Impact of chronic alcohol on neuronal cholinergic signaling

慢性酒精对神经元胆碱能信号的影响

• 批准号: 10667844
• 负责人: Armando Salinas
• 金额: $ 14.6万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667844
• 关键词: Ablation; Acetylcholine; Acetylcholinesterase; Age; Agreement; Alcohol consumption; Alcohols; Autopsy; Axon; Behavior; Behavioral; Brain; Brain region; Choline; Choline O-Acetyltransferase; Cholinergic Agonists; Cholinergic Receptors; Chronic; Cognitive; Congenital Abnormality; Corpus striatum structure; Data; Disease; Dopamine; Economic Burden; Electrodes; Enzymes; Female; Gene Expression; Genes; Grant; Heart; Hydrogen Peroxide; Immune system; Impaired cognition; Lead; Link; Literature; Liver diseases; Macaca; Macaca mulatta; Measurement; Measures; Medial; Mediating; Methods; Monkeys; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Neurobiology; Neurologic; Neurons; Neurotransmitters; Nicotinic Receptors; Occupations; Oregon; Oxidases; Patients; Pattern; Periodicity; Phenotype; Polymers; Prefrontal Cortex; Primates; Proteins; RNA; Receptor Gene; Recording of previous events; Relapse; Research; Resources; Rodent; Role; Sampling; Scanning; Self Administration; Signal Transduction; Slice; Source; Surface; Tissue Banks; Tissues; Work; acetylcholine transporter; adverse outcome; alcohol craving; alcohol exposure; alcohol seeking behavior; alcohol use disorder; basal forebrain; behavioral phenotyping; biomaterial compatibility; brain tissue; carbon fiber; caudate nucleus; cholinergic; cholinergic neuron; chronic alcohol ingestion; cingulate cortex; economic impact; experience; experimental study; fabrication; flexibility; health economics; human model; interest; male; neurotransmission; novel; psychologic; putamen; receptor expression; socioeconomics; temporal measurement; transmission process; varenicline

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.

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不断升级， 尽管后果不利，但对酒精的关注和继续使用酒精。奥德 具有广泛的负面健康和社会经济影响。 AUD与肝病有关，出生 缺陷，神经和心理并发症，免疫系统减弱和心脏 问题。在美国，AUD的经济负担每年超过2200亿美元。一个方面 AUD是对有害行为的持续参与（例如饮酒）。无法 改变这些行为可能是由于慢性酒精引起的乙酰胆碱（ACH）的缺陷 信号。有趣的是，ACH神经元的消融会导致听觉样的行为表型。 因此，本赠款中提出的实验将检查在获得的组织中的ACH信号传导 从恒河猕猴的长期自我管理史。在第一个 实验，用于测量ACH释放的碳纤维电极的制造方法将是 精制并验证了用于测量小鼠脑切片中ACH释放的测量（特定AIM 1A）。 然后，这些经过验证的乙酰胆碱探针将在俄勒冈州的两个年度尸检中使用 国家灵长类动物研究中心，我们将衡量大脑区域的ACH释放 与长期的AUD有关 酒精自我管理和控制猕猴（特定目标1B）。在第二组中 实验（特定目标2），我们将从几个大脑区域获得RNA样品 猴酒精组织研究资源（MATRR）比较ACH的基因表达 使用相同酒精自我助理和对照猕猴的信号转导相关蛋白 在尸体中。这些死灵的受试者总共包括男性和女性， 以及酒精自我管理和控制主题，允许多因素分析 任何获得的数据。此外，我们的ACH测量将与认知灵活性相关 MATRR获得的度量。重要的是，这些结果将填补AUD文献的空白 并利用重要的资源（MATRR），该资源可提供最多的NHP组织 人类aud的相关和可翻译模型。