# Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence

> **NIH NIH R01** · VETERANS MEDICAL RESEARCH FDN/SAN DIEGO · 2022 · $320,625

## Abstract

Project Summary/Abstract
 The medial prefrontal cortex (mPFC) is one of the key brain regions implicated in reinstatement of
ethanol-seeking behaviors. Recent findings from our laboratory demonstrates that the mPFC harbors
progenitors (progeny of stem cells that are characterized by limited self-renewal) that proliferate, mature and
differentiate into premyelinating and myelinating oligodendrocyte progenitor cells (OPCs), and generate
myelinating oligodendroglia. Most notable is that increased ethanol self-administration during chronic
intermittent ethanol vapor inhalation (drinking during dependence; CIE) reduce newly born OPCs during
ethanol experience. However, withdrawal and forced abstinence from CIE produces a rebound effect in the
proliferation and survival of newly born mPFC OPCs, visualized as increases in the number of premyelinating
OPCs and myelinating oligodendroglia and these changes are associated with increased expression of myelin
associated proteins. These alterations in CIE rats also predicted enhanced ethanol seeking behaviors,
indicating that dependence-like behavior in CIE animals produced profound alterations in the cellular
composition of mPFC which could be a risk factor for enhanced propensity for relapse.
 We also demonstrate that increased generation of newly born OPCs during forced abstinence in CIE
rats positively correlate with enhanced expression of platelet endothelial cell adhesion molecule-1 (PECAM-1,
CD-31; a marker of neuroinflammatory response) in the mPFC and enhanced propensity for reinstatement of
ethanol seeking. Furthermore, preliminary whole-cell patch-clamp data from electrophysiology studies
performed during forced abstinence in CIE rats demonstrate that enhanced generation of mPFC OPCs, and
expression of myelin associated proteins and PECAM-1 is associated with enhanced basal synaptic
transmission and neuronal excitability of layer 2/3 mPFC pyramidal neurons indicating hyperexcitability and
enhanced glutamatergic transmission in the mPFC. Based on our published and pilot data we hope to
mechanistically link enhanced generation of OPCs and expression of PECAM-1 in the mPFC in promoting
hyperexcitability of glutamatergic neurons and enhanced relapse to ethanol seeking. We propose that
inhibiting the aberrant generation of newly born OPCs, myelin associated proteins and PECAM-1 response
during forced abstinence will preserve neuronal function within the mPFC and thus reduce reinstatement of
ethanol seeking. Our studies combining robust behavioral models of alcohol addiction and relapse, cellular
and biochemical alterations in the mPFC in combination with functional electrophysiological studies offer a
powerful mechanistic context to better understand the factors associated with enhanced propensity for
relapse.

## Key facts

- **NIH application ID:** 10468061
- **Project number:** 5R01AA020098-11
- **Recipient organization:** VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
- **Principal Investigator:** Chitra D Mandyam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $320,625
- **Award type:** 5
- **Project period:** 2012-09-25 → 2023-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468061

## Citation

> US National Institutes of Health, RePORTER application 10468061, Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence (5R01AA020098-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10468061. Licensed CC0.

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