Across sensory systems, a deprivation of peripheral input is associated with a compensatory increase in neural excitability at the level of sensory cortex. Commonly, this compensatory process overshoots the mark, resulting in hyperactivity along with perceptual hypersensitivity to sensory stimuli. Such observations have a long history in the auditory system: noise-induced damage to the cochlea is associated with a paradoxical cortical hyperactivity and perceptual abnormalities such as hyperacusis, an auditory disorder characterized by an increase in perceived loudness to moderately intense sounds. Although it is believed that cortical hyperactivity is a driving force behind perceptual hypersensitivity, a definitive link is yet unclear. This mentored training project will combine chronic behavioral, two-photon imaging, and optogenetics techniques in mice to understand the neural changes underlying the emergence of a behavioral hypersensitivity phenotype following a high frequency noise-induced hearing loss. Studies pursuant to Aim 1 will develop a two-alternative forced choice task that assesses loudness perception in head-fixed mice. Such a behavior provides two major advances: i) direct evaluation of perceptual hypersensitivity after noise exposure, and ii) the ability to do chronic imaging in behaving mice. Studies in Aim 2 will use chronic two-photon calcium imaging of auditory corticostriatal neurons, a defined cell type directly relevant to auditory-guided behavior. Imaging will take place in both passive and task-engaged conditions both to allow full characterization of frequency and intensity response changes across the tonotopic map and to enable direct comparison of neural activity changes with perceptual decision-making.
Aim 3 will test the hypothesis that inducing auditory corticostriatal hyperexcitability in unexposed control mice with healthy cochleae is sufficient to increase the probability of perceptually categorizing moderately intense sounds as loud. Corticostriatal neurons will be shifted in and out of hyperactive states using stabilized step function opsins to temporarily induce stable and reversible planes of hyperexcitability in normal, behaving mice. Altogether, this project will overcome previous technical limitations to gain a more complete understanding of the neural circuit pathology underlying auditory perceptual hypersensitivity. Beyond peripheral injury, sensory hypersensitivity is associated with other conditions such as aging and neurodevelopmental disorders including autism. Thus, insight from this project into the neural signatures of hyperactivity and behavioral hypersensitivity will prove valuable broadly for hearing impairment, other sensory disorders, and related neurological conditions.
Cortical hyperactivity and accompanying perceptual hypersensitivity are observed among a variety of conditions ranging from neurological disorders to peripheral deprivation or injury. Yet, despite the prevalence of sensory hypersensitivity in human populations, a deeper understanding of its neural signatures is lacking. The proposed training project would apply cutting-edge imaging and optogenetic manipulations of targeted cell types within the mouse auditory cortex to study the neural bases of hyperactivity and perceptual hypersensitivity following noise-induced cochlear damage.
