Project description:Enhanced activity of inhibitory neurons, which is often used to suppress behaviors of pyramidal neurons to treat brain diseases, whereas can enhance spiking to a mixed-mode bursting (MMB) in recent experiments on migraine and seizure. The MMB contains a phase with high level of membrane potential/extracellular potassium concentration ([K+]o), which can propagate to form spreading depolarization (SD) wave. Different from the common view that the MMB/SD is often induced by enhanced positive effect or [K+]o, in the present paper, dynamics and conditions for the uncommon MMB/SD evoked by enhanced inhibitory synaptic current are obtained in a theoretical model. Firstly, in addition to the well-known positive threshold across which the common MMB is induced by positive effect, a spiking pyramidal neuron exhibits a novel negative threshold with a low level of [K+]o for the MMB. A long and strong inhibitory stimulation suppresses the spiking to silence phase via a saddle-node bifurcation on an invariant circle at first and then run across the negative threshold, triggering positive feedback to enhance membrane potential and [K+]o to levels high enough, then resulting in the uncommon MMB. Secondly, in a coupling model, enhanced inhibitory effect for enhanced spiking activity of interneuron and conductance of inhibitory synapse, and enhanced spiking activity of pyramidal neuron, are favorable for the uncommon MMB. Then, reducing these activities or parameters present potential measures to prevent the MMB. Finally, in network model, the uncommon MMB of a pyramidal neuron can induce SD wave. The results present a novel theoretical explanation to the uncommon MMB/SD, counterintuitive function of the inhibitory interneuron, and potential measures to treat the diseases.
Project description:Interactions among chemical and electrical synapses regulate the patterns of electrical activity of vertebrate and invertebrate neurons. In this investigation we studied how electrical coupling influences the integration of excitatory postsynaptic potentials (EPSPs). Pairs of Retzius neurons of the leech are coupled by a nonrectifying electrical synapse by which chemically induced synaptic currents flow from one neuron to the other. Results from electrophysiology and modeling suggest that chemical synaptic inputs are located on the coupled neurites, at 7.5 microm from the electrical synapses. We also showed that the space constant of the coupled neurites was 100 microm, approximately twice their length, allowing the efficient spread of synaptic currents all along both coupled neurites. Based on this cytoarchitecture, our main finding was that the degree of electrical coupling modulates the amplitude of EPSPs in the driving neurite by regulating the leak of synaptic current to the coupled neurite, so that the amplitude of EPSPs in the driving neurite was proportional to the value of the coupling resistance. In contrast, synaptic currents arriving at the coupled neurite through the electrical synapse produced EPSPs of constant amplitude. This was because the coupling resistance value had inverse effects on the amount of current arriving and on the impedance of the neurite. We propose that by modulating the amplitude of EPSPs, electrical synapses could regulate the firing frequency of neurons.
Project description:Antiphase bursting related to the rhythmic motor behavior exhibits complex dynamics modulated by the inhibitory synaptic current (Isyn), especially in the presence of the hyperpolarization-activated cation current (Ih). In the present paper, the dynamics of antiphase bursting modulated by the Ih and Isyn is studied in three aspects with a theoretical model. Firstly, the Isyn and the slow Ih with strong strength are the identified to be the necessary conditions for the antiphase bursting. The dependence of the antiphase bursting on the two currents is different for low (escape mode) and high (release mode) threshold voltages (Vth) of the inhibitory synapse. Secondly, more detailed co-regulations of the two currents to induce opposite changes of the bursting period are obtained. For the escape mode, increase of the Ih induces elevated membrane potential of the silence inhibited by a strong Isyn and shortened silence duration to go beyond Vth, resulting in reduced bursting period. For the release mode, increase of the Ih induces elevated tough value of the former part of the burst modulated by a nearly zero Isyn and lengthen burst duration to fall below Vth, resulting in prolonged bursting period. Finally, the fast-slow dynamics of the antiphase bursting are acquired. Using one-and two-parameter bifurcations of the fast subsystem of a single neuron, the burst of the antiphase bursting is related to the stable limit cycle, and the silence modulated by a strong Isyn to the stable equilibrium to a certain extent. The Ih mainly modulates the dynamics within the burst and quiescent state. Furthermore, with the fast subsystem of the coupled neurons, the silence is associated with the unstable equilibrium point. The results present theoretical explanations to the changes in the bursting period and fast-slow dynamics of the antiphase bursting modulated by the Isyn and Ih, which is helpful for understanding the antiphase bursting and modulating rhythmic motor patterns.
