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Longitudinal imaging of prefrontal cholinergic dynamics and cognitive flexibility in an Alzheimer's model

Award Number: R01AG102720
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Longitudinal imaging of prefrontal cholinergic dynamics and cognitive flexibility in an Alzheimer's model - Project Summary/Abstract Executive dysfunction emerges years before dementia in Alzheimer's disease (AD) and maps to prefrontal-cortex (PFC) circuits that depend critically on acetylcholine (ACh). Sparse cortical cholinergic interneurons (CCINs) remain numerically intact in prodromal AD yet show early transcriptional stress, suggesting that amplifying their output could stabilize vulnerable networks without the systemic side-effects of broad cholinergic drugs. This R01 combines chronic micro-prism two-photon imaging, the GRAB-ACh fluorescent reporter, in-vivo β-amyloid (Aβ) labeling, and cell-type–specific chemogenetic/optogenetic control to test two hypotheses: (i) Aβ pathology propagates preferentially through projection-defined PFC subnetworks, degrading calcium dynamics and ACh tone; and (ii) boosting CCIN activity restores network stability and cognitive flexibility via M1-muscarinic and α7-nicotinic mechanisms. Aim 1 tracks calcium and ACh signals monthly in corticothalamic, corticostriatal, and corticocortical pyramidal neurons of APP^NL-G-F and wild-type mice during a head-fixed two-armed bandit task, quantifying how activity loss and cholinergic hypo-response relate to plaque accrual. Aim 2 tests circuit rescue: (2.1) chronic hM3Dq activation of CCINs from 4–8 months and endpoint stereologic counts of CCINs, basal-forebrain cholinergic neurons, and plaques; (2.2) dual-color calcium imaging in glutamatergic and GABAergic populations under sustained CCIN drive; (2.3) all-optical mapping of acute CCIN stimulation with M1 and α7 agonist/antagonist wash-ins. Mixed- effects models handle the unbalanced longitudinal panel of repeatedly imaged cells. Successful completion will deliver multiscale evidence that endogenous, circuit-delimited cholinergic reinforcement can blunt prefrontal network decay and preserve decision flexibility, providing a mechanistic foundation for precision neuromodulation in early AD.


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 = $780,217 )
2026	2026	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	000	1	8/28/2026	NEW	$780,217
														Subtotal = $780,217

Grand Total All Awards = $780,217

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Longitudinal imaging of prefrontal cholinergic dynamics and cognitive flexibility in an Alzheimer's model

Award Number: R01AG102720

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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