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Maladaptive cortico-amygdalar plasticity after noise-induced hearing loss

Award Number: K99DC022957
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Maladaptive cortico-amygdalar plasticity after noise-induced hearing loss - At the level of the auditory cortex (ACtx) neural representations of acoustic sound properties are modulated by extra-acoustic influences arising from other sensory modalities, internal state variables, past memories, and future predictions. Our effortless perceptual fusion of acoustic and extra-acoustic features likely reflects the dense bi-directional connectivity of the ACtx with higher-order cortical areas, the basal ganglia, the amygdala, and the subcortical auditory pathway. However, the multi-dimensional fusion of physical, emotional, and cognitive variables in sound perception is also vulnerable to neurodegenerative processes in the cochlea and brain linked to aging and noise exposure. For example, hearing disorders such as tinnitus and hyperacusis can be triggered by sensorineural degeneration in the cochlea, but the perceptual experience of these disorders often features extra-acoustic complaints featuring a generalized aversion, irritation, and discomfort to sound. This proposal will provide advanced mentored training to the Candidate focused on a research strategy with three Specific Aims. Aim 1 (K99) will leverage the unique strengths of two-photon calcium imaging to perform chronic tracking of genetically targeted ACtx neural ensembles before and after noise-induced high-frequency sensorineural hearing loss (SNHL). By separately recording from distinct cardinal classes of long-range ACtx projection neurons, we will test the hypothesis that corticoamygdalar (CAmy) neurons – more than inter- hemispheric or corticothalamic neurons – develop the strongest hyperactivity, hyper-responsivity, and hyper- synchrony after SNHL. Experiments in Aim 2 (R00) will leverage fiber-based bulk calcium recordings within the amygdala to contrast varying degrees of auditory hyper-responsivity in thalamo-amygdalar and CAMy afferent inputs after SNHL. We will then use single-unit recordings and optogenetics to test the hypothesis that neural hyperactivity, hyper-responsivity, and hyper-synchrony within the lateral and basolateral amygdala after SNHL can be largely reversed by optogenetic silencing of CAmy synaptic inputs. Aim 3 (R00) will expand these concepts to the behavioral domain by demonstrating poorly discriminative non-extinguishing auditory threat memories observed in mice with SNHL are causally linked to CAmy hyperactivity, such that directly causing CAmy hyperactivity in mice with normal hearing produces the over-generalized threat memory phenotype while silencing CAmy hyperactivity in mice with SNHL reinstates normal discriminative threat memory recall. Overall, the research and training plan will provide a bridge to an independent research career investigating the affective dimensions of hearing loss, with the ultimate goal of identifying therapeutic targets for common sensory disorders that have no widely effective therapies.


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 = $131,552 )
2026	2026	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	2	6/19/2026	NON-COMPETING CONTINUATION	$131,552
														Subtotal = $131,552

Issue Date FY: 2025 ( Subtotal = $131,408 )
2025	2025	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	1	6/5/2025	NEW	$131,408
														Subtotal = $131,408

Grand Total All Awards = $262,960

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Maladaptive cortico-amygdalar plasticity after noise-induced hearing loss

Award Number: K99DC022957

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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