# Psychostimulant-Induced Plasticity of Nucleus Accumbens Interneurons

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $384,720

## Abstract

Psychostimulant drugs of abuse induce persistent changes in the function of neural reward circuits that
underlie the development of addiction. The nucleus accumbens (NAc) plays a significant role in motivation,
reward, and reinforcement learning, and this brain region is a major site of the psychostimulant-induced cellular
adaptations that lead to drug addiction. Substantial data indicate that changes in gene transcription, mediated
by psychostimulant-dependent regulation of chromatin, play a key role in driving persistent changes in NAc
function. Though many past studies have focused on the induction of these transcriptional and chromatin
regulatory events in spiny projections neurons (SPNs) of the NAc, the NAc is comprised of multiple cell types,
and the output of the NAc is powerfully modulated by the activity of several classes of interneurons. We have
shown that silencing the function of one of these interneuron populations, the parvalbumin (PV)-expressing
population of NAc GABAergic interneurons, blocks the expression of locomotor sensitization and conditioned
place preference (CPP) induced by repeated amphetamine exposure in mice. Functional plasticity of striatal
PV+ interneurons has also been implicated in both cocaine self-administration and habit learning, suggesting a
conserved function for these neurons in the circuit adaptations underlying a number of motivational behaviors.
Nonetheless, we know very little about the molecular mechanisms by which psychostimulants modulate the
functional plasticity of PV+ interneurons to effect changes in addictive-like behaviors. In order to identify and
link PV+ interneuron molecular plasticities to the cellular and circuit adaptations in NAc that underlie addictive-
like behaviors, we must identify cell type specific programs of chromatin regulation and gene transcription and
determine their functional consequences. Here we will create this roadmap from transcription through
molecular mediators to behavior. We will use PV+-interneuron specific identification and manipulations of
AMPH-regulated genes in vivo and study convergent effects on the physiology of NAc PV+ interneurons and
the sensitivity of mice to AMPH-induced CPP. The goal of this proposal is to test the overarching hypothesis
that psychostimulant-dependent regulation of transcription in NAc PV+ interneurons alters the function of these
neurons to slow the development of addictive-like behaviors. In Aim 1 we will conduct a specific test of this
hypothesis by determining the functional importance of the perineuronal net protein Brevican as a
psychostimulant-regulated modulator of PV+ interneuron synaptic plasticity and addictive-like behaviors. In
Aim 2 we will use leading edge epigenome-editing and chromatin analysis methods to discover more broadly
how psychostimulant-dependent transcription factor induction in PV+ interneurons of the NAc coordinates
downstream programs of gene expression to mediate long-lasting changes in PV+ neuron f...

## Key facts

- **NIH application ID:** 10089433
- **Project number:** 5R01DA047115-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Anne Elizabeth West
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,720
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089433

## Citation

> US National Institutes of Health, RePORTER application 10089433, Psychostimulant-Induced Plasticity of Nucleus Accumbens Interneurons (5R01DA047115-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10089433. Licensed CC0.

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