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: 10538025
• 负责人: Michael P Dugan
• 金额: $ 4.35万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10538025
• 关键词: Acute; Alcohol consumption; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Ataxia; Behavioral; Behavioral Assay; Binding; Brain; Brain region; Consumption; Development; Drug Targeting; Ethanol; Exocytosis; Future; Genetic Screening; Image; Interruption; Knock-out; Knockout Mice; Knowledge; Lead; Measures; Mediating; Methods; Molecular; Mus; Neurons; PRKCA gene; Persons; Pharmacological Treatment; Phenotype; Physiological; Play; Probability; Procedures; Process; Protein Inhibition; Protein-Serine-Threonine Kinases; RNA Interference; Regulation; Rewards; Role; 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; base; behavioral pharmacology; 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; preference; 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： 酒精使用障碍影响着世界上无数的人，并给社会造成了巨大的成本。这个 可用的药物治疗是有限的，也是适度有效的。酒精的一种机制是 通过改变突触的释放概率来改变突触的传递，从而扰乱大脑功能 水泡。这种作用背后的分子机制尚不清楚。蛋白激酶C受体(PKCε) 调节小鼠突触囊泡的释放和酒精的消耗。酒精对抑制作用的增强 中央杏仁核(CEA)的神经传递与酒精消耗的调节有关，是一种 依赖PKCε的过程，以及抑制CEA中的PKCε可减少小鼠的酒精消耗量。它是 尚不清楚PKCε如何调节突触囊泡的释放。脑丝氨酸/苏氨酸激酶1(BRSK1)是 被蛋白激酶Cε磷酸化，与突触前标志物共定位，并增加了 突触小泡。该项目的目标是确定BRSK1在行为和行为中的作用 酒精的生理反应及其与蛋白激酶Cε信号的关系。根据初步证据， 假设BRSK1通过PKCε信号介导酒精诱导的CEAGABA释放，限制 对酒精中毒的敏感性，并促进酒精消费和奖励。该项目将利用 确定BRSK1在行为反应中作用的几种行为学和药理学方法 酒精(目标1)。BRSK1在酒精增强原代神经元抑制性神经传递中的作用 也将检查来自中央杏仁核的神经元(目标2)。这个项目的结果将增加人们对 介导PKCε调控酒精相关行为和酒精的下游信号 增强CEA神经元的抑制性传递。该项目还可以为 BRSK1作为开发酒精使用障碍新疗法的药物靶点。