mTOR Signaling and Alcohol Use Disorder

哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）是一种在蛋白质合成中起关键作用的激酶， 树突翻译、突触可塑性以及学习和记忆。我们发现mTORC 1发挥着 在与酒精滥用障碍（AUD）相关的行为中起主要作用，包括过度饮酒 和摄入量，以及与酒精奖励相关的记忆。我们进一步发现mTORC 1 通过翻译突触蛋白，促进突触和突触核的结构可塑性。 proteins.最近，我们发现，反复的酗酒和戒断循环激活了 mTORC 1信号在眶额皮层（OFC），一个重要的大脑区域的联想学习和 奖励价值我们进一步表明，抑制大鼠眶额皮层中的mTORC 1会减弱酒精寻求 和习惯性酒精反应最后，我们生成的数据表明，NMDA受体（NMDAR）在 OFC参与mTORC 1激活和酒精寻求和习惯。眶额皮层接受了 来自基底外侧杏仁核（BLA）和丘脑背内侧核（MDmc）的输入，并投射到 背侧纹状体（DS）和BLA。我们假设，脑内巨噬细胞能BLA的募集和/或 MDmc神经元对酒精的反应激活了OFC中的mTORC 1信号，以驱动习惯性酒精 寻找（目标1）。我们进一步假设mTORC 1在特定的OFC投射中被酒精激活， 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。具体而言，我们将研究 mTORC 1下游靶点--β-内酰胺酶反应介体蛋白II（CRMP-2）对 饮酒习惯与嗜好我们还将进行RNA测序分析， OFC中mTORC 1的靶点，其翻译被酒精增加。为了解决这些假设， 并测试mTORC 1信令在OFC电路中的作用，我们计划使用 新的分子工具与大鼠行为模式相结合。总之，这项研究计划 这将使我们第一次阐明酒精的一个重要分子靶点在这种情况下的作用， 关键的神经回路此外，OFC对AUD的贡献一直未得到充分研究， 研究工作将极大地扩展关于这一主题的知识。最后，我们对mTORC 1及其受体的研究表明， 下游目标将有助于治疗AUD的药物开发工作。 相关性（参见说明）： 这项提议旨在研究激酶mTORC 1如何在以大脑为中心的脑回路中发挥作用， 区域，OFC，有助于两个临床相关的表型，酒精寻求和习惯。为此，我们将 使用最先进的分子方法结合大鼠的行为范例。我们的研究将 不仅扩大了我们对大脑中酒精作用的神经适应性的认识， 还能够为未来治疗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.