Testing Dual Mechanism Model of Adolescent Anxiety and Related Sex Differences

焦虑仍然是最常见的精神疾病之一，也是导致残疾的第六大原因。

Anxiety remains one of the most common forms of mental illness and the 6th leading cause of disability. Anxiety tends to emerge during early adolescence, and this occurs differentially between sexes: rates are equal pre-puberty and become 2-fold greater in females. Thus, identifying factors that predispose towards anxiety is crucial for identifying as-risk individuals early. We have proposed that the development of anxiety in adolescence is due, in part, to differences in the maturation of brain networks supporting emotion regulation. However, mechanisms that influence the development of these networks, and their implications for anxiety, are not well understood. We will test a model incorporating two risk factors (pubertal testosterone and axonal myelination) by collecting neuroimaging data from individuals transitioning into adolescence, half of whom are at high risk for developing anxiety . Aim 1: Work from our lab and others in healthy adolescents/ adults indicates that testosterone dampens the effectiveness of key emotion-regulation circuitry, and this dampening predicted anxiety increases. However, it is unclear if this impacts pathological levels of anxiety. Additionally, white matter integrity in this circuitry is weaker in anxiety, likely disrupting the efficiency of communication. Unfortunately, the mechanism by which this occurs remain unknown; we have proposed that weaker integrity impacts anxiety by exacerbating the impact of testosterone. Importantly, a key driver of white matter integrity is myelination, and these circuits begin myelinating during adolescence. Therefore, Aim 1 uses a novel multi-modal myelin measure to test whether testosterone and myelination impact anxiety, as mediated by changes in emotion-regulation circuitry. Aim 2: The mechanisms that confer greater risk for anxiety in females remain unknown. Our work suggests that females have a higher sensitivity to testosterone in key emotion-regulation circuitry. Thus, Aim 2 tests whether testosterone has a greater impact on emotionregulation circuitry/pathological anxiety in girls. In sum, this project aims to identify mechanisms responsible for the development of adolescent anxiety. This work has the potential for tremendous public health impact by harnessing cutting-edge methods to uncover and validate novel risk trajectories for anxiety.