# Emerging Activity Dynamics and Noradrenergic Modulation of Prefrontal Neuronal Ensembles During Heroin Seeking

> **NIH NIH F32** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $66,390

## Abstract

PROJECT SUMMARY
Opioid use disorder is a chronically relapsing disease characterized by compulsive drug seeking, but how precise
neural circuits orchestrate these motivational states is unknown. This is in part due to a lack of experimental
feasibility, as it has been difficult to control and monitor the activity of cell-type specific neurons in vivo. For
example, development of functional hypoactivity in the dorsomedial prefrontal cortex (dmPFC) is a hallmark of
substance use disorder that reliably predicts future relapse susceptibility, while re-exposure to drug-associated
cues evokes robust dmPFC activity. However, how dynamic activity patterns in dmPFC neurons regulate drug
seeking is unclear. Thus, the objective of this project is to use contemporary tools to study the precise activity
dynamics and neurocircuitry that engages dmPFC for the control of drug seeking.
Here I propose to identify the precise activity dynamics and noradrenergic modulation of dmPFC neurons for
heroin-seeking behavior. Single-cell resolution of dmPFC neuronal activity dynamics will be identified using
longitudinal in vivo two-photon calcium imaging in head-restrained mice undergoing heroin self-administration
(Aim 1). Furthermore, as the rapid shifts in neuronal excitability observed during re-exposure to drug-associated
cues may be mediated by noradrenaline, which is released in dmPFC by the locus coeruleus (LC), inhibitory
chemogenetics will be used to determine the function of LC-dmPFC inputs on activity dynamics during cue-
induced heroin seeking (Aim 2). Based on my preliminary data and published work by my sponsors and others,
I hypothesize that cue-induced heroin-seeking reinstatement directly corresponds to excitatory activity
reemergence in dmPFC ensembles (Aim 1) and that LC-dmPFC activation is necessary for both cue-induced
reinstatement and reemergence of excitatory activity in dmPFC ensembles (Aim 2). These data would suggest
heroin-seeking behavior is regulated by discrete activity dynamics in dmPFC neurons which are subject to
noradrenergic regulation. Regardless of the results, the experiments proposed here will be the first to
longitudinally track activity in single neurons from the onset of drug use to relapse. The studies will provide
unprecedented insight into the characteristics and noradrenergic mechanisms of prefrontal excitatory
neuronal ensemble dynamics during heroin seeking.

## Key facts

- **NIH application ID:** 10315748
- **Project number:** 1F32DA053830-01A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Elizabeth Doncheck
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 1
- **Project period:** 2021-07-07 → 2022-07-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315748

## Citation

> US National Institutes of Health, RePORTER application 10315748, Emerging Activity Dynamics and Noradrenergic Modulation of Prefrontal Neuronal Ensembles During Heroin Seeking (1F32DA053830-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10315748. Licensed CC0.

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