CLASSIC AND NOVEL VESTIBULAR NEUROTRANSMITTERS

Mount Sinai School Of Medicine Of Cuny, New York NY

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Abstract

The goal of the proposed research is to identify the neurons and neuronal circuits in the vestibular nuclei and nucleus prepositus hypoglossi that utilize nitric oxide (NO) for intercellular signaling of information related to excitatory amino acid neurotransmission. This objective will be achieved using histochemical and immunocytochemical approaches to localize NO-producing neurons, characterize their fine morphology, identify the somatodendritic distributions of their glutamatergic afferents, visualize the associated NMDA and AMPA receptor subunits, and quantify the subcellular distributions of these receptors. This will be done in adult rabbits and rats, in rabbits and rats during early postnatal development, and in rabbits during gain adaptation of the vestibulo-ocular reflex (VOR) and habituation of its time constant. NO-producing neurons will be identified and studied using three independent methodologies: i) immunocytochemistry employing polyclonal antibodies directed against neuronal NO synthase (nNOS), which oxidizes L-arginine yielding equimolar amounts of NO and L-citrulline, ii) immunocytochemistry employing monoclonal antibodies directed against L- citrulline which, unlike NO, can be fixed in situ by perfusion and therefore can serve as an immunocytochemical marker for nNOS activity, and iii) histochemistry based on the nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) reaction, which can be reliably utilized as a histochemical marker for nNOS under proper tissue fixation conditions. Immunocytochemical techniques will be employed concomitantly to visualize glutamate, NMDA receptors and AMPA receptors in the same tissues, since a major stimulus for NO formation is the activation of ionotropic glutamate receptors. We propose to conduct experiments identifying these markers, in order to characterize the role of NO in the central vestibular system, particularly in mediating signals related to spatial orientation. This work will yield basic neuroanatomic, neurotransmitter and receptor information about the central vestibular system. In addition, the studies are designed to provide insight into the postnatal morphologic development of the vestibular system. Lastly, this research will provide anatomical data defining several of the morphologic and neurotransmission-related correlates of central vestibular adaptation and habituation.