The role of central amygdala somatostatin signaling in binge ethanol drinking

中央杏仁核生长抑素信号在酗酒中的作用

• 批准号: 10343753
• 负责人: Stacey Robinson
• 金额: $ 12.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-05 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343753
• 关键词: Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Animals; Anxiety; Area; Astrocytes; Behavior; Behavioral; Brain; Calcium; Cell Nucleus; Cells; Chelating Agents; Clinical Research; Confocal Microscopy; D Cells; Dangerousness; Data; Dependence; Development; Diabetes Mellitus; Drug abuse; Electrophysiology (science); Emotional; Ethanol; Ethanol dependence; Evaluation; Exposure to; Financial Hardship; Future; Glial Fibrillary Acidic Protein; Health; Heart Diseases; Heavy Drinking; Impact evaluation; Intake; Investigation; Label; Lead; Link; Maintenance; Methods; Morphology; Mus; Neurobiology; Neuromodulator; Neurons; Neuropeptides; Pattern; Peptides; Pharmacotherapy; Phase; Physiologic pulse; Play; Population; Public Health; Regulation; Risk Factors; Role; Signal Transduction; Slice; Somatostatin; Somatostatin Receptor; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; System; Techniques; Technology; Training; United States; Viral; Water; Work; alcohol behavior; alcohol exposure; alcohol response; alcohol use disorder; behavioral pharmacology; binge drinking; chelation; design; designer receptors exclusively activated by designer drugs; drinking; drinking behavior; emotional behavior; gamma-Aminobutyric Acid; in vivo; insight; mouse model; neglect; neurotransmission; neurotrophic factor; novel; optogenetics; patch clamp; postsynaptic; postsynaptic neurons; preclinical study; presynaptic; receptor expression; relating to nervous system; therapeutic target; transmission process

PROJECT SUMMARY Binge ethanol consumption is the most common form of alcohol intake and represents over three-quarters of the financial burden associated with alcohol use in the United States. In addition to associated negative health effects such as heart disease and diabetes, binge intake is a significant risk factor for the development of alcohol dependence, is a widespread public health concern. Despite this, there are limited treatment options available for binge drinking or alcohol use disorders as a whole. Stress-related neuropeptides in the central amygdala (CeA) have emerged as important targets for development of novel pharmacotherapies, however the role of one of the most densely expressed ‘anti-stress’ neuropeptides within the brain, somatostatin (SST), in binge drinking behavior has gone essentially neglected. This omission is of particular note as SST is well known as both a neuromodulator and a neurotrophic factor, allowing it to alter CeA activity by direct interactions with neurons and indirectly through modulating astrocytic activity. I hypothesize binge-ethanol intake will dysregulate SST receptors expressed on both neural and astrocytic populations and, further, that astrocyte modulation of inhibitory transmission on to SST-expressing cells will likewise be dysregulated, resulting in decreased ability of this important ‘anti-stress’ peptide to regulate CeA activity. These dysregulations would be perfectly poised to significantly contribute to the well-established increase in CeA activity known to occur during alcohol dependence. Dissecting binge-ethanol induced alterations in CeA SST system expression and function in non- dependent animals will therefore enable both discovery of novel treatments for this risky pattern of intake and provide important insights into initial ethanol-induced alterations of a region critically involved in the development and maintenance of alcohol dependence. The K00 phase of these proposed studies employ 1) cutting-edged analysis of astrocyte morphology (using training in immunohistochemical and confocal microscopy techniques) to characterize ethanol-induced changes in SST receptor expression on astrocytic and neuronal populations in the CeA, as well as changes in overall astrocyte morphology and expression of the astroglial perisynaptic sheath at synapses onto SST-containing neurons; and 2) use of ex vivo whole cell patch-clamp electrophysiology to assess alterations in GABAergic transmission on to SST-expressing cells, and changes in astrocyte modulation of this transmission (using training in duel-patching technique to silence astrocyte activity). The R00 phase of the proposed studies will use these techniques in combination with my existing expertise in chemogenetic technology and behavioral pharmacology to 1) assess the role of the SST-expressing CeA neuron to bed nucleus of the stria terminalis (BNST) projection in binge-drinking behavior; and 2) assess binge-ethanol induced changes in SST receptor expression within the BNST and BNST astrocyte modulation of CeA SST terminal activity within the BNST.

项目概要 暴饮暴食是最常见的酒精摄入形式，占酒精摄入量的四分之三以上 在美国与饮酒相关的经济负担。除了相关的负面健康影响 例如心脏病和糖尿病，暴饮暴食是酗酒的一个重要危险因素 依赖，是一个广泛的公共卫生问题。尽管如此，可用的治疗选择仍然有限 用于整个酗酒或酒精使用障碍。中央杏仁核中与压力相关的神经肽 （CeA）已成为开发新型药物疗法的重要靶标，然而，其中一个的作用 酗酒时大脑内表达最密集的“抗压力”神经肽——生长抑素（SST） 行为基本上被忽视了。这一遗漏尤其值得注意，因为 SST 众所周知 神经调节剂和神经营养因子，使其能够通过与神经元直接相互作用来改变 CeA 活性 间接通过调节星形胶质细胞活动。我假设过量摄入乙醇会导致 SST 失调 在神经和星形胶质细胞群体上表达的受体，并且进一步，星形胶质细胞的调节 对 SST 表达细胞的抑制性传播同样会失调，导致 SST 表达能力下降 这种重要的“抗应激”肽可调节 CeA 活性。这些失调将完全准备好 显着促进已知酒精期间发生的 CeA 活性增加 依赖性。剖析暴食乙醇引起的非非酒精性脑组织中 CeA SST 系统表达和功能的改变 因此，依赖动物将能够发现针对这种危险的摄入模式的新疗法，并且 为参与发育的关键区域的最初乙醇引起的改变提供重要见解 和维持酒精依赖。 这些拟议研究的 K00 阶段采用了 1) 星形胶质细胞形态的尖端分析（使用 免疫组织化学和共聚焦显微镜技术培训）来表征乙醇诱导的变化 CeA 中星形胶质细胞和神经元群体的 SST 受体表达以及总体变化 星形胶质细胞的形态和突触处星形胶质细胞突触周围鞘的表达到含有SST的 神经元； 2) 使用离体全细胞膜片钳电生理学来评估 GABA 能的变化 传输到表达 SST 的细胞，以及星形胶质细胞对该传输的调节的变化（使用训练 采用双重修补技术来抑制星形胶质细胞的活动）。拟议研究的 R00 阶段将使用这些 技术与我现有的化学遗传学技术和行为药理学专业知识相结合 1) 评估表达 SST 的 CeA 神经元对终纹床核 (BNST) 投影的作用 酗酒行为； 2) 评估酗酒引起的 SST 受体表达变化 BNST 和 BNST 星形胶质细胞对 BNST 内 CeA SST 末端活性的调节。