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

项目摘要 酒精成瘾的发展越来越多地被视为涉及从控制和控制的过渡。 从有节制的饮酒到以强迫性和习惯性为特征的不受控制的饮酒。的近期研究 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。这些变化可能是参与能力不足的基础 目标导向的过程，通常用于抑制习惯性行为。与此相一致的是， 表明成瘾与前额叶皮层（PFC）无法发挥适当的作用有关。 对吸毒和寻毒行为的抑制控制。对这一点的支持来自于人类的成像 研究表明，饮酒者的前额叶皮层和纹状体脑区发生了变化， 与对照组相比，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 顽固的习惯性饮酒我们在小鼠中的初步数据表明，CIE诱导的习惯性易化 对酒精的反应可以通过边缘下（IfL）皮质的化学发生失活来逆转， 大致相当于人类的腹内侧PFC。最重要的假设是 这个ARC研究项目是，重复的CIE曝光周期有助于表达习惯性的 对酒精的反应，以及mPFC中特定神经元集合的活动变化 在这个过程中起着关键作用。进一步假设受损的多巴胺（DA）调节 前额叶功能的变化有助于CIE诱导的习惯性饮酒的转变。以下三种特定 目的将在ARC小鼠模型中测试这一总体假设，该模型是依赖诱导的过度，习惯， 喜欢喝酒：目标1将检验依赖诱导的习惯性反应促进的假设， 酒精与IfL皮层中的群体活动和网络组织的变化有关。目标2将 测试IfL皮质中表达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： 依赖诱导的对酒精习惯性反应的易化与 IfL皮质中DA D1和D2受体表达神经元的生物物理特性。这些研究一起 我将解决差距，在我们的知识有关的差异作用PFC纹状体子电路在过渡 从灵活的目标导向到不灵活的习惯性饮酒，并将为更多的人确定新的治疗目标。 有效治疗AUD。

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 Published and unpublished preliminary data further demonstrate that chronic intermittent ethanol (CIE) exposure can facilitate the transition from flexible goal-directed drinking to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