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.

项目概要/摘要 童年时期持续的症状性焦虑是病态的，是以后发展的危险因素 与压力相关的精神病理学。焦虑的年轻女孩尤其面临风险，因为在向 与青春期女性相比，焦虑症（AD）和抑郁症的患病率显着增加 对男性。我们对儿童的研究表明，持续的、有症状的焦虑与以下因素有一定的相关性： 被确定与威胁反应相关的神经回路功能发生改变。另外，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 对于广告。这些发现，以及早年焦虑带来的风险，为研究 青春期前女孩存在广泛的病理性焦虑。除了白天的担忧和恐惧之外，与睡眠有关的 症状（例如睡前觉醒、睡眠质量差）在焦虑症中很常见，高达 90% 的青少年会出现这种情况 与广告。了解睡眠生理学与儿童焦虑的病理生理学之间的关系至关重要 因为睡眠是一种稳态调节剂，涉及学习和记忆巩固，而且 影响情绪调节。在这里，我们将使用一种利用非人类灵长类动物的转化方法 (NHP) 病理性焦虑模型，用于在青春期前进行并行神经影像和脑电图睡眠研究 患有病理性焦虑的女孩和青春期前的雌性恒河猴。使用多模态成像、hdEEG 睡眠记录和家庭睡眠脑电图数据，对患有病理性焦虑的青春期前女孩的研究将探索 涉及基底外侧杏仁核（BLA）和前岛叶（AI）调节焦虑改变的假设 相关的日间神经回路功能以及快速眼动睡眠和区域慢波睡眠的改变。研究使用 类似的方法将在 NHP 中进行，旨在研究因果机制。通过化学遗传学 在睡前激活 BLA 或 AI 神经元，NHP 研究将测试 BLA 和 AI 在调节睡眠中的作用 与病理相关的睡眠和白天神经回路功能改变之间的联系 焦虑。了解与精神紊乱相关的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 概念化新的治疗方法。