Cholinergic Modulation of Cochlear Plasticity

Project Summary Adult outer hair cells (OHCs) modulate cochlear gain in the mammalian cochlea by amplifying mechanical vibrations. Medial olivocochlear (MOC) efferent neurons originating in the brainstem modulate this gain by hyperpolarizing OHCs via α9α10 cholinergic receptors (nAChRs) coupled to calcium-activated potassium channels, forming a negative feedback loop. The MOC system improves neural representation of transient signals in noise, protects the ear from overexposure to loud sounds, and mitigates age-related hearing loss from accrued ambient sound exposures over time. Additionally, transient efferent inhibition of inner hair cells (IHCs) during postnatal development, before hearing onset, contributes to functional maturation of the peripheral and central auditory pathways. Intriguingly, age-related re-innervation of IHCs by efferent synapses appears to recapitulate this developmental stage. Using novel genetically modified mouse models, including mice with genetically enhanced or diminished MOC activity and fluorescently tagged postsynaptic receptors, our prior work has delineated fundamental synaptic mechanisms of the MOC system, characterized developmental consequences of genetic manipulation of MOC activity on the central auditory system, identified its protective role against hearing dysfunction, and uncovered structural and functional plasticity in MOC neurons associated with hearing loss and age. Most importantly, our mouse models of enhanced MOC feedback show protection from damage produced by loud sounds and delayed progression of age-related hearing loss, offering a potential target for clinical intervention. In the next phase of our work, we propose to advance the mechanistic knowledge of α9α10 receptor-mediated cochlear inhibition and expand its translational potential by pursuing three Specific Aims: 1) engineering olivocochlear inhibition to protect against hearing dysfunction; 2) investigating efferent re-innervation after noise exposure and during aging; 3) characterizing the effects of IHC-MOC manipulations during postnatal development. We will use cutting-edge gene therapy via viral injection into the inner ear to boost MOC function in adult mice, track changes in expression of HA-tagged α9α10 nAChRs with noise exposure and noise-accelerated cochlear aging, and track development of auditory function in gain-of-function nAChR models exposed to different acoustic environments. We will use detailed physiological, behavioral, and anatomical analyses to enhance our understanding of cochlear efferent function and further elucidate preclinical manipulations of efferent activity as potential therapeutic targets to prevent and/or delay hearing loss. Our combined expertise in physiology, anatomy, and behavior brings a powerful integrative approach to studying the MOC system.