mTOR Signaling and Alcohol Use Disorder

雷帕霉素在哺乳动物中的靶点复合体1(MTORC1)是一种在蛋白质中起关键作用的激酶 树突的翻译、突触的可塑性以及学习和记忆。我们发现mTORC1扮演着一种 在与酒精滥用障碍(AUD)相关的行为中发挥主要作用，包括过度饮酒 和摄入，以及与酒精奖励相关的记忆。我们进一步发现mTORC1. 通过突触的翻译参与伏核的突触和结构可塑性 蛋白质。最近，我们发现，反复酗酒和戒酒的循环会激活 眼眶前额叶皮质(OFC)的mTORC1信号传递，这是大脑中对联想学习和 奖励价值。我们进一步表明，抑制大鼠OFC中的mTORC1可以减弱酒精寻求 以及习惯性的酒精反应。最后，我们产生的数据表明NMDA受体(NMDAR)在 OFC参与mTORC1的激活和酗酒和嗜好。OFC接收谷氨酸能 来自杏仁基底外侧核(BLA)和丘脑背内侧核(MDMC)的传入，投射到 背侧纹状体(DS)和BLA。我们假设谷氨酸能白血球蛋白和/或 酒精反应的MDMC神经元激活OFC中的mTORC1信号驱动习惯性酒精 寻求(目标1)。我们进一步假设，在特定的OFC投射中，mTORC1被酒精激活 神经元启动酒精寻求和习惯性反应(目标2)。在目标3中，我们将确定 上述行为结果背后的分子机制。具体来说，我们会研究 MTORC1下游靶向崩塌蛋白反应介体蛋白II(CRMP-2)对 酗酒和酗酒习惯。我们还将进行RNA测序分析，以确定新的下游 OFC中mTORC1的靶点，其翻译被酒精增加。为了解决这些假设， 并在OFC电路的上下文中测试mTORC1信令的贡献，我们计划使用 新的分子工具与大鼠行为模式的结合。总而言之，这项研究提案 将使我们第一次能够阐明酒精的一个重要分子靶标在上下文中的作用 关键的神经回路。此外，公开市场委员会对澳元的贡献研究不足，而我们的 研究工作将极大地扩展关于这一主题的知识。最后，我们对mTORC1及其相关基因进行了研究 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)： 这项提议的目的是研究以大脑为中心的大脑回路中的激酶mTORC1是如何 地区，OFC，有助于两个临床相关的表型，寻求酒精和习惯。要做到这一点，我们将 结合大鼠的行为模式，使用最先进的分子方法。我们的研究将 不仅扩展了我们关于酒精在大脑中作用的神经适应的知识，而且还将 也能够为未来治疗AUD的药物开发确定新的靶点。

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.