Postinhibitory Rebound Firing Research Articles

Post-Inhibitory Rebound Firing of Dorsal Root Ganglia Neurons.

BackgroundIn the central nervous system, post-inhibitory rebound firing (RF) may mediate overactivity of neurons under pathophysiological condition. RF is also observed in dorsal root ganglion (IRA) neurons. However, the functional significance of RF in primary sensory neurons has remained unknown. After peripheral sensory nerve/neuron injury, DRG neurons exhibit hyperexcitability. Therefore, RF may play a role in neuropathic pain.MethodsChronic compression of DRG (CCD) is used as a neuropathic pain model. Rats were divided into 2 groups: Sham and CCD groups. Patch clamp was performed on the whole DRG and cultured DRG neurons to record RF and T-type Ca2+ currents. The blocker of T-type Ca2+ channels, NiCl2, was applied to DRG neurons.ResultsRebound neurons were more excitable than non-rebound neurons. And they discharged RF with prominent after depolarizing potentials, which were blocked by NiCl2. After DRG injury, the proportion of rebound neurons augmented, and rebound neurons’ excitability increased. Meanwhile, the steady-state activation curve of T-type Ca2+ channels was shifted toward the left.ConclusionRF may be related to highly excitable neurons and sensitive to both depolarization and hyperpolarization. T-type Ca2+ channels were critical to RF, potentially enhancing the spontaneous firing of rebound neurons in response to resting membrane potential fluctuations.

Role of HCN Currents in Epileptiform Activity in Subicular Neurons

Subicular neurons play a critical role in Temporal Lobe Epilepsy. While studies have shed light on how synaptic conductances contribute to epileptiform activity in these neurons, it is still unclear how intrinsic conductances influence epileptic discharges. HCN channels play crucial role in pathophysiology by modulating the electrophysiological properties of neurons. To investigate the ability of intrinsic properties in a subicular neuron to generate epileptiform activity, we studied the effects of Ih (HCN) currents in 4‐Aminopyridine magnesium‐free epileptic model in various classes of subicular neurons. To study the modulation of epileptiform activity due to Ih in these neurons, we modeled subicular HCN currents in dynamic clamp that mimicked the effects of blocker and overexpression. We observed similar changes in input resistances with the subtraction and addition of currents in burst firing, regular firing and interneurons. However, the firing rate characteristics during epileptiform activity with the modulation of HCN channels in burst firing and regular firing differed from those observed in interneurons. The results indicated that the burster cells majorly contribute to the epileptic firing characteristics due to HCN in subiculum.During the epileptiform activity, these bursters showed progressive loss of homeostatic compensation characterized by decrease in sag ratio and and loss in theta frequency. The loss of homeostatic compensation incurred was found to be irreversible. These irreversible changes are also characterized by altered HCN channel kinetics. To study how these epilepsy‐induced alterations govern neuronal excitability, we studied the electrophysiological profiles of subicular neurons with altered HCN current kinetics introduced through dynamic clamp in the presence of ZD7288. These irreversible changes are also characterized by altered HCN channel kinetics. To study how these epilepsy‐induced alterations govern neuronal excitability, we studied the electrophysiological profiles of subicular neurons with altered HCN current kinetics introduced through dynamic clamp in the presence of ZD7288. The results showed that the theta selectivity and sag profiles were modulated and post‐inhibitory rebound firing were evoked making the cell hyperexcitable. It is known that the stable neuronal network is homeostatically regulated by intrinsic excitability and synaptic currents. Studies are being conducted to understand the interaction between Ih and synaptic currents before and during the epileptiform activity in neurons with post‐epileptic induced hyperexcitability.

Physiological and anatomical development of glycinergic inhibition in the mouse superior paraolivary nucleus following hearing onset.

