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.

项目摘要 暴饮暴食是最常见的酒精摄入形式，代表超过四分之三 金融伯恩在美国与饮酒有关。除了相关的负面影响 例如心脏病和糖尿病，暴饮暴食是饮酒发展的重要危险因素 Depite此，可用的治疗选择有限 整体上为暴饮暴食或酒精使用障碍。中央杏仁核中与应力相关的神经肽 （CEA）已成为开发新药物疗法的重要目标，但是一个人的作用 在大脑中最垂直的“抗压力”神经肽，生长抑素（SST） 行为基本上被忽略了。这种遗漏特别值得注意，因为SST众所周知 神经调节剂和神经营养因子，从而使其通过与神经元直接相互作用和 通过调节星形胶质活性间接。我假设暴饮暴食 - 乙醇摄入量会使SST失调 在神经元和星形细胞种群上表达的受体，此外，星形胶质细胞调节 抑制性传播向表达SST的细胞也会失调，导致能力降低 这种重要的“抗压力”肽可调节CEA活性。这些失调将被完全中毒 显着促进了已知在酒精期间已知的CEA活性的增长 依赖。剖析暴饮暴食 - 乙醇在非 - 因此 对最初乙醇引起的重要区域的变化提供重要的见解 和维持酒精依赖。 这些拟议研究的K00阶段员工1）星形胶质细胞形态的切割分析（使用 在免疫组织化学和共聚焦显微镜技术中培训以表征乙醇诱导的变化 在CEA中星形细胞和神经元种群的SST受体表达中，总体上的变化 星形胶质细胞的形态和星形胶质细胞性鞘在突触到含SST的鞘 神经元； 2）使用外体全细胞斑块钳电生理学评估GABA能的改变 传输到表达SST的细胞，以及该传输的星形胶质细胞调制的变化（使用训练 在应得的技术以使星形胶质细胞活性沉默的技术中）。拟议研究的R00阶段将使用这些 结合我现有的化学遗传技术和行为药理学专业知识的技术 到1）评估表达SST的CEA神经元对层末端（BNST）投影的床核的作用 在暴饮暴食的行为中； 2）评估暴饮暴食 - 乙醇诱导的SST受体表达变化 BNST和BNST星形胶质细胞调节BNST内的CEA SST末端活性。