Rebound Spikes Research Articles

A Novel Threshold Across which the Negative Stimulation Evokes Action Potential Near a Saddle-Node Bifurcation in a Neuronal Model with Ih Current

The negative or hyperpolarization pulse stimulation induces action potential, i.e. the post-inhibitory rebound spike, which has been widely observed in various single neurons with hyperpolarization-activated cation current ([Formula: see text]) in neuroscience and is suggested to be evoked from a focus near the Hopf bifurcation according to the traditional viewpoint of nonlinear dynamics. In the present paper, a novel viewpoint that post-inhibitory rebound spike can be evoked from a stable node near the saddle-node bifurcation on invariant circle (SNIC) is proposed, which can be well interpreted with hyperpolarization activation characteristic of [Formula: see text] current, bifurcation analysis, and threshold. Especially, the boundary between the subthreshold and suprathreshold initial values which respectively evoke subthreshold potential and action potential is acquired to be a threshold surface containing the saddle. [Formula: see text] current after the negative pulse stimulation for small conductance [Formula: see text] of [Formula: see text] is low enough to evoke just a subthreshold potential while for large [Formula: see text] is high enough to evoke a post-inhibitory rebound spike. For small [Formula: see text], the pulse induces the decrease of membrane potential [Formula: see text] and then the phase trajectory always stays within the subthreshold initial value region locating lower to the threshold surface with a nearly fixed [Formula: see text] value. For large [Formula: see text], the threshold surface changes and is composed of two parts: one part with a nearly fixed [Formula: see text] value and the other with a nearly fixed value of [Formula: see text] variable to describe [Formula: see text] inactivation probability. Although the negative pulse stimulation induces the decrease of [Formula: see text], [Formula: see text] increases to a level high enough and then the phase trajectory runs across the part with a nearly fixed [Formula: see text] value to form a post-inhibitory rebound spike. The appearance of the novel [Formula: see text] threshold is the internal dynamical mechanism for the generation of post-inhibitory rebound spike, and the external cause is that the negative pulse stimulation induces the phase trajectory to run across the [Formula: see text] threshold surface. The results present a novel nonlinear phenomenon and the corresponding dynamical mechanism related to post-inhibitory rebound spike induced by [Formula: see text] current near the SNIC bifurcation point.

Pharmacological Antagonism of T-Type Calcium Channels Constrains Rebound Burst Firing in Two Distinct Subpopulations of GABA Neurons in the Rat Ventral Tegmental Area: Implications for α-Lipoic Acid.

The ventral tegmental area (VTA) is a midbrain region highly involved in motivation and reward. A large body of work has investigated synaptic plasticity and ion channel excitability in this area, which has strong implication in drug abuse. We recently provided electrophysiological and pharmacological evidence that the CaV3.1 isoform of T-type voltage-gated calcium channels contributes to the excitability of VTA dopamine (DA) neurons. However, the role of T-channels in excitability of VTA gamma-amino-butyric acid (GABA) neurons remained unaddressed. Here, with a population study of rat VTA GABA neurons, we provide evidence that T-channels contribute to rebound spiking activity in two phenotypically distinct subpopulations of GABAergic neurons, each with differing electrophysiological characteristics. Additionally, we provide the first study to investigate the effect of α-lipoic acid (ALA) on ion channels in mesolimbic reward circuitry. Taken together, our population study and pharmacology experiments implicate T-channels as a target for therapies aimed at tempering VTA and mesolimbic circuit excitability.

