Friday, May 9, 2025
5/9/2025
Fractionating human defensive circuits across changing levels of threat imminence - 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.
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