The equilibrium receptors of the inner ear detect the position and motion of the body in space. Abnormalities in the receptors or central pathways of the vestibular system can result in oculomotor and postural disturbances. Despite the fact that a great deal of information is available concerning the anatomical and physiological organization, relatively little data exists concerning the neurochemical organization of the vestibular system in general and of the vestibular nuclear complex in particular. The long range goals of the present proposal are to: 1) define the major transmitters and receptors associated with the mammalian vestibular nuclei; 2) determine the major transmitters associated with vestibulocerebellar projections; and 3) ascertain which transmitters are affected by peripheral vestibular lesions or stimulation. These goals will be pursued by the following specific aims: 1) Analyze the presence and distribution of the immunoreactivity for glutamate, aspartate, GABA and their synthesizing enzymes together with glycine, enkephalin and dynorphin and the mRNA expression for these synthesizing enzymes and these opioid peptides In the vestibular complex; 2) Determine which neurotransmitters are associated with vestibulocerebellar projections using immunocytochemistry in combination with retrograde and anterograde tracing procedures; 3) Quantity the location of glycine, GABA-A and excitatory amino acid binding sites in the vestibular nuclei and determine whether they are associated with vestibulocerebellar neurons using in vitro receptor binding procedures alone and in combination with the suicide transport agent, doxorubicin. These studies will be complemented by experiments employing a new combined retrograde transport-in situ hybridization procedure to determine which receptor mRNAs are expressed in vestibulocerebellar neurons; 4) Identify the specific neurotransmitters that interact with vestibulocerebellar neurons by intracellularly injecting Lucifer yellow into retrogradely labeled neurons and then immunochemically localizing certain transmitters The resulting double-labeled sections will then be analyzed using both confocal scanning laser microscopy and transmission electron microscopy; 5) Study the changes in neurotransmitter mRNAs, binding sites and/or release following peripheral vestibular lesions and stimulation. This will be accomplished by using in situ hybridization, receptor binding and in vivo microdialysis techniques. Identification of the major neurotransmitters and receptors associated with the vestibular nuclear complex in combination with data generated concerning which transmitters are affected by vestibular stimulation or damage will provide new information which might facilitate the development of better therapeutic approaches to vestibular disorders.
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