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

基本信息

  • 批准号:
    10617259
  • 负责人:
  • 金额:
    $ 2.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结。经历早年的逆境(ELA),如资源稀缺,与 焦虑相关障碍,包括广泛性焦虑症(GAD)。女性拥有两倍以上的 焦虑症的流行,症状的表现更强烈,对治疗的反应更差。一个 GAD的削弱和核心特征是当威胁不一定存在时,对威胁的高度预期。 虽然对威胁的反应是适应性的,但在没有真正威胁的情况下过度预期可能表现为 病理学。研究神经关联潜在的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),这是一个重要的威胁学习区域。一种神经肽, CEA内的促肾上腺皮质激素释放激素(CRH)对威胁预测线索做出反应并发送远程信息 投射到终纹床核(BNST),这是一个已知的行为调节区域 对压力的反应。然而,ELA对CRH+CEA到BNST投射的影响以及性别差异 在这一预测范围内,威胁的预期可能会发生变化,目前尚不清楚。因此,检查CRH CEA至BNST 作为一种潜在的神经生物学靶点,ELA通过投影增强对威胁的反应将是 了解病理的神经基础和风险中的性别差异。 惊吓反应是一种特别适合研究威胁反应的内表型,因为它是 当威胁被明确提示时,增强的可靠性。它还提供了一个有用的翻译工具,正如行为所具有的 已广泛应用于临床。在初步研究中,我使用了ELA的有限卧床小鼠模型 测试其对惊吓反应的影响,以此作为威胁预期的指标。我发现,经历过ELA的小鼠表现出 在有无条件性语气的情况下,增强了对巨大噪音的惊吓,暗示两者都有 对威胁的高度和不适应的预期。重要的是,这种影响只发生在女性身上。我 假设对威胁的预期是由CeACrh对BNST神经元的激活和ELA驱动的 无论是存在威胁还是不存在威胁,雌性小鼠都表现出这一回路的过度激活。在目标1中,我 当威胁存在或不存在时,将测试CRH CEA到BNST活性的性别和ELA特异性差异 用纤维光度法观察投射到BNST的CEA-CRH神经元的钙活动 在恐惧强化的惊吓任务中。在目标2中,我将测试CEA CRH到BNST预测的必要性 在威胁存在的情况下,通过光遗传抑制来自CEA的CRH BNST终端来预期威胁。 最终,这些知识可能有助于开发适当的焦虑症治疗方法。 根据个人的经历和性别进行个性化。我将通过这个F31奖获得的培训 将支持我成为一名全面独立的研究科学家,专注于研究 病理学的动物模型以及ELA对情绪发育的影响。

项目成果

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