Striatal ensemble plasticity in alcohol use disorder

复发是酒精使用障碍治疗中的一个主要临床挑战。复发的部分原因是 皮质纹状体回路中酒精诱导的突触可塑性。背内侧纹状体（DMS）已被 与酒精寻求和复发有关DMS包含直接通路中型棘神经元（dMSN） 和间接途径MSNs（iMSNs），分别正向和负向调节酒精寻求。 与酒精相关的行为，如操作性自我管理，只激活了一个相对较小的子集， 纹状体中的神经元集合。尽管酒精诱导的可塑性在大块组织中被研究得很多， 不知道它是否在dMSN集合中诱导。表征集合的突触机制 神经元尤其重要的是要与几十年来检测到的药物诱导突触变化的证据相一致 在大量组织分析中。此外，相对于对照组，消退训练对酒精寻求产生更大的抑制作用。 禁欲本身，但机制知之甚少。在消退过程中没有酒精输送 可能会刺激丘脑输入DMS，降低纹状体多巴胺水平，同时诱导 DMS iMSN中的丘脑纹状体长时程增强（LTP）;这增强了“NoGo”作用，抑制了 在复发期间寻求酒精。iMSN中的LTP也可能通过以下方式直接或间接抑制dMSN活性： 降低多巴胺能活性。这个应用程序旨在阐明如何消除训练减少酒精- 诱导的皮质纹状体可塑性的DMS合奏，从而持续减少复发，与长期- 长期目标是确定如何使用这些策略来治疗酒精使用障碍。他们假设 酒精诱导的皮质纹状体可塑性在dMSN集合体中会导致复发， 通过抵消dMSN，直接或间接地促进iMSN系综中的丘脑纹状体可塑性， 活动，抑制复发。三个具体的研究目标将：1）测试的假设，操作性酒精自我- 给药引起DMS dMSN集合体中持久的皮质纹状体可塑性，促进复发; 2） 测试假设，在DMS iMSN中，抑制介导的丘脑纹状体可塑性有助于降低 酒精寻求的复发; 3）检验消退训练加强抑制输出的假设 从iMSN到dMSN或iMSN对缰核投射苍白球神经元的去抑制作用， 抑制复发这个应用程序是高度创新的，因为它应用了最先进的方法， 包括ArcTRAP，Cal-Light和双通道光遗传学刺激的组合，使我们能够 第一次确定如何熄灭酒精诱发的突触可塑性在特定的分子定义 神经元集合体改变它们在体内的活动，从而持续降低复发行为;这些关键的 使用传统方法无法解决这些问题。从本提案中获得的知识 将为酒精使用障碍的长期治疗提供新的策略。

Relapse is a major clinical challenge in the treatment of alcohol use disorder. Relapse is driven in part by alcohol-induced synaptic plasticity at the corticostriatal circuit. The dorsomedial striatum (DMS) has been implicated in alcohol seeking and relapse. The DMS contains direct-pathway medium spiny neurons (dMSNs) and indirect-pathway MSNs (iMSNs), which positively and negatively regulate alcohol seeking, respectively. Alcohol-associated behaviors such as operant self-administration activate only a relatively small subset of neuronal ensembles in the striatum. Although alcohol-induced plasticity is much studied in bulk tissue, it is unknown whether it is induced in dMSN ensembles. Characterizing synaptic mechanisms of the ensemble neurons is especially vital to reconcile with the decades of evidence for drug-induced synaptic changes detected in bulk tissue analysis. In addition, extinction training yields greater suppression of alcohol seeking relative to abstinence alone, but the mechanism is poorly understood. The absence of alcohol delivery during extinction likely stimulates thalamic inputs to the DMS and reduces striatal dopamine levels, concurrently inducing thalamostriatal long-term potentiation (LTP) in DMS iMSNs; this enhances “NoGo” actions, suppressing alcohol seeking during relapse. LTP in iMSNs is also likely to directly or indirectly suppress dMSN activity by reducing dopaminergic activity. This application aims to elucidate how extinction training reduces alcohol- induced corticostriatal plasticity in the DMS ensembles and thereby persistently reduces relapse, with the long- term objective of determining how such strategies can be used to treat alcohol use disorder. They hypothesize that alcohol-induced corticostriatal plasticity in dMSN ensembles drives relapse and that extinction training promotes thalamostriatal plasticity in iMSN ensembles to directly or indirectly, via counteracting dMSN activity, suppress relapse. Three specific research aims will: 1) test the hypothesis that operant alcohol self- administration causes long-lasting corticostriatal plasticity in DMS dMSN ensembles, promoting relapse; 2) test the hypothesis that extinction-mediated thalamostriatal plasticity in DMS iMSN contributes to reduced relapse to alcohol seeking; and 3) test the hypothesis that extinction training potentiates the inhibitory outputs from iMSNs to dMSNs or the disinhibitory effects of iMSNs on habenula-projecting globus pallidus neurons, suppressing relapse. This application is highly innovative because it applies state-of-the-art approaches, including a combination of ArcTRAP, Cal-Light, and dual-channel optogenetic stimulation, allowing us for the first time to determine how extinguishing alcohol-evoked synaptic plasticity in specific molecularly defined neuronal ensembles alters their activities in vivo and thus persistently decreases relapse behavior; these critical questions cannot be addressed using conventional methodologies. Knowledge generated from this proposal will provide novel strategies for the long-term treatment of alcohol use disorder.