Neural circuits require balanced synaptic excitation and inhibition to ensure accurate neural computation. Our knowledge about the development and maturation of inhibitory synaptic inputs is less well developed than that concerning excitation. Here we describe the maturation of an inhibitory circuit within the mammalian auditory brainstem where counterintuitively, inhibition drives action potential firing of principal neurons. With the use of combined anatomical tracing and electrophysiological recordings from mice, neurons of the superior paraolivary nucleus (SPN) are shown to receive converging glycinergic input from at least four neurons of the medial nucleus of the trapezoid body (MNTB). These four axons formed 30.71 ± 2.72 (means ± SE) synaptic boutons onto each SPN neuronal soma, generating a total inhibitory conductance of 80 nS. Such strong inhibition drives the underlying postinhibitory rebound firing mechanism, which is a hallmark of SPN physiology. In contrast to inhibitory projections to the medial and lateral superior olives, the inhibitory projection to the SPN does not exhibit experience-dependent synaptic refinement following the onset of hearing. These findings emphasize that the development and function of neural circuits cannot be inferred from one synaptic target to another, even if both originate from the same neuron.NEW & NOTEWORTHY Neuronal activity regulates development and maturation of neural circuits. This activity can include spontaneous burst firing or firing elicited by sensory input during early development. For example, auditory brainstem circuits involved in sound localization require acoustically evoked activity to form properly. Here we show, that an inhibitory circuit, involved in processing sound offsets, gaps, and rhythmically modulated vocal communication signals, matures before the onset of acoustically evoked activity.

Slow NMDA-Mediated Excitation Accelerates Offset-Response Latencies Generated via a Post-Inhibitory Rebound Mechanism.

In neural circuits, action potentials (spikes) are conventionally caused by excitatory inputs whereas inhibitory inputs reduce or modulate neuronal excitability. We previously showed that neurons in the superior paraolivary nucleus (SPN) require solely synaptic inhibition to generate their hallmark offset response, a burst of spikes at the end of a sound stimulus, via a post-inhibitory rebound mechanism. In addition SPN neurons receive excitatory inputs, but their functional significance is not yet known. Here we used mice of both sexes to demonstrate that in SPN neurons, the classical roles for excitation and inhibition are switched, with inhibitory inputs driving spike firing and excitatory inputs modulating this response. Hodgkin–Huxley modeling suggests that a slow, NMDA receptor (NMDAR)-mediated excitation would accelerate the offset response. We find corroborating evidence from in vitro and in vivo recordings that lack of excitation prolonged offset-response latencies and rendered them more variable to changing sound intensity levels. Our results reveal an unsuspected function for slow excitation in improving the timing of post-inhibitory rebound firing even when the firing itself does not depend on excitation. This shows the auditory system employs highly specialized mechanisms to encode timing-sensitive features of sound offsets which are crucial for sound-duration encoding and have profound biological importance for encoding the temporal structure of speech.

Control of Xenopus Tadpole Locomotion via Selective Expression of Ih in Excitatory Interneurons

SummaryLocomotion relies on the coordinated activity of rhythmic neurons in the hindbrain and spinal cord and depends critically on the intrinsic properties of excitatory interneurons. Therefore, understanding how ion channels sculpt the properties of these interneurons, and the consequences for circuit function and behavior, is an important task. The hyperpolarization-activated cation current, Ih, is known to play important roles in shaping neuronal properties and for rhythm generation in many neuronal networks. We show in stage 42 Xenopus laevis frog tadpoles that Ih is strongly expressed only in excitatory descending interneurons (dINs), an important ipsilaterally projecting population that drives swimming activity. The voltage-dependent HCN channel blocker ZD7288 completely abolished a prominent depolarizing sag potential in response to hyperpolarization, the hallmark of Ih, and hyperpolarized dINs. ZD7288 also affected dIN post-inhibitory rebound firing, upon which locomotor rhythm generation relies, and disrupted locomotor output. Block of Ih also unmasked an activity-dependent ultraslow afterhyperpolarization (usAHP) in dINs following swimming, mediated by a dynamic Na/K pump current. This usAHP, unmasked in dINs by ZD7288, resulted in suprathreshold stimuli failing to evoke swimming at short inter-swim intervals, indicating an important role for Ih in maintaining swim generation capacity and in setting the post-swim refractory period of the network. Collectively, our data suggest that the selective expression of Ih in dINs determines specific dIN properties that are important for rhythm generation and counteracts an activity-dependent usAHP to ensure that dINs can maintain coordinated swimming over a wide range of inter-swim intervals.

Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus

Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation ofinhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of theneuronal population with this post-inhibitory rebound firing by knockout of T-type Ca2+ channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT.

Experimental tests of hypotheses for microsaccade generation.

Fixational eye movements such as microsaccades are important to prevent fading. These miniature eye movements are also necessary to redirect gaze to the target after a drift. Generation of saccades and microsaccades utilizes common neural substrates. We, therefore, hypothesized that physiological modulators of saccades should also affect microsaccades. Test of this hypothesis will also provide support for the models of a microsaccade generation. We performed two experiments. In the first experiment, complete darkness led to a decrease in the frequency and velocity, but increased the amplitude of microsaccades. In the second experiment, active eyelid closure further reduced the velocity and frequency of microsaccades, but increased their amplitude. Darkness reduces the superior colliculus activity leading to a reduction in the velocity and frequency of microsaccades. Eye closure might cause sustained inhibition of the omnipause neurons. Subsequent disinhibition of the burst neurons might cause a reduction in the post-inhibitory rebound firing resulting in a decreased velocity of microsaccades. Sustained inhibition of the omnipause neurons could also reduce the inhibitory drive that would otherwise abort microsaccades. Hence, by inhibiting the activity of omnipause neurons, the eye closure could increase the amplitude of microsaccades.

Postinhibitory rebound neurons and networks are disrupted in retrovirus-induced spongiform neurodegeneration.

Certain retroviruses induce progressive spongiform motor neuron disease with features resembling prion diseases and amyotrophic lateral sclerosis. With the neurovirulent murine leukemia virus (MLV) FrCasE, Env protein expression within glia leads to postsynaptic vacuolation, cellular effacement, and neuronal loss in the absence of neuroinflammation. To understand the physiological changes associated with MLV-induced spongiosis, and its neuronal specificity, we employed patch-clamp recordings and voltage-sensitive dye imaging in brain slices of the mouse inferior colliculus (IC), a midbrain nucleus that undergoes extensive spongiosis. IC neurons characterized by postinhibitory rebound firing (PIR) were selectively affected in FrCasE-infected mice. Coincident with Env expression in microglia and in glia characterized by NG2 proteoglycan expression (NG2 cells), rebound neurons (RNs) lost PIR, became hyperexcitable, and were reduced in number. PIR loss and hyperexcitability were reversed by raising internal calcium buffer concentrations in RNs. PIR-initiated rhythmic circuits were disrupted, and spontaneous synchronized bursting and prolonged depolarizations were widespread. Other IC neuron cell types and circuits within the same degenerative environment were unaffected. Antagonists of NMDA and/or AMPA receptors reduced burst firing in the IC but did not affect prolonged depolarizations. Antagonists of L-type calcium channels abolished both bursts and slow depolarizations. IC infection by the nonneurovirulent isogenic virus Friend 57E (Fr57E), whose Env protein is structurally similar to FrCasE, showed no RN hyperactivity or cell loss; however, PIR latency increased. These findings suggest that spongiform neurodegeneration arises from the unique excitability of RNs, their local regulation by glia, and the disruption of this relationship by glial expression of abnormal protein.

Diverse Precerebellar Neurons Share Similar Intrinsic Excitability

The cerebellum dedicates a majority of the brain's neurons to processing a wide range of sensory, motor, and cognitive signals. Stereotyped circuitry within the cerebellar cortex suggests that similar computations are performed throughout the cerebellum, but little is known about whether diverse precerebellar neurons are specialized for the nature of the information they convey. In vivo recordings indicate that firing responses to sensory or motor stimuli vary dramatically across different precerebellar nuclei, but whether this reflects diverse synaptic inputs or differentially tuned intrinsic excitability has not been determined. We targeted whole-cell patch-clamp recordings to neurons in eight precerebellar nuclei which were retrogradely labeled from different regions of the cerebellum in mice. Intrinsic physiology was compared across neurons in the medial vestibular, external cuneate, lateral reticular, prepositus hypoglossi, supragenual, Roller/intercalatus, reticularis tegmenti pontis, and pontine nuclei. Within the firing domain, precerebellar neurons were remarkably similar. Firing faithfully followed temporally modulated inputs, could be sustained at high rates, and was a linear function of input current over a wide range of inputs and firing rates. Pharmacological analyses revealed common expression of Kv3 currents, which were essential for a wide linear firing range, and of SK (small-conductance calcium-activated potassium) currents, which were essential for a wide linear input range. In contrast, membrane properties below spike threshold varied considerably within and across precerebellar nuclei, as evidenced by variability in postinhibitory rebound firing. Our findings indicate that diverse precerebellar neurons perform similar scaling computations on their inputs but may be differentially tuned to synaptic inhibition.

