Symptoms of anxiety, avoidance and arousal (‘AAA’) can significantly, and negatively, impact on one’s day- to-day functioning and quality of life. This is especially true for girls and women who are more than twice as likely to be diagnosed with an anxiety disorder when compared to men. The proposed project addresses the pathogenesis of AAA, three of the negative valance RDoC systems, in the context of a specific genetic risk for such symptoms in girls with the FMR1 full mutation (i.e. fragile X syndrome, FXS). It is broadly recognized that AAA symptoms are an important and clinically significant problem for girls and women with FXS. Recent survey reports indicate that 56% of girls with FXS have received treatment for an anxiety disorder. Females with FXS, who are underrepresented in research studies, have a more diverse range of symptoms and overall higher IQ than males with FXS, which allows females to play a particularly important translational role in understanding the complexities of the AAA phenotype. Using FXS as a human model system, critical gaps in our knowledge base regarding AAA symptoms will be addressed. This project will employ an accelerated longitudinal design to track symptom development in 60 girls with FXS from ages 8-15 years, and linear mixed modeling to estimate change associated with age. The development of negative valence RDoC systems will be tracked in tandem with key neural systems while considering genetic, hormonal, and environmental factors that may contribute to the clinical presentation of AAA symptoms. This multimodal approach will facilitate comprehensive analysis of gene-brain-behavior interactions that underlie AAA symptoms. Our design will allow us to test novel hypotheses regarding the course of AAA symptoms and examine mediating factors such as HPA axis regulation. Combining traditional functional and structural metrics of brain connectivity will allow us probe the prefrontal-limbic circuitry known to have a key role in AAA symptoms. Utilizing flexible, optical neuroimaging (functional near infrared spectroscopy, fNIRS), we will examine prefrontal cortical responses to anxiety during naturalistic social interactions to yield ecologically valid assessments of real time anxiety response in vivo. The project proposed here builds on substantial research in the past grant period focused on gene- environment-brain-behavior associations in females with FXS. The combination of new knowledge about FXS that has become available in the past several years and new methods for interrogating these associations provides an ideal foundation from which new hypotheses can be tested in the new grant period. Plotting the trajectory of AAA symptom development and examining key linkages with neurobiology, physiology, hormones, genes and environment will advance the scientific knowledge base regarding the pathogenesis of AAA in FXS. These results will advance clinical practice by identifying critical windows when interventions a...