Ethanol drinking and the basal ganglia circuitry

拟议的研究是一个逻辑扩展的目的2和3的母基金，R 01 AA 027768- 02，这决定了“过量的乙醇摄入是否会损害丘脑对纹状体的调节， 胆碱能中间神经元（CIN）和CIN介导的直接通路中型棘神经元的调节 （dMSN），导致不灵活的行为。“这种扩展包括酒精引起的 胆碱能活性有助于阿尔茨海默病中认知缺陷的发生和发展， 相关性痴呆（ADRD），这进一步提高了我们对 酒精使用障碍叠加ADRD。因此，本研究与ADRD相关。 酒精使用障碍的特点是顽固的强迫性饮酒，尽管有负面影响。 类似的认知能力是阿尔茨海默病的一个标志。认知灵活性的缺陷， 疾病可能是由降低的胆碱能活性介导的。纹状体含有dMSN和CIN。 dMSN的活性会因过量的酒精摄入而增强。初步研究发现，dMSN发送GABA能 投射以抑制基底前脑中的纹状体CINs和胆碱能投射神经元（CPNs）。纹状体 CIN还从丘脑接收丘脑能输入。来自父母补助金的研究发现， 酒精摄入减少了丘脑对CIN的输入和CIN活性，损害了逆转学习的灵活性。是 目前尚不清楚酒精是如何调节阿尔茨海默病患者的胆碱能活动的。本研究 探讨过量饮酒如何降低5xFAD小鼠模型中的CIN和CPN活性 老年痴呆症假设是过量的酒精摄入加剧了 增强抑制性dMSN→CIN（或CPN）传递，并减少对CIN的神经递质性丘脑输入， 导致阿尔茨海默病的5xFAD小鼠模型中胆碱能活性降低。我们将测试这个 通过以下两个具体目标来验证这一假设：（1）测试过量乙醇摄入是否会增强dMSN→CIN 在5xFAD小鼠中比在野生型对照中更大程度地传递dMSN或dMSN→CPN;（2）确定 过量的乙醇摄入是否会在更大程度上降低DMS CIN中的丘脑纹状体传递， 5xFAD小鼠中比野生型对照中更高。这项研究在概念上是创新的，因为它侧重于 在这两种疾病中，纹状体介导的胆碱能机制相对被忽视的区域。是 在其组合使用三重转基因小鼠和光遗传学刺激以选择性地 测量三个神经回路，并确定它们对这两种疾病中胆碱能活性低下的贡献。 从这一提议中产生的知识将提供改善胆碱能活性的新策略， 认知灵活性，从而为酒精使用障碍和阿尔茨海默病的治疗提供信息。

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.