underlies Sleep Disturbance in an Alzheimer's Model.

    Science.gov (United States)

    Song, Qian; Feng, Ge; Huang, Zehua; Chen, Xiaoman; Chen, Zhaohuan; Ping, Yong

    2016-10-07

    Impaired sleep patterns are common symptoms of Alzheimer's disease (AD). Cellular mechanisms underlying sleep disturbance in AD remain largely unknown. Here, using a Drosophila Aβ42 AD model, we show that Aβ42 markedly decreases sleep in a large population, which is accompanied with postdevelopmental axonal arborization of wake-promoting pigment-dispersing factor (PDF) neurons. The arborization is mediated in part via JNK activation and can be reversed by decreasing JNK signaling activity. Axonal arborization and impaired sleep are correlated in Aβ42 and JNK kinase hemipterous mutant flies. Image reconstruction revealed that these aberrant fibers preferentially project to pars intercerebralis (PI), a fly brain region analogous to the mammalian hypothalamus. Moreover, PDF signaling in PI neurons was found to modulate sleep/wake activities, suggesting that excessive release of PDF by these aberrant fibers may lead to the impaired sleep in Aβ42 flies. Finally, inhibition of JNK activation in Aβ42 flies restores nighttime sleep loss, decreases Aβ42 accumulation, and attenuates neurodegeneration. These data provide a new mechanism by which sleep disturbance could be induced by Aβ42 burden, a key initiator of a complex pathogenic cascade in AD.

  19. Human motor neuron progenitor transplantation leads to endogenous neuronal sparing in 3 models of motor neuron loss.

    Science.gov (United States)

    Wyatt, Tanya J; Rossi, Sharyn L; Siegenthaler, Monica M; Frame, Jennifer; Robles, Rockelle; Nistor, Gabriel; Keirstead, Hans S

    2011-01-01

    Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control, paralysis, and eventual death in severe cases. In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss. Specifically, we transplanted hMNPs into rodent models of SMA (Δ7SMN), ALS (SOD1 G93A), and spinal cord injury (SCI). The transplanted cells survived and differentiated in all models. In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models. The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

  20. Is realistic neuronal modeling realistic?

    Science.gov (United States)

    Almog, Mara; Korngreen, Alon

    2016-11-01

    Scientific models are abstractions that aim to explain natural phenomena. A successful model shows how a complex phenomenon arises from relatively simple principles while preserving major physical or biological rules and predicting novel experiments. A model should not be a facsimile of reality; it is an aid for understanding it. Contrary to this basic premise, with the 21st century has come a surge in computational efforts to model biological processes in great detail. Here we discuss the oxymoronic, realistic modeling of single neurons. This rapidly advancing field is driven by the discovery that some neurons don't merely sum their inputs and fire if the sum exceeds some threshold. Thus researchers have asked what are the computational abilities of single neurons and attempted to give answers using realistic models. We briefly review the state of the art of compartmental modeling highlighting recent progress and intrinsic flaws. We then attempt to address two fundamental questions. Practically, can we realistically model single neurons? Philosophically, should we realistically model single neurons? We use layer 5 neocortical pyramidal neurons as a test case to examine these issues. We subject three publically available models of layer 5 pyramidal neurons to three simple computational challenges. Based on their performance and a partial survey of published models, we conclude that current compartmental models are ad hoc, unrealistic models functioning poorly once they are stretched beyond the specific problems for which they were designed. We then attempt to plot possible paths for generating realistic single neuron models. Copyright © 2016 the American Physiological Society.

  1. THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

    Science.gov (United States)

    Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

    2016-02-01

    Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach.

  2. Modeling neuronal vulnerability in ALS.

    Science.gov (United States)

    Roselli, Francesco; Caroni, Pico

    2014-08-20

    Using computational models of motor neuron ion fluxes, firing properties, and energy requirements, Le Masson et al. (2014) reveal how local imbalances in energy homeostasis may self-amplify and contribute to neurodegeneration in ALS.

  3. Altered calcium homeostasis in motor neurons following AMPA receptor but not voltage-dependent calcium channels' activation in a genetic model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Guatteo, Ezia; Carunchio, Irene; Pieri, Massimo; Albo, Federica; Canu, Nadia; Mercuri, Nicola B; Zona, Cristina

    2007-10-01

    Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disease characterized by a substantial loss of motor neurons in the spinal cord, brain stem and motor cortex. By combining electrophysiological recordings with imaging techniques, clearance/buffering capacity of cultured spinal cord motor neurons after a calcium accumulation has been analyzed in response to AMPA receptors' (AMPARs') activation and to depolarizing stimuli in a genetic mouse model of ALS (G93A). Our studies demonstrate that the amplitude of the calcium signal in response to AMPARs' or voltage-dependent calcium channels' activation is not significantly different in controls and G93A motor neurons. On the contrary, in G93A motor neurons, the [Ca(2+)](i) recovery to basal level is significantly slower compared to control neurons following AMPARs but not voltage-dependent calcium channels' activation. This difference was not observed in G93A cultured cortical neurons. This observation is the first to indicate a specific alteration of the calcium clearance linked to AMPA receptors' activation in G93A motor neurons and the involvement of AMPA receptor regulatory proteins controlling both AMPA receptor functionality and the sequence of events connected to them.

  4. Active dendrites enhance neuronal dynamic range.

    Directory of Open Access Journals (Sweden)

    Leonardo L Gollo

    2009-06-01

    Full Text Available Since the first experimental evidences of active conductances in dendrites, most neurons have been shown to exhibit dendritic excitability through the expression of a variety of voltage-gated ion channels. However, despite experimental and theoretical efforts undertaken in the past decades, the role of this excitability for some kind of dendritic computation has remained elusive. Here we show that, owing to very general properties of excitable media, the average output of a model of an active dendritic tree is a highly non-linear function of its afferent rate, attaining extremely large dynamic ranges (above 50 dB. Moreover, the model yields double-sigmoid response functions as experimentally observed in retinal ganglion cells. We claim that enhancement of dynamic range is the primary functional role of active dendritic conductances. We predict that neurons with larger dendritic trees should have larger dynamic range and that blocking of active conductances should lead to a decrease in dynamic range.

  5. Effect of Anatomically Realistic Full-Head Model on Activation of Cortical Neurons in Subdural Cortical Stimulation—A Computational Study

    Science.gov (United States)

    Seo, Hyeon; Kim, Donghyeon; Jun, Sung Chan

    2016-06-01

    Electrical brain stimulation (EBS) is an emerging therapy for the treatment of neurological disorders, and computational modeling studies of EBS have been used to determine the optimal parameters for highly cost-effective electrotherapy. Recent notable growth in computing capability has enabled researchers to consider an anatomically realistic head model that represents the full head and complex geometry of the brain rather than the previous simplified partial head model (extruded slab) that represents only the precentral gyrus. In this work, subdural cortical stimulation (SuCS) was found to offer a better understanding of the differential activation of cortical neurons in the anatomically realistic full-head model than in the simplified partial-head models. We observed that layer 3 pyramidal neurons had comparable stimulation thresholds in both head models, while layer 5 pyramidal neurons showed a notable discrepancy between the models; in particular, layer 5 pyramidal neurons demonstrated asymmetry in the thresholds and action potential initiation sites in the anatomically realistic full-head model. Overall, the anatomically realistic full-head model may offer a better understanding of layer 5 pyramidal neuronal responses. Accordingly, the effects of using the realistic full-head model in SuCS are compelling in computational modeling studies, even though this modeling requires substantially more effort.

  6. A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

    Science.gov (United States)

    Eliava, Marina; Melchior, Meggane; Knobloch-Bollmann, H Sophie; Wahis, Jérôme; da Silva Gouveia, Miriam; Tang, Yan; Ciobanu, Alexandru Cristian; Triana del Rio, Rodrigo; Roth, Lena C; Althammer, Ferdinand; Chavant, Virginie; Goumon, Yannick; Gruber, Tim; Petit-Demoulière, Nathalie; Busnelli, Marta; Chini, Bice; Tan, Linette L; Mitre, Mariela; Froemke, Robert C; Chao, Moses V; Giese, Günter; Sprengel, Rolf; Kuner, Rohini; Poisbeau, Pierrick; Seeburg, Peter H; Stoop, Ron; Charlet, Alexandre; Grinevich, Valery

    2016-03-16

    Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

  7. Loss of inhibitory tone on spinal cord dorsal horn spontaneously and nonspontaneously active neurons in a mouse model of neuropathic pain.

    Science.gov (United States)

    Medrano, Maria Carmen; Dhanasobhon, Dhanasak; Yalcin, Ipek; Schlichter, Rémy; Cordero-Erausquin, Matilde

    2016-07-01

    Plasticity of inhibitory transmission in the spinal dorsal horn (SDH) is believed to be a key mechanism responsible for pain hypersensitivity in neuropathic pain syndromes. We evaluated this plasticity by recording responses to mechanical stimuli in silent neurons (nonspontaneously active [NSA]) and neurons showing ongoing activity (spontaneously active [SA]) in the SDH of control and nerve-injured mice (cuff model). The SA and NSA neurons represented 59% and 41% of recorded neurons, respectively, and were predominantly wide dynamic range (WDR) in naive mice. Nerve-injured mice displayed a marked decrease in the mechanical threshold of the injured paw. After nerve injury, the proportion of SA neurons was increased to 78%, which suggests that some NSA neurons became SA. In addition, the response to touch (but not pinch) was dramatically increased in SA neurons, and high-threshold (nociceptive specific) neurons were no longer observed. Pharmacological blockade of spinal inhibition with a mixture of GABAA and glycine receptor antagonists significantly increased responses to innocuous mechanical stimuli in SA and NSA neurons from sham animals, but had no effect in sciatic nerve-injured animals, revealing a dramatic loss of spinal inhibitory tone in this situation. Moreover, in nerve-injured mice, local spinal administration of acetazolamide, a carbonic anhydrase inhibitor, restored responses to touch similar to those observed in naive or sham mice. These results suggest that a shift in the reversal potential for anions is an important component of the abnormal mechanical responses and of the loss of inhibitory tone recorded in a model of nerve injury-induced neuropathic pain.

  8. Active properties of neuronal dendrites.

    Science.gov (United States)

    Johnston, D; Magee, J C; Colbert, C M; Cristie, B R

    1996-01-01

    Dendrites of neurons in the central nervous system are the principal sites for excitatory synaptic input. Although little is known about their function, two disparate perspectives have arisen to describe the activity patterns inherent to these diverse tree-like structures. Dendrites are thus considered either passive or active in their role in integrating synaptic inputs. This review follows the history of dendritic research from before the turn of the century to the present, with a primary focus on the hippocampus. A number of recent techniques, including high-speed fluorescence imaging and dendritic patch clamping, have provided new information and perspectives about the active properties of dendrites. The results support previous notions about the dendritic propagation of action potentials and also indicate which types of voltage-gated sodium and calcium channels are expressed and functionally active in dendrites. Possible roles for the active properties of dendrites in synaptic plasticity and integration are also discussed.

  9. Tamoxifen mediated estrogen receptor activation protects against early impairment of hippocampal neuron excitability in an oxygen/glucose deprivation brain slice ischemia model.

    Science.gov (United States)

    Zhang, Huaqiu; Xie, Minjie; Schools, Gary P; Feustel, Paul F; Wang, Wei; Lei, Ting; Kimelberg, Harold K; Zhou, Min

    2009-01-09

    Pretreatment of ovarectomized rats with estrogen shows long-term protection via activation of the estrogen receptor (ER). However, it remains unknown whether activation of the ER can provide protection against early neuronal damage when given acutely. We simulated ischemic conditions by applying oxygen and glucose deprived (OGD) solution to acute male rat hippocampal slices and examined the neuronal electrophysiological changes. Pyramidal neurons and interneurons showed a time-dependent membrane potential depolarization and reduction in evoked action potential frequency and amplitude over a 10 to 15 min OGD exposure. These changes were largely suppressed by 10 microM TAM. The TAM effect was neuron-specific as the OGD-induced astrocytic membrane potential depolarization was not altered. The TAM effect was mediated through ER activation because it could be simulated by 17beta-estradiol and was completely inhibited by the ER inhibitor ICI 182, 780, and is therefore an example of TAM's selective estrogen receptor modulator (SERM) action. We further show that TAM's effects on OGD-induced impairment of neuronal excitability was largely due to activation of neuroprotective BK channels, as the TAM effect was markedly attenuated by the BK channel inhibitor paxilline at 10 microM. TAM also significantly reduced the frequency and amplitude of AMPA receptor mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons which is an early consequence of OGD. Altogether, this study demonstrates that both 17beta-estradiol and TAM attenuate neuronal excitability impairment early on in a simulated ischemia model via ER activation mediated potentiation of BK K(+) channels and reduction in enhanced neuronal AMPA/NMDA receptor-mediated excitotoxicity.

  10. Qualitative-Modeling-Based Silicon Neurons and Their Networks

    Science.gov (United States)

    Kohno, Takashi; Sekikawa, Munehisa; Li, Jing; Nanami, Takuya; Aihara, Kazuyuki

    2016-01-01

    The ionic conductance models of neuronal cells can finely reproduce a wide variety of complex neuronal activities. However, the complexity of these models has prompted the development of qualitative neuron models. They are described by differential equations with a reduced number of variables and their low-dimensional polynomials, which retain the core mathematical structures. Such simple models form the foundation of a bottom-up approach in computational and theoretical neuroscience. We proposed a qualitative-modeling-based approach for designing silicon neuron circuits, in which the mathematical structures in the polynomial-based qualitative models are reproduced by differential equations with silicon-native expressions. This approach can realize low-power-consuming circuits that can be configured to realize various classes of neuronal cells. In this article, our qualitative-modeling-based silicon neuron circuits for analog and digital implementations are quickly reviewed. One of our CMOS analog silicon neuron circuits can realize a variety of neuronal activities with a power consumption less than 72 nW. The square-wave bursting mode of this circuit is explained. Another circuit can realize Class I and II neuronal activities with about 3 nW. Our digital silicon neuron circuit can also realize these classes. An auto-associative memory realized on an all-to-all connected network of these silicon neurons is also reviewed, in which the neuron class plays important roles in its performance. PMID:27378842

  11. Essential roles of mitochondrial depolarization in neuron loss through microglial activation and attraction toward neurons.

    Science.gov (United States)

    Nam, Min-Kyung; Shin, Hyun-Ah; Han, Ji-Hye; Park, Dae-Wook; Rhim, Hyangshuk

    2013-04-10

    As life spans increased, neurodegenerative disorders that affect aging populations have also increased. Progressive neuronal loss in specific brain regions is the most common cause of neurodegenerative disease; however, key determinants mediating neuron loss are not fully understood. Using a model of mitochondrial membrane potential (ΔΨm) loss, we found only 25% cell loss in SH-SY5Y (SH) neuronal mono-cultures, but interestingly, 85% neuronal loss occurred when neurons were co-cultured with BV2 microglia. SH neurons overexpressing uncoupling protein 2 exhibited an increase in neuron-microglia interactions, which represent an early step in microglial phagocytosis of neurons. This result indicates that ΔΨm loss in SH neurons is an important contributor to recruitment of BV2 microglia. Notably, we show that ΔΨm loss in BV2 microglia plays a crucial role in microglial activation and phagocytosis of damaged SH neurons. Thus, our study demonstrates that ΔΨm loss in both neurons and microglia is a critical determinant of neuron loss. These findings also offer new insights into neuroimmunological and bioenergetical aspects of neurodegenerative disease.

  12. Sericin can reduce hippocampal neuronal apoptosis by activating the Akt signal transduction pathway in a rat model of diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    Zhihong Chen; Yaqiang He; Chengjun Song; Zhijun Dong; Zhejun Su; Jingfeng Xue

    2012-01-01

    In the present study, a rat model of type 2 diabetes mellitus was established by continuous peritoneal injection of streptozotocin. Following intragastric perfusion of sericin for 35 days, blood glucose levels significantly reduced, neuronal apoptosis in the hippocampal CA1 region decreased, hippocampal phosphorylated Akt and nuclear factor kappa B expression were enhanced, but Bcl-xL/Bcl-2 associated death promoter expression decreased. Results demonstrated that sericin can reduce hippocampal neuronal apoptosis in a rat model of diabetes mellitus by regulating abnormal changes in the Akt signal transduction pathway.

  13. Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson's disease models.

    Science.gov (United States)

    Bao, Xiu-Qi; Kong, Xiang-Chen; Kong, Li-Bing; Wu, Liang-Yu; Sun, Hua; Zhang, Dan

    2014-02-14

    Parkinson's disease (PD) is a neurodegenerative disease affecting up to 80% of dopaminergic neurons in the nigrostriatal pathway. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental PD models. In this study, we carried out a set of in vitro and in vivo experiments to address the neuroprotective effect of FLZ and related mechanism. The results showed that FLZ significantly improved motor dysfunction and dopaminergic neuronal loss of rats injured by 6-hydroxydopamine (6-OHDA). The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level and tyrosine hydroxylase (TH) activity. Mechanistic study showed that FLZ protected TH activity and dopaminergic neurons through decreasing α-synuclein (α-Syn) expression and the interaction between α-Syn and TH. Further studies indicated the involvement of phosphoinositide 3-kinases (PI3K)/Akt signaling pathway in the protective effect of FLZ since it showed that blocking PI3K/Akt signaling pathway prevented the expression of α-Syn and attenuated the neuroprotection of FLZ. In addition, FLZ treatment reduced the expression of RTP801, an important protein involved in the pathogenesis of PD. Taken together, these results revealed that FLZ suppressed α-Syn expression and elevated TH activity in dopaminergic neuron through activating Akt survival pathway in 6-OHDA-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising agent for PD treatment.

  14. Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson's disease.

    Science.gov (United States)

    Mudò, Giuseppa; Mäkelä, Johanna; Di Liberto, Valentina; Tselykh, Timofey V; Olivieri, Melania; Piepponen, Petteri; Eriksson, Ove; Mälkiä, Annika; Bonomo, Alessandra; Kairisalo, Minna; Aguirre, Jose A; Korhonen, Laura; Belluardo, Natale; Lindholm, Dan

    2012-04-01

    Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but little is known about the molecular mechanisms controlling these events. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. We show here that transgenic mice overexpressing PGC-1α in dopaminergic neurons are resistant against cell degeneration induced by the neurotoxin MPTP. The increase in neuronal viability was accompanied by elevated levels of mitochondrial antioxidants SOD2 and Trx2 in the substantia nigra of transgenic mice. PGC-1α overexpression also protected against MPTP-induced striatal loss of dopamine, and mitochondria from PGC-1α transgenic mice showed an increased respiratory control ratio compared with wild-type animals. To modulate PGC-1α, we employed the small molecular compound, resveratrol (RSV) that protected dopaminergic neurons against the MPTP-induced cell degeneration almost to the same extent as after PGC-1α overexpression. As studied in vitro, RSV activated PGC-1α in dopaminergic SN4741 cells via the deacetylase SIRT1, and enhanced PGC-1α gene transcription with increases in SOD2 and Trx2. Taken together, the results reveal an important function of PGC-1α in dopaminergic neurons to combat oxidative stress and increase neuronal viability. RSV and other compounds acting via SIRT1/PGC-1α may prove useful as neuroprotective agents in PD and possibly in other neurological disorders.

  15. Parameter estimation in neuronal stochastic differential equation models from intracellular recordings of membrane potentials in single neurons

    DEFF Research Database (Denmark)

    Ditlevsen, Susanne; Samson, Adeline

    2016-01-01

    evolution. One-dimensional models are the stochastic integrate-and-fire neuronal diffusion models. Biophysical neuronal models take into account the dynamics of ion channels or synaptic activity, leading to multidimensional diffusion models. Since only the membrane potential can be measured......Dynamics of the membrane potential in a single neuron can be studied by estimating biophysical parameters from intracellular recordings. Diffusion processes, given as continuous solutions to stochastic differential equations, are widely applied as models for the neuronal membrane potential...

  16. Sodium channel cleavage is associated with aberrant neuronal activity and cognitive deficits in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Corbett, Brian F; Leiser, Steven C; Ling, Huai-Ping; Nagy, Reka; Breysse, Nathalie; Zhang, Xiaohong; Hazra, Anupam; Brown, Jon T; Randall, Andrew D; Wood, Andrew; Pangalos, Menelas N; Reinhart, Peter H; Chin, Jeannie

    2013-04-17

    BACE1 is the rate-limiting enzyme that cleaves amyloid precursor protein (APP) to produce the amyloid β peptides that accumulate in Alzheimer's disease (AD). BACE1, which is elevated in AD patients and APP transgenic mice, also cleaves the β2-subunit of voltage-gated sodium channels (Navβ2). Although increased BACE1 levels are associated with Navβ2 cleavage in AD patients, whether Navβ2 cleavage occurs in APP mice had not yet been examined. Such a finding would be of interest because of its potential impact on neuronal activity: previous studies demonstrated that BACE1-overexpressing mice exhibit excessive cleavage of Navβ2 and reduced sodium current density, but the phenotype associated with loss of function mutations in either Navβ-subunits or pore-forming α-subunits is epilepsy. Because mounting evidence suggests that epileptiform activity may play an important role in the development of AD-related cognitive deficits, we examined whether enhanced cleavage of Navβ2 occurs in APP transgenic mice, and whether it is associated with aberrant neuronal activity and cognitive deficits. We found increased levels of BACE1 expression and Navβ2 cleavage fragments in cortical lysates from APP transgenic mice, as well as associated alterations in Nav1.1α expression and localization. Both pyramidal neurons and inhibitory interneurons exhibited evidence of increased Navβ2 cleavage. Moreover, the magnitude of alterations in sodium channel subunits was associated with aberrant EEG activity and impairments in the Morris water maze. Together, these results suggest that altered processing of voltage-gated sodium channels may contribute to aberrant neuronal activity and cognitive deficits in AD.

  17. A single dose of neuron-binding human monoclonal antibody improves spontaneous activity in a murine model of demyelination.

    Directory of Open Access Journals (Sweden)

    Aleksandar Denic

    Full Text Available Our laboratory demonstrated that a natural human serum antibody, sHIgM12, binds to neurons in vitro and promotes neurite outgrowth. We generated a recombinant form, rHIgM12, with identical properties. Intracerebral infection with Theiler's Murine Encephalomyelitis Virus (TMEV of susceptible mouse strains results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis. To study the effects of rHIgM12 on the motor function of TMEV-infected mice, we monitored spontaneous nocturnal activity over many weeks. Nocturnal behavior is a sensitive measure of rodent neurologic function because maximal activity changes are expected to occur during the normally active night time monitoring period. Mice were placed in activity boxes eight days prior to treatment to collect baseline spontaneous activity. After treatment, activity in each group was continuously recorded over 8 weeks. We chose a long 8-week monitoring period for two reasons: (1 we previously demonstrated that IgM induced remyelination is present by 5 weeks post treatment, and (2 TMEV-induced demyelinating disease in this strain progresses very slowly. Due to the long observation periods and large data sets, differences among treatment groups may be difficult to appreciate studying the original unfiltered recordings. To clearly delineate changes in the highly fluctuating original data we applied three different methods: (1 binning, (2 application of Gaussian low-pass filters (GF and (3 polynomial fitting. Using each of the three methods we showed that compared to control IgM and saline, early treatment with rHIgM12 induced improvement in both horizontal and vertical motor function, whereas later treatment improved only horizontal activity. rHIgM12 did not alter activity of normal, uninfected mice. This study supports the hypothesis that treatment with a neuron-binding IgM not only protects neurons in vitro, but

  18. Stiff substrates enhance cultured neuronal network activity.

    Science.gov (United States)

    Zhang, Quan-You; Zhang, Yan-Yan; Xie, Jing; Li, Chen-Xu; Chen, Wei-Yi; Liu, Bai-Lin; Wu, Xiao-an; Li, Shu-Na; Huo, Bo; Jiang, Lin-Hua; Zhao, Hu-Cheng

    2014-08-28

    The mechanical property of extracellular matrix and cell-supporting substrates is known to modulate neuronal growth, differentiation, extension and branching. Here we show that substrate stiffness is an important microenvironmental cue, to which mouse hippocampal neurons respond and integrate into synapse formation and transmission in cultured neuronal network. Hippocampal neurons were cultured on polydimethylsiloxane substrates fabricated to have similar surface properties but a 10-fold difference in Young's modulus. Voltage-gated Ca(2+) channel currents determined by patch-clamp recording were greater in neurons on stiff substrates than on soft substrates. Ca(2+) oscillations in cultured neuronal network monitored using time-lapse single cell imaging increased in both amplitude and frequency among neurons on stiff substrates. Consistently, synaptic connectivity recorded by paired recording was enhanced between neurons on stiff substrates. Furthermore, spontaneous excitatory postsynaptic activity became greater and more frequent in neurons on stiff substrates. Evoked excitatory transmitter release and excitatory postsynaptic currents also were heightened at synapses between neurons on stiff substrates. Taken together, our results provide compelling evidence to show that substrate stiffness is an important biophysical factor modulating synapse connectivity and transmission in cultured hippocampal neuronal network. Such information is useful in designing instructive scaffolds or supporting substrates for neural tissue engineering.

  19. The PTZ kindling mouse model of epilepsy exhibits exploratory drive deficits and aberrant activity amongst VTA dopamine neurons in both familiar and novel space.

    Science.gov (United States)

    Ahmadi, Mahboubeh; Dufour, Jean-Philippe; Seifritz, Erich; Mirnajafi-Zadeh, Javad; Saab, Bechara J

    2017-07-14

    Recurrent seizures that define epilepsy are often accompanied by psychosocial problems and cognitive deficits with incompletely understood aetiology. We therefore used the pentylenetetrazol (PTZ) kindling model of epilepsy in mice to examine potential seizure-associated neuropathologies, focusing on motivation, memory and novel-environment-induced activation of midbrain dopaminergic neurons. In addition to recurrent seizures, we found that PTZ kindling led to a strong suppression of novelty-driven exploration while largely sparing fear-driven exploration. The deficits in exploratory drive may be relevant for other cognitive impairments since reduced unassisted rearing in a learning arena correlated with poorer spatial memory of object location. Using c-Fos immunofluorescence as a marker of neuronal activity, we observed that dopamine neurons within the ventral tegmental area (VTA) of PTZ kindled mice demonstrate hyperactivity at baseline and hypoactivity in response to a novel environment compared to saline-injected cagemate controls. These data extend previous findings of PTZ kindling-mediated disruptions of hippocampal processes important for novel environment recognition and learning by demonstrating PTZ kindling also induces motivational deficits that are associated with reduced stimulus-evoked activation of VTA dopamine neurons. More broadly, these data help understand the aetiology of complex behavioural changes in the PTZ kindling model, and may assist in the development of superior diagnoses and treatments for epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. A neuron-astrocyte transistor-like model for neuromorphic dressed neurons.

    Science.gov (United States)

    Valenza, G; Pioggia, G; Armato, A; Ferro, M; Scilingo, E P; De Rossi, D

    2011-09-01

    Experimental evidences on the role of the synaptic glia as an active partner together with the bold synapse in neuronal signaling and dynamics of neural tissue strongly suggest to investigate on a more realistic neuron-glia model for better understanding human brain processing. Among the glial cells, the astrocytes play a crucial role in the tripartite synapsis, i.e. the dressed neuron. A well-known two-way astrocyte-neuron interaction can be found in the literature, completely revising the purely supportive role for the glia. The aim of this study is to provide a computationally efficient model for neuron-glia interaction. The neuron-glia interactions were simulated by implementing the Li-Rinzel model for an astrocyte and the Izhikevich model for a neuron. Assuming the dressed neuron dynamics similar to the nonlinear input-output characteristics of a bipolar junction transistor, we derived our computationally efficient model. This model may represent the fundamental computational unit for the development of real-time artificial neuron-glia networks opening new perspectives in pattern recognition systems and in brain neurophysiology.

  1. A Neuron Model for FPGA Spiking Neuronal Network Implementation

    Directory of Open Access Journals (Sweden)

    BONTEANU, G.

    2011-11-01

    Full Text Available We propose a neuron model, able to reproduce the basic elements of the neuronal dynamics, optimized for digital implementation of Spiking Neural Networks. Its architecture is structured in two major blocks, a datapath and a control unit. The datapath consists of a membrane potential circuit, which emulates the neuronal dynamics at the soma level, and a synaptic circuit used to update the synaptic weight according to the spike timing dependent plasticity (STDP mechanism. The proposed model is implemented into a Cyclone II-Altera FPGA device. Our results indicate the neuron model can be used to build up 1K Spiking Neural Networks on reconfigurable logic suport, to explore various network topologies.

  2. Human Motor Neuron Progenitor Transplantation Leads to Endogenous Neuronal Sparing in 3 Models of Motor Neuron Loss

    Directory of Open Access Journals (Sweden)

    Tanya J. Wyatt

    2011-01-01

    Full Text Available Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control, paralysis, and eventual death in severe cases. In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs and examined their histopathological effect in three animal models of motor neuron loss. Specifically, we transplanted hMNPs into rodent models of SMA (Δ7SMN, ALS (SOD1 G93A, and spinal cord injury (SCI. The transplanted cells survived and differentiated in all models. In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models. The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

  3. Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity

    Science.gov (United States)

    Ren, Zhao-xiang; Zhao, Ya-fei; Cao, Ting; Zhen, Xue-chu

    2016-01-01

    Aim: It is general believed that mitochondrial dysfunction and oxidative stress play critical roles in the pathology of Parkinson's disease (PD). Dihydromyricetin (DHM), a natural flavonoid extracted from Ampelopsis grossedentata, has recently been found to elicit potent anti-oxidative effects. In the present study, we explored the role of DHM in protecting dopaminergic neurons. Methods: Male C57BL/6 mice were intraperitoneally injected with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 d to induce PD. Additionally, mice were treated with either 5 or 10 mg/kg DHM for a total of 13 d (3 d before the start of MPTP, during MPTP administration (7 d) and 3 d after the end of MPTP). For the saline or DHM alone treatment groups, mice were injected with saline or DHM for 13 d. On d 14, behavioral tests (locomotor activity, the rotarod test and the pole test) were administered. After the behavioral tests, the mice were sacrificed, and brain tissue was collected for immunofluorescence staining and Western blotting. In addition, MES23.5 cells were treated with MPP+ and DHM, and evaluated using cell viability assays, reactive oxygen species (ROS) measurements, apoptosis analysis and Western blotting. Results: DHM significantly attenuated MPTP-induced mouse behavioral impairments and dopaminergic neuron loss. In the MES23.5 cells, DHM attenuated MPP+-induced cell injury and ROS production in a dose-dependent manner. In addition, DHM increased glycogen synthase kinase-3 beta phosphorylation in a dose- and time-dependent manner, which may be associated with DHM-induced dopaminergic neuronal protection. Conclusion: The present study demonstrated that DHM is a potent neuroprotective agent for DA neurons by modulating the Akt/GSK-3β pathway, which suggests that DHM may be a promising therapeutic candidate for PD. PMID:27374489

  4. Salvianolic acid B attenuates toxin-induced neuronal damage via Nrf2-dependent glial cells-mediated protective activity in Parkinson's disease models.

    Directory of Open Access Journals (Sweden)

    Jie Zhou

    Full Text Available Salvianolic acid B (SalB, a bioactive compound isolated from the plant-derived medicinal herb Danshen, has been shown to exert various anti-oxidative and anti-inflammatory activities in several neurological disorders. In this study, we sought to investigate the potential protective effects and associated molecular mechanisms of SalB in Parkinson's disease (PD models. To determine the neuroprotective effects of SalB in vitro, MPP+- or lipopolysaccharide (LPS-induced neuronal injury was achieved using primary cultures with different compositions of neurons, microglia and astrocytes. Our results showed that SalB reduced both LPS- and MPP+-induced toxicity of dopamine neurons in a dose-dependent manner. Additionally, SalB treatment inhibited the release of microglial pro-inflammatory cytokines and resulted in an increase in the expression and release of glial cell line-derived neurotrophic factor (GDNF from astrocytes. Western blot analysis illustrated that SalB increased the expression and nuclear translocation of nuclear factor (erythroid-derived 2-like 2 (Nrf2. The knockdown of Nrf2 using specific small interfering RNA (siRNA partially reversed the SalB-induced GDNF expression and anti-inflammatory activity. Moreover, SalB treatment significantly attenuated dopaminergic (DA neuronal loss, inhibited neuroinflammation, increased GDNF expression and improved the neurological function in MPTP-treated mice. Collectively, these findings demonstrated that SalB protects DA neurons by an Nrf-2 -mediated dual action: reducing microglia activation-mediated neuroinflammation and inducing astrocyte activation-dependent GDNF expression. Importantly the present study also highlights critical roles of glial cells as targets for developing new strategies to alter the progression of neurodegenerative disorders.

  5. Salvianolic Acid B Attenuates Toxin-Induced Neuronal Damage via Nrf2-Dependent Glial Cells-Mediated Protective Activity in Parkinson’s Disease Models

    Science.gov (United States)

    Li, Zhi-Yun; Wei-Ji; Liu, Qi; Ma, Yi-Hui; He, Jiao-Jiang

    2014-01-01

    Salvianolic acid B (SalB), a bioactive compound isolated from the plant-derived medicinal herb Danshen, has been shown to exert various anti-oxidative and anti-inflammatory activities in several neurological disorders. In this study, we sought to investigate the potential protective effects and associated molecular mechanisms of SalB in Parkinson’s disease (PD) models. To determine the neuroprotective effects of SalB in vitro, MPP+- or lipopolysaccharide (LPS)-induced neuronal injury was achieved using primary cultures with different compositions of neurons, microglia and astrocytes. Our results showed that SalB reduced both LPS- and MPP+-induced toxicity of dopamine neurons in a dose-dependent manner. Additionally, SalB treatment inhibited the release of microglial pro-inflammatory cytokines and resulted in an increase in the expression and release of glial cell line-derived neurotrophic factor (GDNF) from astrocytes. Western blot analysis illustrated that SalB increased the expression and nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The knockdown of Nrf2 using specific small interfering RNA (siRNA) partially reversed the SalB-induced GDNF expression and anti-inflammatory activity. Moreover, SalB treatment significantly attenuated dopaminergic (DA) neuronal loss, inhibited neuroinflammation, increased GDNF expression and improved the neurological function in MPTP-treated mice. Collectively, these findings demonstrated that SalB protects DA neurons by an Nrf-2 -mediated dual action: reducing microglia activation-mediated neuroinflammation and inducing astrocyte activation-dependent GDNF expression. Importantly the present study also highlights critical roles of glial cells as targets for developing new strategies to alter the progression of neurodegenerative disorders. PMID:24991814

  6. Autaptic regulation of electrical activities in neuron under electromagnetic induction

    Science.gov (United States)

    Xu, Ying; Ying, Heping; Jia, Ya; Ma, Jun; Hayat, Tasawar

    2017-01-01

    Realistic neurons may hold complex anatomical structure, for example, autapse connection to some internuncial neurons, which this specific synapse can connect to its body via a close loop. Continuous exchanges of charged ions across the membrane can induce complex distribution fluctuation of intracellular and extracellular charged ions of cell, and a time-varying electromagnetic field is set to modulate the membrane potential of neuron. In this paper, an autapse-modulated neuron model is presented and the effect of electromagnetic induction is considered by using magnetic flux. Bifurcation analysis and sampled time series for membrane potentials are calculated to investigate the mode transition in electrical activities and the biological function of autapse connection is discussed. Furthermore, the Gaussian white noise and electromagnetic radiation are considered on the improved neuron model, it is found appropriate setting and selection for feedback gain and time delay in autapse can suppress the bursting in neuronal behaviors. It indicates the formation of autapse can enhance the self-adaption of neuron so that appropriate response to external forcing can be selected, this biological function is helpful for encoding and signal propagation of neurons. It can be useful for investigation about collective behaviors in neuronal networks exposed to electromagnetic radiation. PMID:28240314

  7. Autaptic regulation of electrical activities in neuron under electromagnetic induction

    Science.gov (United States)

    Xu, Ying; Ying, Heping; Jia, Ya; Ma, Jun; Hayat, Tasawar

    2017-02-01

    Realistic neurons may hold complex anatomical structure, for example, autapse connection to some internuncial neurons, which this specific synapse can connect to its body via a close loop. Continuous exchanges of charged ions across the membrane can induce complex distribution fluctuation of intracellular and extracellular charged ions of cell, and a time-varying electromagnetic field is set to modulate the membrane potential of neuron. In this paper, an autapse-modulated neuron model is presented and the effect of electromagnetic induction is considered by using magnetic flux. Bifurcation analysis and sampled time series for membrane potentials are calculated to investigate the mode transition in electrical activities and the biological function of autapse connection is discussed. Furthermore, the Gaussian white noise and electromagnetic radiation are considered on the improved neuron model, it is found appropriate setting and selection for feedback gain and time delay in autapse can suppress the bursting in neuronal behaviors. It indicates the formation of autapse can enhance the self-adaption of neuron so that appropriate response to external forcing can be selected, this biological function is helpful for encoding and signal propagation of neurons. It can be useful for investigation about collective behaviors in neuronal networks exposed to electromagnetic radiation.

  8. Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus.

    Science.gov (United States)

    Blair, Robert E; Deshpande, Laxmikant S; Sombati, Sompong; Falenski, Katherine W; Martin, Billy R; DeLorenzo, Robert J

    2006-06-01

    Cannabinoids have been shown to have anticonvulsant properties, but no studies have evaluated the effects of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy (AE) and status epilepticus (SE). This study investigated the anticonvulsant properties of the cannabinoid receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolol[1,2,3 de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone (WIN 55,212-2) in primary hippocampal neuronal culture models of both AE and SE. WIN 55,212-2 produced dose-dependent anticonvulsant effects against both spontaneous recurrent epileptiform discharges (SRED) (EC50 = 0.85 microM) and SE (EC50 = 1.51 microM), with total suppression of seizure activity at 3 microM and of SE activity at 5 microM. The anticonvulsant properties of WIN 55,212-2 in these preparations were both stereospecific and blocked by the cannabinoid type-1 (CB1) receptor antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A; 1 microM), showing a CB1 receptor-dependent pathway. The inhibitory effect of WIN 55,212-2 against low Mg2+-induced SE is the first observation in this model of total suppression of SE by a selective pharmacological agent. The clinically used anticonvulsants phenytoin and phenobarbital were not able to abolish low Mg2+-induced SE at concentrations up to 150 microM. The results from this study show CB1 receptor-mediated anticonvulsant effects of the cannabimimetic WIN 55,212-2 against both SRED and low Mg2+-induced SE in primary hippocampal neuronal cultures and show that these in vitro models of AE and SE may represent powerful tools to investigate the molecular mechanisms mediating the effects of cannabinoids on neuronal excitability.

  9. Human neural stem cell transplantation rescues cognitive defects in APP/PS1 model of Alzheimer's disease by enhancing neuronal connectivity and metabolic activity

    Directory of Open Access Journals (Sweden)

    Xueyuan Li

    2016-11-01

    Full Text Available Alzheimer’s disease (AD, the most frequent type of dementia, is featured by Aβ pathology, neural degeneration and cognitive decline. To date, there is no cure for this disease. Neural stem cell (NSC transplantation provides new promise for treating AD. Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement. However, few reports examined the potential of human NSC transplantation for AD. In this study, we implanted human brain-derived NSCs (hNSCs into bilateral hippocampus of an APP/PS1 transgenic mouse model of AD to test the effects of hNSC transplantation on Alzheimer’s behavior and neuropathology. Six weeks later, transplanted hNSCs engrafted into the brains of AD mice, migrated dispersedly in broad brain regions, and some of them differentiated into neural cell types of central nervous system. The hNSC transplantation restored the recognition, learning and memory deficits but not anxiety tasks in AD mice. Although Aβ plaques were not significantly reduced, the neuronal, synaptic and nerve fiber density was significantly increased in the frontal cortex and hippocampus of hNSC-treated AD mice, suggesting of improved neuronal connectivity in AD brains after hNSC transplantation. Ultrastructural analysis confirmed that synapses and nerve fibers maintained relatively well-structured shapes in these mice. Furthermore, in-vivo magnetic resonance spectroscopy showed that hNSC-treated mice had notably increased levels of NAA and Glu in the frontal cortex and hippocampus, suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation. These results suggest that transplanted hNSCs rescued Alzheimer’s cognition by enhancing neuronal connectivity and metabolic activity through a compensation mechanism in APP/PS1 mice. This study provides preclinical evidence that hNSC transplantation

  10. Reverberatory activity in neuronal networks in vitro

    Institute of Scientific and Technical Information of China (English)

    LAU PakMing; BI GuoQiang

    2009-01-01

    It has been proposed that during cognitive processes, "online" memory traces in the brain are carried by reverberatory activity in neuronal circuits. However, the nature of such reverberation has remained elusive from experimental studies, largely due to the enormous complexity of intact circuits. Recent works have attempted to address this issue using cultured neuronal network and have revealed new dynamic properties of network reverberation as well as the underlying cellular mechanisms. These results demonstrate the effectiveness of in vitro networks as a useful tool for mechanistic dissection of neuronal circuit dynamics.

  11. Tamoxifen mediated estrogen receptor activation protects against early impairment of hippocampal neuron excitability in an oxygen/glucose deprivation brain slice ischemia model

    OpenAIRE

    Zhang, Huaqiu; Xie, Minjie; Gary P. Schools; Feustel, Paul F.; Wang, Wei; Lei, Ting; Kimelberg, Harold K.; Zhou, Min

    2008-01-01

    Pretreatment of ovarectomized rats with estrogen shows long-term protection via activation of the estrogen receptor (ER). However, it remains unknown whether activation of the ER can provide protection against early neuronal damage when given acutely, we simulated ischemic conditions by applying oxygen and glucose deprived (OGD) solution to acute male rat hippocampal slices and examined the neuronal electrophysiological changes. Pyramidal neurons and interneurons showed a time-dependent membr...

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

    Directory of Open Access Journals (Sweden)

    Viswanathan Arunachalam

    2013-01-01

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

  13. Background activity drives criticality of neuronal avalanches

    Energy Technology Data Exchange (ETDEWEB)

    Juanico, D E; Monterola, C [National Institute of Physics, University of the Philippines, Diliman, Quezon City 1101 (Philippines)

    2007-08-03

    We establish a general framework that explains how leaky, dissipative systems, such as neuronal networks (NN), can exhibit robust self-organized criticality (SOC). Consistent with recent experiments, we propose that persistent membrane potential fluctuations allow NNs to transform from a sub-critical to a critical state. Our results also account for the tendency in small networks to tip towards an epileptiform state (the case of largely synchronized neurons) when background activity is strong.

  14. Parameter estimation in neuronal stochastic differential equation models from intracellular recordings of membrane potentials in single neurons

    DEFF Research Database (Denmark)

    Ditlevsen, Susanne; Samson, Adeline

    2016-01-01

    Dynamics of the membrane potential in a single neuron can be studied by estimating biophysical parameters from intracellular recordings. Diffusion processes, given as continuous solutions to stochastic differential equations, are widely applied as models for the neuronal membrane potential...... evolution. One-dimensional models are the stochastic integrate-and-fire neuronal diffusion models. Biophysical neuronal models take into account the dynamics of ion channels or synaptic activity, leading to multidimensional diffusion models. Since only the membrane potential can be measured......, this complicates the statistical inference and parameter estimation from these partially observed detailed models. This paper reviews parameter estimation techniques from intracellular recordings in these diffusion models....

  15. Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-γ agonists.

    Science.gov (United States)

    Kane, Cynthia J M; Phelan, Kevin D; Han, Lihong; Smith, Renea R; Xie, Jin; Douglas, James C; Drew, Paul D

    2011-06-01

    Fetal alcohol spectrum disorders (FASD) result from ethanol exposure to the developing fetus and are the most common cause of mental retardation in the United States. These disorders are characterized by a variety of neurodevelopmental and neurodegenerative anomalies which result in significant lifetime disabilities. Thus, novel therapies are required to limit the devastating consequences of FASD. Neuropathology associated with FASD can occur throughout the central nervous system (CNS), but is particularly well characterized in the developing cerebellum. Rodent models of FASD have previously demonstrated that both Purkinje cells and granule cells, which are the two major types of neurons in the cerebellum, are highly susceptible to the toxic effects of ethanol. The current studies demonstrate that ethanol decreases the viability of cultured cerebellar granule cells and microglial cells. Interestingly, microglia have dual functionality in the CNS. They provide trophic and protective support to neurons. However, they may also become pathologically activated and produce inflammatory molecules toxic to parenchymal cells including neurons. The findings in this study demonstrate that the peroxisome proliferator-activated receptor-γ agonists 15-deoxy-Δ12,15 prostaglandin J2 and pioglitazone protect cultured granule cells and microglia from the toxic effects of ethanol. Furthermore, investigations using a newly developed mouse model of FASD and stereological cell counting methods in the cerebellum elucidate that ethanol administration to neonates is toxic to both Purkinje cell neurons as well as microglia, and that in vivo administration of PPAR-γ agonists protects these cells. In composite, these studies suggest that PPAR-γ agonists may be effective in limiting ethanol-induced toxicity to the developing CNS.

  16. Biophysically realistic minimal model of dopamine neuron

    Science.gov (United States)

    Oprisan, Sorinel

    2008-03-01

    We proposed and studied a new biophysically relevant computational model of dopaminergic neurons. Midbrain dopamine neurons are involved in motivation and the control of movement, and have been implicated in various pathologies such as Parkinson's disease, schizophrenia, and drug abuse. The model we developed is a single-compartment Hodgkin-Huxley (HH)-type parallel conductance membrane model. The model captures the essential mechanisms underlying the slow oscillatory potentials and plateau potential oscillations. The main currents involved are: 1) a voltage-dependent fast calcium current, 2) a small conductance potassium current that is modulated by the cytosolic concentration of calcium, and 3) a slow voltage-activated potassium current. We developed multidimensional bifurcation diagrams and extracted the effective domains of sustained oscillations. The model includes a calcium balance due to the fundamental importance of calcium influx as proved by simultaneous electrophysiological and calcium imaging procedure. Although there are significant evidences to suggest a partially electrogenic calcium pump, all previous models considered only elecrtogenic pumps. We investigated the effect of the electrogenic calcium pump on the bifurcation diagram of the model and compared our findings against the experimental results.

  17. PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease.

    Science.gov (United States)

    Quesada, Arnulfo; Lee, Becky Y; Micevych, Paul E

    2008-04-01

    Recently, using the medial forebrain bundle (MFB) 6-hydroxydopmaine (6-OHDA) lesion rat model of Parkinson's disease (PD), we have demonstrated that blockade of central IGF-1 receptors (IGF-1R) attenuated estrogen neuroprotection of substantia nigra pars compacta (SNpc) DA neurons, but exacerbated 6-OHDA lesions in IGF-1 only treated rats (Quesada and Micevych [2004]: J Neurosci Res 75:107-116). This suggested that the IGF-1 system is a central mechanism through which estrogen acts to protect the nigrostriatal DA system. Moreover, these results also suggest that IGF-1R-induced intracellular signaling pathways are involved in the estrogen mechanism that promotes neuronal survival. In vitro, two convergent intracellular signaling pathways used by estrogen and IGF-1, the mitogen-activated protein kinase (MAPK/ERK), and phosphatidyl-inositol-3-kinase/Akt (PI3K/Akt), have been demonstrated to be neuroprotective. Continuous central infusions of MAPK/ERK and PI3K/Akt inhibitors were used to test the hypothesis that one or both of these signal transduction pathways mediates estrogen and/or IGF-1 neuroprotection of SNpc DA neurons after a unilateral administration of 6-OHDA into the MFB of rats. Motor behavior tests and tyrosine hydroxylase immunoreactivity revealed that the inhibitor of the PI3K/Akt pathway (LY294002) blocked the survival effects of both estrogen and IGF-1, while an inhibitor of the MAPK/ERK signaling (PD98059) was ineffective. Western blot analyses showed that estrogen and IGF-1 treatments increased PI3K/Akt activation in the SN; however, MAPK/ERK activation was decreased in the SN. Indeed, continuous infusions of inhibitors blocked phosphorylation of PI3K/Akt and MAPK/ERK. These findings indicate that estrogen and IGF-1-mediated SNpc DA neuronal protection is dependent on PI3K/Akt signaling, but not on the MAPK/ERK pathway.

  18. Activation of Pedunculopontine Glutamate Neurons Is Reinforcing.

    Science.gov (United States)

    Yoo, Ji Hoon; Zell, Vivien; Wu, Johnathan; Punta, Cindy; Ramajayam, Nivedita; Shen, Xinyi; Faget, Lauren; Lilascharoen, Varoth; Lim, Byung Kook; Hnasko, Thomas S

    2017-01-04

    Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders. Uncovering brain circuits underlying reward-seeking is an important step toward understanding the circuit bases of drug addiction and other psychiatric disorders. The dopaminergic system emanating from the ventral tegmental area (VTA) plays a key role in regulating reward-seeking behaviors. We used optogenetics to demonstrate that the pedunculopontine tegmental nucleus sends glutamatergic projections to VTA dopamine neurons, and that stimulation of this circuit promotes behavioral reinforcement. The findings support a critical role for pedunculopontine tegmental nucleus glutamate neurotransmission in modulating VTA dopamine neuron activity and

  19. Fitting Neuron Models to Spike Trains

    Science.gov (United States)

    Rossant, Cyrille; Goodman, Dan F. M.; Fontaine, Bertrand; Platkiewicz, Jonathan; Magnusson, Anna K.; Brette, Romain

    2011-01-01

    Computational modeling is increasingly used to understand the function of neural circuits in systems neuroscience. These studies require models of individual neurons with realistic input–output properties. Recently, it was found that spiking models can accurately predict the precisely timed spike trains produced by cortical neurons in response to somatically injected currents, if properly fitted. This requires fitting techniques that are efficient and flexible enough to easily test different candidate models. We present a generic solution, based on the Brian simulator (a neural network simulator in Python), which allows the user to define and fit arbitrary neuron models to electrophysiological recordings. It relies on vectorization and parallel computing techniques to achieve efficiency. We demonstrate its use on neural recordings in the barrel cortex and in the auditory brainstem, and confirm that simple adaptive spiking models can accurately predict the response of cortical neurons. Finally, we show how a complex multicompartmental model can be reduced to a simple effective spiking model. PMID:21415925

  20. Neuronal avalanches in spontaneous activity in vivo.

    Science.gov (United States)

    Hahn, Gerald; Petermann, Thomas; Havenith, Martha N; Yu, Shan; Singer, Wolf; Plenz, Dietmar; Nikolic, Danko

    2010-12-01

    Many complex systems give rise to events that are clustered in space and time, thereby establishing a correlation structure that is governed by power law statistics. In the cortex, such clusters of activity, called "neuronal avalanches," were recently found in local field potentials (LFPs) of spontaneous activity in acute cortex slices, slice cultures, the developing cortex of the anesthetized rat, and premotor and motor cortex of awake monkeys. At present, it is unclear whether neuronal avalanches also exist in the spontaneous LFPs and spike activity in vivo in sensory areas of the mature brain. To address this question, we recorded spontaneous LFPs and extracellular spiking activity with multiple 4 × 4 microelectrode arrays (Michigan Probes) in area 17 of adult cats under anesthesia. A cluster of events was defined as a consecutive sequence of time bins Δt (1-32 ms), each containing at least one LFP event or spike anywhere on the array. LFP cluster sizes consistently distributed according to a power law with a slope largely above -1.5. In two thirds of the corresponding experiments, spike clusters also displayed a power law that displayed a slightly steeper slope of -1.8 and was destroyed by subsampling operations. The power law in spike clusters was accompanied with stronger temporal correlations between spiking activities of neurons that spanned longer time periods compared with spike clusters lacking power law statistics. The results suggest that spontaneous activity of the visual cortex under anesthesia has the properties of neuronal avalanches.

  1. Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.

    Science.gov (United States)

    Venkatesh, Humsa S; Johung, Tessa B; Caretti, Viola; Noll, Alyssa; Tang, Yujie; Nagaraja, Surya; Gibson, Erin M; Mount, Christopher W; Polepalli, Jai; Mitra, Siddhartha S; Woo, Pamelyn J; Malenka, Robert C; Vogel, Hannes; Bredel, Markus; Mallick, Parag; Monje, Michelle

    2015-05-01

    Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.

  2. A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons.

    Science.gov (United States)

    Hight, Ariel E; Kalluri, Radha

    2016-08-01

    The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182-187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41-51, 1986). Kalluri et al. (J Neurophysiol 104: 2034-2051, 2010) proposed that regularity is controlled by the density of low-voltage-activated potassium currents (IKL). To examine the impact of IKL on spike timing regularity, we implemented a single-compartment model with three conductances known to be present in the vestibular ganglion: transient sodium (gNa), low-voltage-activated potassium (gKL), and high-voltage-activated potassium (gKH). Consistent with in vitro observations, removing gKL depolarized resting potential, increased input resistance and membrane time constant, and converted current step-evoked firing patterns from transient (1 spike at current onset) to sustained (many spikes). Modeled neurons were driven with a time-varying synaptic conductance that captured the random arrival times and amplitudes of glutamate-driven synaptic events. In the presence of gKL, spiking occurred only in response to large events with fast onsets. Models without gKL exhibited greater integration by responding to the superposition of rapidly arriving events. Three synaptic conductance were modeled, each with different kinetics to represent a variety of different synaptic processes. In response to all three types of synaptic conductance, models containing gKL produced spike trains with irregular interspike intervals. Only models lacking gKL when driven by rapidly arriving small excitatory postsynaptic currents were capable of generating regular spiking.

  3. Levodopa activates apoptosis signaling kinase 1 (ASK1) and promotes apoptosis in a neuronal model: implications for the treatment of Parkinson's disease.

    Science.gov (United States)

    Liedhegner, Elizabeth A Sabens; Steller, Kelly M; Mieyal, John J

    2011-10-17

    Oxidative stress is implicated in the etiology of Parkinson's disease (PD), the second most common neurodegenerative disease. PD is treated with chronic administration of l-3,4-dihydroxyphenylalanine (levodopa, L-DOPA), and typically, increasing doses are used during progression of the disease. Paradoxically, L-DOPA is a pro-oxidant and induces cell death in cellular models of PD through disruption of sulfhydryl homeostasis involving loss of the thiol-disulfide oxidoreductase functions of the glutaredoxin (Grx1) and thioredoxin (Trx1) enzyme systems [Sabens, E. A., Distler, A. M., and Mieyal, J. J. (2010) Biochemistry 49 (12), 2715-2724]. Considering this loss of both Grx1 and Trx1 activities upon L-DOPA treatment, we sought to elucidate the mechanism(s) of L-DOPA-induced apoptosis. In other contexts, both the NFκB (nuclear factor κB) pathway and the ASK1 (apoptosis signaling kinase 1) pathway have been shown to be regulated by both Grx1 and Trx1, and both pathways have been implicated in cell death signaling in model systems of PD. Moreover, mixed lineage kinase (MLK) has been considered as a potential therapeutic target for PD. Using SHSY5Y cells as model dopaminergic neurons, we found that NFκB activity was not altered by L-DOPA treatment, and the selective MLK inhibitor (CEP-1347) did not protect the cells from L-DOPA. In contrast, ASK1 was activated with L-DOPA treatment as indicated by phosphorylation of its downstream mitogen-activated protein kinases (MAPK), p38 and JNK. Chemical inhibition of either p38 or JNK provided protection from L-DOPA-induced apoptosis. Moreover, direct knockdown of ASK1 protected from L-DOPA-induced neuronal cell death. These results identify ASK1 as the main pro-apoptotic pathway activated in response to L-DOPA treatment, implicating it as a potential target for adjunct therapy in PD.

  4. Electroacupuncture activates corticotrophin-releasing hormone-containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation

    Directory of Open Access Journals (Sweden)

    Berman Brian M

    2008-05-01

    Full Text Available Abstract Background Studies show that electroacupuncture (EA has beneficial effects in patients with inflammatory diseases. This study investigated the mechanisms of EA anti-inflammation, using a rat model of complete Freund's adjuvant (CFA-induced hind paw inflammation and hyperalgesia. Design Four experiments were conducted on male Sprague-Dawley rats (n = 6–7/per group. Inflammation was induced by injecting CFA into the plantar surface of one hind paw. Experiment 1 examined whether EA increases plasma adrenocorticotropic hormone (ACTH levels. Experiments 2 and 3 studied the effects of the ACTH and corticotropin-releasing hormone (CRH receptor antagonists, ACTH(11–24 and astressin, on the EA anti-edema. Experiment 4 determined whether EA activates CRH neurons in the paraventricular nucleus of the hypothalammus. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice for 20 min each, once immediately post and again 2 hr post-CFA. Plasma ACTH levels, paw thickness, and paw withdrawal latency to a noxious thermal stimulus were measured 2 h and 5 h after the CFA. Results EA significantly increased ACTH levels 5 h (2 folds after CFA compared to sham EA control, but EA alone in naive rats and CFA alone did not induce significant increases in ACTH. ACTH(11–24 and astressin blocked EA anti-edema but not EA anti-hyperalgesia. EA induced phosphorylation of NR1, an essential subunit of the N-methyl-D-aspartic acid (NMDA receptor, in CRH-containing neurons of the paraventricular nucleus. Conclusion The data demonstrate that EA activates CRH neurons to significantly increase plasma ACTH levels and suppress edema through CRH and ACTH receptors in a rat model of inflammation.

  5. Preictal activity of subicular, CA1, and dentate gyrus principal neurons in the dorsal hippocampus before spontaneous seizures in a rat model of temporal lobe epilepsy.

