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中文摘要
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摘要 酒精使用障碍(AUD)的特点是不灵活的强迫性饮酒,尽管有负面影响。 这种行为上的不确定性与逆向学习的缺陷有关。丘脑和背内侧 纹状体(DMS)是灵活行为中关键的逆向学习。DMS含有主要的中等多刺 神经元(MSN)。MSN位于细胞的直接途径(dMSN)或间接途径(iMSN)中。 基底神经节dMSNs和iMSNs都接受皮层输入,并积极和消极地调节神经元的活动。 分别选择“Go”操作。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,丘脑输入刺激DMS CIN产生 突发暂停发射并停止正在进行的动作。尚不清楚丘脑诱发的CIN活性如何调节 MSN在澳元和促成不灵活的行为。这个应用程序的目标是研究如何过度 乙醇的摄入改变了丘脑纹状体的传递,导致行为的不稳定性。我们长远的目标是 开发新的疗法来恢复行为灵活性和治疗AUD。该假设部分基于 申请人的初步结果是过量的乙醇摄入损害了DMS CIN的丘脑调节 以及CIN介导的对dMSN和iMSN的皮质输入的调节,导致不灵活的行为, 可以通过丘脑纹状体传递到CIN的光遗传学激发来抵消。我们将测试这个 通过追求以下三个具体目标的假设。(1)调查过量酒精摄入是否 减少DMS CIN的爆发-暂停反应和CIN的乙酰胆碱释放。(2)确定是否 过量的乙醇摄入损害了CIN介导的对DMS MSN中皮质纹状体传递的调节。 以及(3)评估丘脑输入对DMS CIN的光遗传学激发以改善逆转的能力 在有过量乙醇摄入史的动物中学习。这项研究在概念上是创新的,因为 它集中在胆碱能对AUD的贡献的相对被忽视的区域。它在技术上是创新的, 它使用组合的遗传编码乙酰胆碱传感器,双通道光遗传学和狂犬病- 介导的表达系统在突触与定义的突触前和突触后的网站,以确定 胆碱能对乙醇介导的溶解性的贡献。这些基本的研究问题不可能 使用常规方法解决。从这一建议中产生的知识将提供新的 逆转不灵活行为的策略,从而减少AUD中过量的乙醇摄入。
英文摘要
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.
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