Multiple Types of Cerebellar Target Neurons and Their Circuitry in the Vestibulo-ocular Reflex

The cerebellum influences behavior and cognition exclusively via Purkinje cell synapses onto neurons in the deep cerebellar and vestibular nuclei. In contrast with the rich information available about the organization of the cerebellar cortex and its synaptic inputs, relatively little is known about microcircuitry postsynaptic to Purkinje cells. Here we examined the cell types and microcircuits through which Purkinje cells influence an oculomotor behavior controlled by the cerebellum, the horizontal vestibulo-ocular reflex, which involves only two eye muscles. Using a combination of anatomical tracing and electrophysiological recordings in transgenic mouse lines, we identified several classes of neurons in the medial vestibular nucleus that receive Purkinje cell synapses from the cerebellar flocculus. Glycinergic and glutamatergic flocculus target neurons (FTNs) with somata densely surrounded by Purkinje cell terminals projected axons to the ipsilateral abducens and oculomotor nuclei, respectively. Of three additional types of FTNs that were sparsely innervated by Purkinje cells, glutamatergic and glycinergic neurons projected to the contralateral and ipsilateral abducens, respectively, and GABAergic neurons projected to contralateral vestibular nuclei. Densely innervated FTNs had high spontaneous firing rates and pronounced postinhibitory rebound firing, and were physiologically homogeneous, whereas the intrinsic excitability of sparsely innervated FTNs varied widely. Heterogeneity in the molecular expression, physiological properties, and postsynaptic targets of FTNs implies that Purkinje cell activity influences the neural control of eye movements in several distinct ways. These results indicate that the cerebellum regulates a simple reflex behavior via at least five different cell types that are postsynaptic to Purkinje cells.

Prolonged Postinhibitory Rebound Firing in the Cerebellar Nuclei Mediated by Group I Metabotropic Glutamate Receptor Potentiation of L-Type Calcium Currents

Neurons in the cerebellar nuclei fire at accelerated rates for prolonged periods after trains of synaptic inhibition that interrupt spontaneous firing. Both in vitro and in vivo, however, this prolonged rebound firing is favored by strong stimulation of afferents, suggesting that neurotransmitters other than GABA may contribute to the increased firing rates. Here, we tested whether metabotropic glutamate receptors modulate excitability of nuclear cells in cerebellar slices from mouse. In current clamp, the prolonged rebound firing rate after high-frequency synaptic stimulation was reduced by a variety of group I mGluR antagonists, including CPCCOEt [7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester], JNJ16259685 (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone) plus MPEP, or 3-MATIDA (α-amino-5-carboxy-3-methyl-2-thiopheneacetic acid) plus MPEP, as long as both mGluR1 and mGluR5 were blocked. This mGluR-dependent acceleration of firing was reduced but still evident when IPSPs were prevented by GABA(A) receptor antagonists. In voltage clamp, voltage ramps revealed a non-inactivating, low-voltage-activated, nimodipine-sensitive current that was enhanced by the selective group I mGluR agonist s-DHPG [(S)-3,5-dihydroxyphenylglycine]. This putative L-type current also increased when mGluRs were activated by trains of evoked synaptic currents instead of direct application of agonist. In current clamp, blocking L-type Ca channels with the specific blocker nifedipine greatly reduced prolonged poststimulus firing and occluded the effect of adding group I mGluR antagonists. Thus, potentiation of a low-voltage-activated L-type current by synaptically released glutamate accounted nearly fully for the mGluR-dependent acceleration of firing. Together, these data suggest that prolonged rebound firing in the cerebellar nuclei in vivo is most likely to occur when GABA(A) and mGluRs are simultaneously activated by concurrent excitation and inhibition.