    Science.gov (United States)

    Fujita, Satoshi; Toyoda, Izumi; Thamattoor, Ajoy K; Buckmaster, Paul S

    2014-12-10

    Previous studies suggest that spontaneous seizures in patients with temporal lobe epilepsy might be preceded by increased action potential firing of hippocampal neurons. Preictal activity is potentially important because it might provide new opportunities for predicting when a seizure is about to occur and insight into how spontaneous seizures are generated. We evaluated local field potentials and unit activity of single, putative excitatory neurons in the subiculum, CA1, CA3, and dentate gyrus of the dorsal hippocampus in epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Average action potential firing rates of neurons in the subiculum, CA1, and dentate gyrus, but not CA3, increased significantly and progressively beginning 2-4 min before locally recorded spontaneous seizures. In the subiculum, CA1, and dentate gyrus, but not CA3, 41-57% of neurons displayed increased preictal activity with significant consistency across multiple seizures. Much of the increased preictal firing of neurons in the subiculum and CA1 correlated with preictal theta activity, whereas preictal firing of neurons in the dentate gyrus was independent of theta. In addition, some CA1 and dentate gyrus neurons displayed reduced firing rates preictally. These results reveal that different hippocampal subregions exhibit differences in the extent and potential underlying mechanisms of preictal activity. The finding of robust and significantly consistent preictal activity of subicular, CA1, and dentate neurons in the dorsal hippocampus, despite the likelihood that many seizures initiated in other brain regions, suggests the existence of a broader neuronal network whose activity changes minutes before spontaneous seizures initiate. Copyright © 2014 the authors 0270-6474/14/3416671-17$15.00/0.

  6. Characterization of Disopyramide derivative ADD424042 as a non-cardiotoxic neuronal sodium channel blocker with broad-spectrum anticonvulsant activity in rodent seizure models.

    Science.gov (United States)

    Król, Marek; Ufnal, Marcin; Szulczyk, Bartłomiej; Podsadni, Piotr; Drapała, Adrian; Turło, Jadwiga; Dawidowski, Maciej

    2016-01-01

    It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models. Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the 'classical' models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole-cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety.

  7. Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle.

    Science.gov (United States)

    Patel, Anant B; Lai, James C K; Chowdhury, Golam M I; Hyder, Fahmeed; Rothman, Douglas L; Shulman, Robert G; Behar, Kevin L

    2014-04-01

    Previous (13)C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy-D-glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG6P), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG6P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo, indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions.

  8. Effective stimuli for constructing reliable neuron models.

    Directory of Open Access Journals (Sweden)

    Shaul Druckmann

    2011-08-01

    Full Text Available The rich dynamical nature of neurons poses major conceptual and technical challenges for unraveling their nonlinear membrane properties. Traditionally, various current waveforms have been injected at the soma to probe neuron dynamics, but the rationale for selecting specific stimuli has never been rigorously justified. The present experimental and theoretical study proposes a novel framework, inspired by learning theory, for objectively selecting the stimuli that best unravel the neuron's dynamics. The efficacy of stimuli is assessed in terms of their ability to constrain the parameter space of biophysically detailed conductance-based models that faithfully replicate the neuron's dynamics as attested by their ability to generalize well to the neuron's response to novel experimental stimuli. We used this framework to evaluate a variety of stimuli in different types of cortical neurons, ages and animals. Despite their simplicity, a set of stimuli consisting of step and ramp current pulses outperforms synaptic-like noisy stimuli in revealing the dynamics of these neurons. The general framework that we propose paves a new way for defining, evaluating and standardizing effective electrical probing of neurons and will thus lay the foundation for a much deeper understanding of the electrical nature of these highly sophisticated and non-linear devices and of the neuronal networks that they compose.

  9. A computational model of motor neuron degeneration.

    Science.gov (United States)

    Le Masson, Gwendal; Przedborski, Serge; Abbott, L F

    2014-08-20

    To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations.

  10. PDF neuron firing phase-shifts key circadian activity neurons in Drosophila.

    Science.gov (United States)

    Guo, Fang; Cerullo, Isadora; Chen, Xiao; Rosbash, Michael

    2014-06-17

    Our experiments address two long-standing models for the function of the Drosophila brain circadian network: a dual oscillator model, which emphasizes the primacy of PDF-containing neurons, and a cell-autonomous model for circadian phase adjustment. We identify five different circadian (E) neurons that are a major source of rhythmicity and locomotor activity. Brief firing of PDF cells at different times of day generates a phase response curve (PRC), which mimics a light-mediated PRC and requires PDF receptor expression in the five E neurons. Firing also resembles light by causing TIM degradation in downstream neurons. Unlike light however, firing-mediated phase-shifting is CRY-independent and exploits the E3 ligase component CUL-3 in the early night to degrade TIM. Our results suggest that PDF neurons integrate light information and then modulate the phase of E cell oscillations and behavioral rhythms. The results also explain how fly brain rhythms persist in constant darkness and without CRY.

  11. PDF neuron firing phase-shifts key circadian activity neurons in Drosophila

    Science.gov (United States)

    Guo, Fang; Cerullo, Isadora; Chen, Xiao; Rosbash, Michael

    2014-01-01

    Our experiments address two long-standing models for the function of the Drosophila brain circadian network: a dual oscillator model, which emphasizes the primacy of PDF-containing neurons, and a cell-autonomous model for circadian phase adjustment. We identify five different circadian (E) neurons that are a major source of rhythmicity and locomotor activity. Brief firing of PDF cells at different times of day generates a phase response curve (PRC), which mimics a light-mediated PRC and requires PDF receptor expression in the five E neurons. Firing also resembles light by causing TIM degradation in downstream neurons. Unlike light however, firing-mediated phase-shifting is CRY-independent and exploits the E3 ligase component CUL-3 in the early night to degrade TIM. Our results suggest that PDF neurons integrate light information and then modulate the phase of E cell oscillations and behavioral rhythms. The results also explain how fly brain rhythms persist in constant darkness and without CRY. DOI: http://dx.doi.org/10.7554/eLife.02780.001 PMID:24939987

  12. Respiratory-like rhythmic activity can be produced by an excitatory network of non-pacemaker neuron models.

    Science.gov (United States)

    Kosmidis, Efstratios K; Pierrefiche, Olivier; Vibert, Jean-François

    2004-08-01

    It is still unclear whether the respiratory-like rhythm observed in slice preparations containing the pre-Bötzinger complex is of pacemaker or network origin. The rhythm persists in the absence of inhibition, but blocking pacemaker activity did not always result in rhythm abolition. We developed a computational model of the slice to show that respiratory-like rhythm can emerge as a network property without pacemakers or synaptic inhibition. The key currents of our model cell are the low- and high-threshold calcium currents and the calcium-dependent potassium current. Depolarization of a single unit by current steps or by raising the external potassium concentration can induce periodic bursting activity. Gaussian stimulation increased the excitability of the model without evoking oscillatory activity, as indicated by autocorrelation analysis. In response to hyperpolarizing pulses, the model produces prolonged relative refractory periods. At the network level, an increase of external potassium concentration triggers rhythmic activity that can be attributed to cellular periodic bursting, network properties, or both, depending on different parameters. Gaussian stimulation also induces rhythmic activity that depends solely on network properties. In all cases, the calcium-dependent potassium current has a central role in burst termination and interburst duration. However, when periodic inhibition is considered, the activation of this current is responsible for the characteristic amplification ramp of the emerged rhythm. Our results may explain controversial results from studies blocking pacemakers in vitro and show a shift in the role of the calcium-dependent potassium current in the presence of network inhibition.

  13. Small is beautiful: models of small neuronal networks.

    Science.gov (United States)

    Lamb, Damon G; Calabrese, Ronald L

    2012-08-01

    Modeling has contributed a great deal to our understanding of how individual neurons and neuronal networks function. In this review, we focus on models of the small neuronal networks of invertebrates, especially rhythmically active CPG networks. Models have elucidated many aspects of these networks, from identifying key interacting membrane properties to pointing out gaps in our understanding, for example missing neurons. Even the complex CPGs of vertebrates, such as those that underlie respiration, have been reduced to small network models to great effect. Modeling of these networks spans from simplified models, which are amenable to mathematical analyses, to very complicated biophysical models. Some researchers have now adopted a population approach, where they generate and analyze many related models that differ in a few to several judiciously chosen free parameters; often these parameters show variability across animals and thus justify the approach. Models of small neuronal networks will continue to expand and refine our understanding of how neuronal networks in all animals program motor output, process sensory information and learn.

  14. Mechanisms for multiple activity modes of VTA dopamine neurons

    Directory of Open Access Journals (Sweden)

    Andrew eOster

    2015-07-01

    Full Text Available Midbrain ventral segmental area (VTA dopaminergic neurons send numerous projections to cortical and sub-cortical areas, and diffusely release dopamine (DA to their targets. DA neurons display a range of activity modes that vary in frequency and degree of burst firing. Importantly, DA neuronal bursting is associated with a significantly greater degree of DA release than an equivalent tonic activity pattern. Here, we introduce a single compartmental, conductance-based computational model for DA cell activity that captures the behavior of DA neuronal dynamics and examine the multiple factors that underlie DA firing modes: the strength of the SK conductance, the amount of drive, and GABA inhibition. Our results suggest that neurons with low SK conductance fire in a fast firing mode, are correlated with burst firing, and require higher levels of applied current before undergoing depolarization block. We go on to consider the role of GABAergic inhibition on an ensemble of dynamical classes of DA neurons and find that strong GABA inhibition suppresses burst firing. Our studies suggest differences in the distribution of the SK conductance and GABA inhibition levels may indicate subclasses of DA neurons within the VTA. We further identify, that by considering alternate potassium dynamics, the dynamics display burst patterns that terminate via depolarization block, akin to those observed in vivo in VTA DA neurons and in substantia nigra pars compacta DA cell preparations under apamin application. In addition, we consider the generation of transient burst firing events that are NMDA-initiated or elicited by a sudden decrease of GABA inhibition, that is, disinhibition.

  15. From spiking neuron models to linear-nonlinear models.

    Directory of Open Access Journals (Sweden)

    Srdjan Ostojic

    Full Text Available Neurons transform time-varying inputs into action potentials emitted stochastically at a time dependent rate. The mapping from current input to output firing rate is often represented with the help of phenomenological models such as the linear-nonlinear (LN cascade, in which the output firing rate is estimated by applying to the input successively a linear temporal filter and a static non-linear transformation. These simplified models leave out the biophysical details of action potential generation. It is not a priori clear to which extent the input-output mapping of biophysically more realistic, spiking neuron models can be reduced to a simple linear-nonlinear cascade. Here we investigate this question for the leaky integrate-and-fire (LIF, exponential integrate-and-fire (EIF and conductance-based Wang-Buzsáki models in presence of background synaptic activity. We exploit available analytic results for these models to determine the corresponding linear filter and static non-linearity in a parameter-free form. We show that the obtained functions are identical to the linear filter and static non-linearity determined using standard reverse correlation analysis. We then quantitatively compare the output of the corresponding linear-nonlinear cascade with numerical simulations of spiking neurons, systematically varying the parameters of input signal and background noise. We find that the LN cascade provides accurate estimates of the firing rates of spiking neurons in most of parameter space. For the EIF and Wang-Buzsáki models, we show that the LN cascade can be reduced to a firing rate model, the timescale of which we determine analytically. Finally we introduce an adaptive timescale rate model in which the timescale of the linear filter depends on the instantaneous firing rate. This model leads to highly accurate estimates of instantaneous firing rates.

  16. Long-Term Treatment with Losartan Attenuates Seizure Activity and Neuronal Damage Without Affecting Behavioral Changes in a Model of Co-morbid Hypertension and Epilepsy.

    Science.gov (United States)

    Tchekalarova, Jana D; Ivanova, Natasha; Atanasova, Dimitrina; Pechlivanova, Daniela M; Lazarov, Nikolai; Kortenska, Lidia; Mitreva, Rumiana; Lozanov, Valentin; Stoynev, Alexander

    2016-08-01

    Over the last 10 years, accumulated experimental and clinical evidence has supported the idea that AT1 receptor subtype is involved in epilepsy. Recently, we have shown that the selective AT1 receptor antagonist losartan attenuates epileptogenesis and exerts neuroprotection in the CA1 area of the hippocampus in epileptic Wistar rats. This study aimed to verify the efficacy of long-term treatment with losartan (10 mg/kg) after kainate-induced status epilepticus (SE) on seizure activity, behavioral and biochemical changes, and neuronal damage in a model of co-morbid hypertension and epilepsy. Spontaneous seizures were video- and EEG-monitored in spontaneously hypertensive rats (SHRs) for a 16-week period after SE. The behavior was analyzed by open field, elevated plus maze, sugar preference test, and forced swim test. The levels of serotonin in the hippocampus and neuronal loss were estimated by HPLC and hematoxylin and eosin staining, respectively. The AT1 receptor antagonism delayed the onset of seizures and alleviated their frequency and duration during and after discontinuation of treatment. Losartan showed neuroprotection mostly in the CA3 area of the hippocampus and the septo-temporal hilus of the dentate gyrus in SHRs. However, the AT1 receptor antagonist did not exert a substantial influence on concomitant with epilepsy behavioral changes and decreased 5-HT levels in the hippocampus. Our results suggest that the antihypertensive therapy with an AT1 receptor blocker might be effective against seizure activity and neuronal damage in a co-morbid hypertension and epilepsy.

  17. A Neuron-Based Model of Sleep-Wake Cycles

    Science.gov (United States)

    Postnova, Svetlana; Peters, Achim; Braun, Hans

    2008-03-01

    In recent years it was discovered that a neuropeptide orexin/hypocretin plays a main role in sleep processes. This peptide is produced by the neurons in the lateral hypothalamus, which project to almost all brain areas. We present a computational model of sleep-wake cycles, which is based on the Hodgkin-Huxley type neurons and considers reciprocal glutaminergic projections between the lateral hypothalamus and the prefrontal cortex. Orexin is released as a neuromodulator and is required to keep the neurons firing, which corresponds to the wake state. When orexin is depleted the neurons are getting silent as observed in the sleep state. They can be reactivated by the circadian signal from the suprachiasmatic nucleus and/or external stimuli (alarm clock). Orexin projections to the thalamocortical neurons also can account for their transition from tonic firing activity during wakefulness to synchronized burst discharges during sleep.

  18. Mirror neurons: functions, mechanisms and models.

    Science.gov (United States)

    Oztop, Erhan; Kawato, Mitsuo; Arbib, Michael A

    2013-04-12

    Mirror neurons for manipulation fire both when the animal manipulates an object in a specific way and when it sees another animal (or the experimenter) perform an action that is more or less similar. Such neurons were originally found in macaque monkeys, in the ventral premotor cortex, area F5 and later also in the inferior parietal lobule. Recent neuroimaging data indicate that the adult human brain is endowed with a "mirror neuron system," putatively containing mirror neurons and other neurons, for matching the observation and execution of actions. Mirror neurons may serve action recognition in monkeys as well as humans, whereas their putative role in imitation and language may be realized in human but not in monkey. This article shows the important role of computational models in providing sufficient and causal explanations for the observed phenomena involving mirror systems and the learning processes which form them, and underlines the need for additional circuitry to lift up the monkey mirror neuron circuit to sustain the posited cognitive functions attributed to the human mirror neuron system. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. FLZ protects dopaminergic neuron through activating protein kinase B/mammalian target of rapamycin pathway and inhibiting RTP801 expression in Parkinson's disease models.

    Science.gov (United States)

    Bao, X-Q; Kong, X-C; Qian, C; Zhang, D

    2012-01-27

    The pathogenesis of Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in substantia nigra (SNpc). FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental Parkinson's disease (PD) models. However, it is still unclear whether FLZ protects against PD through regulating the function of dopaminergic system. In this study, we carried out a set of in vitro and in vivo experiments to address these questions. Oral administration of FLZ significantly improved motor dysfunction of mice challenged by MPTP. The beneficial effects of FLZ on motor behavior attributed to the elevation of dopamine level in striatum, tyrosine hydroxylase (TH)-positive cells, and TH activity in the middle brain of mouse. Mechanism study showed that treatment of FLZ increased the phosphorylation of activating protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Using LY294002 to block phosphoinositide 3-kinases (PI3K)/Akt signaling pathway prevented the phosphorylation of mTOR and attenuated the neuroprotection of FLZ in MN9D cells challenged by MPP(+). In addition, FLZ reduced the expression of RTP801, an important protein in PD, in mice and cells intoxicated by MPTP/MPP(+). Taken together, these results revealed a novel role that FLZ elevated TH expression and activity in dopaminergic neuron through activation of Akt/mTOR survival pathway and inhibition of RTP801 in MPTP/MPP(+)-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising anti-PD drug.

  20. How neurons migrate: a dynamic in-silico model of neuronal migration in the developing cortex

    LENUS (Irish Health Repository)

    Setty, Yaki

    2011-09-30

    Abstract Background Neuronal migration, the process by which neurons migrate from their place of origin to their final position in the brain, is a central process for normal brain development and function. Advances in experimental techniques have revealed much about many of the molecular components involved in this process. Notwithstanding these advances, how the molecular machinery works together to govern the migration process has yet to be fully understood. Here we present a computational model of neuronal migration, in which four key molecular entities, Lis1, DCX, Reelin and GABA, form a molecular program that mediates the migration process. Results The model simulated the dynamic migration process, consistent with in-vivo observations of morphological, cellular and population-level phenomena. Specifically, the model reproduced migration phases, cellular dynamics and population distributions that concur with experimental observations in normal neuronal development. We tested the model under reduced activity of Lis1 and DCX and found an aberrant development similar to observations in Lis1 and DCX silencing expression experiments. Analysis of the model gave rise to unforeseen insights that could guide future experimental study. Specifically: (1) the model revealed the possibility that under conditions of Lis1 reduced expression, neurons experience an oscillatory neuron-glial association prior to the multipolar stage; and (2) we hypothesized that observed morphology variations in rats and mice may be explained by a single difference in the way that Lis1 and DCX stimulate bipolar motility. From this we make the following predictions: (1) under reduced Lis1 and enhanced DCX expression, we predict a reduced bipolar migration in rats, and (2) under enhanced DCX expression in mice we predict a normal or a higher bipolar migration. Conclusions We present here a system-wide computational model of neuronal migration that integrates theory and data within a precise

  1. β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.

    Science.gov (United States)

    Ojha, Shreesh; Javed, Hayate; Azimullah, Sheikh; Haque, M Emdadul

    2016-07-01

    Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area. The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD. In the present study, BCP was administered once daily for 4 weeks at a dose of 50 mg/kg body weight prior to a rotenone (2.5 mg/kg body weight) challenge to mimic the progressive neurodegenerative nature of PD. Rotenone administration results in oxidative stress as evidenced by decreased activities of superoxide dismutase, catalase, and depletion of glutathione with a concomitant rise in lipid peroxidation product, malondialdehyde. Rotenone also significantly increased pro-inflammatory cytokines in the midbrain region and elevated the inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Further, immunohistochemical analysis revealed loss of dopaminergic neurons in the SNc area and enhanced expression of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), indicators of microglia activation, and astrocyte hypertrophy, respectively, as an index of inflammation. However, treatment with BCP rescued dopaminergic neurons and decreased microglia and astrocyte activation evidenced by reduced Iba-1 and GFAP expression. BCP in addition to attenuation of pro-inflammatory cytokines and inflammatory mediators such as COX-2 and iNOS, also restored antioxidant enzymes and inhibited lipid peroxidation as well as glutathione depletion. The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.

  2. A developmental approach to predicting neuronal connectivity from small biological datasets: a gradient-based neuron growth model.

    Science.gov (United States)

    Borisyuk, Roman; Al Azad, Abul Kalam; Conte, Deborah; Roberts, Alan; Soffe, Stephen R

    2014-01-01

    Relating structure and function of neuronal circuits is a challenging problem. It requires demonstrating how dynamical patterns of spiking activity lead to functions like cognitive behaviour and identifying the neurons and connections that lead to appropriate activity of a circuit. We apply a "developmental approach" to define the connectome of a simple nervous system, where connections between neurons are not prescribed but appear as a result of neuron growth. A gradient based mathematical model of two-dimensional axon growth from rows of undifferentiated neurons is derived for the different types of neurons in the brainstem and spinal cord of young tadpoles of the frog Xenopus. Model parameters define a two-dimensional CNS growth environment with three gradient cues and the specific responsiveness of the axons of each neuron type to these cues. The model is described by a nonlinear system of three difference equations; it includes a random variable, and takes specific neuron characteristics into account. Anatomical measurements are first used to position cell bodies in rows and define axon origins. Then a generalization procedure allows information on the axons of individual neurons from small anatomical datasets to be used to generate larger artificial datasets. To specify parameters in the axon growth model we use a stochastic optimization procedure, derive a cost function and find the optimal parameters for each type of neuron. Our biologically realistic model of axon growth starts from axon outgrowth from the cell body and generates multiple axons for each different neuron type with statistical properties matching those of real axons. We illustrate how the axon growth model works for neurons with axons which grow to the same and the opposite side of the CNS. We then show how, by adding a simple specification for dendrite morphology, our model "developmental approach" allows us to generate biologically-realistic connectomes.

  3. A developmental approach to predicting neuronal connectivity from small biological datasets: a gradient-based neuron growth model.

    Directory of Open Access Journals (Sweden)

    Roman Borisyuk

    Full Text Available Relating structure and function of neuronal circuits is a challenging problem. It requires demonstrating how dynamical patterns of spiking activity lead to functions like cognitive behaviour and identifying the neurons and connections that lead to appropriate activity of a circuit. We apply a "developmental approach" to define the connectome of a simple nervous system, where connections between neurons are not prescribed but appear as a result of neuron growth. A gradient based mathematical model of two-dimensional axon growth from rows of undifferentiated neurons is derived for the different types of neurons in the brainstem and spinal cord of young tadpoles of the frog Xenopus. Model parameters define a two-dimensional CNS growth environment with three gradient cues and the specific responsiveness of the axons of each neuron type to these cues. The model is described by a nonlinear system of three difference equations; it includes a random variable, and takes specific neuron characteristics into account. Anatomical measurements are first used to position cell bodies in rows and define axon origins. Then a generalization procedure allows information on the axons of individual neurons from small anatomical datasets to be used to generate larger artificial datasets. To specify parameters in the axon growth model we use a stochastic optimization procedure, derive a cost function and find the optimal parameters for each type of neuron. Our biologically realistic model of axon growth starts from axon outgrowth from the cell body and generates multiple axons for each different neuron type with statistical properties matching those of real axons. We illustrate how the axon growth model works for neurons with axons which grow to the same and the opposite side of the CNS. We then show how, by adding a simple specification for dendrite morphology, our model "developmental approach" allows us to generate biologically-realistic connectomes.

  4. Activity of protease-activated receptors in primary cultured human myenteric neurons

    Directory of Open Access Journals (Sweden)

    Eva Maria Kugler

    2012-09-01

    Full Text Available Activity of the four known protease-activated receptors (PARs has been well studied in rodent enteric nervous system and results in animal models established an important role for neuronal PAR2. We recently demonstrated that, unlike in rodents, PAR1 is the dominant neuronal protease receptor in the human submucous plexus. With this study we investigated whether this also applies to the human myenteric plexus. We used voltage sensitive dye recordings to detect action potential discharge in primary cultures of human myenteric neurons in response to PAR activating peptides (AP. Application of the PAR1-AP (TFLLR or PAR4-AP (GYPGQV evoked spike discharge in 79% or 23% of myenteric neurons, respectively. The PAR1-AP response was mimicked by the endogenous PAR1 activator thrombin and blocked by the PAR1 antagonists SCH79797. Human myenteric neurons did not respond to PAR2-AP. This was not due to culture conditions because all three PAR-APs evoked action potentials in cultured guinea pig myenteric neurons. Consecutive application of PAR-APs revealed coexpression (relative to the population responding to PAR-APs of PAR1/PAR2 in 51%, PAR1/PAR4 in 43% and of PAR2/PAR4 in 29% of guinea pig myenteric neurons. Our study provided further evidence for the prominent role of neuronal PAR1 in the human enteric nervous system.

  5. Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Sampathkumar Rangasamy

    2016-09-01

    Full Text Available Rett syndrome (RTT is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene, encoding methyl-CpG-binding protein 2. We have created a mouse model (Mecp2 A140V “knock-in” mutant expressing the recurrent human MECP2 A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN cultures from mutant (Mecp2A140V/y and wild type (Mecp2+/y male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant  (maternal allele and a wild type Mecp2 gene linked to an eGFP transgene (paternal allele. In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1 treatment of neuronal cells from Mecp2 mutant mice rescued the soma size phenotype. We also found that Mecp2  mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i reduced neuronal size is an important in vitro cellular phenotype of Mecp2 mutation in mice, and ii MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput, in vitro assay to screen for compounds that rescue small neuronal phenotype (“phenotypic assay”.

  6. Context-aware modeling of neuronal morphologies

    Directory of Open Access Journals (Sweden)

    Benjamin eTorben-Nielsen

    2014-09-01

    Full Text Available Neuronal morphologies are pivotal for brain functioning: physical overlap between dendrites and axons constrain the circuit topology, and the precise shape and composition of dendrites determine the integration of inputs to produce an output signal. At the same time, morphologies are highly diverse and variant. The variance, presumably, originates from neurons developing in a densely packed brain substrate where they interact (e.g., repulsion or attraction with other actors in this substrate. However, when studying neurons their context is never part of the analysis and they are treated as if they existed in isolation.Here we argue that to fully understand neuronal morphology and its variance it is important to consider neurons in relation to each other and to other actors in the surrounding brain substrate, i.e., their context. We propose a context-aware computational framework, NeuroMaC, in which large numbers of neurons can be grown simultaneously according to growth rules expressed in terms of interactions between the developing neuron and the surrounding brain substrate.As a proof of principle, we demonstrate that by using NeuroMaC we can generate accurate virtual morphologies of distinct classes both in isolation and as part of neuronal forests. Accuracy is validated against population statistics of experimentally reconstructed morphologies. We show that context-aware generation of neurons can explain characteristics of variation. Indeed, plausible variation is an inherent property of the morphologies generated by context-aware rules. We speculate about the applicability of this framework to investigate morphologies and circuits, to classify healthy and pathological morphologies, and to generate large quantities of morphologies for large-scale modeling.

  7. Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors

    Directory of Open Access Journals (Sweden)

    Anne Teissier

    2015-12-01

    Full Text Available Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function.

  8. An introduction to modeling neuronal dynamics

    CERN Document Server

    Börgers, Christoph

    2017-01-01

    This book is intended as a text for a one-semester course on Mathematical and Computational Neuroscience for upper-level undergraduate and beginning graduate students of mathematics, the natural sciences, engineering, or computer science. An undergraduate introduction to differential equations is more than enough mathematical background. Only a slim, high school-level background in physics is assumed, and none in biology. Topics include models of individual nerve cells and their dynamics, models of networks of neurons coupled by synapses and gap junctions, origins and functions of population rhythms in neuronal networks, and models of synaptic plasticity. An extensive online collection of Matlab programs generating the figures accompanies the book. .

  9. DYNAMICS IN A CLASS OF NEURON MODELS

    Institute of Scientific and Technical Information of China (English)

    Wang Junping; Ruan Jiong

    2009-01-01

    In this paper, we investigate the dynamics in a class of discrete-time neuron mo-dels. The neuron model we discussed, defined by such periodic input-output mapping as a sinusoidal function, has a remarkably larger memory capacity than the conven-tional association system with the monotonous function. Our results show that the orbit of the model takes a conventional bifurcation route, from stable equilibrium, to periodicity, even to chaotic region. And the theoretical analysis is verified by numerical simulations.

  10. Characterization of the time course of changes of the evoked electrical activity in a model of a chemically-induced neuronal plasticity

    Directory of Open Access Journals (Sweden)

    Ruaro Maria

    2009-01-01

    Full Text Available Abstract Background Neuronal plasticity is initiated by transient elevations of neuronal networks activity leading to changes of synaptic properties and providing the basis for memory and learning 1. An increase of electrical activity can be caused by electrical stimulation 2 or by pharmacological manipulations: elevation of extracellular K+ 3, blockage of inhibitory pathways 4 or by an increase of second messengers intracellular concentrations 5. Neuronal plasticity is mediated by several biochemical pathways leading to the modulation of synaptic strength, density of ionic channels and morphological changes of neuronal arborisation 6. On a time scale of a few minutes, neuronal plasticity is mediated by local protein trafficking 7 while, in order to sustain modifications beyond 2–3 h, changes of gene expression are required 8. Findings In the present manuscript we analysed the time course of changes of the evoked electrical activity during neuronal plasticity and we correlated it with a transcriptional analysis of the underlying changes of gene expression. Our investigation shows that treatment for 30 min. with the GABAA receptor antagonist gabazine (GabT causes a potentiation of the evoked electrical activity occurring 2–4 hours after GabT and the concomitant up-regulation of 342 genes. Inhibition of the ERK1/2 pathway reduced but did not abolish the potentiation of the evoked response caused by GabT. In fact not all the genes analysed were blocked by ERK1/2 inhibitors. Conclusion These results are in agreement with the notion that neuronal plasticity is mediated by several distinct pathways working in unison.

  11. Avalanches in a stochastic model of spiking neurons.

    Directory of Open Access Journals (Sweden)

    Marc Benayoun

    Full Text Available Neuronal avalanches are a form of spontaneous activity widely observed in cortical slices and other types of nervous tissue, both in vivo and in vitro. They are characterized by irregular, isolated population bursts when many neurons fire together, where the number of spikes per burst obeys a power law distribution. We simulate, using the Gillespie algorithm, a model of neuronal avalanches based on stochastic single neurons. The network consists of excitatory and inhibitory neurons, first with all-to-all connectivity and later with random sparse connectivity. Analyzing our model using the system size expansion, we show that the model obeys the standard Wilson-Cowan equations for large network sizes ( neurons. When excitation and inhibition are closely balanced, networks of thousands of neurons exhibit irregular synchronous activity, including the characteristic power law distribution of avalanche size. We show that these avalanches are due to the balanced network having weakly stable functionally feedforward dynamics, which amplifies some small fluctuations into the large population bursts. Balanced networks are thought to underlie a variety of observed network behaviours and have useful computational properties, such as responding quickly to changes in input. Thus, the appearance of avalanches in such functionally feedforward networks indicates that avalanches may be a simple consequence of a widely present network structure, when neuron dynamics are noisy. An important implication is that a network need not be "critical" for the production of avalanches, so experimentally observed power laws in burst size may be a signature of noisy functionally feedforward structure rather than of, for example, self-organized criticality.

  12. Avalanches in a stochastic model of spiking neurons.

    Science.gov (United States)

    Benayoun, Marc; Cowan, Jack D; van Drongelen, Wim; Wallace, Edward

    2010-07-08

    Neuronal avalanches are a form of spontaneous activity widely observed in cortical slices and other types of nervous tissue, both in vivo and in vitro. They are characterized by irregular, isolated population bursts when many neurons fire together, where the number of spikes per burst obeys a power law distribution. We simulate, using the Gillespie algorithm, a model of neuronal avalanches based on stochastic single neurons. The network consists of excitatory and inhibitory neurons, first with all-to-all connectivity and later with random sparse connectivity. Analyzing our model using the system size expansion, we show that the model obeys the standard Wilson-Cowan equations for large network sizes ( neurons). When excitation and inhibition are closely balanced, networks of thousands of neurons exhibit irregular synchronous activity, including the characteristic power law distribution of avalanche size. We show that these avalanches are due to the balanced network having weakly stable functionally feedforward dynamics, which amplifies some small fluctuations into the large population bursts. Balanced networks are thought to underlie a variety of observed network behaviours and have useful computational properties, such as responding quickly to changes in input. Thus, the appearance of avalanches in such functionally feedforward networks indicates that avalanches may be a simple consequence of a widely present network structure, when neuron dynamics are noisy. An important implication is that a network need not be "critical" for the production of avalanches, so experimentally observed power laws in burst size may be a signature of noisy functionally feedforward structure rather than of, for example, self-organized criticality.

  13. Computational modeling of memory allocation in neuronal and dendritic populations

    Directory of Open Access Journals (Sweden)

    George I Kastellakis

    2014-03-01

    Full Text Available Recent studies using molecular and cellular approaches have established that memory is supported by distributed and sparse populations of neurons. The allocation of neurons and synapses to store a long term memory engram is not random, but depends on properties such as neuronal excitability and CREB activation. The consolidation of synaptic plasticity, which is believed to serve long-term memory storage, is dependent on protein availability, and shaped by the mechanism of synaptic tagging and capture. In addition, dendritic protein synthesis allows for compartmentalized plasticity and synapse clustering. The implications of the rules governing long-term memory allocation in neurons and their dendrites are not yet known. To this aim, we present a model that incorporates multiple plasticity-related mechanisms which are known to be active during memory allocation and consolidation. Using this model, we show that memory allocation in neurons and their dendrites is affected by dendritic protein synthesis, and that the late-LTP associativity mechanisms allow related memories to be stored in overlapping populations of neurons.

  14. Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote PKCδ-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model.

    Science.gov (United States)

    Saminathan, Hariharan; Asaithambi, Arunkumar; Anantharam, Vellareddy; Kanthasamy, Anumantha G; Kanthasamy, Arthi

    2011-10-01

    Oxidative stress and apoptosis are two key pathophysiological mechanisms underlying dopaminergic degeneration in Parkinson's disease (PD). Recently, we identified that proteolytic activation of protein kinase C-delta (PKCδ), a member of the novel PKC family, contributes to oxidative stress-induced dopaminergic degeneration and that phosphorylation of tyrosine residue 311 (tyr311) on PKCδ is a key event preceding the PKCδ proteolytic activation during oxidative damage. Herein, we report that a non-receptor tyrosine kinase Fyn is significantly expressed in a dopaminergic neuronal N27 cell model. Exposure of N27 cells to the dopaminergic toxicant dieldrin (60 μM) rapidly activated Fyn kinase, PKCδ-tyr311 phosphorylation and proteolytic cleavage. Fyn kinase activation precedes the caspase-3-mediated proteolytic activation of PKCδ. Pre-treatment with p60-tyrosine-specific kinase inhibitor (TSKI) almost completely attenuated dieldrin-induced phosphorylation of PKCδ-tyr311 and its proteolytic activation. Additionally, TSKI almost completely blocked dieldrin-induced apoptotic cell death. To further confirm Fyn's role in the pro-apoptotic function of PKCδ, we adopted the RNAi approach. siRNA-mediated knockdown of Fyn kinase also effectively attenuated dieldrin-induced phosphorylation of PKCδ-tyr311, caspase-3-mediated PKCδ proteolytic cleavage, and DNA fragmentation, suggesting that Fyn kinase regulates the pro-apoptotic function of PKCδ. Collectively, these results demonstrate for the first time that Fyn kinase is a pro-apoptotic kinase that regulates upstream signaling of the PKCδ-mediated apoptotic cell death pathway in neurotoxicity models of pesticide exposure. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Hybrid Markov-mass action law model for cell activation by rare binding events: Application to calcium induced vesicular release at neuronal synapses

    Science.gov (United States)

    Guerrier, Claire; Holcman, David

    2016-10-01

    Binding of molecules, ions or proteins to small target sites is a generic step of cell activation. This process relies on rare stochastic events where a particle located in a large bulk has to find small and often hidden targets. We present here a hybrid discrete-continuum model that takes into account a stochastic regime governed by rare events and a continuous regime in the bulk. The rare discrete binding events are modeled by a Markov chain for the encounter of small targets by few Brownian particles, for which the arrival time is Poissonian. The large ensemble of particles is described by mass action laws. We use this novel model to predict the time distribution of vesicular release at neuronal synapses. Vesicular release is triggered by the binding of few calcium ions that can originate either from the synaptic bulk or from the entry through calcium channels. We report here that the distribution of release time is bimodal although it is triggered by a single fast action potential. While the first peak follows a stimulation, the second corresponds to the random arrival over much longer time of ions located in the synaptic terminal to small binding vesicular targets. To conclude, the present multiscale stochastic modeling approach allows studying cellular events based on integrating discrete molecular events over several time scales.

  16. Leaders of neuronal cultures in a quorum percolation model

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Eckmann

    2010-09-01

    Full Text Available We present a theoretical framework using quorum-percolation for describing the initiation of activity in a neural culture. The cultures are modeled as random graphs, whose nodes are neurons with $kin$ inputs and $kout$ outputs, and whose input degrees $kin=k$ obey given distribution functions $p_k$. We examine the firing activity of the population of neurons according to their input degree ($k$ classes and calculate for each class its firing probability $Phi_k(t$ as a function of $t$. The probability of a node to fire is found to be determined by its in-degree $k$, and the first-to-fire neurons are those that have a high $k$. A small minority of high-$k$ classes may be called ``Leaders,'' as they form an inter-connected subnetwork that consistently fires much before the rest of the culture. Once initiated, the activity spreads from the Leaders to the less connected majority of the culture. We then use the distribution of in-degree of the Leaders to study the growth rate of the number of neurons active in a burst, which was experimentally measured to be initially exponential. We find that this kind of growth rate is best described by a population that has an in-degree distribution that is a Gaussian centered around $k=75$ with width $sigma=31$ for the majority of the neurons, but also has a power law tail with exponent $-2$ for ten percent of the population. Neurons in the tail may have as many as $k=4,700$ inputs. We explore and discuss the correspondence between the degree distribution and a dynamic neuronal threshold, showing that from the functional point of view, structure and elementary dynamics are interchangeable. We discuss possible geometric origins of this distribution, and comment on the importance of size, or of having a large number of neurons, in the culture.

  17. Human temporal cortical single neuron activity during working memory maintenance.

    Science.gov (United States)

    Zamora, Leona; Corina, David; Ojemann, George

    2016-06-01

    The Working Memory model of human memory, first introduced by Baddeley and Hitch (1974), has been one of the most influential psychological constructs in cognitive psychology and human neuroscience. However the neuronal correlates of core components of this model have yet to be fully elucidated. Here we present data from two studies where human temporal cortical single neuron activity was recorded during tasks differentially affecting the maintenance component of verbal working memory. In Study One we vary the presence or absence of distracting items for the entire period of memory storage. In Study Two we vary the duration of storage so that distractors filled all, or only one-third of the time the memory was stored. Extracellular single neuron recordings were obtained from 36 subjects undergoing awake temporal lobe resections for epilepsy, 25 in Study one, 11 in Study two. Recordings were obtained from a total of 166 lateral temporal cortex neurons during performance of one of these two tasks, 86 study one, 80 study two. Significant changes in activity with distractor manipulation were present in 74 of these neurons (45%), 38 Study one, 36 Study two. In 48 (65%) of those there was increased activity during the period when distracting items were absent, 26 Study One, 22 Study Two. The magnitude of this increase was greater for Study One, 47.6%, than Study Two, 8.1%, paralleling the reduction in memory errors in the absence of distracters, for Study One of 70.3%, Study Two 26.3% These findings establish that human lateral temporal cortex is part of the neural system for working memory, with activity during maintenance of that memory that parallels performance, suggesting it represents active rehearsal. In 31 of these neurons (65%) this activity was an extension of that during working memory encoding that differed significantly from the neural processes recorded during overt and silent language tasks without a recent memory component, 17 Study one, 14 Study two

  18. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation.

    Science.gov (United States)

    Soares-Cunha, Carina; Coimbra, Barbara; David-Pereira, Ana; Borges, Sonia; Pinto, Luisa; Costa, Patricio; Sousa, Nuno; Rodrigues, Ana J

    2016-06-23

    Striatal dopamine receptor D1-expressing neurons have been classically associated with positive reinforcement and reward, whereas D2 neurons are associated with negative reinforcement and aversion. Here we demonstrate that the pattern of activation of D1 and D2 neurons in the nucleus accumbens (NAc) predicts motivational drive, and that optogenetic activation of either neuronal population enhances motivation in mice. Using a different approach in rats, we further show that activating NAc D2 neurons increases cue-induced motivational drive in control animals and in a model that presents anhedonia and motivational deficits; conversely, optogenetic inhibition of D2 neurons decreases motivation. Our results suggest that the classic view of D1-D2 functional antagonism does not hold true for all dimensions of reward-related behaviours, and that D2 neurons may play a more prominent pro-motivation role than originally anticipated.

  19. Communities in Neuronal Complex Networks Revealed by Activation Patterns

    CERN Document Server

    Costa, Luciano da Fontoura

    2008-01-01

    Recently, it has been shown that the communities in neuronal networks of the integrate-and-fire type can be identified by considering patterns containing the beginning times for each cell to receive the first non-zero activation. The received activity was integrated in order to facilitate the spiking of each neuron and to constrain the activation inside the communities, but no time decay of such activation was considered. The present article shows that, by taking into account exponential decays of the stored activation, it is possible to identify the communities also in terms of the patterns of activation along the initial steps of the transient dynamics. The potential of this method is illustrated with respect to complex neuronal networks involving four communities, each of a different type (Erd\\H{o}s-R\\'eny, Barab\\'asi-Albert, Watts-Strogatz as well as a simple geographical model). Though the consideration of activation decay has been found to enhance the communities separation, too intense decays tend to y...

  20. Neurochemistry of neurons in the ventrolateral medulla activated by hypotension: Are the same neurons activated by glucoprivation?

    Science.gov (United States)

    Parker, Lindsay M; Le, Sheng; Wearne, Travis A; Hardwick, Kate; Kumar, Natasha N; Robinson, Katherine J; McMullan, Simon; Goodchild, Ann K

    2017-06-15

    Previous studies have demonstrated that a range of stimuli activate neurons, including catecholaminergic neurons, in the ventrolateral medulla. Not all catecholaminergic neurons are activated and other neurochemical content is largely unknown hence whether stimulus specific populations exist is unclear. Here we determine the neurochemistry (using in situ hybridization) of catecholaminergic and noncatecholaminergic neurons which express c-Fos immunoreactivity throughout the rostrocaudal extent of the ventrolateral medulla, in Sprague Dawley rats treated with hydralazine or saline. Distinct neuronal populations containing PPCART, PPPACAP, and PPNPY mRNAs, which were largely catecholaminergic, were activated by hydralazine but not saline. Both catecholaminergic and noncatecholaminergic neurons containing preprotachykinin and prepro-enkephalin (PPE) mRNAs were also activated, with the noncatecholaminergic population located in the rostral C1 region. Few GlyT2 neurons were activated. A subset of these data was then used to compare the neuronal populations activated by 2-deoxyglucose evoked glucoprivation (Brain Structure and Function (2015) 220:117). Hydralazine activated more neurons than 2-deoxyglucose but similar numbers of catecholaminergic neurons. Commonly activated populations expressing PPNPY and PPE mRNAs were defined. These likely include PPNPY expressing catecholaminergic neurons projecting to vasopressinergic and corticotrophin releasing factor neurons in the paraventricular nucleus, which when activated result in elevated plasma vasopressin and corticosterone. Stimulus specific neurons included noncatecholaminergic neurons and a few PPE positive catecholaminergic neuron but neurochemical codes were largely unidentified. Reasons for the lack of identification of stimulus specific neurons, readily detectable using electrophysiology in anaesthetized preparations and for which neural circuits can be defined, are discussed. © 2017 Wiley Periodicals, Inc.

  1. Human embryonic stem cell-derived neuronal cells form spontaneously active neuronal networks in vitro.

    Science.gov (United States)

    Heikkilä, Teemu J; Ylä-Outinen, Laura; Tanskanen, Jarno M A; Lappalainen, Riikka S; Skottman, Heli; Suuronen, Riitta; Mikkonen, Jarno E; Hyttinen, Jari A K; Narkilahti, Susanna

    2009-07-01

    The production of functional human embryonic stem cell (hESC)-derived neuronal cells is critical for the application of hESCs in treating neurodegenerative disorders. To study the potential functionality of hESC-derived neurons, we cultured and monitored the development of hESC-derived neuronal networks on microelectrode arrays. Immunocytochemical studies revealed that these networks were positive for the neuronal marker proteins beta-tubulin(III) and microtubule-associated protein 2 (MAP-2). The hESC-derived neuronal networks were spontaneously active and exhibited a multitude of electrical impulse firing patterns. Synchronous bursts of electrical activity similar to those reported for hippocampal neurons and rodent embryonic stem cell-derived neuronal networks were recorded from the differentiated cultures until up to 4 months. The dependence of the observed neuronal network activity on sodium ion channels was examined using tetrodotoxin (TTX). Antagonists for the glutamate receptors NMDA [D(-)-2-amino-5-phosphonopentanoic acid] and AMPA/kainate [6-cyano-7-nitroquinoxaline-2,3-dione], and for GABAA receptors [(-)-bicuculline methiodide] modulated the spontaneous electrical activity, indicating that pharmacologically susceptible neuronal networks with functional synapses had been generated. The findings indicate that hESC-derived neuronal cells can generate spontaneously active networks with synchronous communication in vitro, and are therefore suitable for use in developmental and drug screening studies, as well as for regenerative medicine.

  2. Towards reproducible descriptions of neuronal network models.

    Directory of Open Access Journals (Sweden)

    Eilen Nordlie

    2009-08-01

    Full Text Available Progress in science depends on the effective exchange of ideas among scientists. New ideas can be assessed and criticized in a meaningful manner only if they are formulated precisely. This applies to simulation studies as well as to experiments and theories. But after more than 50 years of neuronal network simulations, we still lack a clear and common understanding of the role of computational models in neuroscience as well as established practices for describing network models in publications. This hinders the critical evaluation of network models as well as their re-use. We analyze here 14 research papers proposing neuronal network models of different complexity and find widely varying approaches to model descriptions, with regard to both the means of description and the ordering and placement of material. We further observe great variation in the graphical representation of networks and the notation used in equations. Based on our observations, we propose a good model description practice, composed of guidelines for the organization of publications, a checklist for model descriptions, templates for tables presenting model structure, and guidelines for diagrams of networks. The main purpose of this good practice is to trigger a debate about the communication of neuronal network models in a manner comprehensible to humans, as opposed to machine-readable model description languages. We believe that the good model description practice proposed here, together with a number of other recent initiatives on data-, model-, and software-sharing, may lead to a deeper and more fruitful exchange of ideas among computational neuroscientists in years to come. We further hope that work on standardized ways of describing--and thinking about--complex neuronal networks will lead the scientific community to a clearer understanding of high-level concepts in network dynamics, and will thus lead to deeper insights into the function of the brain.

  3. Mathematical Modeling of Subthreshold Resonant Properties in Pyloric Dilator Neurons

    Directory of Open Access Journals (Sweden)

    Babak Vazifehkhah Ghaffari

    2015-01-01

    Full Text Available Various types of neurons exhibit subthreshold resonance oscillation (preferred frequency response to fluctuating sinusoidal input currents. This phenomenon is well known to influence the synaptic plasticity and frequency of neural network oscillation. This study evaluates the resonant properties of pacemaker pyloric dilator (PD neurons in the central pattern generator network through mathematical modeling. From the pharmacological point of view, calcium currents cannot be blocked in PD neurons without removing the calcium-dependent potassium current. Thus, the effects of calcium ICa and calcium-dependent potassium IKCa currents on resonant properties remain unclear. By taking advantage of Hodgkin-Huxley-type model of neuron and its equivalent RLC circuit, we examine the effects of changing resting membrane potential and those ionic currents on the resonance. Results show that changing the resting membrane potential influences the amplitude and frequency of resonance so that the strength of resonance (Q-value increases by both depolarization and hyperpolarization of the resting membrane potential. Moreover, hyperpolarization-activated inward current Ih and ICa (in association with IKCa are dominant factors on resonant properties at hyperpolarized and depolarized potentials, respectively. Through mathematical analysis, results indicate that Ih and IKCa affect the resonant properties of PD neurons. However, ICa only has an amplifying effect on the resonance amplitude of these neurons.

  4. Mathematical modeling of subthreshold resonant properties in pyloric dilator neurons.

    Science.gov (United States)

    Vazifehkhah Ghaffari, Babak; Kouhnavard, Mojgan; Aihara, Takeshi; Kitajima, Tatsuo

    2015-01-01

    Various types of neurons exhibit subthreshold resonance oscillation (preferred frequency response) to fluctuating sinusoidal input currents. This phenomenon is well known to influence the synaptic plasticity and frequency of neural network oscillation. This study evaluates the resonant properties of pacemaker pyloric dilator (PD) neurons in the central pattern generator network through mathematical modeling. From the pharmacological point of view, calcium currents cannot be blocked in PD neurons without removing the calcium-dependent potassium current. Thus, the effects of calcium (I(Ca)) and calcium-dependent potassium (I(KCa)) currents on resonant properties remain unclear. By taking advantage of Hodgkin-Huxley-type model of neuron and its equivalent RLC circuit, we examine the effects of changing resting membrane potential and those ionic currents on the resonance. Results show that changing the resting membrane potential influences the amplitude and frequency of resonance so that the strength of resonance (Q-value) increases by both depolarization and hyperpolarization of the resting membrane potential. Moreover, hyperpolarization-activated inward current (I(h)) and I(Ca) (in association with I(KCa)) are dominant factors on resonant properties at hyperpolarized and depolarized potentials, respectively. Through mathematical analysis, results indicate that I h and I(KCa) affect the resonant properties of PD neurons. However, I(Ca) only has an amplifying effect on the resonance amplitude of these neurons.

  5. ELF-magnetic field induced effects on the bioelectric activity of single neurone cells

    Science.gov (United States)

    Azanza, Maria J.; del Moral, A.

    1998-01-01

    The membrane bioelectric activity recorded from single neurones is dramatically modified under applied extremely low frequency magnetic fields (ELF-MF) of 50 Hz and 1-15 mT peak intensity. In ≌27% of the neurones studied a firing rhythm is generated for ≌7 mT, which resembles synchronous oscillations activity. The possibility that ELF-MF could generate neuronal networks synchrony firing does exist as an explanatory physical model shows.

  6. Nonsmooth dynamics in spiking neuron models

    Science.gov (United States)

    Coombes, S.; Thul, R.; Wedgwood, K. C. A.

    2012-11-01

    Large scale studies of spiking neural networks are a key part of modern approaches to understanding the dynamics of biological neural tissue. One approach in computational neuroscience has been to consider the detailed electrophysiological properties of neurons and build vast computational compartmental models. An alternative has been to develop minimal models of spiking neurons with a reduction in the dimensionality of both parameter and variable space that facilitates more effective simulation studies. In this latter case the single neuron model of choice is often a variant of the classic integrate-and-fire model, which is described by a nonsmooth dynamical system. In this paper we review some of the more popular spiking models of this class and describe the types of spiking pattern that they can generate (ranging from tonic to burst firing). We show that a number of techniques originally developed for the study of impact oscillators are directly relevant to their analysis, particularly those for treating grazing bifurcations. Importantly we highlight one particular single neuron model, capable of generating realistic spike trains, that is both computationally cheap and analytically tractable. This is a planar nonlinear integrate-and-fire model with a piecewise linear vector field and a state dependent reset upon spiking. We call this the PWL-IF model and analyse it at both the single neuron and network level. The techniques and terminology of nonsmooth dynamical systems are used to flesh out the bifurcation structure of the single neuron model, as well as to develop the notion of Lyapunov exponents. We also show how to construct the phase response curve for this system, emphasising that techniques in mathematical neuroscience may also translate back to the field of nonsmooth dynamical systems. The stability of periodic spiking orbits is assessed using a linear stability analysis of spiking times. At the network level we consider linear coupling between voltage

  7. Neuronal integrative analysis of the "Dumbbell" model for passive neurons.

    Science.gov (United States)

    Krzyzanski, Wojciech; Bell, Jonathan; Poznanski, Roman R

    2002-12-01

    We analyze the so called "Dumbbell" model of Jackson (J. Neurophysiol. 69 (1993) pp. 464) for a single neuron consisting of a patch-clamped cell body attached to dendritic cable of finite length terminating in an oblique derivative ("natural termination") boundary condition representing a dendritic swelling or a natural ending sealed by a continuous surface of the cell membrane. The model is solved analytically via the Green's function method. Large and small time asymptotic behavior of the membrane potential is developed when there is a somatic voltage-clamp imposed. We discuss the difference in the voltage distribution if a sealed-end (Neumann) termination is used instead of the natural termination boundary condition. If the access resistance is large the differences between the potentials corresponding to the two boundary conditions are small at the soma, but can vary significantly near the dendritic termination. This discrepancy is amplified at the soma if there is a synaptic stimulus introduced between the soma and dendritic tip.

  8. Invisible Brain: Knowledge in Research Works and Neuron Activity

    OpenAIRE

    Aviv Segev; Dorothy Curtis; Sukhwan Jung; Suhyun Chae

    2016-01-01

    If the market has an invisible hand, does knowledge creation and representation have an “invisible brain”? While knowledge is viewed as a product of neuron activity in the brain, can we identify knowledge that is outside the brain but reflects the activity of neurons in the brain? This work suggests that the patterns of neuron activity in the brain can be seen in the representation of knowledge-related activity. Here we show that the neuron activity mechanism seems to represent much of the kn...

  9. Model reduction of strong-weak neurons

    OpenAIRE

    Steven James Cox; Bosen eDu; Danny eSorensen

    2014-01-01

    We consider neurons with large dendritic trees that are weakly excitable in the sense that back propagating action potentials are severly attenuated as they travel from the small, strongly excitable, spike initiation zone. In previous work we have shown that the computational size of weakly excitable cell models may be reduced by two or more orders of magnitude, and that the size of strongly excitable models may be reduced by at least one order of magnitude, without sacrificing the spatio–tem...

  10. Selective regulation of current densities underlies spontaneous changes in the activity of cultured neurons.

    Science.gov (United States)

    Turrigiano, G; LeMasson, G; Marder, E

    1995-05-01

    We study the electrical activity patterns and the expression of conductances in adult stomatogastric ganglion (STG) neurons as a function of time in primary cell culture. When first plated in culture, these neurons had few active properties. After 1 d in culture they produced small action potentials that rapidly inactivated during maintained depolarization. After 2 d in culture they fired large action potentials tonically when depolarized, and their properties resembled very closely the properties of STG neurons pharmacologically isolated in the ganglion. After 3-4 d in culture, however, their electrical properties changed and they fired in bursts when depolarized. We characterized the currents expressed by these neurons in culture. They included two TTX-sensitive sodium currents, a calcium current, a delayed-rectifier-like current, a calcium-dependent potassium current, and two A-type currents. The changes in firing properties with time in culture were accompanied by an increase in inward and decrease in outward current densities. A single-compartment conductance-based model of an STG neuron was constructed by fitting the currents measured in the biological neurons. When the current densities in the model neuron were matched to those measured for the biological neurons in each activity state, the model neuron closely reproduced each state, indicating that the changes in current densities are sufficient to account for the changes in intrinsic properties. These data indicate that STG neurons isolated in culture change their intrinsic electrical properties by selectively adjusting the magnitudes of their ionic conductances.

  11. Activation of c-Jun N-terminal kinase 1/2 regulated by nitric oxide is associated with neuronal survival in hippocampal neurons in a rat model of ischemia

    Institute of Scientific and Technical Information of China (English)

    ZENG Xian-wei; LI Ming-wei; PAN Jing; JI Tai-ling; YANG Bin; ZHANG Bo; WANG Xiao-qiang

    2011-01-01

    Background C-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in cerebral ischemia.Although the mechanistic basis for this activation of JNK1/2 is uncertain,oxidative stress may play a role.The purpose of this study was to investigate whether the activation of JNK1/2 is associated with the production of endogenous nitric oxide (NO).Methods Ischemia and reperfusion (I/R) was induced by cerebral four-vessel occlusion.Sprague-Dawley (SD) rats were divided into 6 groups:sham group,I/R group,neuronal nitric oxide synthase (nNOS) inhibitor (7-nitroindazole,7-NI)given group,inducible nitric oxide synthase (iNOS) inhibitor (2-amino-5,6-dihydro-methylthiazine,AMT) given group,sodium chloride control group,and 1% dimethyl sulfoxide (DMSO) control group.The levels of protein expression and phospho-JNK1/2 were detected by Western blotting and the survival hippocampus neurons in CA1 zone were observed by cresyl violet staining.Results The study illustrated two peaks of JNK1/2 activation occurred at 30 minutes and 3 days during reperfusion.7-NI inhibited JNK1/2 activation during the early reperfusion,whereas AMT preferably attenuated JNK1/2 activation during the later reperfusion.Administration of 7-NI and AMT can decrease I/R-induced neuronal loss in hippocampal CA1 region.Conclusion JNK1/2 activation is associated with endogenous NO in response to ischemic insult.

  12. Model reduction of strong-weak neurons.

    Science.gov (United States)

    Du, Bosen; Sorensen, Danny; Cox, Steven J

    2014-01-01

    We consider neurons with large dendritic trees that are weakly excitable in the sense that back propagating action potentials are severly attenuated as they travel from the small, strongly excitable, spike initiation zone. In previous work we have shown that the computational size of weakly excitable cell models may be reduced by two or more orders of magnitude, and that the size of strongly excitable models may be reduced by at least one order of magnitude, without sacrificing the spatio-temporal nature of its inputs (in the sense we reproduce the cell's precise mapping of inputs to outputs). We combine the best of these two strategies via a predictor-corrector decomposition scheme and achieve a drastically reduced highly accurate model of a caricature of the neuron responsible for collision detection in the locust.

  13. Persistently active, pacemaker-like neurons in neocortex

    Directory of Open Access Journals (Sweden)

    Morgane Le Bon-Jego

    2007-10-01

    Full Text Available The neocortex is spontaneously active, however, the origin of this self-generated, patterned activity remains unknown. To detect potential pacemaker cells, we use calcium imaging to directly identify neurons that discharge action potentials in the absence of synaptic transmissionin slices from juvenile mouse visual cortex. We characterize 60 of these neurons electrophysiologically and morphologically, finding that they belong to two classes of cells: one class composed of pyramidal neurons with a thin apical dendritic tree and a second class composed of ascending axon interneurons (Martinotti cells located in layer 5. In both types of neurons, persistent sodium currents are necessary for the generation of the spontaneous activity. Our data demonstrate that subtypes of neocortical neurons have intrinsic mechanisms to generate persistent activity. Like in central pattern generators (CPGs, these neurons may act as pacemakers to initiate or pattern spontaneous activity in the neocortex.

  14. 50 Hz-Sinusoidal magnetic field induced effects on the bioelectric activity of single unit neurone cells

    Science.gov (United States)

    Azanza, María. J.; Calvo, Ana C.; del Moral, A.

    2001-05-01

    Neurones recruiting and synchronized bioelectric activity recorded from Helix aspersa brain ganglia, under exposure to 50 Hz sinusoidal magnetic fields of 1-15 mT intensity, is reported. We show recruiting responses from single neurones and the synchronization of pairs of neurones activity. Experimental evidence and model theoretical explanation for the spreading of synchronization are presented.

