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

项目概要/摘要： 酒精使用障碍影响到世界各地的许多人，并给社会造成巨大的代价。的 可用的药物治疗是有限的并且适度有效。一种酒精 干扰大脑功能的方法是通过改变突触传递， 囊泡这种作用的分子机制尚不清楚。蛋白激酶C ε 调节小鼠突触囊泡释放和酒精消耗。酒精增强抑制 中央杏仁核（CeA）中的神经传递与酒精消耗的调节有关， 这一过程依赖于PKCε，抑制CeA中的PKCε可降低小鼠的酒精消耗。是 尚不清楚PKCε如何调节突触囊泡释放。脑丝氨酸/苏氨酸激酶1（BRSK 1）是 由PKCε磷酸化，与突触前标志物共定位，并增加释放的可能性， 突触囊泡本项目的目的是确定BRSK 1在行为和 酒精的生理反应及其与PKCε信号的关系根据初步证据， 假设BRSK 1通过PKCε信号传导介导CeA中酒精诱导的GABA释放，限制了 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 几种行为和药理学方法来确定BRSK 1在行为反应中的作用， 酒精（目标1）。BRSK 1在酒精增强原代神经元抑制性神经传递中的作用 还将检查来自中央杏仁核的神经元（目标2）。该项目的成果将增进对 下游信号介导的PKCε调节酒精相关行为和酒精的 增强CeA神经元的抑制性传递。该项目还可以提供证据， BRSK 1作为开发酒精使用障碍新疗法的药物靶点。

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.