Attenuated glycine receptor function reduces excitability of mouse medial vestibular nucleus neurons

Spontaneous activity in medial vestibular nucleus (MVN) neurons is modulated by synaptic inputs. These inputs are crucial for maintaining gaze and posture and contribute to vestibular compensation after lesions of peripheral vestibular organs. We investigated how chronically attenuated glycinergic input affects excitability of MVN neurons. To this end we used three mouse strains (spastic, spasmodic, and oscillator), with well-characterized naturally occurring mutations in the inhibitory glycine receptor (GlyR). First, using whole-cell patch-clamp recordings, we demonstrated that the amplitude of the response to rapidly applied glycine was dramatically reduced by 25 to 90% in MVN neurons from mutant mice. We next determined how reduced GlyR function affected MVN neuron output. Neurons were classified using two schemas: (1) the shape of their action potential afterhyperpolarization (AHP); and (2) responses to hyperpolarizing current injection. In the first schema, neurons were classified as types A, B and C. The prevalence of type C neurons in the mutant strains was significantly increased. In the second schema, the proportion of neurons lacking post inhibitory rebound firing (PRF-deficient) was increased. In both schemas an increase in AHP amplitude was a common feature of the augmented neuron group (type C, PRF-deficient) in the mutant strains. We suggest increased AHP amplitude reduces overall excitability in the MVN and thus maintains network function in an environment of reduced glycinergic input.

Estimation of the information pathway in the neural network in the premotor center of Bombyx mori to generate the flip-flop activity and its validation by the simulation

Event Abstract Back to Event Estimation of the information pathway in the neural network in the premotor center of Bombyx mori to generate the flip-flop activity and its validation by the simulation Ikuko Nishikawa1*, Akira Takashima2, Shigehiro Namiki2, Tomoki Kazawa2, Stephan Shuichi Haupt2, Hidetoshi Ikeno3 and Ryohei Kanzaki2 1 Ritsumeikan University, Human and Computer Intelligence, Japan 2 The University of Tokyo, Japan 3 University of Hyogo, Japan The lateral accessory lobe (LAL) and the ventral protocerebrum (VPC) are known to form a premotor center of brain in insects. The present report focuses on the neural network of the LAL-VPC of Bombyx mori. The neuroethological experiments elucidate LAL-VPC generates a motor command of the pheromone oriented behavior, which is composed of a sequential activity of surge, zigzag-turn and loop [1,2]. The LAL-VPC region has been characterized by its temporal activity with alternating flip-flop patterns between both hemispheres, through the records from the descending neurons. Moreover, electrophysiological and immunohistochemical studies enable the physiological and morphological classification of LAL-VPC neurons, and thereby suggest possible anatomical connections among the neurons.The goal of this study is to estimate the functional connection strengths of the above anatomically found synaptic connections to elucidate the main information pathway for generating the flip-flop activity in LAL-VPC. The available data to challenge this problem is the stimulus-evoked activities of LAL-VPC neurons. Another key is the experimental finding that LAL-VPC consists of multiple neuropile regions [3], and each neuron possesses input branches from one or more regions and output branches to other regions. Based on these experimental findings, first, we define the following self-consistent formula to derive the connection strengths. That is, the activity of each neuropile region is given by the weighted summation of the outputs from the connecting neurons, and at the same time, the activity of each neuron is given by the weighted summation of the inputs from the connecting regions. Then, the formula is solved as an optimization problem, whose evaluation function is the reproducibility of the observed neuron activities, and the constraints are the observed anatomical connections. Finally, the connection strengths obtained as optimal solutions of the above static model are evaluated by a network simulation, in which each neuron has a spiking dynamics.A simulator of LAL-VPC network is described by Integrate-and-Fire model for each neuron and two-state kinetic model for each synapse. All of experimentally observed LAL-VPC neurons are connected by the strengths obtained by the above method. Most bilateral neurons are considered as inhibitory, and all local interneurons are set excitatory for the simplicity. Poisson noise is given to each neuron for the spontaneous activity, and the post inhibitory rebound firing is considered. The obtained connection is evaluated by how the temporal activity of each neuron reproduces the physiological data, especially the alternating flip-flop in both hemispheres.

