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

项目总结/摘要 儿童期持续性和症状性焦虑是病理性的，是日后发展的危险因素 与压力有关的精神病理学未婚少女的风险尤其大，因为在向未婚少女过渡期间， 青春期焦虑症（AD）和抑郁症的患病率在女性中显着增加， 对雄性来说我们对儿童的研究表明，持续性和症状性焦虑与以下因素有关： 神经回路功能的改变被认为与对威胁的反应有关。此外，焦虑 符合和不符合DSM-5标准的儿童的症状和痛苦程度高度重叠 对于AD。这些发现，沿着由早期生活焦虑带来的风险，为研究 青春期前女孩的广泛病理性焦虑。除了白天的担忧和恐惧， 症状（如睡前觉醒，睡眠质量差）是常见的焦虑，发生在高达90%的青年 的AD。了解睡眠生理学与儿童焦虑的病理生理学之间的关系是至关重要的 因为睡眠是一种自我平衡的调节器，参与学习和记忆的巩固， 影响情绪调节在这里，我们将使用一种翻译方法， (NHP)病理性焦虑模型进行平行的神经影像学和脑电图睡眠研究，在青春期前 女孩和青春期前的雌性恒河猴患有病理性焦虑。使用多模态成像，hdEEG 睡眠记录和家庭睡眠脑电图数据，对青春期前患有病理性焦虑的女孩的研究将探索 基底外侧杏仁核（BLA）和前杏仁核（AI）介导焦虑改变的假设- 相关的日间神经回路功能以及REM和局部慢波睡眠的改变。研究使用 类似的方法将在针对因果机制的NHP中进行。通过化学遗传学 NHP研究将测试BLA和AI在调节睡眠前的BLA或AI神经元中的作用。 睡眠和日间神经回路功能改变之间的联系，与病理性 焦虑理解与病理性焦虑相关的日间神经改变， 睡眠生理学与阐明儿童病理性焦虑的潜在机制高度相关， 构思新的治疗方法。

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.