Neuropeptide receptors, behavioral states and acute ethanol effects

神经肽受体、行为状态和急性乙醇效应

• 批准号: 10385729
• 负责人: JILL C BETTINGER
• 金额: $ 34.93万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10385729
• 关键词: Acute; Affect; Affective; Alcohol consumption; Alcohols; Behavior; Behavior Control; Behavioral; Biological; CRISPR/Cas technology; Caenorhabditis elegans; Cells; Chronic; Complex; Coupled; Data; Development; Drug usage; Emotional; Enkephalins; Ethanol; Exploratory Behavior; GTP-Binding Proteins; Genes; Genetic; Genetic Techniques; Genetic Variation; Genetic study; Goals; Human; Human Development; Human Genetics; Individual; Investigation; Life; Locomotion; Maps; Measures; Mediating; Modeling; Molecular; Mutation; Nematoda; Neprilysin; Nervous System Physiology; Nervous system structure; Neurons; Neuropeptide Receptor; Neuropeptides; Neurotransmitters; Organism; Orthologous Gene; Outcome; Output; Pattern; Peptide Signal Sequences; Peptides; Pharmaceutical Preparations; Play; Predisposition; Proteins; RNA Interference; Receptor Gene; Regulation; Research; Resistance; Resources; Role; Serotonin; Signal Transduction; Site; Speed; Substance P; System; Tachykinin; Testing; Time; Variant; Work; alcohol effect; alcohol response; alcohol sensitivity; alcohol use disorder; behavioral outcome; behavioral phenotyping; drug of abuse; experimental study; gene discovery; gene network; in vivo; insight; interest; loss of function mutation; mutant; negative affect; neuronal circuitry; receptor; resistance mutation; response

PROJECT SUMMARY There are two, partially overlapping goals of this research: (1) comprehensively define the array of G protein- coupled neuropeptide receptors that act to modulate and mediate acute actions of ethanol in vivo. (2) investigate the impact of specific behavioral states on acute sensitivity to ethanol. We will characterize the roles of all neuropeptide receptors in C. elegans in basal locomotion behaviors and ethanol-induced behavioral effects. This comprehensive assessment will identify receptors that positively and negatively regulate the neuronal circuit that controls locomotion and those receptors that act to promote or negatively regulate ethanol actions. We will assess both the level of initial sensitivity to ethanol and the time-dependent development of acute functional tolerance to the drug. In addition, for those receptors that act to modify responses to ethanol, we will classify any interactions with the neuropeptidase nep-2, which is orthologous to the mammalian neprilysin protein. The mammalian neprilysin protein is involved in the regulation of levels of multiple important signaling peptides, including enkephalins, tachykinin, substance P and others. A mutation in the nep-2 gene produces an ethanol-resistant behavioral phenotype. We hypothesize that a peptide target of NEP-2, which is likely to be elevated in a nep-2 mutant background, acts to counteract acute effects of ethanol via increased signaling through a neuropeptide receptor. The proposed experiments will identify that receptor and test the hypothesis that the receptor acts in a defined neuronal circuit that controls behavioral state decisions. Our preliminary data has identified several mutants that affect both ethanol responses and a behavioral state decision that affects exploratory behavior. The circuit that regulates that decision is well defined, and includes the sites of action of neuropeptides and serotonin. We will define networks of genes that act to regulate that behavioral decision and ethanol responses, and test specific neurons in the controlling circuit for their role in regulating ethanol responses. The relationship between an emotional (or affective) state in humans and the problematic use of drugs of abuse is of significant interest. The successful outcome of this proposed research will provide a better understanding of how specific behavioral states, controlled by a known regulatory circuit, can impact the acute responses to an abused drug. There is a significant correlation between the level of an individual’s initial response to alcohol and their likelihood to develop an alcohol use disorder (AUD). Genetic variation in any of the human orthologs of the C. elegans genes identified in this study has the potential to alter an individual’s level of response to ethanol, and therefore could impact that individual’s predisposition to develop an AUD later in life.

项目概要 这项研究有两个部分重叠的目标：（1）全面定义 G 蛋白阵列—— 耦合神经肽受体，可调节和介导体内乙醇的急性作用。 (2) 研究特定行为状态对乙醇急性敏感性的影响。我们将表征 线虫中所有神经肽受体在基础运动行为和乙醇诱导的行为中的作用 影响。这项综合评估将识别出正向和负向调节的受体 控制运动的神经元回路以及促进或负向调节乙醇的受体 行动。我们将评估对乙醇的初始敏感性水平和随时间变化的发展 对药物的急性功能耐受。此外，对于那些能够改变对乙醇反应的受体， 我们将对与神经肽酶 nep-2 的任何相互作用进行分类，该酶与哺乳动物是同源的 脑啡肽酶蛋白。哺乳动物中性溶酶蛋白参与多种重要物质水平的调节 信号肽，包括脑啡肽、速激肽、P 物质等。 nep-2基因突变 产生乙醇抗性行为表型。我们假设 NEP-2 的一个肽靶点是 可能在 nep-2 突变背景中升高，通过增加来抵消乙醇的急性作用 通过神经肽受体发出信号。拟议的实验将鉴定该受体并测试 假设受体在控制行为状态决策的特定神经元回路中起作用。我们的 初步数据已经确定了几种影响乙醇反应和行为状态的突变体 影响探索行为的决定。调节该决策的电路已明确定义，包括 神经肽和血清素的作用位点。我们将定义基因网络来调节 行为决策和乙醇反应，并测试控制电路中特定神经元的作用 调节乙醇反应。人类的情绪（或情感）状态与事物之间的关系 滥用药物的问题使用引起了人们的极大兴趣。这项拟议研究的成功成果 将提供更好的理解如何由已知的调节电路控制的特定行为状态， 可能会影响对滥用药物的急性反应。的水平之间存在显着的相关性 个人对酒精的最初反应及其患酒精使用障碍 (AUD) 的可能性。遗传 本研究中确定的秀丽隐杆线虫基因的任何人类直系同源物的变异都有可能改变 个人对乙醇的反应水平，因此可能会影响个人对乙醇的倾向 在以后的生活中积累澳元。