Different dynamics of repetitive neural spiking induced by inhibitory and excitatory autapses near subcritical Hopf bifurcation

Based on the post-inhibitory rebound (PIR) spike induced by inhibitory current pulse, in the present paper, a novel counterintuitive phenomenon that the inhibitory autapse with time delay can induce the resting state changed to stable spiking pattern is identified near subcritical Hopf bifurcation of Hodgkin–Huxley model. The delayed inhibitory autaptic current pulse induced by the preceded action potential can induce the preceding PIR spike via the hyperpolarization, rebound, and depolarization processes, which is compared with spiking induced by excitatory autapse via only a depolarization process. The threshold of inhibitory or excitatory autaptic conductance to induce spiking with increasing time delay, and the threshold curve of inhibitory or excitatory pulse current to evoke a spike exhibit damping oscillations can be well interpreted with the damping dynamics of focus near subcritical Hopf bifurcation. However, due to PIR mechanism, the threshold conductance of inhibitory autapse is stronger than that of excitatory autapse, and the spiking period for inhibitory autapse, which is composed of time delay and durations of the other three processes, is longer than the one for excitatory autapse, which is composed of time delay and duration of only a depolarization process. Therefore, a linear correlation between spiking period and time delay is identified, which shows that autapse can modulate the spike timing related to temporal coding. The results present a novel viewpoint and a potential function that inhibitory autapse can facilitate spiking like the excitatory autapse and provide effective measures to modulate neuronal spiking pattern, which is related to subcritical Hopf bifurcation.

Cellular and molecular mechanisms of new onset seizure generation.

New onset epilepsy and seizures are common neurological disorders in aged people, second only to stroke and dementia. They are frequently related to other pathological conditions including stroke, trauma, tumors and neurological diseases whereas in about one-third of cases the origin is unknown. Besides the origin, the cellular and molecular events that suddenly trigger seizures are poorly defined. Using an acute model of seizure generation that better resembles new onset seizures, we studied GABAergic interneurons and astrocytes during seizure generation. We found that seizures are preceded by a GABAergic rhythmic hyperactivity that synchronizes pyramidal neurons by inducing a rebound spiking that favors seizures' onset. Furthermore, the intense activity in GABAergic interneurons evokes Ca2+ elevations in astrocytes that, by releasing glutamate, further excite neuronal network. Elucidating the cellular and molecular events that generate seizures may reveal new targets for treatment of new onset seizures and epilepsy.

Changes in excitability and ion channel expression in neurons of the major pelvic ganglion in female type II diabetic mice.

Bladder cystopathy and autonomic dysfunction are common complications of diabetes, and have been associated with changes in ganglionic transmission and some measures of neuronal excitability in male mice. To determine whether type II diabetes also impacts excitability of ganglionic neurons in females, we investigated neuronal excitability and firing properties, as well as underlying ion channel expression, in major pelvic ganglion (MPG) neurons in control, 10-week, and 21-week Leprdb/db mice. Type II diabetes in Leprdb/db animals caused a non-linear change in excitability and firing properties of MPG neurons. At 10 weeks, cells exhibited increased excitability as demonstrated by an increased likelihood of firing multiple spikes upon depolarization, decreased rebound spike latency, and overall narrower action potential half-widths as a result of increased depolarization and repolarization slopes. Conversely, at 21 weeks MPG neurons of Leprdb/db mice reversed these changes, with spiking patterns and action-potential properties largely returning to control levels. These changes are associated with numerous time-specific changes in calcium, sodium, and potassium channel subunit mRNA levels. However, Principal Components Analysis of channel expression patterns revealed that rectification of excitability is not simply a return to control levels, but rather a distinct ion channel expression profile in 21-week Leprdb/db neurons. These data indicate that type II diabetes can impact the excitability of post-ganglionic, autonomic neurons of female mice, and suggest that the non-linear progression of these properties with diabetes may be the result of compensatory changes in channel expression that act to rectify disrupted firing patterns of Leprdb/db MPG neurons.

