The role of BRSK1, a PKC epsilon substrate, in behavioral and physiological responses to ethanol

PKC epsilon 底物 BRSK1 在乙醇行为和生理反应中的作用

• 批准号: 10748283
• 负责人: Michael P Dugan
• 金额: $ 2.41万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10748283
• 关键词: Acute; Alcohol consumption; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Ataxia; Behavioral; Behavioral Assay; Binding; Brain; Brain region; Consumption; Cyclic AMP-Dependent Protein Kinases; Development; Drug Targeting; Ethanol; Exocytosis; Future; Genetic Screening; Image; Interruption; Knock-out; Knockout Mice; Knowledge; Measures; Mediating; Methods; Molecular; Mus; Neurons; Persons; Pharmacological Treatment; Phenotype; Phosphorylation; Physiological; Play; Probability; Procedures; Process; Protein Inhibition; Protein-Serine-Threonine Kinases; RNA Interference; Regulation; Rewards; Role; Serine; Signal Transduction; Societies; Synapses; Synaptic Transmission; Synaptic Vesicles; Testing; Total Internal Reflection Fluorescent; Wild Type Mouse; Work; alcohol abuse therapy; alcohol behavior; alcohol consequences; alcohol response; alcohol reward; alcohol sensitivity; alcohol testing; alcohol use disorder; behavioral response; chemical genetics; conditioned place preference; cost; drinking; druggable target; experimental study; gamma-Aminobutyric Acid; inhibitor; knock-down; neurotransmission; neurotransmitter release; new therapeutic target; novel; pharmacologic; preference; presynaptic; protein kinase C epsilon; transmission process; vesicular release

Project Summary/Abstract: Alcohol use disorder effects numerous people around the world and creates an enormous cost on society. The pharmacological treatments available are limited and modestly effective. One mechanism by which alcohol perturbs brain function is by altering synaptic transmission by altering the release probability of synaptic vesicles. The molecular mechanisms underlying this action are not known. Protein kinase C epsilon (PKCε) regulates both synaptic vesicle release and alcohol consumption in mice. Alcohol enhancement of inhibitory neurotransmission in the central amygdala (CeA), which is implicated in regulating alcohol consumption, is a process dependent on PKCε, and inhibition of PKCε in the CeA decreases alcohol consumption in mice. It is not known how PKCε regulates synaptic vesicle release. Brain serine/threonine kinase 1 (BRSK1) is phosphorylated by PKCε, colocalizes with pre-synaptic markers, and increases the release probability of synaptic vesicles. The objective of this project is to determine the role of BRSK1 in behavioral and physiological responses to alcohol and its relation to PKCε signaling. Based on preliminary evidence, the hypothesis is that BRSK1 via PKCε signaling mediates alcohol-induced GABA release in the CeA, limits sensitivity to ethanol intoxication, and promotes ethanol consumption and reward. This project will utilize several behavioral and pharmacological methods to determine the role of BRSK1 in behavioral responses to alcohol (Aim 1). The role of BRSK1 in alcohol-enhancement of inhibitory neurotransmission in primary neurons from the central amygdala will also be examined (Aim 2). The results of this project will increase understanding of the downstream signals that mediate PKCε regulation of alcohol related behaviors and alcohol’s enhancement of inhibitory transmission in neurons of the CeA. This project may also provide evidence for BRSK1 as a drug target for the development of novel treatments for alcohol use disorder.

项目摘要/摘要： 酒精使用障碍会影响世界各地的许多人，并为社会造成成本 可用的药理学治疗是有限的，并且有效。 Perturbs脑功能是通过改变突触的概率来改变突触传播 囊泡。 调节小鼠的突触囊泡和饮酒。 中心杏仁核（CEA）的神经传递与调节酒精消耗有关，是 取决于PKCε的过程和CEAA中PKCε的不可自然性降低了小鼠的饮酒量。 尚不清楚PKCε常规囊泡释放是如何释放的。 由PKCε磷酸化，与促突触标记共定位，并增加了释放概率 突触囊泡。 对酒精的生理反应及其与PKCε信号的关系。 假设是BRSK1通过PKCε信号传导介导了CEA中酒精诱导的GABA释放，极限 对疾病的敏感性，并促进乙醇的建设和奖励。 严重行为和药理学方法来确定BRSK1在行为反应中的作用 酒精（AIM 1）。 还将检查中央杏仁核（AIM 2）。 在介导酒精相关行为的PKCε调节的下游信号中 CEA神经元中抑制性传播的增强。 BRSK1是开发用于饮酒障碍的新型治疗方法的药物靶标。