The role of cortical neuromodulatory discoordination in cognitive impairment associated with alzheimer's disease

The National Institute on Aging awarded the University of Southern California $149,190 on August 6, 2026, under the Aging Research program (CFDA 93.866) to investigate how early-stage Alzheimer's disease disrupts coordinated release dynamics between acetylcholine and norepinephrine in the cortex and how this discoordination impairs cognitive performance.

The research characterizes the evolution of coordinated cortical acetylcholine and norepinephrine release activity in vivo in wildtype mice, with the hypothesis that mice exhibit distinct periods of synchrony and desynchrony of these neuromodulatory dynamics across behavioral events that contribute to task acquisition and learning. The study also utilizes PS19 mice to model Alzheimer's disease tau pathology and identify disruptions in cortical acetylcholine and norepinephrine dynamics across learning, testing the hypothesis that tau aggregation in the locus coeruleus disrupts norepinephrine release in the cortex and basal forebrain, resulting in loss of coordinated cholinergic and noradrenergic function.

The award is a project grant with a period of performance from August 6, 2026, through August 5, 2028. Work is performed in Los Angeles, California. This is an individual predoctoral fellowship supporting doctoral research training under the National Research Service Award mechanism of the Aging Research program.

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.