Effects of GABA Co-Release on Alcohol-Induced Synaptic Plasticity

项目摘要 酒精使用障碍（AUD）是一种慢性复发性疾病，几乎没有有效的治疗方法。 过量饮酒会导致大脑发生许多变化，从而促进酒精使用的增加。之一 已被证明受慢性酒精影响的区域是背内侧纹状体（DMS）， 参与目标导向行为的控制。大量证据显示， 暴露导致DMS中兴奋性传递增加，这增加了酒精摄入。这 大脑区域也接受来自中脑的输入，释放抑制性神经递质GABA， 抵消兴奋性传递。最近的研究表明，这种投射释放的GABA是 由ALDH1a1酶合成，急性酒精减少了GABA的释放量，通过这个 通路在这个建议中，我们将测试这一假设，即这种抑制性输入的损失有助于 通过在DMS中引起过度兴奋性驱动而导致AUD病理学。因为突触的改变 传输导致神经元之间的相对通信效率的长期变化，我们将 检查抑制性传递的丧失是否导致（1）增强的突触强化和（2）减少的 兴奋性传递的突触减弱。使用双光子显微镜，切片电生理学， 荧光生物传感器，我们将机械解剖GABA释放突触可塑性的作用。这些 实验将促进我们对酒精在DMS中的神经生物学的理解，并可能导致更好的 AUD的治疗策略。

PROJECT SUMMARY Alcohol Use Disorder (AUD) is a chronically relapsing disorder for which few effective treatments exist. Excessive alcohol use causes a number of changes in the brain that promote increased alcohol use. One of the regions that has been shown to be affected by chronic alcohol is the dorsomedial striatum (DMS) which is involved in the control of goal-directed behaviors. Substantial evidence now shows that a history of alcohol exposure results in increased excitatory transmission in the DMS and that this increases alcohol intake. This brain region also receives inputs from the midbrain releasing the inhibitory neurotransmitter GABA which counteracts excitatory transmission. It has recently been shown that GABA released by this projection is synthesized by the enzyme ALDH1a1, and that acute alcohol decreases the amount of GABA released via this pathway. In this proposal, we will test the hypothesis that loss of this inhibitory input contributes to the pathology in AUD by causing excessive excitatory drive in the DMS. Because alterations in synaptic transmission cause long-term changes in the relative efficiency of communication between neurons, we will examine whether loss of inhibitory transmission results in (1) enhanced synaptic strengthening and (2) reduced synaptic weakening of excitatory transmission. Using 2-photon microscopy, slice electrophysiology, and fluorescent biosensors, we will mechanistically dissect the role of GABA release on synaptic plasticity. These experiments will advance our understanding of the neurobiology of alcohol in the DMS and may lead to better treatment strategies for AUD.