RESUMO
Neural circuits are endowed with several forms of intrinsic and synaptic plasticity that could contribute to adaptive changes in behavior, but circuit complexities have hindered linking specific cellular mechanisms with their behavioral consequences. Eye movements generated by simple brainstem circuits provide a means for relating cellular plasticity to behavioral gain control. Here we show that firing rate potentiation, a form of intrinsic plasticity mediated by reductions in BK-type calcium-activated potassium currents in spontaneously firing neurons, is engaged during optokinetic reflex compensation for inner ear dysfunction. Vestibular loss triggers transient increases in postsynaptic excitability, occlusion of firing rate potentiation, and reductions in BK currents in vestibular nucleus neurons. Concurrently, adaptive increases in visually evoked eye movements rapidly restore oculomotor function in wild-type mice but are profoundly impaired in BK channel-null mice. Activity-dependent regulation of intrinsic excitability may be a general mechanism for adaptive control of behavioral output in multisensory circuits.
Assuntos
Movimentos Oculares/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/fisiologia , Plasticidade Neuronal/fisiologia , Reflexo Vestíbulo-Ocular/fisiologia , Células Receptoras Sensoriais/fisiologia , Núcleos Vestibulares/fisiologia , Animais , Medições dos Movimentos Oculares , Camundongos , Núcleos Vestibulares/citologia , Vestíbulo do Labirinto/lesõesRESUMO
Signal transfer in neural circuits is dynamically modified by the recent history of neuronal activity. Short-term plasticity endows synapses with nonlinear transmission properties, yet synapses in sensory and motor circuits are capable of signaling linearly over a wide range of presynaptic firing rates. How do such synapses achieve rate-invariant transmission despite history-dependent nonlinearities? Here, ultrastructural, biophysical, and computational analyses demonstrate that concerted molecular, anatomical, and physiological refinements are required for central vestibular nerve synapses to linearly transmit rate-coded sensory signals. Vestibular synapses operate in a physiological regime of steady-state depression imposed by tonic firing. Rate-invariant transmission relies on brief presynaptic action potentials that delimit calcium influx, large pools of rapidly mobilized vesicles, multiple low-probability release sites, robust postsynaptic receptor sensitivity, and efficient transmitter clearance. Broadband linear synaptic filtering of head motion signals is thus achieved by coordinately tuned synaptic machinery that maintains physiological operation within inherent cell biological limitations.
Assuntos
Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Nervo Vestibular/fisiologia , Animais , Animais Recém-Nascidos , Cálcio/fisiologia , Estimulação Elétrica , Modelos Lineares , Camundongos , Camundongos Endogâmicos C57BL , Sinapses/ultraestrutura , Nervo Vestibular/ultraestruturaRESUMO
Identification of marker genes expressed in specific cell types is essential for the genetic dissection of neural circuits. Here we report a new strategy for classifying heterogeneous populations of neurons into functionally distinct types and for identifying associated marker genes. Quantitative single-cell expression profiling of genes related to neurotransmitters and ion channels enables functional classification of neurons; transcript profiles for marker gene candidates identify molecular handles for manipulating each cell type. We apply this strategy to the mouse medial vestibular nucleus (MVN), which comprises several types of neurons subserving cerebellar-dependent learning in the vestibulo-ocular reflex. Ion channel gene expression differed both qualitatively and quantitatively across cell types and could distinguish subtle differences in intrinsic electrophysiology. Single-cell transcript profiling of MVN neurons established six functionally distinct cell types and associated marker genes. This strategy is applicable throughout the nervous system and could facilitate the use of molecular genetic tools to examine the behavioral roles of distinct neuronal populations.
Assuntos
Tronco Encefálico/fisiologia , Cerebelo/fisiologia , Aprendizagem/fisiologia , Neurônios/classificação , Núcleos Vestibulares/fisiologia , Algoritmos , Animais , Cerebelo/citologia , Primers do DNA , DNA Complementar/biossíntese , DNA Complementar/genética , Interpretação Estatística de Dados , Fenômenos Eletrofisiológicos , Amplificação de Genes , Marcadores Genéticos , Gliceraldeído-3-Fosfato Desidrogenases/genética , Imuno-Histoquímica , Hibridização In Situ , Canais Iônicos/genética , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , Análise de Célula Única , Núcleos Vestibulares/citologiaRESUMO
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.
