# Cocaine, Parvalbumin, and Perineuronal Nets

> **NIH NIH R01** · LEGACY EMANUEL HOSPITAL AND HEALTH CENTER · 2024 · $710,298

## Abstract

PROJECT SUMMARY/ABSTRACT
Cocaine use disorder remains a prevalent problem with no FDA-approved treatment and profound societal
consequences. Cocaine-associated memories are strong and resistant to modification but are the basis of
relapse in many individuals. Our long-term goal is to diminish cocaine-associated memories to reduce
drug relapse. The self-administration model in rodents best reproduces strong cocaine-associated memory.
We have found that the removal of perineuronal nets (PNNs) in the rat medial prefrontal cortex (mPFC)
disrupts cocaine self-administration memories by interfering with reconsolidation of these memories. PNNs
form mainly around parvalbumin (PV)-containing, fast spiking interneurons that powerfully regulate mPFC
output, and mPFC output is well known to control drug-seeking behavior in both animals and humans. PV
neurons maintain cortical excitatory:inhibitory balance and contribute to theta and gamma oscillations vital for
communication across brain regions, yet almost nothing is known about how mPFC PV neurons contribute to
cocaine memory reconsolidation. Our Preliminary Data show that PNN removal in the mPFC: (1) decreases
PV neuron firing and increases excitability of pyramidal cells in drug-naïve rats; (2) profoundly disrupts the
reconsolidation of a self-administration cocaine memory, including cue-induced reinstatement and progressive
ratio responding; and (3) disrupts the synchrony of theta and gamma oscillations within the mPFC and
between the mPFC and hippocampus in response to a cocaine cue. These findings are significant because
they are expected to give novel insights into brain oscillatory patterns that may signify disrupted cocaine
memory and how to modify these persistent drug-associated memories. We hypothesize that PNNs allow PV
neurons to stabilize and maintain cocaine memories and that, without PNNs, these memories can be
destabilized and profoundly disrupted. We will use PV-Cre knock-in rats crossed with tdTomato knock-in
rats throughout to determine in Aim 1 how PNN removal alters mPFC PV neuron function and in Aim 2 how
PNN removal alters mPFC circuit function during cocaine memory reconsolidation. In Aim 3, we will assess
two mechanistic pathways by which PNN removal blocks reconsolidation, including Cre-dependent, specific
suppression of PNNs and Cre-dependent inhibition of PV neuron activity with Gi-DREADDs. We will use both
slice and in vivo electrophysiology, transcriptomics, tract tracing, immunohistochemistry, molecular, and
chemogenetic approaches to identify key factors in PV neuron-mediated control of cocaine-seeking behavior
during cocaine memory reconsolidation. Our studies are expected to generate significant advances in
understanding how to diminish powerful memories that drive cocaine-seeking behavior.

## Key facts

- **NIH application ID:** 10816475
- **Project number:** 5R01DA055645-02
- **Recipient organization:** LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
- **Principal Investigator:** SUE A AICHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $710,298
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816475

## Citation

> US National Institutes of Health, RePORTER application 10816475, Cocaine, Parvalbumin, and Perineuronal Nets (5R01DA055645-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10816475. Licensed CC0.

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