Gene-environment interaction: the brain CRF system in alcohol preferring msP rats

基因-环境相互作用：酒精偏好的 mP 大鼠的大脑 CRF 系统

• 批准号: 10442733
• 负责人: MARISA ROBERTO
• 金额: $ 34.62万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442733
• 关键词: Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Behavioral; Biological; Brain; CRF receptor type 1; Cell Nucleus; Chronic; Corticotropin-Releasing Hormone; Dependence; Development; Disease; Emotional; Endocannabinoids; Environmental Risk Factor; Ethanol; Etiology; Fright; Funding; Genetic; Genotype; Glutamates; Goals; Heavy Drinking; Heritability; Human; Hypersensitivity; Instruction; Investigation; Medical; Mental Depression; Modeling; Molecular; Mood Disorders; Peptides; Pharmacological Treatment; Post-Traumatic Stress Disorders; Predisposition; Principal Investigator; Rattus; Relapse; Research; Role; Shapes; Signal Transduction; Stress; Structure; Symptoms; System; Therapeutic Agents; Time; Up-Regulation; Wistar Rats; alcohol exposure; alcohol use disorder; alcoholism therapy; anxiety-related disorders; conditioned fear; drinking; drinking behavior; dysphoria; endocannabinoid signaling; fatty acid amide hydrolase; gamma-Aminobutyric Acid; gene environment interaction; genetic selection; insight; negative affect; negative emotional state; neuroadaptation; neurochemistry; novel; novel therapeutics; overexpression; post-traumatic symptoms; preference; programs; response; segregation; transmission process; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Behavioral; Biological; Brain; CRF receptor type 1; Cell Nucleus; Chronic; Corticotropin-Releasing Hormone; Dependence; Development; Disease; Emotional; Endocannabinoids; Environmental Risk Factor; Ethanol; Etiology; Fright; Funding; Genetic; Genotype; Glutamates; Goals; Heavy Drinking; Heritability; Human; Hypersensitivity; Instruction; Investigation; Medical; Mental Depression; Modeling; Molecular; Mood Disorders; Peptides; Pharmacological Treatment; Post-Traumatic Stress Disorders; Predisposition; Principal Investigator; Rattus; Relapse; Research; Role; Shapes; Signal Transduction; Stress; Structure; Symptoms; System; Therapeutic Agents; Time; Up-Regulation; Wistar Rats; alcohol exposure; alcohol use disorder; alcoholism therapy; anxiety-related disorders; conditioned fear; drinking; drinking behavior; dysphoria; endocannabinoid signaling; fatty acid amide hydrolase; gamma-Aminobutyric Acid; gene environment interaction; genetic selection; insight; negative affect; negative emotional state; neuroadaptation; neurochemistry; novel; novel therapeutics; overexpression; post-traumatic symptoms; preference; programs; response; segregation; transmission process

Program Director/Principal Investigator (Last, First, Middle): Alcoholism is a chronically relapsing disorder that develops over time and is characterized by the transition from recreational alcohol use to abuse and dependence. Negative emotional states, such as posttraumatic stress disorder (PTSD) or anxiety, influenced by genetic factors or determined by environmental conditions contribute to shaping this transition. On the other hand, chronic exposure to alcohol is a major determinant for the occurrence of mood disorders (e.g., anxiety, depression, PTSD) and negative emotional states (i.e., dysphoria, irritability). The amygdalar nuclei [both the central nucleus of the amygdala (CeA) and basolateral amygdala (BLA)] are considered a hub for negative emotional circuitry, and the role of the stress peptide corticotropin-releasing factor (CRF) in this brain structure is critical for both development of alcohol dependence and mood disorders/negative affect. During the previous funding period we provided essential new insight into the relationship between innate overexpression of the CRF1 receptor system, stress hypersensitivity and excessive ethanol consumption in genetically selected Marchigian Sardinian (msP) rats. Our most recent results show that enhanced CRF signaling in msP rats is responsible for increased hydrolytic activity of fatty acid amide hydrolase (FAAH) and blunted endocannabinoid (eCB) signaling in the CeA/BLA, leading to enhanced GABA and glutamate transmission in the amygdala. Our hypothesis is that such alterations contribute to enhance stress sensitivity and to exacerbate anxiety-like symptoms in the msP rats, which may increase drinking to alleviate these negative conditions. Understanding the mechanisms through with innate and environmental factors act/interact to dysregulate CRF/eCB transmission in the BLA and CeA will provide new insight into the etiopathology of alcoholism, aiding the development of new therapeutics for this still largely untreated medical condition. The research plan for this competitive renewal is to investigate how alteration of eCB signaling in the amygdala triggered by innate (in msP rats) or EtOH-induced (post-dependent Wistars) upregulation of the CRF1 system contributes to excessive alcohol drinking and exacerbates maladaptive conditioned fear responses, similar to symptoms of PTSD in humans. The ability to restore normal eCB function by FAAH inhibition, and therefore to counteract excessive drinking and normalize fear responses, will be also studied. A better understanding of the molecular mechanism underlying genotypic differences of the msP compared to outbred Wistar rats and of neuroadaptations following exposure to alcohol, will provide novel insight into the innate susceptibility to develop Alcohol Use Disorder and will be useful toward the development of new therapeutic agents to alleviate alcohol dependence. RELEVANCE (See instructions): The Marchigian Sardinian alcohol-preferring (msP) rats represent an unique rat model in which genetic selection for high alcohol preference has led to co-segregation of elevated sensitivity to stress and anxiety. The goal of this project is to provide a systematic investigation at the molecular, neurochemical and behavioral levels of the impact of these heritable factors and biological mechanisms in the etiology of anxiety and alcohol drinking behavior. These studies may help identify biological targets for the development of pharmacological treatment for alcoholism and the frequent co- occurrence anxiety related disorders, such as post-traumatic stress disorder (PTSD).

