This project will examine the cellular basis of signal transformations that regulate vestibular reflexes, using physiologic, anatomic and neuromodeling approaches. Granule cells of the cerebellar nodulus receive afferent mossy fiber projections which originate as direct inputs from primary vestibular afferents and as second order projections relayed via the brain stem vestibular nuclei. The signal transformations which occur at the synapses between first order mossy fiber projections to the nodulus represent a critical step in the cerebellar regulation of short and long-term multiplicative changes in vestibuloocular and vestibulocollic reflexes. However, no information is currently available regarding athe cellular basis of transmission at this key synapse. The goal of this project is to examine the biophysical basis of synaptic integration at this synapse using a multidisciplinary approach. Primary vestibular fibers will be anatomically characterized by anterograde labeling and immunocytochemistry with in vivo experiments. The physiological and pharmacological properties of transmission between first order vestibular sensory afferents and granule cells in the cerebellar nodulus will be examined using an in vitro mouse brain slice preparation in which this pathway can be selectively activated. The properties of transmission will be examined using both whole-cell and excised patch-clamp recording of granule cells. The kinetics of glutamate receptor-channels mediating the synaptic conductances, and their modulation by metabotropic glutamate receptors, will be examined. These data will then be utilized to develop biophysical models of synaptic processing of vestibular sensory input using representations which incorporate the dynamics of both ligand- and voltage- gated conductances in granule cells. In other brain regions, the temporal dynamics of synaptic transmission has been shown to be closely correlated with the kinetic properties of the specific glutamate receptor subtypes expressed at individual synapses. The ultrastructural localization and identity of these subtypes at the synapse will be obtained by electron microscopic immunolocalization using subtype-specific antibodies. These data will be correlated with those obtained from patch-clamp experiments and computer modeling to develop a comprehensive picture of the temporal dynamics of processing of the vestibular sensory inputs to the cerebellum. This synapse is a key neuronal substrate for the adaptive regulation of vestibular reflexes in brain. This information derived from normal mice will provide the foundation for the future utilization of mutant and knockout mice with relevant genetic defects and of transgenic mice with intrinsically labeled neuronal populations.
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