RECOVERY FOLLOWING DAMAGE TO THE VESTIBULAR SYSTEM

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The partial recovery of function that occurs following a unilateral loss of vestibular function is termed "vestibular compensation." This remarkable example of central nervous system plasticity occurs within days. Although the functional extent of compensation has frequently been overestimated, its most prominent feature, the elimination of vestibular nystagmus appears to depend on the restoration of symmetrical activity of vestibular secondary afferents located bilaterally in the vestibular nuclei. This restoration of symmetrical discharge need not depend on complicated neuronal network properties. Rather vestibular compensation may reflect activity-dependent neuronal self-regulation. If secondary vestibular afferent activity is rendered asymmetrical, then eventually symmetry could be established by activity-dependent expression of synaptic transporters or receptors; molecules that regulate the postsynaptic sensitivity for many transmitter systems. The proposed research has the objective of understanding the subcellular mechanisms that contribute to "compensation." These same mechanisms might also account for the vestibular plasticity observed under normal stimulus conditions. This proposal will: 1) Determine the subcellular mechanisms that are correlated with recovery of function following a unilateral labyrinthectomy in both rats and rabbits. We will use immunocytochemical and oligonucleotide probes for specific synaptic receptors , transporters , growth associated protein-43 (GAP-43), and the subcellular messenger, protein kinase C (PKC). We will investigate the primary afferent vestibular afferent projections to the vestibular nuclei and cerebellar nodulus, as well as secondary vestibular pathways to the inferior olive and nucleus reticularis gigantocellularis. 2) Distinguish experimentally between mechanisms triggered by degeneration and regeneration of the vestibular nerve as opposed to mechanisms that are triggered by increases and decreases in neural activity. This can be achieved by comparing the effects induced by unilateral labyrinthectomy with the effects produced by a unilateral perilymphatic injection of an ototoxic aminoglycoside, such as streptomycin. The streptomycin injection would leave vestibular primary afferents intact. We will also compare the effects of unilateral labyrinthectomy with effects that are induced by long-term optokinetic stimulation. Such stimulation induces a nystagmus that is equivalent in both severity and duration to the nystagmus induced by unilateral labyrinthectomy. 3) Develop cDNA libraries of the cerebellum, vestibular complex, Scarpa's ganglion and inferior olive of the rabbit. One of the technical difficulties in trying to investigate transmitter-specific pathways using either oligonucleotide in any particular species is that the genes of interest may have been cloned for a different species (usually the rat or mouse). However, the functional physiology of the vestibular system is best known for the rabbit brain. The approach that we propose would focus are histochemical, molecular and biochemical techniques on the species for which physiological function is most easily investigated. The proposed experiments will lead to a better understanding of the important molecular participants in vestibular compensation.