mTOR Signaling and Alcohol Use Disorder

mTOR 信号传导和酒精使用障碍

• 批准号: 9770730
• 负责人: DORIT RON
• 金额: $ 32.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770730
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Attenuated; Behavior; Behavioral Paradigm; Brain; Brain region; Complex; Corpus striatum structure; Data; Decision Making; Dendrites; Disease; Dorsal; FRAP1 gene; Future; Glutamates; Habits; Heavy Drinking; Instruction; Knowledge; Label; Learning; Medial Dorsal Nucleus; Mediating; Mediator of activation protein; Memory; Molecular; Molecular Target; N-Methyl-D-Aspartate Receptors; Neurons; Nucleus Accumbens; Phaseolus vulgaris leucoagglutinin; Phenotype; Phosphotransferases; Play; Proteins; Raptors; Rattus; Research; Research Personnel; Research Proposals; Rewards; Rodent; Role; Semaphorin-3A; Signal Transduction; Structure; Synapses; Synaptic plasticity; Testing; Time; Tracer; Transcript; Translations; Withdrawal; alcohol consequences; alcohol response; alcohol reward; alcohol seeking behavior; alcohol use disorder; behavioral outcome; binge drinking; brain circuitry; classical conditioning; clinically relevant; collapsin response mediator protein-2; designer receptors exclusively activated by designer drugs; drinking; drug development; knock-down; neural circuit; neuroadaptation; novel; recruit; response; reward processing; tool; transcriptome sequencing

The mammalian target of rapamycin in complex 1 (mTORC1) is a kinase that plays a key role in protein translation at dendrites, synaptic plasticity, and learning and memory. We discovered that mTORC1 plays a major role in behaviors associated with alcohol abuse disorders (AUD) including excessive alcohol seeking and intake, as well as memories associated with alcohol reward. We further found that mTORC1 contributes to synaptic and structural plasticity in the nucleus accumbens via the translation of synaptic proteins. More recently we found that repeated cycles of alcohol binge drinking and withdrawal activate mTORC1 signaling in the Orbitofrontal Cortex (OFC), a brain region important for associative learning and reward value. We further showed that inhibition of mTORC1 in the OFC of rats attenuates alcohol seeking and habitual alcohol responding. Finally, we generated data suggesting that NMDA receptors (NMDAR) in the OFC participate in mTORC1 activation and alcohol seeking and habit. The OFC receives glutamatergic inputs from the basolateral amygdala (BLA) and mediodorsal thalamic nucleus (MDmc), and projects to the dorsal striatum (DS), and the BLA. We hypothesize that recruitment of glutamatergic BLA and/or MDmc neurons in response to alcohol activates mTORC1 signaling in the OFC to drive habitual alcohol seeking (Aim 1). We further hypothesize that mTORC1 is activated by alcohol in specific OFC projecting neurons to initiate alcohol seeking and habitual responding (Aim 2). In Aim 3, we will determine the molecular mechanisms underlying the aforementioned behavioral outcomes. Specifically, we will study the contribution of the mTORC1 downstream target, collapsin response mediator protein II (CRMP-2), to alcohol seeking and habit. We will also conduct an RNA sequencing analysis to identify novel downstream targets of mTORC1 in the OFC whose translation is increased by alcohol. To address these hypotheses, and test the contribution of the mTORC1 signaling in the context of OFC circuitries, we plan to use novel molecular tools in combination with behavioral paradigms in rats. Together, this research proposal will allow us for the first time, to elucidate the role of an important molecular target of alcohol in the context of key neural circuits. Furthermore, the contribution of the OFC to AUD has been understudied, and our research effort will greatly expand the knowledge on this topic. Finally, our studies on mTORC1 and its downstream targets will contribute to drug development efforts for the treatment of AUD. RELEVANCE (See instructions): This proposal is aimed to study how the kinase mTORC1 in brain circuitries that centers around the brain region, OFC, contributes to two clinically relevant phenotypes, alcohol seeking and habit. To do so, we will use state of the art molecular approaches in combination with behavioral paradigms in rats. Our study will not only expand our knowledge on the neuroadaptations that underlie alcohol actions in the brain but will also enable the identification of new targets for future drug development to treat AUD.

复合物1（MTORC1）中雷帕霉素的哺乳动物靶标是一种激酶，在蛋白质中起关键作用 在树突上翻译，突触可塑性以及学习和记忆。我们发现MTORC1扮演 与酒精滥用障碍有关的行为中的主要作用（AUD），包括过多的酒精 和摄入量，以及与酒精奖励相关的记忆。我们进一步发现mtorc1 通过突触的翻译有助于伏隔核的突触和结构可塑性 蛋白质。最近，我们发现酒精暴饮暴食和戒断的重复循环激活 MTORC1信号传导（OFC）中的轨道额叶（OFC），一个大脑区域对于关联学习和 奖励价值。我们进一步表明，大鼠OFC中MTORC1的抑制会减弱寻求酒精的酒精 和习惯性酒精反应。最后，我们生成的数据表明NMDA受体（NMDAR） OFC参与MTORC1激活和饮酒和习惯。 OFC接收谷氨酸能 来自基底外侧杏仁核（BLA）和中型丘脑核（MDMC）的输入，并项目 背纹状体（DS）和BLA。我们假设募集谷氨酸能BLA和/或 响应酒精的MDMC神经元激活OFC中的MTORC1信号传导以驱动习惯性酒精 寻求（目标1）。我们进一步假设MTORC1在特定的OFC投影中被酒精激活 神经元开始寻求酒精和习惯反应（AIM 2）。在AIM 3中，我们将确定 上述行为结果背后的分子机制。具体来说，我们将研究 MTORC1下游靶标，Collapsin响应介质蛋白II（CRMP-2）的贡献， 寻求酒精和习惯。我们还将进行RNA测序分析以识别下游的新型 MTORC1在OFC中的靶标的靶标会因酒精而增加。为了解决这些假设， 并在OFC电路的背景下测试MTORC1信号的贡献，我们计划使用 新型分子工具与大鼠的行为范式结合使用。这项研究建议在一起 将首次允许我们在上下文中阐明酒精的重要分子靶标的作用 关键的神经回路。此外，OFC对AUD的贡献已经被研究了，我们的 研究工作将大大扩展有关此主题的知识。最后，我们对MTORC1及其的研究 下游目标将有助于治疗AUD的药物开发工作。 相关性（请参阅说明）： 该建议的目的是研究如何以脑电路为中心的激酶mTORC1 OFC地区有助于两种临床相关的表型，寻求酒精和习惯。为此，我们会 将艺术分子方法与大鼠的行为范式结合使用。我们的研究愿意 不仅扩大我们对大脑中酒精作用的神经适应性的知识，而且会扩大我们的知识 还可以识别未来药物开发的新目标，以治疗AUD。