A translational approach for identifying factors and mechanisms underlying pathological anxiety in preadolescent girls

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Project Summary/Abstract Persistent and symptomatic anxiety during childhood is pathological and is a risk factor for the later development of stress-related psychopathology. Anxious young girls are particularly at risk, as during the transition to adolescence the prevalence of anxiety disorders (ADs) and depression markedly increases in females compared to males. Our work in children demonstrates that persistent and symptomatic anxiety is dimensionally related to altered function of neural circuits identified to be associated with responses to threat. Additionally, anxiety symptoms and levels of distress are highly overlapping between children that do and do not meet DSM-5 criteria for ADs. These findings, along with the risk conferred by early-life anxiety, provide a rationale for studying the broad range of pathological anxiety in preadolescent girls. In addition to daytime worries and fears, sleep-related symptoms (e.g. pre-sleep arousal, poor sleep quality) are common in anxiety, occurring in up to 90% of youth with ADs. It is critical to understand how sleep physiology relates to the pathophysiology of childhood anxiety because sleep is a homeostatic regulator that is involved in learning and memory consolidation, and also influences emotion regulation. Here, we will use a translational approach leveraging our nonhuman primate (NHP) model of pathological anxiety to conduct parallel neuroimaging and EEG sleep studies in preadolescent girls and preadolescent female rhesus monkeys with pathological anxiety. Using multimodal imaging, hdEEG sleep recordings, and home sleep EEG data, studies in preadolescent girls with pathological anxiety will explore hypotheses implicating the basolateral amygdala (BLA) and anterior insula (AI) in mediating altered anxiety- related daytime neural circuit function as well as alterations in REM and regional slow wave sleep. Studies using similar methods will be performed in NHPs that will be aimed at causal mechanisms. By chemogenetically activating BLA or AI neurons prior to sleep, the NHP studies will test the roles of the BLA and AI in mediating the linkage between alterations in sleep and daytime neural circuit function that are associated with pathological anxiety. Understanding daytime neural alterations associated with pathological anxiety in relation to disrupted sleep physiology is highly relevant for elucidating mechanisms underlying childhood pathological anxiety and in conceptualizing new treatment approaches.