Neurobiology of increased vulnerability to social stressors during adolescence

描述(申请人提供)：出生后应激源，产生边缘-下丘脑-垂体肾上腺(LHPA)轴的失调，可能对儿童的青春期和心理社会发展产生有害影响。重要的是，在青春期过渡期间，性腺释放雌二醇(E2)可能有助于调节情绪行为的皮质-边缘回路的持续成熟，但应激诱导的青春期延迟可能会危及这种发育。因此，青春期可能是儿童，特别是女孩更容易出现心理社会问题的时期，这是心理社会压力暴露造成的皮质-边缘发育不完全的结果。此外，一些人的基因倾向于对压力做出不同的反应，因为编码5-羟色胺(5-羟色胺)再摄取转运体(SERT)基因特定多态性的人更容易受到应激源的影响。我们认为，心理社会应激与遗传易感性相互作用，导致LHPA轴调节失调，从而扰乱青春期并推迟对E2增加的暴露，从而将这些女性置于神经生物学缺陷和情绪障碍的风险中。该项目将研究在雌性恒河猴青春期期间，由社会从属施加的心理社会压力的行为、生理和神经生物学后果。具体目标1将检验这一假设，即社会从属关系因SERT基因中短等位基因的存在而加剧，会产生LHPA失调并推迟青春期。目的2将验证这一假设，即青春期暴露于心理社会应激源通过延长青春期过渡和减少对E2的暴露而增加情绪反应，特别是在SERT基因短等位基因的女性中。目的3将使用神经成像来测试这一假设，即大脑皮质-边缘回路和调节情绪行为的5HT系统的发育受到心理社会应激源和E2水平降低的不利影响。目的4将验证这样一种假设，即对从属女性进行SSRI治疗可以使LHPA活性正常化，但不会使生长或青春期恢复正常，推迟暴露在E2水平升高的环境中，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、遗传和生殖成熟之间的复杂相互作用，提供对青春期作为女孩情绪障碍出现的关键时期的作用的全面理解。与公共健康相关：该项目使用恒河猴模型，旨在更好地了解社会从属关系造成的心理压力如何影响女性的大脑成熟和情绪发育，以及这种影响是否受到编码5-羟色胺再摄取转运体(SERT)的基因多态性的影响，5-羟色胺再摄取转运体是正常的5-羟色胺神经传递和情绪性所必需的蛋白质。这些研究将阐明行为、遗传学和生殖成熟之间的复杂相互作用，提供对青春期如何代表精神障碍出现的关键时期的全面理解。

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.