  15. Nicotinic activation of laterodorsal tegmental neurons

    DEFF Research Database (Denmark)

    Ishibashi, Masaru; Leonard, Christopher S; Kohlmeier, Kristi A

    2009-01-01

    are unknown. We addressed this issue by examining the effects of nicotine on identified cholinergic and non-cholinergic LDT neurons using whole-cell patch clamp and Ca(2+)-imaging methods in brain slices from mice (P12-P45). Nicotine applied by puffer pipette or bath superfusion elicited membrane...... depolarization that often induced firing and TTX-resistant inward currents. Nicotine also enhanced sensitivity to injected current; and, baseline changes in intracellular calcium were elicited in the dendrites of some cholinergic LDT cells. In addition, activity-dependent calcium transients were increased......, suggesting that nicotine exposure sufficient to induce firing may lead to enhancement of levels of intracellular calcium. Nicotine also had strong actions on glutamate and GABA-releasing presynaptic terminals, as it greatly increased the frequency of miniature EPSCs and IPSCs to both cholinergic and non...

  16. Role of electrical activity of neurons for neuroprotection.

    Science.gov (United States)

    Morimoto, Takeshi

    2012-01-01

    Neurons of the central nervous system (CNS) of adult mammals can be damaged in a variety of ways. Most neurons rapidly die after injury. Even if the injured CNS neurons do not die in a short time, the neurons eventually die because they are not able to regenerate their axons to reconnect with their normal targets. In addition, neurons are normally not replaced. Therefore, much work has been directed toward understanding of the molecular regulation of the CNS degeneration following injury, and different experimental strategies are being used to try to protect the damaged neurons. Following axonal lesion, the neurons not only need to survive but also to reconnect to be functionally relevant, and efforts are directed toward not only survival but also axonal regeneration and proper rewiring of injured neurons. Recent experimental data suggest that electrical activity, endogenous or exogenous, can enhance neuronal survival and regeneration in vitro and in vivo. This chapter reviews the evidence that have been obtained on the role of neuronal electrical activity on neuroprotection. We will develop perspectives toward neuroprotection and regeneration of adult lesioned CNS neurons based on electrical activity-dependent cell survival that may be applicable to various diseases of the CNS. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Memory recall and modifications by activating neurons with elevated CREB.

    Science.gov (United States)

    Kim, Jieun; Kwon, Jeong-Tae; Kim, Hyung-Su; Josselyn, Sheena A; Han, Jin-Hee

    2014-01-01

    Memory is supported by a specific ensemble of neurons distributed in the brain that form a unique memory trace. We previously showed that neurons in the lateral amygdala expressing elevated levels of cAMP response-element binding protein are preferentially recruited into fear memory traces and are necessary for the expression of those memories. However, it is unknown whether artificially activating just these selected neurons in the absence of behavioral cues is sufficient to recall that fear memory. Using an ectopic rat vanilloid receptor TRPV1 and capsaicin system, we found that activating this specific ensemble of neurons was sufficient to recall established fear memory. Furthermore, this neuronal activation induced a reconsolidation-like reorganization process, or strengthening of the fear memory. Thus, our findings establish a direct link between the activation of specific ensemble of neurons in the lateral amygdala and the recall of fear memory and its subsequent modifications.

  18. Model Reduction of Strong-Weak Neurons

    Directory of Open Access Journals (Sweden)

    Steven James Cox

    2014-12-01

    Full Text Available We consider neurons with large dendritic trees that are weakly excitable in the sense that back propagating action potentials are severly attenuated as they travelfrom the small, strongly excitable, spike initiation zone. In previous workwe have shown that the computational size of weakly excitable cell modelsmay be reduced by two or more orders of magnitude, and that the size of stronglyexcitable models may be reduced by at least one order of magnitude,without sacrificing thespatio-temporal nature of its inputs (in the sense we reproduce the cell's precise mapping of inputs to outputs. We combine the best of these twostrategies via a predictor--corrector decomposition scheme andachieve a drastically reduced highly accurate model of a caricature of the neuron responsible for collision detection in the locust.

  19. Firing behavior and network activity of single neurons in human epileptic hypothalamic hamartoma

    Directory of Open Access Journals (Sweden)

    Peter N. Steinmetz

    2013-12-01

    Full Text Available Objective: Human hypothalamic hamartomas (HH are intrinsically epileptogenic and are associated with treatment-resistant gelastic seizures. The basic cellular mechanisms responsible for seizure onset within HH are unknown. We used intra-operative microwire recordings of single neuron activity to measure the spontaneous firing rate of neurons and the degree of functional connection between neurons within the tumor.Technique: Fourteen patients underwent transventricular endoscopic resection of HH for treatment-resistant epilepsy. Prior to surgical resection, single neuron recordings from bundled microwires (total of 9 contacts were obtained from HH tissue. Spontaneous activity was recorded for two or three 5-minute epochs under steady-state general anesthesia. Off-line analysis included cluster analysis of single unit activity and probability analysis of firing relationships between pairs of neurons.Results: Altogether, 222 neurons were identified (mean 6 neurons per recording epoch. Cluster analysis of single neuron firing utilizing a mixture of Gaussians model identified two distinct populations on the basis of firing rate (median firing frequency 0.6 versus 15.0 spikes per second; p<10-5. Cluster analysis identified three populations determined by levels of burst-firing (median burst indices of 0.015, 0.18, and 0.39; p<10-15. Unbiased analysis of spontaneous single unit behavior showed that 51% of all possible neuron pairs within each recording epoch had a significant level of firing synchrony (p<10-15. The subgroup of neurons with higher median firing frequencies was more likely to demonstrate synchronous firing (p<10-7. Conclusions: HH tissue in-vivo contains neurons which fire spontaneously. The activity of single neurons is diverse but distributes into at least two electrophysiological phenoytpes. Functional linkage between single neurons suggests that HH neurons exist within local networks that may contribute to ictogenesis.

  20. Computational modeling of optogenetic neuronal excitation under complex illumination conditions using a Matlab-Neuron interface (Conference Presentation)

    Science.gov (United States)

    Yona, Guy; Weissler, Yonatan; Meitav, Nizan; Guzi, Eliran; Rifold, Dafna D.; Kahn, Itamar; Shoham, Shy

    2016-03-01

    Optogenetics has in recent years become a central tool in neuroscience research. Creating a realistic model of optogenetic neuronal excitation is of crucial importance for controlling the activation levels of various neuronal populations in different depths, predicting experimental results and designing the optical systems. However, current approaches to modeling light propagation through rodents' brain tissue suffer from major shortcomings and comprehensive modeling of local illumination levels together with other important factors governing excitation (i.e., cellular morphology, channel dynamics and expression), are still lacking. To address this challenge we introduce a new simulation tool for optogenetic neuronal excitation under complex and realistic illumination conditions that implements a detailed physical model for light scattering (in MATLAB) together with neuron morphology and channelrhodopsin-2 model (in NEURON). These two disparate simulation environments were interconnected using a newly developed generic interface termed 'NeuroLab'. Applying this method, we show that in a layer-V cortical neuron, the relative contribution of the apical dendrites to neuronal excitation is considerably greater than that of the soma or basal dendrites, when illuminated from the surface.

  1. Progressive retinal degeneration and glial activation in the CLN6 (nclf mouse model of neuronal ceroid lipofuscinosis: a beneficial effect of DHA and curcumin supplementation.

    Directory of Open Access Journals (Sweden)

    Myriam Mirza

    Full Text Available Neuronal ceroid lipofuscinosis (NCL is a group of neurodegenerative lysosomal storage disorders characterized by vision loss, mental and motor deficits, and spontaneous seizures. Neuropathological analyses of autopsy material from NCL patients and animal models revealed brain atrophy closely associated with glial activity. Earlier reports also noticed loss of retinal cells and reactive gliosis in some forms of NCL. To study this phenomenon in detail, we analyzed the ocular phenotype of CLN6 (nclf mice, an established mouse model for variant-late infantile NCL. Retinal morphometry, immunohistochemistry, optokinetic tracking, electroretinography, and mRNA expression were used to characterize retinal morphology and function as well as the responses of Müller cells and microglia. Our histological data showed a severe and progressive degeneration in the CLN6 (nclf retina co-inciding with reactive Müller glia. Furthermore, a prominent phenotypic transformation of ramified microglia to phagocytic, bloated, and mislocalized microglial cells was identified in CLN6 (nclf retinas. These events overlapped with a rapid loss of visual perception and retinal function. Based on the strong microglia reactivity we hypothesized that dietary supplementation with immuno-regulatory compounds, curcumin and docosahexaenoic acid (DHA, could ameliorate microgliosis and reduce retinal degeneration. Our analyses showed that treatment of three-week-old CLN6 (nclf mice with either 5% DHA or 0.6% curcumin for 30 weeks resulted in a reduced number of amoeboid reactive microglia and partially improved retinal function. DHA-treatment also improved the morphology of CLN6 (nclf retinas with a preserved thickness of the photoreceptor layer in most regions of the retina. Our results suggest that microglial reactivity closely accompanies disease progression in the CLN6 (nclf retina and both processes can be attenuated with dietary supplemented immuno-modulating compounds.

  2. Dynamical responses in a new neuron model subjected to electromagnetic induction and phase noise

    Science.gov (United States)

    Wu, Fuqiang; Wang, Chunni; Jin, Wuyin; Ma, Jun

    2017-03-01

    Complex electrical activities in neuron can induce time-varying electromagnetic field and the effect of various electromagnetic inductions should be considered in dealing with electrical activities of neuron. Based on an improved neuron model, the effect of electromagnetic induction is described by using magnetic flux, and the modulation of magnetic flux on membrane potential is realized by using memristor coupling. Furthermore, additive phase noise is imposed on the neuron to detect the dynamical response of neuron and phase transition in modes. The dynamical properties of electrical activities are detected and discussed, and double coherence resonance behavior is observed, respectively. Furthermore, multiple modes of electrical activities can be observed in the sampled time series for membrane potential of the neuron model.

  3. Spiking neuron model for temporal sequence recognition.

    Science.gov (United States)

    Byrnes, Sean; Burkitt, Anthony N; Grayden, David B; Meffin, Hamish

    2010-01-01

    A biologically inspired neuronal network that stores and recognizes temporal sequences of symbols is described. Each symbol is represented by excitatory input to distinct groups of neurons (symbol pools). Unambiguous storage of multiple sequences with common subsequences is ensured by partitioning each symbol pool into subpools that respond only when the current symbol has been preceded by a particular sequence of symbols. We describe synaptic structure and neural dynamics that permit the selective activation of subpools by the correct sequence. Symbols may have varying durations of the order of hundreds of milliseconds. Physiologically plausible plasticity mechanisms operate on a time scale of tens of milliseconds; an interaction of the excitatory input with periodic global inhibition bridges this gap so that neural events representing successive symbols occur on this much faster timescale. The network is shown to store multiple overlapping sequences of events. It is robust to variation in symbol duration, it is scalable, and its performance degrades gracefully with perturbation of its parameters.

  4. Reconstruction of neuronal input through modeling single-neuron dynamics and computations

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Qing; Wang, Jiang; Yu, Haitao; Deng, Bin, E-mail: dengbin@tju.edu.cn; Chan, Wai-lok [School of Electrical Engineering and Automation, Tianjin University, Tianjin 300072 (China)

    2016-06-15

    Mathematical models provide a mathematical description of neuron activity, which can better understand and quantify neural computations and corresponding biophysical mechanisms evoked by stimulus. In this paper, based on the output spike train evoked by the acupuncture mechanical stimulus, we present two different levels of models to describe the input-output system to achieve the reconstruction of neuronal input. The reconstruction process is divided into two steps: First, considering the neuronal spiking event as a Gamma stochastic process. The scale parameter and the shape parameter of Gamma process are, respectively, defined as two spiking characteristics, which are estimated by a state-space method. Then, leaky integrate-and-fire (LIF) model is used to mimic the response system and the estimated spiking characteristics are transformed into two temporal input parameters of LIF model, through two conversion formulas. We test this reconstruction method by three different groups of simulation data. All three groups of estimates reconstruct input parameters with fairly high accuracy. We then use this reconstruction method to estimate the non-measurable acupuncture input parameters. Results show that under three different frequencies of acupuncture stimulus conditions, estimated input parameters have an obvious difference. The higher the frequency of the acupuncture stimulus is, the higher the accuracy of reconstruction is.

  5. Reconstruction of neuronal input through modeling single-neuron dynamics and computations

    Science.gov (United States)

    Qin, Qing; Wang, Jiang; Yu, Haitao; Deng, Bin; Chan, Wai-lok

    2016-06-01

    Mathematical models provide a mathematical description of neuron activity, which can better understand and quantify neural computations and corresponding biophysical mechanisms evoked by stimulus. In this paper, based on the output spike train evoked by the acupuncture mechanical stimulus, we present two different levels of models to describe the input-output system to achieve the reconstruction of neuronal input. The reconstruction process is divided into two steps: First, considering the neuronal spiking event as a Gamma stochastic process. The scale parameter and the shape parameter of Gamma process are, respectively, defined as two spiking characteristics, which are estimated by a state-space method. Then, leaky integrate-and-fire (LIF) model is used to mimic the response system and the estimated spiking characteristics are transformed into two temporal input parameters of LIF model, through two conversion formulas. We test this reconstruction method by three different groups of simulation data. All three groups of estimates reconstruct input parameters with fairly high accuracy. We then use this reconstruction method to estimate the non-measurable acupuncture input parameters. Results show that under three different frequencies of acupuncture stimulus conditions, estimated input parameters have an obvious difference. The higher the frequency of the acupuncture stimulus is, the higher the accuracy of reconstruction is.

  6. [Use of the recurrence plot method in stochastic analysis of neuronal activity].

    Science.gov (United States)

    Novák, V; Schmidt, J

    1996-09-01

    The recurrence plot method is described together with its application to the analysis of inner time relations in the sequences of interspike intervals. The depicted method was employed to analyze results from the computer model of the neuronal stochastic activity. It can be also used to analyze sequences of interspike intervals in the records from life neurons.

  7. Modeling of Auditory Neuron Response Thresholds with Cochlear Implants

    Directory of Open Access Journals (Sweden)

    Frederic Venail

    2015-01-01

    Full Text Available The quality of the prosthetic-neural interface is a critical point for cochlear implant efficiency. It depends not only on technical and anatomical factors such as electrode position into the cochlea (depth and scalar placement, electrode impedance, and distance between the electrode and the stimulated auditory neurons, but also on the number of functional auditory neurons. The efficiency of electrical stimulation can be assessed by the measurement of e-CAP in cochlear implant users. In the present study, we modeled the activation of auditory neurons in cochlear implant recipients (nucleus device. The electrical response, measured using auto-NRT (neural responses telemetry algorithm, has been analyzed using multivariate regression with cubic splines in order to take into account the variations of insertion depth of electrodes amongst subjects as well as the other technical and anatomical factors listed above. NRT thresholds depend on the electrode squared impedance (β = −0.11 ± 0.02, P<0.01, the scalar placement of the electrodes (β = −8.50 ± 1.97, P<0.01, and the depth of insertion calculated as the characteristic frequency of auditory neurons (CNF. Distribution of NRT residues according to CNF could provide a proxy of auditory neurons functioning in implanted cochleas.

  8. Modeling of Auditory Neuron Response Thresholds with Cochlear Implants.

    Science.gov (United States)

    Venail, Frederic; Mura, Thibault; Akkari, Mohamed; Mathiolon, Caroline; Menjot de Champfleur, Sophie; Piron, Jean Pierre; Sicard, Marielle; Sterkers-Artieres, Françoise; Mondain, Michel; Uziel, Alain

    2015-01-01

    The quality of the prosthetic-neural interface is a critical point for cochlear implant efficiency. It depends not only on technical and anatomical factors such as electrode position into the cochlea (depth and scalar placement), electrode impedance, and distance between the electrode and the stimulated auditory neurons, but also on the number of functional auditory neurons. The efficiency of electrical stimulation can be assessed by the measurement of e-CAP in cochlear implant users. In the present study, we modeled the activation of auditory neurons in cochlear implant recipients (nucleus device). The electrical response, measured using auto-NRT (neural responses telemetry) algorithm, has been analyzed using multivariate regression with cubic splines in order to take into account the variations of insertion depth of electrodes amongst subjects as well as the other technical and anatomical factors listed above. NRT thresholds depend on the electrode squared impedance (β = -0.11 ± 0.02, P < 0.01), the scalar placement of the electrodes (β = -8.50 ± 1.97, P < 0.01), and the depth of insertion calculated as the characteristic frequency of auditory neurons (CNF). Distribution of NRT residues according to CNF could provide a proxy of auditory neurons functioning in implanted cochleas.

  9. Neuronal activity in the hub of extrasynaptic Schwann cell-axon interactions

    Directory of Open Access Journals (Sweden)

    Chrysanthi eSamara

    2013-11-01

    Full Text Available The integrity and function of neurons depend on their continuous interactions with glial cells. In the peripheral nervous system glial functions are exerted by Schwann cells (SCs. SCs sense synaptic and extrasynaptic manifestations of action potential propagation and adapt their physiology to support neuronal activity. We review here existing literature data on extrasynaptic bidirectional axon-SC communication, focusing particularly on neuronal activity implications. To shed light on underlying mechanisms, we conduct a thorough analysis of microarray data from SC-rich mouse sciatic nerve at different developmental stages and in neuropathic models. We identify molecules that are potentially involved in SC detection of neuronal activity signals inducing subsequent glial responses. We further suggest that alterations in the activity-dependent axon-SC crosstalk impact on peripheral neuropathies. Together with previously reported data, these observations open new perspectives for deciphering glial mechanisms of neuronal function support.

  10. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression.

    Science.gov (United States)

    Courtin, Julien; Chaudun, Fabrice; Rozeske, Robert R; Karalis, Nikolaos; Gonzalez-Campo, Cecilia; Wurtz, Hélène; Abdi, Azzedine; Baufreton, Jerome; Bienvenu, Thomas C M; Herry, Cyril

    2014-01-02

    Synchronization of spiking activity in neuronal networks is a fundamental process that enables the precise transmission of information to drive behavioural responses. In cortical areas, synchronization of principal-neuron spiking activity is an effective mechanism for information coding that is regulated by GABA (γ-aminobutyric acid)-ergic interneurons through the generation of neuronal oscillations. Although neuronal synchrony has been demonstrated to be crucial for sensory, motor and cognitive processing, it has not been investigated at the level of defined circuits involved in the control of emotional behaviour. Converging evidence indicates that fear behaviour is regulated by the dorsomedial prefrontal cortex (dmPFC). This control over fear behaviour relies on the activation of specific prefrontal projections to the basolateral complex of the amygdala (BLA), a structure that encodes associative fear memories. However, it remains to be established how the precise temporal control of fear behaviour is achieved at the level of prefrontal circuits. Here we use single-unit recordings and optogenetic manipulations in behaving mice to show that fear expression is causally related to the phasic inhibition of prefrontal parvalbumin interneurons (PVINs). Inhibition of PVIN activity disinhibits prefrontal projection neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. Our results identify two complementary neuronal mechanisms mediated by PVINs that precisely coordinate and enhance the neuronal activity of prefrontal projection neurons to drive fear expression.

  11. Glycine activates myenteric neurones in adult guinea-pigs.

    Science.gov (United States)

    Neunlist, M; Michel, K; Reiche, D; Dobreva, G; Huber, K; Schemann, M

    2001-11-01

    1. We studied the effects of glycine on myenteric neurones and muscle activity in the colon and stomach of adult guinea-pigs. 2. Intracellular recordings revealed that myenteric neurones responded to local microejection of glycine (1 mM) with a fast, transient membrane potential depolarisation (57 % of 191 colonic neurones and 26 % of 50 gastric neurones). Most glycine-sensitive neurones had ascending projections and were choline acetyltransferase immunoreactive. Glycine preferentially activated neurones with a late afterhyperpolarisation (AH-neurones) and tonic spiking neurones with fast synaptic inputs (tonic S-neurones) but less frequently phasic S-neurones and inexcitable (non-spiking) neurones. The depolarisation had a reversal potential at -19 +/- 13 mV, which was increased by 18 +/- 10 % upon lowering extracellular chloride concentration and decreased by 38 +/- 14 % in furosemide (frusemide, 2 mM). 3. Strychnine (300 nM) reversibly abolished the glycine-induced depolarisation and the Cl(-) channel blocker picrotoxin (100 microM) reduced the amplitude of the depolarisation by 55 +/- 5 %. The glycine effect was a postsynaptic response because it was not changed after nerve blockade with tetrodotoxin (1 microM) or blockade of synaptic transmission in reduced extracellular [Ca(2+)]. The effect was specific since the response was not changed by the nicotinic antagonists hexamethonium (200 microM) and mecamylamine (100 microM), the GABA(A) receptor antagonist bicuculline (10 microM), the NMDA antagonist MK-801 (20 microM) or the 5-HT(3) antagonist ICS 205930 (1 microM). 4. Glycine (1 mM) induced a tetrodotoxin- and strychnine-sensitive contractile response in the colon; the contractile response in the stomach was tetrodotoxin insensitive. 5. Glycine activated myenteric neurones in the adult enteric nervous system through strychnine-sensitive mechanisms. The glycine-evoked depolarisation was caused by Cl(-) efflux and the maintenance of relatively high

  12. Neuronal modelling of baroreflex response to orthostatic stress

    Science.gov (United States)

    Samin, Azfar

    The accelerations experienced in aerial combat can cause pilot loss of consciousness (GLOC) due to a critical reduction in cerebral blood circulation. The development of smart protective equipment requires understanding of how the brain processes blood pressure (BP) information in response to acceleration. We present a biologically plausible model of the Baroreflex to investigate the neural correlates of short-term BP control under acceleration or orthostatic stress. The neuronal network model, which employs an integrate-and-fire representation of a biological neuron, comprises the sensory, motor, and the central neural processing areas that form the Baroreflex. Our modelling strategy is to test hypotheses relating to the encoding mechanisms of multiple sensory inputs to the nucleus tractus solitarius (NTS), the site of central neural processing. The goal is to run simulations and reproduce model responses that are consistent with the variety of available experimental data. Model construction and connectivity are inspired by the available anatomical and neurophysiological evidence that points to a barotopic organization in the NTS, and the presence of frequency-dependent synaptic depression, which provides a mechanism for generating non-linear local responses in NTS neurons that result in quantifiable dynamic global baroreflex responses. The entire physiological range of BP and rate of change of BP variables is encoded in a palisade of NTS neurons in that the spike responses approximate Gaussian 'tuning' curves. An adapting weighted-average decoding scheme computes the motor responses and a compensatory signal regulates the heart rate (HR). Model simulations suggest that: (1) the NTS neurons can encode the hydrostatic pressure difference between two vertically separated sensory receptor regions at +Gz, and use changes in that difference for the regulation of HR; (2) even though NTS neurons do not fire with a cardiac rhythm seen in the afferents, pulse

  13. Mathematical modelling and numerical simulation of the morphological development of neurons.

    Science.gov (United States)

    Graham, Bruce P; van Ooyen, Arjen

    2006-10-30

    The morphological development of neurons is a very complex process involving both genetic and environmental components. Mathematical modelling and numerical simulation are valuable tools in helping us unravel particular aspects of how individual neurons grow their characteristic morphologies and eventually form appropriate networks with each other. A variety of mathematical models that consider (1) neurite initiation (2) neurite elongation (3) axon pathfinding, and (4) neurite branching and dendritic shape formation are reviewed. The different mathematical techniques employed are also described. Some comparison of modelling results with experimental data is made. A critique of different modelling techniques is given, leading to a proposal for a unified modelling environment for models of neuronal development. A unified mathematical and numerical simulation framework should lead to an expansion of work on models of neuronal development, as has occurred with compartmental models of neuronal electrical activity.

  14. Neuronal avalanches of a self-organized neural network with active-neuron-dominant structure.

    Science.gov (United States)

    Li, Xiumin; Small, Michael

    2012-06-01

    Neuronal avalanche is a spontaneous neuronal activity which obeys a power-law distribution of population event sizes with an exponent of -3/2. It has been observed in the superficial layers of cortex both in vivo and in vitro. In this paper, we analyze the information transmission of a novel self-organized neural network with active-neuron-dominant structure. Neuronal avalanches can be observed in this network with appropriate input intensity. We find that the process of network learning via spike-timing dependent plasticity dramatically increases the complexity of network structure, which is finally self-organized to be active-neuron-dominant connectivity. Both the entropy of activity patterns and the complexity of their resulting post-synaptic inputs are maximized when the network dynamics are propagated as neuronal avalanches. This emergent topology is beneficial for information transmission with high efficiency and also could be responsible for the large information capacity of this network compared with alternative archetypal networks with different neural connectivity.

  15. Sensorimotor locus of the buildup activity in monkey lateral intraparietal area neurons.

    Science.gov (United States)

    Park, Joonkoo; Zhang, Jun

    2010-05-01

    A study in 2002 using a random-dot motion-discrimination paradigm showed that an information accumulation model with a threshold-crossing mechanism can account for activity of the lateral intraparietal area (LIP) neurons. Here, mathematical techniques were applied to the same dataset to quantitatively address the sensory versus motor representation of the neuronal activity during the time course of a trial. A technique based on Signal Detection Theory was applied to provide indices to quantify how neuronal firing activity is responsible for encoding the stimulus or selecting the response at the behavioral level. Additionally, a statistical model based on Poisson regression was used to provide an orthogonal decomposition of the neural activity into stimulus, response, and stimulus-response mapping components. The temporal dynamics of the sensorimotor locus of the LIP activity indicated that there is no stimulus-response mapping-specific neuronal firing activity throughout a trial; the neural activity toward the saccadic onset reflects the development of the motor representation, and the neural activity in the beginning of a trial contains little, if any, information about the sensory representation. Sensorimotor analysis on individual neurons also showed that the neuronal activation, as a population, represent pending saccadic direction and carry little information about the direction of the motion stimulus.

  16. Transient activation of specific neurons in mice by selective expression of the capsaicin receptor

    Science.gov (United States)

    Güler, Ali D.; Rainwater, Aundrea; Parker, Jones G.; Jones, Graham L.; Argilli, Emanuela; Arenkiel, Benjamin R.; Ehlers, Michael D.; Bonci, Antonello; Zweifel, Larry s.; Palmiter, Richard D.

    2013-01-01

    The ability to control the electrical activity of a neuronal subtype is a valuable tool in deciphering the role of discreet cell populations in complex neural circuits. Recent techniques that allow remote control of neurons are either labor intensive and invasive or indirectly coupled to neural electrical potential with low temporal resolution. Here we show the rapid, reversible and direct activation of genetically identified neuronal subpopulations by generating two inducible transgenic mouse models. Confined expression of the capsaicin receptor, TRPV1, allows cell-specific activation after peripheral or oral delivery of ligand in freely moving mice. Capsaicin-induced activation of dopaminergic or serotonergic neurons reversibly alters both physiological and behavioural responses within minutes, and lasts ~10 min. These models showcase a robust and remotely controllable genetic tool that modulates a distinct cell population without the need for invasive and labour-intensive approaches. PMID:22434189

  17. The primary locus of motor neuron death in an ALS–PDC mouse model

    OpenAIRE

    2009-01-01

    A mouse model of amyotrophic lateral sclerosis–parkinsonism–dementia complex based on the consumption of cycad seed flour was used to determine whether the observed pathology of motor neuron loss begins in the distal axons or the spinal cord. Assessments of neuromuscular junction integrity and motor neurons were performed at multiple time points. Mice fed cycad pellets performed worse on the wire hang than controls. Microglial activation in cycad-fed mice was observed with motor neuron degene...

  18. A Neuronal Model of Predictive Coding Accounting for the Mismatch Negativity

    OpenAIRE

    Wacongne, Catherine; Changeux, Jean-Pierre; Dehaene, Stanislas

    2012-01-01

    International audience; The mismatch negativity (MMN) is thought to index the activation of specialized neural networks for active prediction and deviance detection. However, a detailed neuronal model of the neurobiological mechanisms underlying the MMN is still lacking, and its computational foundations remain debated. We propose here a detailed neuronal model of auditory cortex, based on predictive coding, that accounts for the critical features of MMN. The model is entirely composed of spi...

  19. Modanifil activates the histaminergic system through the orexinergic neurons.

    Science.gov (United States)

    Ishizuka, Tomoko; Murotani, Tomotaka; Yamatodani, Atsushi

    2010-10-15

    Modafinil is a drug used to treat hypersomnolence of narcolepsy. We previously reported that modafinil increases hypothalamic histamine release in rats but did not increase locomotor activity in histamine-depleted mice, suggesting that modafinil-induced locomotor activity involves the histaminergic system. Modafinil is also thought to express its effect through the orexinergic neurons, and orexin increases hypothalamic histamine release. These findings led us to investigate whether modafinil activates the histaminergic system via the orexinergic system. In the present study, we performed in vivo microdialysis and c-Fos immunohistochemistry to investigate whether the orexinergic system mediates the activation of the histaminergic system by modafinil using orexin neuron-deficient mice. Two hours after the injection, modafinil (150 mg/kg) caused a significant increase of histamine release compared to the basal release in wild type mice. However, modafinil had no effect on the histamine release in orexin neuron-deficient mice. By immunohistochemical study, we found that there was no neuronal activation in the tuberomammillary nucleus where the cell bodies of the histaminergic neurons exclusively exist in orexin neuron-deficient mice. These findings indicate that modafinil-induced increment of histamine release requires intact orexinergic neurons.

  20. Adenosine Monophosphate-Activated Protein Kinase Abates Hyperglycaemia-Induced Neuronal Injury in Experimental Models of Diabetic Neuropathy: Effects on Mitochondrial Biogenesis, Autophagy and Neuroinflammation.

    Science.gov (United States)

    Yerra, Veera Ganesh; Kumar, Ashutosh

    2017-04-01

    Impaired adenosine monophosphate kinase (AMPK) signalling under hyperglycaemic conditions is known to cause mitochondrial dysfunction in diabetic sensory neurons. Facilitation of AMPK signalling is previously reported to ameliorate inflammation and induce autophagic response in various complications related to diabetes. The present study assesses the role of AMPK activation on mitochondrial biogenesis, autophagy and neuroinflammation in experimental diabetic neuropathy (DN) using an AMPK activator (A769662). A769662 (15 and 30 mg/kg, i.p) was administered to Sprague-Dawley rats (250-270 g) for 2 weeks after 6 weeks of streptozotocin (STZ) injection (55 mg/kg, i.p.). Behavioural parameters (mechanical/thermal hyperalgesia) and functional characteristics (motor/sensory nerve conduction velocities (MNCV and SNCV) and sciatic nerve blood flow (NBF)) were assessed. For in vitro studies, Neuro2a (N2A) cells were incubated with 25 mM glucose to simulate high glucose condition and then studied for mitochondrial dysfunction and protein expression changes. STZ administration resulted in significant hyperglycaemia (>250 mg/dl) in rats. A769662 treatment significantly improved mechanical/thermal hyperalgesia threshold and enhanced MNCV, SNCV and NBF in diabetic animals. A769662 exposure normalised the mitochondrial superoxide production, membrane depolarisation and markedly increased neurite outgrowth of N2A cells. Further, AMPK activation also abolished the NF-κB-mediated neuroinflammation. A769662 treatment increased Thr-172 phosphorylation of AMPK results in stimulated PGC-1α-directed mitochondrial biogenesis and autophagy induction. Our study supports that compromised AMPK signalling in hyperglycaemic conditions causes defective mitochondrial biogenesis ultimately leading to neuronal dysfunction and associated deficits in DN and activation of AMPK can be developed as an attractive therapeutic strategy for the management of DN.

  1. Calcium, synaptic plasticity and intrinsic homeostasis in Purkinje neuron models

    Directory of Open Access Journals (Sweden)

    Pablo Achard

    2008-12-01

    Full Text Available We recently reproduced the complex electrical activity of a Purkinje cell (PC with very different combinations of ionic channel maximum conductances, suggesting that a large parameter space is available to homeostatic mechanisms. It has been hypothesized that cytoplasmic calcium concentrations control the homeostatic activity sensors. This raises many questions for PCs since in these neurons calcium plays an important role in the induction of synaptic plasticity. To address this question, we generated 148 new PC models. In these models the somatic membrane voltages are stable, but the somatic calcium dynamics are very variable, in agreement with experimental results. Conversely, the calcium signal in spiny dendrites shows only small variability. We demonstrate that this localized control of calcium conductances preserves the induction of long-term depression for all models. We conclude that calcium is unlikely to be the sole activity-sensor in this cell but that there is a strong relationship between activity homeostasis and synaptic plasticity.

  2. The sensitivity of neurons with non-periodic activity to sympathetic stimulation in rat injured dorsal root ganglion

    Institute of Scientific and Technical Information of China (English)

    Hong-Jun YANG; San-Jue HU; Pu-Lin GONG; Jian-Hong DUAN

    2006-01-01

    Objective The relationship between firing pattern and sensitivity of neurons was studied in chronically compressed dorsal root ganglion (DRG) neurons and the Hindmarsh-Rose (HR) neuronal model. Methods Spontaneous activities from single fibers of chronically compressed DRG neurons in rats were recorded, and divided into periodic and non-periodic firing patterns. The sensitivity of the two kinds of firing pattern neuron to sympathetic stimulation (SS)was compared. Result It was found that 27.3% of periodic firing neurons and 93.2% of non-periodic firing neurons responded to SS respectively ( periodic vs non-periodic, P < 0.01 ). The responses to SS with different stimulation time were greater non-periodic firing neurons than periodic firing neurons (P < 0.01 ). The non-periodic firing neurons obviously responded to SS. After the firing pattern of these neurons transformed to periodic firing pattern, their responses to SS disappeared or decreased obviously. The HR neuronal model exhibited a significantly greater response to perturbation in non-periodic (chaotic) firing pattern than in periodic firing pattern. Conclusion The non-periodic firing neurons with deterministic chaos are more sensitive to external stimuli than the periodic firing neurons.

  3. Functionalized anatomical models for EM-neuron Interaction modeling

    Science.gov (United States)

    Neufeld, Esra; Cassará, Antonino Mario; Montanaro, Hazael; Kuster, Niels; Kainz, Wolfgang

    2016-06-01

    The understanding of interactions between electromagnetic (EM) fields and nerves are crucial in contexts ranging from therapeutic neurostimulation to low frequency EM exposure safety. To properly consider the impact of in vivo induced field inhomogeneity on non-linear neuronal dynamics, coupled EM-neuronal dynamics modeling is required. For that purpose, novel functionalized computable human phantoms have been developed. Their implementation and the systematic verification of the integrated anisotropic quasi-static EM solver and neuronal dynamics modeling functionality, based on the method of manufactured solutions and numerical reference data, is described. Electric and magnetic stimulation of the ulnar and sciatic nerve were modeled to help understanding a range of controversial issues related to the magnitude and optimal determination of strength-duration (SD) time constants. The results indicate the importance of considering the stimulation-specific inhomogeneous field distributions (especially at tissue interfaces), realistic models of non-linear neuronal dynamics, very short pulses, and suitable SD extrapolation models. These results and the functionalized computable phantom will influence and support the development of safe and effective neuroprosthetic devices and novel electroceuticals. Furthermore they will assist the evaluation of existing low frequency exposure standards for the entire population under all exposure conditions.

  4. Self-organization of synchronous activity propagation in neuronal networks driven by local excitation.

    Science.gov (United States)

    Bayati, Mehdi; Valizadeh, Alireza; Abbassian, Abdolhossein; Cheng, Sen

    2015-01-01

    Many experimental and theoretical studies have suggested that the reliable propagation of synchronous neural activity is crucial for neural information processing. The propagation of synchronous firing activity in so-called synfire chains has been studied extensively in feed-forward networks of spiking neurons. However, it remains unclear how such neural activity could emerge in recurrent neuronal networks through synaptic plasticity. In this study, we investigate whether local excitation, i.e., neurons that fire at a higher frequency than the other, spontaneously active neurons in the network, can shape a network to allow for synchronous activity propagation. We use two-dimensional, locally connected and heterogeneous neuronal networks with spike-timing dependent plasticity (STDP). We find that, in our model, local excitation drives profound network changes within seconds. In the emergent network, neural activity propagates synchronously through the network. This activity originates from the site of the local excitation and propagates through the network. The synchronous activity propagation persists, even when the local excitation is removed, since it derives from the synaptic weight matrix. Importantly, once this connectivity is established it remains stable even in the presence of spontaneous activity. Our results suggest that synfire-chain-like activity can emerge in a relatively simple way in realistic neural networks by locally exciting the desired origin of the neuronal sequence.

  5. A new designer drug 5F-ADB activates midbrain dopaminergic neurons but not serotonergic neurons.

    Science.gov (United States)

    Asaoka, Nozomi; Kawai, Hiroyuki; Nishitani, Naoya; Kinoshita, Haruko; Shibui, Norihiro; Nagayasu, Kazuki; Shirakawa, Hisashi; Kaneko, Shuji

    2016-01-01

    N-[[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl]-3-methyl-D-valine methyl ester (5F-ADB) is one of the most potent synthetic cannabinoids and elicits severe psychotic symptoms in humans, sometimes causing death. To investigate the neuronal mechanisms underlying its toxicity, we examined the effects of 5F-ADB on midbrain dopaminergic and serotonergic systems, which modulate various basic brain functions such as those in reward-related behavior. 5F-ADB-induced changes in spontaneous firing activity of dopaminergic and serotonergic neurons were recorded by ex vivo electrophysiological techniques. In dopaminergic neurons, 5F-ADB (1 μM) significantly increased the spontaneous firing rate, while 5F-ADB failed to activate dopaminergic neurons in the presence of the CB1 antagonist AM251 (1 μM). However, the same concentration of 5F-ADB did not affect serotonergic-neuron activity. These results suggest that 5F-ADB activates local CB1 receptors and potentiates midbrain dopaminergic systems with no direct effects on midbrain serotonergic systems.

  6. Effects of calcium spikes in the layer 5 pyramidal neuron on coincidence detection and activity propagation

    Directory of Open Access Journals (Sweden)

    Yansong Chua

    2016-07-01

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

  7. Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation.

    Science.gov (United States)

    Soden, Marta E; Jones, Graham L; Sanford, Christina A; Chung, Amanda S; Güler, Ali D; Chavkin, Charles; Luján, Rafael; Zweifel, Larry S

    2013-11-20

    The calcium-activated small conductance potassium channel SK3 plays an essential role in the regulation of dopamine neuron activity patterns. Here we demonstrate that expression of a human disease-related SK3 mutation (hSK3Δ) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3Δ suppressed endogenous SK currents, reducing coupling between SK channels and NMDA receptors (NMDARs) and increasing permissiveness for burst firing. Consistent with enhanced excitability of dopamine neurons, hSK3Δ increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3Δ led to deficits in attention and sensory gating and heightened sensitivity to a psychomimetic drug. Sensory-motor alterations and psychomimetic sensitivity were recapitulated in a mouse model of transient, reversible dopamine neuron activation. These results demonstrate the cell-autonomous effects of a human ion channel mutation on dopamine neuron physiology and the impact of activity pattern disruption on behavior.

  8. Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR I and TLR4 pathways.

    Science.gov (United States)

    Zhang, Jie; Niu, Na; Wang, Mingyu; McNutt, Michael A; Zhang, Donghong; Zhang, Baogang; Lu, Shijun; Liu, Yuqing; Liu, Zhihui

    2013-08-01

    Oxidative and immune attacks from the environment or microglia have been implicated in the loss of dopaminergic neurons of Parkinson's disease. The role of IgG which is an important immunologic molecule in the process of Parkinson's disease has been unclear. Evidence suggests that IgG can be produced by neurons in addition to its traditionally recognized source B lymphocytes, but its function in neurons is poorly understood. In this study, extensive expression of neuron-derived IgG was demonstrated in dopaminergic neurons of human and rat mesencephalon. With an in vitro Parkinson's disease model, we found that neuron-derived IgG can improve the survival and reduce apoptosis of dopaminergic neurons induced by 6-hydroxydopamine toxicity, and also depress the release of NO from microglia triggered by 6-hydroxydopamine. Expression of TNF-α and IL-10 in microglia was elevated to protective levels by neuron-derived IgG at a physiologic level via the FcγR I and TLR4 pathways and microglial activation could be attenuated by IgG blocking. All these data suggested that neuron-derived IgG may exert a self-protective function by activating microglia properly, and IgG may be involved in maintaining immunity homeostasis in the central nervous system and serve as an active factor under pathological conditions such as Parkinson's disease.

  9. A modeling approach on why simple central pattern generators are built of irregular neurons.

    Science.gov (United States)

    Reyes, Marcelo Bussotti; Carelli, Pedro Valadão; Sartorelli, José Carlos; Pinto, Reynaldo Daniel

    2015-01-01

    The crustacean pyloric Central Pattern Generator (CPG) is a nervous circuit that endogenously provides periodic motor patterns. Even after about 40 years of intensive studies, the rhythm genesis is still not rigorously understood in this CPG, mainly because it is made of neurons with irregular intrinsic activity. Using mathematical models we addressed the question of using a network of irregularly behaving elements to generate periodic oscillations, and we show some advantages of using non-periodic neurons with intrinsic behavior in the transition from bursting to tonic spiking (as found in biological pyloric CPGs) as building components. We studied two- and three-neuron model CPGs built either with Hindmarsh-Rose or with conductance-based Hodgkin-Huxley-like model neurons. By changing a model's parameter we could span the neuron's intrinsic dynamical behavior from slow periodic bursting to fast tonic spiking, passing through a transition where irregular bursting was observed. Two-neuron CPG, half center oscillator (HCO), was obtained for each intrinsic behavior of the neurons by coupling them with mutual symmetric synaptic inhibition. Most of these HCOs presented regular antiphasic bursting activity and the changes of the bursting frequencies was studied as a function of the inhibitory synaptic strength. Among all HCOs, those made of intrinsic irregular neurons presented a wider burst frequency range while keeping a reliable regular oscillatory (bursting) behavior. HCOs of periodic neurons tended to be either hard to change their behavior with synaptic strength variations (slow periodic burster neurons) or unable to perform a physiologically meaningful rhythm (fast tonic spiking neurons). Moreover, 3-neuron CPGs with connectivity and output similar to those of the pyloric CPG presented the same results.

  10. A modeling approach on why simple central pattern generators are built of irregular neurons.

    Directory of Open Access Journals (Sweden)

    Marcelo Bussotti Reyes

    Full Text Available The crustacean pyloric Central Pattern Generator (CPG is a nervous circuit that endogenously provides periodic motor patterns. Even after about 40 years of intensive studies, the rhythm genesis is still not rigorously understood in this CPG, mainly because it is made of neurons with irregular intrinsic activity. Using mathematical models we addressed the question of using a network of irregularly behaving elements to generate periodic oscillations, and we show some advantages of using non-periodic neurons with intrinsic behavior in the transition from bursting to tonic spiking (as found in biological pyloric CPGs as building components. We studied two- and three-neuron model CPGs built either with Hindmarsh-Rose or with conductance-based Hodgkin-Huxley-like model neurons. By changing a model's parameter we could span the neuron's intrinsic dynamical behavior from slow periodic bursting to fast tonic spiking, passing through a transition where irregular bursting was observed. Two-neuron CPG, half center oscillator (HCO, was obtained for each intrinsic behavior of the neurons by coupling them with mutual symmetric synaptic inhibition. Most of these HCOs presented regular antiphasic bursting activity and the changes of the bursting frequencies was studied as a function of the inhibitory synaptic strength. Among all HCOs, those made of intrinsic irregular neurons presented a wider burst frequency range while keeping a reliable regular oscillatory (bursting behavior. HCOs of periodic neurons tended to be either hard to change their behavior with synaptic strength variations (slow periodic burster neurons or unable to perform a physiologically meaningful rhythm (fast tonic spiking neurons. Moreover, 3-neuron CPGs with connectivity and output similar to those of the pyloric CPG presented the same results.

  11. Mechanical stress activates neurites and somata of myenteric neurons

    Directory of Open Access Journals (Sweden)

    Eva Maria Kugler

    2015-09-01

    Full Text Available The particular location of myenteric neurons, sandwiched between the 2 muscle layers of the gut, implies that their somata and neurites undergo mechanical stress during gastrointestinal motility. Existence of mechanosensitive enteric neurons (MEN is undoubted but many of their basic features remain to be studied. In this study, we used ultra-fast neuroimaging to record activity of primary cultured myenteric neurons of guinea pig and human intestine after von Frey hair evoked deformation of neurites and somata. Independent component analysis was applied to reconstruct neuronal morphology and follow neuronal signals. Of the cultured neurons 45% (114 out of 256, 30 guinea pigs responded to neurite probing with a burst spike frequency of 13.4 Hz. Action potentials generated at the stimulation site invaded the soma and other neurites. Mechanosensitive sites were expressed across large areas of neurites. Many mechanosensitive neurites appeared to have afferent and efferent functions as those that responded to deformation also conducted spikes coming from the soma. Mechanosensitive neurites were also activated by nicotine application. This supported the concept of multifunctional MEN. 14% of the neurons (13 out of 96, 18 guinea pigs responded to soma deformation with burst spike discharge of 17.9 Hz. Firing of MEN adapted rapidly (RAMEN, slowly (SAMEN or ultra-slowly (USAMEN. The majority of MEN showed SAMEN behavior although significantly more RAMEN occurred after neurite probing. Cultured myenteric neurons from human intestine had similar properties. Compared to MEN, dorsal root ganglion neurons were activated by neurite but not by soma deformation with slow adaptation of firing. We demonstrated that MEN exhibit specific features very likely reflecting adaptation to their specialized functions in the gut.

  12. Size-dependent regulation of synchronized activity in living neuronal networks

    Science.gov (United States)

    Yamamoto, Hideaki; Kubota, Shigeru; Chida, Yudai; Morita, Mayu; Moriya, Satoshi; Akima, Hisanao; Sato, Shigeo; Hirano-Iwata, Ayumi; Tanii, Takashi; Niwano, Michio

    2016-07-01

    We study the effect of network size on synchronized activity in living neuronal networks. Dissociated cortical neurons form synaptic connections in culture and generate synchronized spontaneous activity within 10 days in vitro. Using micropatterned surfaces to extrinsically control the size of neuronal networks, we show that synchronized activity can emerge in a network as small as 12 cells. Furthermore, a detailed comparison of small (˜20 cells), medium (˜100 cells), and large (˜400 cells) networks reveal that synchronized activity becomes destabilized in the small networks. A computational modeling of neural activity is then employed to explore the underlying mechanism responsible for the size effect. We find that the generation and maintenance of the synchronized activity can be minimally described by: (1) the stochastic firing of each neuron in the network, (2) enhancement in the network activity in a positive feedback loop of excitatory synapses, and (3) Ca-dependent suppression of bursting activity. The model further shows that the decrease in total synaptic input to a neuron that drives the positive feedback amplification of correlated activity is a key factor underlying the destabilization of synchrony in smaller networks. Spontaneous neural activity plays a critical role in cortical information processing, and our work constructively clarifies an aspect of the structural basis behind this.

  13. Size-dependent regulation of synchronized activity in living neuronal networks.

    Science.gov (United States)

    Yamamoto, Hideaki; Kubota, Shigeru; Chida, Yudai; Morita, Mayu; Moriya, Satoshi; Akima, Hisanao; Sato, Shigeo; Hirano-Iwata, Ayumi; Tanii, Takashi; Niwano, Michio

    2016-07-01

    We study the effect of network size on synchronized activity in living neuronal networks. Dissociated cortical neurons form synaptic connections in culture and generate synchronized spontaneous activity within 10 days in vitro. Using micropatterned surfaces to extrinsically control the size of neuronal networks, we show that synchronized activity can emerge in a network as small as 12 cells. Furthermore, a detailed comparison of small (∼20 cells), medium (∼100 cells), and large (∼400 cells) networks reveal that synchronized activity becomes destabilized in the small networks. A computational modeling of neural activity is then employed to explore the underlying mechanism responsible for the size effect. We find that the generation and maintenance of the synchronized activity can be minimally described by: (1) the stochastic firing of each neuron in the network, (2) enhancement in the network activity in a positive feedback loop of excitatory synapses, and (3) Ca-dependent suppression of bursting activity. The model further shows that the decrease in total synaptic input to a neuron that drives the positive feedback amplification of correlated activity is a key factor underlying the destabilization of synchrony in smaller networks. Spontaneous neural activity plays a critical role in cortical information processing, and our work constructively clarifies an aspect of the structural basis behind this.

  14. The mast cell degranulator compound 48/80 directly activates neurons.

    Directory of Open Access Journals (Sweden)

    Michael Schemann

    Full Text Available BACKGROUND: Compound 48/80 is widely used in animal and tissue models as a "selective" mast cell activator. With this study we demonstrate that compound 48/80 also directly activates enteric neurons and visceral afferents. METHODOLOGY/PRINCIPAL FINDINGS: We used in vivo recordings from extrinsic intestinal afferents together with Ca(++ imaging from primary cultures of DRG and nodose neurons. Enteric neuronal activation was examined by Ca(++ and voltage sensitive dye imaging in isolated gut preparations and primary cultures of enteric neurons. Intraluminal application of compound 48/80 evoked marked afferent firing which desensitized on subsequent administration. In egg albumen-sensitized animals, intraluminal antigen evoked a similar pattern of afferent activation which also desensitized on subsequent exposure to antigen. In cross-desensitization experiments prior administration of compound 48/80 failed to influence the mast cell mediated response. Application of 1 and 10 µg/ml compound 48/80 evoked spike discharge and Ca(++ transients in enteric neurons. The same nerve activating effect was observed in primary cultures of DRG and nodose ganglion cells. Enteric neuron cultures were devoid of mast cells confirmed by negative staining for c-kit or toluidine blue. In addition, in cultured enteric neurons the excitatory action of compound 48/80 was preserved in the presence of histamine H(1 and H(2 antagonists. The mast cell stabilizer cromolyn attenuated compound 48/80 and nicotine evoked Ca(++ transients in mast cell-free enteric neuron cultures. CONCLUSIONS/SIGNIFICANCE: The results showed direct excitatory action of compound 48/80 on enteric neurons and visceral afferents. Therefore, functional changes measured in tissue or animal models may involve a mast cell independent effect of compound 48/80 and cromolyn.

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

    Science.gov (United States)

    de Arcangelis, L.

    2012-05-01

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

  16. Modelling small-patterned neuronal networks coupled to microelectrode arrays

    Science.gov (United States)

    Massobrio, Paolo; Martinoia, Sergio

    2008-09-01

    Cultured neurons coupled to planar substrates which exhibit 'well-defined' two-dimensional network architectures can provide valuable insights into cell-to-cell communication, network dynamics versus topology, and basic mechanisms of synaptic plasticity and learning. In the literature several approaches were presented to drive neuronal growth, such as surface modification by silane chemistry, photolithographic techniques, microcontact printing, microfluidic channel flow patterning, microdrop patterning, etc. This work presents a computational model fit for reproducing and explaining the dynamics exhibited by small-patterned neuronal networks coupled to microelectrode arrays (MEAs). The model is based on the concept of meta-neuron, i.e., a small spatially confined number of actual neurons which perform single macroscopic functions. Each meta-neuron is characterized by a detailed morphology, and the membrane channels are modelled by simple Hodgkin-Huxley and passive kinetics. The two main findings that emerge from the simulations can be summarized as follows: (i) the increasing complexity of meta-neuron morphology reflects the variations of the network dynamics as a function of network development; (ii) the dynamics displayed by the patterned neuronal networks considered can be explained by hypothesizing the presence of several short- and a few long-term distance interactions among small assemblies of neurons (i.e., meta-neurons).

  17. Ginsenoside Rb1 attenuates activated microglia-induced neuronal damage

    Institute of Scientific and Technical Information of China (English)

    Lining Ke; Wei Guo; Jianwen Xu; Guodong Zhang; Wei Wang; Wenhua Huang

    2014-01-01

    The microglia-mediated inlfammatory reaction promotes neuronal damage under cerebral isch-emia/hypoxia conditions. We therefore speculated that inhibition of hypoxia-induced microglial activation may alleviate neuronal damage. To test this hypothesis, we co-cultured ginsenoside Rb1, an active component of ginseng, and cortical neurons. Ginsenoside Rb1 protected neuronal morphology and structure in a single hypoxic culture system and in a hypoxic co-culture system with microglia, and reduced neuronal apoptosis and caspase-3 production. The protective effect was observable prior to placing in co-culture. Additionally, ginsenoside Rb1 inhibited levels of tumor necrosis factor-αin a co-culture system containing activated N9 microglial cells. Ginse-noside Rb1 also signiifcantly decreased nitric oxide and superoxide production induced by N9 microglia. Our ifndings indicate that ginsenoside Rb1 attenuates damage to cerebral cortex neu-rons by downregulation of nitric oxide, superoxide, and tumor necrosis factor-αexpression in hypoxia-activated microglia.

  18. Human Temporal Cortical Single Neuron Activity during Language: A Review

    Directory of Open Access Journals (Sweden)

    George A. Ojemann

    2013-04-01

    Full Text Available Findings from recordings of human temporal cortical single neuron activity during several measures of language, including object naming and word reading are reviewed and related to changes in activity in the same neurons during recent verbal memory and verbal associative learning measures, in studies conducted during awake neurosurgery for the treatment of epilepsy. The proportion of neurons changing activity with language tasks was similar in either hemisphere. Dominant hemisphere activity was characterized by relative inhibition, some of which occurred during overt speech, possibly to block perception of one’s own voice. However, the majority seems to represent a dynamic network becoming active with verbal memory encoding and especially verbal learning, but inhibited during performance of overlearned language tasks. Individual neurons are involved in different networks for different aspects of language, including naming or reading and naming in different languages. The majority of the changes in activity were tonic sustained shifts in firing. Patterned phasic activity for specific language items was very infrequently recorded. Human single neuron recordings provide a unique perspective on the biologic substrate for language, for these findings are in contrast to many of the findings from other techniques for investigating this.

  19. Nitric oxide regulates neuronal activity via calcium-activated potassium channels.

    Directory of Open Access Journals (Sweden)

    Lei Ray Zhong

    Full Text Available Nitric oxide (NO is an unconventional membrane-permeable messenger molecule that has been shown to play various roles in the nervous system. How NO modulates ion channels to affect neuronal functions is not well understood. In gastropods, NO has been implicated in regulating the feeding motor program. The buccal motoneuron, B19, of the freshwater pond snail Helisoma trivolvis is active during the hyper-retraction phase of the feeding motor program and is located in the vicinity of NO-producing neurons in the buccal ganglion. Here, we asked whether B19 neurons might serve as direct targets of NO signaling. Previous work established NO as a key regulator of growth cone motility and neuronal excitability in another buccal neuron involved in feeding, the B5 neuron. This raised the question whether NO might modulate the electrical activity and neuronal excitability of B19 neurons as well, and if so whether NO acted on the same or a different set of ion channels in both neurons. To study specific responses of NO on B19 neurons and to eliminate indirect effects contributed by other cells, the majority of experiments were performed on single cultured B19 neurons. Addition of NO donors caused a prolonged depolarization of the membrane potential and an increase in neuronal excitability. The effects of NO could mainly be attributed to the inhibition of two types of calcium-activated potassium channels, apamin-sensitive and iberiotoxin-sensitive potassium channels. NO was found to also cause a depolarization in B19 neurons in situ, but only after NO synthase activity in buccal ganglia had been blocked. The results suggest that NO acts as a critical modulator of neuronal excitability in B19 neurons, and that calcium-activated potassium channels may serve as a common target of NO in neurons.

  20. Caenorhabditis elegans glia modulate neuronal activity and behavior

    OpenAIRE

    Randy F Stout; Alexei eVerkhratsky; Vladimir eParpura

    2014-01-01

    Glial cells of Caenorhabditis elegans can modulate neuronal activity and behavior, which is the focus of this review. Initially, we provide an overview of neuroglial evolution, making a comparison between C. elegans glia and their genealogical counterparts. What follows is a brief discussion on C. elegans glia characteristics in terms of their exact numbers, germ layers origin, their necessity for proper development of sensory organs, and lack of their need for neuronal survival. The more spe...

  1. Interneuron-mediated inhibition synchronizes neuronal activity during slow oscillation

    Science.gov (United States)

    Chen, Jen-Yung; Chauvette, Sylvain; Skorheim, Steven; Timofeev, Igor; Bazhenov, Maxim

    2012-01-01

    The signature of slow-wave sleep in the electroencephalogram (EEG) is large-amplitude fluctuation of the field potential, which reflects synchronous alternation of activity and silence across cortical neurons. While initiation of the active cortical states during sleep slow oscillation has been intensively studied, the biological mechanisms which drive the network transition from an active state to silence remain poorly understood. In the current study, using a combination of in vivo electrophysiology and thalamocortical network simulation, we explored the impact of intrinsic and synaptic inhibition on state transition during sleep slow oscillation. We found that in normal physiological conditions, synaptic inhibition controls the duration and the synchrony of active state termination. The decline of interneuron-mediated inhibition led to asynchronous downward transition across the cortical network and broke the regular slow oscillation pattern. Furthermore, in both in vivo experiment and computational modelling, we revealed that when the level of synaptic inhibition was reduced significantly, it led to a recovery of synchronized oscillations in the form of seizure-like bursting activity. In this condition, the fast active state termination was mediated by intrinsic hyperpolarizing conductances. Our study highlights the significance of both intrinsic and synaptic inhibition in manipulating sleep slow rhythms. PMID:22641778

  2. Estimation of the neuronal activation using fMRI data: An observer-based approach

    KAUST Repository

    Laleg-Kirati, Taous-Meriem

    2013-06-01

    This paper deals with the estimation of the neuronal activation and some unmeasured physiological information using the Blood Oxygenation Level Dependent (BOLD) signal measured using functional Magnetic Resonance Imaging (fMRI). We propose to use an observer-based approach applied to the balloon hemodynamic model. The latter describes the relation between the neural activity and the BOLD signal. The balloon model can be expressed in a nonlinear state-space representation where the states, the parameters and the input (neuronal activation), are unknown. This study focuses only on the estimation of the hidden states and the neuronal activation. The model is first linearized around the equilibrium and an observer is applied to this linearized version. Numerical results performed on synthetic data are presented.

