# Chronic Alcohol Effects on Orbitofrontal Cortex Function and Projection Circuitry

> **NIH NIH P50** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $222,335

## Abstract

PROJECT SUMMARY
Alcoholism is characterized by a loss of control over drinking and increased risk of adverse events including
traumatic injury, organ damage and loss of normal social interactions. The neural substrates that underlie the
transition from controlled social drinking to uncontrolled alcohol abuse are not fully understood, but they likely
involve disruption of brain areas responsible for assessing risk versus reward and in inhibiting maladaptive
behaviors. During the current funding cycle, we have focused on defining the actions of acute and chronic
ethanol on neurons within the orbitofrontal cortex (OFC), a part of the prefrontal cortex that is critical for choice
and decision-making. Results from these studies show that acute ethanol inhibits OFC neuron activity via
effects on processes that regulate intrinsic excitability and synaptic glutamatergic transmission. Further,
chronic ethanol exposure disrupts OFC-dependent behaviors and results in marked enhancement of OFC
excitability and glutamate synaptic plasticity, which may contribute to escalation in drinking associated with
ethanol dependence.
In this continued Center Project, we propose three major aims designed to expand on our findings by
addressing the selectivity of these changes with respect to connections between OFC neurons and brain areas
involved in goal-directed and habit-based behaviors. These studies will use our well-characterized mouse
model of chronic intermittent ethanol (CIE) exposure and will: (1) use retrograde labeling, slice
electrophysiology and optogenetic stimulation to interrogate the input and output function of OFC neurons
projecting to areas involved in reward, action and habit (e.g., ventral tegmental area and dorsal and ventral
striatum). Alterations in dendritic complexity and spine morphology of OFC neurons that project to these areas
will be examined using a novel AAV/Rabies transynaptic labeling technique and Cre-dependent lines (e.g., TH-
Cre; D1-Cre; D2-Cre) that provide synapse specific control of connectivity; (2) test how CIE treatment alters
the intrinsic excitability of OFC neurons and alters the ability of local (glycine) and long-distance (monoamines)
modulators to regulate OFC neuron excitability and synaptic function. These studies will also use retrograde
labeling and slice electrophysiology to identify projection-specific changes in the modulation of neuronal
function of OFC neurons in control and CIE exposed animals; and (3) test how controlling OFC output via
excitotoxic lesions and inhibitory and excitatory DREADDs impacts drinking before and following repeated
cycles of CIE exposure. Results from these studies will yield important new insights into the role that OFC
neurons play in the escalation of drinking observed during the development of ethanol dependence.

## Key facts

- **NIH application ID:** 9843631
- **Project number:** 5P50AA010761-25
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** John J. Woodward
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $222,335
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843631

## Citation

> US National Institutes of Health, RePORTER application 9843631, Chronic Alcohol Effects on Orbitofrontal Cortex Function and Projection Circuitry (5P50AA010761-25). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9843631. Licensed CC0.

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