Multiple lines of evidence suggest that acoustic overexposure results in cochlear damage and decreased inhibition in auditory centers, contributing to deficits in temporal processing, tinnitus, and hyperacusis. Previous attempts to correct this hyper-excitable state have focused on increasing GABAergic inhibitory tone systemically, with some success in providing tinnitus relief. However, the side effect profile of these drugs impose constraints on the dose, duration, and safety of use. A more precise treatment that locally increases inhibition in auditory nuclei could potentially treat the underlying pathology while minimizing off-target side effects. The inferior colliculus (IC), a major subcortical integration center of the central auditory pathway, is a particularly apt target to explore the effects of local increases in inhibition, as it plays an important role in mediating some acoustic behaviors (such as gap detection and pre-pulse inhibition) and demonstrates hyper- excitable response properties following acoustic overexposure. A potential approach to increase inhibition locally in the IC is through transplantation of cells from the medial ganglionic eminence (MGE), the birthplace of eventual cortical inhibitory interneurons. While naturally destined for the cerebral cortex, transplanted MGE cells have been shown to survive, integrate, and increase the number of inhibitory events in non-cortical circuits, such as the spinal cord. As a first step toward understanding the potential role local increases in inhibition may have in mitigating the effects of acoustic exposure, I propose to test the hypothesis that transplanted MGE cells will functionally integrate into IC circuits in adult CBA/CaJ mice, mitigating the reduced inhibition seen in noise exposed subjects.
Three specific aims are proposed: 1) Characterize the migration and differentiation of MGE cells transplanted into the IC of nave and noise exposed mice. 2) Determine how transplantation of MGE cells affects auditory behavior in adult CBA/CaJ mice. 3) Determine the effects of MGE cell transplantation on spontaneous and sound-evoked responses of IC neurons in vivo. These experiments represent a novel application of MGE cell transplantation and will improve our understanding of the pathological inhibition that might underlie the formation and persistence of auditory pathologies such as tinnitus and hyperacusis, and in the long run may lead to the development of novel treatment strategies.
Acoustic overexposure not only increases hearing thresholds but can result in complex auditory pathologies that can have a detrimental effect on quality of life and account for a major source of financial burden. Current treatment options for deficits resulting from acoustic overexposure provide symptomatic relief in select cases but are often inadequate and are limited by the fact that the underlying neural mechanisms are not well understood. The proposed studies will investigate how local changes in the excitatory/inhibitory balance in the inferior colliculus, a critical site of auditory processing in the midbrain, may contribute to the formation and persistence of auditory pathologies, such as tinnitus and hyperacusis, and in the long run may lead to the development of novel treatment strategies.