Project description:Neuronal networks can generate complex patterns of activity that depend on membrane properties of individual neurons as well as on functional synapses. To decipher the impact of synaptic properties and connectivity on neuronal network behavior, we investigate the responses of neuronal ensembles from small (5-30 cells in a restricted sphere) and large (acute hippocampal slice) networks to single electrical stimulation: in both cases, a single stimulus generated a synchronous long-lasting bursting activity. While an initial spike triggered a reverberating network activity that lasted 2-5 seconds for small networks, we found here that it lasted only up to 300 milliseconds in slices. To explain this phenomena present at different scales, we generalize the depression-facilitation model and extracted the network time constants. The model predicts that the reverberation time has a bell shaped relation with the synaptic density, revealing that the bursting time cannot exceed a maximum value. Furthermore, before reaching its maximum, the reverberation time increases sub-linearly with the synaptic density of the network. We conclude that synaptic dynamics and connectivity shape the mean burst duration, a property present at various scales of the networks. Thus bursting reverberation is a property of sufficiently connected neural networks, and can be generated by collective depression and facilitation of underlying functional synapses.
Project description:Single neurons in the cerebral cortex are immersed in a fluctuating electric field, the local field potential (LFP), which mainly originates from synchronous synaptic input into the local neural neighborhood. As shown by recent studies in visual and auditory cortices, the angular phase of the LFP at the time of spike generation adds significant extra information about the external world, beyond the one contained in the firing rate alone. However, no biologically plausible mechanism has yet been suggested that allows downstream neurons to infer the phase of the LFP at the soma of their pre-synaptic afferents. Therefore, so far there is no evidence that the nervous system can process phase information. Here we study a model of a bursting pyramidal neuron, driven by a time-dependent stimulus. We show that the number of spikes per burst varies systematically with the phase of the fluctuating input at the time of burst onset. The mapping between input phase and number of spikes per burst is a robust response feature for a broad range of stimulus statistics. Our results suggest that cortical bursting neurons could play a crucial role in translating LFP phase information into an easily decodable spike count code.
Project description:Purkinje neurons are central to cerebellar function and show membrane bistability when recorded in vitro or in vivo under anesthesia. The existence of bistability in vivo in awake animals is disputed. Here, by recording intracellularly from Purkinje neurons in unanesthetized larval zebrafish (Danio rerio), we unequivocally demonstrate bistability in these neurons. Tonic firing was seen in depolarized regimes and bursting at hyperpolarized membrane potentials. In addition, Purkinje neurons could switch from one state to another spontaneously or with current injection. While GABAAR or NMDAR were not required for bursting, activation of AMPARs by climbing fibers (CFs) was sufficient to trigger bursts. Further, by recording Purkinje neuron membrane potential intracellularly, and motor neuron spikes extracellularly, we show that initiation of motor neuron spiking is correlated with increased incidence of CF EPSPs and membrane depolarization. Developmentally, bistability was observed soon after Purkinje neuron specification and persists at least until late larval stages.
