# 3/8: INIA Stress and Chronic Alcohol Interactions: Norepinephrine and corticostriatal circuit regulation of cognitive effort after chronic alcohol and stress

> **NIH NIH U01** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2022 · $446,161

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic alcohol use disrupts a number of cognitive functions, including attention, memory, flexibility, and other
aspects of executive control. This is exacerbated by both exogenous stress and stress associated with alcohol
use and withdrawal. We hypothesize that a key factor relating widespread cognitive dysfunction to problematic
alcohol use is cognitive effort, which is needed to sustain diverse cognitive functions, particularly under
conditions of heavy demand. In particular, we hypothesize that a history of chronic alcohol and stress disrupts
the willingness and ability to exert cognitive effort, and conversely, that pre-alcohol limitations in cognitive effort
predict future problematic alcohol use. There is strong interest in the neural basis of cognitive effort, but to our
knowledge, no studies have examined the relationship between cognitive effort and alcohol at either a behavioral
or neural level. Here we will investigate a neural circuit critical for cognitive effort and impacted by stress and
alcohol use. This circuit is formed by the locus coeruleus norepinephrine (LC-NE) system, its strong projections
to the anterior cingulate cortex (ACC), and ACC projections to the dorsomedial striatum (DMS). Unique to this
proposal is 1) the integration of these systems into a unified circuit and 2) the investigation of this circuit in the
integrated framework of cognitive effort, alcohol, and stress.
We will measure the impact of chronic intermittent ethanol (CIE) and/or forced swim stress (FSS) on willingness
and ability to perform two cognitively-demanding tasks (extradimensional set shifting and cognitive effort
discounting in a sustained attention task) in mice. We will identify CIE/FSS associated changes in ACC
noradrenergic regulation using RNAscope and probe them with CRISPR-mediated NE receptor knockdown (Aim
1). We will record neural dynamics in this network during cognitive performance after CIE/FSS (Aim 2), and
manipulate the activity of this circuit using optogenetics to reversibly disrupt or rescue cognitive effort (Aim 3).
Finally, we will collaborate with INIA Neuroimmune investigators to identify the impact of the phosphodiesterase
inhibitor apremilast on cognitive function after CIE/FSS and characterize its effect in this circuit (Aim 4). Studies
will integrate individual and sex differences to capitalize on heterogeneity in behavior and its relationship to
underlying neural function.
Cognitive effort is a novel and powerful framework for investigating the impact of alcohol and stress on cognition.
Our studies have the potential to unite diverse findings related to the cognition and AUD. By identifying changes
in neural circuitry underlying CIE/FSS-induced changes in cognitive effort, there is significant potential for
identifying broadly-influential treatments for AUD that strengthen cognitive abilities to serve as a bulwark against
the combined influences of alcohol and stress.

## Key facts

- **NIH application ID:** 10411762
- **Project number:** 2U01AA025481-06
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** DAVID E MOORMAN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $446,161
- **Award type:** 2
- **Project period:** 2017-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10411762

## Citation

> US National Institutes of Health, RePORTER application 10411762, 3/8: INIA Stress and Chronic Alcohol Interactions: Norepinephrine and corticostriatal circuit regulation of cognitive effort after chronic alcohol and stress (2U01AA025481-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10411762. Licensed CC0.

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