Ethanol drinking and the basal ganglia circuitry

拟议的研究是对父赠款R01AA027768的目标2和3的合乎逻辑的扩展- 02，这决定了过量的酒精摄入是否损害了丘脑对纹状体的调节 胆碱能中间神经元(CINs)和CIN对直接通路中棘神经元的调节 (DMSNS)，导致不灵活的行为。这种扩展包括酒精如何诱导减少 胆碱能活动参与阿尔茨海默病认知障碍的发生和发展 相关痴呆症(ADRD)，进一步加深了我们对痴呆发病机制的理解 酒精使用障碍叠加在ADRD上。因此，本研究与ADRD有一定的相关性。 酒精使用障碍的特点是僵化的强迫性饮酒，尽管有负面后果。 类似的认知不灵活也是阿尔茨海默病的一个特征。两者认知灵活性的缺陷 疾病很可能是由胆碱能活动减少引起的。纹状体含有dMSN和CINs。 过量饮酒会增强dMSN的活性。初步研究发现，DMSNS发送GABA能 抑制纹状体CIN和基底前脑胆碱能投射神经元(CPN)的投射。纹状体 CINS也接受来自丘脑的谷氨酸能输入。来自父母资助的研究发现，过度 酒精摄入减少了丘脑对CINs和CIN活性的输入，损害了反转学习的灵活性。它是 尚不清楚酒精如何在阿尔茨海默病的背景下调节胆碱能活动。这项研究 探讨过量饮酒如何降低5xFAD小鼠模型中CIN和CPN的活性 阿尔茨海默氏症。假设是过量的酒精摄入会加剧高血压的发病和程度。 增强抑制性dMSN→CIN(或Cpn)传递，减少谷氨酸能丘脑对CIN的传入， 导致阿尔茨海默病5xFAD小鼠模型中的低胆碱能活动。我们将对此进行测试 假设通过以下两个特定的目的：(1)测试过量的酒精摄入是否会增加dMSN→CIN 或dmsn→cpn在5xFAD小鼠中的传播程度高于野生型对照；(2)确定 过量酒精摄入是否在更大程度上减少DMS CINs的丘脑纹状体传递 5只FAD小鼠比野生型对照组小鼠高5倍。这项研究在概念上是创新的，因为它关注的是 在这两种疾病中，纹状体介导的低胆碱能机制相对被忽视的区域。它是 在技术创新方面，它结合使用三重转基因小鼠和光遗传刺激来选择性地 测量三个神经回路，并确定它们在两种疾病中对低胆碱能活动的贡献。 这项提议产生的知识将为改善胆碱能活动和 认知灵活性，从而指导酒精使用障碍和阿尔茨海默病的治疗。

The proposed research is a logical expansion of Aims 2 and 3 of the parent grant, R01AA027768- 02, which determines whether "excessive ethanol intake compromises thalamic regulation of striatal cholinergic interneurons (CINs) and CIN-mediated regulation of direct-pathway medium spiny neurons (dMSNs), leading to inflexible behaviors." This expansion includes how the alcohol-induced reduction of cholinergic activity contributes to the onset and progression of cognitive deficit in Alzheimer's disease and related dementias (ADRD), which further improve our understanding of the pathogenesis of alcohol use disorder superimposed on ADRD. Therefore, this research is relevant to ADRD. Alcohol use disorder is characterized by inflexible compulsive drinking, despite negative consequences. Similar cognitive inflexibility is a hallmark of Alzheimer's disease. Deficits in cognitive flexibility in both diseases are likely mediated by reduced cholinergic activity. The striatum contains dMSNs and CINs. dMSN activity is enhanced by excessive alcohol intake. Preliminary studies found that dMSNs sent GABAergic projections to inhibit striatal CINs and cholinergic projection neurons (CPNs) in the basal forebrain. Striatal CINs also receive glutamatergic inputs from the thalamus. Studies from the parent grant found that excessive alcohol intake reduces thalamic inputs to CINs and CIN activity, impairing flexibility in reversal learning. It is not known how alcohol regulates cholinergic activity in the context of Alzheimer's disease. This research explores how excessive alcohol intake reduces CIN and CPN activity in the 5xFAD mouse model of Alzheimer's disease. The hypothesis is that excessive alcohol intake exacerbates the onset and extent of enhanced inhibitory dMSN→CIN (or CPN) transmission and reduces glutamatergic thalamic inputs to CINs, leading to hypocholinergic activity in the 5xFAD mouse model of Alzheimer's disease. We will test this hypothesis via the following two specific aims: (1) Test whether excessive ethanol intake enhances dMSN→CIN or dMSN→CPN transmission to a greater extent in 5xFAD mice than in wild-type controls; (2) Determine whether excessive ethanol intake reduces thalamostriatal transmission in DMS CINs to a greater extent in 5xFAD mice than in wild-type controls. This research is conceptually innovative because it focuses on the relatively neglected area of the striatum-mediated hypocholinergic mechanisms in both disorders. It is technically innovative in its combined use of triple transgenic mice and optogenetic stimulation to selectively measure three neural circuits and determine their contributions to hypocholinergic activity in both diseases. Knowledge generated from this proposal will provide novel strategies for improving cholinergic activity and cognitive flexibility, thereby informing the treatment of alcohol use disorder and Alzheimer's disease.