Impact of chronic alcohol on neuronal cholinergic signaling

项目摘要 酒精使用障碍(AUD)是一种慢性疾病，其特征是酒精摄入量增加， 沉溺于酒精，不顾不良后果继续饮酒。澳元 对健康和社会经济有广泛的负面影响。AUD与肝病、出生有关 缺陷、神经和心理并发症、免疫系统减弱和心脏 有问题。在美国，每年澳元的经济负担超过2200亿美元。的一个方面 AUD是指持续从事有害行为(如饮酒)。无能为力 改变这些行为可能是由于慢性酒精诱导的乙酰胆碱(ACh)缺乏 发信号。有趣的是，消融ACh神经元会导致AUD样的行为表型。 因此，这项拨款中提出的实验将检查获得的组织中的ACh信号。 来自长期饮酒的恒河猴。在第一个 实验中，用于测量ACh释放的碳纤维电极的制作方法将是 改进并验证了小鼠脑片ACh释放的测量(特定目标1a)。 这些经过验证的乙酰胆碱探针将在俄勒冈州的两次年度尸检中使用 国家灵长类动物研究中心，我们将在那里测量大脑区域ACh的释放 长期累及AUD(如尾状核、壳核、扣带回和前额叶皮质) 酒精自我管理和控制猕猴(具体目标1b)。在第二组 实验(特定目标2)，我们将从大脑的几个区域获取RNA样本 比较ACh基因表达的猴酒精组织研究资源(MATRR) 来自酒精自身给药和对照猕猴的信号相关蛋白 在尸检中。总的来说，这些尸检的对象将包括男性和女性， 以及酒精自我给药和对照受试者，允许进行多因素分析 任何获得的数据。此外，我们的ACH测量将与认知灵活性相关 由MATRR获得的措施。重要的是，这些结果将填补澳元文献中的一个空白 并利用一种重要的资源(MATRR)，从最大限度地提供NHP组织 相关的和可翻译的人类AUD模型。

Project Summary Alcohol use disorder (AUD) is a chronic condition characterized by escalating alcohol intake, preoccupation with alcohol, and continued alcohol use despite adverse consequences. AUD has broad negative health and socioeconomic impacts. AUD is linked to liver disease, birth defects, neurological and psychological complications, weakened immune system, and heart problems. In the US, the economic burden of AUD exceeds $220 billion annually. One facet of AUD is persistent engagement in deleterious behaviors (e.g. alcohol consumption). The inability to alter these behaviors may be due to chronic alcohol-induced deficits in acetylcholine (ACh) signaling. Interestingly, ablation of ACh neurons results in AUD-like behavioral phenotypes. Thus, the experiments proposed in this grant will examine ACh signaling in tissues obtained from rhesus macaques with a history of long-term alcohol self-administration. In the first experiment, the fabrication method for carbon fiber electrodes to measure ACh release will be refined and validated for measurement of ACh release in mouse brain slices (Specific Aim 1a). These validated acetylcholine probes will then be used in two annual necropsies at the Oregon National Primate Research Center where we will measure ACh release in brain regions implicated in AUD (e.g. caudate nucleus, putamen, cingulate & prefrontal cortex) from long-term alcohol self-administering and control macaques (Specific Aim 1b). In the second set of experiments (Specific Aim 2), we will obtain RNA samples from several brain regions from the Monkey Alcohol Tissue Research Resource (MATRR) to compare gene expression of ACh signaling related proteins from the same alcohol self-administering and control macaques used in the necropsies. Altogether, the subjects from these necropsies will include male and female, as well as, alcohol self-administering and control subjects, allowing for multifactorial analysis of any obtained data. Further, our ACh measurements will be correlated with cognitive flexibility measures obtained by the MATRR. Importantly, these results will fill a gap in the AUD literature and make use of an important resource (MATRR) that provides NHP tissues from the most relevant and translatable model of human AUD.