Changes in membrane properties of rat deep cerebellar nuclear projection neurons during acquisition of eyeblink conditioning

Previous studies have shown changes in membrane properties of neurons in rat deep cerebellar nuclei (DCN) as a function of development, but due to technical difficulties in obtaining viable DCN slices from adult animals, it remains unclear whether there are learning-related alterations in the membrane properties of DCN neurons in adult rats. This study was designed to record from identified DCN cells in cerebellar slices from postnatal day 25-26 (P25-26) rats that had a relatively mature sensory nervous system and were able to acquire learning as a result of tone-shock eyeblink conditioning (EBC) and to document resulting changes in electrophysiological properties. After electromyographic electrode implantation at P21 and inoculation with a fluorescent pseudorabies virus (PRV-152) at P22-23, rats received either four sessions of paired delay EBC or unpaired stimulus presentations with a tone conditioned stimulus and a shock unconditioned stimulus or sat in the training chamber without stimulus presentations. Compared with rats given unpaired stimuli or no stimulus presentations, rats given paired EBC showed an increase in conditioned responses across sessions. Whole-cell recordings of both fluorescent and nonfluorescent DCN projection neurons showed that delay EBC induced significant changes in membrane properties of evoked DCN action potentials including a reduced after-hyperpolarization amplitude and shortened latency. Similar findings were obtained in hyperpolarization-induced rebound spikes of DCN neurons. In sum, delay EBC produced significant changes in the membrane properties of juvenile rat DCN projection neurons. These learning-specific changes in DCN excitability have not previously been reported in any species or task.

Dynamical Mechanism of Hyperpolarization-Activated Non-specific Cation Current Induced Resonance and Spike-Timing Precision in a Neuronal Model.

Hyperpolarization-activated cyclic nucleotide-gated cation current (Ih) plays important roles in the achievement of many physiological/pathological functions in the nervous system by modulating the electrophysiological activities, such as the rebound (spike) to hyperpolarization stimulations, subthreshold membrane resonance to sinusoidal currents, and spike-timing precision to stochastic factors. In the present paper, with increasing gh (conductance of Ih), the rebound (spike) and subthreshold resonance appear and become stronger, and the variability of the interspike intervals (ISIs) becomes lower, i.e., the enhancement of spike-timing precision, which are simulated in a conductance-based theoretical model and well explained by the nonlinear concept of bifurcation. With increasing gh, the stable node to stable focus, to coexistence behavior, and to firing via the codimension-1 bifurcations (Hopf bifurcation, saddle-node bifurcation, saddle-node bifurcations on an invariant circle, and saddle homoclinic orbit) and codimension-2 bifurcations such as Bogdanov-Takens (BT) point related to the transition between saddle-node and Hopf bifurcations, are acquired with 1- and 2-parameter bifurcation analysis. The decrease of variability of ISIs with increasing gh is induced by the fast decrease of the standard deviation of ISIs, which is related to the increase of the capacity of resisting noisy disturbance due to the firing becomes far away from the bifurcation point. The enhancement of the rebound (spike) with increasing gh builds up a relationship to the decrease of the capacity of resisting disturbance like the hyperpolarization stimulus as the resting state approaches the bifurcation point. The “typical”-resonance and non-resonance appear in the parameter region of the stable focus and node far away from the bifurcation points, respectively. The complex or “strange” dynamics, such as the “weak”-resonance for the stable node near the transition point between the stable node and focus and the non-resonance for the stable focus close to the codimension-1 and −2 bifurcation points, are discussed.

