Alcohol dependence induced aberrant persistence of reward-seeking and its corticostriatal determinants.

项目摘要 酒精依赖者会出现决策功能障碍，并被假设为从最初的 从目标导向型决策到习惯性/强迫性控制。自上而下的大脑皮层控制对目标至关重要 指导决策。前SMA/SMA是这样的皮质回路之一，其活动在AUD中被破坏。 酒精依赖如何影响目标导向决策和相关的皮质神经机制 仍不清楚目标导向的决策源于对价值变化的敏感性， 后果（即我想要它）以及对决策本身的反馈的敏感性（即，是否成功）。 虽然研究集中在酒精依赖导致对价值变化不敏感的能力上， 对决策反馈的敏感性的依赖性的影响被忽略了。这是一个至关重要的组成部分， 对反馈敏感性的皮层机制的研究将告知酗酒者如何从目标- 导致强迫性控制为了评估运动前皮质纹状体回路在酒精依赖中的作用，我们 已经适应了啮齿类动物的操作性任务，将价值敏感性与决策反馈分离开来。我们 小鼠的初步数据显示，长期酒精暴露会导致异常的持续使用决策。 反馈; CIE暴露的小鼠继续调整它们的行为以获得奖励，即使在 而对照组小鼠则没有。此外，慢性酒精暴露增加了继发性神经元的兴奋性。 运动皮层（M2）锥体神经元，我们已经证明，当使用反馈时， 决策的我们的中心假设是，慢性酒精暴露增加了M2输出到DS， 导致在决策过程中异常地持续使用反馈。我们会解决这个问题 假设1）确定慢性酒精暴露如何影响M2群体活动和输出控制 2）操纵M2投射神经元活动，以建立决策之间的因果关系 酒精依赖诱导的M2活动和持续反馈控制的变化。我们会好好利用- 经验证的慢性间歇性乙醇蒸汽暴露模型酒精依赖， 行为分析结合体内钙纤维光度测定和体内化学和光遗传学， 为了了解慢性酒精暴露如何影响目标导向决策期间M2内的活动， 制作。前SMA/SMA，M2的人类同源物，与反应抑制相关，并在M2中被破坏。 澳元。由于SMA前/SMA可用于TMS等治疗，因此这项工作的影响将是确定 一种新的治疗靶向皮质纹状体通路，通过该通路，慢性酒精暴露会破坏目标- 指导决策。

Project Summary Dysfunctional decision-making is found in alcohol dependence and is hypothesized to involve a shift from initial goal-directed decision-making to habitual/compulsive control. Top-down, cortical control is essential for goal- directed decision-making. The pre-SMA/SMA is one such cortical circuit and its activity is disrupted in AUD. How alcohol dependence affects goal-directed decision-making and the associated cortical neural mechanisms remains unclear. Goal-directed decision-making is derived from sensitivity to changes in the value of the consequence (i.e. do I want it) as well as sensitivity to feedback on the decision itself (i.e., was it successful). While research has focused on the ability for alcohol dependence to induce insensitivity to value change, the effects of dependence on sensitivity to decision feedback has been neglected. This is a crucial component of AUD; research into the cortical mechanisms of feedback sensitivity will inform how alcoholics shift from goal- directed to compulsive control. To assess the role of premotor corticostriatal circuits in alcohol dependence, we have adapted an operant task in rodents to dissociate value sensitivity from feedback on the decision. Our preliminary data in mice show chronic alcohol exposure leads to the aberrant persistent use of decision feedback; CIE exposed mice continue to adjust their behavior to get reward even under circumstances when control mice do not. Furthermore, chronic alcohol exposure increases the excitability of secondary motor cortex (M2) pyramidal neurons, which we have shown to be involved when using feedback during decision-making. Our central hypothesis is that chronic alcohol exposure increases M2 output into DS, leading to the aberrant persistent use of feedback during decision-making. We will address this hypothesis by 1) determining how chronic alcohol exposure affects M2 population activity and output to control decision-making and by 2) manipulating M2 projection neuron activity to establish a causal link between alcohol dependence-induced changes in M2 activity and persistent feedback control. We will utilize the well- validated chronic intermittent ethanol vapor exposure to model alcohol dependence, and sophisticated behavioral analyses combined with in vivo calcium fiber photometry and in vivo chemo- and optogenetics in order to understand how chronic alcohol exposure affects activity within M2 during goal-directed decision- making. The pre-SMA/SMA, M2’s human homologue, is associated with response inhibition and is disrupted in AUD. Since the pre-SMA/SMA is accessible to treatments like TMS, the impact of this work will be to identify a novel and therapeutically targetable corticostriatal pathway by which chronic alcohol exposure disrupts goal- directed decision-making.