# Glial-mediated synaptic remodeling in drug addiction

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $545,397

## Abstract

Abstract
This grant application proposes to understand the role of astrocytes in mediating cocaine-induced circuit
alterations that drive cocaine seeking and relapse. Outcomes of the first funding period for this R01 project
demonstrate that cocaine self-administration (SA) activates an astrocyte-mediated synaptogenic mechanism to
generate AMPA receptor (AMPAR)-silent synapses in principal medium spiny neurons (MSNs) in nucleus
accumbens shell (NAcSh). During withdrawal from cocaine SA, a subset of these cocaine-generated NAcSh
synapses mature and strengthen by recruiting AMPARs. Experimentally converting and locking cocaine-
generated NAcSh synapses within their silent state during drug withdrawal substantially decreases cue-
induced cocaine seeking. By measuring intracellular Ca2+ activities, preliminary studies reveal that NAcSh
astrocyte activities are upregulated by cocaine administration, and that this upregulation is increased after 5-d
cocaine SA, indicating a ‘sensitization’ process in astrocytes. Furthermore, after cocaine SA, NAcSh astrocytes
acquire the ability to respond to cocaine-associated cues by increasing their activities, and experimentally
increasing astrocyte activities re-silences cocaine-generated NAcSh synapses. These and other preliminary
results lead to the current hypothesis: NAcSh astrocytes gain unique properties through cocaine experience to
regulate cocaine-generated synapses and formulate specific neuronal ensembles that drive cue-induced
cocaine seeking after drug withdrawal. This hypothesis will be tested by three lines of experimentation. First,
using astrocyte-specific molecular tools, proposed experiments will test the specific hypothesis that astrocytic
levels of mGluR5 are upregulated by cocaine SA, which, in turn, mediates sensitized in vivo responses of
NAcSh astrocytes to cocaine and cocaine-associated cues after cocaine withdrawal. In parallel, selective RNA-
seq of NAc astrocytes will reveal novel molecular substrates for cocaine action in this cell type. Second, using
in vivo two-photon microscopy combined with slice electrophysiology, proposed experiments will test the
specific hypothesis that increased activities of NAcSh astrocytes is both sufficient and necessary for cue re-
exposure-induced re-silencing of cocaine-generated NAcSh synapses, and thus can be used to reduce cue-
induced cocaine seeking after drug withdrawal. Third, using GCaMP-mediated in vivo Ca2+ imaging, proposed
experiments will test the specific hypothesis that the neuronal ensembles are formed, in part, by astrocyte-
mediated synaptogenesis in response to cocaine, and then drive cue-induced cocaine seeking after drug
withdrawal. These proposed experiments will characterize several novel astrocyte-associated substrates
through which addiction-related memories can be manipulated for therapeutic benefits.

## Key facts

- **NIH application ID:** 10829931
- **Project number:** 5R01DA040620-08
- **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:** $545,397
- **Award type:** 5
- **Project period:** 2016-06-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10829931

## Citation

> US National Institutes of Health, RePORTER application 10829931, Glial-mediated synaptic remodeling in drug addiction (5R01DA040620-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10829931. Licensed CC0.

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