Neural mechanisms of stress-based effects on fear circuitry

摘要/项目摘要 在厌恶的刺激和它们的预测因素之间形成联系，并在以后回忆这些联系的能力，对于生存是至关重要的。相反，在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。恐惧回路的不适应功能可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，但这些缺陷只出现在一部分人身上。易受压力影响的一个因素是所采用的应对策略(Veenema等人，2003年)，其中被动应对和积极应对分别分为脆弱或弹性特征(Wood&Bhatnagar，2015；Pearson-Leary等人，2017)。然而，将压力易损性或恢复力与恐惧学习差异联系起来的具体大脑回路尚不清楚。丘脑室旁核(PVT)在解剖学上和功能上都被认为是应激和恐惧整合部位的主要候选者。食欲素是在下丘脑外侧合成的神经肽，在整个边缘系统中投射，调节与压力相关的障碍和恐惧的许多区域，如基底外侧杏仁核、前额叶皮质和PVT。OX表达减少与应激事件后的应激恢复能力和对恐惧学习中的损伤的保护有关。这项提议的目标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，因此由设计药物(DREADD)独占激活的设计受体将被用来阻断或增强PVT中的OX活性，并在脆弱和有弹性的人群之间进行比较。性行为也将被分析，因为来自Bhatnagar实验室的初步数据表明，雌性大鼠表现出高表达的食欲素，这会推迟对压力的适应。由于PVT有可能不是整合的中心，因此也将检查周围已知在压力和恐惧方面都很重要的区域。目标2将阐述如何：对压力具有明显和可测量影响的OX浓度如何使这些影响持续存在？OX受体是G蛋白偶联受体，因此将仔细研究这些受体的相互作用和随后的信号级联，以确定压力影响恐惧学习的机制。目标3将解决电路级的What：应力和随后的OX变化对该网络内的局部场电势有什么影响？确定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。这项建议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结合起来，为候选人的独立职业生涯做好准备，她计划在那里进一步研究压力对学习和记忆的影响。

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.