Neurobiology of increased vulnerability to social stressors during adolescence

青春期社会压力源脆弱性增加的神经生物学

• 批准号: 7799931
• 负责人: Mark E Wilson
• 金额: $ 77.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799931
• 关键词: Adolescence; Adolescent; Adolescent Development; Adrenal Glands; Adult; Adverse effects; Affect; Alleles; Anxiety; Argipressin; Attenuated; Behavior; Behavioral; Behavioral Genetics; Binding; Brain; Child; Childhood; Circadian Rhythms; Complex; Corticotropin-Releasing Hormone; Data; Defect; Delayed Puberty; Development; Emotional; Estradiol; Excision; Exposure to; Feedback; Female; Fright; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Glucocorticoids; Growth; Hypothalamic structure; Individual; Limbic System; Macaca mulatta; Measures; Mental disorders; Modeling; Monkeys; Mood Disorders; Neurobiology; Neurons; Neuropeptides; Pharmaceutical Preparations; Physiological; Pituitary Gland; Proteins; Psychosocial Stress; Puberty; Risk; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Transduction; Sleep Wake Cycle; Social status; Stress; System; Testing; Time; behavior influence; cortico-limbic circuits; critical period; design; effective intervention; girls; hypothalamic-pituitary-adrenal axis; inhibitor/antagonist; neuroimaging; neurotransmission; postnatal; psychobiologic; psychosocial; public health relevance; reproductive; reuptake; serotonin receptor; serotonin transporter; social; social stress; stressor; uptake

DESCRIPTION (provided by applicant): Postnatal stressors, producing a dysregulation of the limbic-hypothalamic pituitary adrenal (LHPA) axis, can have a deleterious effect on a child's pubertal and psychosocial development. Importantly, the gonadal release of estradiol (E2) occurring during the pubertal transition likely contributes to the continued maturation of cortico-limbic circuits that regulate emotional behavior but stress-induced delayed puberty could compromise this development. Puberty may, thus, be a time when children, particularly girls, show an increased vulnerability to the emergence of psychosocial problems as a result of incomplete cortico-limbic development resulting from psychosocial stress exposure. In addition, some individuals are genetically predisposed to respond differentially to stress, as individuals with a specific polymorphism in the gene encoding the serotonin (5HT) reuptake transporter (SERT) are more susceptible to stressors. We propose that psychosocial stress interacts with genetic vulnerability to induce dysregulation of the LHPA axis to disrupt puberty and delay exposure to increases in E2, thus placing these females at risk for neurobiological defects and mood disorders. This project will study the behavioral, physiological, and neurobiological consequences of psychosocial stress, imposed by social subordination, during adolescence in female rhesus monkeys. Specific Aim 1 will test the hypothesis that social subordination, exacerbated by the presence of the short allele in the SERT gene, produces LHPA dysregulation and delays puberty. Aim 2 will test the hypothesis that exposure to psychosocial stressors during adolescence increases emotional reactivity by prolonging the pubertal transition and reducing exposure to E2, particularly in females with the short allele in the SERT gene. Aim 3 will use neuroimaging to test the hypothesis that development of cortico-limbic circuits and 5HT systems regulating emotional behavior are adversely affected by exposure to psychosocial stressors and reduced levels of E2. Aim 4 will test the hypothesis that SSRI therapy to subordinate females may normalize LHPA activity but not growth or puberty, delaying exposure to increasing levels of E2, and attenuating maturation of cortico-limbic circuits and 5HT systems. These studies will elucidate the complex interplay between behavior, genetics, and reproductive maturation, providing a comprehensive understanding of the role of adolescence as a critical period for the emergence of mood disorders in girls. PUBLIC HEALTH RELEVANCE: Using a rhesus monkey model, this project is designed to provide a better understanding of how psychosocial stress, imposed by social subordination, affects brain maturations and emotional development in females and whether this is influenced by polymorphisms in the gene that encodes the serotonin re-uptake transporter (SERT), a protein essential for normal serotonin neurotransmission and emotionality. These studies will elucidate the complex interplay between behavior, genetics, and reproductive maturation, providing a comprehensive understanding of how adolescence represents a critical period for the emergence of psychiatric disorders.

描述（由申请人提供）：产后压力源会导致边缘-下丘脑垂体肾上腺（LHPA）轴失调，可能对儿童的青春期和社会心理发育产生有害影响。重要的是，青春期过渡期间发生的雌二醇（E2）的性腺释放可能有助于调节情绪行为的皮质边缘回路的持续成熟，但压力引起的青春期延迟可能会损害这种发展。因此，青春期可能是儿童，特别是女孩，由于心理社会压力导致皮质边缘发育不完全而更容易出现心理社会问题的时期。此外，一些个体在遗传上倾向于对压力做出不同的反应，因为编码血清素（5HT）再摄取转运蛋白（SERT）的基因具有特定多态性的个体更容易受到压力源的影响。我们认为，社会心理压力与遗传脆弱性相互作用，导致 LHPA 轴失调，扰乱青春期并延迟 E2 增加，从而使这些女性面临神经生物学缺陷和情绪障碍的风险。该项目将研究雌性恒河猴青春期期间社会从属所施加的社会心理压力的行为、生理和神经生物学后果。具体目标 1 将检验以下假设：SERT 基因中短等位基因的存在加剧了社会从属关系，导致 LHPA 失调并延迟青春期。目标 2 将检验以下假设：青春期期间暴露于社会心理压力源会通过延长青春期过渡和减少 E2 暴露来增加情绪反应性，特别是在 SERT 基因中具有短等位基因的女性中。目标 3 将使用神经影像学来检验以下假设：暴露于社会心理压力源和 E2 水平降低会对调节情绪行为的皮质边缘回路和 5HT 系统的发育产生不利影响。目标 4 将检验以下假设：对从属女性进行 SSRI 治疗可能会使 LHPA 活性正常化，但不会使生长或青春期正常化，从而延迟暴露于 E2 水平的升高，并减弱皮质边缘回路和 5HT 系统的成熟。这些研究将阐明行为、遗传学和生殖成熟之间复杂的相互作用，从而全面了解青春期作为女孩出现情绪障碍的关键时期的作用。公共健康相关性：该项目旨在利用恒河猴模型，更好地了解社会从属带来的社会心理压力如何影响女性的大脑成熟和情绪发展，以及这是否受到编码血清素再摄取转运蛋白（SERT）的基因多态性的影响，SERT是正常血清素神经传递和情绪所必需的蛋白质。这些研究将阐明行为、遗传学和生殖成熟之间复杂的相互作用，从而全面了解青春期如何代表精神疾病出现的关键时期。