Anxiety affects nearly one in three adolescents and contributes to substantial burden on both individuals and
society. Although evidence-based interventions for adolescent anxiety exist, treatment response is modest and
relapse rates are unacceptably high. Outcomes are even worse among low resource and racial/ethnic minority
populations. Recent studies have pinpointed neurodevelopmentally-informed targets that are relevant to
current evidence-based treatments for adolescent anxiety; namely, exposure-based cognitive behavioral
therapy (CBT), which relies on principles of fear extinction. Our group and others have shown that fear
extinction and frontolimbic circuitry change dynamically across the first two decades of life, and is modulated
by the endocannabinoid (eCB) system. Further, our exciting preliminary data show that acute exercise is
associated with lower anxiety and elevated eCB signaling in youth, and is therefore a promising approach for
optimizing efficacious treatments for adolescent anxiety. However, these advances have not yet translated to
improved therapeutic outcomes for youth. The proposed project will leverage a multi-modal experimental
therapeutics approach to test whether acute exercise modifies hypothesized targets that are relevant for the
pathophysiology and treatment of anxiety in youth. One hundred and twenty adolescents will be recruited from
a diverse population at elevated risk of anxiety and randomized into either an acute moderate-intensity aerobic
exercise or sedentary control condition, performed immediately after a fear extinction paradigm (i.e., during the
memory consolidation phase). Our hypothesis is that acute exercise will boost eCB signaling, which will result
in increased fear extinction recall and enhanced frontolimbic activation and coupling. Concurrent
neuroimaging, psychophysiological recordings, self-reported fear and anxiety, and circulating biomarkers will
allow us to evaluate target engagement at several levels; specifically, we will test fear extinction, frontolimbic
circuitry, and eCB signaling as targets for exercise’s effects on fear extinction and anxiety risk. This project is
ideally suited for the NIMH BRAINS award because it will support the development of a productive early-stage
investigator in innovative, high-impact research. Results of the proposed project will demonstrate that a
relatively low cost and low risk (compared to pharmacotherapy, for example) behavioral intervention may be
used alone or in conjunction with current treatments to improve outcomes for youth. This significant and timely
study is an essential first step in a continuum of research that will ultimately lead to efficacious treatments for
adolescent anxiety, and novel preventive interventions for at-risk youth. This work will also further our
understanding of how fear is acquired and regulated in the adolescent brain. These outcomes are highly
aligned with the NIMH goals of delineating brain mechanisms (Goal 1), understanding risk factors and
biomarkers of illness and treatment response (Goal 2), improving prevention (Goal 3), and strengthening the
public health impact (Goal 4), given our group’s ties to mental health providers and school programs.