CRF neurons of the extended amygdala and alcohol drinking

扩展杏仁核的 CRF 神经元和饮酒

• 批准号: 9367375
• 负责人: ROBERT O. MESSING
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9367375
• 关键词: Address; Affinity; Alcohol consumption; Amino Acids; Amygdaloid structure; Animals; Automobile Driving; Behavior; Behavioral; Biology; Brain region; CRH gene; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dorsal; Enterobacteria phage P1 Cre recombinase; Ethanol; Ethanol dependence; FDA approved; Genetic; Genetic Transcription; Goals; Growth Associated Protein 43; Heavy Drinking; Human; Hypothalamic structure; Immunoprecipitation; Intervention; Knowledge; Laboratories; Lateral; Limbic System; Literature; Maintenance; Messenger RNA; Modeling; Molecular; Naltrexone; Negative Reinforcements; Neurons; Neuropeptides; Neurotensin; Neurotransmitters; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Physiological; Play; Population; Procedures; Property; Public Health; RNA Interference; Rattus; Relapse; Ribosomes; Rodent; Role; Somatostatin; Source; Stress; Structure of terminal stria nuclei of preoptic region; Testing; Therapeutic; Transgenic Organisms; Translating; Viral Vector; Wistar Rats; Withdrawal; acamprosate; alcohol abuse therapy; alcohol craving; alcohol measurement; alcohol use disorder; base; designer receptors exclusively activated by designer drugs; drinking; drug testing; experimental study; gamma-Aminobutyric Acid; knock-down; neurobiological mechanism; next generation; pro-corticotropin releasing hormone; prodynorphin; promoter; psychosocial; release factor; response; sex; small hairpin RNA; success; synergism; tool; transcriptome; transcriptome sequencing

PROJECT SUMMARY Alcohol use disorder is a major public health problem. To date, available treatment options are limited to psychosocial intervention, three FDA approved medications (disulfuram, acamprosate, and naltrexone) and a few drugs approved for other indications, all with relatively small effect sizes. There is a clear need for additional treatments based on a deeper understanding of neurobiological mechanisms. Corticotrophin releasing factor (CRF) is a 41-amino acid neuropeptide produced mainly by neurons of the paraventricular hypothalamus, central amygdala (CeA), and bed nucleus of the stria terminalis (BNST) where it plays an important role in behavioral and physiological responses to stress. CRF has been long implicated in driving excessive ethanol consumption through prior studies that used CRF receptor antagonists in rodents. However, recent attempts to test CRF receptor antagonists as treatments for alcohol craving in humans have been disappointing. Part of this lack of success may be due to inadequate drug-like properties of some compounds and by a need for different human laboratory models that test drug effects on withdrawal and negative reinforcement in dependent subjects. Another reason may be due to the fact that CRF is released from neurons with other peptides and neurotransmitters that may act in synergy to drive excessive drinking. Understanding which of these co-released factors is important necessitates a different strategy that focuses on the CRF neurons themselves rather than on CRF receptors. The lack of genetic access to subpopulations of CRF neurons has made it difficult to study the biology of CRF neurons, the sources of CRF in different brain regions, and the circuitry underlying CRF-regulated behaviors. To fill this gap, we generated a BAC transgenic Wistar rat line in which Cre recombinase is expressed from the Crh gene promoter to enable genetic access to CRF neurons. In this project, we will use these rats to pursue the hypothesis that as animals develop ethanol dependence, CRF neurons in the CeA and BNST promote ethanol consumption through the coordinated release of GABA, CRF, and other neuropeptides. We will examine this hypothesis by selectively activating or inhibiting these neuronal populations and their projections using chemogenetic tools, and we will address the relative importance of the different transmitters and modulators released from these neurons using Cre-dependent RNA interference. Finally, we will investigate the role of repeated ethanol consumption on the transcriptome of these CRF neuronal populations to understand how ethanol changes their phenotype, which should provide us with important new clues as to how they drive excessive drinking. !

项目摘要 酒精使用障碍是一个重大的公共卫生问题。迄今为止，可用的治疗方案仅限于 心理社会干预，三种FDA批准的药物（双硫仑，阿坎酸和纳洛酮）和一种 很少有药物被批准用于其他适应症，所有这些药物的效应量都相对较小。显然需要 基于对神经生物学机制的更深入理解的额外治疗。皮质激素 释放因子（CRF）是一种由41个氨基酸组成的神经肽，主要由室旁核神经元产生 下丘脑，中央杏仁核（CeA）和终纹床核（BNST），在那里它起着重要的作用。 在应对压力的行为和生理反应中发挥重要作用。CRF长期以来一直与驾驶有关 通过先前在啮齿动物中使用CRF受体拮抗剂的研究，然而，在这方面， 最近尝试测试CRF受体拮抗剂作为人类酒精渴望的治疗， 失望这种缺乏成功的部分原因可能是由于某些化合物的药物样特性不足 以及需要不同的人类实验室模型来测试药物对戒断和阴性的影响， 强化依赖性主体。另一个原因可能是由于CRF从 神经元与其他肽和神经递质可能协同作用，以驱动过度饮酒。 了解这些共同释放的因素中的哪一个是重要的，需要一个不同的策略， CRF神经元本身，而不是CRF受体。 缺乏对CRF神经元亚群的遗传访问使得CRF生物学的研究变得困难 神经元，CRF在不同脑区的来源，以及CRF调节行为的电路。 为了填补这一空白，我们产生了BAC转基因Wistar大鼠系，其中Cre重组酶从 Crh基因启动子，使基因进入CRF神经元。在这个项目中，我们将用这些老鼠来追踪 这一假说认为，当动物产生乙醇依赖时，CeA和BNST中的CRF神经元促进了 乙醇消耗通过协调释放GABA，CRF和其他神经肽。我们将 通过选择性地激活或抑制这些神经元群体及其投射来检验这一假设 使用化学遗传学工具，我们将解决不同的发射机的相对重要性， 调节剂释放这些神经元使用Cre依赖的RNA干扰。最后，我们将调查 反复饮用乙醇对这些CRF神经元群体转录组的作用， 了解乙醇如何改变它们的表型，这应该为我们提供重要的新线索， 他们过度饮酒。 !