# Parvalbumin interneurons regulate nucleus accumbens synapses and behavior

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $477,967

## Abstract

PROJECT SUMMARY
Substance use disorders (SUDs) remain a medical and societal burden with a relative paucity of prevention and
treatment options. The nucleus accumbens (NAc) is an essential hub integrating cognitive, contextual, sensory
and affective information into behavioral outcomes. Changes in excitatory (glutamatergic) synaptic function in
the NAc is a leading molecular mechanism by which illicit drug exposure leads to the behavioral manifestations
represented by SUDs. However, a gap in the input specificity, temporal dynamic, mechanism(s) and
consequences of plasticity and drug-induced plasticity onto parvalbumin expressing fast spiking interneurons
(PV-FSIs) remains. The long-term goal is to understand the mechanisms by which NAc circuits mediate
reinforced behaviors. The overall objective of this application is: (1) to define input-specific plasticity mechanisms
controlling excitatory synaptic strength onto PV-FSIs, (2) to elucidate mechanistic contributions of these
synapses to reinforcement behavior, and (3) to determine contribution of NAc PV-FSI AMPA receptors to
cocaine-evoked plasticity of MSN excitatory synapses. The central hypothesis is that functionally-distinct
corticolimbic and thalamic synapses onto PV-FSIs in the NAc support cocaine-evoked adaptations in
reinforcement behavior and circuit function. Aim 1 is designed to determine mechanisms of stimulus and
cocaine-evoked synaptic plasticity of specific excitatory inputs onto NAc PV-FSIs. Aim 2 will determine the role
of glutamatergic signaling onto NAc PV-FSIs in modulating reinforcement behavior in an input specific manner.
And, Aim 3 will elucidate the contribution of NAc PV-FSI AMPA receptors to cocaine-induced plasticity of MSNs.
The rationale for the proposed studies is that they will provide a detailed understanding of the functional
organization of NAc PV-FSI microcircuitry, revealing synaptic mechanisms by which PV-FSIs adapt to stimuli
and support reinforcement behavior as well as influence cocaine-evoked reorganization of output circuits. To
accomplish these aims a combination of whole-cell patch clamp electrophysiology, Drugs Acutely Restricted by
Tethering (DART) pharmacology, optogenetics, reinforcement behavior and transgenic mice will be used. The
proposed research is innovative because it represents a new and substantive departure from the status quo by
shifting focus to the modulation of PV-FSI feedforward inhibition as a master regulator of NAc function and thus
reward-related behavior. Completion of the work in this proposal will: (1) establish plasticity mechanisms at
specific excitatory inputs onto PV-FSIs. (2) Establish a causal relationship between NAc PV-FSI AMPA receptors
and reinforcement behavior and (3) demonstrate that NAc PV-FSI AMPA receptors are necessary for cocaine-
evoked plasticity of MSN excitatory synapses. Completion of this work is expected to have a positive translational
impact by examining an understudied but integral component of th...

## Key facts

- **NIH application ID:** 10842270
- **Project number:** 5R01DA040630-09
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Brad Alan Grueter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $477,967
- **Award type:** 5
- **Project period:** 2016-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842270

## Citation

> US National Institutes of Health, RePORTER application 10842270, Parvalbumin interneurons regulate nucleus accumbens synapses and behavior (5R01DA040630-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842270. Licensed CC0.

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