Fractionating human defensive circuits across changing levels of threat imminence

项目摘要 这项提议的基本目标是破坏人类的防御回路和行为。我们的方法 解决了三个关键问题。这些包括以下知识：（一）实验范式未能打破 不同的主观情绪和神经表征在不同级别的威胁紧迫性;（ii）未能创造更丰富的 在人类中的行为测定，以解决啮齿动物和人类情感研究之间日益增长的测量差距;以及（iii） 缺乏对这些神经表征和行为如何作为性别的函数而发散的关注，因此提供很少或没有 对焦虑症性别差异的认识要回答这些问题，关键的第一步是了解 人类大脑对不同级别的威胁紧迫性作出反应。在本提案中，我们将创建一套新的范例， 提供了一个全面的人类防御系统，包括恐惧和焦虑的情绪， 将它们与一系列丰富的隐蔽行为分析和公开决策联系起来，这些分析和决策随着威胁模式的沿着而变化 迫在眉睫 我们通过四个具体目标应对这些挑战： 目标1。提供人类防御回路、身体情绪和行为的全面细分。目标1 三个关键目标。这包括在遭遇战前和遭遇战后（潜在的威胁）， 以及使用单个任务的循环攻击（急性威胁）威胁模式。我们将为每一个人确定新的行为措施， 的威胁方式。最后，我们将测量每个威胁紧迫性水平的主观身体情绪状态， 与Expt相关。1-3. 目标二。哪些大脑区域控制攻击和防御状态之间的转换？在这里，我们的目标是验证目标1， 研究遭遇战后和周围攻击威胁的防御行为和神经基础。此外，我们扩展了目标1 通过研究下丘脑、杏仁核和vmPFC在攻击和防御之间转换的作用， 生存状态。 目标3：防御回路的哪些部分协调回避决策？扩大目标1和2，评估 部分防御回路参与了明确的、先发制人的回避决定。此外，我们将研究 攻击可预测性对风险或安全决策和学习的影响，从而扩展到更隐式的行为 在目标1-2中测量。 目标4。研究男性和女性防御回路的不同部分在应对威胁时的不同。给定 女性表现出更高的焦虑症发病率，我们将研究性是如何与大脑活动相关联的， 目标1-3中测量的主观情绪、防御行为和决策。我们会交叉验证性别差异 通过比较重叠的回路和行为，发现目标1-3。 总之，这项工作将提供基本的见解，如何不同的部分，人类防御系统 在明确定义的威胁紧迫模式下运行。我们的目标之间的密切联系也提供了几个 优势，包括我们的结果的交叉验证，检查行为和大脑系统如何分歧的能力， 跨性别，提供与当代动物模型更紧密的联系。

Project Abstract The fundamental objective of this proposal is to fractionate human defensive circuits and behaviors. Our approach addresses three key issues. These include the knowledge that: (i) experimental paradigms have failed to fractionate the diverse subjective emotions and neural representations across different levels of threat imminence; (ii) a failure to create richer behavioral assays in humans to address the growing measurement gap between rodent and human studies of emotion; and (iii) a lack of focus on how these neural representations and behaviors diverge as a function of sex, therefore providing little or no insight in the sex disparity in anxiety disorders. To answer these questions, a critical first step is to understand how the human brain responds to different levels of threat imminence. In this proposal, we will create a new set of paradigms that provide a comprehensive fractionation of the human defensive system that include the emotions of fear and anxiety, and link them to a rich set of covert behavioral assays and overt decisions that vary along changing modes of threat imminence. We address these challenges via four specific aims: Aim 1. Provide a comprehensive fractionation of human defensive circuits, bodily emotions, and behaviors. Aim 1 has three key goals. This includes fractionating the defensive circuits involved in pre- and post-encounter (potential threat) and circa-strike (acute threat) modes of threat using a single task. We will identify novel behavioral measures for each mode of threat. Finally, we will measure subjective bodily emotional states for each level of threat imminence and correlate with Expts. 1-3. Aim 2. What brain regions direct the switching between offensive and defensive states? Here we aim to validate Aim 1 by examining the defensive behaviors and neural basis of post-encounter and circa-strike threat. Further, we extend on Aim 1 by investigating the role of the hypothalamus, amygdala, and vmPFC during switching between offensive and defensive survival states. Aim 3. What parts of the defensive circuit coordinate avoidance decisions? Extends on Aims 1 and 2 by assessing which parts of the defensive circuitry are involved in explicit, pre-emptive avoidance decisions. Further, we will examine the effects of attack predictability on risky or safe decisions and learning, thereby extending on the more implicit behaviors measured in Aims 1-2. Aim 4. Investigate how different parts of the defensive circuits differ in response to threats in males and females. Given that females demonstrate higher rates of anxiety disorders, we will investigate how sex is associated with brain activity, subjective emotions, defense behaviors, and decisions measured in Aims 1-3. We will cross-validate the sex difference findings across Aims 1-3 by comparing overlapping circuits and behaviors. At conclusion, this work will provide fundamental insights into how different parts of the human defensive systems operate under well-defined modes of threat imminence. The close links between our aims also provides several advantages, including a cross-validation of our results, the ability to examine how behaviors and brain systems diverge across the sexes, provide closer links with contemporary animal models.