All hair cell systems, including lateral-line organs, vestibular organs and the cochlea, contain an efferent innervations, originating in the brainstem and projecting to the hair cells and/or neural elements in the sensory epithelium. In the mammalian cochlea, this efferent system originates in the superior olivary complex and has been called the olivocochlear (OC) pathway and consists of a medial (MOC) and lateral (LOC) component. Cochlear efferent is likely to serve two functions: protection from acoustic over stimulation and enhancement of sound recognition in the presence of background noises. In the last project period, we determined that the MOC efferent could protect the cochlea from acoustic over stimulation working through the newly discovered alpha 9/10 nACh receptor complex. In this next project period, we will focus on the LOC efferent fibers that contain calcitonin gene-related peptide (CGRP). We determined that the loss of CGRP in knockout mice reduced sound-evoked activity of the cochlear nerve, which would then cause a reduction in the dynamic range of sound perception. However there are several CGRP-ergic neuronal systems in hair cell organs: the efferent as well as pathways innervating the vasculature, which could have contributed to the auditory phenotype. Our goal is to determine the molecular mechanism by which CGRP released from efferent fibers influences neuronal afferents. In these aims we will (1) determine effect of CGRP receptor signaling on sound-evoked activity; (2) determine biochemical time course for CGRP receptor signaling; (3) determine physiological target cells for CGRP receptor signaling. We will use adenoviral gene transfer, DPOAE, ABR, and CAP testing for auditory function, immunohistochemisty, coimmunoprecipitation, biolistic transfection, and FRET imaging to carry out these aims. Information gained from these studies will provide direct assessment of the molecular mechanisms used by the CGRP efferent feedback pathway to enhance sound-evoked activity in the cochlear nerve. [unreadable] [unreadable] [unreadable]