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

Award Number: R01DC023999
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $701,848 )
2026	2026	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	1	7/14/2026	NEW	$701,848
														Subtotal = $701,848

Grand Total All Awards = $701,848

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

Award Number: R01DC023999

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/10/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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