RECOVERY OF DAMAGE TO THE VESTIBULAR-AUDITORY SYSTEM

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Partial recovery of function following a unilateral labyrinthectomy (UL), termed "vestibular compensation," has served as a model for investigations of subcellular investigations of central nervous system plasticity. Previous studies of compensation have "targeted" particular genes for study, using immunohistochemical and hybridization histochemical probes. Rather than target a particular genes, we propose to use the technique of "differential display" (DD-PCR) to screen gene products isolated from vestibular-and auditory-related regions the rabbit brain. Unlike the "targeted gene" approach, DD-PCR screens all differentially transcribed gene products. First, we will screen Scarpa's ganglion, medial vestibular nucleus, nodulus and inferior colliculus following UL. Since the primary vestibular-auditory afferent projects to the nodules and the DCN are unilateral, the structures on the side of the UL will receive a decreased primary afferent input and those on the intact side will receive a normal input. Second, we will use oligonucleotide probes identified by DD-PCR to reveal the tissue distribution and the time course of changes in tissue distribution of different mRNAs in animals that have received a UL. Third, promising molecules will be studied under more physiological conditions. Maintained static tilt will be used to provide asymmetric vestibular stimulation. Unilateral removal of the ossicular chain will be used to create asymmetric acoustic stimulation. Horizontal optokinetic stimulation will be used to provide asymmetric visual climbing fiber inputs to the nodulus. The optokinetic inputs will allow us to screen molecules that are differential expressed in the same structure, the nodulus, under stimulus conditions mediate db two different afferent pathways. Fourth, in analogous screening experiment at the protein level we will use two-dimensional electrophoresis to screen for proteins that are differential expressed following UL. Fifth, some molecules may participate in compensation or plasticity merely by changing their distribution within a cell rather than by changing expression. We will examine such a molecule, PKC-delta, in "activated" Purkinje cells using combined physiological, immunohistochemical and ultrastructural methods. Gene products uncovered by these experiments might play a role in both vestibular and auditory adaptation and provide important clues for the pharmacological treatment of central neural disorders such as motion sickness and tinnitus.