# Dissecting the role of ventral pallidal projections to nucleus accumbens in reward processing

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $331,017

## Abstract

PROJECT SUMMARY
Impairments in reward processing and related behavior is a core symptom of addiction, chronic pain, and
mood disorders. Dysfunction of the ventral basal ganglia, which is comprised of the ventral pallidum (VP) and
nucleus accumbens shell (NAcSh) has been implicated in the etiology of affective symptoms in each of these
disorders. Canonical basal ganglia models posit that the VP is exclusively an output of the NAc. However, a
subpopulation of VP neurons project to the NAcSh, and reward-related neural activity in the VP precedes
reward-related activity in the NAcSh. It is completely unknown whether VP terminals in the NAcSh form
functional synapses, or whether this pathway modulates reward-related neural activity in the NAcSh or reward
behavior. Moreover, infusion of GABA or endogenous opioid (EOs) receptor agonists in the NAcSh potently
increases hedonic reactions to and consumption of reward. While VP neurons synthesize GABA and EOs, it
is not known whether the VP is a source of these compounds in the NAcSh. To mechanistically understand
how the basal ganglia coordinates reward behavior in health and disease, it is crucial to elucidate the
functional role of the VP-NAcSh pathway. The objective of this proposal is to determine whether NAcSh
projecting-VP neurons release GABA and EOs to inhibit NAcSh neurons, which increases hedonic responses
to rewards. To dissect the contribution of the VP-NAcSh pathway on reward-related behavior, we will first
establish the post-synaptic targets and neurochemical identity of VP-NAcSh pathway using viral tracing and
optogenetic-assisted circuit mapping (aim 1). We will next use in vivo electrophysiology and optogenetic
manipulations to determine the effect of VP-NAcSh pathway activation on reward-related behavior and
reward-related NAcSh activity in vivo (aim 2). We will determine whether the VP-NAcSh pathway releases
EOs in the NAcSh using a novel opto-dialysis approach to detect evoked peptide release in vivo. Finally, we
will elucidate whether EOs modulate function of the VP-NAcSh pathway using fISH and patch clamp
electrophysiology (aim 3). This proposal will re-examine the classical model of the basal ganglia, which posits
that the VP is exclusively an output structure of the NAc, and will determine the role of this pathway on NAcSh
activity reward-related behavior. Our long-term goal is to elucidate the circuit basis of impaired reward
processing in disease states, and to leverage this understanding to develop circuit-based therapies (such as
deep brain stimulation) to treat deficits in reward processing and related behavior in addiction, chronic pain
and substance use disorders.

## Key facts

- **NIH application ID:** 10769771
- **Project number:** 5R01DA049924-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Meaghan C Creed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $331,017
- **Award type:** 5
- **Project period:** 2020-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769771

## Citation

> US National Institutes of Health, RePORTER application 10769771, Dissecting the role of ventral pallidal projections to nucleus accumbens in reward processing (5R01DA049924-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10769771. Licensed CC0.

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