Assuntos
Cerebelo/citologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Reflexo Vestíbulo-Ocular/fisiologia , Animais , Biofísica , Biotina/análogos & derivados , Biotina/metabolismo , Calbindinas , Cerebelo/ultraestrutura , Dextranos/metabolismo , Estimulação Elétrica , Feminino , Glutamato Descarboxilase/genética , Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Técnicas In Vitro , Proteínas Luminescentes/genética , Masculino , Potenciais da Membrana/genética , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão/métodos , Rede Nervosa/citologia , Rede Nervosa/ultraestrutura , Neurônios/classificação , Neurônios/ultraestrutura , Técnicas de Patch-Clamp , Rodaminas/metabolismo , Proteína G de Ligação ao Cálcio S100/metabolismo , Sinapses/genética , Sinapses/fisiologia , Núcleos Vestibulares/citologia , Núcleos Vestibulares/fisiologia , Proteínas tau/genéticaRESUMO
The vestibular system is responsible for transforming head motion into precise eye, head, and body movements that rapidly stabilize gaze and posture. How do central excitatory synapses mediate behavioral outputs accurately matched to sensory inputs over a wide dynamic range? Here we demonstrate that vestibular afferent synapses in vitro express frequency-independent transmission that spans their in vivo dynamic range (5-150 spikes/s). As a result, the synaptic charge transfer per unit time is linearly related to vestibular afferent activity in both projection and intrinsic neurons of the vestibular nuclei. Neither postsynaptic glutamate receptor desensitization nor saturation affect the relative amplitude or frequency-independence of steady-state transmission. Finally, we show that vestibular nucleus neurons can transduce synaptic inputs into linear changes in firing rate output without relying on one-to-one calyceal transmission. These data provide a physiological basis for the remarkable linearity of vestibular reflexes.
Assuntos
Equilíbrio Postural/fisiologia , Reflexo Vestíbulo-Ocular/fisiologia , Células Receptoras Sensoriais/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Núcleos Vestibulares/fisiologia , Potenciais de Ação/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios/citologia , Interneurônios/fisiologia , Modelos Lineares , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Receptores de Glutamato/fisiologia , Células Receptoras Sensoriais/citologia , Sinapses/ultraestrutura , Nervo Vestibular/fisiologia , Núcleos Vestibulares/citologia , Vestíbulo do Labirinto/fisiologiaRESUMO
The hedgehog tenrec, Echinops telfairi, has certain basal mammalian features, like a cloaca and a sparsely differentiated brain with smooth cerebral hemispheres. The peripheral auditory capabilities of this species were investigated by means of distortion product otoacoustic emissions (DPOAE). For comparison, we determined auditory evoked potentials (AEP) in the inferior colliculus and the auditory cortex. Both methods show that the auditory range of E. telfairi extends well into ultrasonic frequencies, with a region of highest sensitivity at around 16 kHz. The total auditory range spans about 4 octaves at 40 dB SPL. The low-frequency limit of auditory processing is found at frequencies of about 2-3 kHz. The DPOAE and the AEP thresholds of E. telfairi do not run fully parallel in the high-frequency range. For a threshold value of 40 dB SPL, cochlear mechanical thresholds as measured with DPOAE extend up to 50 kHz, whereas neuronal thresholds reach the high-frequency limit at about 30 kHz. Frequency tuning, as assessed from DPOAE suppression tuning curves, was low to moderate with Q(10 dB) values ranging from 1.7 to 8. The lack of discontinuity in the group delay (derived from DPOAE measurements) reveals that cochlear frequency representation is tonotopic without any region of specialized mechanical tuning.
Assuntos
Eulipotyphla/fisiologia , Potenciais Evocados Auditivos/fisiologia , Emissões Otoacústicas Espontâneas/fisiologia , Estimulação Acústica , Animais , Córtex Auditivo/fisiologia , Limiar Auditivo/fisiologia , Feminino , Colículos Inferiores/fisiologia , MasculinoRESUMO
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.