# Parvalbumin interneurons regulate nucleus accumbens synapses and behavior

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $366,644

## Abstract

PROJECT SUMMARY
Drug abuse and addiction 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 synaptic function in the NAc is a
leading molecular mechanism by which illicit drug exposure leads to the behavioral manifestations represented
by addiction. While excitatory synaptic connections drive NAc neuronal firing, inhibitory synaptic transmission
is important for coordinating and constraining neuronal excitability. Our work focuses on mechanisms of
communication between NAc parvalbumin expressing fast-spiking interneurons (PV-FSIs) and specific medium
spiny neuron subtypes (MSNs; D1 or D2 dopamine receptor expressing) in the NAc core. PV-FSIs, although
limited in number, make vast inhibitory connections to MSNs thereby greatly influencing NAc output. Thus, PV-
FSI synaptic activity is a putative mediator of NAc circuit adaptations. Changes in NAc excitatory and inhibitory
circuit dynamics or the balance between excitation and inhibition, likely underlie addiction behaviors. Indeed,
we find that manipulation of these PV-FSIs in the NAc modulate drug-related behaviors. Our data suggests
that the strength of PV-FSI to MSN inhibitory synapses can be suppressed by endocannabinoid (eCB)
signaling through cannabinoid receptor 1 (CB1R) and transient receptor potential vanillod 1 (TRPV1). We
hypothesize that NAc PV-FSIs and MSNs communicate bi-directionally via the eCB system to regulate
inhibitory synaptic function on MSNs underlying NAc-related behaviors and exposure to drugs of abuse leads
to dysregulation of this process. In this grant, we will characterize the precise mechanisms by which PV-FSIs
and eCB signaling at PV-FSI to MSN synapses mediate these actions. We will identify signaling mechanisms
that alter synaptic strength at synapses onto NAc D1 or D2 MSNs using rigorous electrophysiological,
optogenetic, and behavioral approaches in combinations of transgenic mouse lines. In turn, we will apply these
protocols used to identify mechanisms of plasticity ex vivo to awake/behaving animals to determine behavioral
responding. Furthermore, we will determine if manipulation of this signaling can regulate behavioral responding
to drugs of abuse. The contribution of the proposed research is expected to be advancement in our knowledge
of mechanisms by which PV-FSIs and more specifically, eCB signaling at PV-FSIs to MSN synapses, remodel
NAc excitatory and inhibitory synaptic activity patterns and membrane firing properties, and the contribution
this process likely plays in addiction-related disorders. These studies will identify mechanisms which can be
exploited for the development of improved therapeutic tools for treating addiction.

## Key facts

- **NIH application ID:** 9935032
- **Project number:** 5R01DA040630-05
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Brad Alan Grueter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,644
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935032

## Citation

> US National Institutes of Health, RePORTER application 9935032, Parvalbumin interneurons regulate nucleus accumbens synapses and behavior (5R01DA040630-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9935032. Licensed CC0.

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