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

项目总结 越来越多的人认为酒精成瘾的发展涉及到从受控和 有节制的消费到无节制的饮酒，以强迫性和习惯性为特征。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 皮质纹状体环路的神经生物学变化。这些变化可能是参与能力不足的根源。 目标导向的过程通常起到抑制习惯性行为的作用。与此一致的是，证据也 表明成瘾与前额叶皮质(PFC)不能施加适当的 对吸毒和寻毒行为的抑制性控制。对此的支持来自于人类成像 研究显示饮酒个体前额叶皮质和纹状体脑区的变化 与对照组相比，精神障碍(AUD)。已公布和未公布的初步数据进一步证明， 慢性间歇性酒精(CIE)暴露可促进从灵活的目标导向饮酒向 不灵活的习惯性饮酒。我们在小鼠身上的初步数据表明，CIE诱导的习惯性易化 对酒精的反应可以通过下缘皮质的化学发生失活而逆转，下缘皮质是一个亚区域 这大致相当于人类的腹内侧PFC。最重要的假设是 这项ARC研究项目是，重复的CIE暴露周期促进习惯性的表达 对酒精的反应，以及mPFC中特定神经元集合活动的变化 在这一过程中起着至关重要的作用。进一步假设，受损的多巴胺(DA)调制 前额叶功能的改变有助于CIE诱导的向习惯性饮酒的转变。下面是三个具体的 AIMS将在ARC小鼠依赖诱导的过度习惯模型中测试这一压倒一切的假设。 像饮酒一样：目标1将测试依赖诱导的习惯性反应易化的假设 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 验证假设，即IfL皮质中表达DAD1和D2受体的神经元调节依赖- 诱导对酒精习惯性反应表达的易化。目标3将检验这一假设 依赖诱导的对酒精习惯性反应的易化与 IfL皮质DA_(1)和D_2受体表达神经元的生物物理特性。总而言之，这些研究 将解决我们关于PFC-纹状体亚路在过渡中的不同作用的知识差距 从灵活的目标导向到僵化的习惯性饮酒，并将为更多 对AUD的有效治疗。

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 Published and unpublished preliminary data further demonstrate that chronic intermittent ethanol (CIE) exposure can facilitate the transition from flexible goal-directed drinking to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