ORIGINS AND EMERGENCE OF MALADAPTIVE SOCIOEMOTIONAL BEHAVIOR DURING THE TRANSITION TO ADULTHOOD IN PRIMATES

灵长类动物成年过渡期间不良社会情绪行为的起源和出现

• 批准号: 10655314
• 负责人: Andrew S Fox
• 金额: $ 68.06万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655314
• 关键词: 5 year old; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Age; Amygdaloid structure; Animals; Anterior; Anxiety; Anxiety Disorders; Behavior; Behavior assessment; Behavioral; Behavioral inhibition; Brain; Brain imaging; Brothers; California; Cell Nucleus; Clinical Psychology; Complement; Complex; Computer Vision Systems; Coupled; Data; Depressive disorder; Development; Disease; E-learning; Environment; Exposure to; Failure; Family; Female; Foundations; Freezing; Functional Magnetic Resonance Imaging; Genetic; Geography; Heritability; Housing; Human; Individual; Infant; Infant Behavior; Inherited; Insula of Reil; Intervention; Lead; Life; Life Stress; Link; Magnetic Resonance Imaging; Measures; Mediating; Mental Depression; Mental disorders; Metabolism; Modeling; Monitor; Network-based; Neurobiology; Pathway interactions; Phenotype; Physiological; Prefrontal Cortex; Prevalence; Prevention; Primates; Psychiatry; Psychopathology; Puberty; Records; Research; Resources; Rest; Risk; Risk Factors; Sex Differences; Social Behavior; Social Environment; Stress; Structure; Structure of terminal stria nuclei of preoptic region; System; Techniques; Technology; Temperament; Testing; Variant; Work; anxiety symptoms; anxiety-like behavior; anxious temperament; biobehavior; boys; brain circuitry; comorbidity; deep learning; deep neural network; depressive symptoms; emerging adult; emotional behavior; fluorodeoxyglucose positron emission tomography; genetic pedigree; girls; imaging study; innovation; insight; longitudinal design; longitudinal, prospective study; mature animal; midbrain central gray substance; multimodal neuroimaging; multimodality; neural; neural circuit; neural network; neuroimaging; nonhuman primate; novel; pharmacologic; preadolescence; prevent; prospective; response; sex; symptomatology; tool; young adult

Specific Aims: Anxiety and depressive disorders are common, comorbid, and challenging to treat, ranking them among the greatest contributors to human suffering. An early-life extreme inhibited or anxious temperament, characterized by behavioral inhibition and extreme physiological responses to novel and/or potentially threatening contexts, is among the strongest predictors of the later development of anxiety and depressive disorders. Understanding the neurobiology of this early-life risk will identify treatment targets and provide a unique opportunity to develop scientifically founded behavioral and pharmacological interventions to treat and prevent stress-related psychopathology. Here, we propose a prospective longitudinal study in nonhuman primates (NHPs) to understand how inborn risk-factors and early-life inhibition lead to anxiety and maladaptive social behavior during adolescence and early adulthood. We will do this by leveraging the resources at the California National Primate Research Center (CNPRC), including previous early-life assessments of behavioral inhibition, a multi-generational family pedigree, and large outdoor housing, alongside cutting-edge tools and analysis techniques, including multimodal neuroimaging and neural network-based animal tracking and behavioral analyses. We will use a prospective longitudinal design, and select 176 NHPs (88 F) previously phenotyped for early-life inhibition (3-4 months old) from the CNPRC’s large, multi-generational family pedigree. To study the emergence of anxiety- and depression-like symptomatology, half of the NHPs will be "adolescents" and half will be "young adults". We will perform in-lab behavioral and neuroimaging assessments, and longitudinal large-scale monitoring as animals navigate the entirety of their socio-geographic environment. First, we will examine how heritable-risk and early- life inhibition contribute to maladaptive socio-emotional behaviors in ecologically-valid contexts during adolescence and early adulthood (Aim 1). Starting in puberty, the risk for anxiety disorders is greater for girls than boys. Therefore, we also aim to demonstrate adolescent and young-adult sex differences in anxiety- and depression-like behaviors (Aim 2). To understand how these factors are mediated by alterations in relevant brain circuitry, including the extended amygdala, each animal will undergo multimodal structural and functional neuroimaging assessments. Using these data, we will test specific hypotheses regarding the extent to which extended amygdala circuits link early-life inhibition to the progression of anxiety- and depression-like behaviors (Aim 3). This combination of approaches promises to provide unprecedented insight into the neural substrates of maladaptive socio-emotional behavior during the transition to adulthood.

具体目标：焦虑症和抑郁症是常见的、共存的并且具有挑战性 治疗，将他们列为造成人类痛苦的最大罪魁祸首之一。早年的极端经历 压抑或焦虑的气质，其特征是行为抑制和极端 对新奇和/或潜在威胁环境的生理反应是最强烈的 焦虑症和抑郁症后期发展的预测因素。了解 这种早期生命风险的神经生物学将确定治疗目标并提供独特的机会 开发科学依据的行为和药物干预措施来治疗和 预防与压力相关的精神病理学。在这里，我们提出一项前瞻性纵向研究 非人类灵长类动物（NHP）了解先天危险因素和生命早期抑制如何导致 青春期和成年早期的焦虑和适应不良的社会行为。我们会这样做 通过利用加州国家灵长类动物研究中心 (CNPRC) 的资源， 包括以前对行为抑制的早期生命评估、多代家庭 血统和大型户外房屋，以及尖端的工具和分析技术， 包括多模式神经影像和基于神经网络的动物跟踪和行为 分析。我们将采用前瞻性纵向设计，预先选择 176 个 NHP（88 F） 来自 CNPRC 大型多代细胞的早期生命抑制表型（3-4 个月大） 家族血统。为了研究焦虑和抑郁样症状的出现，一半的人 NHP 中的一半将是“青少年”，一半将是“年轻人”。我们将在实验室内进行行为 和神经影像评估，以及动物导航时的纵向大规模监测 他们的整个社会地理环境。首先，我们将研究遗传风险和早期风险如何 在生态有效的环境中，生活抑制会导致适应不良的社会情感行为 青春期和成年早期（目标 1）。从青春期开始，患焦虑症的风险 对于女孩来说比男孩更大。因此，我们还旨在向青少年和年轻人展示 焦虑和抑郁样行为的性别差异（目标 2）。要了解这些如何 因素是通过相关大脑回路的改变介导的，包括扩展的杏仁核， 每只动物都将接受多模式结构和功能神经影像评估。使用 这些数据，我们将测试有关杏仁核扩展程度的具体假设 电路将早期生命抑制与焦虑和抑郁样行为的进展联系起来（Aim 3）。这种方法的结合有望为神经网络提供前所未有的洞察力 向成年过渡期间适应不良的社会情感行为的根源。