  3. NAA and NAAG variation in neuronal activation during visual stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Castellano, G.; Dias, C.S.B. [Grupo de Neurofísica, Departamento de Raios Cósmicos e Cronologia, Instituto de Física Gleb Wataghin, Universidade Estadual de Campinas, Campinas, SP (Brazil); Programa de Cooperação Interinstitucional de Apoio à Pesquisa sobre o Cérebro (CInAPCe), SP (Brazil); Foerster, B. [Philips Medical Systems, São Paulo, SP (Brazil); Programa de Cooperação Interinstitucional de Apoio à Pesquisa sobre o Cérebro (CInAPCe), SP (Brazil); Li, L.M. [Departamento de Neurologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP (Brazil); Programa de Cooperação Interinstitucional de Apoio à Pesquisa sobre o Cérebro (CInAPCe), SP (Brazil); Covolan, R.J.M. [Grupo de Neurofísica, Departamento de Raios Cósmicos e Cronologia, Instituto de Física Gleb Wataghin, Universidade Estadual de Campinas, Campinas, SP (Brazil); Programa de Cooperação Interinstitucional de Apoio à Pesquisa sobre o Cérebro (CInAPCe), SP (Brazil)

    2012-08-17

    N-acetyl-aspartyl-glutamate (NAAG) and its hydrolysis product N-acetyl-aspartate (NAA) are among the most important brain metabolites. NAA is a marker of neuron integrity and viability, while NAAG modulates glutamate release and may have a role in neuroprotection and synaptic plasticity. Investigating on a quantitative basis the role of these metabolites in brain metabolism in vivo by magnetic resonance spectroscopy (MRS) is a major challenge since the main signals of NAA and NAAG largely overlap. This is a preliminary study in which we evaluated NAA and NAAG changes during a visual stimulation experiment using functional MRS. The paradigm used consisted of a rest period (5 min and 20 s), followed by a stimulation period (10 min and 40 s) and another rest period (10 min and 40 s). MRS from 17 healthy subjects were acquired at 3T with TR/TE = 2000/288 ms. Spectra were averaged over subjects and quantified with LCModel. The main outcomes were that NAA concentration decreased by about 20% with the stimulus, while the concentration of NAAG concomitantly increased by about 200%. Such variations fall into models for the energy metabolism underlying neuronal activation that point to NAAG as being responsible for the hyperemic vascular response that causes the BOLD signal. They also agree with the fact that NAAG and NAA are present in the brain at a ratio of about 1:10, and with the fact that the only known metabolic pathway for NAAG synthesis is from NAA and glutamate.

  4. Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?

    Directory of Open Access Journals (Sweden)

    Janelle Drouin-Ouellet

    2017-09-01

    Full Text Available Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i what constitutes an iN cell, ii which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications.

  5. Mathematical modeling of the neuron morphology using two dimensional images.

    Science.gov (United States)

    Rajković, Katarina; Marić, Dušica L; Milošević, Nebojša T; Jeremic, Sanja; Arsenijević, Valentina Arsić; Rajković, Nemanja

    2016-02-01

    In this study mathematical analyses such as the analysis of area and length, fractal analysis and modified Sholl analysis were applied on two dimensional (2D) images of neurons from adult human dentate nucleus (DN). Using mathematical analyses main morphological properties were obtained including the size of neuron and soma, the length of all dendrites, the density of dendritic arborization, the position of the maximum density and the irregularity of dendrites. Response surface methodology (RSM) was used for modeling the size of neurons and the length of all dendrites. However, the RSM model based on the second-order polynomial equation was only possible to apply to correlate changes in the size of the neuron with other properties of its morphology. Modeling data provided evidence that the size of DN neurons statistically depended on the size of the soma, the density of dendritic arborization and the irregularity of dendrites. The low value of mean relative percent deviation (MRPD) between the experimental data and the predicted neuron size obtained by RSM model showed that model was suitable for modeling the size of DN neurons. Therefore, RSM can be generally used for modeling neuron size from 2D images.

  6. Multiscale modeling of brain dynamics: from single neurons and networks to mathematical tools.

    Science.gov (United States)

    Siettos, Constantinos; Starke, Jens

    2016-09-01

    The extreme complexity of the brain naturally requires mathematical modeling approaches on a large variety of scales; the spectrum ranges from single neuron dynamics over the behavior of groups of neurons to neuronal network activity. Thus, the connection between the microscopic scale (single neuron activity) to macroscopic behavior (emergent behavior of the collective dynamics) and vice versa is a key to understand the brain in its complexity. In this work, we attempt a review of a wide range of approaches, ranging from the modeling of single neuron dynamics to machine learning. The models include biophysical as well as data-driven phenomenological models. The discussed models include Hodgkin-Huxley, FitzHugh-Nagumo, coupled oscillators (Kuramoto oscillators, Rössler oscillators, and the Hindmarsh-Rose neuron), Integrate and Fire, networks of neurons, and neural field equations. In addition to the mathematical models, important mathematical methods in multiscale modeling and reconstruction of the causal connectivity are sketched. The methods include linear and nonlinear tools from statistics, data analysis, and time series analysis up to differential equations, dynamical systems, and bifurcation theory, including Granger causal connectivity analysis, phase synchronization connectivity analysis, principal component analysis (PCA), independent component analysis (ICA), and manifold learning algorithms such as ISOMAP, and diffusion maps and equation-free techniques. WIREs Syst Biol Med 2016, 8:438-458. doi: 10.1002/wsbm.1348 For further resources related to this article, please visit the WIREs website.

  7. Activation of Dopamine Neurons is Critical for Aversive Conditioning and Prevention of Generalized Anxiety

    OpenAIRE

    2011-01-01

    Generalized anxiety is thought to result, in part, from impairments in contingency awareness during conditioning to cues that predict aversive or fearful outcomes. Dopamine neurons of the ventral midbrain exhibit heterogeneous responses to aversive stimuli that are thought to provide a critical modulatory signal to facilitate orienting to environmental changes and assignment of motivational value to unexpected events. Here, we describe a mouse model in which activation of dopamine neurons in ...

  8. Pituitary Adenylate cyclase-activating polypeptide orchestrates neuronal regulation of the astrocytic glutamate-releasing mechanism system xc (.).

    Science.gov (United States)

    Kong, Linghai; Albano, Rebecca; Madayag, Aric; Raddatz, Nicholas; Mantsch, John R; Choi, SuJean; Lobner, Doug; Baker, David A

    2016-05-01

    Glutamate signaling is achieved by an elaborate network involving neurons and astrocytes. Hence, it is critical to better understand how neurons and astrocytes interact to coordinate the cellular regulation of glutamate signaling. In these studies, we used rat cortical cell cultures to examine whether neurons or releasable neuronal factors were capable of regulating system xc (-) (Sxc), a glutamate-releasing mechanism that is expressed primarily by astrocytes and has been shown to regulate synaptic transmission. We found that astrocytes cultured with neurons or exposed to neuronal-conditioned media displayed significantly higher levels of Sxc activity. Next, we demonstrated that the pituitary adenylate cyclase-activating polypeptide (PACAP) may be a neuronal factor capable of regulating astrocytes. In support, we found that PACAP expression was restricted to neurons, and that PACAP receptors were expressed in astrocytes. Interestingly, blockade of PACAP receptors in cultures comprised of astrocytes and neurons significantly decreased Sxc activity to the level observed in purified astrocytes, whereas application of PACAP to purified astrocytes increased Sxc activity to the level observed in cultures comprised of neurons and astrocytes. Collectively, these data reveal that neurons coordinate the actions of glutamate-related mechanisms expressed by astrocytes, such as Sxc, a process that likely involves PACAP. A critical gap in modeling excitatory signaling is how distinct components of the glutamate system expressed by neurons and astrocytes are coordinated. In these studies, we found that system xc (-) (Sxc), a glutamate release mechanism expressed by astrocytes, is regulated by releasable neuronal factors including PACAP. This represents a novel form of neuron-astrocyte communication, and highlights the possibility that pathological changes involving astrocytic Sxc may stem from altered neuronal activity.

  9. Stochastic models for spike trains of single neurons

    CERN Document Server

    Sampath, G

    1977-01-01

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

  10. Stochastic ion channel gating in dendritic neurons: morphology dependence and probabilistic synaptic activation of dendritic spikes.

    Directory of Open Access Journals (Sweden)

    Robert C Cannon

    Full Text Available Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels. While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology. We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes. Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location. For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability. Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one. At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model. These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments. Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites.

  11. Methamphetamine Regulation of Firing Activity of Dopamine Neurons.

    Science.gov (United States)

    Lin, Min; Sambo, Danielle; Khoshbouei, Habibeh

    2016-10-05

    Methamphetamine (METH) is a substrate for the dopamine transporter that increases extracellular dopamine levels by competing with dopamine uptake and increasing reverse transport of dopamine via the transporter. METH has also been shown to alter the excitability of dopamine neurons. The mechanism of METH regulation of the intrinsic firing behaviors of dopamine neurons is less understood. Here we identified an unexpected and unique property of METH on the regulation of firing activity of mouse dopamine neurons. METH produced a transient augmentation of spontaneous spike activity of midbrain dopamine neurons that was followed by a progressive reduction of spontaneous spike activity. Inspection of action potential morphology revealed that METH increased the half-width and produced larger coefficients of variation of the interspike interval, suggesting that METH exposure affected the activity of voltage-dependent potassium channels in these neurons. Since METH has been shown to affect Ca(2+) homeostasis, the unexpected findings that METH broadened the action potential and decreased the amplitude of afterhyperpolarization led us to ask whether METH alters the activity of Ca(2+)-activated potassium (BK) channels. First, we identified BK channels in dopamine neurons by their voltage dependence and their response to a BK channel blocker or opener. While METH suppressed the amplitude of BK channel-mediated unitary currents, the BK channel opener NS1619 attenuated the effects of METH on action potential broadening, afterhyperpolarization repression, and spontaneous spike activity reduction. Live-cell total internal reflection fluorescence microscopy, electrophysiology, and biochemical analysis suggest METH exposure decreased the activity of BK channels by decreasing BK-α subunit levels at the plasma membrane.

  12. Network activity of mirror neurons depends on experience.

    Science.gov (United States)

    Ushakov, Vadim L; Kartashov, Sergey I; Zavyalova, Victoria V; Bezverhiy, Denis D; Posichanyuk, Vladimir I; Terentev, Vasliliy N; Anokhin, Konstantin V

    2013-03-01

    In this work, the investigation of network activity of mirror neurons systems in animal brains depending on experience (existence or absence performance of the shown actions) was carried out. It carried out the research of mirror neurons network in the C57/BL6 line mice in the supervision task of swimming mice-demonstrators in Morris water maze. It showed the presence of mirror neurons systems in the motor cortex M1, M2, cingular cortex, hippocampus in mice groups, having experience of the swimming and without it. The conclusion is drawn about the possibility of the new functional network systems formation by means of mirror neurons systems and the acquisition of new knowledge through supervision by the animals in non-specific tasks.

  13. A Phase-Locking Analysis of Neuronal Firing Rhythms with Transcranial Magneto-Acoustical Stimulation Based on the Hodgkin-Huxley Neuron Model.

    Science.gov (United States)

    Yuan, Yi; Pang, Na; Chen, Yudong; Wang, Yi; Li, Xiaoli

    2017-01-01

    Transcranial magneto-acoustical stimulation (TMAS) uses ultrasonic waves and a static magnetic field to generate electric current in nerve tissues for the purpose of modulating neuronal activities. It has the advantage of high spatial resolution and penetration depth. Neuronal firing rhythms carry and transmit nerve information in neural systems. In this study, we investigated the phase-locking characteristics of neuronal firing rhythms with TMAS based on the Hodgkin-Huxley neuron model. The simulation results indicate that the modulation frequency of ultrasound can affect the phase-locking behaviors. The results of this study may help us to explain the potential firing mechanism of TMAS.

  14. Comparison of icilin- and cold-evoked responses of spinal neurones, and their modulation of mechanical activity, in a model of neuropathic pain.

    Science.gov (United States)

    Brignell, Jennifer L; Chapman, Victoria; Kendall, David A

    2008-06-18

    Cold allodynia is a poorly understood symptom of neuropathic pain. Two members of the transient receptor potential (TRP) family of proteins, TRPM8 and TRPA1, may contribute to cold somatosensation. The aim of the present study was to investigate the usefulness of icilin as a pharmacological tool to study primary afferent fibre responses to cold stimuli and to determine whether there are differences in the responses of spinal neurones to cooling of peripheral receptive fields in control versus neuropathic rats. The effects of icilin, a TRPM8 and TRPA1 agonist, on intracellular Ca(2+) ([Ca(2+)](i)) responses of small diameter adult dorsal root ganglia (DRG) neurones were determined. Icilin (10 nM-10 microM) produced a concentration-related increase in [Ca(2+)](i) in DRG neurones, which was attenuated by the non-selective TRP channel antagonist ruthenium red (10 microM). In vivo electrophysiology in naïve, sham-operated and SNL rats demonstrated that application of ice to receptive fields evoked firing of wide dynamic range (WDR) neurones, which was significantly greater in SNL rats than naïve and sham-operated rats. Intraplantar injection of icilin did not evoke firing of WDR neurones in naïve, sham-operated or SNL rats but inhibited mechanically-evoked responses of WDR neurones in naïve and sham-operated rats, whilst facilitating mechanically-evoked responses in SNL rats. Icilin increased both innocuous (sham-operated and SNL rats) and noxious (SNL rats) receptive field sizes of WDR neurones. Our data suggests that icilin modulates the mechanosensitivity of dorsal horn neurones. The differing effects of ice and icilin on dorsal horn neurones indicate different mechanisms of action.

  15. Evidence that adiponectin receptor 1 activation exacerbates ischemic neuronal death

    Directory of Open Access Journals (Sweden)

    Thundyil John

    2010-08-01

    Full Text Available Abstract Background- Adiponectin is a hormone produced in and released from adipose cells, which has been shown to have anti-diabetic and anti-inflammatory actions in peripheral cells. Two cell surface adiponectin receptors (ADRs mediate the majority of the known biological actions of adiponectin. Thus far, ADR expression in the brain has been demonstrated in the arcuate and the paraventricular nucleus of hypothalamus, where its activation affects food intake. Recent findings suggest that levels of circulating adiponectin increase after an ischemic stroke, but the role of adiponectin receptor activation in stroke pathogenesis and its functional outcome is unclear. Methods- Ischemic stroke was induced in C57BL/6 mice by middle cerebral artery occlusion (MCAO for 1 h, followed by reperfusion. Primary cortical neuronal cultures were established from individual embryonic neocortex. For glucose deprivation (GD, cultured neurons were incubated in glucose-free Locke's medium for 6, 12 or 24 h. For combined oxygen and glucose deprivation (OGD, neurons were incubated in glucose-free Locke's medium in an oxygen-free chamber with 95% N2/5% CO2 atmosphere for either 3, 6, 9, 12 or 24 h. Primary neurons and brain tissues were analysed for Adiponectin and ADRs using reverse transcriptase polymerase chain reaction (RT-PCR, immunoblot and immunochemistry methods. Results- Cortical neurons express ADR1 and ADR2, and that the levels of ADR1 are increased in neurons in response to in vitro or in vivo ischemic conditions. Neurons treated with either globular or trimeric adiponectin exhibited increased vulnerability to oxygen and glucose deprivation which was associated with increased activation of a pro-apoptotic signaling cascade involving p38 mitogen-activated protein kinase (p38MAPK and AMP-activated protein kinase (AMPK. Conclusions- This study reveals a novel pathogenic role for adiponectin and adiponectin receptor activation in ischemic stroke. We show that

  16. The impact of neuronal Notch-1/JNK pathway on intracerebral hemorrhage-induced neuronal injury of rat model.

    Science.gov (United States)

    Chen, Maohua; Sun, Jun; Lu, Chuan; Chen, Xiandong; Ba, Huajun; Lin, Qun; Cai, Jianyong; Dai, Junxia

    2016-11-08

    Notch signaling is a highly conserved pathway that regulates cell fate decisions during embryonic development. Notch activation endangers neurons by modulating NF-κB and HIF-1α pathways, however, the role of Notch signaling in activating JNK/c-Jun following intracerebral hemorrhage (ICH) has not been investigated. In this study, we used rat ICH models and thrombin-induced cell models to investigate the potential role of Notch-1/JNK signals. Our findings revealed that Notch-1 and JNK increased in hematoma-surrounding neurons tissues following ICH during ischemic conditions (all pNotch-1, p-JNK, and active caspase-3 were all up-regulated in cell viability-decreasing ICH cell models (all pNotch-1 or JNK suppressed the phosphorylation of JNK and the expression of active caspase-3, and cell viability was obviously ameliorated. In conclusion, this work suggested Notch-1 activates JNK pathway to induce the active caspase-3, leading to neuronal injury when intracerebral hemorrhage or ischemia occurred. Thus the Notch-1/JNK signal pathway has an important role in ICH process, and may be a therapeutic target to prevent brain injury.

  17. Self-organization of synchronous activity propagation in neuronal networks driven by local excitation

    Directory of Open Access Journals (Sweden)

    Mehdi eBayati

    2015-06-01

    Full Text Available Many experimental and theoretical studies have suggested that the reliable propagation of synchronous neural activity is crucial for neural information processing. The propagation of synchronous firing activity in so-called synfirechains has been studied extensively in feed-forward networks ofspiking neurons. However, it remains unclear how such neural activity could emerge in recurrentneuronal networks through synaptic plasticity. In this study, we investigate whether local excitation, i.e., neurons that fire at a higherfrequency than the other, spontaneously active neurons in the network, can shapea network to allow for synchronous activity propagation. We use two-dimensional,locally connected and heterogeneous neuronal networks with spike-timingdependent plasticity (STDP. We find that, in our model, local excitation drives profound network changes within seconds. In the emergent network, neural activity propagates synchronously through the network. Thisactivity originates from the site of the local excitation and propagates throughthe network.The synchronous activity propagation persists, even when the local excitation is removed, since it derives from the synaptic weight matrix. Importantly, once this connectivity is established it remains stable even inthe presence of spontaneous activity. Our results suggest that synfire-chain-like activity can emerge in a relativelysimple way in realistic neural networks by locally exciting the desired originof the neuronal sequence.

  18. Toward on-chip functional neuronal networks: computational study on the effect of synaptic connectivity on neural activity.

    Science.gov (United States)

    Foroushani, Armin Najarpour; Ghafar-Zadeh, Ebrahim

    2014-01-01

    This paper presents a new unified computational-experimental approach to study the role of the synaptic activity on the activity of neurons in the small neuronal networks (NNs). In a neuronal tissue/organ, this question is investigated with higher complexities by recording action potentials from population of neurons in order to find the relationship between connectivity and the recorded activities. In this approach, we study the dynamics of very small cortical neuronal networks, which can be experimentally synthesized on chip with constrained connectivity. Multi-compartmental Hodgkin-Huxley model is used in NEURON software to reproduce cells by extracting the experimental data from the synthesized NNs. We thereafter demonstrate how the type of synaptic activity affects the network response to specific spike train using the simulation results.

  19. Astrocyte plasticity: implications for synaptic and neuronal activity.

    Science.gov (United States)

    Pirttimaki, Tiina M; Parri, H Rheinallt

    2013-12-01

    Astrocytes are increasingly implicated in a range of functions in the brain, many of which were previously ascribed to neurons. Much of the prevailing interest centers on the role of astrocytes in the modulation of synaptic transmission and their involvement in the induction of forms of plasticity such as long-term potentiation and long-term depression. However, there is also an increasing realization that astrocytes themselves can undergo plasticity. This plasticity may be manifest as changes in protein expression which may modify calcium activity within the cells, changes in morphology that affect the environment of the synapse and the extracellular space, or changes in gap junction astrocyte coupling that modify the transfer of ions and metabolites through astrocyte networks. Plasticity in the way that astrocytes release gliotransmitters can also have direct effects on synaptic activity and neuronal excitability. Astrocyte plasticity can potentially have profound effects on neuronal network activity and be recruited in pathological conditions. An emerging principle of astrocyte plasticity is that it is often induced by neuronal activity, reinforcing our emerging understanding of the working brain as a constant interaction between neurons and glial cells.

  20. Loss of STAT3 signaling during elevated activity causes vulnerability in hippocampal neurons

    OpenAIRE

    2012-01-01

    Chronically altered levels of network activity lead to changes in the morphology and functions of neurons. However, little is known of how changes in neuronal activity alter the intracellular signaling pathways mediating neuronal survival. Here we use primary cultures of rat hippocampal neurons to show that elevated neuronal activity impairs phosphorylation of the serine/threonine kinase, Erk1/2 and the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylatio...

  1. NKCC1 Activation Is Required for Myelinated Sensory Neurons Regeneration through JNK-Dependent Pathway.

    Science.gov (United States)

    Mòdol, Laura; Santos, Daniel; Cobianchi, Stefano; González-Pérez, Francisco; López-Alvarez, Víctor; Navarro, Xavier

    2015-05-13

    After peripheral nerve injury, axons are able to regenerate, although specific sensory reinnervation and functional recovery are usually worse for large myelinated than for small sensory axons. The mechanisms that mediate the regeneration of different sensory neuron subpopulations are poorly known. The Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) is particularly relevant in setting the intracellular chloride concentration. After axotomy, increased NKCC1 phosphorylation has been reported to be important for neurite outgrowth of sensory neurons; however, the mechanisms underlying its effects are still unknown. In the present study we used in vitro and in vivo models to assess the differential effects of blocking NKCC1 activity on the regeneration of different types of dorsal root ganglia (DRGs) neurons after sciatic nerve injury in the rat. We observed that blocking NKCC1 activity by bumetanide administration induces a selective effect on neurite outgrowth and regeneration of myelinated fibers without affecting unmyelinated DRG neurons. To further study the mechanism underlying NKCC1 effects, we also assessed the changes in mitogen-activated protein kinase (MAPK) signaling under NKCC1 modulation. The inhibition of NKCC1 activity in vitro and in vivo modified pJNK1/2/3 expression in DRG neurons. Together, our study identifies a mechanism selectively contributing to myelinated axon regeneration, and point out the role of Cl(-) modulation in DRG neuron regeneration and in the activation of MAPKs, particularly those belonging to the JNK family. Copyright © 2015 the authors 0270-6474/15/357414-14$15.00/0.

  2. Simple cortical and thalamic neuron models for digital arithmetic circuit implementation

    Directory of Open Access Journals (Sweden)

    Takuya eNanami

    2016-05-01

    Full Text Available Trade-off between reproducibility of neuronal activities and computational efficiency is one ofcrucial subjects in computational neuroscience and neuromorphic engineering. A wide variety ofneuronal models have been studied from different viewpoints. The digital spiking silicon neuron(DSSN model is a qualitative model that focuses on efficient implementation by digital arithmeticcircuits. We expanded the DSSN model and found appropriate parameter sets with which itreproduces the dynamical behaviors of the ionic-conductance models of four classes of corticaland thalamic neurons. We first developed a 4-variable model by reducing the number of variablesin the ionic-conductance models and elucidated its mathematical structures using bifurcationanalysis. Then, expanded DSSN models were constructed that reproduce these mathematicalstructures and capture the characteristic behavior of each neuron class. We confirmed thatstatistics of the neuronal spike sequences are similar in the DSSN and the ionic-conductancemodels. Computational cost of the DSSN model is larger than that of the recent sophisticatedIntegrate-and-Fire-based models, but smaller than the ionic-conductance models. This modelis intended to provide another meeting point for above trade-off that satisfies the demand forlarge-scale neuronal network simulation with closer-to-biology models.

  3. Phasic dopamine neuron activity elicits unique mesofrontal plasticity in adolescence.

    Science.gov (United States)

    Mastwal, Surjeet; Ye, Yizhou; Ren, Ming; Jimenez, Dennisse V; Martinowich, Keri; Gerfen, Charles R; Wang, Kuan Hong

    2014-07-16

    The mesofrontal dopaminergic circuit, which connects the midbrain motivation center to the cortical executive center, is engaged in control of motivated behaviors. In addition, deficiencies in this circuit are associated with adolescent-onset psychiatric disorders in humans. Developmental studies suggest that the mesofrontal circuit exhibits a protracted maturation through adolescence. However, whether the structure and function of this circuit are modifiable by activity in dopaminergic neurons during adolescence remains unknown. Using optogenetic stimulation and in vivo two-photon imaging in adolescent mice, we found that phasic, but not tonic, dopamine neuron activity induces the formation of mesofrontal axonal boutons. In contrast, in adult mice, the effect of phasic activity diminishes. Furthermore, our results showed that dopaminergic and glutamatergic transmission regulate this axonal plasticity in adolescence and inhibition of dopamine D2-type receptors restores this plasticity in adulthood. Finally, we found that phasic activation of dopamine neurons also induces greater changes in mesofrontal circuit activity and psychomotor response in adolescent mice than in adult mice. Together, our findings demonstrate that the structure and function of the mesofrontal circuit are modifiable by phasic activity in dopaminergic neurons during adolescence and suggest that the greater plasticity in adolescence may facilitate activity-dependent strengthening of dopaminergic input and improvement in behavioral control.

  4. Leptin excites POMC neurons via activation of TRPC channels

    Science.gov (United States)

    Qiu, Jian; Fang, Yuan; Rønnekleiv, Oline K.; Kelly, Martin J.

    2010-01-01

    Leptin can exert its potent appetite-suppressing effects via activation of hypothalamic proopiomelanocortin (POMC) neurons. It depolarizes POMC neurons via activation of a yet unidentified non-selective cation current. Therefore, we sought to identify the conductance activated by leptin using whole cell recording in EGFP-POMC neurons from transgenic mice. The TRPC channel blockers SKF96365, FFA and 2-APB potently inhibited the leptin-induced current. Also, lanthanum (La3+) and intracellular Ca2+ potentiated the effects of leptin. Moreover, the DAG permeable analog OAG failed to activate any TRPC current. Using a Cs+-gluconate-based internal solution, leptin-activated current reversed near -20 mV. After replacement of external Na+ and K+ with Cs+, the reversal shifted to near 0 mV, and the I/V curve exhibited a negative slope conductance at voltages more negative than –40 mV. Based on scRT-PCR, TRPC1 and TRPC4-7 mRNA were expressed in POMC neurons with TRPC5 being the most prevalent. The leptin-induced current was blocked by Jak2 inhibitor AG490, the PI3 Kinase inhibitor wortmannin and the phospholipase C inhibitors, U73122 and ET-18-OCH3. Notably, we identified PLCγ1 transcripts in the majority of POMC neurons. Therefore, leptin through a Jak2-PI3 kinase-PLCγ pathway activates TRPC channels, and TRPC1, 4 and 5 appear to be the key channels mediating the depolarizing effects of leptin in POMC neurons. PMID:20107083

  5. Importance of being Nernst: Synaptic activity andfunctional relevance in stem cell-derived neurons

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Functional synaptogenesis and network emergence aresignature endpoints of neurogenesis. These behaviorsprovide higher-order confirmation that biochemicaland cellular processes necessary for neurotransmitterrelease, post-synaptic detection and network propagation of neuronal activity have been properly expressed andcoordinated among cells. The development of synapticneurotransmission can therefore be considered a definingproperty of neurons. Although dissociated primaryneuron cultures readily form functioning synapsesand network behaviors in vitro , continuously culturedneurogenic cell lines have historically failed to meet thesecriteria. Therefore, in vitro -derived neuron models thatdevelop synaptic transmission are critically needed for awide array of studies, including molecular neuroscience,developmental neurogenesis, disease research andneurotoxicology. Over the last decade, neurons derivedfrom various stem cell lines have shown varying ability todevelop into functionally mature neurons. In this review,we will discuss the neurogenic potential of various stemcells populations, addressing strengths and weaknessesof each, with particular attention to the emergenceof functional behaviors. We will propose methods tofunctionally characterize new stem cell-derived neuron(SCN) platforms to improve their reliability as physiologicalrelevant models. Finally, we will review howsynaptically active SCNs can be applied to accelerateresearch in a variety of areas. Ultimately, emphasizingthe critical importance of synaptic activity and networkresponses as a marker of neuronal maturation is anticipatedto result in in vitro findings that better translateto efficacious clinical treatments.

  6. SIMPEL: Circuit model for photonic spike processing laser neurons

    CERN Document Server

    Shastri, Bhavin J; Tait, Alexander N; Wu, Ben; Prucnal, Paul R

    2014-01-01

    We propose an equivalent circuit model for photonic spike processing laser neurons with an embedded saturable absorber---a simulation model for photonic excitable lasers (SIMPEL). We show that by mapping the laser neuron rate equations into a circuit model, SPICE analysis can be used as an efficient and accurate engine for numerical calculations, capable of generalization to a variety of different laser neuron types found in literature. The development of this model parallels the Hodgkin--Huxley model of neuron biophysics, a circuit framework which brought efficiency, modularity, and generalizability to the study of neural dynamics. We employ the model to study various signal-processing effects such as excitability with excitatory and inhibitory pulses, binary all-or-nothing response, and bistable dynamics.

  7. Somatostatin and Somatostatin-Containing Neurons in Shaping Neuronal Activity and Plasticity.

    Science.gov (United States)

    Liguz-Lecznar, Monika; Urban-Ciecko, Joanna; Kossut, Malgorzata

    2016-01-01

    Since its discovery over four decades ago, somatostatin (SOM) receives growing scientific and clinical interest. Being localized in the nervous system in a subset of interneurons somatostatin acts as a neurotransmitter or neuromodulator and its role in the fine-tuning of neuronal activity and involvement in synaptic plasticity and memory formation are widely recognized in the recent literature. Combining transgenic animals with electrophysiological, anatomical and molecular methods allowed to characterize several subpopulations of somatostatin-containing interneurons possessing specific anatomical and physiological features engaged in controlling the output of cortical excitatory neurons. Special characteristic and connectivity of somatostatin-containing neurons set them up as significant players in shaping activity and plasticity of the nervous system. However, somatostatin is not just a marker of particular interneuronal subpopulation. Somatostatin itself acts pre- and postsynaptically, modulating excitability and neuronal responses. In the present review, we combine the knowledge regarding somatostatin and somatostatin-containing interneurons, trying to incorporate it into the current view concerning the role of the somatostatinergic system in cortical plasticity.

  8. Stochastic biomathematical models with applications to neuronal modeling

    CERN Document Server

    Batzel, Jerry; Ditlevsen, Susanne

    2013-01-01

    Stochastic biomathematical models are becoming increasingly important as new light is shed on the role of noise in living systems. In certain biological systems, stochastic effects may even enhance a signal, thus providing a biological motivation for the noise observed in living systems. Recent advances in stochastic analysis and increasing computing power facilitate the analysis of more biophysically realistic models, and this book provides researchers in computational neuroscience and stochastic systems with an overview of recent developments. Key concepts are developed in chapters written by experts in their respective fields. Topics include: one-dimensional homogeneous diffusions and their boundary behavior, large deviation theory and its application in stochastic neurobiological models, a review of mathematical methods for stochastic neuronal integrate-and-fire models, stochastic partial differential equation models in neurobiology, and stochastic modeling of spreading cortical depression.

  9. Neuronal activity enhances tau propagation and tau pathology in vivo.

    Science.gov (United States)

    Wu, Jessica W; Hussaini, S Abid; Bastille, Isle M; Rodriguez, Gustavo A; Mrejeru, Ana; Rilett, Kelly; Sanders, David W; Cook, Casey; Fu, Hongjun; Boonen, Rick A C M; Herman, Mathieu; Nahmani, Eden; Emrani, Sheina; Figueroa, Y Helen; Diamond, Marc I; Clelland, Catherine L; Wray, Selina; Duff, Karen E

    2016-08-01

    Tau protein can transfer between neurons transneuronally and trans-synaptically, which is thought to explain the progressive spread of tauopathy observed in the brain of patients with Alzheimer's disease. Here we show that physiological tau released from donor cells can transfer to recipient cells via the medium, suggesting that at least one mechanism by which tau can transfer is via the extracellular space. Neuronal activity has been shown to regulate tau secretion, but its effect on tau pathology is unknown. Using optogenetic and chemogenetic approaches, we found that increased neuronal activity stimulates the release of tau in vitro and enhances tau pathology in vivo. These data have implications for disease pathogenesis and therapeutic strategies for Alzheimer's disease and other tauopathies.

  10. Action observation activates neurons of the monkey ventrolateral prefrontal cortex

    Science.gov (United States)

    Simone, Luciano; Bimbi, Marco; Rodà, Francesca; Fogassi, Leonardo; Rozzi, Stefano

    2017-01-01

    Prefrontal cortex is crucial for exploiting contextual information for the planning and guidance of behavioral responses. Among contextual cues, those provided by others’ behavior are particularly important, in primates, for selecting appropriate reactions and suppressing the inappropriate ones. These latter functions deeply rely on the ability to understand others’ actions. However, it is largely unknown whether prefrontal neurons are activated by action observation. To address this issue, we recorded the activity of ventrolateral prefrontal (VLPF) neurons of macaque monkeys during the observation of videos depicting biological movements performed by a monkey or a human agent, and object motion. Our results show that a population of VLPF neurons respond to the observation of biological movements, in particular those representing goal directed actions. Many of these neurons also show a preference for the agent performing the action. The neural response is present also when part of the observed movement is obscured, suggesting that these VLPF neurons code a high order representation of the observed action rather than a simple visual description of it. PMID:28290511

  11. Modelling spatiotemporal olfactory data in two steps: from binary to Hodgkin-Huxley neurones.

    Science.gov (United States)

    Quenet, Brigitte; Dubois, Rémi; Sirapian, Sevan; Dreyfus, Gérard; Horn, David

    2002-01-01

    Network models of synchronously updated McCulloch-Pitts neurones exhibit complex spatiotemporal patterns that are similar to activities of biological neurones in phase with a periodic local field potential, such as those observed experimentally by Wehr and Laurent (1996, Nature 384, 162-166) in the locust olfactory pathway. Modelling biological neural nets with networks of simple formal units makes the dynamics of the model analytically tractable. It is thus possible to determine the constraints that must be satisfied by its connection matrix in order to make its neurones exhibit a given sequence of activity (see, for instance, Quenet et al., 2001, Neurocomputing 38-40, 831-836). In the present paper, we address the following question: how can one construct a formal network of Hodgkin-Huxley (HH) type neurones that reproduces experimentally observed neuronal codes? A two-step strategy is suggested in the present paper: first, a simple network of binary units is designed, whose activity reproduces the binary experimental codes; second, this model is used as a guide to design a network of more realistic formal HH neurones. We show that such a strategy is indeed fruitful: it allowed us to design a model that reproduces the Wehr-Laurent olfactory codes, and to investigate the robustness of these codes to synaptic noise.

  12. Behavioural effects of chemogenetic dopamine neuron activation

    NARCIS (Netherlands)

    Boekhoudt, L

    2016-01-01

    Various psychiatric disorders, including schizophrenia, attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder, have been associated with altered dopamine signalling in the brain. However, it remains unclear which specific changes in dopamine activity are related to specific p

  13. Silibinin activates AMP-activated protein kinase to protect neuronal cells from oxygen and glucose deprivation-re-oxygenation.

    Science.gov (United States)

    Xie, Zhi; Ding, Sheng-quan; Shen, Ya-fang

    2014-11-14

    In this study, we explored the cytoprotective potential of silibinin against oxygen-glucose deprivation (OGD)-induced neuronal cell damages, and studied underling mechanisms. In vitro model of ischemic stroke was created by keeping neuronal cells (SH-SY5Y cells and primary mouse cortical neurons) in an OGD condition followed by re-oxygenation. Pre-treatment of silibinin significantly inhibited OGD/re-oxygenation-induced necrosis and apoptosis of neuronal cells. OGD/re-oxygenation-induced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) reduction were also inhibited by silibinin. At the molecular level, silibinin treatment in SH-SY5Y cells and primary cortical neurons led to significant AMP-activated protein kinase (AMPK) signaling activation, detected by phosphorylations of AMPKα1, its upstream kinase liver kinase B1 (LKB1) and the downstream target acetyl-CoA Carboxylase (ACC). Pharmacological inhibition or genetic depletion of AMPK alleviated the neuroprotective ability of silibinin against OGD/re-oxygenation. Further, ROS scavenging ability by silibinin was abolished with AMPK inhibition or silencing. While A-769662, the AMPK activator, mimicked silibinin actions and suppressed ROS production and neuronal cell death following OGD/re-oxygenation. Together, these results show that silibinin-mediated neuroprotection requires activation of AMPK signaling.

  14. Central vagal stimulation activates enteric cholinergic neurons in the stomach and VIP neurons in the duodenum in conscious rats.

    Science.gov (United States)

    Yuan, Pu-Qing; Kimura, Hiroshi; Million, Mulugeta; Bellier, Jean-Pierre; Wang, Lixin; Ohning, Gordon V; Taché, Yvette

    2005-04-01

    The influence of central vagal stimulation induced by 2h cold exposure or intracisternal injection of thyrotropin-releasing hormone (TRH) analog, RX-77368, on gastro-duodenal enteric cholinergic neuronal activity was assessed in conscious rats with Fos and peripheral choline acetyltransferase (pChAT) immunoreactivity (IR). pChAT-IR was detected in 68%, 70% and 73% of corpus, antrum and duodenum submucosal neurons, respectively, and in 65% of gastric and 46% of duodenal myenteric neurons. Cold and RX-77368 induced Fos-IR in over 90% of gastric submucosal and myenteric neurons, while in duodenum only 25-27% of submucosal and 50-51% myenteric duodenal neurons were Fos positive. In the stomach, cold induced Fos-IR in 93% of submucosal and 97% of myenteric pChAT-IR neurons, while in the duodenum only 7% submucosal and 5% myenteric pChAT-IR neurons were Fos positive. In the duodenum, cold induced Fos in 91% of submucosal and 99% of myenteric VIP-IR neurons. RX-77368 induces similar percentages of Fos/pChAT-IR and Fos/VIP-IR neurons. These results indicate that increased central vagal outflow activates cholinergic neurons in the stomach while in the duodenum, VIP neurons are preferentially stimulated.

  15. Neuron Loss in Transgenic Mouse Models of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Oliver Wirths

    2010-01-01

    Full Text Available Since their initial generation in the mid 1990s, transgenic mouse models of Alzheimers's disease (AD have been proven to be valuable model systems which are indispensable for modern AD research. Whereas most of these models are characterized by extensive amyloid plaque pathology, inflammatory changes and often behavioral deficits, modeling of neuron loss was much less successful. The present paper discusses the current achievements of modeling neuron loss in transgenic mouse models based on APP/Aβ and Tau overexpression and provides an overview of currently available AD mouse models showing these pathological alterations.

  16. Neuronal Activity Regulates Hippocampal miRNA Expression

    NARCIS (Netherlands)

    Eacker, Stephen M.; Keuss, Matthew J.; Berezikov, Eugene; Dawson, Valina L.; Dawson, Ted M.

    2011-01-01

    Neuronal activity regulates a broad range of processes in the hippocampus, including the precise regulation of translation. Disruptions in proper translational control in the nervous system are associated with a variety of disorders that fall in the autistic spectrum. MicroRNA (miRNA) represent a re

  17. A Neuron Model Based Ultralow Current Sensor System for Bioapplications

    Directory of Open Access Journals (Sweden)

    A. K. M. Arifuzzman

    2016-01-01

    Full Text Available An ultralow current sensor system based on the Izhikevich neuron model is presented in this paper. The Izhikevich neuron model has been used for its superior computational efficiency and greater biological plausibility over other well-known neuron spiking models. Of the many biological neuron spiking features, regular spiking, chattering, and neostriatal spiny projection spiking have been reproduced by adjusting the parameters associated with the model at hand. This paper also presents a modified interpretation of the regular spiking feature in which the firing pattern is similar to that of the regular spiking but with improved dynamic range offering. The sensor current ranges between 2 pA and 8 nA and exhibits linearity in the range of 0.9665 to 0.9989 for different spiking features. The efficacy of the sensor system in detecting low amount of current along with its high linearity attribute makes it very suitable for biomedical applications.

  18. Pseudorabies virus infection alters neuronal activity and connectivity in vitro.

    Directory of Open Access Journals (Sweden)

    Kelly M McCarthy

    2009-10-01

    Full Text Available Alpha-herpesviruses, including human herpes simplex virus 1 & 2, varicella zoster virus and the swine pseudorabies virus (PRV, infect the peripheral nervous system of their hosts. Symptoms of infection often include itching, numbness, or pain indicative of altered neurological function. To determine if there is an in vitro electrophysiological correlate to these characteristic in vivo symptoms, we infected cultured rat sympathetic neurons with well-characterized strains of PRV known to produce virulent or attenuated symptoms in animals. Whole-cell patch clamp recordings were made at various times after infection. By 8 hours of infection with virulent PRV, action potential (AP firing rates increased substantially and were accompanied by hyperpolarized resting membrane potentials and spikelet-like events. Coincident with the increase in AP firing rate, adjacent neurons exhibited coupled firing events, first with AP-spikelets and later with near identical resting membrane potentials and AP firing. Small fusion pores between adjacent cell bodies formed early after infection as demonstrated by transfer of the low molecular weight dye, Lucifer Yellow. Later, larger pores formed as demonstrated by transfer of high molecular weight Texas red-dextran conjugates between infected cells. Further evidence for viral-induced fusion pores was obtained by infecting neurons with a viral mutant defective for glycoprotein B, a component of the viral membrane fusion complex. These infected neurons were essentially identical to mock infected neurons: no increased AP firing, no spikelet-like events, and no electrical or dye transfer. Infection with PRV Bartha, an attenuated circuit-tracing strain delayed, but did not eliminate the increased neuronal activity and coupling events. We suggest that formation of fusion pores between infected neurons results in electrical coupling and elevated firing rates, and that these processes may contribute to the altered neural

  19. Computational Study of Subdural Cortical Stimulation: Effects of Simulating Anisotropic Conductivity on Activation of Cortical Neurons.

    Directory of Open Access Journals (Sweden)

    Hyeon Seo

    Full Text Available Subdural cortical stimulation (SuCS is an appealing method in the treatment of neurological disorders, and computational modeling studies of SuCS have been applied to determine the optimal design for electrotherapy. To achieve a better understanding of computational modeling on the stimulation effects of SuCS, the influence of anisotropic white matter conductivity on the activation of cortical neurons was investigated in a realistic head model. In this paper, we constructed pyramidal neuronal models (layers 3 and 5 that showed primary excitation of the corticospinal tract, and an anatomically realistic head model reflecting complex brain geometry. The anisotropic information was acquired from diffusion tensor magnetic resonance imaging (DT-MRI and then applied to the white matter at various ratios of anisotropic conductivity. First, we compared the isotropic and anisotropic models; compared to the isotropic model, the anisotropic model showed that neurons were activated in the deeper bank during cathodal stimulation and in the wider crown during anodal stimulation. Second, several popular anisotropic principles were adapted to investigate the effects of variations in anisotropic information. We observed that excitation thresholds varied with anisotropic principles, especially with anodal stimulation. Overall, incorporating anisotropic conductivity into the anatomically realistic head model is critical for accurate estimation of neuronal responses; however, caution should be used in the selection of anisotropic information.

  20. Laser speckle contrast reveals cerebral blood flow dynamics evoked by optogenetically controlled neuronal activity

    Science.gov (United States)

    Li, Nan; Thakor, Nitish V.; Pelled, Galit

    2013-03-01

    As a critical basis of functional brain imaging, neurovascular coupling describes the link between neuronal and hemodynamic changes. The majority of in vivo neurovascular coupling studies was performed by inducing sensory stimulation via afferent inputs. Unfortunately such an approach results in recruiting of multiple types of cells, which confounds the explanation of neuronal roles in stimulus evoked hemodynamic changes. Recently optogenetics has emerged to provide immediate control of neurons by exciting or inhibiting genetically engineered neurons expressing light sensitive proteins. However, there is a need for optical methods capable of imaging the concurrent hemodynamic changes. We utilize laser speckle contrast imaging (LSCI) to obtain high resolution display of cerebral blood flow (CBF) in the vicinity of the targeted neural population. LSCI is a minimally invasive method for imaging CBF in microvessels through thinned skull, and produces images with high spatiotemporal resolution, wide field of view. In the integrated system light sources with different wavelengths and band-passing/blocking filters were used to allow simultaneous optical manipulation of neuronal activities and optical imaging of corresponding CBF. Experimental studies were carried out in a rodent model expressing channalrhodopsin (ChR2) in excitatory neurons in the somatosensory cortex (S1). The results demonstrated significant increases of CBF in response to ChR2 stimulation (exciting neuronal firing) comparable to the CBF response to contralateral forepaw stimulation. The approach promises to be an exciting minimally invasive method to study neurovascular coupling. The complete system provides a novel approach for broad neuroscience applications.

  1. Direct Evaluation of L-DOPA Actions on Neuronal Activity of Parkinsonian Tissue In Vitro

    Science.gov (United States)

    Plata, Víctor; Pérez-Ortega, Jesús E.; Galarraga, Elvira; Bargas, José

    2013-01-01

    Physiological and biochemical experiments in vivo and in vitro have explored striatal receptor signaling and neuronal excitability to posit pathophysiological models of Parkinson's disease. However, when therapeutic approaches, such as dopamine agonists, need to be evaluated, behavioral tests using animal models of Parkinson's disease are employed. To our knowledge, recordings of population neuronal activity in vitro to assess anti-Parkinsonian drugs and the correlation of circuit dynamics with disease state have only recently been attempted. We have shown that Parkinsonian pathological activity of neuronal striatal circuits can be characterized in in vitro cerebral tissue. Here, we show that calcium imaging techniques, capable of recording dozens of neurons simultaneously with single-cell resolution, can be extended to assess the action of therapeutic drugs. We used L-DOPA as a prototypical anti-Parkinsonian drug to show the efficiency of this proposed bioassay. In a rodent model of early Parkinson's disease, Parkinsonian neuronal activity can be returned to control levels by the bath addition of L-DOPA in a reversible way. This result raises the possibility to use calcium imaging techniques to measure, quantitatively, the actions of anti-Parkinsonian drugs over time and to obtain correlations with disease evolution and behavior. PMID:24151606

  2. Direct Evaluation of L-DOPA Actions on Neuronal Activity of Parkinsonian Tissue In Vitro

    Directory of Open Access Journals (Sweden)

    Víctor Plata

    2013-01-01

    Full Text Available Physiological and biochemical experiments in vivo and in vitro have explored striatal receptor signaling and neuronal excitability to posit pathophysiological models of Parkinson's disease. However, when therapeutic approaches, such as dopamine agonists, need to be evaluated, behavioral tests using animal models of Parkinson's disease are employed. To our knowledge, recordings of population neuronal activity in vitro to assess anti-Parkinsonian drugs and the correlation of circuit dynamics with disease state have only recently been attempted. We have shown that Parkinsonian pathological activity of neuronal striatal circuits can be characterized in in vitro cerebral tissue. Here, we show that calcium imaging techniques, capable of recording dozens of neurons simultaneously with single-cell resolution, can be extended to assess the action of therapeutic drugs. We used L-DOPA as a prototypical anti-Parkinsonian drug to show the efficiency of this proposed bioassay. In a rodent model of early Parkinson's disease, Parkinsonian neuronal activity can be returned to control levels by the bath addition of L-DOPA in a reversible way. This result raises the possibility to use calcium imaging techniques to measure, quantitatively, the actions of anti-Parkinsonian drugs over time and to obtain correlations with disease evolution and behavior.

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

    Science.gov (United States)

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

    2017-03-01

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

  4. A Statistical Model for In Vivo Neuronal Dynamics.

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    Simone Carlo Surace

    Full Text Available Single neuron models have a long tradition in computational neuroscience. Detailed biophysical models such as the Hodgkin-Huxley model as well as simplified neuron models such as the class of integrate-and-fire models relate the input current to the membrane potential of the neuron. Those types of models have been extensively fitted to in vitro data where the input current is controlled. Those models are however of little use when it comes to characterize intracellular in vivo recordings since the input to the neuron is not known. Here we propose a novel single neuron model that characterizes the statistical properties of in vivo recordings. More specifically, we propose a stochastic process where the subthreshold membrane potential follows a Gaussian process and the spike emission intensity depends nonlinearly on the membrane potential as well as the spiking history. We first show that the model has a rich dynamical repertoire since it can capture arbitrary subthreshold autocovariance functions, firing-rate adaptations as well as arbitrary shapes of the action potential. We then show that this model can be efficiently fitted to data without overfitting. We finally show that this model can be used to characterize and therefore precisely compare various intracellular in vivo recordings from different animals and experimental conditions.

  5. SUN11602 has basic fibroblast growth factor-like activity and attenuates neuronal damage and cognitive deficits in a rat model of Alzheimer's disease induced by amyloid β and excitatory amino acids.

    Science.gov (United States)

    Ogino, Ryoko; Murayama, Norihito; Noshita, Takafumi; Takemoto, Naohiro; Toba, Tetsuya; Oka, Tetsushi; Narii, Nobuhiro; Yoshida, Sayaka; Ueno, Nobuhiro; Inoue, Teruyoshi

    2014-10-17

    Basic fibroblast growth factor (bFGF/FGF-2) is known to possess neuroprotective and neurite outgrowth activity properties. In this study, the effects of a novel synthetic compound that mimics the neuroprotective properties of bFGF - SUN11602 - were examined in vitro and in vivo. SUN11602 promoted neurite outgrowth of primarily cultured rat hippocampal neurons. For the in vivo study, an Alzheimer's disease (AD) model with severe damage to the hippocampal tissue was constructed by injecting the hippocampi of rats with aggregated Aβ1-40, followed 48 h later by an injection of ibotenate [an agonist for N-methyl-d-aspartate (NMDA) receptor]. Oral administration of SUN11602 at the midpoint of Aβ1-40 and ibotenate injections attenuated short-term memory impairment in the Y-maze test, as well as spatial learning deficits in the water maze task. In addition, the SUN11602 treatment inhibited the increase of peripheral-type benzodiazepine-binding sites (PTBBS), which are a marker for gliosis. A negative correlation was found between PTBBS numbers and learning capacity in the water maze task. These results suggest that SUN111602 improved memory and learning deficits in the hippocampally lesioned rats by preventing neuronal death and/or promotion of neurite outgrowth. Taken together, these results indicate that SUN11602, a bFGF-like compound with neuroprotective and neurite outgrowth activity, may be beneficial for the treatment of progressive neurodegenerative diseases such as AD.

  6. Probing the dynamics of identified neurons with a data-driven modeling approach.

    Directory of Open Access Journals (Sweden)

    Thomas Nowotny

    Full Text Available In controlling animal behavior the nervous system has to perform within the operational limits set by the requirements of each specific behavior. The implications for the corresponding range of suitable network, single neuron, and ion channel properties have remained elusive. In this article we approach the question of how well-constrained properties of neuronal systems may be on the neuronal level. We used large data sets of the activity of isolated invertebrate identified cells and built an accurate conductance-based model for this cell type using customized automated parameter estimation techniques. By direct inspection of the data we found that the variability of the neurons is larger when they are isolated from the circuit than when in the intact system. Furthermore, the responses of the neurons to perturbations appear to be more consistent than their autonomous behavior under stationary conditions. In the developed model, the constraints on different parameters that enforce appropriate model dynamics vary widely from some very tightly controlled parameters to others that are almost arbitrary. The model also allows predictions for the effect of blocking selected ionic currents and to prove that the origin of irregular dynamics in the neuron model is proper chaoticity and that this chaoticity is typical in an appropriate sense. Our results indicate that data driven models are useful tools for the in-depth analysis of neuronal dynamics. The better consistency of responses to perturbations, in the real neurons as well as in the model, suggests a paradigm shift away from measuring autonomous dynamics alone towards protocols of controlled perturbations. Our predictions for the impact of channel blockers on the neuronal dynamics and the proof of chaoticity underscore the wide scope of our approach.

  7. Activating STAT3 Alpha for Promoting Healing of Neurons

    Science.gov (United States)

    Conway, Greg

    2008-01-01

    A method of promoting healing of injured or diseased neurons involves pharmacological activation of the STAT3 alpha protein. Usually, injured or diseased neurons heal incompletely or not at all for two reasons: (1) they are susceptible to apoptosis (cell death); and (2) they fail to engage in axogenesis that is, they fail to re-extend their axons to their original targets (e.g., muscles or other neurons) because of insufficiency of compounds, denoted neurotrophic factors, needed to stimulate such extension. The present method (see figure) of treatment takes advantage of prior research findings to the effect that the STAT3 alpha protein has anti-apoptotic and pro-axogenic properties.

  8. Both barium and calcium activate neuronal potassium currents

    Energy Technology Data Exchange (ETDEWEB)

    Ribera, A.B.; Spitzer, N.C.

    1987-09-01

    Amphibian spinal neurons in culture possess both rapidly inactivating and sustained calcium-dependent potassium current components, similar to those described for other cells. Divalent cation-dependent whole-cell outward currents were isolated by subtracting the voltage-dependent potassium currents recorded from Xenopus laevis neurons in the presence of impermeant cadmium from the currents produced without cadmium but in the presence of permeant divalent cations. These concentrations of permeant ions were low enough to avoid contamination by macroscopic inward currents through calcium channels. Calcium-dependent potassium currents were reduced by 1 ..mu..M tetraethylammonium. These currents can also be activated by barium or strontium. Barium as well as calcium activated outward currents in young neurons (6-8 hr) and in relatively mature neurons (19-26 hr in vitro). However, barium influx appeared to suppress the sustained voltage-dependent potassium current in most cells. Barium also activated at least one class of potassium channels observed in excised membrane patches, whole blocking others. The blocking action may have masked and hindered detection of the stimulatory action of barium in other systems.

  9. The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity

    Directory of Open Access Journals (Sweden)

    Yves eKellner

    2014-03-01

    Full Text Available The fine tuning of neural networks during development and learning relies upon both functional and structural plastic processes. Changes in the number as well as in the size and shape of dendritic spines are associated to long-term activity-dependent synaptic plasticity. However, the molecular mechanisms translating functional into structural changes are still largely unknown. In this context, neurotrophins, like Brain-Derived Neurotrophic Factor (BDNF, are among promising candidates. Specifically BDNF-TrkB receptor signaling is crucial for activity-dependent strengthening of synapses in different brain regions. BDNF application has been shown to positively modulate dendritic and spine architecture in cortical and hippocampal neurons as well as structural plasticity in vitro. However, a global BDNF deprivation throughout the central nervous system (CNS resulted in very mild structural alterations of dendritic spines, questioning the relevance of the endogenous BDNF signaling in modulating the development and the mature structure of neurons in vivo. Here we show that a loss-of-function approach, blocking BDNF results in a significant reduction in dendritic spine density, associated with an increase in spine length and a decrease in head width. These changes are associated with a decrease in F-actin levels within spine heads. On the other hand, a gain-of-function approach, applying exogenous BDNF, could not reproduce the increase in spine density or the changes in spine morphology previously described. Taken together, we show here that the effects exerted by BDNF on the dendritic architecture of hippocampal neurons are dependent on the neuron’s maturation stage. Indeed, in mature hippocampal neurons in vitro as shown in vivo BDNF is specifically required for the activity-dependent maintenance of the mature spine phenotype.

  10. Automatic fitting of spiking neuron models to electrophysiological recordings

    Directory of Open Access Journals (Sweden)

    Cyrille Rossant

    2010-03-01

    Full Text Available Spiking models can accurately predict the spike trains produced by cortical neurons in response to somatically injected currents. Since the specific characteristics of the model depend on the neuron, a computational method is required to fit models to electrophysiological recordings. The fitting procedure can be very time consuming both in terms of computer simulations and in terms of code writing. We present algorithms to fit spiking models to electrophysiological data (time-varying input and spike trains that can run in parallel on graphics processing units (GPUs. The model fitting library is interfaced with Brian, a neural network simulator in Python. If a GPU is present it uses just-in-time compilation to translate model equations into optimized code. Arbitrary models can then be defined at script level and run on the graphics card. This tool can be used to obtain empirically validated spiking models of neurons in various systems. We demonstrate its use on public data from the INCF Quantitative Single-Neuron Modeling 2009 competition by comparing the performance of a number of neuron spiking models.

  11. Hyperbolic Plykin attractor can exist in neuron models

    DEFF Research Database (Denmark)

    Belykh, V.; Belykh, I.; Mosekilde, Erik

    2005-01-01

    Strange hyperbolic attractors are hard to find in real physical systems. This paper provides the first example of a realistic system, a canonical three-dimensional (3D) model of bursting neurons, that is likely to have a strange hyperbolic attractor. Using a geometrical approach to the study...... of the neuron model, we derive a flow-defined Poincare map giving ail accurate account of the system's dynamics. In a parameter region where the neuron system undergoes bifurcations causing transitions between tonic spiking and bursting, this two-dimensional map becomes a map of a disk with several periodic...... holes. A particular case is the map of a disk with three holes, matching the Plykin example of a planar hyperbolic attractor. The corresponding attractor of the 3D neuron model appears to be hyperbolic (this property is not verified in the present paper) and arises as a result of a two-loop (secondary...

  12. Inhibitory short-term plasticity modulates neuronal activity in the rat entopeduncular nucleus in vitro.

    Science.gov (United States)

    Lavian, Hagar; Korngreen, Alon

    2016-04-01

    The entopeduncular nucleus (EP) is one of the basal ganglia output nuclei integrating synaptic information from several pathways within the basal ganglia. The firing of EP neurons is modulated by two streams of inhibitory synaptic transmission, the direct pathway from the striatum and the indirect pathway from the globus pallidus. These two inhibitory pathways continuously modulate the firing of EP neurons. However, the link between these synaptic inputs to neuronal firing in the EP is unclear. To investigate this input-output transformation we performed whole-cell and perforated-patch recordings from single neurons in the entopeduncular nucleus in rat brain slices during repetitive stimulation of the striatum and the globus pallidus at frequencies within the in vivo activity range of these neurons. These recordings, supplemented by compartmental modelling, showed that GABAergic synapses from the striatum, converging on EP dendrites, display short-term facilitation and that somatic or proximal GABAergic synapses from the globus pallidus show short-term depression. Activation of striatal synapses during low presynaptic activity decreased postsynaptic firing rate by continuously increasing the inter-spike interval. Conversely, activation of pallidal synapses significantly affected postsynaptic firing during high presynaptic activity. Our data thus suggest that low-frequency striatal output may be encoded as progressive phase shifts in downstream nuclei of the basal ganglia while high-frequency pallidal output may continuously modulate EP firing.

