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The role of cortical neuromodulatory discoordination in cognitive impairment associated with Alzheimer’s Disease

Award Number: F31AG099547
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/06/2026
PERIOD OF PERFORMANCE END DATE: 08/05/2027

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The role of cortical neuromodulatory discoordination in cognitive impairment associated with Alzheimer’s Disease - Project Summary/Abstract Cholinergic and noradrenergic atrophy are among the earliest neurodegenerative markers in the onset of Alzheimer’s Disease (AD), but the effect of this degeneration on coordinated neuromodulator dynamics and the degree to which the resulting dysregulation impairs cognitive performance remains unresolved. Locus coeruleus (LC), the primary source of norepinephrine (NE), is widely recognized as the earliest site of neurofibrillary tangle formation in AD and a structure where patients experience significant reduction in the size and function. At the same time, the cholinergic hypothesis of AD pathogenesis suggests that abnormal cholinergic changes induce a cascade of cellular injury which ultimately accelerates cognitive dysfunction. Across learning, distinct codeveloped patterns of neuromodulatory release emerge in cortex, suggesting a level of coordination between task related noradrenergic and cholinergic dynamics. Given that noradrenergic and cholinergic activity drives network wide brain state coordination to promote learning and arousal, this proposal aims to identify how early-stage AD related tau aggregation in the LC disrupts coordinated release dynamics between acetylcholine (ACh) and NE, and how discoordination impacts cognitive performance. In this study we will first characterize the evolution of coordinated cortical ACh and NE release activity in vivo in wildtype mice. Our hypothesis is that mice exhibit distinct periods of synchrony and desynchrony of ACh and NE dynamics across behavioral events that contribute to task acquisition and learning. We will also utilize PS19 mice to model AD tau pathology to identify disruptions in cortical ACh and NE dynamics across learning. Our hypothesis is that tauopathy in LC disrupts NE release in cortex and basal forebrain resulting in a loss of coordinated cholinergic and noradrenergic tone contributing to decreased task learning and performance. Finally, we will determine the interdependence of cognitive performance and ACh release on LC activity by artificially silencing LC activity during task execution and characterizing neuromodulator activity. The proposed study will be the first to simultaneously record ACh and NE dynamics through two-photon imaging of GRABrACh and GRABNE fluorescent sensors in primary somatosensory cortex during tactile discrimination learning, allowing us to identify behavioral events which drive synchronous or asynchronous ACh and NE release. The results of this proposal will clarify the extent to which cognitive impairments in AD are driven by structural degeneration or disruptions in neuromodulator dynamics resulting from structural changes. Understanding the role of coordinated neuromodulatory dynamics in this context will provide a foundation for designing more effective treatment interventions for 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 = $49,538 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Aging Research	000	1	2/6/2026	NEW	$49,538
														Subtotal = $49,538

Grand Total All Awards = $49,538

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The role of cortical neuromodulatory discoordination in cognitive impairment associated with Alzheimer’s Disease

Award Number: F31AG099547

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/06/2026

PERIOD OF PERFORMANCE END DATE: 08/05/2027

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