Cell-Types Specific Neuroadaptations in the Nucleus Accumbens Shell Associated with Individual Differences in Cocaine-Seeking

项目总结/摘要 虽然可卡因是强有力的奖励，但并不是所有接触这种药物的人都同样容易滥用它。 这些差异的原因尚不清楚，但可能涉及诱发因素，这些因素的阐明可能导致 在未来，这些疗法可能会预防可卡因成瘾。一个这样的诱发因素是行为敏感性， 可卡因的令人厌恶的属性，这与奖励效应重叠，以防止寻求可卡因。初步 该提案中的数据表明，可卡因的厌恶效应在某些人中可能比其他人强得多。 也可能是可卡因成瘾的决定因素这种变异性的潜在细胞机制 仍然未知。然而，我们的初步数据显示，在高血压大鼠中，RhoA活性和D2-MSN兴奋性较高， mNACshell与表现出可卡因的较高厌恶效应（并因此较低的寻求驱动力）的大鼠相关 可卡因）。然而，尚不清楚mNAC壳层中的这些细胞和分子适应是否参与了 可卡因令人厌恶的特性因此，为了弥补这一知识差距，我提出了两个目标。在目标1中，我将 确定D2 MSN对可卡因回避行为的作用，为此，我将接受纤维光度学的培训， 光遗传学方法。我假设D2-而不是D1-MSN在可卡因的厌恶阶段被激活，并且D2 活动反过来驱动可卡因的条件性负面属性。在目标2中，我将研究RhoA和相关的 基因对神经兴奋性和可卡因回避在细胞特异性的方式。首先，我将使用mRNA TRAP方法， 分析与RhoA信号传导或与可卡因回避相关的兴奋性相关的细胞特异性基因翻译 表型此外，为了测试RhoA在兴奋性和可卡因回避行为中的因果作用，我将减少或 使用腺相关基因操作策略以细胞特异性方式增加RhoA活性。我假设 D2-MSN中RhoA活性的增加而不是D1-MSN中RhoA活性的增加增强了mNAC壳的兴奋性， 反对收购可卡因寻求。一个密集而全面的培训，指导和研究计划， 为实现这些目标而开发。该计划将由一个强大的导师和合作者团队指导， 在我继续建立自己的框架时，我将帮助我将目前的技能与新的概念和技术框架相结合 成瘾神经科学的独特和创新的研究计划。

Project Summary/Abstract Although cocaine is powerfully rewarding, not all people who are exposed to this drug are equally prone to abusing it. The reasons for these differences remain unknown but may involve predisposing factors whose elucidation could lead to therapies that, in the future, may prevent cocaine addiction. One such predisposing factor is behavioral sensitivity to the aversive attributes of cocaine, which overlap with the rewarding effects to protect against cocaine-seeking. Preliminary data in this proposal suggest that the aversive effect of cocaine may be much stronger in some individuals than others and potentially a determinant for cocaine addiction vulnerability. The underlying cellular mechanism of this variability remains unknown. However, our preliminary data revealed that higher RhoA activity and D2-MSN excitability in the mNACshell correlate with rats displaying higher aversive effects of cocaine (and consequently lower drive to seek cocaine). Nevertheless, it is unknown if these cellular and molecular adaptations in the mNACshell are involved in the aversive attributes of cocaine. Accordingly, to address this gap in knowledge, I’m proposing two aims. In aim 1, I will determine the roles of D2MSN on cocaine avoidance behavior, and for this, I will be trained in fiber photometric and optogenetic methods. I hypothesize that D2- but not D1-MSNs are activated during cocaine’s aversive phase, and that D2 activity in turn drives conditioned negative attributes of cocaine. In aim 2, I will examine the roles of RhoA and related genes on neural excitability and cocaine avoidance in a cell-specific manner. First, I will use mRNA TRAP methods to analyze cell-specific gene translation associated with RhoA signaling or excitability linked to cocaine avoidance phenotypes. In addition, to test the causal role of RhoA in excitability and cocaine avoidance behavior, I will decrease or increase RhoA activity in a cell-specific manner using an adeno-associated gene manipulation strategy. I hypothesize that increases in RhoA activity in D2-MSN but not D1-MSN enhances excitability in the mNACshell confer protection against the acquisition of cocaine-seeking. An intense and comprehensive training, mentoring, and research plan has been developed to achieve these goals. This plan will be guided by a powerful team of mentors and collaborators that will help blend my current skill set with new conceptual and technical frameworks as I continue to establish my own unique and innovative research program in addiction neuroscience.