A Precisely Timed Asynchronous Pattern of ON and OFF Retinal Ganglion Cell Activity during Propagation of Retinal Waves

Patterns of coordinated spontaneous activity have been proposed to guide circuit refinement in many parts of the developing nervous system. It is unclear, however, how such patterns, which are thought to indiscriminately synchronize nearby cells, could provide the cues necessary to segregate functionally distinct circuits within overlapping cell populations. Here, we report that glutamatergic retinal waves possess a substructure in the bursting of neighboring retinal ganglion cells with opposite light responses (ON or OFF). Within a wave, cells fire repetitive nonoverlapping bursts in a fixed order: ON before OFF. This pattern is absent from cholinergic waves, which precede glutamate-dependent activity, providing a developmental sequence of distinct activity-encoded cues. Asynchronous bursting of ON and OFF retinal ganglion cells depends on inhibition between these parallel pathways. Similar asynchronous activity patterns could arise throughout the nervous system, as inhibition matures and might help to separate connections of functionally distinct subnetworks.

Physiological and Anatomical Properties of Mouse Medial Vestibular Nucleus Neurons Projecting to the Oculomotor Nucleus

Neurons in the medial vestibular nucleus (MVN) vary in their projection patterns, responses to head movement, and intrinsic firing properties. To establish whether neurons that participate in the vestibulo-ocular reflex (VOR) have distinct intrinsic physiological properties, oculomotor nucleus (OMN)-projecting neurons were identified in mouse brainstem slices by fluorescent retrograde labeling from the oculomotor complex and targeted for patch-clamp recordings. Such neurons were located in the magnocellular portion of the MVN contralateral to tracer injection, were mostly multipolar, and had soma diameters of around 20 mum. They fired spontaneous action potentials at rates higher than those of other MVN neurons and their spikes were of unusually short duration. OMN-projecting neurons responded to 1-s intracellular current injection with exceptionally high firing rates of >500 spikes/s. Their current-firing relationship was highly linear, with weak firing response adaptation during steady depolarization and little postinhibitory rebound firing after membrane hyperpolarization. Their firing responses were approximately in phase with sinusoidal current injection. The response dynamics of OMN-projecting neurons could be simulated with a simple integrate-and-fire model modified with the addition of small adaptation and rebound conductances. These findings indicate that the membrane properties of OMN-projecting neurons allow them to respond to head movements reliably and with high sensitivity but without substantially altering input dynamics.

Analog LSI neuron model inspired by biological excitable membrane

AbstractAn analog hardware neuron model having biological neuron characteristics is proposed and its basic characteristics are reported. The proposed circuit model is constructed from a membrane capacitance part, negative resistance circuit part, and reactance circuit part, and realizes the membrane excitability observed in biological neurons by voltage‐controlled negative resistance characteristics. This model exhibits an action potential generation mechanism similar to that of biological neurons. HSPICE simulation reveals that this model can reproduce both the well‐known responses to excitatory inputs and the postinhibitory rebound (PIR) firing which is a neuronal activity occurring by the release from an inhibitory input discharge, and that the characteristics of the input pulse amplitude‐latency and entrained response to the periodic input are similar to those of biological neurons. In addition, this model is developed by considering compatibility with integrated circuit processes, and design results of LSI implementation of the model are also presented in this article. PIR firing cannot be reproduced by the simple neuronal model used in conventional neurochips, but it plays an important role in information processing in the brain. The functionality of neurochips is expected to be improved by simulating biological neurons by such a biologically inspired hardware neuron model. © 2005 Wiley Periodicals, Inc. Syst Comp Jpn, 36(6): 84–91, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.10676

