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

项目摘要/摘要 尽管可卡因有很强的回报，但并不是所有接触这种药物的人都有同样的滥用倾向。 这些差异的原因尚不清楚，但可能涉及易感因素，这些因素的阐明可能会导致 未来可能防止可卡因成瘾的疗法。其中一个易感因素是行为上对 可卡因的令人厌恶的属性，与防止寻找可卡因的奖励作用重叠。初步 这项建议中的数据表明，可卡因对某些人的厌恶作用可能比其他人强得多 而且可能是可卡因成瘾易感性的决定因素。这种变异性的潜在细胞机制 仍然不为人知。然而，我们的初步数据显示，较高的RhoA活性和D2-MSN兴奋性 MNAC壳与表现出更高的可卡因厌恶效应(从而降低寻找动力)的大鼠相关 可卡因)。然而，目前尚不清楚mNAC外壳中的这些细胞和分子适应是否参与了 可卡因的可恶属性。因此，为了解决这一知识差距，我提出了两个目标。在《目标1》中，我将 确定D2MSN在可卡因回避行为中的作用，为此，我将接受光纤光度学和 光遗传学方法。我假设在可卡因的厌恶阶段，D2-MSN被激活，而D2-MSN不被激活 活动反过来又会驱动可卡因的条件性负面属性。在目标2中，我将研究RhoA和相关的角色 以细胞特有的方式影响神经兴奋性和可卡因避免的基因。首先，我将使用信使核糖核酸捕获方法 分析与RhoA信号相关的细胞特异性基因翻译或与可卡因戒除相关的兴奋性 表型。此外，为了测试RhoA在兴奋性和可卡因避免行为中的因果作用，我将减少或 使用腺相关基因操作策略以细胞特异性的方式增加RhoA的活性。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外壳授予保护中的兴奋性 反对吸食可卡因。密集而全面的培训、指导和研究计划 是为实现这些目标而开发的。该计划将由一支强大的导师和合作者团队指导， 将有助于将我当前的技能与新的概念和技术框架相结合，因为我将继续建立自己的 在成瘾神经科学方面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.