Inner hair cells (IHCs) are the primary sensory receptors of the auditory system. In the developing cochlea, IHCs receive efferent input that is thought to pattern their intrinsic spiking behavior. During the second postnatal week, IHCs lose their efferent contacts. In the mature cochlea, transduction currents and intrinsic basolateral potassium currents govern the receptor potential of IHCs, allowing them to accurately encode and transmit acoustic information. There is ultrastructural evidence, however, that efferent innervation returns to IHCs in mice suffering hearing loss. We will perform whole cell patch clamp recordings of IHCs from animals suffering age-related hearing loss in order to determine if functional efferent innervation does indeed return to IHCs. After characterizing the proportion of IHCs innervated at three ages (and levels of hearing impairment), we will identify the molecular components of these synapses. In order to determine the specific pathological factors underlying the formation of these synapses, we will selectively ablate outer hair cells (which are contacted by medial efferents) and Type 1 spiral ganglion neurons (which are contacted by lateral efferents) and test if these manipulations (in isolation or together) induce efferent innervation of IHCs. A number of peripheral factors have been implicated in hearing loss, including outer hair cell death, stereocilia damage, and afferent synaptic loss. Little attention hs been paid, however, to the role of efferent fibers in the damaged cochlea. Our preliminary data indicate that the efferents contacting IHCs in the damaged cochlea are functionally inhibitory. It is possible that efferent activity further exacerbates hearing impairment by reducing information transfer from the periphery to the central nervous system. On the other hand, efferent inhibition of IHCs might serve to protect afferent neurons from excitotoxic retraction. By characterizing these synapses and the specific cochlear pathology that underlies their formation, we are taking the first steps in understanding the efferent-IHC synapse's role in auditory processing. If we are able to induce efferent innervation of IHCs (via outer hair cell and/or spiral ganglia ablation), i may serve as a valuable model of synaptogenesis in the adult animal. The extent to which the nervous system responds to insults with synaptic formation is currently unknown, but our work suggests that such a process occurs in the cochlea. Of additional interest is the idea that the nervous system might respond to damage by assuming characteristics that are found during development, and the robust efferent-IHC innervation we observe recapitulates the developmental synaptic organization of the cochlea.
A mechanistic understanding of hearing loss requires a complete description of the damaged/aged cochlea. We have found that efferent neurons form synapses with inner hair cells in mice suffering age related hearing loss, and this research proposal aims to describe these synapses and identify pathological causes of efferent innervation of inner hair cells. The efferent-inner hair cell synapses found in mature animals closely resemble those described in the immature cochlea, suggesting that the hearing impaired cochlea takes on some characteristics of the developing cochlea.
| Zachary, Stephen Paul; Fuchs, Paul Albert (2015) Re-Emergent Inhibition of Cochlear Inner Hair Cells in a Mouse Model of Hearing Loss. J Neurosci 35:9701-6 |