The Effects of Quinine on Neurophysiological Properties of Dopaminergic Neurons

Quinine is an antimalarial drug that is toxic to the auditory system by commonly inducing hearing loss and tinnitus, presumably due to its ototoxic effects on disruption of cochlear hair cells and blockade of ion channels of neurons in the auditory system. To a lesser extent, quinine also causes ataxia, tremor, and dystonic reactions. As dopaminergic neurons are implicated to play a role in all of these diseases, we tested the toxicity of quinine on induced dopaminergic (iDA) neurons derived from human pluripotent stem cells (iPSCs) and primary dopaminergic (DA) neurons of substantia nigra from mice brain slices. Patch clamp recordings and combined drug treatments were performed to examine key physiological properties of the DA neurons. We found that quinine (12.5-200μM) depolarized the resting membrane potential and attenuated the amplitudes of rebound spikes induced by hyperpolarization. Action potentials were also broadened in spontaneously spiking neurons. In addition to quinine attenuating hyperpolarization-dependent conductance, the tail currents following withdrawal of hyperpolarizing currents were also attenuated. Taken together, we found that iPSC-derived DA neurons recapitulated all the tested physiological properties of human DA neurons, and quinine had distinct effects on the physiology of both iDA and primary DA neurons. This toxicity of quinine may be the underlying mechanism for the movement disorders of cinchonism or quinism and may play a role in tinnitus modulation.

Cooperation of Demand Response and Traditional Power Generations for Providing Spinning Reserve

Spinning reserve in the electric power system is vital in dealing with the sudden drop of electricity supply caused by failure, which used to be provided by traditional power generations. With the development of information and communication technologies (ICTs), demand response (DR) is deployed gradually for providing spinning reserve by shedding flexible loads. Air conditioners (ACs) are one of the most high-quality flexible loads due to its high proportion of capacity in electricity consumption. However, power rebound spike (PRS) of AC loads tend to emerge at the end of DR. Therefore, traditional spinning reserve providers (TSRPs) have to ramp to cooperate with ACs immediately. In this paper, a DR management approach is proposed for controlling DR duration time and capacity by sequent temperature configuration. Meanwhile, the connection between PRS and DR duration time is studied. Reliability indices have also been applied to evaluate different cooperation strategies between ACs and TSRPs. Simulations based on Monte Carlo methods are performed quantitatively.

Segregated Excitatory-Inhibitory Recurrent Subnetworks in Layer 5 of the Rat Frontal Cortex.

A prominent feature of neocortical pyramidal cells (PCs) is their numerous projections to diverse brain areas. In layer 5 (L5) of the rat frontal cortex, there are 2 major subtypes of PCs that differ in their long-range axonal projections, corticopontine (CPn) cells and crossed corticostriatal (CCS) cells. The outputs of these L5 PCs can be regulated by feedback inhibition from neighboring cortical GABAergic cells. Two major subtypes of GABAergic cells are parvalbumin (PV)-positive and somatostatin (SOM)-positive cells. PV cells have a fast-spiking (FS) firing pattern, while SOM cells have a low threshold spike (LTS) and regular spiking. In this study, we found that the 2 PC subtypes in L5 selectively make recurrent connections with LTS cells. The connection patterns correlated with the morphological and physiological diversity of LTS cells. LTS cells with high input resistance (Ri) exhibited more compact dendrites and more rebound spikes than LTS cells with low Ri, which had vertically elongated dendrites. LTS subgroups differently inhibited the PC subtypes, although FS cells made nonselective connections with both projection subtypes. These results demonstrate a novel recurrent network of inhibitory and projection-specific excitatory neurons within the neocortex.

Brief activation of GABAergic interneurons initiates the transition to ictal events through post-inhibitory rebound excitation

Activation of γ-aminobutyric acid (GABAA) receptors have been associated with the onset of epileptiform events. To investigate if a causal relationship exists between GABAA receptor activation and ictal event onset, we activated inhibitory GABAergic networks in the superficial layer (2/3) of the somatosensory cortex during hyperexcitable conditions using optogenetic techniques in mice expressing channelrhodopsin-2 in all GABAergic interneurons. We found that a brief 30ms light pulse reliably triggered either an interictal-like event (IIE) or ictal-like (“ictal”) event in the in vitro cortical 4-Aminopyridine (4-AP) slice model. The link between light pulse and epileptiform event onset was lost following blockade of GABAA receptors with bicuculline methiodide. Additionally, recording the chronological sequence of events following a light pulse in a variety of configurations (whole-cell, gramicidin-perforated patch, and multi-electrode array) demonstrated an initial hyperpolarization followed by post-inhibitory rebound spiking and a subsequent slow depolarization at the transition to epileptiform activity. Furthermore, the light-triggered ictal events were independent of the duration or intensity of the initiating light pulse, suggesting an underlying regenerative mechanism. Moreover, we demonstrated that brief GABAA receptor activation can initiate ictal events in the in vivo 4-AP mouse model, in another common in vitro model of epileptiform activity, and in neocortical tissue resected from epilepsy patients. Our findings reveal that the synchronous activation of GABAergic interneurons is a robust trigger for ictal event onset in hyperexcitable cortical networks.

