Investigations into the mouse olivocochlear system

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DESCRIPTION (provided by applicant): Corticotropin releasing hormone (CRH) receptors, and urocortin, a member of the CRH family of peptides, has recently been discovered expressed in outer hair cells and olivocochlear terminals, respectively. While analysis of the role played by urocorUn, the only known ligand expressed in the inner ear capable of activating the CRH receptors, has been analyzed using urocortin deficient mice, nothing is known of the developmental expression pattern or role of the CRH receptors in the inner ear. The CRH receptors are G protein coupled receptors, and stimulate the cAMP second messenger-signaling cascade. We hypothesize that activation of the CRH receptors may represent one phenomenon underlying protection from noise induced hearing loss. The mechanisms of action may include phosphorylation and inactivation of the sK2 calcium-activated apamin-sensitive potassium channel. In order to further analyze the morphological aspects of the CRH system in the cochlea, its functional role in hearing and protection from noise induced hearing loss, and finally, to assess the cellular mechanisms of action associated with activation of the CRH receptors, three specific aims are proposed. First, we will establish the developmental and adult expression pattern of the CRH receptors in the inner ear. Successful completion of the experiments of this specific aim will establish the precise identity of the cells within the inner ear that express the CRH receptors, and identify the postsynaptic elements of the urocortin immunopositive fibers at the ultra structural level. Second, we will establish the functional roles CRH plays in hearing, and whether they participate in protection of the inner ear from noise induced hearing loss. This aim will be accomplished using mice that lack the gene for either the type 1 or the type 2 CRH receptor, or that lack both. Finally, we will use these mice to establish whether there are alterations in cAMP induced phosphorylation of targets in the outer hair cells following CRH receptors gene ablation. Success in this aim will allow us to identify individual proteins phosphorylated due to activation of the CRH receptors, as well as their role in modulating normal olivocochlear synaptic activity. This will functionally link the urocortin hormone/CRH receptor and classical ACh neurotransmitter systems together in a unified model explaining inner ear based protection from noise induced hearing loss.