Time-Dependent Effects of Stress on Learning: Physiological and Genetic Associations

 描述（由申请人提供）：压力引起的学习和记忆改变对于理解创伤后应激障碍（PTSD）的发展具有重要意义。研究人员推测，创伤应激可能会促进创伤后应激障碍的发病，这是由于预先存在的遗传因素和创伤前后的生理反应影响学习，从而影响创伤记忆的形成。事实上，研究人员已经在某些基因多态性、情绪记忆和创伤后应激障碍的发病之间建立了明确的联系。然而，系统的检查，在临床样本中，可能促进创伤记忆形成的易感因素是有问题的，使基本模型的压力记忆相互作用的必要性。目前还不清楚哪些因素是决定压力对学习和记忆的影响类型的最重要因素，以及这些影响何时促进了侵入性记忆的形成。关于压力对学习的影响的一个主要理论是情绪记忆处理的时间动力学模型。根据这一理论，应激对学习产生双相影响，这是杏仁核诱导的海马突触可塑性调制的结果。具体来说，压力会迅速激活杏仁核，从而增强海马体的可塑性，促进强大的情感记忆的形成;然而，随着压力的持续，海马体进入不应状态，在此期间海马体的可塑性受损，从而学习能力受损。我们有初步的数据支持这些预测人类的陈述性学习;然而，这些影响的机制仍然不清楚，以及压力源时间如何影响其他形式的学习，可能更好地与创伤记忆的形成，如恐惧条件反射和灭绝，尚未进行检查。此外，性别差异在压力记忆文献中很常见，但很少有研究探讨性别在压力对学习的时间依赖性影响中的作用。因此，在目标1中，我们将研究学习前压力的时间如何与个体特征（例如，自主和内分泌应激反应，性别）影响陈述性学习和恐惧条件反射。由于几乎没有研究与情绪记忆和压力相关的基因多态性如何增加创伤记忆形成的风险，这将是目标2的重点。我们将对目标1中研究的参与者进行单核苷酸多态性（SNP）基因分型，这些SNP与生理应激反应、情感记忆和/或PTSD风险相关，并检查这些SNP是否与参与者对应激暴露的生理反应/恢复以及任何观察到的应激诱导的学习和记忆改变相关。这些研究将有助于重要的知识，当压力增强与损害学习和记忆，以及这种影响的生理机制。这些发现也可能有助于深入了解创伤记忆形成的风险因素，并可能促进未来更有针对性的创伤后应激障碍治疗方案的发展。

 DESCRIPTION (provided by applicant): Stress-induced alterations of learning and memory have important implications for understanding the development of post-traumatic stress disorder (PTSD). Researchers have speculated that traumatic stress may promote the onset of PTSD as a result of pre-existing genetic factors and peri-traumatic physiological responses influencing learning and, thus, traumatic memory formation. Indeed, investigators have established a clear association between certain genetic polymorphisms, emotional memory and the onset of PTSD. However, systematic examination, in clinical samples, of susceptibility factors that could promote traumatic memory formation is problematic, making basic models of stress-memory interactions a necessity. It is still unclear as to what factors are most important for dictating te types of effects stress exerts on learning and memory and when the effects promote the formation of intrusive, debilitating memories. One leading theory regarding stress effects on learning is the temporal dynamics model of emotional memory processing. According to this theory, stress exerts biphasic effects on learning as a result of amygdala-induced modulation of hippocampal synaptic plasticity. Specifically, stress rapidly activates the amygdala, which enhances hippocampal plasticity and promotes the formation of powerful emotional memories; however, as stress continues, the hippocampus enters a refractory state during which hippocampal plasticity, and thus learning, is impaired. We have preliminary data supporting these predictions for declarative learning in humans; however, the mechanisms underlying these effects are still unclear, and an examination of how stressor timing influences other forms of learning that may relate better to traumatic memory formation, such as fear conditioning and extinction, has not yet been conducted. Moreover, sex differences are common in the stress-memory literature, yet little work has examined the role of sex in time-dependent effects of stress on learning. Thus, in Aim 1, we will examine how the timing of pre-learning stress interacts with individual characteristics (e.g., autonomic and endocrine stress responses, sex) to influence declarative learning and fear conditioning. Since there has been little work examining how genetic polymorphisms associated with emotional memory and stress increases one's risk for traumatic memory formation, this will be the focus of Aim 2. We will genotype participants from the studies in Aim 1 for single nucleotide polymorphisms (SNPs) that have been associated with the physiological stress response, emotional memory and/or risk for PTSD and examine whether such SNPs are associated with participants' physiological response to/recovery from stress exposure, as well as any observed stress-induced alterations of learning and memory. These studies will contribute important knowledge about when stress enhances versus impairs learning and memory and the physiological mechanisms underlying such effects. The findings may also lend insight into risk factors for traumatic memory formation and potentially facilitate the development of more targeted treatment options for PTSD in the future.