An Analysis of Waves Underlying Grid Cell Firing in the Medial Enthorinal Cortex

Layer II stellate cells in the medial enthorinal cortex (MEC) express hyperpolarisation-activated cyclic-nucleotide-gated (HCN) channels that allow for rebound spiking via an I_{text{h}} current in response to hyperpolarising synaptic input. A computational modelling study by Hasselmo (Philos. Trans. R. Soc. Lond. B, Biol. Sci. 369:20120523, 2013) showed that an inhibitory network of such cells can support periodic travelling waves with a period that is controlled by the dynamics of the I_{text{h}} current. Hasselmo has suggested that these waves can underlie the generation of grid cells, and that the known difference in I_{text{h}} resonance frequency along the dorsal to ventral axis can explain the observed size and spacing between grid cell firing fields. Here we develop a biophysical spiking model within a framework that allows for analytical tractability. We combine the simplicity of integrate-and-fire neurons with a piecewise linear caricature of the gating dynamics for HCN channels to develop a spiking neural field model of MEC. Using techniques primarily drawn from the field of nonsmooth dynamical systems we show how to construct periodic travelling waves, and in particular the dispersion curve that determines how wave speed varies as a function of period. This exhibits a wide range of long wavelength solutions, reinforcing the idea that rebound spiking is a candidate mechanism for generating grid cell firing patterns. Importantly we develop a wave stability analysis to show how the maximum allowed period is controlled by the dynamical properties of the I_{text{h}} current. Our theoretical work is validated by numerical simulations of the spiking model in both one and two dimensions.

S192 The role of the cerebellum in motion control

Objectives To assess the roles of the cerebellum in motion control on the basis of clinical, anatomical, functional imaging and electrophysiological investigations. Methods (a) Review of experimental findings starting from works of pioneers of the 19th century until 2017, (b) assessment of the theory of internal models. Results Anatomically, the cerebellum has a modular organization. Parasagittal bands of Purkinje cells (PCs) project to specific areas of cerebellar nuclei (CN). Functionally, cerebellar cortex (CC) is composed of microzones gathering groups of about 1000 PCs having the same somatotopic receptive field. The intrinsic connectivity networks (ICNs) derived from fMRI studies overlap with maps of structural connectivity. Transsynaptic tracer studies reveal disynaptic pathways linking the cerebellum and basal ganglia. Neurophysiologically, a very robust property of CN is their ability to fire rebound spike bursts following strong hyperpolarization, turning inhibition in CN output spiking. The timing of spiking is critical for the CC and is a pre-requisite for internal models. Anticipation of action is mandatory to plan the sequential movements on the basis of internal/external constraints. Cerebellar dysmetria can now be explained by biased internal models of limb dynamics. Similarly, in Schmahmann’s syndrome a mismatch between reality and perceived reality is suspected. Conclusions The leading theory of forward models is now embracing not only the motor symptoms but also the cognitive deficits observed in cerebellar ataxias. Significance The redundant architecture of the CC makes of the cerebellum an ideal structure to convey signals across microzones in a time-dependent fashion.

The modulation of two motor behaviors by persistent sodium currents in Xenopus laevis tadpoles.

