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Using nicotine to reverse age-related auditory processing deficits

Award Number: R01AG067073
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Using nicotine to reverse age-related auditory processing deficits - Age-related decline in central auditory function significantly affects quality of life in the elderly, with impaired speech perception leading to increased risk for depression, social isolation and cognitive decline. A 2017 Lancet Commission report cites hearing loss as the largest modifiable risk factor for developing cognitive decline, exceeding smoking, high blood pressure, lack of exercise and social isolation. Remarkably, a 2019 large-scale study found that even mild hearing loss, i.e., still within the normal range, produced an even closer association with cognitive decline. Currently, there is no effective therapy for age-related central auditory decline—hearing aids only address audibility—and no drug treatment. Ideally, a combination of drug treatment with hearing aids and behavioral training could restore auditory function, but the development of pharmacological treatments requires a better understanding of the mechanisms by which candidate drugs improve hearing. The goals of this proposal are to develop biomarkers of altered auditory processing in aging mice and humans, and using these biomarkers, to test the hypothesis that nicotine can normalize these age-related central auditory deficits. Because nicotine enhances cortical and cognitive function, pharmaceutical companies are developing nicotine-like drugs to target cognitive deficits in aging. These drugs are non-addictive (unlike nicotine in tobacco), yet nicotine also is non-addictive when given topically or orally. However, its clinical benefits have not been exploited except as an aid to stop smoking. We hypothesize that: 1) acute nicotine compensates for the age-related decline in inhibition by exciting the remaining inhibitory neurons; 2) chronic nicotine exposure (CNE) upregulates nicotinic acetylcholine receptors (nAChRs); and, as a result, 3) acute nicotine and/or CNE will reduce or reverse the age-related auditory decline. We will test these hypotheses in both mouse and human at the level of cells (mouse in vitro brain slice), neural systems (mouse in vivo physiology; human brain imaging and EEG) and behavior (human psychoacoustics). Aim 1 will determine in mouse whether age-related decline in auditory spectrotemporal processing is reversed by acute nicotine or CNE, and characterize the associated cellular mechanisms. Aim 2 will identify, in humans, age-related changes in receptive field properties in auditory cortex using novel fMRI techniques and determine if nicotine reverses these changes using psychoacoustics, fMRI and EEG. This project features a multifaceted, parallel approach in mouse and human. Each Aim will: 1) examine auditory processing at multiple adult ages; 2) use similar acoustic stimuli in both species, accounting for species differences in hearing, to target common mechanisms; 3) test the effects of nicotine. A successful outcome will promote an integrated understanding across levels, from cellular mechanisms to perception, and facilitate translation of nicotine-based therapeutic treatments to clinical populations.


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: 2025 ( Subtotal = $543,878 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	5	3/19/2025	NON-COMPETING CONTINUATION	$499,478
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	001	5	6/10/2025	NON-COMPETING CONTINUATION	$44,400
														Subtotal = $543,878

Issue Date FY: 2024 ( Subtotal = $568,997 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	001	4	6/4/2024	NON-COMPETING CONTINUATION	$56,899
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	002	4	7/4/2024	NON-COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	4	12/21/2023	NON-COMPETING CONTINUATION	$512,098
														Subtotal = $568,997

Issue Date FY: 2023 ( Subtotal = $581,628 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	002	3	1/18/2023	NON-COMPETING CONTINUATION	$581,628
2023	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	2	10/21/2022	NON-COMPETING CONTINUATION	$0
2023	2022	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	001	2	1/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $581,628

Issue Date FY: 2022 ( Subtotal = $600,705 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	2	12/22/2021	NON-COMPETING CONTINUATION	$540,634
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	001	2	4/26/2022	NON-COMPETING CONTINUATION	$60,071
														Subtotal = $600,705

Issue Date FY: 2021 ( Subtotal = $640,473 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	1	12/17/2020	NEW	$640,473
														Subtotal = $640,473

Grand Total All Awards = $2,935,681

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Using nicotine to reverse age-related auditory processing deficits

Award Number: R01AG067073

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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