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Plasticity of auditory cortex microglia and perineuronal nets after hearing loss

Award Number: K08DC022004
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/06/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Plasticity of auditory cortex microglia and perineuronal nets after hearing loss - PROJECT SUMMARY/ABSTRACT Suprathreshold hearing disorders like hyperacusis are marked by dysfunction of fast-spiking Parvalbumin positive interneuron (PVI) signaling and heightened cortical activity following peripheral sensorineural hearing loss (SNHL). After cochlear injury, a rapid loss of interneuron-mediated inhibition in the auditory cortex occurs, resulting in heightened spontaneous firing rates in cortical principal neurons, leading to hyper-synchrony and hyper-responsiveness to sound. The extent of PVI dysfunction can predict auditory plasticity and cortical response recovery after cochlear damage. While many attribute PVI hypofunction solely to neuronal dysfunction, recent studies suggest non- neural mechanisms may also play a role. Perineuronal nets (PNNs) are extracellular structures crucial for PVI function, regulating synaptic inputs, neuronal activity, and intrinsic excitability. PNNs tighten around PVI during development, limiting plasticity, but their disruption can reopen a plasticity window. Noise exposure degrades PNNs and reduces PV expression in PVI, increasing cortical excitability akin to hyperacusis. PNN degradation may result from noise-induced trauma to PVIs or an inflammatory response involving activated microglia. Microglia, primarily associated with immune responses, also regulate homeostasis, synaptic connectivity, and neural activity. In CNS diseases, activated microglia can have detrimental effects, such as excessive synaptic pruning, neuroinflammation, and alterations in neuronal excitability. However, they can also promote regeneration and cellular remodeling. The hypothesis underlying this research suggests that PNNs and microglia play critical roles in PV hypofunction and may be early factors in central gain disorders. The study aims to: 1) Investigate chronic PNN degradation in deafferented regions of the auditory cortex after cochlear SNHL, alongside an increase in activated microglia. 2) Examine the impact of regional microglia elimination shortly before SNHL on central gain and hyperacusis symptoms. 3) Explore targeted activation of PVI, potentially normalizing PNN and microglia expression, and reversing loudness hyperacusis symptoms. In summary, suprathreshold hearing disorders like hyperacusis are associated with PVI dysfunction leading to cortical hyperexcitability following SNHL. PNNs and microglia are proposed as crucial contributors to PVI hypofunction and central gain disorders, and this research aims to uncover their roles and potential therapeutic avenues for restoring normal auditory function.


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 = $194,400 )
2026	2026	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	3	5/25/2026	NON-COMPETING CONTINUATION	$194,400
														Subtotal = $194,400

Issue Date FY: 2025 ( Subtotal = $194,400 )
2025	2025	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	2	5/22/2025	NON-COMPETING CONTINUATION	$194,400
														Subtotal = $194,400

Issue Date FY: 2024 ( Subtotal = $194,400 )
2024	2024	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	1	6/6/2024	NEW	$194,400
														Subtotal = $194,400

Grand Total All Awards = $583,200

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Plasticity of auditory cortex microglia and perineuronal nets after hearing loss

Award Number: K08DC022004

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/06/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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