Investigating the role of BNST GluN2D subunit-containing NMDARs in ethanol-induced plasticity and behavior

研究含有 BNST GluN2D 亚基的 NMDAR 在乙醇诱导的可塑性和行为中的作用

• 批准号: 10312440
• 负责人: Marie Althea Doyle
• 金额: $ 6.56万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312440
• 关键词: Abstinence; Acute; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Anxiety; Area; Automobile Driving; Behavior; Behavioral; Brain region; Cells; Chronic; Corticotropin-Releasing Hormone; Data; Development; Electrophysiology (science); Ethanol; Exhibits; Exposure to; Glutamate Receptor; Glutamates; Healthcare; Knockout Mice; Label; Lead; Measures; Mediating; Mental Depression; Messenger RNA; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Neuropeptides; Optics; Pharmacology; Population; Property; Recurrent disease; Regulation; Reporter; Research; Role; Series; Signal Transduction; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; United States; Withdrawal; Work; alcohol abuse therapy; alcohol behavior; alcohol effect; alcohol exposure; alcohol relapse; alcohol reward; alcohol seeking behavior; alcohol sensitivity; alcohol use disorder; cell type; comorbidity; economic cost; experience; experimental study; insight; interest; mouse model; negative affect; new therapeutic target; novel therapeutics; postsynaptic; receptor expression; short-term potentiation; therapeutic target; transmission process

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. In fact, these states of negative affect experienced during withdrawal are hypothesized to drive alcohol seeking and relapse behavior. The bed nucleus of the stria terminalis (BNST) is a key brain region responsible for the integration of negative affect and alcohol-related behaviors. Within this highly heterogeneous region, synaptic plasticity driven by ethanol exposure is a significant contributor to maladaptive behavior. N-methyl-D-aspartate receptors (NMDARs) are a major target of ethanol, known to modulate BNST synaptic plasticity and transmission following both acute and chronic exposure. However, to date, no work has investigated the role of GluN2D-subunit containing NMDARs in mediating ethanol’s effects in the BNST. Moreover, these subunits are expressed by corticotropin-releasing factor (CRF)-positive BNST neurons (BNSTCRF), a key subpopulation for driving anxiety-like and ethanol seeking behaviors. Together, these data suggest a role for GluN2D expression in regulating ethanol intake and reward following chronic ethanol exposure. Thus, I propose a series of experiments to investigate the role of BNST GluN2D-containing NMDARs in ethanol-induced plasticity and behavior, with a focus on BNSTCRF neurons. First, I will assess the ability of GluN2D expression to regulate ethanol sensitivity of BNSTCRF neurons. Second, I will dissect the contribution of GluN2D-containing NMDARs to altered glutamatergic plasticity of BNSTCRF neurons following chronic ethanol exposure. Lastly, I will test the hypothesis that abstinence following chronic ethanol exposure regulates GluN2D-containg NMDAR expression in a behaviorally relevant manner.

项目总结/摘要 酒精使用障碍（AUD）是一种慢性、复发性疾病，与焦虑和抑郁高度共病。在 事实上，这些在戒断过程中经历的负面情绪状态被假设为驱使酒精寻求 和复发行为。终纹床核（BNST）是负责脑功能的关键脑区。 负面情绪和酒精相关行为的整合。在这个高度异质性的区域内，突触 由乙醇暴露驱动的可塑性是适应不良行为的重要因素。n-甲基-d-天冬 受体（NMDAR）是乙醇的主要靶点，已知其调节BNST突触可塑性， 急性和慢性接触后的传播。然而，到目前为止，还没有工作调查的作用， 含有GluN 2D亚基的NMDAR介导乙醇在BNST中的作用。此外，这些亚单位是 表达促肾上腺皮质激素释放因子（CRF）阳性BNST神经元（BNSTCRF），一个关键的亚群， 导致焦虑和寻求酒精的行为。总之，这些数据表明GluN 2D表达的作用 调节乙醇摄入量和慢性乙醇暴露后的奖励。因此，我提出了一系列 研究BNST含GluN 2D的NMDAR在乙醇诱导的可塑性中的作用的实验， 行为，重点是BNSTCRF神经元。首先，我将评估GluN 2D表达调节 BNSTCRF神经元的乙醇敏感性。其次，我将剖析含GluN 2D的NMDAR的贡献， 慢性乙醇暴露后BNSTCRF神经元的突触可塑性改变。最后，我将测试 慢性乙醇暴露后禁欲调节含GluN 2D的NMDAR表达的假说 以行为相关的方式。