Mechanisms of sex selective enhancement of threat anticipation following early life adversity

早年逆境后性别选择性增强威胁预期的机制

• 批准号: 10617259
• 负责人: Camila Demaestri
• 金额: $ 2.28万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617259
• 关键词: Adaptive Behaviors; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Automobile Driving; Award; Beds; Behavior; Behavioral; Behavioral Assay; Biological; Brain; Calcium; Cells; Clinical; Corticotropin-Releasing Hormone; Cues; Data; Development; Disease; Emotional; Exhibits; Female; Fiber; Fluorescence; Fright; Generalized Anxiety Disorder; Goals; Human; Hyperactivity; Incidence; Individual; Intervention; Knowledge; Learning; Loudness; Measures; Mediating; Mus; Neurobiology; Neurons; Neuropeptides; Noise; Pathology; Photometry; Population; Predisposition; Prevalence; Research; Research Personnel; Resources; Risk; Role; Scientist; Sex Differences; Shock; Signal Transduction; Startle Reaction; Stimulus; Stress; Structure of terminal stria nuclei of preoptic region; Symptoms; Techniques; Testing; Training; Visualization; Woman; anxiety-related disorders; behavioral response; clinical care; clinically relevant; comorbidity; comparison control; conditioning; diagnostic criteria; early experience; early life adversity; effective therapy; endophenotype; experience; hormonal signals; improved; in vivo; indexing; insight; male; mouse model; neural; neural correlate; neuromechanism; novel; optogenetics; pharmacologic; recruit; response; sensor; sex; tool; treatment of anxiety disorders; treatment response; vigilance

PROJECT SUMMARY. Experiencing early life adversity (ELA), such as resource scarcity, is associated with anxiety-related disorders, including generalized anxiety disorder (GAD). Women have a two-fold greater prevalence of anxiety disorders, more robust presentation of symptoms, and poorer response to treatments. A debilitating and core feature of GAD is heightened anticipation of threat when it is not necessarily present. While responding to threat is adaptive, excessive anticipation in the absence of real threat can manifest as pathology. Examining the neural correlates underlying threat anticipation is critical to understanding sex- specific risk and developing effective treatments. ELA alters threat response circuitry, associated with excessive recruitment of the central amygdala (CeA), a region important for threat learning. A neuropeptide, corticotropin releasing hormone (Crh), within the CeA responds to threat-predictive cues and send long-range projections to the bed nucleus of the stria terminalis (BNST), a region known for behavioral modulation in response to stress. However, the impact of ELA on the Crh+ CeA to BNST projection and how sex-differences within this projection may alter threat anticipation remains unclear. Thus, examining the Crh CeA to BNST projection as a potential neurobiological target by which ELA enhances responses to threat will be central to understanding neural underpinnings of pathology and sex differences in risk. The startle response is an especially suitable endophenotype to study threat responding because it is reliably enhanced when threat is explicitly cued. It also provides a useful translational tool, as the behavior has been widely used in clinical settings. In preliminary studies, I used the limited bedding mouse model of ELA to test its effects on startle response as an index of threat anticipation. I found that mice who experience ELA exhibit enhanced startle to a loud noise both in the presence and absence of the conditioned tone, suggesting both heightened and maladaptive anticipation of threat. Importantly, this effect was exclusive to females. I hypothesize that anticipation of threat is driven by activation of CeACrh to BNST neurons and that ELA female mice show excessive activation of this circuit both when threat is present and absent. In Aim 1, I will test for sex- and ELA-specific differences of Crh CeA to BNST activity when threat is either present or absent by using fiber photometry to visualize calcium activity from a population of CeA Crh neurons projecting to BNST during the fear-potentiated startle task. In Aim 2, I will test the necessity of the CeA Crh to BNST projection for anticipated threat by optogenetically inhibiting Crh BNST terminals from CeA in the presence of threat. Ultimately, this knowledge may contribute to the development of proper treatments for anxiety disorders that are individualized to the experience and sex of the individual. The training I will gain through this F31 award will support my path towards becoming a well-rounded and independent research scientist focused on studying animal models of pathology and the consequences of ELA on emotional development.

项目摘要。经历早期生活逆境（ELA），例如资源稀缺，与 与焦虑有关的疾病，包括普遍的焦虑症（GAD）。女人有两个大的 焦虑症的患病率，症状的更强大表现以及对治疗的反应较差。一个 当不一定存在威胁时，GAD的衰弱和核心特征会加剧对威胁的预期。 虽然应对威胁是适应性的，但在没有真正威胁的情况下过度期待会表现为 病理。检查神经相关的潜在威胁预期对于理解性行为至关重要 - 具体风险和开发有效的治疗方法。 ELA改变威胁响应电路，与 过度招募中央杏仁核（CEA），这是威胁学习重要的地区。神经肽， CEA内部释放激素（CRH）的皮质激素释放激素（CRH）对威胁预测性提示做出反应并发送远距离 对质末端（BNST）的床核的投影，该区域因行为调制而闻名 对压力的反应。但是，ELA对CRH+ CEA对BNST投影的影响以及性别差异如何 在此预测中可能会改变威胁预期尚不清楚。因此，检查CRH CEA到BNST 投影是一种潜在的神经生物学目标，ELA增强对威胁的反应将是 了解病理学和性别差异的神经基础。 惊吓反应是研究威胁响应的特别合适的内表型，因为它是 当威胁明确提示时，可靠地增强。它还提供了一个有用的翻译工具，因为行为已有 被广泛用于临床环境。在初步研究中，我使用了有限的ELA床上用小鼠模型 测试其对惊吓反应的影响，作为威胁预期的指数。我发现体验ELA展览的老鼠 在有条件的语调的情况下和没有 对威胁的预期增加和适应不良的期望。重要的是，这种影响是女性独有的。我 假设对威胁的预期是由CACRH激活到BNST神经元的驱动的，而ELA则驱动 雌性小鼠在存在威胁和不存在时表现出该电路过多的激活。在AIM 1中，我 当存在或不存在威胁​​时 通过使用纤维光度法来可视化投射到BNST的CEA CRH神经元的钙活性 在恐惧的惊吓任务中。在AIM 2中，我将测试CEA CRH的必要性 在存在威胁的情况下，光遗传学上抑制CEA的CRH BNST码头的预期威胁。 最终，这种知识可能有助于发展焦虑症的适当治疗 被个性化与个人的经验和性别相关。我将通过此F31奖获得的培训 将支持我成为一名专注于研究的全面和独立的研究科学家的道路 病理学的动物模型以及ELA对情绪发展的后果。