Identifying Neural Substrates of Dependence-induced Behavioral Inflexibility.

描述(申请人提供)：酒精使用障碍的发展涉及从随意饮酒到僵化的习惯性饮酒的过渡。习惯性饮酒不再由酒精的强化特性所调节，而是由与药物配对的线索所调节。我们的初步数据表明，长期间歇接触酒精会导致酒精习惯的快速形成--也就是说，长期接触酒精的小鼠变得不能灵活地调节 寻酒行为。大量研究强调了PFC在调节刺激反应习惯的发展和表达方面的作用。特别是，已证明下缘PFC(IL)是养成习惯所必需的。最近的数据表明，慢性酒精暴露后，皮质边缘回路中mGluR2的表达可能受到失调。目前的建议是为了验证这一新的假设，即IL投射神经元上mGluR2表达的减少介导了慢性酒精暴露诱导的刺激反应习惯的快速转变。我们认为，IL-mGluR2表达的减少导致皮质下靶点IL-谷氨酸能信号的增强，从而促进习惯性奖赏寻求的过早表达。我们的初步数据表明，系统地增强mGluR2信号可以在过渡到习惯性饮酒后恢复目标导向的饮酒。AIM 1旨在证实慢性酒精的影响 对习惯性饮酒暴露的影响，并评估这些影响对饮酒习惯的特异性。这些数据对于理解慢性酒精诱导的皮质边缘回路的变化是否会促进灵活行为的普遍缺陷，或者这些影响是否是酒精寻求所特有的，是至关重要的。目的2利用细胞示踪和免疫组织化学技术研究慢性酒精诱导的IL环路mGluR2减少的程度。在目标3中，我们将使用药理学和光遗传学技术，使用一种新型的光开关来证明IL-mGluR2信号在恢复目标导向的乙醇寻求过程中的因果作用。最后，我们将通过在IL-PFC中病毒过表达mGluR2来验证这一假说，即mGluR2信号的丢失是CIE诱导的酒精寻找习惯发展加速所必需的。这些研究的结果有望为长期酒精暴露对行为灵活性的影响提供大量信息，并进一步提供恢复这种损失的机制。我们相信，从这些实验中获得的知识将为酒精使用障碍的发展机制提供洞察，最终将为开发新的预防和治疗策略提供信息。

DESCRIPTION (provided by applicant): The development of alcohol use disorders involves a transition from casual drinking, to inflexible habitual drinking. Habitual alcohol seeking is no longer mediated by the reinforcing properties of alcohol but rather by drug-paired cues. Our preliminary data suggest that chronic intermittent exposure to ethanol results in rapid formation of alcohol habits - that is, mice chronically exposed to alcohol become unable to flexibly regulate alcohol seeking behavior. Considerable research has highlighted the role of the PFC in regulating the development and expression of stimulus-response habits. In particular, the infralimbic PFC (IL) has been shown to be required for habit formation. Recent data suggest that mGluR2 expression in corticolimbic circuits may be dysregulated after chronic exposure to alcohol. The current proposal is designed to test the novel hypothesis that decreased expression of mGluR2 on IL projection neurons mediates the rapid transition to stimulus-response habits induced by chronic alcohol exposure. We believe that reductions in IL mGluR2 expression result in enhanced IL glutamatergic signaling in subcortical targets, therefore promoting premature expression of habitual reward seeking. Our preliminary data suggest that systemic enhancement of mGluR2 signaling can restore goal-directed alcohol seeking after the transition to habitual alcohol seeking. Aim 1 is designed to confirm the effects of chronic alcohol exposure on habitual ethanol seeking, and to assess the specificity of these effects to alcohol seeking habits. These data are critical for understanding whether chronic alcohol-induced alterations in corticolimbic circuitry promote a general deficit in flexible behavior, or if these effects are specific to alcohol seeking. Aim 2 is designed characterize the full extent of chronic alcohol induced mGluR2 reduction in IL circuitry using cell tracing and immunohistochemical techniques. In Aim 3 we will employ pharmacological and optogenetic techniques using a novel photoswitch to demonstrate a causal role for IL mGluR2 signaling in the restoration of goal-directed ethanol seeking. Finally, we will test the hypothesis that loss of mGluR2 signaling is required for the CIE-induced acceleration of the development of alcohol- seeking habits through the use of viral overexpression of mGluR2 in the IL PFC. The results of these studies are expected to provide considerable information about the effects of chronic alcohol exposure on behavioral flexibility, and further, the mechanisms through which this loss can be restored. We believe that the knowledge gained from these experiments will provide insight into the mechanisms of the development of alcohol use disorders that will ultimately inform the development of novel prevention and therapeutic strategies.