# Cellular and Behavioral Function of Astrocytic Dopamine Signaling

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $446,408

## Abstract

Abstract
It has long been known that that astrocytes in the nucleus accumbens (NAc) and other motivation-regulatory
brain regions express dopamine receptors, but the cellular and behavioral function of astrocytic dopamine-
signaling remains underexplored. Experiments designed in this application aim at elucidating the synaptic role
of astrocytic dopamine D1 receptors (D1R) in the NAc in the context of cue-conditioned motivational behaviors
and cue-induced cocaine relapse. When animals search for reward, previously neutral environmental cues that
are paired with reward taking acquire motivational value that drives subsequent reward seeking. Such cue-
reward conditioning is essential for survival, but it is also usurped by drugs of abuse to establish the cue-drug
association that promotes drug seeking and relapse. The NAc is a key brain region where conditioned cues are
tagged with motivational value. When animals search and take reward, cue-encoding inputs from the ventral
hippocampus (vH) are simultaneously activated with reward-encoding inputs from the basolateral amygdala
(BLA), resulting in synced activation of vH and BLA synapses that are heterosynaptically aligned on the
dendrites of principal medium spiny neurons (MSNs) in the NAc. In brain slices, previous and preliminary
results from the PI’s lab demonstrate that synced activation of vH and BLA synapses selectively induces long-
term potentiation (LTP) in vH-to-NAc glutamatergic transmission. This novel form of heterosynaptic LTP,
termed hLTP, can increase the likelihood of vH-to-NAc transmission that encodes reward-contingent cues to
excite NAc MSNs for operant responding. Additional results from the PI’s lab show that either a general
inhibition of D1R or selective disruption of astrocyte function prevents the induction of hLTP. These and other
results lead to the overarching hypothesis that D1R-coupled astrocytic signaling is essential for hLTP at vH-to-
BLA synapses and cue-conditioned motivated behaviors. Guided by this hypothesis, proposed experiments will
characterize the role of NAc astrocytic D1R and its downstream signaling in the induction and expression of
hLTP as well as in the acquisition and performance of cue-induced nondrug versus drug seeking. Synaptic
plasticity has long been thought to be primarily mediated by neuronal signaling within the pre- and postsynaptic
terminals. The proposed research is conceptually innovative in that it will generate novel results demonstrating
the essential role of astrocytic signaling in sophisticated forms of synaptic plasticity that involve extracellular
signaling. Furthermore, characterizing behavioral roles of astrocytic D1R-signaling may reveal new cellular
targets through which cue-conditioned drug seeking and relapse can be manipulated. As such, the proposed
research is also clinically important and consistent with the mission of NIH in identifying and characterizing
novel therapeutic targets to treat substance use disorders.

## Key facts

- **NIH application ID:** 10939501
- **Project number:** 1R01DA060868-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yan Dong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $446,408
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939501

## Citation

> US National Institutes of Health, RePORTER application 10939501, Cellular and Behavioral Function of Astrocytic Dopamine Signaling (1R01DA060868-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10939501. Licensed CC0.

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