The effects of biological sex, intolerance of uncertainty and anxious states on threat acquisition and extinction learning - Project Summary
Fear learning and regulatory processes have been the focus of intense scientific inquiry in recent years, as
converging evidence shows these processes play a crucial role in the emergence and treatment of stress and
anxiety disorders. Much research has focused on fear extinction learning, in which an individual learns to
update their representation of a conditioned fear stimulus after multiple presentations of that stimulus unpaired
with an aversive outcome. Exposure-based cognitive behavioral therapy is based on this form of learning.
While this form of therapy is highly effective, return of fear is common after treatment. To further optimize
exposure-based therapies, it’s important to better understand factors that mediate fear extinction learning
performance. One such factor is anxiety/stress. Research shows stress elicited prior to extinction can enhance
or attenuate extinction performance. But the paradigms used in these studies elicit acute physiological stress,
not the kind of anxious anticipation that characterizes threat-related disorders. States of anxious anticipation
could play a unique modulatory role on fear extinction learning performance. Furthermore, there is evidence
for sex-specific differences in stress sensitivity, suggesting a potential interactive effect of anxiety and sex on
fear extinction learning. Finally, evidence suggests individual differences in intolerance of uncertainty play a
role in modulating fear regulatory processes. Here, we will use a Pavlovian fear learning paradigm to test the
impact of anticipatory anxiety on fear extinction learning and extinction retrieval. We will also measure
neurobiological correlates of anxious anticipation and test the extent to which any differences in extinction
learning are associated with different levels, balance and timing of noradrenergic and glucocorticoid
expression. To address the substantial sex-specific disparity in prevalence of fear-related disorders, we will
test the interactive effects of anxiety and biological sex on fear extinction learning. Finally, we will examine
potential interactive effects of individual variability in Intolerance of Uncertainty, independent of trait anxiety,
and states of anxious anticipation on fear extinction learning. This study is in line with the mission and goals of
the NIH in several ways. For one, by studying anxious states, biological sex and trait differences as mediators
of fear extinction learning, this research will contribute to a growing knowledge base that’s being used to
develop more personalized treatment approaches for fear-related disorders. This is in accordance with the
broad goals of advancing brain science to better understand mental illness and to improve therapeutic
interventions, both of which are central to NIH’s strategic plan for research. The Negative Valence Systems
and Arousal and Regulatory Systems parts of the RDoC Matrix served as a guiding force in the development of
this proposal. Finally, this project will provide outstanding training opportunities for undergraduate students,
including many underrepresented minorities and students from disadvantaged backgrounds at York College
(CUNY), in accordance with NIH’s Notice of Interest in Diversity (NOT-OD-20-031).
