Alcoholism is characterized by a loss of control over drinking, suggesting that there are long-lasting changes in higher cortical brain areas that normally control compulsive behaviors. Despite this general understanding, there is little known about the specific actions of alcohol on neurons within these cortical circuits. During the last funding cycle, we addressed this shortcoming and completed a series of electrophysiological studies that examined the effects of ethanol on "persistent" activity in the medial prefrontal cortex (PFC). This activity is characterized by spontaneous and rhythmic transitions between quiescent down-states and depolarized up-states that generate relevant patterns of firing. Persistent activity may allow PFC neurons to integrate and process sensory information derived from internal and external cues and to use this information to control sub-cortical circuits. The results from these pioneering studies showed that prefrontal up-states and associated firing are inhibited by concentrations of ethanol associated with mild to moderate intoxication. They also demonstrated that this effect resulted from inhibition of synaptic NMDA receptors and that PFC AMPA receptors and GABA{A} receptors are largely insensitive to behaviorally relevant concentrations of ethanol. In this application, we extend these studies and will investigate the effects of chronic ethanol on prefrontal cortex function. These studies use a well-established mouse model of chronic intermittent ethanol (CIE) exposure that increases levels of drinking as compared to non-dependent animals. We hypothesize that repeated cycles of CIE exposure will produce long-lasting changes in the excitability and plasticity of neurons within the orbitofrontal region (OFC) of the prefrontal cortex, an area known to be dysfunctional in human alcoholics. This hypothesis will be tested using four specific aims that will i) Assess the effect of chronic ethanol exposure on behaviors that require a functional OFC network;ii) Determine the acute ethanol sensitivity of glutamatergic and GABAergic transmission in OFC neurons;iii) Monitor changes in glutamatergic and GABAergic synaptic transmission in OFC neurons from control and ethanol dependent mice and iv) Determine the effects of chronic ethanol exposure on plasticity mechanisms of OFC neurons. The results from these studies will be critical in advancing our understanding of the effects of chronic ethanol on higher cortical function.

Public Health Relevance

Alcoholism is associated with deficits in brain function that result in impaired judgment and poor decision making. However, how alcohol produces these effects is unknown. Studies carried out in this proposal will determine the ways in which chronic exposure to alcohol changes the function of neurons in the prefrontal cortex, a brain area critical for evaluating potential outcomes and making good choices.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA010761-19
Application #
8601278
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
19
Fiscal Year
2014
Total Cost
$184,150
Indirect Cost
$58,585
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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