Neurobiology of increased vulnerability to social stressors during adolescence

描述（由申请人提供）：产后应激源，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育产生有害影响。重要的是，在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，但压力诱导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，由于心理社会压力暴露导致皮质边缘系统发育不全，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，因为在编码5-羟色胺（5-HT）再摄取转运蛋白（SERT）的基因中具有特定多态性的个体更容易受到压力的影响。我们认为，心理社会压力与遗传易感性相互作用，诱导LHPA轴失调，破坏青春期和延迟暴露于E2的增加，从而使这些女性处于神经生物学缺陷和情绪障碍的风险中。本计画将研究雌性恒河猴在青春期因社会从属关系所造成的心理社会压力，在行为、生理和神经生物学上的后果。具体目标1将测试的假设，社会从属地位，加剧了SERT基因中的短等位基因的存在，产生LHPA失调和延迟青春期。目的2将测试的假设，即在青春期暴露于心理社会压力增加情绪反应，延长青春期的过渡和减少暴露于E2，特别是在女性与短等位基因的SERT基因。目标3将使用神经影像学来检验这一假设，即皮质边缘回路和5 HT系统调节情绪行为的发展受到心理社会应激源和E2水平降低的不利影响。目的4将检验以下假设：SSRI治疗下级女性可能使LHPA活性正常化，但不使生长或青春期正常化，延迟暴露于增加的E2水平，并减弱皮质边缘回路和5-HT系统的成熟。这些研究将阐明行为、遗传和生殖成熟之间复杂的相互作用，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。公共卫生相关性：使用恒河猴模型，这个项目的目的是提供一个更好的理解，如何心理社会压力，施加社会从属地位，影响大脑成熟和情感发展的女性，这是否是受多态性的基因编码的血清素再摄取转运蛋白（SERT），蛋白质的正常血清素神经传递和情绪。这些研究将阐明行为、遗传和生殖成熟之间复杂的相互作用，全面了解青春期是如何成为精神疾病出现的关键时期。

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.