Persistent sodium currents (INaP) are common in neuronal circuitries and have been implicated in several diseases, such as amyotrophic lateral sclerosis (ALS) and epilepsy. However, the role of INaP in the regulation of specific behaviors is still poorly understood. In this study we have characterized INaP and investigated its role in the swimming and struggling behavior of Xenopus tadpoles. INaP was identified in three groups of neurons, namely, sensory Rohon-Beard neurons (RB neurons), descending interneurons (dINs), and non-dINs (neurons rhythmically active in swimming). All groups of neurons expressed INaP, but the currents differed in decay time constants, amplitudes, and the membrane potential at which INaP peaked. Low concentrations (1 µM) of the INaP blocker riluzole blocked INaP ~30% and decreased the excitability of the three neuron groups without affecting spike amplitudes or cellular input resistances. Riluzole reduced the number of rebound spikes in dINs and depressed repetitive firing in RB neurons and non-dINs. At the behavior level, riluzole at 1 µM shortened fictive swimming episodes. It also reduced the number of action potentials neurons fired on each struggling cycle. The results show that INaP may play important modulatory roles in motor behaviors.NEW & NOTEWORTHY We have characterized persistent sodium currents in three groups of spinal neurons and their role in shaping spiking activity in the Xenopus tadpole. We then attempted to evaluate the role of persistent sodium currents in regulating tadpole swimming and struggling motor outputs by using low concentrations of the persistent sodium current antagonist riluzole.

Hyperbolic Modeling of Subthalamic Nucleus Cells to Investigate the Effect of Dopamine Depletion.

To investigate how different types of neurons can produce well-known spiking patterns, a new computationally efficient model is proposed in this paper. This model can help realize the neuronal interconnection issues. The model can demonstrate various neuronal behaviors observed in vivo through simple parameter modification. The behaviors include tonic and phasic spiking, tonic and phasic bursting, class 1 and class 2 excitability, rebound spike, rebound burst, subthreshold oscillation, and accommodated spiking along with inhibition neuron responses. Here, we investigate the neuronal spiking patterns in Parkinson's disease through our proposed model. Abnormal pattern of subthalamic nucleus in Parkinson's disease can be studied through variations in the shape and frequency of firing patterns. Our proposed model introduces mathematical equations, where these patterns can be derived and clearly differentiated from one another. The irregular and arrhythmic behaviors of subthalamic nucleus firing pattern under normal conditions can easily be transformed to those caused by Parkinson's disease through simple parameter modifications in the proposed model. This model can explicitly show the change of neuronal activity patterns in Parkinson's disease, which may eventually lead to effective treatment with deep brain stimulation devices.

Whole-Cell Properties of Cerebellar Nuclei Neurons In Vivo.

