EARLY BIOCHEMICAL SIGNALS AFTER VESTIBULAR INJURY

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Abrupt dysfunction of one vestibular labyrinth or nerve produces a syndrome that includes acute vertigo, postural asymmetry and instability, nystagmus and autonomic manifestations. These signs resolve over a period of days to weeks, in a process that has been termed vestibular compensation. Although previous studies implicate a variety of neurotransmitter mechanisms in the compensatory process, the intracellular events that produce vestibular compensation remain obscure. The proposed studies are based upon initial results indicating that the expression of a particular class of intracellular signal, protein kinase C (PKC), changes in a regionally specific manner in the vestibular nuclei and flocculonodular lobe within 6 hours of unilateral labyrinthectomy. The proposed experiments will extend these findings by a detailed examination of the regional expression of enzymes involved with intracellular signalling substrates (protein kinase C (PKC), phospholipase C (PLC; inositol lipid system) and phospholipase A2 )PLA2: arachidonic acid path) in the cerebellar cortex, vestibular nuclei and inferior olive during the early stages of vestibular compensation in rats (6 hours-8 days). These studies will provide insights into early intracellular signalling events during vestibular compensation and the anatomical distribution of neurons involved in these compensatory responses. The first experiment will use immunohistochemistry, Western blots, enzyme activity assays and Northern blots to test the hypothesis that vestibular compensation is accompanied by regionally specific changes in expression of six PKC isoforms, PLA2 and PLC by inferior olive neurons, vestibular nucleus neurons and Purkinje cells in the cerebellar flocculo-nodular lobe, paramedian lobule and vermal regions of the posterior and anterior lobes. The second experiment will test the hypothesis that an intact climbing fiber pathway is essential for producing regionally specific changes in Purkinje cell PKCs, PLC and PLA2 expression after unilateral labyrinthectomy. These studies will test the prediction that destruction of the inferior olive with 3-actylpyridine or neuropeptide transmitter ablation with antisense oligonucleotide injections in the inferior olive will retard compensation and will block regionally specific changes in expression of PKC isoforms, PLA2 and PLC.