  13. Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution.

    Science.gov (United States)

    Herculano-Houzel, Suzana

    2011-03-01

    It is usually considered that larger brains have larger neurons, which consume more energy individually, and are therefore accompanied by a larger number of glial cells per neuron. These notions, however, have never been tested. Based on glucose and oxygen metabolic rates in awake animals and their recently determined numbers of neurons, here I show that, contrary to the expected, the estimated glucose use per neuron is remarkably constant, varying only by 40% across the six species of rodents and primates (including humans). The estimated average glucose use per neuron does not correlate with neuronal density in any structure. This suggests that the energy budget of the whole brain per neuron is fixed across species and brain sizes, such that total glucose use by the brain as a whole, by the cerebral cortex and also by the cerebellum alone are linear functions of the number of neurons in the structures across the species (although the average glucose consumption per neuron is at least 10× higher in the cerebral cortex than in the cerebellum). These results indicate that the apparently remarkable use in humans of 20% of the whole body energy budget by a brain that represents only 2% of body mass is explained simply by its large number of neurons. Because synaptic activity is considered the major determinant of metabolic cost, a conserved energy budget per neuron has several profound implications for synaptic homeostasis and the regulation of firing rates, synaptic plasticity, brain imaging, pathologies, and for brain scaling in evolution.

  14. Iterative learning control algorithm for spiking behavior of neuron model

    Science.gov (United States)

    Li, Shunan; Li, Donghui; Wang, Jiang; Yu, Haitao

    2016-11-01

    Controlling neurons to generate a desired or normal spiking behavior is the fundamental building block of the treatment of many neurologic diseases. The objective of this work is to develop a novel control method-closed-loop proportional integral (PI)-type iterative learning control (ILC) algorithm to control the spiking behavior in model neurons. In order to verify the feasibility and effectiveness of the proposed method, two single-compartment standard models of different neuronal excitability are specifically considered: Hodgkin-Huxley (HH) model for class 1 neural excitability and Morris-Lecar (ML) model for class 2 neural excitability. ILC has remarkable advantages for the repetitive processes in nature. To further highlight the superiority of the proposed method, the performances of the iterative learning controller are compared to those of classical PI controller. Either in the classical PI control or in the PI control combined with ILC, appropriate background noises are added in neuron models to approach the problem under more realistic biophysical conditions. Simulation results show that the controller performances are more favorable when ILC is considered, no matter which neuronal excitability the neuron belongs to and no matter what kind of firing pattern the desired trajectory belongs to. The error between real and desired output is much smaller under ILC control signal, which suggests ILC of neuron’s spiking behavior is more accurate.

  15. Relaxation and self-sustained oscillations in the time elapsed neuron network model

    CERN Document Server

    Pakdaman, Khashayar; Salort, Delphine

    2011-01-01

    The time elapsed model describes the firing activity of an homogeneous assembly of neurons thanks to the distribution of times elapsed since the last discharge. It gives a mathematical description of the probability density of neurons structured by this time. In an earlier work, based on generalized relative entropy methods, it is proved that for highly or weakly connected networks the model exhibits relaxation to the steady state and for moderately connected networks it is obtained numerical evidence of appearance of self-sustained periodic solutions. Here, we go further and, using the particular form of the model, we quantify the regime where relaxation to a stationary state occurs in terms of the network connectivity. To introduce our methodology, we first consider the case where the neurons are not connected and we give a new statement showing that total asynchronous firing of neurons appears asymptotically. In a second step, we consider the case with connections and give a low connectivity condition that...

  16. Brain stimulation used as biofeedback in neuronal activation of the temporal lobe area in autistic children

    Directory of Open Access Journals (Sweden)

    Vernon Furtado da Silva

    2016-08-01

    Full Text Available ABSTRACT This study focused upon the functional capacity of mirror neurons in autistic children. 30 individuals, 10 carriers of the autistic syndrome (GCA, 10 with intellectual impairments (GDI, and 10 non-autistics (GCN had registered eletroencephalogram from the brain area theoretically related to mirror neurons. Data collection procedure occurred prior to brain stimulation and after the stimulation session. During the second session, participants had to alternately process figures evoking neutral, happy, and/or sorrowful feelings. Results proved that, for all groups, the stimulation process in fact produced additional activation in the neural area under study. The level of activation was related to the format of emotional stimuli and the likelihood of boosting such stimuli. Since the increase of activation occurred in a model similar to the one observed for the control group, we may suggest that the difficulty people with autism have at expressing emotions is not due to nonexistence of mirror neurons.

  17. Modeling the Development of Goal-Specificity in Mirror Neurons.

    Science.gov (United States)

    Thill, Serge; Svensson, Henrik; Ziemke, Tom

    2011-12-01

    Neurophysiological studies have shown that parietal mirror neurons encode not only actions but also the goal of these actions. Although some mirror neurons will fire whenever a certain action is perceived (goal-independently), most will only fire if the motion is perceived as part of an action with a specific goal. This result is important for the action-understanding hypothesis as it provides a potential neurological basis for such a cognitive ability. It is also relevant for the design of artificial cognitive systems, in particular robotic systems that rely on computational models of the mirror system in their interaction with other agents. Yet, to date, no computational model has explicitly addressed the mechanisms that give rise to both goal-specific and goal-independent parietal mirror neurons. In the present paper, we present a computational model based on a self-organizing map, which receives artificial inputs representing information about both the observed or executed actions and the context in which they were executed. We show that the map develops a biologically plausible organization in which goal-specific mirror neurons emerge. We further show that the fundamental cause for both the appearance and the number of goal-specific neurons can be found in geometric relationships between the different inputs to the map. The results are important to the action-understanding hypothesis as they provide a mechanism for the emergence of goal-specific parietal mirror neurons and lead to a number of predictions: (1) Learning of new goals may mostly reassign existing goal-specific neurons rather than recruit new ones; (2) input differences between executed and observed actions can explain observed corresponding differences in the number of goal-specific neurons; and (3) the percentage of goal-specific neurons may differ between motion primitives.

  18. 3D-printer visualization of neuron models

    Directory of Open Access Journals (Sweden)

    Robert A McDougal

    2015-06-01

    Full Text Available Neurons come in a wide variety of shapes and sizes. In a quest to understand this neuronal diversity, researchers have three-dimensionally traced tens of thousands of neurons; many of these tracings are freely available through online repositories like NeuroMorpho.Org and ModelDB. Tracings can be visualized on the computer screen, used for statistical analysis of the properties of different cell types, used to simulate neuronal behavior, and more. We introduce the use of 3D printing as a technique for visualizing traced morphologies. Our method for generating printable versions of a cell or group of cells is to expand dendrite and axon diameters and then to transform the wireframe tracing into a 3D object with a neuronal surface generating algorithm like Constructive Tessellated Neuronal Geometry (CTNG. We show that 3D printed cells can be readily examined, manipulated, and compared with other neurons to gain insight into both the biology and the reconstruction process. We share our printable models in a new database, 3DModelDB, and encourage others to do the same with cells that they generate using our code or other methods. To provide additional context, 3DModelDB provides a simulatable version of each cell, links to papers that use or describe it, and links to associated entries in other databases.

  19. 3D-printer visualization of neuron models.

    Science.gov (United States)

    McDougal, Robert A; Shepherd, Gordon M

    2015-01-01

    Neurons come in a wide variety of shapes and sizes. In a quest to understand this neuronal diversity, researchers have three-dimensionally traced tens of thousands of neurons; many of these tracings are freely available through online repositories like NeuroMorpho.Org and ModelDB. Tracings can be visualized on the computer screen, used for statistical analysis of the properties of different cell types, used to simulate neuronal behavior, and more. We introduce the use of 3D printing as a technique for visualizing traced morphologies. Our method for generating printable versions of a cell or group of cells is to expand dendrite and axon diameters and then to transform the tracing into a 3D object with a neuronal surface generating algorithm like Constructive Tessellated Neuronal Geometry (CTNG). We show that 3D printed cells can be readily examined, manipulated, and compared with other neurons to gain insight into both the biology and the reconstruction process. We share our printable models in a new database, 3DModelDB, and encourage others to do the same with cells that they generate using our code or other methods. To provide additional context, 3DModelDB provides a simulatable version of each cell, links to papers that use or describe it, and links to associated entries in other databases.

  20. An experimental electronic model for a neuronal cell

    Science.gov (United States)

    Campos-Cantón, I.; Rangel-López, A.; Martel-Gallegos, G.; Zarazúa, S.; Vertiz-Hérnandez, A.

    2014-04-01

    Over the last two decades, the study of information transmission in living beings has acquired great relevance, because it regulates and conducts the functioning of all of the organs in the body. In information transmission pathways, the neuron plays an important role in that it receives, transmits, and processes electrical signals from different parts of the human body; these signals are transmitted as electrical impulses called action potentials, and they transmit information from one neuron to another. In this work, and with the aim of developing experiments for teaching biological processes, we implemented an electronic circuit of the neuron cell device and its mathematical model based on piecewise linear functions.

  1. Persistent dynamic attractors in activity patterns of cultured neuronal networks

    Science.gov (United States)

    Wagenaar, Daniel A.; Nadasdy, Zoltan; Potter, Steve M.

    2006-05-01

    Three remarkable features of the nervous system—complex spatiotemporal patterns, oscillations, and persistent activity—are fundamental to such diverse functions as stereotypical motor behavior, working memory, and awareness. Here we report that cultured cortical networks spontaneously generate a hierarchical structure of periodic activity with a strongly stereotyped population-wide spatiotemporal structure demonstrating all three fundamental properties in a recurring pattern. During these “superbursts,” the firing sequence of the culture periodically converges to a dynamic attractor orbit. Precursors of oscillations and persistent activity have previously been reported as intrinsic properties of the neurons. However, complex spatiotemporal patterns that are coordinated in a large population of neurons and persist over several hours—and thus are capable of representing and preserving information—cannot be explained by known oscillatory properties of isolated neurons. Instead, the complexity of the observed spatiotemporal patterns implies large-scale self-organization of neurons interacting in a precise temporal order even in vitro, in cultures usually considered to have random connectivity.

  2. Activity deprivation induces neuronal cell death: mediation by tissue-type plasminogen activator.

    Directory of Open Access Journals (Sweden)

    Eldi Schonfeld-Dado

    Full Text Available Spontaneous activity is an essential attribute of neuronal networks and plays a critical role in their development and maintenance. Upon blockade of activity with tetrodotoxin (TTX, neurons degenerate slowly and die in a manner resembling neurodegenerative diseases-induced neuronal cell death. The molecular cascade leading to this type of slow cell death is not entirely clear. Primary post-natal cortical neurons were exposed to TTX for up to two weeks, followed by molecular, biochemical and immunefluorescence analysis. The expression of the neuronal marker, neuron specific enolase (NSE, was down-regulated, as expected, but surprisingly, there was a concomitant and striking elevation in expression of tissue-type plasminogen activator (tPA. Immunofluorescence analysis indicated that tPA was highly elevated inside affected neurons. Transfection of an endogenous tPA inhibitor, plasminogen activator inhibitor-1 (PAI-1, protected the TTX-exposed neurons from dying. These results indicate that tPA is a pivotal player in slowly progressing activity deprivation-induced neurodegeneration.

  3. Insulin-Dependent Activation of MCH Neurons Impairs Locomotor Activity and Insulin Sensitivity in Obesity.

    Science.gov (United States)

    Hausen, A Christine; Ruud, Johan; Jiang, Hong; Hess, Simon; Varbanov, Hristo; Kloppenburg, Peter; Brüning, Jens C

    2016-12-06

    Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus (LH) are critical regulators of energy and glucose homeostasis. Here, we demonstrate that insulin increases the excitability of these neurons in control mice. In vivo, insulin promotes phosphatidylinositol 3-kinase (PI3K) signaling in MCH neurons, and cell-type-specific deletion of the insulin receptor (IR) abrogates this response. While lean mice lacking the IR in MCH neurons (IR(ΔMCH)) exhibit no detectable metabolic phenotype under normal diet feeding, they present with improved locomotor activity and insulin sensitivity under high-fat-diet-fed, obese conditions. Similarly, obesity promotes PI3 kinase signaling in these neurons, and this response is abrogated in IR(ΔMCH) mice. In turn, acute chemogenetic activation of MCH neurons impairs locomotor activity but not insulin sensitivity. Collectively, our experiments reveal an insulin-dependent activation of MCH neurons in obesity, which contributes via distinct mechanisms to the manifestation of impaired locomotor activity and insulin resistance.

  4. The effect of neuronal conditional knock-out of peroxisome proliferator-activated receptors in the MPTP mouse model of Parkinson's disease.

    Science.gov (United States)

    Mounsey, R B; Martin, H L; Nelson, M C; Evans, R M; Teismann, P

    2015-08-06

    Activation of peroxisome proliferator-activated receptors (PPARs), namely PPARγ and PPARδ, has been shown to provide neuroprotection in a number of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease (PD). The observed neuroprotective effects in experimental models of PD have been linked to anti-oxidant and anti-inflammatory actions. This study aimed to analyze the full influence of these receptors in neuroprotection by generating a nerve cell-specific conditional knock-out of these receptors and subjecting these genetically modified mice to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to model dopaminergic degeneration. Mice null for both receptors show the lowest levels of tyrosine hydroxylase (TH)-positive cell bodies following MPTP administration. Presence of one or both these receptors show a trend toward protection against this degeneration, as higher dopaminergic cell immunoreactivity and striatal monoamine levels are evident. These data supplement recent studies that have elected to use agonists of the receptors to regulate immune responses. The results place further importance on the activation of PPARs and the neuroprotective roles these have in inflammatory processes linked to neurodegenerative processes. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. An electromechanical model of neuronal dynamics using Hamilton's principle

    Science.gov (United States)

    Drapaca, Corina S.

    2015-01-01

    Damage of the brain may be caused by mechanical loads such as penetration, blunt force, shock loading from blast, and by chemical imbalances due to neurological diseases and aging that trigger not only neuronal degeneration but also changes in the mechanical properties of brain tissue. An understanding of the interconnected nature of the electro-chemo-mechanical processes that result in brain damage and ultimately loss of functionality is currently lacking. While modern mathematical models that focus on how to link brain mechanics to its biochemistry are essential in enhancing our understanding of brain science, the lack of experimental data required by these models as well as the complexity of the corresponding computations render these models hard to use in clinical applications. In this paper we propose a unified variational framework for the modeling of neuronal electromechanics. We introduce a constrained Lagrangian formulation that takes into account Newton's law of motion of a linear viscoelastic Kelvin–Voigt solid-state neuron as well as the classic Hodgkin–Huxley equations of the electronic neuron. The system of differential equations describing neuronal electromechanics is obtained by applying Hamilton's principle. Numerical simulations of possible damage dynamics in neurons will be presented. PMID:26236195

  6. An electromechanical model of neuronal dynamics using Hamilton's principle.

    Science.gov (United States)

    Drapaca, Corina S

    2015-01-01

    Damage of the brain may be caused by mechanical loads such as penetration, blunt force, shock loading from blast, and by chemical imbalances due to neurological diseases and aging that trigger not only neuronal degeneration but also changes in the mechanical properties of brain tissue. An understanding of the interconnected nature of the electro-chemo-mechanical processes that result in brain damage and ultimately loss of functionality is currently lacking. While modern mathematical models that focus on how to link brain mechanics to its biochemistry are essential in enhancing our understanding of brain science, the lack of experimental data required by these models as well as the complexity of the corresponding computations render these models hard to use in clinical applications. In this paper we propose a unified variational framework for the modeling of neuronal electromechanics. We introduce a constrained Lagrangian formulation that takes into account Newton's law of motion of a linear viscoelastic Kelvin-Voigt solid-state neuron as well as the classic Hodgkin-Huxley equations of the electronic neuron. The system of differential equations describing neuronal electromechanics is obtained by applying Hamilton's principle. Numerical simulations of possible damage dynamics in neurons will be presented.

  7. An Electromechanical Model of Neuronal Dynamics using Hamilton's Principle

    Directory of Open Access Journals (Sweden)

    Corina Stefania Drapaca

    2015-07-01

    Full Text Available Damage of the brain may be caused by mechanical loads such as penetration, blunt force, shock loading from blast, and by chemical imbalances due to neurological diseases and aging that trigger not only neuronal degeneration but also changes in the mechanical properties of brain tissue. An understanding of the interconnected nature of the electro-chemo-mechanical processes that result in brain damage and ultimately loss of functionality is currently lacking. While modern mathematical models that focus on how to link brain mechanics to its biochemistry are essential in enhancing our understanding of brain science, the lack of experimental data required by these models as well as the complexity of the corresponding computations render these models hard to use in clinical applications. In this paper we propose a unified variational framework for the modeling of neuronal electromechanics. We introduce a constrained Lagrangian formulation that takes into account Newton's law of motion of a linear viscoelastic Kelvin-Voigt solid-state neuron as well as the classic Hodgkin-Huxley equations of the electronic neuron. The system of differential equations describing neuronal electromechanics is obtained by applying Hamilton's principle. Numerical simulations of possible damage dynamics in neurons will be presented.

  8. Modelling of the enteric nervous network: 3. Adrenergic neuron.

    Science.gov (United States)

    Miftakhov, R N; Wingate, D L

    1994-11-01

    A mathematical model is developed to investigate the coupled electrochemical processes of nerve-pulse transmission via adrenergic synapse. Based on pharmacological and morphophysiological data, the model describes the dynamics of the propagation of the electric signal along the unmyelinated geometrically non-uniform axon of the neuron and the chemical mechanisms of the transformation of the electrical signal in the synaptic zone into the post-synaptic output. The combined nonlinear system of partial and ordinary differential equations has been obtained and solved numerically. The results of computer simulation of the function of the idealized adrenergic neuron quantitatively and qualitatively describe the dynamics of Ca2+ ion influx into the terminal, noradrenaline release from the free 'releasable' store, its diffusion into the synaptic cleft, binding with the adrenoceptors on the pre- and post-synaptic structures with the generation of the inhibitory post-synaptic potential, and utilization of noradrenaline by neuronal and non-neuronal capture mechanisms.

  9. The influence of neuronal density and maturation on network activity of hippocampal cell cultures: a methodological study

    National Research Council Canada - National Science Library

    Biffi, Emilia; Regalia, Giulia; Menegon, Andrea; Ferrigno, Giancarlo; Pedrocchi, Alessandra

    2013-01-01

    .... Neuronal cultures plated with different cell densities differ in number of synapses per neuron and thus in single neuron synaptic transmission, which results in a density-dependent neuronal network activity...

  10. Mathematical Modeling of Subthreshold Resonant Properties in Pyloric Dilator Neurons

    OpenAIRE

    Vazifehkhah Ghaffari, Babak; Kouhnavard, Mojgan; Aihara, Takeshi; Kitajima, Tatsuo

    2015-01-01

    Various types of neurons exhibit subthreshold resonance oscillation (preferred frequency response) to fluctuating sinusoidal input currents. This phenomenon is well known to influence the synaptic plasticity and frequency of neural network oscillation. This study evaluates the resonant properties of pacemaker pyloric dilator (PD) neurons in the central pattern generator network through mathematical modeling. From the pharmacological point of view, calcium currents cannot be blocked in PD neur...

  11. Cofilin Inhibition Restores Neuronal Cell Death in Oxygen-Glucose Deprivation Model of Ischemia.

    Science.gov (United States)

    Madineni, Anusha; Alhadidi, Qasim; Shah, Zahoor A

    2016-03-01

    Ischemia is a condition associated with decreased blood supply to the brain, eventually leading to death of neurons. It is associated with a diverse cascade of responses involving both degenerative and regenerative mechanisms. At the cellular level, the changes are initiated prominently in the neuronal cytoskeleton. Cofilin, a cytoskeletal actin severing protein, is known to be involved in the early stages of apoptotic cell death. Evidence supports its intervention in the progression of disease states like Alzheimer's and ischemic kidney disease. In the present study, we have hypothesized the possible involvement of cofilin in ischemia. Using PC12 cells and mouse primary cultures of cortical neurons, we investigated the potential role of cofilin in ischemia in two different in vitro ischemic models: chemical induced oxidative stress and oxygen-glucose deprivation/reperfusion (OGD/R). The expression profile studies demonstrated a decrease in phosphocofilin levels in all models of ischemia, implying stress-induced cofilin activation. Furthermore, calcineurin and slingshot 1L (SSH) phosphatases were found to be the signaling mediators of the cofilin activation. In primary cultures of cortical neurons, cofilin was found to be significantly activated after 1 h of OGD. To delineate the role of activated cofilin in ischemia, we knocked down cofilin by small interfering RNA (siRNA) technique and tested the impact of cofilin silencing on neuronal viability. Cofilin siRNA-treated neurons showed a significant reduction of cofilin levels in all treatment groups (control, OGD, and OGD/R). Additionally, cofilin siRNA-reduced cofilin mitochondrial translocation and caspase 3 cleavage, with a concomitant increase in neuronal viability. These results strongly support the active role of cofilin in ischemia-induced neuronal degeneration and apoptosis. We believe that targeting this protein mediator has a potential for therapeutic intervention in ischemic brain injury and stroke.

  12. Visual input controls the functional activity of goldfish Mauthner neuron through the reciprocal synaptic mechanism.

    Science.gov (United States)

    Moshkov, Dmitry A; Shtanchaev, Rashid S; Mikheeva, Irina B; Bezgina, Elena N; Kokanova, Nadezhda A; Mikhailova, Gulnara Z; Tiras, Nadezhda R; Pavlik, Lyubov' L

    2013-03-01

    decrease of active zones dimensions in both serotonergic and inhibitory synapses. Finally, it was determined in model experiments that the interaction of globular actin with glycine, a main inhibitory neurotransmitter supposedly directly and chronically affecting the ventral dendrite, results in actin filaments formation. It is assumed that glycine-induced cytosolic actin polymerization is a cause of reduction in the ventral dendrite size under stimulation. Thus, it was established that a rather small group of synapses situated on an individual dendrite of the neuron determines the execution of the important form of animal behavior.

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

    Science.gov (United States)

    Chua, Yansong; Morrison, Abigail

    2016-01-01

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

  14. A Discrete Population of Neurons in the Lateral Amygdala Is Specifically Activated by Contextual Fear Conditioning

    Science.gov (United States)

    Wilson, Yvette M.; Murphy, Mark

    2009-01-01

    There is no clear identification of the neurons involved in fear conditioning in the amygdala. To search for these neurons, we have used a genetic approach, the "fos-tau-lacZ" (FTL) mouse, to map functionally activated expression in neurons following contextual fear conditioning. We have identified a discrete population of neurons in the lateral…

  15. A Discrete Population of Neurons in the Lateral Amygdala Is Specifically Activated by Contextual Fear Conditioning

    Science.gov (United States)

    Wilson, Yvette M.; Murphy, Mark

    2009-01-01

    There is no clear identification of the neurons involved in fear conditioning in the amygdala. To search for these neurons, we have used a genetic approach, the "fos-tau-lacZ" (FTL) mouse, to map functionally activated expression in neurons following contextual fear conditioning. We have identified a discrete population of neurons in the lateral…

  16. Neuronal chains for actions in the parietal lobe: a computational model.

    Directory of Open Access Journals (Sweden)

    Fabian Chersi

    Full Text Available The inferior part of the parietal lobe (IPL is known to play a very important role in sensorimotor integration. Neurons in this region code goal-related motor acts performed with the mouth, with the hand and with the arm. It has been demonstrated that most IPL motor neurons coding a specific motor act (e.g., grasping show markedly different activation patterns according to the final goal of the action sequence in which the act is embedded (grasping for eating or grasping for placing. Some of these neurons (parietal mirror neurons show a similar selectivity also during the observation of the same action sequences when executed by others. Thus, it appears that the neuronal response occurring during the execution and the observation of a specific grasping act codes not only the executed motor act, but also the agent's final goal (intention.In this work we present a biologically inspired neural network architecture that models mechanisms of motor sequences execution and recognition. In this network, pools composed of motor and mirror neurons that encode motor acts of a sequence are arranged in form of action goal-specific neuronal chains. The execution and the recognition of actions is achieved through the propagation of activity bursts along specific chains modulated by visual and somatosensory inputs.The implemented spiking neuron network is able to reproduce the results found in neurophysiological recordings of parietal neurons during task performance and provides a biologically plausible implementation of the action selection and recognition process.Finally, the present paper proposes a mechanism for the formation of new neural chains by linking together in a sequential manner neurons that represent subsequent motor acts, thus producing goal-directed sequences.

  17. Piezo Is Essential for Amiloride-Sensitive Stretch-Activated Mechanotransduction in Larval Drosophila Dorsal Bipolar Dendritic Sensory Neurons.

    Science.gov (United States)

    Suslak, Thomas J; Watson, Sonia; Thompson, Karen J; Shenton, Fiona C; Bewick, Guy S; Armstrong, J Douglas; Jarman, Andrew P

    2015-01-01

    Stretch-activated afferent neurons, such as those of mammalian muscle spindles, are essential for proprioception and motor co-ordination, but the underlying mechanisms of mechanotransduction are poorly understood. The dorsal bipolar dendritic (dbd) sensory neurons are putative stretch receptors in the Drosophila larval body wall. We have developed an in vivo protocol to obtain receptor potential recordings from intact dbd neurons in response to stretch. Receptor potential changes in dbd neurons in response to stretch showed a complex, dynamic profile with similar characteristics to those previously observed for mammalian muscle spindles. These profiles were reproduced by a general in silico model of stretch-activated neurons. This in silico model predicts an essential role for a mechanosensory cation channel (MSC) in all aspects of receptor potential generation. Using pharmacological and genetic techniques, we identified the mechanosensory channel, DmPiezo, in this functional role in dbd neurons, with TRPA1 playing a subsidiary role. We also show that rat muscle spindles exhibit a ruthenium red-sensitive current, but found no expression evidence to suggest that this corresponds to Piezo activity. In summary, we show that the dbd neuron is a stretch receptor and demonstrate that this neuron is a tractable model for investigating mechanisms of mechanotransduction.

  18. An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons.

    Science.gov (United States)

    Zhang, Shuang; Johnson, Christopher M; Cui, Ningren; Xing, Hao; Zhong, Weiwei; Wu, Yang; Jiang, Chun

    2016-10-01

    Rett syndrome (RTT) is a neurodevelopmental disorder affecting multiple functions, including the norepinephrine (NE) system. In the CNS, NE is produced mostly by neurons in the locus coeruleus (LC), where defects in intrinsic neuronal properties, NE biosynthetic enzymes, neuronal CO2 sensitivity, and synaptic currents have been reported in mouse models of RTT. LC neurons in methyl-CpG-binding protein 2 gene (Mecp2) null mice show a high rate of spontaneous firing, although whether such hyperexcitability might increase or decrease the NE release from synapses is unknown. To activate the NEergic axonal terminals selectively, we generated an optogenetic mouse model of RTT in which NEergic neuronal excitability can be manipulated with light. Using commercially available mouse breeders, we produced a new strain of double-transgenic mice with Mecp2 knockout and channelrhodopsin (ChR) knockin in catecholaminergic neurons. Several RTT-like phenotypes were found in the tyrosine hydroxylase (TH)-ChR-Mecp2(-/Y) mice, including hypoactivity, low body weight, hindlimb clasping, and breathing disorders. In brain slices, optostimulation produced depolarization and an increase in the firing rate of LC neurons from TH-ChR control mice. In TH-ChR control mice, optostimulation of presynaptic NEergic neurons augmented the firing rate of hypoglossal neurons (HNs), which was blocked by the α-adrenoceptor antagonist phentolamine. Such optostimulation of NEergic terminals had almost no effect on HNs from two or three TH-ChR-Mecp2(-/Y) mice, indicating that excessive excitation of presynaptic neurons does not benefit NEergic modulation in mice with Mecp2 disruption. These results also demonstrate the feasibility of generating double-transgenic mice for studies of RTT with commercially available mice, which are inexpensive, labor/time efficient, and promising for cell-specific stimulation. © 2016 Wiley Periodicals, Inc.

  19. Neuronal Activity Regulates Hippocampal miRNA Expression

    Science.gov (United States)

    Eacker, Stephen M.; Keuss, Matthew J.; Berezikov, Eugene; Dawson, Valina L.; Dawson, Ted M.

    2011-01-01

    Neuronal activity regulates a broad range of processes in the hippocampus, including the precise regulation of translation. Disruptions in proper translational control in the nervous system are associated with a variety of disorders that fall in the autistic spectrum. MicroRNA (miRNA) represent a relatively recently discovered player in the regulation of translation in the nervous system. We have conducted an in depth analysis of how neuronal activity regulates miRNA expression in the hippocampus. Using deep sequencing we exhaustively identify all miRNAs, including 15 novel miRNAs, expressed in hippocampus of the adult mouse. We identified 119 miRNAs documented in miRBase but less than half of these miRNA were expressed at a level greater than 0.1% of total miRNA. Expression profiling following induction of neuronal activity by electroconvulsive shock demonstrates that most miRNA show a biphasic pattern of expression: rapid induction of specific mature miRNA expression followed by a decline in expression. These results have important implications into how miRNAs influence activity-dependent translational control. PMID:21984899

  20. Neuronal activity regulates hippocampal miRNA expression.

    Directory of Open Access Journals (Sweden)

    Stephen M Eacker

    Full Text Available Neuronal activity regulates a broad range of processes in the hippocampus, including the precise regulation of translation. Disruptions in proper translational control in the nervous system are associated with a variety of disorders that fall in the autistic spectrum. MicroRNA (miRNA represent a relatively recently discovered player in the regulation of translation in the nervous system. We have conducted an in depth analysis of how neuronal activity regulates miRNA expression in the hippocampus. Using deep sequencing we exhaustively identify all miRNAs, including 15 novel miRNAs, expressed in hippocampus of the adult mouse. We identified 119 miRNAs documented in miRBase but less than half of these miRNA were expressed at a level greater than 0.1% of total miRNA. Expression profiling following induction of neuronal activity by electroconvulsive shock demonstrates that most miRNA show a biphasic pattern of expression: rapid induction of specific mature miRNA expression followed by a decline in expression. These results have important implications into how miRNAs influence activity-dependent translational control.

  1. Role of BDNF epigenetics in activity-dependent neuronal plasticity.

    Science.gov (United States)

    Karpova, Nina N

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is a key mediator of the activity-dependent processes in the brain that have a major impact on neuronal development and plasticity. Impaired control of neuronal activity-induced BDNF expression mediates the pathogenesis of various neurological and psychiatric disorders. Different environmental stimuli, such as the use of pharmacological compounds, physical and learning exercises or stress exposure, lead to activation of specific neuronal networks. These processes entail tight temporal and spatial transcriptional control of numerous BDNF splice variants through epigenetic mechanisms. The present review highlights recent findings on the dynamic and long-term epigenetic programming of BDNF gene expression by the DNA methylation, histone-modifying and microRNA machineries. The review also summarizes the current knowledge on the activity-dependent BDNF mRNA trafficking critical for rapid local regulation of BDNF levels and synaptic plasticity. Current data open novel directions for discovery of new promising therapeutic targets for treatment of neuropsychiatric disorders. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits.

    Science.gov (United States)

    Haam, Juhee; Halmos, Katalin C; Di, Shi; Tasker, Jeffrey G

    2014-04-30

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal-glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal-glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal-glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis.

  3. Inhibition of propofol on single neuron and neuronal ensemble activity in prefrontal cortex of rats during working memory task.

    Science.gov (United States)

    Xu, Xinyu; Tian, Yu; Wang, Guolin; Tian, Xin

    2014-08-15

    Working memory (WM) refers to the temporary storage and manipulation of information necessary for performance of complex cognitive tasks. There is a growing interest in whether and how propofol anesthesia inhibits WM function. The aim of this study is to investigate the possible inhibition mechanism of propofol anesthesia from the view of single neuron and neuronal ensemble activities. Adult SD rats were randomly divided into two groups: propofol group (0.9 mg kg(-1)min(-1), 2h via a tail vein catheter) and control group. All the rats were tested for working memory performances in a Y-maze-rewarded alternation task (a task of delayed non-matched-to-sample) at 24, 48, 72 h after propofol anesthesia, and the behavior results of WM tasks were recorded at the same time. Spatio-temporal trains of action potentials were obtained from the original signals. Single neuron activity was characterized by peri-event time histograms analysis and neuron ensemble activities were characterized by Granger causality to describe the interactions within the neuron ensemble. The results show that: comparing with the control group, the percentage of neurons excited and related to WM was significantly decreased (pneuron ensemble were significantly weakened (p0.05), which were consistent with the behavior results. These findings could lead to improved understanding of the mechanism of anesthesia inhibition on WM functions from the view of single neuron activity and neuron ensemble interactions.

  4. Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Powis, Rachael A; Gillingwater, Thomas H

    2016-03-01

    Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared.

  5. Manipulating neuronal activity with low frequency transcranial ultrasound

    Science.gov (United States)

    Moore, Michele Elizabeth

    Stimulation of the rodent cerebral cortex is used to investigate the underlying biological basis for the restorative effects of slow wave sleep. Neuronal activation by optogenetic and ultrasound stimulation elicits changes in action potentials across the cerebral cortex that are recorded as electroencephalograms. Optogenetic stimulation requires an invasive implantation procedure limiting its application in human studies. We sought to determine whether ultrasound stimulation could be as effective as optogenetic techniques currently used, in an effort to further understand the physiological and metabolic requirements of sleep. We successfully recorded electroencephalograms in response to transcranial ultrasound stimulation of the barrel cortex at 1 and 7 Hz frequencies, comparing them to those recorded in response to optogenetic stimuli applied at the same frequencies. Our results showed application of a 473 nm blue LED positioned 6 cm above the skull and ultrasound stimulation at an output voltage of 1000 mVpp produced electroencephalograms with physiological responses of similar amplitude. We concluded that there exists an intensity-proportionate response in the optogenetic stimulation, but not with ultrasound stimulation at the frequencies we surveyed. Activation of neuronal cells in response to optogenetic stimulation in a Thy1-ChR2 transgenic mouse line is specifically targeted to pyramidal cells in the cerebral cortex. ChR2 responses to optogenetic stimulation are mediated by a focal activation of neuronal ion channels. We measured electrophysiological responses to ultrasound stimulation, comparing them to those recorded from optogenetic stimuli. Our results show striking similarities between ultrasound-induced responses and optogenetically-induced responses, which may indicate that transcranial ultrasound stimulation is also mediated by ion channel dependent processes in cerebral cortical neurons. The biophysical substrates for electrical excitability of

  6. Aβ induces PUMA activation: a new mechanism for Aβ-mediated neuronal apoptosis.

    Science.gov (United States)

    Feng, Jie; Meng, Chengbo; Xing, Da

    2015-02-01

    p53 upregulated modulator of apoptosis (PUMA) is a promising tumor therapy target because it elicits apoptosis and profound sensitivity to radiation and chemotherapy. However, inhibition of PUMA may be beneficial for curbing excessive apoptosis associated with neurodegenerative disorders. Alzheimer's disease (AD) is a representative neurodegenerative disease in which amyloid-β (Aβ) deposition causes neurotoxicity. The regulation of PUMA during Aβ-induced neuronal apoptosis remains poorly understood. Here, we reported that PUMA expression was significantly increased in the hippocampus of transgenic mice models of AD and hippocampal neurons in response to Aβ. PUMA knockdown protected the neurons against Aβ-induced apoptosis. Furthermore, besides p53, PUMA transactivation was also regulated by forkhead box O3a through p53-independent manner following Aβ treatment. Notably, PUMA contributed to neuronal apoptosis through competitive binding of apoptosis repressor with caspase recruitment domain to activate caspase-8 that cleaved Bid into tBid to accelerate Bax mitochondrial translocation, revealing a novel pathway of Bax activation by PUMA to mediate Aβ-induced neuronal apoptosis. Together, we demonstrated that PUMA activation involved in Aβ-induced apoptosis, representing a drug target to antagonize AD progression.

  7. Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement.

    Science.gov (United States)

    Tolu, S; Eddine, R; Marti, F; David, V; Graupner, M; Pons, S; Baudonnat, M; Husson, M; Besson, M; Reperant, C; Zemdegs, J; Pagès, C; Hay, Y A H; Lambolez, B; Caboche, J; Gutkin, B; Gardier, A M; Changeux, J-P; Faure, P; Maskos, U

    2013-03-01

    Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.

  8. Bistable dynamics underlying excitability of ion homeostasis in neuron models.

    Directory of Open Access Journals (Sweden)

    Niklas Hübel

    2014-05-01

    Full Text Available When neurons fire action potentials, dissipation of free energy is usually not directly considered, because the change in free energy is often negligible compared to the immense reservoir stored in neural transmembrane ion gradients and the long-term energy requirements are met through chemical energy, i.e., metabolism. However, these gradients can temporarily nearly vanish in neurological diseases, such as migraine and stroke, and in traumatic brain injury from concussions to severe injuries. We study biophysical neuron models based on the Hodgkin-Huxley (HH formalism extended to include time-dependent ion concentrations inside and outside the cell and metabolic energy-driven pumps. We reveal the basic mechanism of a state of free energy-starvation (FES with bifurcation analyses showing that ion dynamics is for a large range of pump rates bistable without contact to an ion bath. This is interpreted as a threshold reduction of a new fundamental mechanism of ionic excitability that causes a long-lasting but transient FES as observed in pathological states. We can in particular conclude that a coupling of extracellular ion concentrations to a large glial-vascular bath can take a role as an inhibitory mechanism crucial in ion homeostasis, while the Na⁺/K⁺ pumps alone are insufficient to recover from FES. Our results provide the missing link between the HH formalism and activator-inhibitor models that have been successfully used for modeling migraine phenotypes, and therefore will allow us to validate the hypothesis that migraine symptoms are explained by disturbed function in ion channel subunits, Na⁺/K⁺ pumps, and other proteins that regulate ion homeostasis.

  9. LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity.

    Science.gov (United States)

    Zhang, Zhaohuan; Xu, Xiaohui; Xiang, Zhenghua; Yu, Zhongwang; Feng, Jifeng; He, Cheng

    2013-04-26

    LINGO-1 is a functional component of the Nogo receptor 1 · p75(NTR) · LINGO-1 and Nogo receptor 1 · TAJ (TNFRSF19/TROY)·LINGO-1 signaling complexes. It has recently been shown that LINGO-1 antagonists significantly improve neuronal survival after neural injury. However, the mechanism by which LINGO-1 signaling influences susceptibility to apoptosis remains unknown. In an effort to better understand how LINGO-1 regulates these signaling pathways, we used an established model of serum deprivation (SD) to induce neuronal apoptosis. We demonstrate that treatment either with a construct containing the intracellular domain of LINGO-1 or with Nogo66, a LINGO-1 receptor complex agonist, resulted in an enhanced rate of apoptosis in primary cultured cortical neurons under SD. Reducing the expression levels of the serine/threonine kinase WNK3 using shRNA or inhibiting its kinase activity had similar effects on the survival of serum-deprived neurons. Consistent with these observations, we found that LINGO-1 and WNK3 co-localized and co-precipitated in cultured cortical neurons and brain tissue. Significantly, this co-association was enhanced by Nogo66 treatment. Binding of WNK3 to the intracellular domain of LINGO-1 led to a reduction in WNK3 kinase activity, as did Nogo66 stimulation. Moreover, in vitro and in vivo evidence indicates that endogenous WNK3 suppresses SD-induced neuronal apoptosis in a kinase-dependent manner, as the expression of either a WNK3 RNAi construct or a kinase-dead N-terminal fragment of WNK3 led to increased apoptosis. Taken together, our results show that LINGO-1 potentiates neuronal apoptosis, likely by inhibiting WNK3 kinase activity.

  10. CCL2 Mediates Neuron-Macrophage Interactions to Drive Proregenerative Macrophage Activation Following Preconditioning Injury.

    Science.gov (United States)

    Kwon, Min Jung; Shin, Hae Young; Cui, Yuexian; Kim, Hyosil; Thi, Anh Hong Le; Choi, Jun Young; Kim, Eun Young; Hwang, Dong Hoon; Kim, Byung Gon

    2015-12-01

    CNS neurons in adult mammals do not spontaneously regenerate axons after spinal cord injury. Preconditioning peripheral nerve injury allows the dorsal root ganglia (DRG) sensory axons to regenerate beyond the injury site by promoting expression of regeneration-associated genes. We have previously shown that peripheral nerve injury increases the number of macrophages in the DRGs and that the activated macrophages are critical to the enhancement of intrinsic regeneration capacity. The present study identifies a novel chemokine signal mediated by CCL2 that links regenerating neurons with proregenerative macrophage activation. Neutralization of CCL2 abolished the neurite outgrowth activity of conditioned medium obtained from neuron-macrophage cocultures treated with cAMP. The neuron-macrophage interactions that produced outgrowth-promoting conditioned medium required CCL2 in neurons and CCR2/CCR4 in macrophages. The conditioning effects were abolished in CCL2-deficient mice at 3 and 7 d after sciatic nerve injury, but CCL2 was dispensable for the initial growth response and upregulation of GAP-43 at the 1 d time point. Intraganglionic injection of CCL2 mimicked conditioning injury by mobilizing M2-like macrophages. Finally, overexpression of CCL2 in DRGs promoted sensory axon regeneration in a rat spinal cord injury model without harmful side effects. Our data suggest that CCL2-mediated neuron-macrophage interaction plays a critical role for amplification and maintenance of enhanced regenerative capacity by preconditioning peripheral nerve injury. Manipulation of chemokine signaling mediating neuron-macrophage interactions may represent a novel therapeutic approach to promote axon regeneration after CNS injury.

  11. Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra

    OpenAIRE

    Ding, Shengyuan; Wei, Wei; Zhou, Fu-Ming

    2011-01-01

    GABA projection neurons (GABA neurons) in the substantia nigra pars reticulata (SNr) and dopamine projection neurons (DA neurons) in substantia nigra pars compacta (SNc) have strikingly different firing properties. SNc DA neurons fire low-frequency, long-duration spikes, whereas SNr GABA neurons fire high-frequency, short-duration spikes. Since voltage-activated sodium (NaV) channels are critical to spike generation, the different firing properties raise the possibility that, compared with DA...

  12. INCREASE IN DOPAMINE RELEASE FROM THE NUCLEUS-ACCUMBENS IN RESPONSE TO FEEDING - A MODEL TO STUDY INTERACTIONS BETWEEN DRUGS AND NATURALLY ACTIVATED DOPAMINERGIC-NEURONS IN THE RAT-BRAIN

    NARCIS (Netherlands)

    WESTERINK, BHC; TEISMAN, A; DEVRIES, JB

    1994-01-01

    The aim of the present study was to investigate the interactions between the in vivo release of dopamine and certain drugs, during conditions of increased dopaminergic activity. Dopaminergic neurons in the nucleus accumbens were activated by feeding hungry rats. 48-96 h after implantation of a micro

  13. Bidirectional coupling between astrocytes and neurons mediates learning and dynamic coordination in the brain: a multiple modeling approach.

    Directory of Open Access Journals (Sweden)

    John J Wade

    Full Text Available In recent years research suggests that astrocyte networks, in addition to nutrient and waste processing functions, regulate both structural and synaptic plasticity. To understand the biological mechanisms that underpin such plasticity requires the development of cell level models that capture the mutual interaction between astrocytes and neurons. This paper presents a detailed model of bidirectional signaling between astrocytes and neurons (the astrocyte-neuron model or AN model which yields new insights into the computational role of astrocyte-neuronal coupling. From a set of modeling studies we demonstrate two significant findings. Firstly, that spatial signaling via astrocytes can relay a "learning signal" to remote synaptic sites. Results show that slow inward currents cause synchronized postsynaptic activity in remote neurons and subsequently allow Spike-Timing-Dependent Plasticity based learning to occur at the associated synapses. Secondly, that bidirectional communication between neurons and astrocytes underpins dynamic coordination between neuron clusters. Although our composite AN model is presently applied to simplified neural structures and limited to coordination between localized neurons, the principle (which embodies structural, functional and dynamic complexity, and the modeling strategy may be extended to coordination among remote neuron clusters.

  14. Modeling ALS and FTD with iPSC-derived neurons.

    Science.gov (United States)

    Lee, Sebum; Huang, Eric J

    2017-02-01

    Recent advances in genetics and neuropathology support the idea that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTD) are two ends of a disease spectrum. Although several animal models have been developed to investigate the pathogenesis and disease progression in ALS and FTD, there are significant limitations that hamper our ability to connect these models with the neurodegenerative processes in human diseases. With the technical breakthrough in reprogramming biology, it is now possible to generate patient-specific induced pluripotent stem cells (iPSCs) and disease-relevant neuron subtypes. This review provides a comprehensive summary of studies that use iPSC-derived neurons to model ALS and FTD. We discuss the unique capabilities of iPSC-derived neurons that capture some key features of ALS and FTD, and underscore their potential roles in drug discovery. There are, however, several critical caveats that require improvements before iPSC-derived neurons can become highly effective disease models. This article is part of a Special Issue entitled SI: Exploiting human neurons.

  15. Dynamic changes in proprotein convertase 2 activity in cortical neurons after ischemia/reperfusion and oxygen-glucose deprivation

    Institute of Scientific and Technical Information of China (English)

    Shuqin Zhan; An Zhou; Chelsea Piper; Tao Yang

    2013-01-01

    In this study, a rat model of transient focal cerebral ischemia was established by performing 100 minutes of middle cerebral artery occlusion, and an in vitro model of experimental oxygen-glucose deprivation using cultured rat cortical neurons was established. Proprotein convertase 2 activity gradually decreased in the ischemic cortex with increasing duration of reperfusion. In cultured rat cortical neurons, the number of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling-positive neurons significantly increased and proprotein convertase 2 activity also decreased gradually with increasing duration of oxygen-glucose deprivation. These experimental findings indicate that proprotein convertase 2 activity decreases in ischemic rat cortex after reperfusion, as well as in cultured rat cortical neurons after oxygen-glucose deprivation. These changes in enzyme activity may play an important pathological role in brain injury.

  16. Aspects of calcium-activated chloride currents: a neuronal perspective.

    Science.gov (United States)

    Scott, R H; Sutton, K G; Griffin, A; Stapleton, S R; Currie, K P

    1995-06-01

    Ca(2+)-activated Cl- channels are expressed in a variety of cell types, including central and peripheral neurones. These channels are activated by a rise in intracellular Ca2+ close to the cell membrane. This can be evoked by cellular events such as Ca2+ entry through voltage- and ligandgated channels or release of Ca2+ from intracellular stores. Additionally, these Ca(2+)-activated Cl currents (ICl(Ca)) can be activated by raising intracellular Ca2+ through artificial experimental procedures such as intracellular photorelease of Ca2+ from "caged" photolabile compounds (e.g. DM-nitrophen) or by treating cells with Ca2+ ionophores. The potential changes that result from activation of Ca(2+)-activated Cl- channels are dependent on resting membrane potential and the equilibrium potential for Cl-. Ca2+ entry during a single action potential is sufficient to produce substantial after potentials, suggesting that the activity of these Cl- channels can have profound effects on cell excitability. The whole cell ICl(Ca) can be identified by sensitivity to increased Ca2+ buffering capacity of the cell, anion substitution studies and reversal potential measurements, as well as by the actions of Cl- channel blockers. In cultured sensory neurones, there is evidence that the ICl(Ca) deactivates as Ca2+ is buffered or removed from the intracellular environment. To date, there is no evidence in mammalian neurones to suggest these Ca(2+)-sensitive Cl- channels undergo a process of inactivation. Therefore, ICl(Ca) can be used as a physiological index of intracellular Ca2+ close to the cell membrane. The ICl(Ca) has been shown to be activated or prolonged as a result of metabolic stress, as well as by drugs that disturb intracellular Ca2+ homeostatic mechanisms or release Ca2+ from intracellular stores. In addition to sensitivity to classic Cl- channel blockers such as niflumic acid, derivatives of stilbene (4,4'diisothiocyanostilbene-2,2'-disulphonic acid, 4-acetamido-4

  17. Activity-Dependent Neurorehabilitation Beyond Physical Trainings: "Mental Exercise" Through Mirror Neuron Activation.

    Science.gov (United States)

    Yuan, Ti-Fei; Chen, Wei; Shan, Chunlei; Rocha, Nuno; Arias-Carrión, Oscar; Paes, Flávia; de Sá, Alberto Souza; Machado, Sergio

    2015-01-01

    The activity dependent brain repair mechanism has been widely adopted in many types of neurorehabilitation. The activity leads to target specific and non-specific beneficial effects in different brain regions, such as the releasing of neurotrophic factors, modulation of the cytokines and generation of new neurons in adult hood. However physical exercise program clinically are limited to some of the patients with preserved motor functions; while many patients suffered from paralysis cannot make such efforts. Here the authors proposed the employment of mirror neurons system in promoting brain rehabilitation by "observation based stimulation". Mirror neuron system has been considered as an important basis for action understanding and learning by mimicking others. During the action observation, mirror neuron system mediated the direct activation of the same group of motor neurons that are responsible for the observed action. The effect is clear, direct, specific and evolutionarily conserved. Moreover, recent evidences hinted for the beneficial effects on stroke patients after mirror neuron system activation therapy. Finally some music-relevant therapies were proposed to be related with mirror neuron system.

  18. Parthanatos Mediates AIMP2 Activated Age Dependent Dopaminergic Neuronal Loss

    Science.gov (United States)

    Lee, Yunjong; Karuppagounder, Senthilkumar S.; Shin, Joo-Ho; Lee, Yun-Il; Ko, Han Seok; Swing, Debbie; Jiang, Haisong; Kang, Sung-Ung; Lee, Byoung Dae; Kang, Ho Chul; Kim, Donghoon; Tessarollo, Lino; Dawson, Valina L.; Dawson, Ted M.

    2013-01-01

    The defining pathogenic feature of Parkinson’s disease is the age dependent loss of dopaminergic neurons. Mutations and inactivation of parkin, an ubiquitin E3 ligase, cause Parkinson’s disease through accumulation of pathogenic substrates. Here we show that transgenic overexpression of the parkin substrate, aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2) leads to a selective, age-dependent progressive loss of dopaminergic neurons via activation of poly(ADP-ribose) polymerase-1 (PARP1). AIMP2 accumulation in vitro and in vivo results in PARP1 overactivation and dopaminergic cell toxicity via direct association of these proteins in the nucleus providing a new path to PARP1 activation other than DNA damage. Inhibition of PARP1 through gene deletion or drug inhibition reverses behavioral deficits and protects in vivo against dopamine neuron death in AIMP2 transgenic mice. These data indicate that brain permeable PARP inhibitors could be effective in delaying or preventing disease progression in Parkinson’s disease. PMID:23974709

  19. Spider Silk as Guiding Biomaterial for Human Model Neurons

    Directory of Open Access Journals (Sweden)

    Frank Roloff

    2014-01-01

    Full Text Available Over the last years, a number of therapeutic strategies have emerged to promote axonal regeneration. An attractive strategy is the implantation of biodegradable and nonimmunogenic artificial scaffolds into injured peripheral nerves. In previous studies, transplantation of decellularized veins filled with spider silk for bridging critical size nerve defects resulted in axonal regeneration and remyelination by invading endogenous Schwann cells. Detailed interaction of elongating neurons and the spider silk as guidance material is unknown. To visualize direct cellular interactions between spider silk and neurons in vitro, we developed an in vitro crossed silk fiber array. Here, we describe in detail for the first time that human (NT2 model neurons attach to silk scaffolds. Extending neurites can bridge gaps between single silk fibers and elongate afterwards on the neighboring fiber. Culturing human neurons on the silk arrays led to an increasing migration and adhesion of neuronal cell bodies to the spider silk fibers. Within three to four weeks, clustered somata and extending neurites formed ganglion-like cell structures. Microscopic imaging of human neurons on the crossed fiber arrays in vitro will allow for a more efficient development of methods to maximize cell adhesion and neurite growth on spider silk prior to transplantation studies.

  20. Spider silk as guiding biomaterial for human model neurons.

    Science.gov (United States)

    Roloff, Frank; Strauß, Sarah; Vogt, Peter M; Bicker, Gerd; Radtke, Christine

    2014-01-01

    Over the last years, a number of therapeutic strategies have emerged to promote axonal regeneration. An attractive strategy is the implantation of biodegradable and nonimmunogenic artificial scaffolds into injured peripheral nerves. In previous studies, transplantation of decellularized veins filled with spider silk for bridging critical size nerve defects resulted in axonal regeneration and remyelination by invading endogenous Schwann cells. Detailed interaction of elongating neurons and the spider silk as guidance material is unknown. To visualize direct cellular interactions between spider silk and neurons in vitro, we developed an in vitro crossed silk fiber array. Here, we describe in detail for the first time that human (NT2) model neurons attach to silk scaffolds. Extending neurites can bridge gaps between single silk fibers and elongate afterwards on the neighboring fiber. Culturing human neurons on the silk arrays led to an increasing migration and adhesion of neuronal cell bodies to the spider silk fibers. Within three to four weeks, clustered somata and extending neurites formed ganglion-like cell structures. Microscopic imaging of human neurons on the crossed fiber arrays in vitro will allow for a more efficient development of methods to maximize cell adhesion and neurite growth on spider silk prior to transplantation studies.

  1. Modulatory Mechanism of Nociceptive Neuronal Activity by Dietary Constituent Resveratrol

    Directory of Open Access Journals (Sweden)

    Mamoru Takeda

    2016-10-01

    Full Text Available Changes to somatic sensory pathways caused by peripheral tissue, inflammation or injury can result in behavioral hypersensitivity and pathological pain, such as hyperalgesia. Resveratrol, a plant polyphenol found in red wine and various food products, is known to have several beneficial biological actions. Recent reports indicate that resveratrol can modulate neuronal excitability, including nociceptive sensory transmission. As such, it is possible that this dietary constituent could be a complementary alternative medicine (CAM candidate, specifically a therapeutic agent. The focus of this review is on the mechanisms underlying the modulatory effects of resveratrol on nociceptive neuronal activity associated with pain relief. In addition, we discuss the contribution of resveratrol to the relief of nociceptive and/or pathological pain and its potential role as a functional food and a CAM.

  2. Sprouty2 and -4 hypomorphism promotes neuronal survival and astrocytosis in a mouse model of kainic acid induced neuronal damage.

    Science.gov (United States)

    Thongrong, Sitthisak; Hausott, Barbara; Marvaldi, Letizia; Agostinho, Alexandra S; Zangrandi, Luca; Burtscher, Johannes; Fogli, Barbara; Schwarzer, Christoph; Klimaschewski, Lars

    2016-05-01

    Sprouty (Spry) proteins play a key role as negative feedback inhibitors of the Ras/Raf/MAPK/ERK pathway downstream of various receptor tyrosine kinases. Among the four Sprouty isoforms, Spry2 and Spry4 are expressed in the hippocampus. In this study, possible effects of Spry2 and Spry4 hypomorphism on neurodegeneration and seizure thresholds in a mouse model of epileptogenesis was analyzed. The Spry2/4 hypomorphs exhibited stronger ERK activation which was limited to the CA3 pyramidal cell layer and to the hilar region. The seizure threshold of Spry2/4(+/-) mice was significantly reduced at naive state but no difference to wildtype mice was observed 1 month following KA treatment. Histomorphological analysis revealed that dentate granule cell dispersion (GCD) was diminished in Spry2/4(+/-) mice in the subchronic phase after KA injection. Neuronal degeneration was reduced in CA1 and CA3 principal neuron layers as well as in scattered neurons of the contralateral CA1 and hilar regions. Moreover, Spry2/4 reduction resulted in enhanced survival of somatostatin and neuropeptide Y expressing interneurons. GFAP staining intensity and number of reactive astrocytes markedly increased in lesioned areas of Spry2/4(+/-) mice as compared with wildtype mice. Taken together, although the seizure threshold is reduced in naive Spry2/4(+/-) mice, neurodegeneration and GCD is mitigated following KA induced hippocampal lesions, identifying Spry proteins as possible pharmacological targets in brain injuries resulting in neurodegeneration. The present data are consistent with the established functions of the ERK pathway in astrocyte proliferation as well as protection from neuronal cell death and suggest a novel role of Spry proteins in the migration of differentiated neurons.

  3. Activity of Caudate Nucleus Neurons in a Visual Fixation Paradigm in Behaving Cats.

    Directory of Open Access Journals (Sweden)

    Tamás Nagypál

    Full Text Available Beside its motor functions, the caudate nucleus (CN, the main input structure of the basal ganglia, is also sensitive to various sensory modalities. The goal of the present study was to investigate the effects of visual stimulation on the CN by using a behaving, head-restrained, eye movement-controlled feline model developed recently for this purpose. Extracellular multielectrode recordings were made from the CN of two cats in a visual fixation paradigm applying static and dynamic stimuli. The recorded neurons were classified in three groups according to their electrophysiological properties: phasically active (PAN, tonically active (TAN and high-firing (HFN neurons. The response characteristics were investigated according to this classification. The PAN and TAN neurons were sensitive primarily to static stimuli, while the HFN neurons responded primarily to changes in the visual environment i.e. to optic flow and the offset of the stimuli. The HFNs were the most sensitive to visual stimulation; their responses were stronger than those of the PANs and TANs. The majority of the recorded units were insensitive to the direction of the optic flow, regardless of group, but a small number of direction-sensitive neurons were also found. Our results demonstrate that both the static and the dynamic components of the visual information are represented in the CN. Furthermore, these results provide the first piece of evidence on optic flow processing in the CN, which, in more general terms, indicates the possible role of this structure in dynamic visual information processing.

