Ethanol drinking and the basal ganglia circuitry

摘要 酒精使用障碍(AUD)的特点是尽管有负面后果，但仍顽固地强迫饮酒。 这种行为上的僵化与反转学习的缺陷有关。丘脑和背内侧 纹状体(DMS)是灵活行为中的关键反转学习。DMS含有主要的中刺 神经元(MSN)。MSN位于直接途径(DMSN)或间接途径(IMSN)中 基底节。DMSN和iMSN都接受皮质输入，并积极和消极地调节 分别选择“GO”动作。DMS还含有胆碱能中间神经元(CINs)。CIN释放 乙酰胆碱调节MSN活性。在反向学习过程中，丘脑的输入刺激DMS CIN产生 突发-暂停发射并停止正在进行的操作。目前尚不清楚丘脑诱发的CIN活性如何调节 AUD中的MSNS，并导致行为僵化。这个应用程序的目标是研究过度 酒精摄入改变了丘脑纹状体的传递，导致行为不灵活。我们的长期目标是 开发新的治疗方法以恢复行为灵活性和治疗AUD。这一假说，部分基于 申请人的初步结果是，过量的酒精摄入损害了丘脑对DMS CINs的调节 和CIN介导的皮质输入对dMSN和IMSN的调节，导致不灵活的行为，这 可被丘脑纹状体传递到CINs的光遗传兴奋所抵消。我们将对此进行测试 通过追求以下三个具体目标来实现假设。(1)调查过量饮酒是否 减少DMS CINs的突发-暂停反应和CINs释放的乙酰胆碱。(2)确定是否 过量的乙醇摄入损害了CIN介导的DMS MSN皮质纹状体传递的调节。 以及(3)评价丘脑对DMS CINs的光发生兴奋促进逆转的能力 有过量酒精摄取史的动物的学习。这项研究在概念上是创新的，因为 它集中在相对被忽视的胆碱能对AUD的贡献领域。它在技术上是创新的 它结合了基因编码的乙酰胆碱传感器、双通道光遗传学和狂犬病- 突触上具有确定的突触前和突触后位置的中介表达系统来确定 胆碱能在乙醇介导的僵硬中的作用。这些基本的研究问题不可能是 使用传统方法解决问题。从这项提案中产生的知识将提供新的 扭转僵化行为的策略，从而减少AUD的过量酒精摄入量。

ABSTRACT Alcohol use disorder (AUD) is characterized by inflexible compulsive drinking despite negative consequences. This behavioral inflexibility is associated with deficits in reversal learning. The thalamus and the dorsomedial striatum (DMS) are critical reversal learning in flexible behavior. The DMS contains principal medium spiny neurons (MSNs). MSNs are located either in the direct-pathway (dMSNs) or indirect-pathway (iMSNs) of the basal ganglia. Both dMSNs and iMSNs receive cortical inputs and positively and negatively regulate the selection of “Go” actions, respectively. The DMS also contains cholinergic interneurons (CINs). CIN release acetylcholine to modulate MSN activity. During reversal learning, thalamic inputs excite DMS CINs to generate burst-pause firing and stop ongoing actions. It is not known how thalamically evoked CIN activity regulates MSNs in AUD and contributes to inflexible behavior. The goal of this application is to study how excessive ethanol intake alters thalamostriatal transmission, leading to behavioral inflexibility. Our long-term objective is to develop new therapeutics to restore behavioral flexibility and treat AUD. The hypothesis, based in part on applicant’s preliminary results, is that excessive ethanol intake compromises thalamic regulation of DMS CINs and CIN-mediated regulation of cortical inputs onto dMSNs and iMSN, leading to inflexible behaviors, which can be counteracted by optogenetic excitation of thalamostriatal transmission onto CINs. We will test this hypothesis by pursuing the following three specific aims. (1) Investigate whether excessive ethanol intake reduces the burst-pause response of DMS CINs and acetylcholine release from CINs. (2) Determine whether excessive ethanol intake compromises CIN-mediated regulation of corticostriatal transmission in DMS MSNs. And (3) evaluate the ability of optogenetic excitation of thalamic inputs onto DMS CINs to improve reversal learning in animals with a history of excessive ethanol intake. This research is conceptually innovative because it focuses on the relatively neglected area of the cholinergic contribution to AUD. It is technically innovative in its use of combined genetically encoded acetylcholine sensors, dual-channel optogenetics, and rabies- mediated expression systems at a synapse with defined pre- and postsynaptic sites to determine the cholinergic contribution to ethanol-mediated inflexibility. These essential research questions cannot be addressed using conventional methodologies. Knowledge generated from this proposal will provide novel strategies for reversing inflexible behavior and thereby reduce excessive ethanol intake in AUD.