# Project 4: Convergent behavioral and neurobiological adaptations promoted by rodent models of vulnerability to alcohol use disorder and post-traumatic stress disorder

> **NIH NIH P50** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $311,101

## Abstract

PROJECT 4: Convergent behavioral and neurobiological adaptations promoted by rodent models of
 vulnerability to alcohol use disorder and post-traumatic stress disorder
 Jeff Weiner, Sara Jones, Robert Gould, Eva Bach, and Lindsey Kuiper
Individuals diagnosed with PTSD are up to four times more likely to develop alcohol use disorder (AUD) and
most evidence suggests that PTSD usually precedes the development of AUD. Anxiety, depression, and sleep
disruptions are significant risk factors for AUD as well as major symptoms of both disorders. Despite the
clinical importance of this problem, the neural mechanisms responsible for the frequent co-occurance of these
disorders are not fully understood. The overarching goal of this project is to employ a rodent early life social
isolation (eSI) model of AUD vulnerability and a PTSD model, single prolonged stress, to test the hypothesis
that both stressors promote similar behavioral phenotypes that are mediated by convergent neural adaptations.
These studies will also determine if the “double hit” of eSI + SPS exacerbates these maladaptive changes and
test a therapeutic intervention to mitigate these effects. Behavioral studies will focus on measures of anxiety-
like behavior and negative affect, deficits in fear extinction, and ethanol self-administration. Neurobiological
studies will test the innovative hypothesis that these models strengthen a glutamatergic projection from the
ventral subiculum (vSub) to the nucleus accumbens shell (NAc). Extensive evidence suggests that stress
enhances vSub-NAc activity and that stimulation of this pathway modulates many AUD/PTSD-related
behaviors (e.g. motivation, negative affect) and indirectly increases accumbal dopamine (DA) release.
Although this circuit is thought to play an integral role in many neuropsychiatric disorders, it has been largely
ignored in the AUD field. To address this knowledge gap, multidisciplinary in vivo and ex vivo approaches will
be employed to test the hypotheses that eSI + SPS strengthens vSub-NAc shell synaptic excitation and alters
NAc shell DA release dynamics, in part via an increase in kappa opioid receptor function. These studies will
also determine if the double hit increases ethanol-stimulated NAc DA release and use closed loop in vivo
optogenetics and pharmacological approaches to determine if these synaptic adaptations play a causal role in
the ethanol drinking phenotypes promoted by these models. A final aim will use longitudinal wireless EEG to
determine if eSI + SPS and ethanol drinking disrupt sleep architecture and duration and whether these
changes can be mitigated by a kappa opioid receptor antagonist. Collectively, these studies will provide the
first detailed characterization of the effects of eSI and SPS on critical behavioral phenotypes associated with
AUD vulnerability and PTSD. Complementary neurobiological studies may identify a relatively uncharacterized
hippocamapal-striatal circuitry that contributes to these malad...

## Key facts

- **NIH application ID:** 10758555
- **Project number:** 5P50AA026117-07
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jeffrey L. Weiner
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $311,101
- **Award type:** 5
- **Project period:** 2017-12-10 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758555

## Citation

> US National Institutes of Health, RePORTER application 10758555, Project 4: Convergent behavioral and neurobiological adaptations promoted by rodent models of vulnerability to alcohol use disorder and post-traumatic stress disorder (5P50AA026117-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10758555. Licensed CC0.

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