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.

项目总结 酗酒是最常见的酒精摄入形式，占 在美国，与饮酒相关的经济负担。除了相关的负面健康影响之外 例如心脏病和糖尿病，暴饮暴食是酗酒的重要风险因素。 依赖，是一个广泛的公共卫生问题。尽管如此，可用的治疗选择有限。 对于酗酒或酒精使用障碍作为一个整体。杏仁中央核中的应激相关神经肽 (CEA)已成为开发新药物疗法的重要靶点，然而一种 在酗酒中，生长抑素(SST)是大脑中表达最密集的抗应激神经肽之一 行为已经从根本上被忽视了。这一省略特别值得注意，因为SST既是众所周知的 神经调节剂和神经营养因子，使其能够通过与神经元和 间接地通过调节星形胶质细胞的活动。我假设过量摄入酒精会扰乱SST 受体在神经细胞和星形胶质细胞群体上表达，进一步，星形胶质细胞对 同样，对表达SST的细胞的抑制传递也会受到失调，导致SST的能力下降 这种重要的“抗应激”多肽可以调节CEA活性。这些不规范的行为将完全有可能 极大地促进了已知的在饮酒期间CEA活性的增加 依赖。狂饮-乙醇诱导的非小鼠CEA-SST系统表达和功能改变 因此，依赖动物将使这种危险的摄取模式的新疗法的发现和 提供了对最初乙醇引起的区域变化的重要见解，该区域对开发至关重要 以及保持对酒精的依赖。 这些拟议研究的K00阶段采用1)星形胶质细胞形态的边缘分析(使用 免疫组织化学和共聚焦显微镜技术方面的培训)来表征酒精引起的变化 在CEA的星形细胞和神经元群体上的SST受体的表达以及总体上的变化 星形胶质细胞形态和星形胶质细胞突触周鞘在含SST突触的表达 2)用体外全细胞膜片钳电生理学方法评价GABA能神经元的变化。 传递到表达SST的细胞，以及星形胶质细胞对这种传递的调节变化(使用训练 在对决修补技术中，以抑制星形胶质细胞的活动)。拟议研究的R00阶段将使用这些 技术结合我在化学遗传技术和行为药理学方面的现有专业知识 1)观察表达SST的CEA神经元向终纹床核(BNST)投射的作用 以及2)评估酗酒引起的SST受体表达的变化。 BNST和BNST星形胶质细胞对BNST内CEA-SST末端活性的调节。