Auditory encoding, perception, and plasticity in the deaf adult brain following inner ear gene therapy

About This Grant

Hearing – the perceptual awareness of sound – arises from the tandem operation of the ear and brain. This project introduces a multidisciplinary approach to determine how the peripheral and central auditory pathway of congenitally deaf mice are transformed when cochlear afferent signaling is switched on in adulthood. We initiate acoustic hearing in adult mice using AAV-based otoferlin gene therapy (OGT) – the only form of inner ear gene therapy that has been widely and successfully documented in human clinical trials. Our preliminary studies show that within weeks of OGT, otoferlin-deficient Deaf5 mice can perform complex hearing tasks (e.g., detection in noise, phoneme discrimination) with the same accuracy as age-matched controls, despite having no developmental hearing experience. Although cochlear afferent synapses, auditory nerve response amplitudes, and involuntary acoustic reflexes are markedly reduced in deaf adults receiving OGT, neural decoding of sound features at the level of the auditory cortex (ACtx) is virtually normal. Robust cortical sound responses emerge within 48 hours of OGT, leading the emergence of sound-evoked brainstem and auditory nerve electrical potentials by as much as one week. These findings challenge long-standing critical period dogma and invite a deeper investigation into how adult auditory system plasticity both succeeds and fails to overwrite the effects of prolonged developmental deafness. Aim 1a will use simultaneous recordings from ACtx and inferior colliculus single-unit ensembles as adult-treated Deaf5 mice perform a multimodal detection task. We predict that subcortical ensembles will exhibit a slow, incomplete maturation of sensory coding, whereas ACtx ensembles will initially decode acoustic features before converting to a representation of perceptual outcomes as mice acquire behavioral sound awareness. Aim 1b will test the hypothesis that adult- onset hearing creates an abnormal dependence on cortical sound processing, even for basic detection behaviors. Aim 2 will track ACtx excitatory neuron dynamics with chronic two-photon calcium imaging before and after OGT. Aim 2a will use a strong inference design to determine whether repeated exposure to fixed frequency tone pips at adult hearing onset is associated with an age-appropriate plasticity (habituation) or an experience-appropriate plasticity (tonotopic map expansion). Aim2b will test the hypothesis that automatic and learned sensorimotor integration processes that suppress predictable self-generated sounds will be irreversibly disrupted in mice with adult-onset hearing. Aim 3 will combine chronic microwire recordings of sound-evoked activity arising from the auditory nerve, brainstem, midbrain, and cortex with post-mortem reconstructions of morphological plasticity at the primary afferent synapse using light and 3D electron microscopy. By comparing OGT initiated at 6 versus 35 weeks of age, we will isolate peripheral and central factors that constrain the rate and extent of auditory plasticity in older adults. Collectively, these studies will reveal plasticity processes across the auditory neuroaxis that support a surprisingly rapid and complete initiation of hearing in adulthood.