  4. Cannabidiol Exposure During Neuronal Differentiation Sensitizes Cells Against Redox-Active Neurotoxins.

    Science.gov (United States)

    Schönhofen, Patrícia; de Medeiros, Liana M; Bristot, Ivi Juliana; Lopes, Fernanda M; De Bastiani, Marco A; Kapczinski, Flávio; Crippa, José Alexandre S; Castro, Mauro Antônio A; Parsons, Richard B; Klamt, Fábio

    2015-08-01

    Cannabidiol (CBD), one of the most abundant Cannabis sativa-derived compounds, has been implicated with neuroprotective effect in several human pathologies. Until now, no undesired side effects have been associated with CBD. In this study, we evaluated CBD's neuroprotective effect in terminal differentiation (mature) and during neuronal differentiation (neuronal developmental toxicity model) of the human neuroblastoma SH-SY5Y cell line. A dose-response curve was performed to establish a sublethal dose of CBD with antioxidant activity (2.5 μM). In terminally differentiated SH-SY5Y cells, incubation with 2.5 μM CBD was unable to protect cells against the neurotoxic effect of glycolaldehyde, methylglyoxal, 6-hydroxydopamine, and hydrogen peroxide (H2O2). Moreover, no difference in antioxidant potential and neurite density was observed. When SH-SY5Y cells undergoing neuronal differentiation were exposed to CBD, no differences in antioxidant potential and neurite density were observed. However, CBD potentiated the neurotoxicity induced by all redox-active drugs tested. Our data indicate that 2.5 μM of CBD, the higher dose tolerated by differentiated SH-SY5Y neuronal cells, does not provide neuroprotection for terminally differentiated cells and shows, for the first time, that exposure of CBD during neuronal differentiation could sensitize immature cells to future challenges with neurotoxins.

  5. Dissecting the Phase Response of a Model Bursting Neuron

    CERN Document Server

    Sherwood, William Erik

    2009-01-01

    We investigate the phase response properties of the Hindmarsh-Rose model of neuronal bursting using burst phase response curves (BPRCs) computed with an infinitesimal perturbation approximation and by direct simulation of synaptic input. The resulting BPRCs have a significantly more complicated structure than the usual Type I and Type II PRCs of spiking neuronal models, and they exhibit highly timing-sensitive changes in the number of spikes per burst that lead to large magnitude phase responses. We use fast-slow dissection and isochron calculations to analyze the phase response dynamics in both weak and strong perturbation regimes.

  6. A model for experience-dependent changes in the responses of inferotemporal neurons.

    Science.gov (United States)

    Sohal, V S; Hasselmo, M E

    2000-08-01

    Neurons in inferior temporal (IT) cortex exhibit selectivity for complex visual stimuli and can maintain activity during the delay following the presentation of a stimulus in delayed match to sample tasks. Experimental work in awake monkeys has shown that the responses of IT neurons decline during presentation of stimuli which have been seen recently (within the past few seconds). In addition, experiments have found that the responses of IT neurons to visual stimuli also decline as the stimuli become familiar, independent of recency. Here a biologically based neural network simulation is used to model these effects primarily through two processes. The recency effects are caused by adaptation due to a calcium-dependent potassium current, and the familiarity effects are caused by competitive self-organization of modifiable feedforward synapses terminating on IT cortex neurons.

  7. Amalaki Rasayana improved memory and neuronal metabolic activity in AβPP-PS1 mouse model of Alzheimer’s disease

    Indian Academy of Sciences (India)

    VIVEK TIWARI; KAMAL SABA; PANDICHELVAM VEERAIAH; JEDY JOSE; SUBHASH C LAKHOTIA; ANANT B PATEL

    2017-09-01

    Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive loss of memoryand cognitive function. The cerebral metabolic rate of glucose oxidation has been shown to be reduced in AD. The presentstudy evaluated efficacy of dietary Amalaki Rasayana (AR), an Ayurvedic formulation used in Indian traditional system, inAβPP-PS1 mouse model of AD in ameliorating memory and neurometabolism, and compared with donepezil, a standardFDA approved drug for AD. The memory of mice was measured using Morris Water Maze analysis. The cerebralmetabolism was followed by 13C labelling of brain amino acids in tissue extracts ex vivo using ${}^{1}$H-[${}^{13}$C]-NMR spectroscopytogether with a short time infusion of [1,6-${}^{13}$C2]glucose to mice. The intervention with Amalaki Rasayana showedimproved learning and memory in AbPP-PS1 mice. The ${}^{13}$C labelings of GluC4, GABAC2 and GlnC4 were reduced inAbPP-PS1 mice when compared with wild-type controls. Intervention of AR increased the ${}^{13}$C labelling of amino acidssuggesting a significant enhancement in glutamatergic and GABAergic metabolic activity in AβPP-PS1 mice similar to thatobserved with donepezil treatment. These data suggest that AR has potential to improve memory and cognitive function inAD.

  8. Thalamic neuron models encode stimulus information by burst-size modulation

    Directory of Open Access Journals (Sweden)

    Daniel Henry Elijah

    2015-09-01

    Full Text Available Thalamic neurons have been long assumed to fire in tonic mode during perceptive states, and in burst mode during sleep and unconsciousness. However, recent evidence suggests that bursts may also be relevant in the encoding of sensory information. Here we explore the neural code of such thalamic bursts. In order to assess whether the burst code is generic or whether it depends on the detailed properties of each bursting neuron, we analyzed two neuron models incorporating different levels of biological detail. One of the models contained no information of the biophysical processes entailed in spike generation, and described neuron activity at a phenomenological level. The second model represented the evolution of the individual ionic conductances involved in spiking and bursting, and required a large number of parameters. We analyzed the models' input selectivity using reverse correlation methods and information theory. We found that n-spike bursts from both models transmit information by modulating their spike count in response to changes to instantaneous input features, such as slope, phase, amplitude, etc. The stimulus feature that is most efficiently encoded by bursts, however, need not coincide with one of such classical features. We therefore searched for the optimal feature among all those that could be expressed as a linear transformation of the time-dependent input current. We found that bursting neurons transmitted 6 times more information about such more general features. The relevant events in the stimulus were located in a time window spanning ~100 ms before and ~20 ms after burst onset. Most importantly, the neural code employed by the simple and the biologically realistic models was largely the same, implying that the simple thalamic neuron model contains the essential ingredients that account for the computational properties of the thalamic burst code. Thus, our results suggest the n-spike burst code is a general property of

  9. Thalamic neuron models encode stimulus information by burst-size modulation.

    Science.gov (United States)

    Elijah, Daniel H; Samengo, Inés; Montemurro, Marcelo A

    2015-01-01

    Thalamic neurons have been long assumed to fire in tonic mode during perceptive states, and in burst mode during sleep and unconsciousness. However, recent evidence suggests that bursts may also be relevant in the encoding of sensory information. Here, we explore the neural code of such thalamic bursts. In order to assess whether the burst code is generic or whether it depends on the detailed properties of each bursting neuron, we analyzed two neuron models incorporating different levels of biological detail. One of the models contained no information of the biophysical processes entailed in spike generation, and described neuron activity at a phenomenological level. The second model represented the evolution of the individual ionic conductances involved in spiking and bursting, and required a large number of parameters. We analyzed the models' input selectivity using reverse correlation methods and information theory. We found that n-spike bursts from both models transmit information by modulating their spike count in response to changes to instantaneous input features, such as slope, phase, amplitude, etc. The stimulus feature that is most efficiently encoded by bursts, however, need not coincide with one of such classical features. We therefore searched for the optimal feature among all those that could be expressed as a linear transformation of the time-dependent input current. We found that bursting neurons transmitted 6 times more information about such more general features. The relevant events in the stimulus were located in a time window spanning ~100 ms before and ~20 ms after burst onset. Most importantly, the neural code employed by the simple and the biologically realistic models was largely the same, implying that the simple thalamic neuron model contains the essential ingredients that account for the computational properties of the thalamic burst code. Thus, our results suggest the n-spike burst code is a general property of thalamic neurons.

  10. Edge detection based on Hodgkin-Huxley neuron model simulation.

    Science.gov (United States)

    Yedjour, Hayat; Meftah, Boudjelal; Lézoray, Olivier; Benyettou, Abdelkader

    2017-04-03

    In this paper, we propose a spiking neural network model for edge detection in images. The proposed model is biologically inspired by the mechanisms employed by natural vision systems, more specifically by the biologically fulfilled function of simple cells of the human primary visual cortex that are selective for orientation. Several aspects are studied in this model according to three characteristics: feedforward spiking neural structure; conductance-based model of the Hodgkin-Huxley neuron and Gabor receptive fields structure. A visualized map is generated using the firing rate of neurons representing the orientation map of the visual cortex area. We have simulated the proposed model on different images. Successful computer simulation results are obtained. For comparison, we have chosen five methods for edge detection. We finally evaluate and compare the performances of our model toward contour detection using a public dataset of natural images with associated contour ground truths. Experimental results show the ability and high performance of the proposed network model.

  11. Extracellular potassium dynamics in the hyperexcitable state of the neuronal ictal activity

    Science.gov (United States)

    Florence, Gerson; Pereira, Tiago; Kurths, Jürgen

    2012-12-01

    An enduring question in epilepsy research concerns with the mechanisms responsible for the neuronal hyperexcitability. This theme is under debate and different hypotheses have been put forward. One hypothesis relates to extracellular ionic variations, especially the increase of the extracellular potassium concentration ([K+]o). During the epileptiform bursting, an increase of [K+]o is observed which raises the cellular excitability. It remains unclear, however, how the extracellular potassium variation could affect the generation and persistence of epileptiform bursting within the ictal phase, that is, during the epileptic seizure. The neuronal mechanisms responsible for this cellular hyperexcitability are not yet fully understood, hindering the development of more efficient therapies to control epilepsy. Mathematical models with biological plausibility have provided considerable insights into the mechanisms underlying epileptiform pattern. This paper reviews experimental evidences and computational studies concerning effects of the extracellular potassium dynamics on the cellular excitability within the neuronal ictal activity.

  12. Role of neuronal Ras activity in adult hippocampal neurogenesis and cognition

    Directory of Open Access Journals (Sweden)

    Martina eManns

    2011-02-01

    Full Text Available Hippocampal neurogenesis in the adult mammalian brain is modulated by various signals like growth factors, hormones, neuropeptides, and neurotransmitters. All of these factors can (but not necessarily do converge on the activation of the G protein p21Ras. We used a transgenic mouse model (synRas mice expressing constitutively activated G12V-Harvey Ras selectively in differentiated neurons to investigate the possible effects onto neurogenesis. Ras activation in neurons attenuates hippocampal precursor cell generation at an early stage of the proliferative cascade before neuronal lineage determination occurs. Therefore it is unlikely that the transgenically activated Ras in neurons mediates this effect by a direct, intracellular signaling mechanism. Voluntary exercise restores neurogenesis up to wild type level presumably mediated by brain derived neurotrophic factor. Reduced neurogenesis is linked to impairments in spatial short-term memory and object recognition, the latter can be rescued by voluntary exercise, as well. These data support the view that new cells significantly increase complexity that can be processed by the hippocampal network when experience requires high demands to associate stimuli over time and/or space.

  13. Thrombin-induced apoptosis in neurons through activation of c-Jun-N-terminal kinase.

    Science.gov (United States)

    Bao, Lei; Zu, Jie; He, Qianqian; Zhao, Hui; Zhou, Su; Ye, Xinchun; Yang, Xinxin; Zan, Kun; Zhang, Zuohui; Shi, Hongjuan; Cui, Guiyun

    2017-01-01

    Studies have shown that thrombin activation played a central role in cell injuries associated with intracerebral hemorrhage (ICH). Here, our study investigated the cytotoxicity of thrombin on neurons, and determined the involvement of JNK pathways in thrombin-induced neuronal apoptosis. Primary cultured neurons were treated with different doses of thrombin. Some neurons were given either SP600125 or vehicle. LDH release assay and flow cytometry were used to measure neuronal apoptosis caused by thrombin. The activation of JNK and capases-3 were measured by Western blot. Our results showed large doses of thrombin that increased the LDH release, the level of cleaved caspase-3 and apoptosis rate of neurons. JNK was activated by thrombin in a time-dependent manner. Administration of SP600125 protects neurons from thrombin-induced apoptosis. These data indicate that the activation of JNK is crucial for thrombin-induced neuronal apoptosis, and inhibition of JNK may be a potential therapeutic target for ICH.

  14. A robust cellular associative memory for pattern recognitions using composite trigonometric chaotic neuron models

    Directory of Open Access Journals (Sweden)

    Wimol San-Um

    2015-12-01

    Full Text Available This paper presents a robust cellular associative memory for pattern recognitions using composite trigonometric chaotic neuron models. Robust chaotic neurons are designed through a scan of positive Lyapunov Exponent (LE bifurcation structures, which indicate the quantitative measure of chaoticity for one-dimensional discrete-time dynamical systems. The proposed chaotic neuron model is a composite of sine and cosine chaotic maps, which are independent from the output activation function. Dynamics behaviors are demonstrated through bifurcation diagrams and LE-based bifurcation structures. An application to associative memories of binary patterns in Cellular Neural Networks (CNN topology is demonstrated using a signum output activation function. Examples of English alphabets are stored using symmetric auto-associative matrix of n-binary patterns. Simulation results have demonstrated that the cellular neural network can quickly and effectively restore the distorted pattern to expected information.

  15. Properties of bilateral spinocerebellar activation of cerebellar cortical neurons

    Directory of Open Access Journals (Sweden)

    Pontus eGeborek

    2014-10-01

    Full Text Available We aimed to explore the cerebellar cortical inputs from two spinocerebellar pathways, the spinal border cell-component of the ventral spinocerebellar tract (SBC-VSCT and the dorsal spinocerebellar tract (DSCT, respectively, in the sublobule C1 of the cerebellar posterior lobe. The two pathways were activated by electrical stimulation of the contralateral lateral funiculus (coLF and the ipsilateral LF (iLF at lower thoracic levels. Most granule cells in sublobule C1 did not respond at all but part of the granule cell population displayed high-intensity responses to either coLF or iLF stimulation. As a rule, Golgi cells and Purkinje cell simple spikes responded to input from both LFs, although Golgi cells could be more selective. In addition, a small population of granule cells responded to input from both the coLF and the iLF. However, in these cases, similarities in the temporal topography and magnitude of the responses suggested that the same axons were stimulated from the two LFs, i.e. that the axons of individual spinocerebellar neurons could be present in both funiculi. This was also confirmed for a population of spinal neurons located within known locations of SBC-VSCT neurons and dorsal horn DSCT neurons. We conclude that bilateral spinocerebellar responses can occur in cerebellar granule cells, but the VSCT and DSCT systems that provide the input can also be organized bilaterally. The implications for the traditional functional separation of VSCT and DSCT systems and the issue whether granule cells primarily integrate functionally similar information or not are discussed.

  16. Complex Behavior in an Integrate-and-Fire Neuron Model Based on Small World Networks

    Institute of Scientific and Technical Information of China (English)

    LIN Min; CHEN Tian-Lun

    2005-01-01

    Based on our previously pulse-coupled integrate-and-fire neuron model in small world networks, we investigate the complex behavior of electroencephalographic (EEG)-like activities produced by such a model. We find EEG-like activities have obvious chaotic characteristics. We also analyze the complex behaviors of EEG-like signals,such as spectral analysis, reconstruction of the phase space, the correlation dimension, and so on.

  17. Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Liu, Kevin X; Edwards, Benjamin; Lee, Sheena; Finelli, Mattéa J; Davies, Ben; Davies, Kay E; Oliver, Peter L

    2015-05-01

    Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

  18. The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states

    Science.gov (United States)

    Barry, Guy; Briggs, James A.; Hwang, Do Won; Nayler, Sam P.; Fortuna, Patrick R. J.; Jonkhout, Nicky; Dachet, Fabien; Maag, Jesper L. V.; Mestdagh, Pieter; Singh, Erin M.; Avesson, Lotta; Kaczorowski, Dominik C.; Ozturk, Ezgi; Jones, Nigel C.; Vetter, Irina; Arriola-Martinez, Luis; Hu, Jianfei; Franco, Gloria R.; Warn, Victoria M.; Gong, Andrew; Dinger, Marcel E.; Rigo, Frank; Lipovich, Leonard; Morris, Margaret J.; O’Brien, Terence J.; Lee, Dong Soo; Loeb, Jeffrey A.; Blackshaw, Seth; Mattick, John S.; Wolvetang, Ernst J.

    2017-01-01

    Despite their abundance, the molecular functions of long non-coding RNAs in mammalian nervous systems remain poorly understood. Here we show that the long non-coding RNA, NEAT1, directly modulates neuronal excitability and is associated with pathological seizure states. Specifically, NEAT1 is dynamically regulated by neuronal activity in vitro and in vivo, binds epilepsy-associated potassium channel-interacting proteins including KCNAB2 and KCNIP1, and induces a neuronal hyper-potentiation phenotype in iPSC-derived human cortical neurons following antisense oligonucleotide knockdown. Next generation sequencing reveals a strong association of NEAT1 with increased ion channel gene expression upon activation of iPSC-derived neurons following NEAT1 knockdown. Furthermore, we show that while NEAT1 is acutely down-regulated in response to neuronal activity, repeated stimulation results in NEAT1 becoming chronically unresponsive in independent in vivo rat model systems relevant to temporal lobe epilepsy. We extended previous studies showing increased NEAT1 expression in resected cortical tissue from high spiking regions of patients suffering from intractable seizures. Our results indicate a role for NEAT1 in modulating human neuronal activity and suggest a novel mechanistic link between an activity-dependent long non-coding RNA and epilepsy. PMID:28054653

  19. Optogenetic mimicry of the transient activation of dopamine neurons by natural reward is sufficient for operant reinforcement.

    Directory of Open Access Journals (Sweden)

    Kyung Man Kim

    Full Text Available Activation of dopamine receptors in forebrain regions, for minutes or longer, is known to be sufficient for positive reinforcement of stimuli and actions. However, the firing rate of dopamine neurons is increased for only about 200 milliseconds following natural reward events that are better than expected, a response which has been described as a "reward prediction error" (RPE. Although RPE drives reinforcement learning (RL in computational models, it has not been possible to directly test whether the transient dopamine signal actually drives RL. Here we have performed optical stimulation of genetically targeted ventral tegmental area (VTA dopamine neurons expressing Channelrhodopsin-2 (ChR2 in mice. We mimicked the transient activation of dopamine neurons that occurs in response to natural reward by applying a light pulse of 200 ms in VTA. When a single light pulse followed each self-initiated nose poke, it was sufficient in itself to cause operant reinforcement. Furthermore, when optical stimulation was delivered in separate sessions according to a predetermined pattern, it increased locomotion and contralateral rotations, behaviors that are known to result from activation of dopamine neurons. All three of the optically induced operant and locomotor behaviors were tightly correlated with the number of VTA dopamine neurons that expressed ChR2, providing additional evidence that the behavioral responses were caused by activation of dopamine neurons. These results provide strong evidence that the transient activation of dopamine neurons provides a functional reward signal that drives learning, in support of RL theories of dopamine function.

  20. Activity-dependent Phosphorylation of Neuronal Kv2.1 Potassium Channels by CDK5*

    OpenAIRE

    Cerda, Oscar; Trimmer, James S.

    2011-01-01

    Dynamic modulation of ion channel expression, localization, and/or function drives plasticity in intrinsic neuronal excitability. Voltage-gated Kv2.1 potassium channels are constitutively maintained in a highly phosphorylated state in neurons. Increased neuronal activity triggers rapid calcineurin-dependent dephosphorylation, loss of channel clustering, and hyperpolarizing shifts in voltage-dependent activation that homeostatically suppress neuronal excitability. These changes are reversible,...

  1. Reevaluating Metabolism in Alzheimer's Disease from the Perspective of the Astrocyte-Neuron Lactate Shuttle Model

    Directory of Open Access Journals (Sweden)

    Jordan T. Newington

    2013-01-01

    Full Text Available The conventional view of central nervous system (CNS metabolism is based on the assumption that glucose is the main fuel source for active neurons and is processed in an oxidative manner. However, since the early 1990s research has challenged the idea that the energy needs of nerve cells are met exclusively by glucose and oxidative metabolism. This alternative view of glucose utilization contends that astrocytes metabolize glucose to lactate, which is then released and taken up by nearby neurons and used as a fuel source, commonly known as the astrocyte-neuron lactate shuttle (ANLS model. Once thought of as a waste metabolite, lactate has emerged as a central player in the maintenance of neuronal function and long-term memory. Decreased neuronal metabolism has traditionally been viewed as a hallmark feature of Alzheimer's disease (AD. However, a more complex picture of CNS metabolism is emerging that may provide valuable insight into the pathophysiological changes that occur during AD and other neurodegenerative diseases. This review will examine the ANLS model and present recent evidence highlighting the critical role that lactate plays in neuronal survival and memory. Moreover, the role of glucose and lactate metabolism in AD will be re-evaluated from the perspective of the ANLS.

  2. Hopf Bifurcation and Chaos in a Single Inertial Neuron Model with Time Delay

    OpenAIRE

    Li, Chunguang; Chen, Guanrong; Liao, Xiaofeng; Yu, Juebang

    2004-01-01

    A delayed differential equation modelling a single neuron with inertial term is considered in this paper. Hopf bifurcation is studied by using the normal form theory of retarded functional differential equations. When adopting a nonmonotonic activation function, chaotic behavior is observed. Phase plots, waveform plots, and power spectra are presented to confirm the chaoticity.

  3. Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse.

    Science.gov (United States)

    Yowtak, June; Wang, Jigong; Kim, Hee Young; Lu, Ying; Chung, Kyungsoon; Chung, Jin Mo

    2013-11-01

    One feature of neuropathic pain is a reduced spinal gamma-aminobutyric acid (GABA)-ergic inhibitory function. However, the mechanisms behind this attenuation remain to be elucidated. This study investigated the involvement of reactive oxygen species in the spinal GABA neuron loss and reduced GABA neuron excitability in spinal nerve ligation (SNL) model of neuropathic pain in mice. The importance of spinal GABAergic inhibition in neuropathic pain was tested by examining the effects of intrathecally administered GABA receptor agonists and antagonists in SNL and naïve mice, respectively. The effects of SNL and antioxidant treatment on GABA neuron loss and functional changes were examined in transgenic GAD67-enhanced green fluorescent protein positive (EGFP+) mice. GABA receptor agonists transiently reversed mechanical hypersensitivity of the hind paw in SNL mice. On the other hand, GABA receptor antagonists made naïve mice mechanically hypersensitive. Stereological analysis showed that the numbers of enhanced green fluorescent protein positive (EGFP+) GABA neurons were significantly decreased in the lateral superficial laminae (I-II) on the ipsilateral L5 spinal cord after SNL. Repeated antioxidant treatments significantly reduced the pain behaviors and prevented the reduction in EGFP+ GABA neurons. The response rate of the tonic firing GABA neurons recorded from SNL mice increased with antioxidant treatment, whereas no change was seen in those recorded from naïve mice, which suggested that oxidative stress impaired some spinal GABA neuron activity in the neuropathic pain condition. Together the data suggest that neuropathic pain, at least partially, is attributed to oxidative stress, which induces both a GABA neuron loss and dysfunction of surviving GABA neurons. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  4. Energetics of neuronal signaling and fMRI activity.

    Science.gov (United States)

    Maandag, Natasja J G; Coman, Daniel; Sanganahalli, Basavaraju G; Herman, Peter; Smith, Arien J; Blumenfeld, Hal; Shulman, Robert G; Hyder, Fahmeed

    2007-12-18

    Energetics of resting and evoked fMRI signals were related to localized ensemble firing rates (nu) measured by electrophysiology in rats. Two different unstimulated, or baseline, states were established by anesthesia. Halothane and alpha-chloralose established baseline states of high and low energy, respectively, in which forepaw stimulation excited the contralateral primary somatosensory cortex (S1). With alpha-chloralose, forepaw stimulation induced strong and reproducible fMRI activations in the contralateral S1, where the ensemble firing was dominated by slow signaling neurons (SSN; nu range of 1-13 Hz). Under halothane, weaker and less reproducible fMRI activations were observed in the contralateral S1 and elsewhere in the cortex, but ensemble activity in S1 was dominated by rapid signaling neurons (RSN; nu range of 13-40 Hz). For both baseline states, the RSN activity (i.e., higher frequencies, including the gamma band) did not vary upon stimulation, whereas the SSN activity (i.e., alpha band and lower frequencies) did change. In the high energy baseline state, a large majority of total oxidative energy [cerebral metabolic rate of oxygen consumption (CMR(O2))] was devoted to RSN activity, whereas in the low energy baseline state, it was roughly divided between SSN and RSN activities. We hypothesize that in the high energy baseline state, the evoked changes in fMRI activation in areas beyond S1 are supported by rich intracortical interactions represented by RSN. We discuss implications for interpreting fMRI data where stimulus-specific DeltaCMR(O2) is generally small compared with baseline CMR(O2).

  5. Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models

    Directory of Open Access Journals (Sweden)

    Kung PJ

    2014-10-01

    Full Text Available Pin-Jui Kung,1,* Yu-Chen Tao,1,* Ho-Chiang Hsu,1 Wan-Ling Chen,1 Te-Hsien Lin,1 Donala Janreddy,2 Ching-Fa Yao,2 Kuo-Hsuan Chang,3 Jung-Yaw Lin,1 Ming-Tsan Su,1 Chung-Hsin Wu,1 Guey-Jen Lee-Chen,1 Hsiu-Mei Hsieh-Li1 1Department of Life Science, 2Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan; 3Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan *These authors contributed equally to this work Abstract: In spinocerebellar ataxia type 17 (SCA17, the expansion of a translated CAG repeat in the TATA box binding protein (TBP gene results in a long polyglutamine (polyQ tract in the TBP protein, leading to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On SH-SY5Y cells with inducible SCA17 TBP/Q79-green fluorescent protein (GFP expression to test indole and synthetic derivative NC001-8 for neuroprotection. We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q79 cells. The effects on promoting neurite outgrowth and on reduction of aggregation on Purkinje cells were also confirmed with cerebellar primary and slice cultures of SCA17 transgenic mice. Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment. Keywords: spinocerebellar ataxia type 17, TATA box binding protein, polyQ aggregation, indole and derivative, therapeutics

  6. Neuron to astrocyte communication via cannabinoid receptors is necessary for sustained epileptiform activity in rat hippocampus.

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    Guyllaume Coiret

    Full Text Available Astrocytes are integral functional components of synapses, regulating transmission and plasticity. They have also been implicated in the pathogenesis of epilepsy, although their precise roles have not been comprehensively characterized. Astrocytes integrate activity from neighboring synapses by responding to neuronally released neurotransmitters such as glutamate and ATP. Strong activation of astrocytes mediated by these neurotransmitters can promote seizure-like activity by initiating a positive feedback loop that induces excessive neuronal discharge. Recent work has demonstrated that astrocytes express cannabinoid 1 (CB1 receptors, which are sensitive to endocannabinoids released by nearby pyramidal cells. In this study, we tested whether this mechanism also contributes to epileptiform activity. In a model of 4-aminopyridine induced epileptic-like activity in hippocampal slice cultures, we show that pharmacological blockade of astrocyte CB1 receptors did not modify the initiation, but significantly reduced the maintenance of epileptiform discharge. When communication in astrocytic networks was disrupted by chelating astrocytic calcium, this CB1 receptor-mediated modulation of epileptiform activity was no longer observed. Thus, endocannabinoid signaling from neurons to astrocytes represents an additional significant factor in the maintenance of epileptiform activity in the hippocampus.

  7. The Emerging Nexus of Active DNA Demethylation and Mitochondrial Oxidative Metabolism in Post-Mitotic Neurons

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    Huan Meng

    2014-12-01

    Full Text Available The variable patterns of DNA methylation in mammals have been linked to a number of physiological processes, including normal embryonic development and disease pathogenesis. Active removal of DNA methylation, which potentially regulates neuronal gene expression both globally and gene specifically, has been recently implicated in neuronal plasticity, learning and memory processes. Model pathways of active DNA demethylation involve ten-eleven translocation (TET methylcytosine dioxygenases that are dependent on oxidative metabolites. In addition, reactive oxygen species (ROS and oxidizing agents generate oxidative modifications of DNA bases that can be removed by base excision repair proteins. These potentially link the two processes of active DNA demethylation and mitochondrial oxidative metabolism in post-mitotic neurons. We review the current biochemical understanding of the DNA demethylation process and discuss its potential interaction with oxidative metabolism. We then summarise the emerging roles of both processes and their interaction in neural plasticity and memory formation and the pathophysiology of neurodegeneration. Finally, possible therapeutic approaches for neurodegenerative diseases are proposed, including reprogramming therapy by global DNA demethylation and mitohormesis therapy for locus-specific DNA demethylation in post-mitotic neurons.

  8. Alterations in Neuronal Activity in Basal Ganglia-Thalamocortical Circuits in the Parkinsonian State

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    Adriana eGalvan

    2015-02-01

    Full Text Available In patients with Parkinson’s disease and in animal models of this disorder, neurons in the basal ganglia and related regions in thalamus and cortex show changes that can be recorded by using electrophysiologic single-cell recording techniques, including altered firing rates and patterns, pathologic oscillatory activity and increased inter-neuronal synchronization. In addition, changes in synaptic potentials or in the joint spiking activities of populations of neurons can be monitored as alterations in local field potentials, electroencephalograms or electrocorticograms. Most of the mentioned electrophysiologic changes are probably related to the degeneration of diencephalic dopaminergic neurons, leading to dopamine loss in the striatum and other basal ganglia nuclei, although degeneration of non-dopaminergic cell groups may also have a role. The altered electrical activity of the basal ganglia and associated nuclei may contribute to some of the motor signs of the disease. We here review the current knowledge of the electrophysiologic changes at the single cell level, the level of local populations of neural elements, and the level of the entire basal ganglia-thalamocortical network in parkinsonism, and discuss the possible use of this information to optimize treatment approaches to Parkinson’s disease, such as deep brain stimulation therapy.

  9. Microglia in Glia-Neuron Co-cultures Exhibit Robust Phagocytic Activity Without Concomitant Inflammation or Cytotoxicity.

    Science.gov (United States)

    Adams, Alexandra C; Kyle, Michele; Beaman-Hall, Carol M; Monaco, Edward A; Cullen, Matthew; Vallano, Mary Lou

    2015-10-01

    A simple method to co-culture granule neurons and glia from a single brain region is described, and microglia activation profiles are assessed in response to naturally occurring neuronal apoptosis, excitotoxin-induced neuronal death, and lipopolysaccharide (LPS) addition. Using neonatal rat cerebellar cortex as a tissue source, glial proliferation is regulated by omission or addition of the mitotic inhibitor cytosine arabinoside (AraC). After 7-8 days in vitro, microglia in AraC(-) cultures are abundant and activated based on their amoeboid morphology, expressions of ED1 and Iba1, and ability to phagocytose polystyrene beads and the majority of neurons undergoing spontaneous apoptosis. Microglia and phagocytic activities are sparse in AraC(+) cultures. Following exposure to excitotoxic kainate concentrations, microglia in AraC(-) cultures phagocytose most dead neurons within 24 h without exacerbating neuronal loss or mounting a strong or sustained inflammatory response. LPS addition induces a robust inflammatory response, based on microglial expressions of TNF-α, COX-2 and iNOS proteins, and mRNAs, whereas these markers are essentially undetectable in control cultures. Thus, the functional effector state of microglia is primed for phagocytosis but not inflammation or cytotoxicity even after kainate exposure that triggers death in the majority of neurons. This model should prove useful in studying the progressive activation states of microglia and factors that promote their conversion to inflammatory and cytotoxic phenotypes.

  10. Pharmacological activation/inhibition of the cannabinoid system affects alcohol withdrawal-induced neuronal hypersensitivity to excitotoxic insults.

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    Marina Rubio

    Full Text Available Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716 during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.

  11. Satellite microglia show spontaneous electrical activity that is uncorrelated with activity of the attached neuron.

    Science.gov (United States)

    Wogram, Emile; Wendt, Stefan; Matyash, Marina; Pivneva, Tatyana; Draguhn, Andreas; Kettenmann, Helmut

    2016-06-01

    Microglia are innate immune cells of the brain. We have studied a subpopulation of microglia, called satellite microglia. This cell type is defined by a close morphological soma-to-soma association with a neuron, indicative of a direct functional interaction. Indeed, ultrastructural analysis revealed closely attached plasma membranes of satellite microglia and neurons. However, we found no apparent morphological specializations of the contact, and biocytin injection into satellite microglia showed no dye-coupling with the apposed neurons or any other cell. Likewise, evoked local field potentials or action potentials and postsynaptic potentials of the associated neuron did not lead to any transmembrane currents or non-capacitive changes in the membrane potential of the satellite microglia in the cortex and hippocampus. Both satellite and non-satellite microglia, however, showed spontaneous transient membrane depolarizations that were not correlated with neuronal activity. These events could be divided into fast-rising and slow-rising depolarizations, which showed different characteristics in satellite and non-satellite microglia. Fast-rising and slow-rising potentials differed with regard to voltage dependence. The frequency of these events was not affected by the application of tetrodotoxin, but the fast-rising event frequency decreased after application of GABA. We conclude that microglia show spontaneous electrical activity that is uncorrelated with the activity of adjacent neurons.

  12. The satiety signaling neuropeptide perisulfakinin inhibits the activity of central neurons promoting general activity

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    Dieter Wicher

    2007-12-01

    Full Text Available The metabolic state is one of the determinants of the general activity level. Satiety is related to resting or sleep whereas hunger correlates to wakefulness and activity. The counterpart to the mammalian satiety signal cholecystokinin (CCK in insects are the sulfakinins. The aim of this study was to resolve the mechanism by which the antifeedant activity of perisulfakinin (PSK in Periplaneta americana is mediated. We identified the sources of PSK which is used both as hormone and as paracrine messenger. PSK is found in the neurohemal organ of the brain and in nerve endings throughout the central nervous system. To correlate the distributions of PSK and its receptor (PSKR, we cloned the gene coding for PSKR and provide evidence for its expression within the nervous system. It occurs only in a few neurons, among them are the dorsal unpaired median (DUM neurons which release octopamine thereby regulating the general level of activity. Application of PSK to DUM neurons attenuated the spiking frequency (EC50=11pM due to reduction of a pacemaker Ca2+ current through cAMP-inhibited pTRPγ channels. PSK increased the intracellular cAMP level while decreasing the intracellular Ca2+ concentration in DUM neurons. Thus, the satiety signal conferred by PSK acts antagonistically to the hunger signal, provided by the adipokinetic hormone (AKH: PSK depresses the electrical activity of DUM neurons by inhibiting the pTRPγ channel that is activated by AKH under conditions of food shortage.

  13. Ionic current correlations underlie the global tuning of large numbers of neuronal activity attributes.

    Science.gov (United States)

    Zhao, Shunbing; Golowasch, Jorge

    2012-09-26

    Ionic conductances in identified neurons are highly variable. This poses the crucial question of how such neurons can produce stable activity. Coexpression of ionic currents has been observed in an increasing number of neurons in different systems, suggesting that the coregulation of ionic channel expression, by thus linking their variability, may enable neurons to maintain relatively constant neuronal activity as suggested by a number of recent theoretical studies. We examine this hypothesis experimentally using the voltage- and dynamic-clamp techniques to first measure and then modify the ionic conductance levels of three currents in identified neurons of the crab pyloric network. We quantify activity by measuring 10 different attributes (oscillation period, spiking frequency, etc.), and find linear, positive and negative relationships between conductance pairs and triplets that can enable pyloric neurons to maintain activity attributes invariant. Consistent with experimental observations, some of the features most tightly regulated appear to be phase relationships of bursting activity. We conclude that covariation (and probably a tightly controlled coregulation) of ionic conductances can help neurons maintain certain attributes of neuronal activity invariant while at the same time allowing conductances to change over wide ranges in response to internal or environmental inputs and perturbations. Our results also show that neurons can tune neuronal activity globally via coordinate expression of ion currents.

  14. Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling

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    Zhi-Dong Liu

    2016-08-01

    Full Text Available Abstract Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein malfunction and mitochondrial dysfunction contribute to the loss of neuronal architecture; however, less is known about the intracellular signaling pathways that can protect against or delay this pathogenic process. Here, we show that the DYNC1I1 deficiency, a neuron-specific dynein intermediate chain, causes neuronal atrophy in primary hippocampal neurons. With this cellular model, we are able to find that activation of RAS-RAF-MEK signaling protects against neuronal atrophy induced by DYNC1I1 deficiency, which relies on MEK-dependent autophagy in neuron. Moreover, we further reveal that BRAF also protects against neuronal atrophy induced by mitochondrial impairment. These findings demonstrate protective roles of the RAS-RAF-MEK axis against neuronal atrophy, and imply a new therapeutic target for clinical intervention.

  15. Transient epileptiform signaling during neuronal network development: regulation by external stimulation and bimodal GABAergic activity.

    Science.gov (United States)

    Zemianek, Jill M; Shultz, Abraham M; Lee, Sangmook; Guaraldi, Mary; Yanco, Holly A; Shea, Thomas B

    2013-04-01

    A predominance of excitatory activity, with protracted appearance of inhibitory activity, accompanies cortical neuronal development. It is unclear whether or not inhibitory neuronal activity is solicited exclusively by excitatory neurons or whether the transient excitatory activity displayed by developing GABAergic neurons contributes to an excitatory threshold that fosters their conversion to inhibitory activity. We addressed this possibility by culturing murine embryonic neurons on multi-electrode arrays. A wave of individual 0.2-0.4 mV signals ("spikes") appeared between approx. 20-30 days in culture, then declined. A transient wave of high amplitude (>0.5 mV) epileptiform activity coincided with the developmental decline in spikes. Bursts (clusters of ≥3 low-amplitude spikes within 0.7s prior to returning to baseline) persisted following this decline. Addition of the GABAergic antagonist bicuculline initially had no effect on signaling, consistent with delayed development of GABAergic synapses. This was followed by a period in which bicuculline inhibited overall signaling, confirming that GABAergic neurons initially display excitatory activity in ex vivo networks. Following the transient developmental wave of epileptiform signaling, bicuculline induced a resurgence of epileptiform signaling, indicating that GABAergic neurons at this point displayed inhibitory activity. The appearance of transition after the developmental and decline of epileptiform activity, rather than immediately after the developmental decline in lower-amplitude spikes, suggests that the initial excitatory activity of GABAergic neurons contributes to their transition into inhibitory neurons, and that inhibitory GABAergic activity is essential for network development. Prior studies indicate that a minority (25%) of neurons in these cultures were GABAergic, suggesting that inhibitory neurons regulate multiple excitatory neurons. A similar robust increase in signaling following cessation of

  16. Nicotine Elicits Convulsive Seizures by Activating Amygdalar Neurons

    Science.gov (United States)

    Iha, Higor A.; Kunisawa, Naofumi; Shimizu, Saki; Tokudome, Kentaro; Mukai, Takahiro; Kinboshi, Masato; Ikeda, Akio; Ito, Hidefumi; Serikawa, Tadao; Ohno, Yukihiro

    2017-01-01

    Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of epileptic disorders; however, the mechanisms of nACh receptors in seizure generation remain unknown. Here, we performed behavioral and immunohistochemical studies in mice and rats to clarify the mechanisms underlying nicotine-induced seizures. Treatment of animals with nicotine (1–4 mg/kg, i.p.) produced motor excitement in a dose-dependent manner and elicited convulsive seizures at 3 and 4 mg/kg. The nicotine-induced seizures were abolished by a subtype non-selective nACh antagonist, mecamylamine (MEC). An α7 nACh antagonist, methyllycaconitine, also significantly inhibited nicotine-induced seizures whereas an α4β2 nACh antagonist, dihydro-β-erythroidine, affected only weakly. Topographical analysis of Fos protein expression, a biological marker of neural excitation, revealed that a convulsive dose (4 mg/kg) of nicotine region-specifically activated neurons in the piriform cortex, amygdala, medial habenula, paratenial thalamus, anterior hypothalamus and solitary nucleus among 48 brain regions examined, and this was also suppressed by MEC. In addition, electric lesioning of the amygdala, but not the piriform cortex, medial habenula and thalamus, specifically inhibited nicotine-induced seizures. Furthermore, microinjection of nicotine (100 and 300 μg/side) into the amygdala elicited convulsive seizures in a dose-related manner. The present results suggest that nicotine elicits convulsive seizures by activating amygdalar neurons mainly via α7 nACh receptors.

  17. In vitro neuronal network activity in NMDA receptor encephalitis

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    Jantzen Sabine U

    2013-02-01

    Full Text Available Abstract Background Anti-NMDA-encephalitis is caused by antibodies against the N-methyl-D-aspartate receptor (NMDAR and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. It predominantly occurs in young women and is associated in 59% with an ovarian teratoma. Results We describe effects of cerebrospinal fluid (CSF from an anti-N-methyl-D-aspartate receptor (NMDAR encephalitis patient on in vitro neuronal network activity (ivNNA. In vitro NNA of dissociated primary rat cortical populations was recorded by the microelectrode array (MEA system. The 23-year old patient was severely affected but showed an excellent recovery following multimodal immunomodulatory therapy and removal of an ovarian teratoma. Patient CSF (pCSF taken during the initial weeks after disease onset suppressed global spike- and burst rates of ivNNA in contrast to pCSF sampled after clinical recovery and decrease of NMDAR antibody titers. The synchrony of pCSF-affected ivNNA remained unaltered during the course of the disease. Conclusion Patient CSF directly suppresses global activity of neuronal networks recorded by the MEA system. In contrast, pCSF did not regulate the synchrony of ivNNA suggesting that NMDAR antibodies selectively regulate distinct parameters of ivNNA while sparing their functional connectivity. Thus, assessing ivNNA could represent a new technique to evaluate functional consequences of autoimmune encephalitis-related CSF changes.

  18. Integrate-and-fire neurons with threshold noise: A tractable model of how interspike interval correlations affect neuronal signal transmission

    Science.gov (United States)

    Lindner, Benjamin; Chacron, Maurice J.; Longtin, André

    2017-01-01

    Many neurons exhibit interval correlations in the absence of input signals. We study the influence of these intrinsic interval correlations of model neurons on their signal transmission properties. For this purpose, we employ two simple firing models, one of which generates a renewal process, while the other leads to a nonrenewal process with negative interval correlations. Different methods to solve for spectral statistics in the presence of a weak stimulus (spike train power spectra, cross spectra, and coherence functions) are presented, and their range of validity is discussed. Using these analytical results, we explore a lower bound on the mutual information rate between output spike train and input stimulus as a function of the system’s parameters. We demonstrate that negative correlations in the baseline activity can lead to enhanced information transfer of a weak signal by means of noise shaping of the background noise spectrum. We also show that an enhancement is not compulsory—for a stimulus with power exclusively at high frequencies, the renewal model can transfer more information than the nonrenewal model does. We discuss the application of our analytical results to other problems in neuroscience. Our results are also relevant to the general problem of how a signal affects the power spectrum of a nonlinear stochastic system. PMID:16196608

  19. Activation of neuronal defense mechanisms in response to pathogenic factors triggering induction of amyloidosis in Alzheimer's disease.

    Science.gov (United States)

    Maltsev, Alexander V; Santockyte, Rasa; Bystryak, Simon; Galzitskaya, Oxana V

    2014-01-01

    We present a new model for etiology of Alzheimer's disease (AD) which postulates early involvement of specialized neuroprotective mechanisms in the pathology of AD. These neuroprotective mechanisms work in concert to regulate metabolic homeostasis in healthy neuronal cells, but contribute to the distinctive cytopathic phenotype of neuronal degeneration in AD. According to this model, two molecular/genetic hallmarks of AD, amyloid-β (Aβ) deposition and tau hyperphosphorylation, are associated with neuronal mechanisms for dissipating thermal energy associated with high levels of protein synthesis in highly temperature-sensitive neuronal cells. Development of effective methods of AD treatment will require a better understanding of how this neuronal defense system is activated in response to cytopathological triggers in sporadic AD. The cause and effect link between synthesis and processing of amyloid-β protein precursor (AβPP) and the AD terminal phenotype of neurofibrillary tangles and neuron loss involve the formation of Aβ peptides that accumulate as oligomers, cannot be controlled by neurons, and are toxic to the surrounding neuronal membranes. We analyze experimental and clinical studies that have investigated the correlation between phosphorylation of some transport proteins and increased synthesis of proteins in neurons. We also review the evidence related to the possibility that protein hyperphosphorylation may be a byproduct of energetic imbalances in AD cells associated with high levels of protein synthesis, and that activation of defense systems, through which energy-rich molecules are eliminated from the site of protein synthesis and are sequestered to the peripheral neuronal areas, may bring about some of the distinctive morphological features of AD.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2003-07-01

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

  1. Theoretical analysis of transcranial magneto-acoustical stimulation with Hodgkin–Huxley neuron model

    Directory of Open Access Journals (Sweden)

    Yi eYuan

    2016-04-01

    Full Text Available Transcranial magneto-acoustical stimulation (TMAS is a novel stimulation technology in which an ultrasonic wave within a magnetostatic field generates an electric current in an area of interest in the brain to modulate neuronal activities. As a key part of the neural network, neurons transmit information in the nervous system. However, the effect of TMAS on the neuronal firing rhythm remains unknown. To address this problem, we investigated the stimulatory mechanism of TMAS on neurons with a Hodgkin-Huxley neuron model. The simulation results indicate that the magnetostatic field intensity and ultrasonic power can affect the amplitude and interspike interval of neuronal action potential under continuous wave ultrasound. The simulation results also show that the ultrasonic power, duty cycle and repetition frequency can alter the firing rhythm of neural action potential under pulsed ultrasound. This study can help to reveal and explain the biological mechanism of TMAS and to provide a theoretical basis for TMAS in the treatment or rehabilitation of neuropsychiatric disorders.

  2. Changes in response properties of nociceptive dorsal horn neurons in a murine model of cancer pain

    Institute of Scientific and Technical Information of China (English)

    Donald A. Simone; Sergey G. Khasabov; Darryl T. Hamamoto

    2008-01-01

    Pain associated with cancer that metastasizes to bone is often severe and debilitating. A better understanding of the neural mechanisms that mediate cancer pain is needed for the development of more effective treatments. In this study, we used an established model of cancer pain to characterize changes in response properties of dorsal horn neurons. Fibrosarcoma cells were implanted into and around the calcaneus bone in mice and extracellular electrophysiological recordings were made from wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons. Responses of WDR and HT neurons evoked by mechanical, heat, and cold stimuli applied to the plantar surface of the hind paw were compared between tumor bearing mice and control mice. Mice exhibited hyperalgesia to mechanical and heat stimuli applied to their tumor-bearing hind paw. WDR neurons in tumor-beating mice exhibited an increase in spontaneous activity, and enhanced responses to mechanical, heat, and cold stimuli as compared to controls. Our findings show that sensitization of WDR neurons, but not HT neurons, contributes to tumor-evoked hyperalgesia.

  3. Theoretical Analysis of Transcranial Magneto-Acoustical Stimulation with Hodgkin-Huxley Neuron Model.

    Science.gov (United States)

    Yuan, Yi; Chen, Yudong; Li, Xiaoli

    2016-01-01

    Transcranial magneto-acoustical stimulation (TMAS) is a novel stimulation technology in which an ultrasonic wave within a magnetostatic field generates an electric current in an area of interest in the brain to modulate neuronal activities. As a key part of the neural network, neurons transmit information in the nervous system. However, the effect of TMAS on the neuronal firing pattern remains unknown. To address this problem, we investigated the stimulatory mechanism of TMAS on neurons, by using a Hodgkin-Huxley neuron model. The simulation results indicated that the magnetostatic field intensity and ultrasonic power affect the amplitude and interspike interval of neuronal action potential under a continuous wave ultrasound. The simulation results also showed that the ultrasonic power, duty cycle and repetition frequency can alter the firing pattern of neural action potential under pulsed wave ultrasound. This study may help to reveal and explain the biological mechanism of TMAS and to provide a theoretical basis for TMAS in the treatment or rehabilitation of neuropsychiatric disorders.

  4. Role of myelin plasticity in oscillations and synchrony of neuronal activity.

    Science.gov (United States)

    Pajevic, S; Basser, P J; Fields, R D

    2014-09-12

    Conduction time is typically ignored in computational models of neural network function. Here we consider the effects of conduction delays on the synchrony of neuronal activity and neural oscillators, and evaluate the consequences of allowing conduction velocity (CV) to be regulated adaptively. We propose that CV variation, mediated by myelin, could provide an important mechanism of activity-dependent nervous system plasticity. Even small changes in CV, resulting from small changes in myelin thickness or nodal structure, could have profound effects on neuronal network function in terms of spike-time arrival, oscillation frequency, oscillator coupling, and propagation of brain waves. For example, a conduction delay of 5ms could change interactions of two coupled oscillators at the upper end of the gamma frequency range (∼100Hz) from constructive to destructive interference; delays smaller than 1ms could change the phase by 30°, significantly affecting signal amplitude. Myelin plasticity, as another form of activity-dependent plasticity, is relevant not only to nervous system development but also to complex information processing tasks that involve coupling and synchrony among different brain rhythms. We use coupled oscillator models with time delays to explore the importance of adaptive time delays and adaptive synaptic strengths. The impairment of activity-dependent myelination and the loss of adaptive time delays may contribute to disorders where hyper- and hypo-synchrony of neuronal firing leads to dysfunction (e.g., dyslexia, schizophrenia, epilepsy). Published by Elsevier Ltd.

  5. How modeling can reconcile apparently discrepant experimental results: the case of pacemaking in dopaminergic neurons.

    Directory of Open Access Journals (Sweden)

    Guillaume Drion

    2011-05-01

    Full Text Available Midbrain dopaminergic neurons are endowed with endogenous slow pacemaking properties. In recent years, many different groups have studied the basis for this phenomenon, often with conflicting conclusions. In particular, the role of a slowly-inactivating L-type calcium channel in the depolarizing phase between spikes is controversial, and the analysis of slow oscillatory potential (SOP recordings during the blockade of sodium channels has led to conflicting conclusions. Based on a minimal model of a dopaminergic neuron, our analysis suggests that the same experimental protocol may lead to drastically different observations in almost identical neurons. For example, complete L-type calcium channel blockade eliminates spontaneous firing or has almost no effect in two neurons differing by less than 1% in their maximal sodium conductance. The same prediction can be reproduced in a state of the art detailed model of a dopaminergic neuron. Some of these predictions are confirmed experimentally using single-cell recordings in brain slices. Our minimal model exhibits SOPs when sodium channels are blocked, these SOPs being uncorrelated with the spiking activity, as has been shown experimentally. We also show that block of a specific conductance (in this case, the SK conductance can have a different effect on these two oscillatory behaviors (pacemaking and SOPs, despite the fact that they have the same initiating mechanism. These results highlight the fact that computational approaches, besides their well known confirmatory and predictive interests in neurophysiology, may also be useful to resolve apparent discrepancies between experimental results.

  6. Extending the mirror neuron system model, II: what did I just do? A new role for mirror neurons.

    Science.gov (United States)

    Bonaiuto, James; Arbib, Michael A

    2010-04-01

    A mirror system is active both when an animal executes a class of actions (self-actions) and when it sees another execute an action of that class. Much attention has been given to the possible roles of mirror systems in responding to the actions of others but there has been little attention paid to their role in self-actions. In the companion article (Bonaiuto et al. Biol Cybern 96:9-38, 2007) we presented MNS2, an extension of the Mirror Neuron System model of the monkey mirror system trained to recognize the external appearance of its own actions as a basis for recognizing the actions of other animals when they perform similar actions. Here we further extend the study of the mirror system by introducing the novel hypotheses that a mirror system may additionally help in monitoring the success of a self-action and may also be activated by recognition of one's own apparent actions as well as efference copy from one's intended actions. The framework for this computational demonstration is a model of action sequencing, called augmented competitive queuing, in which action choice is based on the desirability of executable actions. We show how this "what did I just do?" function of mirror neurons can contribute to the learning of both executability and desirability which in certain cases supports rapid reorganization of motor programs in the face of disruptions.

  7. Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels.

    Science.gov (United States)

    Korsgaard, M P G; Hartz, B P; Brown, W D; Ahring, P K; Strøbaek, D; Mirza, N R

    2005-07-01

    Neuronal Kv7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal Kv7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing Kv7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal Kv7 channels, whereas its R-enantiomer was a negative modulator. By contrast, at the Kv7.1 and the large conductance Ca2+-activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA(A) receptors (alpha1beta2gamma2s and alpha2beta2gamma2s) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S- and R-forms exhibited opposing effects on neuronal Kv7 channel subtypes allowed us to assess the potential role of Kv7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive Kv7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the Kv7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal Kv7 channels are a target for developing novel anxiolytics.

  8. Activation of perineuronal net-expressing excitatory neurons during associative memory encoding and retrieval

    Science.gov (United States)

    Morikawa, Shota; Ikegaya, Yuji; Narita, Minoru; Tamura, Hideki

    2017-01-01

    Perineuronal nets (PNNs), proteoglycan-rich extracellular matrix structures, are thought to be expressed around inhibitory neurons and contribute to critical periods of brain function and synaptic plasticity. However, in some specific brain regions such as the amygdala, PNNs were predominantly expressed around excitatory neurons. These neurons were recruited during auditory fear conditioning and memory retrieval. Indeed, the activation of PNN-expressing excitatory neurons predicted cognitive performance. PMID:28378772

  9. A Thalamo-Hypothalamic Pathway That Activates Oxytocin Neurons in Social Contexts in Female Rats.

    Science.gov (United States)

    Cservenák, Melinda; Keller, Dávid; Kis, Viktor; Fazekas, Emese A; Öllös, Hanna; Lékó, András H; Szabó, Éva R; Renner, Éva; Usdin, Ted B; Palkovits, Miklós; Dobolyi, Árpád

    2017-02-01

    Oxytocin is released from neurons in the paraventricular hypothalamic nucleus (PVN) in mothers upon suckling and during adult social interactions. However, neuronal pathways that activate oxytocin neurons in social contexts are not yet established. Neurons in the posterior intralaminar complex of the thalamus (PIL), which contain tuberoinfundibular peptide 39 (TIP39) and are activated by pup exposure in lactating mothers, provide a candidate projection. Innervation of oxytocin neurons by TIP39 neurons was examined by double labeling in combination with electron microscopy and retrograde tract-tracing. Potential classic neurotransmitters in TIP39 neurons were investigated by in situ hybridization histochemistry. Neurons activated after encounter with a familiar conspecific female in a familiar environment were mapped with the c-Fos technique. PVN and the supraoptic nucleus oxytocin neurons were closely apposed by an average of 2.0 and 0.4 TIP39 terminals, respectively. Asymmetric (presumed excitatory) synapses were found between TIP39 terminals and cell bodies of oxytocin neurons. In lactating rats, PIL TIP39 neurons were retrogradely labeled from the PVN. TIP39 neurons expressed vesicular glutamate transporter 2 but not glutamic acid decarboxylase 67. PIL contained a markedly increased number of c-Fos-positive neurons in response to social encounter with a familiar conspecific female. Furthermore, the PIL received ascending input from the spinal cord and the inferior colliculus. Thus, TIP39 neurons in the PIL may receive sensory input in response to social interactions and project to the PVN to innervate and excite oxytocin neurons, suggesting that the PIL-PVN projection contributes to the activation of oxytocin neurons in social contexts. Copyright © 2017 by the Endocrine Society.

  10. Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways

    Science.gov (United States)

    2012-01-01

    Background Expression of active c-Abl in adult mouse forebrain neurons in the AblPP/tTA mice resulted in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocytosis. In contrast, expression of constitutively active Arg (Abl-related gene) in mouse forebrain neurons (ArgPP/tTA mice) caused no detectable neuronal loss or gliosis, although protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice. Methods To begin to elucidate the mechanism of c-Abl-induced neuronal loss and gliosis, gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology was performed. Selected results from gene expression studies were validated with quantitative reverse transcription PCR , immunoblotting and bromodeoxyuridine (BrdU) labeling, and by immunocytochemistry. Results Two of the top pathways upregulated in AblPP/tTA mice with c-Abl expression for 2 weeks were cell cycle and interferon signaling. However, only the expression of interferon signaling pathway genes remained elevated at 4 weeks of c-Abl induction. BrdU incorporation studies confirm that, while the cell cycle pathway is upregulated in AblPP/tTA mice at 2 weeks of c-Abl induction, the anatomical localization of the pathway is not consistent with previous pathology seen in the AblPP/tTA mice. Increased expression and activation of STAT1, a known component of interferon signaling and interferon-induced neuronal excitotoxicity, is an early consequence of c-Abl activation in AblPP/tTA mice and occurs in the CA1 region of the hippocampus, the same region that goes on to develop severe neurodegenerative pathology and neuroinflammation. Interestingly, no upregulation of gene expression of interferons themselves was detected. Conclusions Our data suggest that the interferon signaling pathway may play a role in the pathologic processes caused by c-Abl expression in

  11. Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways

    Directory of Open Access Journals (Sweden)

    Schlatterer Sarah D

    2012-08-01

    Full Text Available Abstract Background Expression of active c-Abl in adult mouse forebrain neurons in the AblPP/tTA mice resulted in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocytosis. In contrast, expression of constitutively active Arg (Abl-related gene in mouse forebrain neurons (ArgPP/tTA mice caused no detectable neuronal loss or gliosis, although protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice. Methods To begin to elucidate the mechanism of c-Abl-induced neuronal loss and gliosis, gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology was performed. Selected results from gene expression studies were validated with quantitative reverse transcription PCR , immunoblotting and bromodeoxyuridine (BrdU labeling, and by immunocytochemistry. Results Two of the top pathways upregulated in AblPP/tTA mice with c-Abl expression for 2 weeks were cell cycle and interferon signaling. However, only the expression of interferon signaling pathway genes remained elevated at 4 weeks of c-Abl induction. BrdU incorporation studies confirm that, while the cell cycle pathway is upregulated in AblPP/tTA mice at 2 weeks of c-Abl induction, the anatomical localization of the pathway is not consistent with previous pathology seen in the AblPP/tTA mice. Increased expression and activation of STAT1, a known component of interferon signaling and interferon-induced neuronal excitotoxicity, is an early consequence of c-Abl activation in AblPP/tTA mice and occurs in the CA1 region of the hippocampus, the same region that goes on to develop severe neurodegenerative pathology and neuroinflammation. Interestingly, no upregulation of gene expression of interferons themselves was detected. Conclusions Our data suggest that the interferon signaling pathway may play a role in the pathologic processes

  12. Apolipoprotein E isoform-dependent dendritic recovery of hippocampal neurons following activation of innate immunity

    Directory of Open Access Journals (Sweden)

    Maezawa Izumi

    2006-08-01

    while that within TR APOE4 hippocampus failed to support dendrite regeneration in this model of reversible paracrine damage to neurons from innate immune activation, and suggest an explanation for the stratification of clinical outcome with APOE seen in several degenerative diseases or brain that are associated with activated innate immune response.

