Stress and Pubertal Timing Affect Amygdala Functional Circuitry in Females

压力和青春期时间影响女性杏仁核功能回路

• 批准号: 9042410
• 负责人: Anne Marie Clare Kelly
• 金额: $ 8.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042410
• 关键词: Address; Adolescence; Affect; Age; Age of Onset; Agonist; Amygdaloid structure; Animals; Anterior; Anxiety; Base of the Brain; Behavior; Behavioral; Biological; Brain; Chronic stress; Comorbidity; Data; Data Set; Delayed Puberty; Development; Disease; Drops; Emotional; Enantone; Environment; Estradiol; Etiology; Exhibits; Exposure to; Female; Fright; Functional Magnetic Resonance Imaging; Future; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Health; Housing; Human; Human Characteristics; Incidence; Intervention; Investigation; Life; Link; Long-Term Effects; Longitudinal Studies; Macaca; Macaca mulatta; Measures; Menarche; Mental Health; Mental disorders; Modeling; Mood Disorders; Moods; Neurobiology; Pharmaceutical Preparations; Phenotype; Physical environment; Physiological; Prefrontal Cortex; Prospective Studies; Psychopathology; Psychosocial Stress; Puberty; Public Health; Regulation; Rest; Risk; Severities; Skin; Social Dominance; Social Environment; Social status; Stress; Structure; Testing; Thalamic structure; Time; Translating; Woman; Work; Youth; base; brain behavior; cingulate cortex; cohort; cost; early experience; early life exposure; emotion dysregulation; hypercortisolemia; hypothalamic-pituitary-adrenal axis; indexing; member; neurobehavioral; neurodevelopment; neuroimaging; nonhuman primate; prepuberty; psychostimulant; pubertal timing; remediation; reproductive; research study; response; social; white matter

 DESCRIPTION: Early life exposure to psychosocial stress is one of the strongest predictors of psychopathology, particularly for conditions that are more prevalent in females, such as mood disorders. The incidence of these disorders dramatically increases during adolescence, suggesting that the interaction between psychosocial stress and the neurodevelopmental changes of puberty, such as changing levels of sex hormones, may be a critical mechanism for the emergence of emotional dysregulation during this developmental period. Identifying the neurobehavioral bases of these links is crucial to our understanding of the etiology of mental illness, its emergence during adolescence, and the development of intervention strategies aimed at ameliorating the long- term effects of psychosocial stress. We propose to investigate the neurobiological bases of these links by examining the effects of psychosocial stress and the timing of puberty on intrinsic brain functional organization in a female rhesus macaque model. Socially housed female macaques organize into a dominance hierarchy in which subordinates are subject to frequent harassment in an environment that mimics the unpredictable nature of human social environments, providing an ethologically valid model for studying long-term neurobehavioral effects of psychosocial stress. This model overcomes many challenges inherent to longitudinal studies of chronic stress in humans. More important, the model permits experimental manipulations to disentangle the effects of stress, chronological age, and puberty. Our proposal capitalizes on a unique opportunity to examine pre-existing resting fMRI data collected from dominant (DOM; n=10) and subordinate (SUB; n=16) female macaques 12 months after the onset of puberty (menarche) and from a matched cohort of DOM (n=12) and SUB (n=13) females treated with a drug (Lupron) that experimentally delayed puberty. Using this unique dataset, we will examine the separate and interacting effects of social subordination stress and the timing of puberty (and associated elevations in gonadal steroids) on functional circuitry during adolescence. We focus on amygdala circuitry, particularly connections with ventromedial prefrontal cortex, based on neuroimaging evidence of stress-related alterations in this circuit as well as its sensitivity to gonadal steroids. We will also examine the relationship between amygdala circuitry and socio-emotional phenotypes (e.g., response to threats), thus revealing brain-behavior links that are relevant to human psychopathology. Investigation of these links is timely, given the steep drop in the age of the onset of puberty in the US, the substantial rise in rates of psychological disorders among youth, and the ensuing public health burden. Attainment of our aims will add further scientific value to our translational model of psychosocial stress at minimal additional cost, and will suggest future studies that may reveal causal mechanisms linking psychosocial stress and puberty-related increases in gonadal steroids to emotional dysregulation, as well as targets for interventions aimed at ameliorating the long-term effects of psychosocial stress and reducing women's psychopathological burden.

 产品说明：早期生活中暴露于心理社会压力是精神病理学最强的预测因素之一，特别是对于女性更普遍的情况，如情绪障碍。这些疾病的发病率显着增加，在青春期，这表明心理社会压力和青春期的神经发育变化，如性激素水平的变化之间的相互作用，可能是一个关键的机制出现的情绪失调在这个发展时期。确定这些联系的神经行为基础对于我们理解精神疾病的病因、青春期精神疾病的出现以及制定旨在改善心理社会压力长期影响的干预策略至关重要。我们建议研究这些联系的神经生物学基础，通过研究心理社会压力和青春期的时间对雌性恒河猴模型内在脑功能组织的影响。社会安置的雌性猕猴组织成一个统治阶层，其中下属受到频繁的骚扰，在一个环境中，模仿人类社会环境的不可预测性，提供了一个行为学上有效的模型，研究长期的神经行为的心理压力的影响。该模型克服了人类慢性应激纵向研究固有的许多挑战。更重要的是，该模型允许实验操作，以解开压力，实足年龄和青春期的影响。我们的建议利用了一个独特的机会，检查预先存在的休息功能磁共振成像数据收集的占主导地位的（DOM; n=10）和下属（n=16）雌性猕猴青春期开始（初潮）后12个月，并从一个匹配的队列DOM（n=12）和雌猴（n=13）的女性治疗药物（Lupron），实验性地延迟青春期。使用这个独特的数据集，我们将研究社会从属压力和青春期的时间（以及性腺类固醇的相关升高）对青春期功能电路的单独和相互作用的影响。我们专注于杏仁核电路，特别是腹内侧前额叶皮层的连接，基于神经影像学证据的压力相关的改变，在这个电路，以及其敏感性性腺类固醇。我们还将研究杏仁核回路和社会情绪表型之间的关系（例如，对威胁的反应），从而揭示了与人类精神病理学相关的大脑行为联系。鉴于美国青春期开始的年龄急剧下降，青年心理障碍的发病率大幅上升，以及随之而来的公共卫生负担，对这些联系的调查是及时的。我们的目标的实现将以最小的额外成本为我们的社会心理压力转化模型增加进一步的科学价值，并将建议未来的研究，可能揭示因果机制，将社会心理压力和青春期相关的性腺类固醇增加与情绪失调，以及旨在改善社会心理压力的长期影响和减少妇女的精神病理学负担的干预措施的目标。