DESCRIPTION (provided by applicant): Persistent and high levels of sustained anxiety during childhood are a strong predictor of the development of anxiety and depressive disorders during adolescence. This is particularly relevant to females because after puberty girls are twice as likely to develop these disorders. The goal of this proposal is to understand the biological mechanisms of sustained anxiety in highly anxious girls, how it changes over time, and how it can transform into psychopathology. Capitalizing on our unique experience with studies of anxiety in both human and nonhuman primates, we will use a translational neuroscience approach to understand the neurobiology of sustained anxiety in highly anxious girls and young anxious female rhesus monkeys. Neuroimaging studies will focus on the bed nucleus of the stria terminalis (BST) because it is thought to be involved in sustained anxiety and prolonged threat preparedness. Similar paradigms will be used in humans and monkeys to: 1) characterize developmental trajectories of brain function in highly anxious girls; 2) examine the relevance of altered BST function in relation to the onset of anxiety and depressive disorders; 3) test the causal role of the BST in anxiety as young anxious female monkeys mature into adolescence; and 4) define BST molecular alterations that are linked to altered BST function and sustained anxiety. Although sustained anxiety responses can be adaptive, many patients with stress-related psychopathology experience extreme levels of maladaptive sustained anxiety, especially under conditions of uncertainty. To understand the neural underpinnings of sustained anxiety in anxious girls across the transition to adolescence, 170 highly anxious girls will be followed from age 10/11 to age 13/14 with clinical assessments, multimodal neuroimaging, and behavioral and hormonal measures of sustained anxiety. Based on previous work, it is expected that 40% of these girls will maintain high levels of anxiety into adolescence, with up to half of these stably anxious girls developing bona fide anxiety and/or depressive disorders. Parallel functional neuroimaging tasks will be used with anxious girls and anxious female nonhuman primates to assess brain activation associated with sustained anxiety during exposure to prolonged and uncertain threat. Mechanistic studies in young anxious female monkeys will use precise MRI-guided lesions of BST neurons to test the causal role of the BST in anxious behavioral and to identify, for the first time in primates, regions that are functionally modulated by BST input. Finally, BST neurons will be harvested from monkey brains using laser capture microdissection, and RNA deep sequencing will be used to link variations in gene expression to anxiety severity and BST metabolism. These translational studies provide the opportunity to test hypotheses about the clinical relevance and causal role of BST function. In addition, examining the molecular composition of BST neurons provides an invaluable opportunity to identify novel molecular mechanisms that contribute to the at-risk child phenotype. This combination of modalities and methods has high translational potential for developing novel, BST-focused, anti-anxiety treatments.

PUBLIC HEALTH RELEVANCE: Persistent and high levels of sustained anxiety during childhood are a risk factor for the development of anxiety and depressive disorders during adolescence, especially in girls who are twice as likely to develop these disorders after puberty. The proposed studies use a translational approach to study brain development in anxious girls and anxious female monkeys to understand the biological mechanisms that support sustained anxiety, how they change with development, and their role in the emergence of psychopathology. These studies will allow for the examination of markers of risk and resilience, and may inform the development of novel treatments to reduce the suffering of girls with anxiety and depressive disorders.