  13. Study on dynamic characteristics' change of hippocampal neuron reduced models caused by the Alzheimer's disease.

    Science.gov (United States)

    Peng, Yueping; Wang, Jue; Zheng, Chongxun

    2016-01-01

    In the paper, based on the electrophysiological experimental data, the Hippocampal neuron reduced model under the pathology condition of Alzheimer's disease (AD) has been built by modifying parameters' values. The reduced neuron model's dynamic characteristics under effect of AD are comparatively studied. Under direct current stimulation, compared with the normal neuron model, the AD neuron model's dynamic characteristics have obviously been changed. The neuron model under the AD condition undergoes supercritical Andronov-Hopf bifurcation from the rest state to the continuous discharge state. It is different from the neuron model under the normal condition, which undergoes saddle-node bifurcation. So, the neuron model changes into a resonator with monostable state from an integrator with bistable state under AD's action. The research reveals the neuron model's dynamic characteristics' changing under effect of AD, and provides some theoretic basis for AD research by neurodynamics theory.

  14. Pipe-cleaner Model of Neuronal Network Dynamics

    CERN Document Server

    Armstrong, Eve

    2016-01-01

    We present a functional model of neuronal network connectivity in which the single architectural element is the object commonly known in handicraft circles as a pipe cleaner. We argue that the dual nature of a neuronal circuit - that it be at times highly robust to external manipulation and yet sufficiently flexible to allow for learning and adaptation - is embodied in the pipe cleaner, and thus that a pipe cleaner framework serves as an instructive scaffold in which to examine network dynamics. Regarding the dynamics themselves: as pipe cleaners possess no intrinsic dynamics, in our model we attribute the emergent circuit dynamics to magic. Magic is a strategy that has been largely neglected in the neuroscience community, and may serve as an illuminating comparison to the common physics-based approaches. This model makes predictions that it would be really awesome to test experimentally. Moreover, the relative simplicity of the pipe cleaner - setting aside the fact that it comes in an overwhelming variety of...

  15. Neuronal and brain morphological changes in animal models of schizophrenia.

    Science.gov (United States)

    Flores, Gonzalo; Morales-Medina, Julio César; Diaz, Alfonso

    2016-03-15

    Schizophrenia, a severe and debilitating disorder with a high social burden, affects 1% of the adult world population. Available therapies are unable to treat all the symptoms, and result in strong side effects. For this reason, numerous animal models have been generated to elucidate the pathophysiology of this disorder. All these models present neuronal remodeling and abnormalities in spine stability. It is well known that the complexity in dendritic arborization determines the number of receptive synaptic contacts. Also the loss of dendritic spines and arbor stability are strongly associated with schizophrenia. This review evaluates changes in spine density and dendritic arborization in animal models of schizophrenia. By understanding these changes, pharmacological treatments can be designed to target specific neural systems to attenuate neuronal remodeling and associated behavioral deficits.

  16. Study on the Hippocampal Neuron's Minimal Models' Discharge Patterns

    Directory of Open Access Journals (Sweden)

    Yueping Peng

    2011-06-01

    Full Text Available The hippocampal CA1 pyramid neuron has plenty of discharge actions. The one-compartment model of CA1 pyramid neuron developed by David is a nine-dimension complex dynamic model. In the thesis, the currents related to the nine-dimension complex model are analyzed and classified by the model’s reduction theory and methods based on neurodynamics, and four minimal models are gotten: (I_Na+I_Kdr-minimal model, (I_Na+I_M-minimal model, (I_Na+I_Ca+I_y-minimal model, and (I_Na+I_Ca+I_sAHP-minimal model. These minimal models have plenty of dynamic actions, and under the current’s stimulation, they can all generate regular discharge and have period discharge pattern, bursting pattern, the chaos discharge pattern, and so on. Compared with the initial nine-dimension complex model, these minimal models’ dimension are much reduced, and are more convenient to numerical simulation, calculating, and analyzing. In addition, these minimal models provide a simpler and flexible method to discuss the specific currents’ dynamic characteristics and functions of the initial nine-dimension complex model by the theory of neurodynamics.

  17. From neural plate to cortical arousal-a neuronal network theory of sleep derived from in vitro "model" systems for primordial patterns of spontaneous bioelectric activity in the vertebrate central nervous system.

    Science.gov (United States)

    Corner, Michael A

    2013-05-22

    In the early 1960s intrinsically generated widespread neuronal discharges were discovered to be the basis for the earliest motor behavior throughout the animal kingdom. The pattern generating system is in fact programmed into the developing nervous system, in a regionally specific manner, already at the early neural plate stage. Such rhythmically modulated phasic bursts were next discovered to be a general feature of developing neural networks and, largely on the basis of experimental interventions in cultured neural tissues, to contribute significantly to their morpho-physiological maturation. In particular, the level of spontaneous synchronized bursting is homeostatically regulated, and has the effect of constraining the development of excessive network excitability. After birth or hatching, this "slow-wave" activity pattern becomes sporadically suppressed in favor of sensory oriented "waking" behaviors better adapted to dealing with environmental contingencies. It nevertheless reappears periodically as "sleep" at several species-specific points in the diurnal/nocturnal cycle. Although this "default" behavior pattern evolves with development, its essential features are preserved throughout the life cycle, and are based upon a few simple mechanisms which can be both experimentally demonstrated and simulated by computer modeling. In contrast, a late onto- and phylogenetic aspect of sleep, viz., the intermittent "paradoxical" activation of the forebrain so as to mimic waking activity, is much less well understood as regards its contribution to brain development. Some recent findings dealing with this question by means of cholinergically induced "aroused" firing patterns in developing neocortical cell cultures, followed by quantitative electrophysiological assays of immediate and longterm sequelae, will be discussed in connection with their putative implications for sleep ontogeny.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Kazuhiko Nishida

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

  20. Neuronal activity in the preoptic hypothalamus during sleep deprivation and recovery sleep.

    Science.gov (United States)

    Alam, Md Aftab; Kumar, Sunil; McGinty, Dennis; Alam, Md Noor; Szymusiak, Ronald

    2014-01-01

    The preoptic hypothalamus is implicated in sleep regulation. Neurons in the median preoptic nucleus (MnPO) and the ventrolateral preoptic area (VLPO) have been identified as potential sleep regulatory elements. However, the extent to which MnPO and VLPO neurons are activated in response to changing homeostatic sleep regulatory demands is unresolved. To address this question, we continuously recorded the extracellular activity of neurons in the rat MnPO, VLPO and dorsal lateral preoptic area (LPO) during baseline sleep and waking, during 2 h of sleep deprivation (SD) and during 2 h of recovery sleep (RS). Sleep-active neurons in the MnPO (n = 11) and VLPO (n = 13) were activated in response to SD, such that waking discharge rates increased by 95.8 ± 29.5% and 59.4 ± 17.3%, respectively, above waking baseline values. During RS, non-rapid eye movement (REM) sleep discharge rates of MnPO neurons initially increased to 65.6 ± 15.2% above baseline values, then declined to baseline levels in association with decreases in EEG delta power. Increase in non-REM sleep discharge rates in VLPO neurons during RS averaged 40.5 ± 7.6% above baseline. REM-active neurons (n = 16) in the LPO also exhibited increased waking discharge during SD and an increase in non-REM discharge during RS. Infusion of A2A adenosine receptor antagonist into the VLPO attenuated SD-induced increases in neuronal discharge. Populations of LPO wake/REM-active and state-indifferent neurons and dorsal LPO sleep-active neurons were unresponsive to SD. These findings support the hypothesis that sleep-active neurons in the MnPO and VLPO, and REM-active neurons in the LPO, are components of neuronal circuits that mediate homeostatic responses to sustained wakefulness.

  1. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model.

    Science.gov (United States)

    Takagi, Yasushi; Takahashi, Jun; Saiki, Hidemoto; Morizane, Asuka; Hayashi, Takuya; Kishi, Yo; Fukuda, Hitoshi; Okamoto, Yo; Koyanagi, Masaomi; Ideguchi, Makoto; Hayashi, Hideki; Imazato, Takayuki; Kawasaki, Hiroshi; Suemori, Hirofumi; Omachi, Shigeki; Iida, Hidehiko; Itoh, Nobuyuki; Nakatsuji, Norio; Sasai, Yoshiki; Hashimoto, Nobuo

    2005-01-01

    Parkinson disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic (DA) neurons. ES cells are currently the most promising donor cell source for cell-replacement therapy in PD. We previously described a strong neuralizing activity present on the surface of stromal cells, named stromal cell-derived inducing activity (SDIA). In this study, we generated neurospheres composed of neural progenitors from monkey ES cells, which are capable of producing large numbers of DA neurons. We demonstrated that FGF20, preferentially expressed in the substantia nigra, acts synergistically with FGF2 to increase the number of DA neurons in ES cell-derived neurospheres. We also analyzed the effect of transplantation of DA neurons generated from monkey ES cells into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated (MPTP-treated) monkeys, a primate model for PD. Behavioral studies and functional imaging revealed that the transplanted cells functioned as DA neurons and attenuated MPTP-induced neurological symptoms.

  2. Network dynamics in nociceptive pathways assessed by the neuronal avalanche model

    Directory of Open Access Journals (Sweden)

    Wu José

    2012-04-01

    Full Text Available Abstract Background Traditional electroencephalography provides a critical assessment of pain responses. The perception of pain, however, may involve a series of signal transmission pathways in higher cortical function. Recent studies have shown that a mathematical method, the neuronal avalanche model, may be applied to evaluate higher-order network dynamics. The neuronal avalanche is a cascade of neuronal activity, the size distribution of which can be approximated by a power law relationship manifested by the slope of a straight line (i.e., the α value. We investigated whether the neuronal avalanche could be a useful index for nociceptive assessment. Findings Neuronal activity was recorded with a 4 × 8 multichannel electrode array in the primary somatosensory cortex (S1 and anterior cingulate cortex (ACC. Under light anesthesia, peripheral pinch stimulation increased the slope of the α value in both the ACC and S1, whereas brush stimulation increased the α value only in the S1. The increase in α values was blocked in both regions under deep anesthesia. The increase in α values in the ACC induced by peripheral pinch stimulation was blocked by medial thalamic lesion, but the increase in α values in the S1 induced by brush and pinch stimulation was not affected. Conclusions The neuronal avalanche model shows a critical state in the cortical network for noxious-related signal processing. The α value may provide an index of brain network activity that distinguishes the responses to somatic stimuli from the control state. These network dynamics may be valuable for the evaluation of acute nociceptive processes and may be applied to chronic pathological pain conditions.

  3. Self-organized Criticality and Synchronization in a Pulse-coupled Integrate-and-Fire Neuron Model Based on Small World Networks

    Institute of Scientific and Technical Information of China (English)

    LIN Min; CHEN Tian-Lun

    2005-01-01

    A lattice model for a set of pulse-coupled integrate-and-fire neurons with small world structure is introduced.We find that our model displays the power-law behavior accompanied with the large-scale synchronized activities among the units. And the different connectivity topologies lead to different behaviors in models of integrate-and-fire neurons.

  4. Mathematical modelling of the enteric nervous network. 1: Cholinergic neuron.

    Science.gov (United States)

    Miftakhov, R N; Wingate, D L

    1994-01-01

    A mathematical model is proposed to describe the coupled electrochemical mechanisms of nerve-pulse transmission via cholinergic synapse. Based on pharmacological and morphophysiological data, the model describes the dynamics of the propagation of the electric signal along the unmyelinated geometrically non-uniform axon of the neuron and the chemical mechanisms of the transformation of the electrical signal in the synaptic zone into the postsynaptic output. The combined nonlinear system of partial and ordinary differential equations has been obtained and solved numerically. The results of numerical simulation of the function of the cholinergic neuron quantitatively and qualitatively describe the dynamics of Ca2+ ions influx into the terminal, acetylcholine release from the vesicles, accumulation of its free fraction, diffusion into the synaptic cleft, and binding with the receptors on the postsynaptic structures with the generation of the fast excitatory postsynaptic potential. They are in good agreement with the observed experimental findings.

  5. Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Zhu Yong

    2012-01-01

    Full Text Available Abstract Background Causes of neuropathic pain following nerve injury remain unclear, limiting the development of mechanism-based therapeutic approaches. Animal models have provided some directions, but little is known about the specific sensory neurons that undergo changes in such a way as to induce and maintain activation of sensory pain pathways. Our previous studies implicated changes in the Aβ, normally non-nociceptive neurons in activating spinal nociceptive neurons in a cuff-induced animal model of neuropathic pain and the present study was directed specifically at determining any change in excitability of these neurons. Thus, the present study aimed at recording intracellularly from Aβ-fiber dorsal root ganglion (DRG neurons and determining excitability of the peripheral receptive field, of the cell body and of the dorsal roots. Methods A peripheral neuropathy was induced in Sprague Dawley rats by inserting two thin polyethylene cuffs around the right sciatic nerve. All animals were confirmed to exhibit tactile hypersensitivity to von Frey filaments three weeks later, before the acute electrophysiological experiments. Under stable intracellular recording conditions neurons were classified functionally on the basis of their response to natural activation of their peripheral receptive field. In addition, conduction velocity of the dorsal roots, configuration of the action potential and rate of adaptation to stimulation were also criteria for classification. Excitability was measured as the threshold to activation of the peripheral receptive field, the response to intracellular injection of depolarizing current into the soma and the response to electrical stimulation of the dorsal roots. Results In control animals mechanical thresholds of all neurons were within normal ranges. Aβ DRG neurons in neuropathic rats demonstrated a mean mechanical threshold to receptive field stimulation that were significantly lower than in control rats, a

  6. Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

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    Sandra Almeida

    2012-10-01

    Full Text Available The pathogenic mechanisms of frontotemporal dementia (FTD remain poorly understood. Here we generated multiple induced pluripotent stem cell lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel heterozygous GRN mutation (progranulin [PGRN] S116X. In neurons and microglia differentiated from PGRN S116X induced pluripotent stem cells, the levels of intracellular and secreted PGRN were reduced, establishing patient-specific cellular models of PGRN haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by PGRN expression. Our findings identify cell-autonomous, reversible defects in patient neurons with PGRN deficiency, and provide a compelling model for studying PGRN-dependent pathogenic mechanisms and testing potential therapies.

  7. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression

    Energy Technology Data Exchange (ETDEWEB)

    Li, B.; Schulz, D.; Li, B; Piriz, J.; Mirrione, M.; Chung, C.H.; Proulx, C.D.; Schulz, D.; Henn, F.; Malinow, R.

    2011-02-24

    The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

  8. Linked Gauss-Diffusion processes for modeling a finite-size neuronal network.

    Science.gov (United States)

    Carfora, M F; Pirozzi, E

    2017-08-02

    A Leaky Integrate-and-Fire (LIF) model with stochastic current-based linkages is considered to describe the firing activity of neurons interacting in a (2×2)-size feed-forward network. In the subthreshold regime and under the assumption that no more than one spike is exchanged between coupled neurons, the stochastic evolution of the neuronal membrane voltage is subject to random jumps due to interactions in the network. Linked Gauss-Diffusion processes are proposed to describe this dynamics and to provide estimates of the firing probability density of each neuron. To this end, an iterated integral equation-based approach is applied to evaluate numerically the first passage time density of such processes through the firing threshold. Asymptotic approximations of the firing densities of surrounding neurons are used to obtain closed-form expressions for the mean of the involved processes and to simplify the numerical procedure. An extension of the model to an (N×N)-size network is also given. Histograms of firing times obtained by simulations of the LIF dynamics and numerical firings estimates are compared. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Ligands for pheromone-sensing neurons are not conformationally activated odorant binding proteins.

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    Carolina Gomez-Diaz

    Full Text Available Pheromones form an essential chemical language of intraspecific communication in many animals. How olfactory systems recognize pheromonal signals with both sensitivity and specificity is not well understood. An important in vivo paradigm for this process is the detection mechanism of the sex pheromone (Z-11-octadecenyl acetate (cis-vaccenyl acetate [cVA] in Drosophila melanogaster. cVA-evoked neuronal activation requires a secreted odorant binding protein, LUSH, the CD36-related transmembrane protein SNMP, and the odorant receptor OR67d. Crystallographic analysis has revealed that cVA-bound LUSH is conformationally distinct from apo (unliganded LUSH. Recombinantly expressed mutant versions of LUSH predicted to enhance or diminish these structural changes produce corresponding alterations in spontaneous and/or cVA-evoked activity when infused into olfactory sensilla, leading to a model in which the ligand for pheromone receptors is not free cVA, but LUSH that is "conformationally activated" upon cVA binding. Here we present evidence that contradicts this model. First, we demonstrate that the same LUSH mutants expressed transgenically affect neither basal nor pheromone-evoked activity. Second, we compare the structures of apo LUSH, cVA/LUSH, and complexes of LUSH with non-pheromonal ligands and find no conformational property of cVA/LUSH that can explain its proposed unique activated state. Finally, we show that high concentrations of cVA can induce neuronal activity in the absence of LUSH, but not SNMP or OR67d. Our findings are not consistent with the model that the cVA/LUSH complex acts as the pheromone ligand, and suggest that pheromone molecules alone directly activate neuronal receptors.

  10. Chimera in a neuronal network model of the cat brain

    OpenAIRE

    Santos, M. S.; Szezech Jr., J. D.; Borges, F. S.; Iarosz, K. C.; Caldas, I. L.; Batista, A. M.; Viana, R. L.; Kurths, J.

    2016-01-01

    Neuronal systems have been modeled by complex networks in different description levels. Recently, it has been verified that networks can simultaneously exhibit one coherent and other incoherent domain, known as chimera states. In this work, we study the existence of chimera states in a network considering the connectivity matrix based on the cat cerebral cortex. The cerebral cortex of the cat can be separated in 65 cortical areas organised into the four cognitive regions: visual, auditory, so...

  11. Calcium imaging of sleep-wake related neuronal activity in the dorsal pons.

    Science.gov (United States)

    Cox, Julia; Pinto, Lucas; Dan, Yang

    2016-02-25

    The dorsal pons has long been implicated in the generation of rapid eye movement (REM) sleep, but the underlying circuit mechanisms remain poorly understood. Using cell-type-specific microendoscopic Ca(2+) imaging in and near the laterodorsal tegmental nucleus, we found that many glutamatergic neurons are maximally active during REM sleep (REM-max), while the majority of GABAergic neurons are maximally active during wakefulness (wake-max). Furthermore, the activity of glutamatergic neurons exhibits a medio-lateral spatial gradient, with medially located neurons more selectively active during REM sleep.

  12. Plasticity-modulated seizure dynamics for seizure termination in realistic neuronal models

    Science.gov (United States)

    Koppert, M. M. J.; Kalitzin, S.; Lopes da Silva, F. H.; Viergever, M. A.

    2011-08-01

    In previous studies we showed that autonomous absence seizure generation and termination can be explained by realistic neuronal models eliciting bi-stable dynamics. In these models epileptic seizures are triggered either by external stimuli (reflex epilepsies) or by internal fluctuations. This scenario predicts exponential distributions of the duration of the seizures and of the inter-ictal intervals. These predictions were validated in rat models of absence epilepsy, as well as in a few human cases. Nonetheless, deviations from the predictions with respect to seizure duration distributions remained unexplained. The objective of the present work is to implement a simple but realistic computational model of a neuronal network including synaptic plasticity and ionic current dynamics and to explore the dynamics of the model with special emphasis on the distributions of seizure and inter-ictal period durations. We use as a basis our lumped model of cortical neuronal circuits. Here we introduce 'activity dependent' parameters, namely post-synaptic voltage-dependent plasticity, as well as a voltage-dependent hyperpolarization-activated current driven by slow and fast activation conductances. We examine the distributions of the durations of the seizure-like model activity and the normal activity, described respectively by the limit cycle and the steady state in the dynamics. We use a parametric γ-distribution fit as a quantifier. Our results show that autonomous, activity-dependent membrane processes can account for experimentally obtained statistical distributions of seizure durations, which were not explainable using the previous model. The activity-dependent membrane processes that display the strongest effect in accounting for these distributions are the hyperpolarization-dependent cationic (Ih) current and the GABAa plastic dynamics. Plastic synapses (NMDA-type) in the interneuron population show only a minor effect. The inter-ictal statistics retain their

  13. Imaging electrical activity of neurons with metamaterial nanosensors

    CERN Document Server

    Beletskiy, Roman V

    2013-01-01

    A technology for recording electrical activity of large neuron populations at arbitrary depth in brain tissues with less than cell spatial and millisecond temporal resolutions was the most craving dream of neuroscientists and a long pursued goal of engineers for decades. Even though many imaging techniques have been devised up to date, none of them is capable to deliver either quantitatively valid data nor able to meet contradictory requirements posed for sensors to be safe, non-invasive and reliably working either within cultured cell populations or during chronic implantations in vivo. In my research project, I design and justify a novel nanobiosensors, capable to detect and optically report the electric fields across cellular membrane and investigate properties of that specially engineered plasmonic nanoantennas. In the following literature survey, I observe the current state of electrophysiology methods and after recalling the basics of fluorescence, discuss benefits and drawbacks of today's voltage sensi...

  14. Analysis of Chaotic Resonance in Izhikevich Neuron Model.

    Science.gov (United States)

    Nobukawa, Sou; Nishimura, Haruhiko; Yamanishi, Teruya; Liu, Jian-Qin

    2015-01-01

    In stochastic resonance (SR), the presence of noise helps a nonlinear system amplify a weak (sub-threshold) signal. Chaotic resonance (CR) is a phenomenon similar to SR but without stochastic noise, which has been observed in neural systems. However, no study to date has investigated and compared the characteristics and performance of the signal responses of a spiking neural system in some chaotic states in CR. In this paper, we focus on the Izhikevich neuron model, which can reproduce major spike patterns that have been experimentally observed. We examine and classify the chaotic characteristics of this model by using Lyapunov exponents with a saltation matrix and Poincaré section methods in order to address the measurement challenge posed by the state-dependent jump in the resetting process. We found the existence of two distinctive states, a chaotic state involving primarily turbulent movement and an intermittent chaotic state. In order to assess the signal responses of CR in these classified states, we introduced an extended Izhikevich neuron model by considering weak periodic signals, and defined the cycle histogram of neuron spikes as well as the corresponding mutual correlation and information. Through computer simulations, we confirmed that both chaotic states in CR can sensitively respond to weak signals. Moreover, we found that the intermittent chaotic state exhibited a prompter response than the chaotic state with primarily turbulent movement.

  15. Estimation of the input parameters in the Feller neuronal model

    Science.gov (United States)

    Ditlevsen, Susanne; Lansky, Petr

    2006-06-01

    The stochastic Feller neuronal model is studied, and estimators of the model input parameters, depending on the firing regime of the process, are derived. Closed expressions for the first two moments of functionals of the first-passage time (FTP) through a constant boundary in the suprathreshold regime are derived, which are used to calculate moment estimators. In the subthreshold regime, the exponentiality of the FTP is utilized to characterize the input parameters. The methods are illustrated on simulated data. Finally, approximations of the first-passage-time moments are suggested, and biological interpretations and comparisons of the parameters in the Feller and the Ornstein-Uhlenbeck models are discussed.

  16. Asymmetric pallidal neuronal activity in patients with cervical dystonia

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    Christian KE eMoll

    2014-02-01

    Full Text Available The origin of asymmetric clinical manifestation of symptoms in patients suffering from cervical dystonia (CD is hitherto poorly understood. Dysregulated neuronal activity in the basal ganglia has been suggested to have a role in the pathophysiology of CD. Here, we re-assessed the question to what extent relative changes occur in the direct versus indirect basal ganglia pathway in CD, whether these circuit changes are lateralized, and how these alterations relate to CD symptoms. To this end, we recorded ongoing single cell and local field potential (LFP activity from the external (GPe and internal pallidal segment (GPi of thirteen CD patients undergoing microelectrode-guided stereotactic surgery for deep brain stimulation in the GPi. We compared pallidal recordings from CD patients operated under local anaesthesia (LA with those obtained in CD patients operated under general anaesthesia (GA. In awake patients, mean GPe discharge rate (52 Hz was lower than that of GPi (72 Hz. Mean GPi discharge ipsilateral to the side of head turning was higher than contralateral and correlated with torticollis symptom severity. Lateralized differences were absent at the level of the GPe and in recordings from patients operated under GA. Furthermore, in the GPi of CD patients there was a subpopulation of theta-oscillatory cells with unique bursting characteristics. Power and coherence of GPe- and GPi-LFPs were dominated by a theta peak and also exhibited band-specific interhemispheric differences. Strong cross-frequency coupling of low-gamma amplitude to theta phase was a feature of pallidal LFPs recorded under LA, but not GA. These results indicate that CD is associated with an asymmetric pallidal outflow. Based on the finding of symmetric neuronal discharges in the GPe, we propose that an imbalanced interhemispheric direct pathway gain may be involved in CD pathophysiology.

  17. Activity and High-Order Effective Connectivity Alterations in Sanfilippo C Patient-Specific Neuronal Networks

    Science.gov (United States)

    Canals, Isaac; Soriano, Jordi; Orlandi, Javier G.; Torrent, Roger; Richaud-Patin, Yvonne; Jiménez-Delgado, Senda; Merlin, Simone; Follenzi, Antonia; Consiglio, Antonella; Vilageliu, Lluïsa; Grinberg, Daniel; Raya, Angel

    2015-01-01

    Summary Induced pluripotent stem cell (iPSC) technology has been successfully used to recapitulate phenotypic traits of several human diseases in vitro. Patient-specific iPSC-based disease models are also expected to reveal early functional phenotypes, although this remains to be proved. Here, we generated iPSC lines from two patients with Sanfilippo type C syndrome, a lysosomal storage disorder with inheritable progressive neurodegeneration. Mature neurons obtained from patient-specific iPSC lines recapitulated the main known phenotypes of the disease, not present in genetically corrected patient-specific iPSC-derived cultures. Moreover, neuronal networks organized in vitro from mature patient-derived neurons showed early defects in neuronal activity, network-wide degradation, and altered effective connectivity. Our findings establish the importance of iPSC-based technology to identify early functional phenotypes, which can in turn shed light on the pathological mechanisms occurring in Sanfilippo syndrome. This technology also has the potential to provide valuable readouts to screen compounds, which can prevent the onset of neurodegeneration. PMID:26411903

  18. Activity and High-Order Effective Connectivity Alterations in Sanfilippo C Patient-Specific Neuronal Networks

    Directory of Open Access Journals (Sweden)

    Isaac Canals

    2015-10-01

    Full Text Available Induced pluripotent stem cell (iPSC technology has been successfully used to recapitulate phenotypic traits of several human diseases in vitro. Patient-specific iPSC-based disease models are also expected to reveal early functional phenotypes, although this remains to be proved. Here, we generated iPSC lines from two patients with Sanfilippo type C syndrome, a lysosomal storage disorder with inheritable progressive neurodegeneration. Mature neurons obtained from patient-specific iPSC lines recapitulated the main known phenotypes of the disease, not present in genetically corrected patient-specific iPSC-derived cultures. Moreover, neuronal networks organized in vitro from mature patient-derived neurons showed early defects in neuronal activity, network-wide degradation, and altered effective connectivity. Our findings establish the importance of iPSC-based technology to identify early functional phenotypes, which can in turn shed light on the pathological mechanisms occurring in Sanfilippo syndrome. This technology also has the potential to provide valuable readouts to screen compounds, which can prevent the onset of neurodegeneration.

  19. Activity and High-Order Effective Connectivity Alterations in Sanfilippo C Patient-Specific Neuronal Networks.

    Science.gov (United States)

    Canals, Isaac; Soriano, Jordi; Orlandi, Javier G; Torrent, Roger; Richaud-Patin, Yvonne; Jiménez-Delgado, Senda; Merlin, Simone; Follenzi, Antonia; Consiglio, Antonella; Vilageliu, Lluïsa; Grinberg, Daniel; Raya, Angel

    2015-10-13

    Induced pluripotent stem cell (iPSC) technology has been successfully used to recapitulate phenotypic traits of several human diseases in vitro. Patient-specific iPSC-based disease models are also expected to reveal early functional phenotypes, although this remains to be proved. Here, we generated iPSC lines from two patients with Sanfilippo type C syndrome, a lysosomal storage disorder with inheritable progressive neurodegeneration. Mature neurons obtained from patient-specific iPSC lines recapitulated the main known phenotypes of the disease, not present in genetically corrected patient-specific iPSC-derived cultures. Moreover, neuronal networks organized in vitro from mature patient-derived neurons showed early defects in neuronal activity, network-wide degradation, and altered effective connectivity. Our findings establish the importance of iPSC-based technology to identify early functional phenotypes, which can in turn shed light on the pathological mechanisms occurring in Sanfilippo syndrome. This technology also has the potential to provide valuable readouts to screen compounds, which can prevent the onset of neurodegeneration.

  20. Optically-Induced Neuronal Activity Is Sufficient to Promote Functional Motor Axon Regeneration In Vivo.

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    Patricia J Ward

    Full Text Available Peripheral nerve injuries are common, and functional recovery is very poor. Beyond surgical repair of the nerve, there are currently no treatment options for these patients. In experimental models of nerve injury, interventions (such as exercise and electrical stimulation that increase neuronal activity of the injured neurons effectively enhance axon regeneration. Here, we utilized optogenetics to determine whether increased activity alone is sufficient to promote motor axon regeneration. In thy-1-ChR2/YFP transgenic mice in which a subset of motoneurons express the light-sensitive cation channel, channelrhodopsin (ChR2, we activated axons in the sciatic nerve using blue light immediately prior to transection and surgical repair of the sciatic nerve. At four weeks post-injury, direct muscle EMG responses evoked with both optical and electrical stimuli as well as the ratio of these optical/electrical evoked EMG responses were significantly greater in mice that received optical treatment. Thus, significantly more ChR2+ axons successfully re-innervated the gastrocnemius muscle in mice that received optical treatment. Sections of the gastrocnemius muscles were reacted with antibodies to Synaptic Vesicle Protein 2 (SV2 to quantify the number of re-occupied motor endplates. The number of SV2+ endplates was greater in mice that received optical treatment. The number of retrogradely-labeled motoneurons following intramuscular injection of cholera toxin subunit B (conjugated to Alexa Fluor 555 was greater in mice that received optical treatment. Thus, the acute (1 hour, one-time optical treatment resulted in robust, long-lasting effects compared to untreated animals as well as untreated axons (ChR2-. We conclude that neuronal activation is sufficient to promote motor axon regeneration, and this regenerative effect is specific to the activated neurons.

  1. Neuroligin-1 links neuronal activity to sleep-wake regulation

    Science.gov (United States)

    El Helou, Janine; Bélanger-Nelson, Erika; Freyburger, Marlène; Dorsaz, Stéphane; Curie, Thomas; La Spada, Francesco; Gaudreault, Pierre-Olivier; Beaumont, Éric; Pouliot, Philippe; Lesage, Frédéric; Frank, Marcos G.; Franken, Paul; Mongrain, Valérie

    2013-01-01

    Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-d-aspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strain-specific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation. PMID:23716671

  2. Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens.

    Science.gov (United States)

    Steinberg, Elizabeth E; Boivin, Josiah R; Saunders, Benjamin T; Witten, Ilana B; Deisseroth, Karl; Janak, Patricia H

    2014-01-01

    The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.

  3. Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens.

    Directory of Open Access Journals (Sweden)

    Elizabeth E Steinberg

    Full Text Available The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS, a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc, a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.

  4. Relationship between inter-stimulus-intervals and intervals of autonomous activities in a neuronal network.

    Science.gov (United States)

    Ito, Hidekatsu; Minoshima, Wataru; Kudoh, Suguru N

    2015-08-01

    To investigate relationships between neuronal network activity and electrical stimulus, we analyzed autonomous activity before and after electrical stimulus. Recordings of autonomous activity were performed using dissociated culture of rat hippocampal neurons on a multi-electrodes array (MEA) dish. Single stimulus and pared stimuli were applied to a cultured neuronal network. Single stimulus was applied every 1 min, and paired stimuli was performed by two sequential stimuli every 1 min. As a result, the patterns of synchronized activities of a neuronal network were changed after stimulus. Especially, long range synchronous activities were induced by paired stimuli. When 1 s inter-stimulus-intervals (ISI) and 1.5 s ISI paired stimuli are applied to a neuronal network, relatively long range synchronous activities expressed in case of 1.5 s ISI. Temporal synchronous activity of neuronal network is changed according to inter-stimulus-intervals (ISI) of electrical stimulus. In other words, dissociated neuronal network can maintain given information in temporal pattern and a certain type of an information maintenance mechanism was considered to be implemented in a semi-artificial dissociated neuronal network. The result is useful toward manipulation technology of neuronal activity in a brain system.

  5. High-resolution eye tracking using V1 neuron activity

    Science.gov (United States)

    McFarland, James M.; Bondy, Adrian G.; Cumming, Bruce G.; Butts, Daniel A.

    2014-01-01

    Studies of high-acuity visual cortical processing have been limited by the inability to track eye position with sufficient accuracy to precisely reconstruct the visual stimulus on the retina. As a result, studies on primary visual cortex (V1) have been performed almost entirely on neurons outside the high-resolution central portion of the visual field (the fovea). Here we describe a procedure for inferring eye position using multi-electrode array recordings from V1 coupled with nonlinear stimulus processing models. We show that this method can be used to infer eye position with one arc-minute accuracy – significantly better than conventional techniques. This allows for analysis of foveal stimulus processing, and provides a means to correct for eye-movement induced biases present even outside the fovea. This method could thus reveal critical insights into the role of eye movements in cortical coding, as well as their contribution to measures of cortical variability. PMID:25197783

  6. Bursting and Synchrony in Networks of Model Neurons

    CERN Document Server

    Geier, Christian; Elger, Christian E; Lehnertz, Klaus

    2016-01-01

    Bursting neurons are considered to be a potential cause of over-excitability and seizure susceptibility. The functional influence of these neurons in extended epileptic networks is still poorly understood. There is mounting evidence that the dynamics of neuronal networks is influenced not only by neuronal and synaptic properties but also by network topology. We investigate numerically the influence of different neuron dynamics on global synchrony in neuronal networks with complex connection topologies.

  7. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator.

    Science.gov (United States)

    Tsirka, S E; Gualandris, A; Amaral, D G; Strickland, S

    1995-09-28

    Neuronal degeneration in the hippocampus, a region of the brain important for acquisition of memory in humans, occurs in various pathological conditions, including Alzheimer's disease, brain ischaemia and epilepsy. When neuronal activity is stimulated in the adult rat and mouse hippocampus, tissue plasminogen activator (tPA), a serine protease that converts inactive plasminogen to the active protease plasmin, is transcriptionally induced. The activity of tPA in neural tissue is correlated with neurite outgrowth, regeneration and migration, suggesting that it might be involved in neuronal plasticity. Here we show that tPA is produced primarily by microglia in the hippocampus. Using excitotoxins to induce neuronal cell loss, we demonstrate that tPA-deficient mice are resistant to neuronal degeneration. These mice are also less susceptible to pharmacologically induced seizures than wild-type mice. These findings identify a role for tPA in neuronal degeneration and seizure.

  8. Loss of glutathione homeostasis associated with neuronal senescence facilitates TRPM2 channel activation in cultured hippocampal pyramidal neurons

    Directory of Open Access Journals (Sweden)

    Belrose Jillian C

    2012-04-01

    Full Text Available Abstract Background Glutathione (GSH plays an important role in neuronal oxidant defence. Depletion of cellular GSH is observed in neurodegenerative diseases and thereby contributes to the associated oxidative stress and Ca2+ dysregulation. Whether depletion of cellular GSH, associated with neuronal senescence, directly influences Ca2+ permeation pathways is not known. Transient receptor potential melastatin type 2 (TRPM2 is a Ca2+ permeable non-selective cation channel expressed in several cell types including hippocampal pyramidal neurons. Moreover, activation of TRPM2 during oxidative stress has been linked to cell death. Importantly, GSH has been reported to inhibit TRPM2 channels, suggesting they may directly contribute to Ca2+ dysregulation associated with neuronal senescence. Herein, we explore the relation between cellular GSH and TRPM2 channel activity in long-term cultures of hippocampal neurons. Results In whole-cell voltage-clamp recordings, we observe that TRPM2 current density increases in cultured pyramidal neurons over time in vitro. The observed increase in current density was prevented by treatment with NAC, a precursor to GSH synthesis. Conversely, treatment of cultures maintained for 2 weeks in vitro with L-BSO, which depletes GSH by inhibiting its synthesis, augments TRPM2 currents. Additionally, we demonstrate that GSH inhibits TRPM2 currents through a thiol-independent mechanism, and produces a 3.5-fold shift in the dose-response curve generated by ADPR, the intracellular agonist for TRPM2. Conclusion These results indicate that GSH plays a physiologically relevant role in the regulation of TRPM2 currents in hippocampal pyramidal neurons. This interaction may play an important role in aging and neurological diseases associated with depletion of GSH.

  9. Computational and experimental analysis of TMS-induced electric field vectors critical to neuronal activation

    Science.gov (United States)

    Krieg, Todd D.; Salinas, Felipe S.; Narayana, Shalini; Fox, Peter T.; Mogul, David J.

    2015-08-01

    Objective. Transcranial magnetic stimulation (TMS) represents a powerful technique to noninvasively modulate cortical neurophysiology in the brain. However, the relationship between the magnetic fields created by TMS coils and neuronal activation in the cortex is still not well-understood, making predictable cortical activation by TMS difficult to achieve. Our goal in this study was to investigate the relationship between induced electric fields and cortical activation measured by blood flow response. Particularly, we sought to discover the E-field characteristics that lead to cortical activation. Approach. Subject-specific finite element models (FEMs) of the head and brain were constructed for each of six subjects using magnetic resonance image scans. Positron emission tomography (PET) measured each subject’s cortical response to image-guided robotically-positioned TMS to the primary motor cortex. FEM models that employed the given coil position, orientation, and stimulus intensity in experimental applications of TMS were used to calculate the electric field (E-field) vectors within a region of interest for each subject. TMS-induced E-fields were analyzed to better understand what vector components led to regional cerebral blood flow (CBF) responses recorded by PET. Main results. This study found that decomposing the E-field into orthogonal vector components based on the cortical surface geometry (and hence, cortical neuron directions) led to significant differences between the regions of cortex that were active and nonactive. Specifically, active regions had significantly higher E-field components in the normal inward direction (i.e., parallel to pyramidal neurons in the dendrite-to-axon orientation) and in the tangential direction (i.e., parallel to interneurons) at high gradient. In contrast, nonactive regions had higher E-field vectors in the outward normal direction suggesting inhibitory responses. Significance. These results provide critical new

  10. Neuronal activation by mucosal biopsy supernatants from irritable bowel syndrome patients is linked to visceral sensitivity.

    Science.gov (United States)

    Buhner, Sabine; Braak, Breg; Li, Qin; Kugler, Eva Maria; Klooker, Tamira; Wouters, Mira; Donovan, Jemma; Vignali, Sheila; Mazzuoli-Weber, Gemma; Grundy, David; Boeckxstaens, Guy; Schemann, Michael

    2014-10-01

    Based on the discomfort/pain threshold during rectal distension, irritable bowel syndrome (IBS) patients may be subtyped as normo- or hypersensitive. We previously showed that mucosal biopsy supernatants from IBS patients activated enteric and visceral afferent neurons. We tested the hypothesis that visceral sensitivity is linked to the degree of neuronal activation. Normo- and hypersensitive IBS patients were distinguished by their discomfort/pain threshold to rectal balloon distension with a barostat. Using potentiometric and Ca(2+) dye imaging, we recorded the response of guinea-pig enteric submucous and mouse dorsal root ganglion (DRG) neurons, respectively, to mucosal biopsy supernatants from normosensitive (n = 12 tested in enteric neurons, n = 9 tested in DRG) and hypersensitive IBS patients (n = 9, tested in both types of neurons). In addition, we analysed the association between neuronal activation and individual discomfort/pain pressure thresholds. The IBS supernatants evoked Ca(2+) transients in DRG neurons and spike discharge in submucous neurons. Submucous and DRG neurons showed significantly stronger responses to supernatants from hypersensitive IBS patients as reflected by higher spike frequency or stronger [Ca(2+)]i transients in a larger proportion of neurons. The neuroindex as a product of spike frequency or [Ca(2+)]i transients and proportion of responding neurons correlated significantly with the individual discomfort/pain thresholds of the IBS patients. Supernatants from hypersensitive IBS patients caused stronger activation of enteric and DRG neurons. The level of activation correlated with the individual discomfort/pain threshold pressure values. These findings support our hypothesis that visceral sensitivity is linked to activation of peripheral neurons by biopsy supernatants.

  11. Tissue Specific Expression of Cre in Rat Tyrosine Hydroxylase and Dopamine Active Transporter-Positive Neurons.

    Directory of Open Access Journals (Sweden)

    Zhenyi Liu

    Full Text Available The rat is a preferred model system over the mouse for neurological studies, and cell type-specific Cre expression in the rat enables precise ablation of gene function in neurons of interest, which is especially valuable for neurodegenerative disease modeling and optogenetics. Yet, few such Cre rats are available. Here we report the characterization of two Cre rats, tyrosine hydroxylase (TH-Cre and dopamine active transporter (DAT or Slc6a3-Cre, by using a combination of immunohistochemistry (IHC and mRNA fluorescence in situ hybridization (FISH as well as a fluorescent reporter for Cre activity. We detected Cre expression in expected neurons in both Cre lines. Interestingly, we also found that in Th-Cre rats, but not DAT-Cre rats, Cre is expressed in female germ cells, allowing germline excision of the floxed allele and hence the generation of whole-body knockout rats. In summary, our data demonstrate that targeted integration of Cre cassette lead to faithful recapitulation of expression pattern of the endogenous promoter, and mRNA FISH, in addition to IHC, is an effective method for the analysis of the spatiotemporal gene expression patterns in the rat brain, alleviating the dependence on high quality antibodies that are often not available against rat proteins. The Th-Cre and the DAT-Cre rat lines express Cre in selective subsets of dopaminergic neurons and should be particularly useful for researches on Parkinson's disease.

  12. Tissue Specific Expression of Cre in Rat Tyrosine Hydroxylase and Dopamine Active Transporter-Positive Neurons.

    Science.gov (United States)

    Liu, Zhenyi; Brown, Andrew; Fisher, Dan; Wu, Yumei; Warren, Joe; Cui, Xiaoxia

    2016-01-01

    The rat is a preferred model system over the mouse for neurological studies, and cell type-specific Cre expression in the rat enables precise ablation of gene function in neurons of interest, which is especially valuable for neurodegenerative disease modeling and optogenetics. Yet, few such Cre rats are available. Here we report the characterization of two Cre rats, tyrosine hydroxylase (TH)-Cre and dopamine active transporter (DAT or Slc6a3)-Cre, by using a combination of immunohistochemistry (IHC) and mRNA fluorescence in situ hybridization (FISH) as well as a fluorescent reporter for Cre activity. We detected Cre expression in expected neurons in both Cre lines. Interestingly, we also found that in Th-Cre rats, but not DAT-Cre rats, Cre is expressed in female germ cells, allowing germline excision of the floxed allele and hence the generation of whole-body knockout rats. In summary, our data demonstrate that targeted integration of Cre cassette lead to faithful recapitulation of expression pattern of the endogenous promoter, and mRNA FISH, in addition to IHC, is an effective method for the analysis of the spatiotemporal gene expression patterns in the rat brain, alleviating the dependence on high quality antibodies that are often not available against rat proteins. The Th-Cre and the DAT-Cre rat lines express Cre in selective subsets of dopaminergic neurons and should be particularly useful for researches on Parkinson's disease.

  13. Synaptic network activity induces neuronal differentiation of adult hippocampal precursor cells through BDNF signaling

    Directory of Open Access Journals (Sweden)

    Harish Babu

    2009-09-01

    Full Text Available Adult hippocampal neurogenesis is regulated by activity. But how do neural precursor cells in the hippocampus respond to surrounding network activity and translate increased neural activity into a developmental program? Here we show that long-term potential (LTP-like synaptic activity within a cellular network of mature hippocampal neurons promotes neuronal differentiation of newly generated cells. In co-cultures of precursor cells with primary hippocampal neurons, LTP-like synaptic plasticity induced by addition of glycine in Mg2+-free media for 5 min, produced synchronous network activity and subsequently increased synaptic strength between neurons. Furthermore, this synchronous network activity led to a significant increase in neuronal differentiation from the co-cultured neural precursor cells. When applied directly to precursor cells, glycine and Mg2+-free solution did not induce neuronal differentiation. Synaptic plasticity-induced neuronal differentiation of precursor cells was observed in the presence of GABAergic neurotransmission blockers but was dependent on NMDA-mediated Ca2+ influx. Most importantly, neuronal differentiation required the release of brain-derived neurotrophic factor (BDNF from the underlying substrate hippocampal neurons as well as TrkB receptor phosphorylation in precursor cells. This suggests that activity-dependent stem cell differentiation within the hippocampal network is mediated via synaptically evoked BDNF signaling.

  14. ERP adaptation provides direct evidence for early mirror neuron activation in the inferior parietal lobule.

    Science.gov (United States)

    Möhring, Nicole; Brandt, Emily S L; Mohr, Bettina; Pulvermüller, Friedemann; Neuhaus, Andres H

    2014-10-01

    Mirror neuron systems are frequently investigated by assessing overlapping brain activity during observation and execution of actions; however, distinct neuronal subpopulations may be activated that fall below the spatial resolution of magnetic resonance techniques. This shortfall can be resolved using repetition suppression paradigms that identify physiological adaptation processes caused by repeated activation of identical neuronal circuits. Here, event-related potentials were used to investigate the time course of mirror neuron circuit activation using repetition suppression within and across action observation and action execution modalities. In a lip-reading and speech production paradigm, the N170 component indexed stimulus repetition by adapting to both cross-modal and intra-modal repetitions in the left hemisphere. Neuronal source localization revealed activation of the left inferior parietal lobule during cross-modal relative to intra-modal trials. These results provide support for the position that the same neuronal circuits are activated in perceiving and performing articulatory actions. Moreover, our data strongly suggest that inferior parietal lobule mirror neurons are activated relatively early in time, which indicates partly automatic processes of linguistic perception and mirroring. Repetition suppression paradigms therefore help to elucidate neuronal correlates of different cognitive processes and may serve as a starting point for advanced electrophysiological research on mirror neurons.

  15. Digital hardware implementation of a stochastic two-dimensional neuron model.

    Science.gov (United States)

    Grassia, F; Kohno, T; Levi, T

    2017-02-22

    This study explores the feasibility of stochastic neuron simulation in digital systems (FPGA), which realizes an implementation of a two-dimensional neuron model. The stochasticity is added by a source of current noise in the silicon neuron using an Ornstein-Uhlenbeck process. This approach uses digital computation to emulate individual neuron behavior using fixed point arithmetic operation. The neuron model's computations are performed in arithmetic pipelines. It was designed in VHDL language and simulated prior to mapping in the FPGA. The experimental results confirmed the validity of the developed stochastic FPGA implementation, which makes the implementation of the silicon neuron more biologically plausible for future hybrid experiments.

  16. Statistics of a neuron model driven by asymmetric colored noise.

    Science.gov (United States)

    Müller-Hansen, Finn; Droste, Felix; Lindner, Benjamin

    2015-02-01

    Irregular firing of neurons can be modeled as a stochastic process. Here we study the perfect integrate-and-fire neuron driven by dichotomous noise, a Markovian process that jumps between two states (i.e., possesses a non-Gaussian statistics) and exhibits nonvanishing temporal correlations (i.e., represents a colored noise). Specifically, we consider asymmetric dichotomous noise with two different transition rates. Using a first-passage-time formulation, we derive exact expressions for the probability density and the serial correlation coefficient of the interspike interval (time interval between two subsequent neural action potentials) and the power spectrum of the spike train. Furthermore, we extend the model by including additional Gaussian white noise, and we give approximations for the interspike interval (ISI) statistics in this case. Numerical simulations are used to validate the exact analytical results for pure dichotomous noise, and to test the approximations of the ISI statistics when Gaussian white noise is included. The results may help to understand how correlations and asymmetry of noise and signals in nerve cells shape neuronal firing statistics.

  17. Magnetic-activated cell sorting (MACS) can be used as a large-scale method for establishing zebrafish neuronal cell cultures

    OpenAIRE

    Georg Welzel; Daniel Seitz; Stefan Schuster

    2015-01-01

    Neuronal cell cultures offer a crucial tool to mechanistically analyse regeneration in the nervous system. Despite the increasing importance of zebrafish (Danio rerio) as an in vivo model in neurobiological and biomedical research, in vitro approaches to the nervous system are lagging far behind and no method is currently available for establishing enriched neuronal cell cultures. Here we show that magnetic-activated cell sorting (MACS) can be used for the large-scale generation of neuronal-r...

  18. Simultaneous activation of mitophagy and autophagy by staurosporine protects against dopaminergic neuronal cell death.

    Science.gov (United States)

    Ha, Ji-Young; Kim, Ji-Soo; Kim, Seo-Eun; Son, Jin H

    2014-02-21

    Abnormal autophagy is frequently observed during dopaminergic neurodegeneration in Parkinson's disease (PD). However, it is not yet firmly established whether active autophagy is beneficial or pathogenic with respect to dopaminergic cell loss. Staurosporine, a common inducer of apoptosis, is often used in mechanistic studies of dopaminergic cell death. Here we report that staurosporine activates both autophagy and mitophagy simultaneously during dopaminergic neuronal cell death, and evaluate the physiological significance of these processes during cell death. First, staurosporine treatment resulted in induction of autophagy in more than 75% of apoptotic cells. Pharmacological inhibition of autophagy by bafilomycin A1 decreased significantly cell viability. In addition, staurosporine treatment resulted in activation of the PINK1-Parkin mitophagy pathway, of which deficit underlies some familial cases of PD, in the dopaminergic neuronal cell line, SN4741. The genetic blockade of this pathway by PINK1 null mutation also dramatically increased staurosporine-induced cell death. Taken together, our data suggest that staurosporine induces both mitophagy and autophagy, and that these pathways exert a significant neuroprotective effect, rather than a contribution to autophagic cell death. This model system may therefore be useful for elucidating the mechanisms underlying crosstalk between autophagy, mitophagy, and cell death in dopaminergic neurons.

  19. Lévy noise improves the electrical activity in a neuron under electromagnetic radiation.

    Science.gov (United States)

    Wu, Juan; Xu, Yong; Ma, Jun

    2017-01-01

    As the fluctuations of the internal bioelectricity of nervous system is various and complex, the external electromagnetic radiation induced by magnet flux on membrane can be described by the non-Gaussian type distribution of Lévy noise. Thus, the electrical activities in an improved Hindmarsh-Rose model excited by the external electromagnetic radiation of Lévy noise are investigated and some interesting modes of the electrical activities are exhibited. The external electromagnetic radiation of Lévy noise leads to the mode transition of the electrical activities and spatial phase, such as from the rest state to the firing state, from the spiking state to the spiking state with more spikes, and from the spiking state to the bursting state. Then the time points of the firing state versus Lévy noise intensity are depicted. The increasing of Lévy noise intensity heightens the neuron firing. Also the stationary probability distribution functions of the membrane potential of the neuron induced by the external electromagnetic radiation of Lévy noise with different intensity, stability index and skewness papremeters are analyzed. Moreover, through the positive largest Lyapunov exponent, the parameter regions of chaotic electrical mode of the neuron induced by the external electromagnetic radiation of Lévy noise distribution are detected.

  20. Active dendrites support efficient initiation of dendritic spikes in hippocampal CA3 pyramidal neurons

    OpenAIRE

    Kim, Sooyun; Guzman, Segundo J.; Hu, Hua; Jonas, Peter

    2012-01-01

    CA3 pyramidal neurons are important for memory formation and pattern completion in the hippocampal network. It is generally thought that proximal synapses from the mossy fibers activate these neurons most efficiently, whereas distal inputs from the perforant path have a weaker modulatory influence. We used confocally targeted patch-clamp recording from dendrites and axons to map the activation of rat CA3 pyramidal neurons at the subcellular level. Our results reveal two distinct dendritic dom...

  1. Statins decrease dendritic arborization in rat sympathetic neurons by blocking RhoA activation

    OpenAIRE

    Kim, Woo-Yang; Gonsiorek, Eugene A.; Barnhart, Chris; Davare, Monika A.; Engebose, Abby J.; Lauridsen, Holly; Bruun, Donald; Lesiak, Adam; Wayman, Gary; Bucelli, Robert; Higgins, Dennis; Lein, Pamela J.

    2009-01-01

    Clinical and experimental evidence suggest that statins decrease sympathetic activity, but whether peripheral mechanisms involving direct actions on post-ganglionic sympathetic neurons contribute to this effect is not known. Because tonic activity of these neurons is directly correlated with the size of their dendritic arbor, we tested the hypothesis that statins decrease dendritic arborization in sympathetic neurons. Oral administration of atorvastatin (20 mg/kg/day for 7 days) significantly...

  2. Serotonergic neurons in the caudal raphe nuclei discharge in association with activity of masticatory muscles

    Directory of Open Access Journals (Sweden)

    Ribeiro-do-Valle L.E.

    1997-01-01

    Full Text Available There is a dense serotonergic projection from nucleus raphe pallidus and nucleus raphe obscurus to the trigeminal motor nucleus and serotonin exerts a strong facilitatory action on the trigeminal motoneurons. Some serotonergic neurons in these caudal raphe nuclei increase their discharge during feeding. The objective of the present study was to investigate the possibility that the activity of these serotonergic neurons is related to activity of masticatory muscles. Cats were implanted with microelectrodes and gross electrodes. Caudal raphe single neuron activity, electrocorticographic activity, and splenius, digastric and masseter electromyographic activities were recorded during active behaviors (feeding and grooming, during quiet waking and during sleep. Seven presumed serotonergic neurons were identified. These neurons showed a long duration action potential (>2.0 ms, and discharged slowly (2-7 Hz and very regularly (interspike interval coefficient of variation <0.3 during quiet waking. The activity of these neurons decreased remarkably during fast wave sleep (78-100%. Six of these neurons showed tonic changes in their activity positively related to digastric and/or masseter muscle activity but not to splenius muscle activity during waking. These data are consistent with the hypothesis that serotonergic neurons in the caudal raphe nuclei play an important role in the control of jaw movements

  3. Opposing Effects of Neuronal Activity on Structural Plasticity.

    Science.gov (United States)

    Fauth, Michael; Tetzlaff, Christian

    2016-01-01

    The connectivity of the brain is continuously adjusted to new environmental influences by several activity-dependent adaptive processes. The most investigated adaptive mechanism is activity-dependent functional or synaptic plasticity regulating the transmission efficacy of existing synapses. Another important but less prominently discussed adaptive process is structural plasticity, which changes the connectivity by the formation and deletion of synapses. In this review, we show, based on experimental evidence, that structural plasticity can be classified similar to synaptic plasticity into two categories: (i) Hebbian structural plasticity, which leads to an increase (decrease) of the number of synapses during phases of high (low) neuronal activity and (ii) homeostatic structural plasticity, which balances these changes by removing and adding synapses. Furthermore, based on experimental and theoretical insights, we argue that each type of structural plasticity fulfills a different function. While Hebbian structural changes enhance memory lifetime, storage capacity, and memory robustness, homeostatic structural plasticity self-organizes the connectivity of the neural network to assure stability. However, the link between functional synaptic and structural plasticity as well as the detailed interactions between Hebbian and homeostatic structural plasticity are more complex. This implies even richer dynamics requiring further experimental and theoretical investigations.

  4. Recombinant AAV-mediated Expression of Human BDNF Protects Neurons against Cell Apoptosis in Aβ-induced Neuronal Damage Model

    Institute of Scientific and Technical Information of China (English)

    LIU Zhaohui; MA Dongliang; FENG Gaifeng; MA Yanbing; HU Haitao

    2007-01-01

    The human brain-derived neurotrophic factor (hBDNF) gene was cloned by polymerase chain reaction and the recombinant adeno-associated viral vector inserted with hBDNF gene (AAV-hBDNF) was constructed. Cultured rat hippocampal neurons were treated with Aβ25-35 and serued as the experimental Aβ-induced neuronal damage model (AD model), and the AD model was infected with AAV-hBDNF to explore neuroprotective effects of expression of BDNF. Cell viability was assayed by MTT. The expression of bcl-2 anti-apoptosis protein was detected by immunocytochemical staining. The change of intracellular free Ca ion ([Ca2+]i) was measured by laser scanning confocal microscopy. The results showed that BDNF had protective effects against Aβ-induced neuronal damage. The expression of the bcl-2 anti-apoptosis protein was raised significantly and the balance of [Ca2+]i was maintained in the AAV-hBDNF treatment group as compared with AD model group. These data suggested that recombinant AAV mediated a stable expression of hBDNF in cultured hippocampal neurons and resulted in significant neuron protective effects in AD model. The BDNF may reduce neuron apoptosis through increasing the expression of the bcl-2 anti-apoptosis protein and inhibiting intracellular calcium overload. The viral vector-mediated gene expression of BDNF may pave the way of a novel therapeutic strategy for the treatment of neurodegenerative diseases such as Alzheimer's disease.

  5. Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naïve rats and in rat models of inflammatory and neuropathic pain.

    Science.gov (United States)

    Elmes, Steven J R; Jhaveri, Maulik D; Smart, Darren; Kendall, David A; Chapman, Victoria

    2004-11-01

    Peripheral cannabinoid 2 receptors (CB2 receptors) modulate immune responses and attenuate nociceptive behaviour in models of acute and persistent pain. The aim of the present study was to investigate whether peripheral CB2 receptors modulate spinal processing of innocuous and noxious responses and to determine whether there are altered roles of CB2 receptors in models of persistent pain. Effects of local administration of the CB2 receptor agonist JWH-133 (5 and 15 microg/50 microL) on mechanically evoked responses of spinal wide dynamic range (WDR) neurons in noninflamed rats, rats with carrageenan-induced hindpaw inflammation, sham operated rats and spinal nerve-ligated (SNL) rats were determined in anaesthetized rats in vivo. Mechanical stimulation (von Frey filaments, 6-80 g) of the peripheral receptive field evoked firing of WDR neurons. Mechanically evoked responses of WDR neurons were similar in noninflamed, carrageenan-inflamed, sham-operated and SNL rats. Intraplantar injection of JWH-133 (15 microg), but not vehicle, significantly (P pain.

