Neural mechanisms of stress-based effects on fear circuitry

摘要/项目摘要 在厌恶性刺激和它们的预测因子之间形成联系的能力，以及后来回忆这些联系的能力，对于生存是必不可少的。相反，恐惧记忆消失后抑制恐惧反应的能力对于适应不断变化的环境是必要的。恐惧回路的适应不良功能见于创伤后应激障碍、抑郁症和焦虑症等疾病;因此，恐惧条件反射被广泛用作临床焦虑症的模型。慢性压力会影响恐惧回路的功能，但这些缺陷只会在一部分人中发展。易受压力影响的一个因素是所采用的应对策略（Veenema等人，2003），被动应对和主动应对分别分离为脆弱或弹性特征（Wood & Bhatnagar，2015; Pearson-Leary等人，2017年）。然而，连接压力脆弱性或恢复力与恐惧学习差异的特定大脑回路尚不清楚。丘脑室旁核（PVT）在解剖学和功能上都是压力和恐惧整合位点的主要候选者。食欲素，在外侧下丘脑合成的神经肽，项目在整个边缘系统，调节许多领域参与应激相关的疾病和恐惧，如基底外侧杏仁核，前额叶皮层，和PVT. Reduced OX的表达与压力事件后的压力恢复力和保护免受恐惧学习障碍。本提案的目标1解决了在哪里的问题：压力和恐惧的整合发生在哪里？我们的假设是，这种整合的位置是PVT，因此，设计师受体专门激活的设计师药物（DREADD）将被用来阻止或增强OX活动的PVT和脆弱和弹性人群之间的比较。还将分析性别，因为来自Bhatnagar实验室的初步数据表明雌性大鼠显示食欲素表达升高，从而延迟对压力的适应。由于PVT有可能不是整合的位点，因此也将检查已知在压力和恐惧中也很重要的周围区域。目标2将解决如何：如何集中的OX，它有明确的和可测量的影响，在应对压力，延续这些影响？OX受体是G蛋白偶联受体，因此这些受体的相互作用和随后的信号级联将被仔细检查，以确定压力影响恐惧学习的机制。目标3将解决一个电路级什么：什么是影响的压力，和随后的氧变化，对当地的场电位在这个网络？表征和量化压力对恐惧网络的影响对于开发未来情感障碍的治疗方法至关重要。该提案旨在将候选人在体内电生理学方面的专业知识与药理学和内分泌学方面的培训相结合，为候选人计划进一步研究压力对学习和记忆的影响的独立职业做好准备。

Abstract/Project Summary The ability to form associations between aversive stimuli and their predictors, and to later recall these associations, are imperative to survival. Conversely, the ability to inhibit fear responses following extinction of a fear memory is necessary for adaptation to changing environments. Maladaptive function of fear circuitry is seen in diseases such as post-traumatic stress disorder, depression, and anxiety; as such, fear conditioning is widely used as a model of clinical anxiety disorders. Chronic stress affects the function of the fear circuit, but these deficits develop in only a subset of individuals. One factor in vulnerability to stress is the adopted coping strategy (Veenema et al., 2003), with passive coping and active coping segregating into vulnerable or resilient traits respectively (Wood & Bhatnagar, 2015; Pearson-Leary et al., 2017). However, the specific brain circuits linking stress vulnerability or resilience to differences in fear learning are unknown. The paraventricular nucleus of the thalamus (PVT) is poised both anatomically and functionally to be a prime candidate for the locus of integration for stress and fear. Orexins, neuropeptides synthesized in the lateral hypothalamus, project throughout the limbic system, modulating many of the areas involved in stress-associated disorders and fear, such as the basolateral amygdala, the prefrontal cortex, and the PVT. Reduced OX expression is associated with resilience to stress following stressful events and protection from impairments in fear learning. Aim 1 of this proposal addresses the where question: Where does the integration of stress and fear take place? Our hypothesis is that the location of this integration is the PVT, therefore designer receptors exclusively activated by designer drugs (DREADDs) will be used to block or enhance OX activity within the PVT and compared between vulnerable and resilient populations. Sex will also be analyzed as there is preliminary data from the Bhatnagar lab suggesting that female rats display elevated orexin expression which delays adaptations to stress. Because there is potential for the PVT to not be the locus of integration, surrounding regions also known to be important in both stress and fear will also be examined. Aim 2 will address the how: How does the concentration of OX, which has clear and measurable effects in response to stress, perpetuate these effects? OX receptors are G-protein-coupled receptors, therefore the interactions and subsequent signaling cascades of these receptors will be closely examined to determine the mechanism through which stress affects fear learning. Aim 3 will address a circuit- level what: What is the effect of stress, and subsequent OX variation, on the local field potential within this network? Characterizing and quantifying the effects of stress on the fear network is crucial for developing future treatments for affective disorders. This proposal has been designed to combine the candidate's expertise in in vivo electrophysiology with training in pharmacology and endocrinology to prepare the candidate for an independent career where she plans to further examine the effects of stress on learning and memory.