Neuronal control of cochlear stress responses - Project Summary Animals, including humans, navigate through a noisy environment that can damage the ear and elicit whole body changes in physiology and emotional state. The response to stressors such as noise is important for survival, for instance by altering gain for improved detection of salient stimuli. However, excessive noise has dire consequences, such as death of hair cells or neurons and their synapses. It is therefore essential to have a balanced response to stress that is appropriate for the internal state of the animal. The goal of this project is to study how neurons outside of the cochlea work together to protect both the cochlea and the animal from environmental stressors. We hypothesize that stress recruits two parallel sets of efferent inputs to the cochlea: the lateral olivocochlear neurons (LOCs) and the inner ear sympathetic neurons (IESNs). LOC axons project from the brainstem to the organ of Corti, where they terminate on a variety of SGN subtypes across many frequencies. IESNs housed in the stellate ganglion innervate the cochlear vasculature and regulate cochlear blood flow, consistent with the sympathetic nervous system’s role in the fight-or-flight response. In addition, IESNs in the superior cervical ganglion extend axons through the osseous spiral lamina, intermingling with afferent and efferent fibers here and terminating close to the unmyelinated endings of the SGN peripheral processes. Although a role in stress response has long been proposed, we know very little about the impact of LOCs and IESNs on cochlear function or resilience, due in large part to the inability to manipulate either population selectively. In preliminary studies, we characterized the molecular and anatomical properties of LOCs and showed that they induce neuropeptides in response to noise. In addition, using genetic tools that we established, we showed that mice lacking LOCs are more vulnerable noise-induced hearing loss than control littermates, providing compelling evidence for a protective role in the cochlea. In parallel, we showed that IESN axons contain pre-synaptic puncta that are apposed to afferent and efferent fibers, as well as cochlear macrophages. Based on these observations and the known importance of neuropeptides for neuroimmune responses in other systems, we propose that stressful stimuli activate LOCs and IESNs, which cooperate to alter both auditory circuit activity, via their interactions with each other and the SGNs, and the immune response, with long-lasting effects on cochlear function. To test this idea, we will use mouse genetics, viral tracing methods, slice electrophysiology, modern in vivo recording approaches, single cell RNA-sequencing, and in vivo assays to characterize LOC responses to noise and other stressors, to map the molecular and anatomical properties of IESNs, and to investigate how LOCs and IESNs impact the immune system and hence cochlear health.
