The Impact of Individual Vulnerability to Stress on Alcohol and Drug Seeking

项目总结 压力会增强人和动物的记忆力。这种压力增强的记忆力 与压力相关的精神障碍的相关性，如创伤后应激障碍(PTSD)，这是明显的 通过对创伤的高度、坚持不懈的记忆。有趣的是，只有大约10%-20%的人 创伤后应激障碍的持久症状，尽管几乎每个人在他们的 一辈子。此外，女性和军人患创伤后应激障碍的比例更高。制定了一项协议 这会导致一个遥远的(一个月大的)恐惧对应激增强的不同易感性 雄性小鼠的记忆力和雌性小鼠更大的增强倾向。尽管有明显的重要性 了解支持持久、持久记忆的机制，大多数基本记忆 研究的重点是最近的(~1天大的)，而不是远程记忆，并且没有纳入压力成分。 该小组使用该方案进行的另一项研究发现，基底外侧杏仁核(BLA)具有 关键中枢调节压力增强的恐惧记忆和相关的差异敏感性。初级阶段 当前应用的目标是描绘应激如何参与和改变BLA的功能以驱动 对压力增强的恐惧记忆的不同敏感性。这部作品将把性作为一种 血乳酸的生物学变量和偏侧化函数。对于后者，右半球BLA是 与负价相关联，而左边与正价相关联。这是保守的，因为 从人类到啮齿动物，但在基础研究中研究不足。这一提议的中心假设是，压力 导致对血乳酸的持久影响，导致对远程应激增强恐惧的不同易感性 记忆。有待探索的工作假设是，强烈的急性应激源会改变随后的恐惧记忆。 通过影响特定BLA细胞群体的募集来增强记忆的痕迹。通向的工作 本提案(F99目标1A)详细描述了神经集合支持的同一性和偏侧性的研究 压力诱导的记忆增强。为了研究压力影响如何经历编码来影响压力- 增强恐惧记忆(F99目标1B)，我将训练执行和体内钙成像的数据分析 BLA。在过渡到博士后研究员职位时，我将专注于基于高发病率的研究 应激障碍与酒精和物质障碍之间(K00)。这项研究将纳入 神经生理学和深度测序方法进一步研究应激是如何单独影响脑功能的 影响酒精或毒品寻求的血乳酸及相关回路。拟议的工作将提供更多- 在差异应激的背景下，需要对应激对大脑的影响进行深入的表征 敏感度。这些信息将被用来指导细胞、分子和电路水平的机制研究， 目的是确定治疗策略。

PROJECT SUMMARY Stress leads to the enhancement of memory in both humans and animals. This stress-enhanced memory has relevance to stress-related psychiatric disorders, such as posttraumatic stress disorder (PTSD), which is marked by heightened, perseverant memories of trauma. Interestingly, only approximately 10-20% of people develop the enduring symptoms of PTSD, despite nearly everyone experiencing at least one traumatic event in their lifetime. In addition, rates of PTSD are higher among women and military personnel. A protocol was developed by this group that results in differential susceptibility to stress enhancement of a remote (one month old) fear memory among male mice and a greater propensity for enhancement in females. Despite the clear importance of understanding the mechanisms supporting long-lasting, perseverant memory, the majority of basic memory research focuses on recent (~ 1 day old), not remote memory and does not incorporate a stress component. Additional research performed by the group with this protocol identified the basolateral amygdala (BLA) has a critical hub mediating stress-enhanced fear memory and the associated differential susceptibility. The primary goal of the current application is to delineate how stress engages and alters the function of the BLA to drive differential susceptibility to stress-enhanced fear memory. The work will place particular focus on sex as a biological variable and lateralized function of the BLA. Regarding the latter, the right hemisphere BLA is associated with negative valence, while the left is associated with positive valence. This is conserved from humans to rodents but is understudied in basic research. The central hypothesis of this proposal is that stress leads to lasting impacts on the BLA, resulting in differential susceptibility to remote stress-enhanced fear memory. The working hypothesis to be explored is that an intense acute stressor alters subsequent fear memory strength by influencing the recruitment of specific BLA cell populations to the memory trace. Work leading up to this proposal (F99 Aim 1A) details studies characterizing identity and laterality of neural ensembles supporting stress-induced memory enhancement. To examine how stress impacts experience coding to influence stress- enhanced fear memory (F99 Aim 1B), I will train in execution and data analysis of in vivo calcium imaging of the BLA. In transitioning to a postdoctoral fellowship, I will focus on research based on the high rate of co-morbidity between stress disorders and alcohol and substance sue disorders (K00). The research will incorporate neurophysiological and deep sequencing measures to further study how stress individually impacts function of the BLA and associated circuitry to influence alcohol or drug seeking. The proposed work will provide a much- needed, deep characterization of the impact of stress on the brain in the context of differential stress susceptibility. This information will then be used to guide cellular, molecular and circuit level mechanistic studies, with the goal of identifying therapeutic strategies.