计划主任/首席研究员（最后，第一，中间）： 酒精中毒是一种长期复发性疾病，随着时间的流逝而发展，以过渡为特征 从休闲饮酒到滥用和依赖。负面情绪状态，例如创伤后 应激障碍（PTSD）或焦虑，受遗传因素影响或由环境条件决定 有助于塑造这种过渡。另一方面，长期暴露于酒精是主要的决定因素 为了发生情绪障碍（例如焦虑，抑郁，PTSD）和负面情绪状态（即 烦躁不安，烦躁）。杏仁核核[杏仁核的中央核（CEA）和 基底外侧杏仁核（BLA）被认为是负面情绪电路的枢纽，应力的作用 该大脑结构中肽促脂蛋白释放因子（CRF）的肽皮质激素的发展至关重要 依赖性和情绪障碍/负面影响。在上一个资金期间，我们提供了必不可少的 对CRF1受体系统的先天过表达之间的关系的新洞察力，压力 遗传选择的马尔基吉亚撒丁岛（MSP）中的高敏性和过度乙醇消耗 老鼠。我们最近的结果表明，MSP大鼠中的CRF信号增强是导致增加的 在 CEA/BLA，导致杏仁核中增强的GABA和谷氨酸传播。我们的假设是 这种改变有助于提高压力敏感性并加剧类似焦虑的症状 MSP大鼠可能会增加饮酒以减轻这些负面状况。了解 通过先天和环境因素通过/互动而使CRF/ECB的机制通过/互动 BLA和CEA中的传播将为酒精中毒病理学提供新的见解，以帮助 开发新的治疗疗法仍在很大程度上未经治疗的医学状况。为此的研究计划 竞争性更新是为了调查如何触发的杏仁核中欧洲央行信号的改变是如何由先天触发的（in MSP大鼠）或ETOH诱导的CRF1系统的（依赖于后的Wistars）上调有助于 过量饮酒和加剧的症状适应性恐惧反应，类似于症状 人类的PTSD。通过FAAH抑制恢复正常欧洲央行功能的能力，因此 还将研究抵消过多的饮酒并标准化恐惧反应。更好地理解 MSP的基因型差异与杂种Wistar大鼠相比，MSP的分子机制和 暴露于酒精后的神经照射，将提供对先天性敏感性的新颖见解 发展饮酒障碍，将有助于开发新的治疗剂 减轻酒精依赖。 相关性（请参阅说明）：马尔基尼亚人撒丁岛饮酒（MSP）大鼠代表独特的老鼠 高酒精偏好遗传选择的模型导致了升高的共隔离 对压力和焦虑的敏感性。该项目的目的是在 这些可遗传因素和生物学影响的分子，神经化学和行为水平 焦虑和饮酒行为病因的机制。这些研究可能有助于确定 用于开发酒精中毒的药理治疗的生物学靶标和频繁的共同处理 发生与焦虑有关的疾病，例如创伤后应激障碍（PTSD）。