The long-range goal of this research is to understand how cellular and molecular mechanisms operate in the context of neuronal circuitry to mediate the normal performance and adaptive plasticity of the vestibulo- ocular reflex (VOR). The VOR prevents blurred vision during self-motion by producing eye movements that precisely compensate for motion of the head. Neuronal m3echanisms of plasticity enable the COR to perform accurately in the face of development, trauma, and disease. Although the contributions of identified classes of neurons to signal transformations and plasticity have been elucidated, little is understood about the cellular mechanisms that underlie the day-to-day performance and adaptive capabilities of the VOR. The objective of the proposed research is to elucidate how intrinsic cellular mechanisms control the firing properties of brainstem neurons that are critical for ensuring image stability during head movement. In particular, the studies aim to identify the role of distinct sources of intracellular calcium in regulating the firing properties of identified classes of neurons in the medial vestibular nucleus (MVN) and nucleus prepositus hypoglossi nuclei (NPH). The dynamic properties of spike generation (the transformation from neuronal inputs into time-varying patterns of action potentials) will be examined in NPH and MVN neurons recorded intracellularly in living brainstem slices. Specific pharmacological agonists and antagonists of voltage-sensitive calcium channels, intracellular calcium release mechanisms, and NMDA and metabotropic glutamate receptors will be used to assess how the spontaneous firing rate and the gain and dynamics of spike generation are regulated by calcium-dependent mechanisms. The correspondence between neurons recorded in vitro and cell classes that have been identified automatically and physiologically in vivo will be determined by labeling neurons intracellularly with dye, targeting neurons for recording that have been retrogradely labeled from the cerebellar flocculus and abducens nucleus, and activating synaptic inputs from the cerebellum and vestibular nerve. These studies will provide foundations for targeted investigations of the molecular mechanisms that underlie vestibulo-ocular reflex plasticity as well as for pharmacological treatments for oculomotor disorders that cause nystagmus.
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