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Adaptations in Corticostriatal Networks in Alcohol Dependence Related Goal-Directed and Habitual Drinking

皮质纹状体网络在酒精依赖相关目标导向和习惯性饮酒中的适应

基本信息

批准号：
10549788
负责人：
L Judson Chandler
金额：
$ 18.35万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-12-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549788
关键词：
Acute Alcohol dependence Alcohols Animal Model Animals Behavior Behavior Control Behavioral Brain Brain region Calcium Cells Chronic Clinical Research Consumption Corpus striatum structure Data Dependence Development Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Electrodes Electrophysiology (science)Elements Ethanol Fiber Genetic Goals Habits Human Impairment Individual Knowledge Laboratories Medial Mediating Mus Neurobiology Neurons Outcome Pharmaceutical Preparations Photometry Play Population Prefrontal Cortex Process Publishing Reporting Research Research Project Grants Rewards Role Site Slice Sucrose Testing Visual addiction alcohol exposure alcohol research alcohol seeking behavior alcohol use disorder biophysical properties cell type comparison control drinking drinking behavior drug seeking behavior effective therapy experimental study flexibility human imaging imaging study in vivo male mouse model neural circuit neural network neurotransmission new therapeutic target patch clamp pre-clinical research problem drinker response treatment center

项目摘要

PROJECT SUMMARY The development of alcohol addiction is increasingly viewed as involving transition from controlled and regulated consumption to uncontrolled drinking characterized as compulsive and habitual. Recent studies in human alcoholics and animal models have suggested that chronic alcohol exposure may induce neurobiological changes in corticostriatal circuits. These changes may underlie deficits in the ability to engage goal-directed processes that normally function to suppress habitual actions. Consistent with this, evidence also indicates that addiction is associated with an inability of the prefrontal cortex (PFC) to exert appropriate inhibitory control over drug-taking and drug-seeking behaviors. Support for this comes from human imaging studies that reveal alterations in prefrontal cortex and striatal brain regions in individuals with alcohol use disorder (AUD) as compared to controls. Published and unpublished preliminary data further demonstrate that chronic intermittent ethanol (CIE) exposure can facilitate the transition from flexible goal-directed drinking to inflexible habitual drinking. Our preliminary data in mice demonstrates that CIE-induced facilitation of habitual responding for alcohol can be reversed by chemogenetic inactivation of the infralimbic (IfL) cortex, a sub-region of the mPFC that is roughly equivalent to the ventromedial PFC of humans. The overarching hypothesis of this ARC research project is that repeated cycles of CIE exposure facilitates the expression of habitual responding for alcohol, and that changes in activity of specific ensembles of neurons in the mPFC plays a critical role in this process. It is further hypothesized that compromised dopamine (DA) modulation of prefrontal function contributes to this CIE-induced transition to habitual drinking. The following three specific aims will test this overarching hypothesis in the ARC mouse model of dependence-induced excessive, habit- like drinking: Aim 1 will test the hypothesis that dependence-induced facilitation of habitual responding for alcohol is associated with changes in population activity and network organization in the IfL cortex. Aim 2 will test the hypothesis that DA D1 and D2 receptor-expressing neurons in the IfL cortex modulate dependence- induced facilitation of the expression of habitual responding for alcohol. Aim 3 will test the hypothesis that dependence-induced facilitation of habitual responding for alcohol is associated with alterations in the biophysical properties of DA D1 and D2 receptor-expressing neurons in the IfL cortex. Together, these studies will address the gap in our knowledge concerning the differential role of PFC-striatal subcircuits in the transition from flexible goal-directed to inflexible habitual drinking, and will identify novel therapeutic targets for more effective treatment of AUD.

项目总结