Project description:The descending auditory system modulates the ascending system at every level. The final descending, or efferent, stage comprises lateral olivocochlear and medial olivocochlear (MOC) neurons. MOC somata in the ventral brainstem project axons to the cochlea to synapse onto outer hair cells (OHC), inhibiting OHC-mediated cochlear amplification. MOC suppression of OHC function is implicated in cochlear gain control with changing sound intensity, detection of salient stimuli, attention and protection against acoustic trauma. Thus, sound excites MOC neurons to provide negative feedback of the cochlea. Sound also inhibits MOC neurons via medial nucleus of the trapezoid body (MNTB) neurons. However, MNTB-MOC synapses exhibit short-term depression, suggesting reduced MNTB-MOC inhibition during sustained stimuli. Further, due to high rates of both baseline and sound-evoked activity in MNTB neurons in vivo, MNTB-MOC synapses may be tonically depressed. To probe this, we characterized short-term plasticity of MNTB-MOC synapses in mouse brain slices. We mimicked in vivo-like temperature and extracellular calcium conditions, and in vivo-like activity patterns of fast synaptic activation rates, sustained activation and prior tonic activity. Synaptic depression was sensitive to extracellular calcium concentration and temperature. During rapid MNTB axon stimulation, postsynaptic currents in MOC neurons summated but with concurrent depression, resulting in smaller, sustained currents, suggesting tonic inhibition of MOC neurons during rapid circuit activity. Low levels of baseline MNTB activity did not significantly reduce responses to subsequent rapid activity that mimics sound stimulation, indicating that, in vivo, MNTB inhibition of MOC neurons persists despite tonic synaptic depression. KEY POINTS: Inhibitory synapses from the medial nucleus of the trapezoid body (MNTB) onto medial olivocochlear (MOC) neurons exhibit short-term plasticity that is sensitive to calcium and temperature, with enhanced synaptic depression occurring at higher calcium concentrations and at room temperature. High rates of background synaptic activity that mimic the upper limits of spontaneous MNTB activity cause tonic synaptic depression of MNTB-MOC synapses that limits further synaptic inhibition. High rates of activity at MNTB-MOC synapses cause synaptic summation with concurrent depression to yield a response with an initial large amplitude that decays to a tonic inhibition.
Project description:The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates NMDA-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the GluN2B subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestations of depression.
Project description:During spatial navigation, the frequency and timing of spikes from spatial neurons including place cells in hippocampus and grid cells in medial entorhinal cortex are temporally organized by continuous theta oscillations (6-11 Hz). The theta rhythm is regulated by subcortical structures including the medial septum, but it is unclear how spatial information from place cells may reciprocally organize subcortical theta-rhythmic activity. Here we recorded single-unit spiking from a constellation of subcortical and hippocampal sites to study spatial modulation of rhythmic spike timing in rats freely exploring an open environment. Our analysis revealed a novel class of neurons that we termed 'phaser cells,' characterized by a symmetric coupling between firing rate and spike theta-phase. Phaser cells encoded space by assigning distinct phases to allocentric isocontour levels of each cell's spatial firing pattern. In our dataset, phaser cells were predominantly located in the lateral septum, but also the hippocampus, anteroventral thalamus, lateral hypothalamus, and nucleus accumbens. Unlike the unidirectional late-to-early phase precession of place cells, bidirectional phase modulation acted to return phaser cells to the same theta-phase along a given spatial isocontour, including cells that characteristically shifted to later phases at higher firing rates. Our dynamical models of intrinsic theta-bursting neurons demonstrated that experience-independent temporal coding mechanisms can qualitatively explain (1) the spatial rate-phase relationships of phaser cells and (2) the observed temporal segregation of phaser cells according to phase-shift direction. In open-field phaser cell simulations, competitive learning embedded phase-code entrainment maps into the weights of downstream targets, including path integration networks. Bayesian phase decoding revealed error correction capable of resetting path integration at subsecond timescales. Our findings suggest that phaser cells may instantiate a subcortical theta-rhythmic loop of spatial feedback. We outline a framework in which location-dependent synchrony reconciles internal idiothetic processes with the allothetic reference points of sensory experience.
Project description:The role of preoptic GABAergic inhibitory neurons was addressed in parenting, anxiety and depression. Pup exposure and forced swimming resulted in similar c-Fos activation pattern in neurons expressing vesicular GABA transporter in the preoptic area with generally stronger labeling and different distributional pattern in females than in males. Chemogenetic stimulation of preoptic GABAergic cells resulted in elevated maternal motivation and caring behavior in females and mothers but aggression toward pups in males. Behavioral effects were the opposite following inhibition of preoptic GABAergic neurons suggesting their physiological relevance. In addition, increased anxiety-like and depression-like behaviors were found following chemogenetic stimulation of the same neurons in females, whereas previous pup exposure increased only anxiety-like behavior suggesting that not the pups, but overstimulation of the cells can lead to depression-like behavior. A sexually dimorphic projection pattern of preoptic GABAergic neurons was also identified, which could mediate sex-dependent parenting and associated emotional behaviors.