Behavioral, molecular and sex-specific mechanisms of indirectly learned fear memory

项目总结/摘要 这项计划的主要目标是了解恐惧记忆是如何形成和储存在大脑中的。后 创伤性应激障碍（PTSD）影响了近5%的世界人口，然而，目前的治疗方法 逆转这种疾病症状的疗效有限。此外，女性比男性更有可能 发展PTSD，尽管控制这种性别依赖倾向的机制仍然不明确。而 已建立的啮齿动物恐惧条件反射模型有助于阐明神经生物学机制 支持形成恐惧记忆的创伤后应激障碍，这些几乎完全集中在个人 经历创伤性事件然而，一些创伤后应激障碍和相关的焦虑症的病例可能是 通过目睹创伤性事件发生在附近的其他人身上而获得。尽管如此， 已经研究了间接获得的恐惧记忆的神经生物学，以及它们是否不同于那些间接获得的恐惧记忆。 直接经历创伤事件的记忆此外，是否存在性别差异， 间接恐惧记忆的行为和分子机制还有待探索。在我们的初步调查中 使用间接恐惧条件反射程序的研究，其中观察者大鼠观察演示者大鼠 将听觉提示与轻微的足震联系起来，我们发现雄性和雌性大鼠都可以间接地 获得恐惧记忆Fmr 1基因的缺失会导致社会行为的缺陷， 间接恐惧记忆的增强，这表明社会线索可能不是驱动恐惧的主要因素。 获得性恐惧重要的是，我们发现了蛋白质降解靶点的独特变化， 杏仁核的示范和观察大鼠，表明独特的分子签名，直接与间接 获得恐惧记忆本提案中的工作旨在建立这些初步数据和答案 关于行为的重要问题，分子和性别特异性机制控制的形成， 间接获得的恐惧记忆使用遗传大鼠品系和特定操作进行训练（学习） 目标1将系统地测试行为机制（社会，视觉，嗅觉，听觉）， 哪些间接恐惧记忆是后天获得的，以及这一点如何因性别而异。Aim 2将使用全基因组 转录组学和蛋白质组学方法以及成熟的药理学操作，以确定 直接和间接获得的恐惧记忆的形成需要类似的转录，翻译和 蛋白质降解机制以及这是否因性别而异。总的来说，这项研究将回答重要的 关于控制间接获得恐惧记忆形成的性别特异性机制的问题 协会，这将是至关重要的发展适当的治疗干预措施，以治疗 创伤后应激障碍是通过移情作用获得的。

Project Summary/Abstract The broad goal of this proposal is to understand how fear memories are formed and stored in the brain. Post- traumatic stress disorder (PTSD) affects nearly 5% of the world population, however, current treatments have limited efficacy in reversing the symptoms of this disorder. Furthermore, females are more likely than males to develop PTSD, though the mechanisms controlling this sex-dependent predisposition remain equivocal. While established rodent fear conditioning models have aided in the elucidating the neurobiological mechanisms supporting the formation of fear memories that underlie PTSD, these focus almost exclusively on the individual experiencing the traumatic event. However, some cases of PTSD and associated anxiety disorders can be acquired by witnessing a traumatic event happen to someone else in close proximity. Despite this, few studies have examined the neurobiology of indirectly acquired fear memories and whether they differ from those of memories for directly experienced traumatic events. Furthermore, whether there are sex differences in the behavioral and molecular mechanisms of indirectly fear memories has yet to be explored. In our preliminary studies using an indirect fear conditioning procedure in which an observer rat watches a demonstrator rat associate an auditory cue with a mild footshock, we found that both male and female rats could indirectly acquire fear memories. Genetic loss of Fmr1, which produces deficits in social behavior, resulted in an enhancement of indirect fear memories, suggesting that social cues may not be the primary factor driving empathetically acquired fear. Importantly, we found unique changes in protein degradation targets in the amygdala of demonstrator and observer rats, suggesting unique molecular signatures for directly vs indirectly acquired fear memories. The work in this proposal is designed to build off of these preliminary data and answer important questions about the behavioral, molecular and sex-specific mechanisms controlling the formation of indirectly acquired fear memories. Using genetic rat lines and specific manipulations to the training (learning) experience, Aim 1 will systematically test the behavioral mechanisms (social, visual, olfactory, auditory) by which indirect fear memories are acquired and how this varies by sex. Aim 2 will use whole genome transcriptomic and proteomic approaches and well-established pharmacological manipulations to determine if the formation of directly and indirectly acquired fear memories requires similar transcriptional, translational and protein degradation mechanisms and whether this varies by sex. Collectively, this study will answer important questions about the sex-specific mechanisms controlling the formation of memories for indirectly acquired fear associations, which will be critical for the development of proper therapeutic interventions for the treatment of PTSD that is acquired empathetically.