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社会心理发育产生有害影响。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，但压力引起的青春期延迟可能会损害这一发展。因此，青春期可能是儿童，特别是女孩，由于暴露于社会心理压力而导致皮质边缘发育不完全，对出现社会心理问题表现出更大脆弱性的时期。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5 -羟色胺（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易感性相互作用，诱导LHPA轴的失调，从而扰乱青春期，延迟E2的增加，从而使这些女性面临神经生物学缺陷和情绪障碍的风险。本项目将研究雌性恒河猴在青春期由社会从属地位所施加的社会心理压力的行为、生理和神经生物学后果。特异性目标1将检验社会从属的假设，SERT基因中短等位基因的存在加剧了LHPA失调和青春期延迟。目的2将验证这样的假设，即在青春期暴露于社会心理压力源会通过延长青春期过渡和减少暴露于E2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将使用神经影像学来验证皮质边缘回路和调节情绪行为的5HT系统的发育受到暴露于社会心理压力源和E2水平降低的不利影响的假设。目的4将验证以下假设：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，延迟暴露于E2水平升高，并减缓皮质边缘回路和5HT系统的成熟。这些研究将阐明行为、遗传和生殖成熟之间复杂的相互作用，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。公共卫生相关性：使用猕猴模型，该项目旨在更好地了解社会从属关系所施加的社会心理压力如何影响女性的大脑成熟和情感发展，以及这是否受到编码5 -羟色胺再摄取转运蛋白（SERT）基因多态性的影响，SERT是正常5 -羟色胺神经传递和情绪所必需的蛋白质。这些研究将阐明行为、遗传和生殖成熟之间复杂的相互作用，提供对青春期如何代表精神疾病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.