Purkinje Cell Synapses Target Physiologically Unique Brainstem Neurons

The cerebellum controls motor learning via Purkinje cell synapses onto discrete populations of neurons in the deep cerebellar nuclei and brainstem vestibular nuclei. In the circuitry that subserves the vestibulo-ocular reflex, the postsynaptic targets of Purkinje cells, termed flocculus target neurons (FTNs), are thought to be a critical site of learning. Little is known, however, about the intrinsic cellular properties of FTNs, which are sparsely distributed in the medial vestibular nucleus. To identify these neurons, we used the L7 promoter to express a tau-green fluorescent protein fusion protein selectively in Purkinje cells. Fluorescent Purkinje cell axons and terminal boutons surrounded the somata and proximal dendrites of a small subset of neurons, presumed FTNs, in the medial vestibular nucleus. Targeted intracellular recordings revealed that FTNs fired spontaneously at high rates in brain slices (mean, 47 spikes/sec) and exhibited dramatic postinhibitory rebound firing after the offset of membrane hyperpolarization. These intrinsic firing properties were exceptional among brainstem vestibular nucleus neurons but strikingly similar to neurons in the deep cerebellar nuclei, indicating a common role for intrinsic firing mechanisms in cerebellar control of diverse behaviors.

Intrinsic Firing Dynamics of Vestibular Nucleus Neurons

Individual brainstem neurons involved in vestibular reflexes respond to identical head movements with a wide range of firing responses. This diversity of firing dynamics has been commonly assumed to arise from differences in the types of vestibular nerve inputs to vestibular nucleus neurons. In this study we show that, independent of the nature of inputs, the intrinsic membrane properties of neurons in the medial vestibular nucleus substantially influence firing response dynamics. Hyperpolarizing and depolarizing inputs evoked a markedly heterogenous range of firing responses. Strong postinhibitory rebound firing (PRF) was associated with strong firing rate adaptation (FRA) and occurred preferentially in large multipolar neurons. In response to sinusoidally modulated input current, these neurons showed a pronounced phase lead with respect to neurons lacking strong PRF and FRA. A combination of the hyperpolarization-activated H current and slow potassium currents contributed to PRF, whereas FRA was predominantly mediated by slow potassium currents. An integrate-and-fire-type model, which simulated FRA and PRF, reproduced the phase lead observed in large neurons and showed that adaptation currents were primarily responsible for variations in response phase. We conclude that the heterogeneity of firing dynamics observed in response to head movements in intact animals reflects intrinsic as well as circuit properties.

A GABAergic, Strongly Inhibitory Projection to a Thalamic Nucleus in the Zebra Finch Song System

The anterior forebrain pathway (AFP) of the oscine song system is essential for song learning but not song production. Most cells recorded in this serially connected pathway show increased firing in response to song playback, suggesting largely excitatory connections among AFP nuclei. However, the neurons forming a key projection in this pathway, from area X to the medial nucleus of the dorsolateral thalamus (DLM), express glutamic acid decarboxylase in their somata and terminals, suggesting an inhibitory connection. To investigate the firing properties of DLM neurons and the functional influence of area X afferents in DLM, we made whole-cell recordings from DLM neurons in brain slices from adult male zebra finches. Most cells had intrinsic properties closely resembling those of mammalian thalamocortical cells, including a low-threshold Ca(2+) spike and time-dependent, hyperpolarization-activated inward rectification. Activation of afferents from area X evoked a strong, all-or-none IPSP whose amplitude and latency were unchanged by application of glutamate antagonists, consistent with a monosynaptic contact. The IPSP had a reversal potential near -70 mV and was blocked by the GABA(A) receptor antagonist bicuculline methiodide. Post-inhibitory rebound firing occurred in DLM neurons with a delay near 50 msec. Strong inhibition can combine with the intrinsic properties of DLM neurons to allow signaling on disinhibition. Our data are consistent with the hypothesis that the AFP corresponds to the mammalian corticobasal ganglia-thalamocortical loop. The similar functional properties of avian and mammalian thalamic neurons suggest conserved forebrain mechanisms of sensorimotor information processing across vertebrate taxa.