Cerebellar nuclei neurons integrate sensorimotor information and form the final output of the cerebellum, projecting to premotor brainstem targets. This implies that, in contrast to specialized neurons and interneurons in cortical regions, neurons within the nuclei encode and integrate complex information that is most likely reflected in a large variation of intrinsic membrane properties and integrative capacities of individual neurons. Yet, whether this large variation in properties is reflected in a heterogeneous physiological cell population of cerebellar nuclei neurons with well or poorly defined cell types remains to be determined. Indeed, the cell electrophysiological properties of cerebellar nuclei neurons have been identified in vitro in young rodents, but whether these properties are similar to the in vivo adult situation has not been shown. In this comprehensive study we present and compare the in vivo properties of 144 cerebellar nuclei neurons in adult ketamine-xylazine anesthetized mice. We found regularly firing (N = 88) and spontaneously bursting (N = 56) neurons. Membrane-resistance, capacitance, spike half-width and firing frequency all widely varied as a continuum, ranging from 9.63 to 3352.1 MΩ, from 6.7 to 772.57 pF, from 0.178 to 1.98 ms, and from 0 to 176.6 Hz, respectively. At the same time, several of these parameters were correlated with each other. Capacitance decreased with membrane resistance (R2 = 0.12, P<0.001), intensity of rebound spiking increased with membrane resistance (for 100 ms duration R2 = 0.1503, P = 0.0011), membrane resistance decreased with membrane time constant (R2 = 0.045, P = 0.031) and increased with spike half-width (R2 = 0.023, P<0.001), while capacitance increased with firing frequency (R2 = 0.29, P<0.001). However, classes of neuron subtypes could not be identified using merely k-clustering of their intrinsic firing properties and/or integrative properties following activation of their Purkinje cell input. Instead, using whole-cell parameters in combination with morphological criteria revealed by intracellular labelling with Neurobiotin (N = 18) allowed for electrophysiological identification of larger (29.3–50 μm soma diameter) and smaller (< 21.2 μm) cerebellar nuclei neurons with significant differences in membrane properties. Larger cells had a lower membrane resistance and a shorter spike, with a tendency for higher capacitance. Thus, in general cerebellar nuclei neurons appear to offer a rich and wide continuum of physiological properties that stand in contrast to neurons in most cortical regions such as those of the cerebral and cerebellar cortex, in which different classes of neurons operate in a narrower territory of electrophysiological parameter space. The current dataset will help computational modelers of the cerebellar nuclei to update and improve their cerebellar motor learning and performance models by incorporating the large variation of the in vivo properties of cerebellar nuclei neurons. The cellular complexity of cerebellar nuclei neurons may endow the nuclei to perform the intricate computations required for sensorimotor coordination.

Temporal processing capacity in auditory-deprived superior paraolivary neurons is rescued by sequential plasticity during early development

The leading treatments for severe hearing disabilities work on the principle of conveying electrical pulses to the auditory brainstem that enable perception of speech. It is currently not known how well the brainstem neurons specialized for decoding such coarse sound information develop when deprived of auditory input activity. Here, we used congenitally deaf α1D−/− mice, lacking activity in the auditory nerve, to investigate the superior paraolivary nucleus (SPON) – a prominent mammalian brainstem structure that responds selectively to sound pulses by rebound spiking. Whole-cell patch-clamp recordings from SPON neurons in the α1D−/− and control mice were obtained at equivalent pre- and post-hearing onset ages. The results show that SPON neurons in the α1D−/− display less precise, plateau-like rebound spiking compared to control neurons. However, the rebound spiking mechanism undergoes strong compensation with age in the α1D−/−. Voltage-activated Ca2+-currents lower the spike threshold, rescuing the capacity for spike initiation at pre-hearing onset ages. Gradual up-regulation of the inwardly rectifying h-current contributes to depolarize the membrane potential. Reduction of the membrane time constant and less recruitment of Ca2+-currents thereby normalize precise rebound spiking at post-hearing onset ages. We found the soluble form of the neurotrophic factor neuritin to be up-regulated in SPON of deaf mice, which may have promoted neuronal survival and prolonged plasticity of the SPON circuitry. A stereotyped timeline of compensation of rebound spiking in deaf SPON neurons indicates robust intrinsic regulation of the brainstem circuitry encoding sound rhythms. This may be a prerequisite for successful cochlear implants.

Distinct Functional Groups Emerge from the Intrinsic Properties of Molecularly Identified Entorhinal Interneurons and Principal Cells.

Inhibitory interneurons are an important source of synaptic inputs that may contribute to network mechanisms for coding of spatial location by entorhinal cortex (EC). The intrinsic properties of inhibitory interneurons in the EC of the mouse are mostly undescribed. Intrinsic properties were recorded from known cell types, such as, stellate and pyramidal cells and 6 classes of molecularly identified interneurons (regulator of calcineurin 2, somatostatin, serotonin receptor 3a, neuropeptide Y neurogliaform (NGF), neuropeptide Y non-NGF, and vasoactive intestinal protein) in acute brain slices. We report a broad physiological diversity between and within cell classes. We also found differences in the ability to produce postinhibitory rebound spikes and in the frequency and amplitude of incoming EPSPs. To understand the source of this intrinsic variability we applied hierarchical cluster analysis to functionally classify neurons. These analyses revealed physiologically derived cell types in EC that mostly corresponded to the lines identified by biomarkers with a few unexpected and important differences. Finally, we reduced the complex multidimensional space of intrinsic properties to the most salient five that predicted the cellular biomolecular identity with 81.4% accuracy. These results provide a framework for the classification of functional subtypes of cortical neurons by their intrinsic membrane properties.

