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Principal Investigator: Dean Mobbs
Organization: CALIFORNIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $673,808
Funding agency: National Institute of Mental Health
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.
Terms: <Acute><Address><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Animal Model><Animal Models and Related Studies><Anxiety><Anxiety Disorders><Behavior><Behavioral><Behavioral Assay><Brain><Brain Nervous System><Brain region><Chemical Fractionation><Diagnostic><Differences between sexes><Differs between sexes><Emotional><Emotions><Encephalon><Equilibrium><Event><FRACN><Failure><Fear><Female><Fractionation><Fractionation Radiotherapy><Fright><Future><Glossary><Goals><Human><Hypothalamic structure><Hypothalamus><Knowledge><Learning><Link><Measurement><Measures><Modern Man><Outcome><RDoC><Research><Research Domain Criteria><Rodent><Rodentia><Rodents Mammals><Role><Sex Differences><Sexual differences><System><Validation><Work><affective neuroscience><amygdaloid nuclear complex><avoidance behavior><balance><balance function><behavior measurement><behavioral measure><behavioral measurement><disparities in sex><emotional experience><hypothalamic><insight><interest><male><model of animal><neural><novel><psychiatric symptom><response><sex><sex based differences><sex disparity><sex-dependent differences><sex-related differences><sex-specific differences><social role><validations>