Cortical plasticity mediates behavioral hypersensitivity following noise-induced sensorineural hearing loss

Abstract

The sensory periphery is specialized to transduce environmental stimuli into interpretable signals carried up afferent sensory pathways. It would follow that damage to these sensory receptor cells would result in a loss of sensitivity, yet often the most debilitating consequences of peripheral afferent injury come from a paradoxical hypersensitivity to sensory stimuli. Perceptual hypersensitivity is thought to arise from a compensatory plasticity process in sensory regions of the neocortex, but the definitive experiments have yet to be performed. The auditory system is ideally suited for this question given the precise control of stimulus delivery and the well-documented methods for cochlear damage. Here we characterize the development of hyperexcitability and hyper-responsivity in the auditory cortex of mice following sensorineural hearing loss such that these changes can be accurately compared to behavioral measures. Specifically, we performed chronic two-photon calcium imaging to document the single-neuron changes across the topographic map of primary auditory cortex following noise-induced sensorineural hearing loss. We developed Go/NoGo acoustic and optogenetic detection tasks to assess evidence of perceptual hypersensitivity, and we found daily location-specific and stimulus-specific changes in neural activity that matched resulting behavioral changes after hearing loss. Variability in single neuron hyperactivity could be predicted by pre-exposure properties indicative of local inhibitory network strength. We then expanded upon our behavioral measurements by developing a two-alternative forced-choice classification task that allowed direct assessment of loudness perception and sensory hypersensitivity. Following noise-induced sensorineural hearing loss, mice reported that sounds of a fixed intensity were louder than they were at baseline, demonstrating loudness hypersensitivity. To test the cortical dependency of task performance, we optogenetically activated parvalbumin positive interneurons in auditory cortex, which did not affect sound detection but biased mice towards soft reporting and thus demonstrated a bi-directional effect on loudness perception dependent on auditory cortical excitability. The link between cortical plasticity and sensory hypersensitivity is ubiquitous across sensory systems, aging, and related neurological conditions. Collectively, these findings identify neural circuit pathology underlying perceptual hypersensitivity. Furthermore, they pinpoint manipulations of cortical excitability and inhibitory strength as a locus of therapeutic potential in sensory hypersensitivity disorders.