Neural mechanisms of stress-based effects on fear circuitry

压力对恐惧回路影响的神经机制

• 批准号: 10264133
• 负责人: Valerie J. Estela-Pro
• 金额: $ 8.35万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-31 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264133
• 关键词: Address; Adopted; Affect; Amygdaloid structure; Anatomy; Animals; Anxiety; Anxiety Disorders; Area; Arrestins; Aversive Stimulus; Behavior; Behavioral; Brain; Chronic stress; Data; Disease; Electrophysiology (science); Endocrinology; Environment; Exhibits; Exposure to; Extinction (Psychology); Extracellular Signal Regulated Kinases; FOS gene; Family; Female; Fiber; Fright; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Hypothalamic structure; Immediate-Early Genes; Impairment; Individual; Lateral; Learning; Limbic System; Link; Location; Maintenance; Measurable; Measures; Medial; Memory; Mental Depression; Modeling; Mood Disorders; Neurons; Neuropeptides; Peptides; Pharmacology; Phospholipase C; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Proteins; Rattus; Reporting; Retrieval; Role; Signal Transduction; Site; Stress; Stressful Event; Structure; Structure of paraventricular nucleus of thalamus; Synaptic plasticity; Testing; Time; Training; Variant; Vulnerable Populations; Withdrawal; Wood material; base; biological adaptation to stress; career; clinical anxiety; conditioned fear; coping; depressive behavior; desensitization; design; designer receptors exclusively activated by designer drugs; fear memory; fighting; habituation; hypocretin; in vivo; nerve supply; neuromechanism; postsynaptic; postsynaptic neurons; receptor; receptor internalization; resilience; response; sex; social defeat; trait

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.

摘要/项目摘要 在厌恶刺激及其预测因子和后来回忆这些关联之间形成关联的能力对于生存至关重要。相反，对于适应不断变化的环境，必须抑制恐惧回应后抑制恐惧反应的能力。恐惧回路的适应不良功能在诸如创伤后应激障碍，抑郁和焦虑之类的疾病中可见；因此，恐惧调节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，但是这些缺陷仅在一个个体的一部分中出现。压力脆弱性的一个因素是采用的应对策略（Veenema等，2003），分别被动应对和主动应对分别隔离为脆弱或弹性的特征（Wood＆Bhatnagar，2015; Pearson-Leary et al。，2017，2017）。但是，将压力脆弱性或韧性与恐惧学习差异联系起来的特定大脑电路是未知的。丘脑（PVT）的室室核在解剖学和功能上既可以成为压力和恐惧的综合基因座的主要候选者。在下丘脑中合成的Orexins，神经肽在整个边缘系统中均进行了突出，调节了与压力相关疾病和恐惧所涉及的许多领域，例如基底外侧杏仁核，前额叶皮层和PVT。减少的OX表达与压力事件发生压力事件和免受恐惧学习障碍的保护有关。本提案的目标1解决了一个问题：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，由设计师药物（Dreadds）专门激活的设计器受体将用于阻止或增强PVT内的OX活性，并在脆弱和弹性人群之间进行比较。性别也将被分析，因为来自Bhatnagar实验室的初步数据表明，雌性大鼠表现出升高的Orexin表达，这延迟了压力的适应性。由于PVT可能没有融合的源头，因此还将研究周围地区在压力和恐惧中也很重要的区域。 AIM 2将解决以下方式：如何使这些效果永久化，其氧气的浓度如何具有清晰可测量的作用？ OX受体是G蛋白偶联受体，因此将仔细检查这些受体的相互作用和随后的信号级联反应，以确定压力影响恐惧学习的机制。 AIM 3将解决一个电路级别：什么：压力和随后的OX变化对该网络内的本地场电位有什么影响？表征和量化压力对恐惧网络的影响对于发展未来的情感障碍治疗至关重要。该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相结合，以便为候选人做好独立职业的准备，她计划进一步研究压力对学习和记忆的影响。