# The influence of noradrenergic circuitry on prefrontal neuronal ensemble dynamics and cue-induced heroin seeking

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $369,646

## Abstract

SUMMARY/ABSTRACT
Substance use disorder (SUD) is associated with abnormalities in the dorsomedial prefrontal cortex (dmPFC), a
brain region that is activated by drug-predictive cues and contributes to drug seeking. Recent studies show that
non-overlapping cell populations within dmPFC, defined by gene expression or projection target, display unique
activity profiles during reward seeking. Interestingly, even within these defined cell populations considerable cell-
to-cell variability is found suggesting that greater resolution is needed to understand the influence of unique
dmPFC neuronal ensembles on behavior. Overall, the influence of unique dmPFC neuronal ensemble activity
patterns on drug seeking is unclear.
 Activity in the dmPFC is highly suppressed following persistent drug use in rodents and humans, in part due
to the reduced function of channels that control the intrinsic excitability of dmPFC output neurons. Considering
this suppressed excitability, it is surprising that the presentation of drug-associated cues can evoke robust activity
in dmPFC of patients with SUD, with that activity being a reliable predictor of future relapse. Thus, a rapid shift
in the excitability of dmPFC neurons likely occurs during drug-associated cue exposure, a change that may be
controlled by the neuromodulator noradrenaline. In support of this idea, here I show that chemogenetic inhibition
of locus coeruleus noradrenergic axons in dmPFC (LC dmPFC) abolishes cue-induced reinstatement of heroin
seeking. Furthermore, I confirm that downstream dmPFC excitatory output neurons display bidirectional plasticity
following heroin use, becoming hypoactive following heroin self-administration but recovering normal activity
during cue-induced relapse. Considering these findings, here I investigate the hypotheses that noradrenergic
LC dmPFC neurons become active during the presentation of drug-predictive cues (Aim 1), that noradrenergic
activity in dmPFC is critical for cue-induced drug seeking and for amplifying activity in downstream dmPFC
neuronal ensembles (Aim 2), and that activity in select dmPFC neuronal ensembles modulates cue-induced drug
seeking behavior (Aim 3). Overall, these experiments will characterize the activity dynamics and function of
precisely defined dmPFC circuit elements during cue-induced heroin seeking. Findings from these studies are
critical for the development of strategies that could normalize dmPFC activity and reduce relapse vulnerability in
patients suffering from SUD.

## Key facts

- **NIH application ID:** 10807010
- **Project number:** 5R01DA051650-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** James M Otis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $369,646
- **Award type:** 5
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807010

## Citation

> US National Institutes of Health, RePORTER application 10807010, The influence of noradrenergic circuitry on prefrontal neuronal ensemble dynamics and cue-induced heroin seeking (5R01DA051650-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10807010. Licensed CC0.

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