Fractionating human defensive circuits across changing levels of threat imminence

项目摘要 这项提议的基本目标是分割人类的防御回路和行为。我们的方法 解决了三个关键问题。其中包括以下知识：(1)实验范式未能将 不同级别威胁迫在眉睫的不同主观情绪和神经表征；(Ii)未能创造更丰富的 人类行为分析，以解决啮齿动物和人类情感研究之间日益扩大的测量差距；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分化的关注，因此提供的信息很少或根本没有 对焦虑症的性别差异的洞察。要回答这些问题，关键的第一步是理解 人脑对不同程度的威胁迫在眉睫做出反应。在这个提案中，我们将创建一套新的范例， 提供包括恐惧和焦虑情绪在内的人类防御系统的全面细分，以及 将它们与一套丰富的隐蔽行为分析和公开决策联系起来，这些分析和决策会随着威胁模式的变化而变化 迫在眉睫。 我们通过四个具体目标应对这些挑战： 目标1.提供对人类防御回路、身体情绪和行为的全面细分。目标1有 三个关键目标。这包括细分遭遇前和遭遇后的防御回路(潜在威胁)。 以及使用单一任务的约-打击(急性威胁)威胁模式。我们将为每个人确定新的行为衡量标准 威胁的方式。最后，我们将测量每个威胁迫在性级别的主观身体情绪状态和 与摘录相关。1比3。 目标2.大脑中的哪些区域控制着攻防状态之间的转换？在这里，我们旨在通过以下方式验证目标1 考察遭遇后和打击前后威胁的防御行为和神经基础。此外，我们在目标1上进行了扩展 通过研究下丘脑、杏仁核和vmPFC在攻防转换中的作用 生存状态。 目标3.防御回路的哪些部分协调回避决定？通过评估以下哪项扩展了目标1和2 防御回路的一部分参与了明确的、先发制人的回避决定。此外，我们将研究 攻击可预测性对危险或安全的决策和学习的影响，从而延伸到更内隐的行为 以AIMS 1-2衡量。 目的4.调查男性和女性防御回路的不同部分对威胁的反应有何不同。vt.给出 女性表现出更高的焦虑症发病率，我们将调查性行为与大脑活动之间的关系， 目标1-3中测量的主观情绪、防御行为和决策。我们将交叉验证性别差异 通过比较重叠的电路和行为，跨目标1-3的发现。 总之，这项工作将为人类防御系统的不同部分提供基本的见解 在明确定义的威胁迫在眉睫模式下运行。我们的目标之间的密切联系也提供了几个 优势，包括对我们的结果进行交叉验证，能够检查行为和大脑系统的差异 在两性之间，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.