  6. An artificial network model for estimating the network structure underlying partially observed neuronal signals.

    Science.gov (United States)

    Komatsu, Misako; Namikawa, Jun; Chao, Zenas C; Nagasaka, Yasuo; Fujii, Naotaka; Nakamura, Kiyohiko; Tani, Jun

    2014-01-01

    Many previous studies have proposed methods for quantifying neuronal interactions. However, these methods evaluated the interactions between recorded signals in an isolated network. In this study, we present a novel approach for estimating interactions between observed neuronal signals by theorizing that those signals are observed from only a part of the network that also includes unobserved structures. We propose a variant of the recurrent network model that consists of both observable and unobservable units. The observable units represent recorded neuronal activity, and the unobservable units are introduced to represent activity from unobserved structures in the network. The network structures are characterized by connective weights, i.e., the interaction intensities between individual units, which are estimated from recorded signals. We applied this model to multi-channel brain signals recorded from monkeys, and obtained robust network structures with physiological relevance. Furthermore, the network exhibited common features that portrayed cortical dynamics as inversely correlated interactions between excitatory and inhibitory populations of neurons, which are consistent with the previous view of cortical local circuits. Our results suggest that the novel concept of incorporating an unobserved structure into network estimations has theoretical advantages and could provide insights into brain dynamics beyond what can be directly observed.

  7. Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model.

    Directory of Open Access Journals (Sweden)

    Jan Tønnesen

    Full Text Available Intrastriatal grafts of stem cell-derived dopamine (DA neurons induce behavioral recovery in animal models of Parkinson's disease (PD, but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2 and halorhodopsin (NpHR, respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.

  8. Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model.

    Science.gov (United States)

    Tønnesen, Jan; Parish, Clare L; Sørensen, Andreas T; Andersson, Angelica; Lundberg, Cecilia; Deisseroth, Karl; Arenas, Ernest; Lindvall, Olle; Kokaia, Merab

    2011-03-04

    Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.

  9. Differential regulation of Aβ42-induced neuronal C1q synthesis and microglial activation

    Directory of Open Access Journals (Sweden)

    Tenner Andrea J

    2005-01-01

    Full Text Available Abstract Expression of C1q, an early component of the classical complement pathway, has been shown to be induced in neurons in hippocampal slices, following accumulation of exogenous Aβ42. Microglial activation was also detected by surface marker expression and cytokine production. To determine whether C1q induction was correlated with intraneuronal Aβ and/or microglial activation, D-(--2-amino-5-phosphonovaleric acid (APV, an NMDA receptor antagonist and glycine-arginine-glycine-aspartic acid-serine-proline peptide (RGD, an integrin receptor antagonist, which blocks and enhances Aβ42 uptake, respectively, were assessed for their effect on neuronal C1q synthesis and microglial activation. APV inhibited, and RGD enhanced, microglial activation and neuronal C1q expression. However, addition of Aβ10–20 to slice cultures significantly reduced Aβ42 uptake and microglial activation, but did not alter the Aβ42-induced neuronal C1q expression. Furthermore, Aβ10–20 alone triggered C1q production in neurons, demonstrating that neither neuronal Aβ42 accumulation, nor microglial activation is required for neuronal C1q upregulation. These data are compatible with the hypothesis that multiple receptors are involved in Aβ injury and signaling in neurons. Some lead to neuronal C1q induction, whereas other(s lead to intraneuronal accumulation of Aβ and/or stimulation of microglia.

  10. The Timing for Neuronal Maturation in the Adult Hippocampus Is Modulated by Local Network Activity

    Science.gov (United States)

    Piatti, Verónica C.; Davies-Sala, M. Georgina; Espósito, M. Soledad; Mongiat, Lucas A.; Trinchero, Mariela F.; Schinder, Alejandro F.

    2013-01-01

    The adult hippocampus continuously generates new cohorts of immature neurons with increased excitability and plasticity. The window for the expression of those unique properties in each cohort is determined by the time required to acquire a mature neuronal phenotype. Here, we show that local network activity regulates the rate of maturation of adult-born neurons along the septotemporal axis of the hippocampus. Confocal microscopy and patch-clamp recordings were combined to assess marker expression, morphological development, and functional properties in retrovirally labeled neurons over time. The septal dentate gyrus displayed higher levels of basal network activity and faster rates of newborn neuron maturation than the temporal region. Voluntary exercise enhanced network activity only in the temporal region and, in turn, accelerated neuronal development. Finally, neurons developing within a highly active environment exhibited a delayed maturation when their intrinsic electrical activity was reduced by the cell-autonomous overexpression of Kir2.1, an inward-rectifying potassium channel. Our findings reveal a novel type of activity-dependent plasticity acting on the timing of neuronal maturation and functional integration of newly generated neurons along the longitudinal axis of the adult hippocampus. PMID:21613484

  11. Spontaneous Neuronal Activity in Developing Neocortical Networks: From Single Cells to Large-Scale Interactions.

    Science.gov (United States)

    Luhmann, Heiko J; Sinning, Anne; Yang, Jenq-Wei; Reyes-Puerta, Vicente; Stüttgen, Maik C; Kirischuk, Sergei; Kilb, Werner

    2016-01-01

    Neuronal activity has been shown to be essential for the proper formation of neuronal circuits, affecting developmental processes like neurogenesis, migration, programmed cell death, cellular differentiation, formation of local and long-range axonal connections, synaptic plasticity or myelination. Accordingly, neocortical areas reveal distinct spontaneous and sensory-driven neuronal activity patterns already at early phases of development. At embryonic stages, when immature neurons start to develop voltage-dependent channels, spontaneous activity is highly synchronized within small neuronal networks and governed by electrical synaptic transmission. Subsequently, spontaneous activity patterns become more complex, involve larger networks and propagate over several neocortical areas. The developmental shift from local to large-scale network activity is accompanied by a gradual shift from electrical to chemical synaptic transmission with an initial excitatory action of chloride-gated channels activated by GABA, glycine and taurine. Transient neuronal populations in the subplate (SP) support temporary circuits that play an important role in tuning early neocortical activity and the formation of mature neuronal networks. Thus, early spontaneous activity patterns control the formation of developing networks in sensory cortices, and disturbances of these activity patterns may lead to long-lasting neuronal deficits.

  12. High-Sugar, but Not High-Fat, Food Activates Supraoptic Nucleus Neurons in the Male Rat.

    Science.gov (United States)

    Hume, Catherine; Sabatier, Nancy; Menzies, John

    2017-07-01

    Oxytocin is a potent anorexigen and is believed to have a role in satiety signaling. We developed rat models to study the activity of oxytocin neurons in response to voluntary consumption or oral gavage of foods using c-Fos immunohistochemistry and in vivo electrophysiology. Using c-Fos expression as an indirect marker of neural activation, we showed that the percentage of magnocellular oxytocin neurons expressing c-Fos increased with voluntary consumption of sweetened condensed milk (SCM). To model the effect of food in the stomach, we gavaged anesthetized rats with SCM. The percentage of supraoptic nucleus and paraventricular nucleus magnocellular oxytocin-immunoreactive neurons expressing c-Fos increased with SCM gavage but not with gastric distention. To further examine the activity of the supraoptic nucleus, we made in vivo electrophysiological recordings from SON neurons, where anesthetized rats were gavaged with SCM or single cream. Pharmacologically identified oxytocin neurons responded to SCM gavage with a linear, proportional, and sustained increase in firing rate, but cream gavage resulted in a transient reduction in firing rate. Blood glucose increased after SCM gavage but not cream gavage. Plasma osmolarity and plasma sodium were unchanged throughout. We show that in response to high-sugar, but not high-fat, food in the stomach, there is an increase in the activity of oxytocin neurons. This does not appear to be a consequence of stomach distention or changes in osmotic pressure. Our data suggest that the presence of specific foods with different macronutrient profiles in the stomach differentially regulates the activity of oxytocin neurons. Copyright © 2017 Endocrine Society.

  13. Intervention of Peiyuan Huayu Decoction on the neuron damage in model rats with acute subdural hematoma

    Directory of Open Access Journals (Sweden)

    Xiao-Xuan Fan

    2017-07-01

    Full Text Available Objective: To study the intervention effect of Peiyuan Huayu Decoction on the neuron damage in model rats with acute subdural hematoma (ASDH. Methods: 160 SD rats were randomly divided into four groups, and the ASDH model rats were made by stereotactic autoblood injection, and sham operation group received craniotomy without blood injection. Sham operation group and model group were normally bred after model establishment, and 6 h after model establishment, the treatment group received intragastric administration of Peiyuan Huayu Decoction, and control group received intragastric administration of Piracetam Tablets, 1 time a day. On the 1d, 3d, 5d and 7d after model establishment, the general conditions of rats (activity, food intake and mental state were observed, blood was collected via auricula dextra, ELISA method was used to determine peripheral plasma NSE and S100毬 protein contents, routine HE staining was conducted after perfusion fixation, the neurons in blood injection side of brain tissue were counted, and the neuron damage was observed. Results: 26 rats were dead in the experiment. The general conditions of sham operation group were significantly better than those of other groups, treatment group was significantly better than model group and control group on the 5d group (P0.05; neuron count of sham operation group was basically stable, treatment group was not different from model group and control group on the 1d (P>0.05, treatment group was better than model group (P0.05 on the 3d, and treatment group was better than model group and control group on the 5d and 7d (P0.05, S100毬 protein and NSE contents decreased significantly on the 3d, and treatment group was significantly different from model group and control group (P<0.05, S100毬 protein and NSE contents increased on the 5d and 7d, the increase in treatment group was slower than that in model group and control group, and there was significant difference (P<0.05. Conclusion

  14. Apolipoprotein A-IV inhibits AgRP/NPY neurons and activates POMC neurons in the arcuate nucleus

    Science.gov (United States)

    Apolipoprotein A-IV (apoA-IV) in the brain potently suppresses food intake. However the mechanisms underlying its anorexigenic effects remain to be identified. We first examined the effects of apoA-IV on cellular activities in hypothalamic neurons that co-express agouti-related peptide (AgRP) and ne...

  15. Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease.

    Science.gov (United States)

    Chen, Yuejun; Xiong, Man; Dong, Yi; Haberman, Alexander; Cao, Jingyuan; Liu, Huisheng; Zhou, Wenhao; Zhang, Su-Chun

    2016-06-01

    Transplantation of human pluripotent stem cell (hPSC)-derived neurons is a promising avenue for treating disorders including Parkinson's disease (PD). Precise control over engrafted cell activity is highly desired, as cells do not always integrate properly into host circuitry and can cause suboptimal graft function or undesired outcomes. Here, we show tunable rescue of motor function in a mouse model of PD, following transplantation of human midbrain dopaminergic (mDA) neurons differentiated from hPSCs engineered to express DREADDs (designer receptors exclusively activated by designer drug). Administering clozapine-N-oxide (CNO) enabled precise DREADD-dependent stimulation or inhibition of engrafted neurons, revealing D1 receptor-dependent regulation of host neuronal circuitry by engrafted cells. Transplanted cells rescued motor defects, which could be reversed or enhanced by CNO-based control of graft function, and activating engrafted cells drives behavioral changes in transplanted mice. These results highlight the ability to exogenously and noninvasively control and refine therapeutic outcomes following cell transplantation.

  16. Deterministic and stochastic bifurcations in the Hindmarsh-Rose neuronal model.

    Science.gov (United States)

    Dtchetgnia Djeundam, S R; Yamapi, R; Kofane, T C; Aziz-Alaoui, M A

    2013-09-01

    We analyze the bifurcations occurring in the 3D Hindmarsh-Rose neuronal model with and without random signal. When under a sufficient stimulus, the neuron activity takes place; we observe various types of bifurcations that lead to chaotic transitions. Beside the equilibrium solutions and their stability, we also investigate the deterministic bifurcation. It appears that the neuronal activity consists of chaotic transitions between two periodic phases called bursting and spiking solutions. The stochastic bifurcation, defined as a sudden change in character of a stochastic attractor when the bifurcation parameter of the system passes through a critical value, or under certain condition as the collision of a stochastic attractor with a stochastic saddle, occurs when a random Gaussian signal is added. Our study reveals two kinds of stochastic bifurcation: the phenomenological bifurcation (P-bifurcations) and the dynamical bifurcation (D-bifurcations). The asymptotical method is used to analyze phenomenological bifurcation. We find that the neuronal activity of spiking and bursting chaos remains for finite values of the noise intensity.

  17. Light activates output from evening neurons and inhibits output from morning neurons in the Drosophila circadian clock.

    Directory of Open Access Journals (Sweden)

    Marie Picot

    2007-11-01

    Full Text Available Animal circadian clocks are based on multiple oscillators whose interactions allow the daily control of complex behaviors. The Drosophila brain contains a circadian clock that controls rest-activity rhythms and relies upon different groups of PERIOD (PER-expressing neurons. Two distinct oscillators have been functionally characterized under light-dark cycles. Lateral neurons (LNs that express the pigment-dispersing factor (PDF drive morning activity, whereas PDF-negative LNs are required for the evening activity. In constant darkness, several lines of evidence indicate that the LN morning oscillator (LN-MO drives the activity rhythms, whereas the LN evening oscillator (LN-EO does not. Since mutants devoid of functional CRYPTOCHROME (CRY, as opposed to wild-type flies, are rhythmic in constant light, we analyzed transgenic flies expressing PER or CRY in the LN-MO or LN-EO. We show that, under constant light conditions and reduced CRY function, the LN evening oscillator drives robust activity rhythms, whereas the LN morning oscillator does not. Remarkably, light acts by inhibiting the LN-MO behavioral output and activating the LN-EO behavioral output. Finally, we show that PDF signaling is not required for robust activity rhythms in constant light as opposed to its requirement in constant darkness, further supporting the minor contribution of the morning cells to the behavior in the presence of light. We therefore propose that day-night cycles alternatively activate behavioral outputs of the Drosophila evening and morning lateral neurons.

  18. Realistic modeling of neurons and networks: towards brain simulation.

    Science.gov (United States)

    D'Angelo, Egidio; Solinas, Sergio; Garrido, Jesus; Casellato, Claudia; Pedrocchi, Alessandra; Mapelli, Jonathan; Gandolfi, Daniela; Prestori, Francesca

    2013-01-01

    Realistic modeling is a new advanced methodology for investigating brain functions. Realistic modeling is based on a detailed biophysical description of neurons and synapses, which can be integrated into microcircuits. The latter can, in turn, be further integrated to form large-scale brain networks and eventually to reconstruct complex brain systems. Here we provide a review of the realistic simulation strategy and use the cerebellar network as an example. This network has been carefully investigated at molecular and cellular level and has been the object of intense theoretical investigation. The cerebellum is thought to lie at the core of the forward controller operations of the brain and to implement timing and sensory prediction functions. The cerebellum is well described and provides a challenging field in which one of the most advanced realistic microcircuit models has been generated. We illustrate how these models can be elaborated and embedded into robotic control systems to gain insight into how the cellular properties of cerebellar neurons emerge in integrated behaviors. Realistic network modeling opens up new perspectives for the investigation of brain pathologies and for the neurorobotic field.

  19. Subpopulations of rat dorsal root ganglion neurons express active vesicular acetylcholine transporter.

    Science.gov (United States)

    Tata, Ada Maria; De Stefano, M Egle; Tomassy, Giulio Srubek; Vilaró, M Teresa; Levey, Allan I; Biagioni, Stefano

    2004-01-15

    The vesicular acetylcholine transporter (VAChT) is a transmembrane protein required, in cholinergic neurons, for selective storage of acetylcholine into synaptic vesicles. Although dorsal root ganglion (DRG) neurons utilize neuropeptides and amino acids for neurotransmission, we have previously demonstrated the presence of a cholinergic system. To investigate whether, in sensory neurons, the vesicular accumulation of acetylcholine relies on the same mechanisms active in classical cholinergic neurons, we investigated VAChT presence, subcellular distribution, and activity. RT-PCR and Western blot analysis demonstrated the presence of VAChT mRNA and protein product in DRG neurons and in the striatum and cortex, used as positive controls. Moreover, in situ hybridization and immunocytochemistry showed VAChT staining located mainly in the medium/large-sized subpopulation of the sensory neurons. A few small neurons were also faintly labeled by immunocytochemistry. In the electron microscope, immunolabeling was associated with vesicle-like elements distributed in the neuronal cytoplasm and in both myelinated and unmyelinated intraganglionic nerve fibers. Finally, [(3)H]acetylcholine active transport, evaluated either in the presence or in the absence of ATP, also demonstrated that, as previously reported, the uptake of acetylcholine by VAChT is ATP dependent. This study suggests that DRG neurons not only are able to synthesize and degrade ACh and to convey cholinergic stimuli but also are capable of accumulating and, possibly, releasing acetylcholine by the same mechanism used by the better known cholinergic neurons.

  20. Activity of basal forebrain neurons in the rat during motivated behaviors.

    Science.gov (United States)

    Mink, J W; Sinnamon, H M; Adams, D B

    1983-04-01

    The activity of single neurons in the basal forebrain was recorded in the freely-moving rat with moveable fine-wire electrodes. Neural activity was observed while the water-deprived male rat was exposed to three different types of motivating stimuli that elicit locomotion in a running wheel: an estrous female rat; a drinking tube containing water; and grasping and lifting by the experimenter. The neural activity was also observed when the subject was presented with standardized sensory tests and during single pulse stimulation of other brain structures. A majority of the 76 neurons recorded in the forebrain changed their firing rate during orienting and/or locomotion in general (23 neurons) or during behavior related to only one of the specific motivational contexts: the conspecific female (4 neurons); water (7 neurons); or grasp by the experimenter (8 neurons). Whereas the neurons related to orienting and/or locomotion in general were scattered through various brain structures, those neurons related to specific motivational contexts were concentrated in specific areas: the sexually dimorphic nucleus of the medial preoptic area (conspecific female); lateral septum (water); and lateral preoptic area (water and grasp). The present results, although based on relatively few neurons, are consonant with results of research using other techniques. This indicates that analyses at the level of the single neuron promise to be useful for understanding the role of the basal forebrain in motivational systems.

  1. Dual-energy precursor and nuclear erythroid-related factor 2 activator treatment additively improve redox glutathione levels and neuron survival in aging and Alzheimer mouse neurons upstream of reactive oxygen species.

    Science.gov (United States)

    Ghosh, Debolina; LeVault, Kelsey R; Brewer, Gregory J

    2014-01-01

    To determine whether glutathione (GSH) loss or increased reactive oxygen species (ROS) are more important to neuron loss, aging, and Alzheimer's disease (AD), we stressed or boosted GSH levels in neurons isolated from aging 3xTg-AD neurons compared with those from age-matched nontransgenic (non-Tg) neurons. Here, using titrating with buthionine sulfoximine, an inhibitor of γ-glutamyl cysteine synthetase (GCL), we observed that GSH depletion increased neuronal death of 3xTg-AD cultured neurons at increasing rates across the age span, whereas non-Tg neurons were resistant to GSH depletion until old age. Remarkably, the rate of neuron loss with ROS did not increase in old age and was the same for both genotypes, which indicates that cognitive deficits in the AD model were not caused by ROS. Therefore, we targeted for neuroprotection activation of the redox sensitive transcription factor, nuclear erythroid-related factor 2 (Nrf2) by 18 alpha glycyrrhetinic acid to stimulate GSH synthesis through GCL. This balanced stimulation of a number of redox enzymes restored the lower levels of Nrf2 and GCL seen in 3xTg-AD neurons compared with those of non-Tg neurons and promoted translocation of Nrf2 to the nucleus. By combining the Nrf2 activator together with the NADH precursor, nicotinamide, we increased neuron survival against amyloid beta stress in an additive manner. These stress tests and neuroprotective treatments suggest that the redox environment is more important for neuron survival than ROS. The dual neuroprotective treatment with nicotinamide and an Nrf2 inducer indicates that these age-related and AD-related changes are reversible.

  2. Peripherally injected CCK-8S activates CART positive neurons of the paraventricular nucleus in rats

    Science.gov (United States)

    Noetzel, Steffen; Inhoff, Tobias; Goebel, Miriam; Taché, Yvette; Veh, Rüdiger W.; Bannert, Norbert; Grötzinger, Carsten; Wiedenmann, Bertram; Klapp, Burghard F.; Mönnikes, Hubert; Kobelt, Peter

    2014-01-01

    Cholecystokinin (CCK) plays a role in the short-term inhibition of food intake. Cocaine- and amphetamine-regulated transcript (CART) peptide has been observed in neurons of the paraventricular nucleus (PVN). It has been reported that intracerebroventricular injection of CART peptide inhibits food intake in rodents. The aim of the study was to determine whether intraperitoneally (ip) injected CCK-8S affects neuronal activity of PVN-CART neurons. Ad libitum fed male Sprague-Dawley rats received 6 or 10 μg/kg CCK-8S or 0.15 M NaCl ip (n = 4/group). The number of c-Fos-immunoreactive neurons was determined in the PVN, arcuate nucleus (ARC), and the nucleus of the solitary tract (NTS). CCK-8S dose-dependently increased the number of c-Fos-immunoreactive neurons in the PVN (mean ± SEM: 102 ± 6 vs. 150 ± 5 neurons/section, p < 0.05) and compared to vehicle treated rats (18 ± 7, p < 0.05 vs. 6 and 10 μg/kg CCK-8S). CCK-8S at both doses induced an increase in the number of c-Fos-immunoreactive neurons in the NTS (65 ± 13, p < 0.05, and 182 ± 16, p < 0.05). No effect on the number of c-Fos neurons was observed in the ARC. Immunostaining for CART and c-Fos revealed a dose-dependent increase of activated CART neurons (19 ± 3 vs. 29 ± 7; p < 0.05), only few activated CART neuron were observed in the vehicle group (1 ± 0). The present observation shows that CCK-8S injected ip induces an increase in neuronal activity in PVN-CART neurons and suggests that CART neurons in the PVN may play a role in the mediation of peripheral CCK-8S's anorexigenic effects. PMID:20307613

  3. Chimera-like states in a neuronal network model of the cat brain

    Science.gov (United States)

    Santos, M. S.; Szezech, J. D.; Borges, F. S.; Iarosz, K. C.; Caldas, I. L.; Batista, A. M.; Viana, R. L.; Kurths, J.

    2017-08-01

    Neuronal systems have been modeled by complex networks in different description levels. Recently, it has been verified that networks can simultaneously exhibit one coherent and other incoherent domain, known as chimera states. In this work, we study the existence of chimera states in a network considering the connectivity matrix based on the cat cerebral cortex. The cerebral cortex of the cat can be separated in 65 cortical areas organised into the four cognitive regions: visual, auditory, somatosensory-motor and frontolimbic. We consider a network where the local dynamics is given by the Hindmarsh-Rose model. The Hindmarsh-Rose equations are a well known model of neuronal activity that has been considered to simulate membrane potential in neuron. Here, we analyse under which conditions chimera states are present, as well as the affects induced by intensity of coupling on them. We observe the existence of chimera states in that incoherent structure can be composed of desynchronised spikes or desynchronised bursts. Moreover, we find that chimera states with desynchronised bursts are more robust to neuronal noise than with desynchronised spikes.

  4. Oral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion

    NARCIS (Netherlands)

    Smeets, P.A.M.; Vidarsdottir, S.; Graaf, C. de; Stafleu, A.; Osch, M.J.P. van; Viergever, M.A.; Pijl, H.; Grond, J. van der

    2007-01-01

    We previously showed that hypothalamic neuronal activity, as measured by the blood oxygen level-dependent (BOLD) functional MRI signal, declines in response to oral glucose intake. To further explore the mechanism driving changes in hypothalamic neuronal activity in response to an oral glucose load,

  5. Rhythmic activity of feline dorsal and ventral spinocerebellar tract neurons during fictive motor actions

    DEFF Research Database (Denmark)

    Fedirchuk, Brent; Stecina, Katinka; Kristensen, Kasper Kyhl

    2013-01-01

    Neurons of the dorsal spinocerebellar tracts (DSCT) have been described to be rhythmically active during walking on a treadmill in decerebrate cats, but this activity ceased following deafferentation of the hindlimb. This observation supported the hypothesis that DSCT neurons primarily relay the ...

  6. Insulin Excites Anorexigenic Proopiomelanocortin Neurons via Activation of Canonical Transient Receptor Potential Channels

    Science.gov (United States)

    Qiu, Jian; Zhang, Chunguang; Borgquist, Amanda; Nestor, Casey C; Smith, Arik W.; Bosch, Martha A.; Ku, Stephen; Wagner, Edward J.; Rønnekleiv, Oline K.; Kelly, Martin J.

    2014-01-01

    SUMMARY Proopiomelanocortin (POMC) neurons within the hypothalamic arcuate nucleus are vital anorexigenic neurons. Although both the leptin receptor and insulin receptor are coupled to activation of phosphatidylinositide3-kinase (PI3K) in POMC neurons, they are thought to have disparate actions on POMC excitability. Using whole-cell recording and selective pharmacological tools, we have found that similar to leptin, purified insulin depolarized POMC, and adjacent kisspeptin neurons via activation of TRPC5 channels, which are highly expressed in these neurons. In contrast, insulin hyperpolarized and inhibited NPY/AgRP neurons via activation of KATP channels. Moreover, Zn2+, which is found in insulin formulations at nanomolar concentrations, inhibited POMC neurons via activation of KATP channels. Finally as predicted, insulin given intracerebroventrically robustly inhibited food intake and activated c-fos expression in arcuate POMC neurons. Our results show that purified insulin excites POMC neurons in the arcuate nucleus, which we propose is a major mechanism by which insulin regulates energy homeostasis. PMID:24703699

  7. Increased acid responsiveness in vagal sensory neurons in a guinea pig model of eosinophilic esophagitis.

    Science.gov (United States)

    Hu, Youtian; Liu, Zhenyu; Yu, Xiaoyun; Pasricha, Pankaj J; Undem, Bradley J; Yu, Shaoyong

    2014-07-15

    Eosinophilic esophagitis (EoE) is characterized with eosinophils and mast cells predominated allergic inflammation in the esophagus and present with esophageal dysfunctions such as dysphagia, food impaction, and heartburn. However, the underlying mechanism of esophageal dysfunctions is unclear. This study aims to determine whether neurons in the vagal sensory ganglia are modulated in a guinea pig model of EoE. Animals were actively sensitized by ovalbumin (OVA) and then challenged with aerosol OVA inhalation for 2 wk. This results in a mild esophagitis with increases in mast cells and eosinophils in the esophageal wall. Vagal nodose and jugular neurons were disassociated, and their responses to acid, capsaicin, and transient receptor potential vanilloid type 1 (TRPV1) antagonist AMG-9810 were studied by calcium imaging and whole cell patch-clamp recording. Compared with naïve animals, antigen challenge significantly increased acid responsiveness in both nodose and jugular neurons. Their responses to capsaicin were also increased after antigen challenge. AMG-9810, at a concentration that blocked capsaicin-evoked calcium influx, abolished the increase in acid-induced activation in both nodose and jugular neurons. Vagotomy strongly attenuated those increased responses of nodose and jugular neurons to both acid and capsaicin induced by antigen challenge. These data for the first time demonstrated that prolonged antigen challenge significantly increases acid responsiveness in vagal nodose and jugular ganglia neurons. This sensitization effect is mediated largely through TRPV1 and initiated at sensory nerve endings in the peripheral tissues. Allergen-induced enhancement of responsiveness to noxious stimulation by acid in sensory nerve may contribute to the development of esophageal dysfunctions such as heartburn in EoE.

  8. Imaging activity in astrocytes and neurons with genetically encoded calcium indicators following in utero electroporation

    Directory of Open Access Journals (Sweden)

    J. Michael eGee

    2015-04-01

    Full Text Available Complex interactions between networks of astrocytes and neurons are beginning to be appreciated, but remain poorly understood. Transgenic mice expressing fluorescent protein reporters of cellular activity, such as the GCaMP family of genetically encoded calcium indicators, have been used to explore network behavior. However, in some cases, it may be desirable to use long-established rat models that closely mimic particular aspects of human conditions such as Parkinson’s disease and the development of epilepsy following status epilepticus. Methods for expressing reporter proteins in the rat brain are relatively limited. Transgenic rat technologies exist but are fairly immature. Viral-mediated expression is robust but unstable, requires invasive injections, and only works well for fairly small genes (< 5 kb. In utero electroporation offers a valuable alternative. IUE is a proven method for transfecting populations of astrocytes and neurons in the rat brain without the strict limitations on transgene size. We built a toolset of IUE plasmids carrying GCaMP variants 3, 6s or 6f driven by CAG and targeted to the cytosol or the plasma membrane. Because low baseline fluorescence of GCaMP can hinder identification of transfected cells, we included the option of co-expressing a cytosolic tdTomato protein. A binary system consisting of a plasmid carrying a piggyBac inverted terminal repeat-flanked CAG-GCaMP-IRES-tdTomato cassette and a separate plasmid encoding for expression of piggyBac transposase was employed to stably express GCaMP and tdTomato. The plasmids were co-electroporated on embryonic days 13.5-14.5 and astrocytic and neuronal activity was subsequently imaged in acute or cultured brain slices prepared from the cortex or hippocampus. Large spontaneous transients were detected in slices obtained from rats of varying ages up to 127 days. In this report, we demonstrate the utility of this toolset for interrogating astrocytic and neuronal

  9. Real-time prediction of neuronal population spiking activity using FPGA.

    Science.gov (United States)

    Li, Will X Y; Cheung, Ray C C; Chan, Rosa H M; Song, Dong; Berger, Theodore W

    2013-08-01

    A field-programmable gate array (FPGA)-based hardware architecture is proposed and utilized for prediction of neuronal population firing activity. The hardware system adopts the multi-input multi-output (MIMO) generalized Laguerre-Volterra model (GLVM) structure to describe the nonlinear dynamic neural process of mammalian brain and can switch between the two important functions: estimation of GLVM coefficients and prediction of neuronal population spiking activity (model outputs). The model coefficients are first estimated using the in-sample training data; then the output is predicted using the out-of-sample testing data and the field estimated coefficients. Test results show that compared with previous software implementation of the generalized Laguerre-Volterra algorithm running on an Intel Core i7-2620M CPU, the FPGA-based hardware system can achieve up to 2.66×10(3) speedup in doing model parameters estimation and 698.84 speedup in doing model output prediction. The proposed hardware platform will facilitate research on the highly nonlinear neural process of the mammal brain, and the cognitive neural prosthesis design.

  10. Nonlinear Dynamical Behavior in Neuron Model Based on Small World Network with Attack and Repair Strategy

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xue; YANG Qiu-Ying; ZHENG Tai-Yu; ZHANG Ying-Yue; ZHENG Li; ZHANG Gui-Qing; CHEN Tian-Lun

    2008-01-01

    In this paper, we investigate the effect due to the change of topology structure of network on the nonlinear dynamical behavior, by virtue of the OFC neuron evolution model with attack and repair strategy based on the small world. In particular, roles of various parameters relating to the dynamical behavior are carefully studied and analyzed. In addition, the avalanche and EEG-like wave activities with attack and repair strategy are also explored in detail in this work.

  11. Ethanol Activation of PKA Mediates Single-Minded 2 Expression in Neuronal Cells.

    Science.gov (United States)

    Wang, Xiaolan; Yang, Zhihua; Sun, Yinan; Zhou, Hanjing; Chu, Guangpin; Zhang, Jing; Meng, Xianfang

    2015-12-01

    Prenatal ethanol exposure can cause extensive apoptotic neurodegeneration throughout the developing central nervous system (CNS), which results in cognitive deficits and memory decline. However, the underlying mechanisms need further study. Single-minded 2 (Sim2), a transcriptional repressor, is reportedly involved in diseases that impair learning and memory, such as Down syndrome (DS) and Alzheimer's disease. It is still unknown whether Sim2 is involved in regulating ethanol-mediated neuronal injury that might ultimately lead to neuronal dysfunction and subsequent learning and memory deficits. To study the effects of ethanol on Sim2 expression and neuronal injury, we used animal models and cell culture experiments. Our results indicated that in SH-SY5Y cells, ethanol exposure increased Sim2 expression and levels of cleaved caspase 3, which is a marker for cells undergoing apoptosis. Silencing Sim2 expression attenuated caspase 3 activation and cellular apoptosis. We also found that protein kinase A (PKA) activation induced Sim2 expression, as did ethanol. Inhibiting the PKA signaling pathway with H-89 decreased Sim2 expression and cleavage of caspase 3 that was induced by ethanol in vivo and in vitro. We further found that PKA regulated Sim2 expression at the transcriptional level. These results demonstrate that ethanol leads to increased Sim2 expression via the PKA pathway, ultimately resulting in apoptotic cell death.

  12. Emulating the electrical activity of the neuron using a silicon oxide RRAM cell

    Directory of Open Access Journals (Sweden)

    Adnan eMehonic

    2016-02-01

    Full Text Available In recent years, formidable effort has been devoted to exploring the potential of Resistive RAM (RRAM devices to model key features of biological synapses. This is done to strengthen the link between neuro-computing architectures and neuroscience, bearing in mind the extremely low power consumption and immense parallelism of biological systems. Here we demonstrate the feasibility of using the RRAM cell to go further and to model aspects of the electrical activity of the neuron. We focus on the specific operational procedures required for the generation of controlled voltage transients, which resemble spike-like responses. Further, we demonstrate that RRAM devices are capable of integrating input current pulses over time to produce thresholded voltage transients. We show that the frequency of the output transients can be controlled by the input signal, and we relate recent models of the redox-based nanoionic resistive memory cell to two common neuronal models, the Hodgkin-Huxley (HH conductance model and the leaky integrate-and-fire model. We employ a simplified circuit model to phenomenologically describe voltage transient generation.

  13. Hypoglycemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion.

    Science.gov (United States)

    Lamy, Christophe M; Sanno, Hitomi; Labouèbe, Gwenaël; Picard, Alexandre; Magnan, Christophe; Chatton, Jean-Yves; Thorens, Bernard

    2014-03-04

    Glucose-sensing neurons in the brainstem participate in the regulation of energy homeostasis but have been poorly characterized because of the lack of specific markers to identify them. Here we show that GLUT2-expressing neurons of the nucleus of the tractus solitarius form a distinct population of hypoglycemia-activated neurons. Their response to low glucose is mediated by reduced intracellular glucose metabolism, increased AMP-activated protein kinase activity, and closure of leak K(+) channels. These are GABAergic neurons that send projections to the vagal motor nucleus. Light-induced stimulation of channelrhodospin-expressing GLUT2 neurons in vivo led to increased parasympathetic nerve firing and glucagon secretion. Thus GLUT2 neurons of the nucleus tractus solitarius link hypoglycemia detection to counterregulatory response. These results may help identify the cause of hypoglycemia-associated autonomic failure, a major threat in the insulin treatment of diabetes.

  14. Primary motor cortex neurons classified in a postural task predict muscle activation patterns in a reaching task.

    Science.gov (United States)

    Heming, Ethan A; Lillicrap, Timothy P; Omrani, Mohsen; Herter, Troy M; Pruszynski, J Andrew; Scott, Stephen H

    2016-04-01

    Primary motor cortex (M1) activity correlates with many motor variables, making it difficult to demonstrate how it participates in motor control. We developed a two-stage process to separate the process of classifying the motor field of M1 neurons from the process of predicting the spatiotemporal patterns of its motor field during reaching. We tested our approach with a neural network model that controlled a two-joint arm to show the statistical relationship between network connectivity and neural activity across different motor tasks. In rhesus monkeys, M1 neurons classified by this method showed preferred reaching directions similar to their associated muscle groups. Importantly, the neural population signals predicted the spatiotemporal dynamics of their associated muscle groups, although a subgroup of atypical neurons reversed their directional preference, suggesting a selective role in antagonist control. These results highlight that M1 provides important details on the spatiotemporal patterns of muscle activity during motor skills such as reaching.

  15. Chaos and stability in a model of inhibitory neuronal network

    CERN Document Server

    Catsigeras, Eleonora

    2011-01-01

    We analyze the dynamics of a deterministic model of inhibitory neuronal networks proving that the discontinuities of the Poincare map produce a never empty chaotic set, while its continuity pieces produce stable orbits. We classify the systems in three types: the almost everywhere (a.e.) chaotic, the a.e. stable, and the combined systems. The a.e. stable are periodic and chaos appears as bifurcations. We prove that a.e. stable systems exhibit limit cycles, attracting a.e. the orbits.

  16. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

    Science.gov (United States)

    Saloman, Jami L; Albers, Kathryn M; Li, Dongjun; Hartman, Douglas J; Crawford, Howard C; Muha, Emily A; Rhim, Andrew D; Davis, Brian M

    2016-03-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

  17. Loss of signal transducer and activator of transcription 3 (STAT3) signaling during elevated activity causes vulnerability in hippocampal neurons.

    Science.gov (United States)

    Murase, Sachiko; Kim, Eunyoung; Lin, Lin; Hoffman, Dax A; McKay, Ronald D

    2012-10-31

    Chronically altered levels of network activity lead to changes in the morphology and functions of neurons. However, little is known of how changes in neuronal activity alter the intracellular signaling pathways mediating neuronal survival. Here, we use primary cultures of rat hippocampal neurons to show that elevated neuronal activity impairs phosphorylation of the serine/threonine kinase, Erk1/2, and the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation of serine 727. Chronically stimulated neurons go through apoptosis when they fail to activate another serine/threonine kinase, Akt. Gain- and loss-of-function experiments show that STAT3 plays the key role directly downstream from Erk1/2 as the alternative survival pathway. Elevated neuronal activity resulted in increased expression of a tumor suppressor, p53, and its target gene, Bax. These changes are observed in Kv4.2 knock-out mouse hippocampal neurons, which are also sensitive to the blockade of TrkB signaling, confirming that the alteration occurs in vivo. Thus, this study provides new insight into a mechanism by which chronic elevation of activity may cause neurodegeneration.

  18. Phase Locking Phenomena and Electroencephalogram-Like Activities in Dynamic Neuronal Systems

    Institute of Scientific and Technical Information of China (English)

    XU Xin-Jian; WANG Sheng-Jun; TANG Wei; WANG Ying-Hai

    2005-01-01

    @@ We study signal detection and transduction of dynamic neuronal systems under the influence of external noise,white and coloured. Based on simulations, we show explicitly phase locking phenomena between the output and the input of a single neuron and Electroencephalogram-like activities on neural networks with small-world connectivity. The numerical results prove that the dynamic neuronal system can be adjusted to an optimal sensitive state for signal processing in the presence of additive noise.

  19. Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model

    Directory of Open Access Journals (Sweden)

    Imène Achour

    2016-08-01

    Full Text Available Parkinson’s disease (PD is a progressive neurodegenerative disorder, primarily affecting dopaminergic neurons in the substantia nigra. There is currently no cure for PD and present medications aim to alleviate clinical symptoms, thus prevention remains the ideal strategy to reduce the prevalence of this disease. The goal of this study was to investigate whether oleuropein (OLE, the major phenolic compound in olive derivatives, may prevent neuronal degeneration in a cellular dopaminergic model of PD, differentiated PC12 cells exposed to the potent parkinsonian toxin 6-hydroxydopamine (6-OHDA. We also investigated OLE’s ability to mitigate mitochondrial oxidative stress and modulate the autophagic flux. Our results obtained by measuring cytotoxicity and apoptotic events demonstrate that OLE significantly decreases neuronal death. OLE could also reduce mitochondrial production of reactive oxygen species resulting from blocking superoxide dismutase activity. Moreover, quantification of autophagic and acidic vesicles in the cytoplasm alongside expression of specific autophagic markers uncovered a regulatory role for OLE against autophagic flux impairment induced by bafilomycin A1. Altogether, our results define OLE as a neuroprotective, anti-oxidative and autophagy-regulating molecule, in a neuronal dopaminergic cellular model.

  20. Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model

    Science.gov (United States)

    Achour, Imène; Arel-Dubeau, Anne-Marie; Renaud, Justine; Legrand, Manon; Attard, Everaldo; Germain, Marc; Martinoli, Maria-Grazia

    2016-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disorder, primarily affecting dopaminergic neurons in the substantia nigra. There is currently no cure for PD and present medications aim to alleviate clinical symptoms, thus prevention remains the ideal strategy to reduce the prevalence of this disease. The goal of this study was to investigate whether oleuropein (OLE), the major phenolic compound in olive derivatives, may prevent neuronal degeneration in a cellular dopaminergic model of PD, differentiated PC12 cells exposed to the potent parkinsonian toxin 6-hydroxydopamine (6-OHDA). We also investigated OLE’s ability to mitigate mitochondrial oxidative stress and modulate the autophagic flux. Our results obtained by measuring cytotoxicity and apoptotic events demonstrate that OLE significantly decreases neuronal death. OLE could also reduce mitochondrial production of reactive oxygen species resulting from blocking superoxide dismutase activity. Moreover, quantification of autophagic and acidic vesicles in the cytoplasm alongside expression of specific autophagic markers uncovered a regulatory role for OLE against autophagic flux impairment induced by bafilomycin A1. Altogether, our results define OLE as a neuroprotective, anti-oxidative and autophagy-regulating molecule, in a neuronal dopaminergic cellular model. PMID:27517912

  1. Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease.

    Science.gov (United States)

    Hanzel, Cecilia E; Pichet-Binette, Alexa; Pimentel, Luisa S B; Iulita, M Florencia; Allard, Simon; Ducatenzeiler, Adriana; Do Carmo, Sonia; Cuello, A Claudio

    2014-10-01

    Chronic brain inflammation is associated with Alzheimer's disease (AD) and is classically attributed to amyloid plaque deposition. However, whether the amyloid pathology can trigger early inflammatory processes before plaque deposition remains a matter of debate. To address the possibility that a pre-plaque inflammatory process occurs, we investigated the status of neuronal, astrocytic, and microglial markers in pre- and post-amyloid plaque stages in a novel transgenic rat model of an AD-like amyloid pathology (McGill-R-Thy1-APP). In this model, we found a marked upregulation of several classical inflammatory markers such as COX-2, IL-1β, TNF-α, and fractalkine (CX3CL1) in the cerebral cortex and hippocampus. Interestingly, many of these markers were highly expressed in amyloid beta-burdened neurons. Activated astrocytes and microglia were associated with these Aβ-burdened neurons. These findings confirm the occurrence of a proinflammatory process preceding amyloid plaque deposition and suggest that Aβ-burdened neurons play a crucial role in initiating inflammation in AD. Copyright © 2014. Published by Elsevier Inc.

  2. Plasminogen activator inhibitor-1 aids survival of neurites on neurons derived from pheochromocytoma (PC-12) cells.

    Science.gov (United States)

    Soeda, Shinji; Imatoh, Takuya; Ochiai, Takashi; Koyanagi, Satoru; Shimeno, Hiroshi

    2004-04-09

    Plasminogen activator inhibitor-1 is a serpin that regulates the activities of plasminogen activators. However, its physiological roles in the CNS are incompletely understood. We have found that plasminogen activator inhibitor-1 has a novel biological function in the CNS: the contribution to survival of neurites on neurons. PC-12 cells treated with nerve growth factor differentiated into neurons and formed a network of neurites. In a serum-free culture medium, these neurites disappeared within 24 h. The addition of plasminogen activator inhibitor-1 prevented the disintegration of the neuronal networks, while the addition of the serpin inhibitors aprotinin and antipain did not. The plasminogen activator inhibitor-1 maintained or promoted the phosphorylated state of extracellular signal-regulated kinase (ERK), but not of protein kinase B (Akt). These results are the first evidence that plasminogen activator inhibitor-1 in the CNS acts to maintain the morphology of neurites via activation of the ERK-related pathway in the neurons.

  3. ATP released by injured neurons activates Schwann cells

    Directory of Open Access Journals (Sweden)

    Samuele eNegro

    2016-05-01

    Full Text Available Injured nerve terminals of neuromuscular junctions (NMJs can regenerate. This remarkable and complex response is governed by molecular signals that are exchanged among the cellular components of this synapse: motor axon nerve terminal (MAT, perisynaptic Schwann cells (PSCs, and muscle fibre. The nature of signals that govern MAT regeneration is ill-known. In the present study the spider toxin α-Latrotoxin has been used as tool to investigate the mechanisms underlying peripheral neuroregeneration. Indeed this neurotoxin induces an acute, specific, localized and fully reversible damage of the presynaptic nerve terminal, and its action mimics the cascade of events that leads to nerve terminal degeneration in injured patients and in many neurodegenerative conditions. Here we provide evidence of an early release by degenerating neurons of ATP as alarm messenger, that contributes to the activation of a series of intracellular pathways within SCs that are crucial for nerve regeneration: Ca2+, cAMP, ERK1/2, and CREB. These results contribute to define the cross-talk taking place among degenerating nerve terminals and PSCs, involved in the functional recovery of the NMJ.

  4. Functional crosstalk in culture between macrophages and trigeminal sensory neurons of a mouse genetic model of migraine

    Directory of Open Access Journals (Sweden)

    Franceschini Alessia

    2012-11-01

    Full Text Available Abstract Background Enhanced activity of trigeminal ganglion neurons is thought to underlie neuronal sensitization facilitating the onset of chronic pain attacks, including migraine. Recurrent headache attacks might establish a chronic neuroinflammatory ganglion profile contributing to the hypersensitive phenotype. Since it is difficult to study this process in vivo, we investigated functional crosstalk between macrophages and sensory neurons in primary cultures from trigeminal sensory ganglia of wild-type (WT or knock-in (KI mice expressing the Cacna1a gene mutation (R192Q found in familial hemiplegic migraine-type 1. After studying the number and morphology of resident macrophages in culture, the consequences of adding host macrophages on macrophage phagocytosis and membrane currents mediated by pain-transducing P2X3 receptors on sensory neurons were examined. Results KI ganglion cultures constitutively contained a larger number of active macrophages, although no difference in P2X3 receptor expression was found. Co-culturing WT or KI ganglia with host macrophages (active as much as resident cells strongly stimulated single cell phagocytosis. The same protocol had no effect on P2X3 receptor expression in WT or KI co-cultures, but it largely enhanced WT neuron currents that grew to the high amplitude constitutively seen for KI neurons. No further potentiation of KI neuronal currents was observed. Conclusions Trigeminal ganglion cultures from a genetic mouse model of migraine showed basal macrophage activation together with enhanced neuronal currents mediated by P2X3 receptors. This phenotype could be replicated in WT cultures by adding host macrophages, indicating an important functional crosstalk between macrophages and sensory neurons.

  5. Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death

    Science.gov (United States)

    Jean, Ying Y.; Ribe, Elena M.; Pero, Maria Elena; Moskalenko, Marina; Iqbal, Zarah; Marks, Lianna J.; Greene, Lloyd A.; Troy, Carol M.

    2014-01-01

    SYNOPSIS Neuronal apoptotic death generally requires de novo transcription, and activation of the transcription factor c-Jun has been shown to be necessary in multiple neuronal death paradigms. Caspase-2 has been implicated in death of neuronal and non-neuronal cells, but its relationship to transcriptional activation has not been clearly elucidated. Here, using two different neuronal apoptotic paradigms, β-amyloid treatment and NGF withdrawal, we examined the hierarchical role of caspase-2 activation in the transcriptional control of neuron death. Both paradigms induce rapid activation of caspase-2 as well as activation of the transcription factor c-Jun and subsequent induction of the pro-apoptotic BH-3 only protein Bim. Caspase-2 activation is dependent on the adaptor protein RAIDD, and both caspase-2 and RAIDD are required for c-Jun activation and Bim induction. Our work, thus, shows that rapid caspase-2 activation is essential for c-Jun activation and Bim induction in neurons subjected to apoptotic stimuli. This places caspase-2 at an apical position in the apoptotic cascade and demonstrates for the first time that caspase-2 can regulate transcription. PMID:23815625

  6. Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

    Directory of Open Access Journals (Sweden)

    M. Catarina Silva

    2016-09-01

    Full Text Available Frontotemporal dementia (FTD and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.

  7. BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB

    Science.gov (United States)

    Hu, Peter; Kalb, Robert G.; Walton, K. D. (Principal Investigator)

    2003-01-01

    The survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3'-kinase (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3'K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.

  8. Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines.

    Science.gov (United States)

    Lai, Aaron Y; Todd, Kathryn G

    2006-06-01

    The tetracycline derivatives minocycline (MINO) and doxycycline (DOXY) have been shown to be neuroprotective in in vivo and in vitro models of stroke. This neuroprotection is thought to be due to the suppression of microglial activation. However, the specific molecular parameters in microglia of the tetracyclines' effect are not understood. We subjected cultured rat microglial and neuronal cells to in vitro hypoxia and examined the effects of MINO and DOXY pre-treatments. Our data showed that MINO and DOXY protect against hypoxia-induced neuronal death by a mechanism dependent on regulation of microglial factors, but likely unrelated to regulation of microglial proliferation/viability. Both MINO and DOXY suppressed the hypoxic activation of ED-1, a marker for microglial activation. Morphological analyses of hypoxic microglia using the microglial marker Iba1 revealed that treatment with MINO and DOXY caused a higher percentage of microglia to remain in a non-activated state. MINO suppressed the hypoxic upregulation of pro-inflammatory agents nitric oxide (NO), interleukin-1 beta (IL-1beta), and tumor necrosis factor alpha (TNF-alpha), while DOXY down-regulated only NO and IL-1beta. In contrast, the hypoxic activation of pro-survival/neuroprotective microglial proteins, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), were unaffected by tetracycline treatments. Taken together, these results suggest that MINO and DOXY may provide neuroprotection against stroke by selectively down-regulating microglial toxic factors while maintaining functional pro-survival factors.

  9. Identification of optogenetically activated striatal medium spiny neurons by Npas4 expression.

    Directory of Open Access Journals (Sweden)

    Asim K Bepari

    Full Text Available Optogenetics is a powerful neuromodulatory tool with many unique advantages to explore functions of neuronal circuits in physiology and diseases. Yet, interpretation of cellular and behavioral responses following in vivo optogenetic manipulation of brain activities in experimental animals often necessitates identification of photoactivated neurons with high spatial resolution. Although tracing expression of immediate early genes (IEGs provides a convenient approach, neuronal activation is not always followed by specific induction of widely used neuronal activity markers like c-fos, Egr1 and Arc. In this study we performed unilateral optogenetic stimulation of the striatum in freely moving transgenic mice that expressed a channelrhodopsin-2 (ChR2 variant ChR2(C128S in striatal medium spiny neurons (MSNs. We found that in vivo blue light stimulation significantly altered electrophysiological activity of striatal neurons and animal behaviors. To identify photoactivated neurons we then analyzed IEG expression patterns using in situ hybridization. Upon light illumination an induction of c-fos was not apparent whereas another neuronal IEG Npas4 was robustly induced in MSNs ipsilaterally. Our results demonstrate that tracing Npas4 mRNA expression following in vivo optogenetic modulation can be an effective tool for reliable and sensitive identification of activated MSNs in the mouse striatum.

  10. Both barium and calcium activate neuronal potassium currents.

    OpenAIRE

    Ribera, A B; Spitzer, N C

    1987-01-01

    Amphibian spinal neurons in culture possess both rapidly inactivating and sustained calcium-dependent potassium current components, similar to those described for other cells. Divalent cation-dependent whole-cell outward currents were isolated by subtracting the voltage-dependent potassium currents recorded from Xenopus laevis neurons in the presence of impermeant cadmium (100-500 microM) from the currents produced without cadmium but in the presence of permeant divalent cations (50-100 micro...

  11. Experimental evidence and modeling studies support a synchronizing role for electrical coupling in the cat thalamic reticular neurons in vivo

    Science.gov (United States)

    Fuentealba, Pablo; Crochet, Sylvain; Timofeev, Igor; Bazhenov, Maxim; Sejnowski, Terrence J.; Steriade, Mircea

    2010-01-01

    Thalamic reticular (RE) neurons are crucially implicated in brain rhythms. Here, we report that RE neurons of adult cats, recorded and stained intracellularly in vivo, displayed spontaneously occurring spikelets, which are characteristic of central neurons that are coupled electrotonically via gap junctions. Spikelets occurred spontaneously during spindles, an oscillation in which RE neurons play a leading role, as well as during interspindle lulls. They were significantly different from excitatory postsynaptic potentials and also distinct from fast prepotentials that are presumably dendritic spikes generated synaptically. Spikelets were strongly reduced by halothane, a blocker of gap junctions. Multi-site extracellular recordings performed before, during and after administration of halothane demonstrated a role for electrical coupling in the synchronization of spindling activity within the RE nucleus. Finally, computational models of RE neurons predicted that gap junctions between these neurons could mediate the spread of low-frequency activity at great distances. These experimental and modeling data suggest that electrotonic coupling within the RE nucleus plays an important role in the generation and synchronization of low-frequency (spindling) activities in the thalamus. PMID:15245484

  12. Task-dependent changes in cross-level coupling between single neurons and oscillatory activity in multiscale networks.

    Directory of Open Access Journals (Sweden)

    Ryan T Canolty

    Full Text Available Understanding the principles governing the dynamic coordination of functional brain networks remains an important unmet goal within neuroscience. How do distributed ensembles of neurons transiently coordinate their activity across a variety of spatial and temporal scales? While a complete mechanistic account of this process remains elusive, evidence suggests that neuronal oscillations may play a key role in this process, with different rhythms influencing both local computation and long-range communication. To investigate this question, we recorded multiple single unit and local field potential (LFP activity from microelectrode arrays implanted bilaterally in macaque motor areas. Monkeys performed a delayed center-out reach task either manually using their natural arm (Manual Control, MC or under direct neural control through a brain-machine interface (Brain Control, BC. In accord with prior work, we found that the spiking activity of individual neurons is coupled to multiple aspects of the ongoing motor beta rhythm (10-45 Hz during both MC and BC, with neurons exhibiting a diversity of coupling preferences. However, here we show that for identified single neurons, this beta-to-rate mapping can change in a reversible and task-dependent way. For example, as beta power increases, a given neuron may increase spiking during MC but decrease spiking during BC, or exhibit a reversible shift in the preferred phase of firing. The within-task stability of coupling, combined with the reversible cross-task changes in coupling, suggest that task-dependent changes in the beta-to-rate mapping play a role in the transient functional reorganization of neural ensembles. We characterize the range of task-dependent changes in the mapping from beta amplitude, phase, and inter-hemispheric phase differences to the spike rates of an ensemble of simultaneously-recorded neurons, and discuss the potential implications that dynamic remapping from oscillatory activity to

  13. Rescue of neuronal migration deficits in a mouse model of fetal Minamata disease by increasing neuronal Ca2+ spike frequency.

    Science.gov (United States)

    Fahrion, Jennifer K; Komuro, Yutaro; Li, Ying; Ohno, Nobuhiko; Littner, Yoav; Raoult, Emilie; Galas, Ludovic; Vaudry, David; Komuro, Hitoshi

    2012-03-27

    In the brains of patients with fetal Minamata disease (FMD), which is caused by exposure to methylmercury (MeHg) during development, many neurons are hypoplastic, ectopic, and disoriented, indicating disrupted migration, maturation, and growth. MeHg affects a myriad of signaling molecules, but little is known about which signals are primary targets for MeHg-induced deficits in neuronal development. In this study, using a mouse model of FMD, we examined how MeHg affects the migration of cerebellar granule cells during early postnatal development. The cerebellum is one of the most susceptible brain regions to MeHg exposure, and profound loss of cerebellar granule cells is detected in the brains of patients with FMD. We show that MeHg inhibits granule cell migration by reducing the frequency of somal Ca(2+) spikes through alterations in Ca(2+), cAMP, and insulin-like growth factor 1 (IGF1) signaling. First, MeHg slows the speed of granule cell migration in a dose-dependent manner, independent of the mode of migration. Second, MeHg reduces the frequency of spontaneous Ca(2+) spikes in granule cell somata in a dose-dependent manner. Third, a unique in vivo live-imaging system for cell migration reveals that reducing the inhibitory effects of MeHg on somal Ca(2+) spike frequency by stimulating internal Ca(2+) release and Ca(2+) influxes, inhibiting cAMP activity, or activating IGF1 receptors ameliorates the inhibitory effects of MeHg on granule cell migration. These results suggest that alteration of Ca(2+) spike frequency and Ca(2+), cAMP, and IGF1 signaling could be potential therapeutic targets for infants with MeHg intoxication.

  14. Naphthazarin protects against glutamate-induced neuronal death via activation of the Nrf2/ARE pathway

    Energy Technology Data Exchange (ETDEWEB)

    Son, Tae Gen; Kawamoto, Elisa M.; Yu, Qian-Sheng; Greig, Nigel H. [Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224 (United States); Mattson, Mark P. [Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224 (United States); Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD (United States); Camandola, Simonetta, E-mail: camandolasi@mail.nih.gov [Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224 (United States)

    2013-04-19

    Highlights: •Naphthazarin activates the Nrf2/ARE pathway. •Naphthazarin induces Nrf2-driven genes in neurons and astrocytes. •Naphthazarin protects neurons against excitotoxicity. -- Abstract: Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. We previously screened several natural phytochemicals and identified plumbagin as a novel activator of the Nrf2/ARE pathway that can protect neurons against ischemic injury. Here we extended our studies to natural and synthetic derivatives of plumbagin. We found that 5,8-dimethoxy-1,4-naphthoquinone (naphthazarin) is a potent activator of the Nrf2/ARE pathway, up-regulates the expression of Nrf2-driven genes in primary neuronal and glial cultures, and protects neurons against glutamate-induced excitotoxicity.

  15. Involvement of serotonin 2A receptor activation in modulating medial prefrontal cortex and amygdala neuronal activation during novelty-exposure

    DEFF Research Database (Denmark)

    Hervig, Mona El-Sayed; Jensen, Nadja Cecilie Hvid; Rasmussen, Nadja Bredo

    2017-01-01

    -field arena affects medial PFC activation and basolateral amygdala (BLA) reactivity. We used c-Fos immunoreactivity (IR) as a marker of neuronal activation and stereological quantifi