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

• 批准号: 10055948
• 负责人: L Judson Chandler
• 金额: $ 18.29万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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/10055948
• 关键词: Acute; Address; 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; 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; Slice; Sucrose; Testing; addiction; alcohol exposure; alcohol research; alcohol seeking behavior; alcohol use disorder; biophysical properties; cell type; 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

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 Published and unpublished preliminary data further demonstrate that chronic intermittent ethanol (CIE) exposure can facilitate the transition from flexible goal-directed drinking to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.

项目概要 人们越来越多地认为，酒精成瘾的发展涉及从受控到成瘾的转变。 从有节制的消费到不受控制的饮酒，其特征是强迫性和习惯性。最近的研究 人类酗酒者和动物模型表明，长期接触酒精可能会导致 皮质纹状体回路的神经生物学变化。这些变化可能会导致参与能力的缺陷 通常用于抑制习惯性行为的目标导向过程。与此相一致的是，证据还 表明成瘾与前额皮质（PFC）无法发挥适当的作用有关 对吸毒和寻药行为的抑制控制。对此的支持来自人类成像 研究揭示饮酒者前额皮质和纹状体大脑区域的变化 与对照组相比，紊乱（AUD）。已发表和未发表的初步数据进一步表明 慢性间歇性乙醇（CIE）暴露可以促进从灵活的目标导向饮酒过渡到 不灵活的饮酒习惯。我们在小鼠身上的初步数据表明，CIE 诱导的习惯性促进 对酒精的反应可以通过边缘下皮层（IfL）的化学遗传学失活来逆转，该皮层是一个亚区域 mPFC 大致相当于人类的腹内侧 PFC。总体假设是 这个 ARC 研究项目的目的是重复循环 CIE 暴露有助于习惯性表达 对酒精的反应，以及 mPFC 中特定神经元群活动的变化 在此过程中发挥着关键作用。进一步假设多巴胺 (DA) 调节受损 前额叶功能的下降有助于 CIE 诱导的饮酒习惯的转变。具体有以下三项 目标将在 ARC 小鼠模型中测试这一总体假设，即依赖引起的过度、习惯- 就像喝酒一样：目标 1 将检验以下假设：依赖诱导促进习惯性反应 酒精与 IfL 皮层的群体活动和网络组织的变化有关。目标2将 检验 IfL 皮层中表达 DA D1 和 D2 受体的神经元调节依赖性的假设 - 诱导促进对酒精的习惯性反应的表达。目标 3 将检验以下假设： 依赖引起的对酒精的习惯性反应的促进与 IfL 皮质中表达 DA D1 和 D2 受体的神经元的生物物理特性。这些研究共同 将解决我们关于 PFC 纹状体亚电路在转变中不同作用的知识空白 从灵活的目标导向到不灵活的习惯性饮酒，并将为更多人确定新的治疗靶点 AUD的有效治疗。