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

识别青春期前女孩病理性焦虑的因素和机制的转化方法

• 批准号: 10637744
• 负责人: Ned H Kalin
• 金额: $ 73万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-21 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637744
• 关键词: Adolescence; Affect; Age; Amygdaloid structure; Anterior; Anxiety; Anxiety Disorders; Arousal; Behavioral; Brain; Child; Childhood; Chronic; Clinical; DSM-V; Data; Depressive disorder; Development; Dimensions; Disease; Distress; Ecological momentary assessment; Electroencephalography; Extinction; Female; Female Adolescents; Frequencies; Fright; Functional disorder; Generalized Anxiety Disorder; Genetic; Goals; Home; Hour; Individual Differences; Insula of Reil; Laboratories; Learning; Life; Link; Macaca mulatta; Measures; Mediating; Memory; Mental Depression; Methods; Modeling; Monkeys; Multimodal Imaging; Nature; Neuroanatomy; Neurons; Neurophysiology - biologic function; Pathologic; Pathological anxiety; Performance; Phenotype; Physiological; Prevalence; Psychopathology; Puberty; REM Sleep; Rest; Risk; Risk Factors; Role; Separation Anxiety Disorder; Sleep; Sleep disturbances; Slow-Wave Sleep; Social Anxiety Disorder; Source; Stress; Structure; Symptoms; Telemetry; Testing; Time; Uncertainty; Variant; Viral Vector; Work; Youth; anxiety symptoms; anxious; childhood anxiety; density; designer receptors exclusively activated by designer drugs; emotion regulation; fluorodeoxyglucose positron emission tomography; girls; imaging modality; interest; male; memory consolidation; neural; neural circuit; neuroimaging; nonhuman primate; novel; novel therapeutic intervention; poor sleep; preadolescence; rapid eye movement; response; sleep physiology; sleep quality; stressor; translational approach; translational study

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.

项目摘要/摘要 童年时期的持续性和症状焦虑是病理，是后来发展的危险因素 与压力有关的心理病理学。焦虑的年轻女孩特别有风险，例如过渡到 青春期的焦虑症患病率（AD）和抑郁症明显增加 对男性。我们在儿童中的工作表明，持续和症状的焦虑与 神经回路的功能的变化与对威胁的反应有关。另外，焦虑 症状和痛苦水平是DSM-5标准的儿童之间高度重叠的 广告。这些发现，以及早期焦虑的风险，为研究该研究提供了理由 前女孩的多种病理焦虑。除了白天的忧虑和恐惧之外，还与睡眠有关 症状（例如，睡眠前唤醒，睡眠质量较差）在焦虑中很常见，最多90％的年轻人发生 有广告。了解睡眠生理学与儿童焦虑的病理生理学的关系至关重要 因为睡眠是一种体内平衡的调节器，参与学习和记忆巩固，也是 影响情绪调节。在这里，我们将使用一种转化方法来利用我们的非人类灵长类动物 （NHP）病理焦虑的模型在春季进行平行神经影像学和脑电图研究 女孩和前雌性恒河猴患有病理焦虑。使用多模式成像，HDEEG 睡眠记录和家庭睡眠脑电图数据，病理性焦虑症的预成年女孩的研究将探索 假设涉及基底外侧杏仁核（BLA）和前岛（AI）（AI）介导焦虑改变 - 相关的白天神经回路功能以及REM和区域慢波睡眠的改变。使用的研究 将在NHP中进行类似的方法，该方法将针对因果机制。通过化学上的 在睡眠之前激活BLA或AI神经元，NHP研究将测试BLA和AI在介导的作用 与病理相关的睡眠改变与白天神经电路功能之间的联系 焦虑。了解与破坏有关的病理焦虑相关的白天神经改变 睡眠生理学与阐明儿童病理焦虑的基础机制高度相关 概念化新的治疗方法。