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: 10432094
• 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 2023-03-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432094
• 关键词: Address; Adopted; Affect; Amygdaloid structure; Anatomy; Animals; Anxiety; Anxiety Disorders; Area; Arrestins; Aversive Stimulus; Behavior; Behavioral; Brain; Chronic stress; Coping Skills; 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 在厌恶刺激与其预测因子之间形成关联并在以后回忆起这些关联的能力对于生存至关重要。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中。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，但这些缺陷仅在一小部分人身上出现。易受压力影响的因素之一是所采用的应对策略（Veenema et al., 2003），其中被动应对和主动应对分别分为脆弱或弹性特征（Wood & Bhatnagar, 2015；Pearson-Leary et al., 2017）。然而，将压力脆弱性或恢复力与恐惧学习差异联系起来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准备成为压力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，投射到整个边缘系统，调节许多与压力相关的疾病和恐惧有关的区域，例如基底外侧杏仁核、前额皮质和PVT。 OX 表达减少与应激事件后的应激恢复能力以及免受恐惧学习障碍的保护有关。该提案的目标 1 解决了“哪里”的问题：压力和恐惧的融合发生在哪里？我们的假设是，这种整合的位置是 PVT，因此专门由设计药物 (DREADD) 激活的设计受体将用于阻断或增强 PVT 内的 OX 活性，并在脆弱群体和恢复群体之间进行比较。性别也将被分析，因为巴特纳加尔实验室的初步数据表明雌性大鼠的食欲素表达升高，从而延迟了对压力的适应。由于 PVT 有可能不是整合的场所，因此也将检查在压力和恐惧方面也很重要的周围区域。目标 2 将解决“如何”问题：OX 的浓度对压力具有明显且可测量的影响，如何使这些影响永久存在？ 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，以确定压力影响恐惧学习的机制。目标 3 将解决电路级问题：应力以及随后的 OX 变化对该网络内的局部场电位有何影响？表征和量化压力对恐惧网络的影响对于开发情感障碍的未来治疗方法至关重要。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结合起来，为候选人的独立职业做好准备，她计划进一步研究压力对学习和记忆的影响。

项目成果

Differential recruitment of brain circuits during fear extinction in non-stressed compared to stress resilient animals.

与应激恢复动物相比，无应激动物在恐惧消退过程中大脑回路的募集存在差异。

• 发表时间: 2024-01-25
• 影响因子: 4.6
• 作者: Pearson;Abramenko, Alexander P;Estela;Feindt;Yan, Jason;Vigderman, Abigail;Luz, Sandra;Bangasser, Debra;Ross, Richard;Kubin, Leszek;Bhatnagar, Seema
• 通讯作者: Bhatnagar, Seema