Post-Inhibitory Rebound Spikes in Rat Medial Entorhinal Layer II/III Principal Cells: In Vivo, In Vitro, and Computational Modeling Characterization.

Medial entorhinal cortex Layer-II stellate cells (mEC-LII-SCs) primarily interact via inhibitory interneurons. This suggests the presence of alternative mechanisms other than excitatory synaptic inputs for triggering action potentials (APs) in stellate cells during spatial navigation. Our intracellular recordings show that the hyperpolarization-activated cation current (Ih) allows post-inhibitory-rebound spikes (PIRS) in mEC-LII-SCs. In vivo, strong inhibitory-post-synaptic potentials immediately preceded most APs shortening their delay and enhancing excitability. In vitro experiments showed that inhibition initiated spikes more effectively than excitation and that more dorsal mEC-LII-SCs produced faster and more synchronous spikes. In contrast, PIRS in Layer-II/III pyramidal cells were harder to evoke, voltage-independent, and slower in dorsal mEC. In computational simulations, mEC-LII-SCs morphology and Ih homeostatically regulated the dorso-ventral differences in PIRS timing and most dendrites generated PIRS with a narrow range of stimulus amplitudes. These results suggest inhibitory inputs could mediate the emergence of grid cell firing in a neuronal network.

Rebound depolarization of substantia gelatinosa neurons and its modulatory mechanisms in rat spinal dorsal horn

To investigate the rebound depolarization of substantia gelatinosa (SG) neurons in rat spinal dorsal horn and explore its modulatory mechanisms to provide better insights into rebound depolarization-related diseases. Parasagittal slices of the spinal cord were prepared from 3- to 5-week-old Sprague-Dawley rats. The electrophysiologic characteristics and responses to hyperpolarization stimulation were recorded using whole-cell patch-clamp technique. The effects of hyperpolarization-activated cyclic nucleotide gated cation (HCN) channel blockers and T-type calcium channel blockers on rebound depolarization of the neurons were studied. A total of 63 SG neurons were recorded. Among them, 23 neurons showed no rebound depolarization, 19 neurons showed rebound depolarization without spikes, and 21 neurons showed rebound depolarization with spikes. The action potential thresholds of the neurons without rebound depolarization were significantly higher than those of the neurons with rebound depolarization and spikes (-28.7∓1.6 mV vs -36.0∓2.0 mV, P<0.05). The two HCN channel blockers CsCl and ZD7288 significantly delayed the latency of rebound depolarization with spike from 45.9∓11.6 ms to 121.6∓51.3 ms (P<0.05) and from 36.2∓10.3 ms to 73.6∓13.6 ms (P<0.05), respectively. ZD7288 also significantly prolonged the latency of rebound depolarization without spike from 71.9∓35.1 ms to 267.0∓68.8 ms (P<0.05). The T-type calcium channel blockers NiCl2 and mibefradil strongly decreased the amplitude of rebound depolarization with spike from 19.9∓6.3 mV to 9.5∓4.5 mV (P<0.05) and from 26.1∓9.4 mV to 15.5∓5.0 mV (P<0.05), respectively. Mibefradil also significantly decreased the amplitude of rebound depolarization without spike from 14.3∓3.0 mV to 7.9∓2.0 mV (P<0.05). Nearly two-thirds of the SG neurons have rebound depolarizations modulated by HCN channel and T-type calcium channel.