Immediate early genes as a molecular switch for lasting vulnerability following pubertal stress in mice.
Immediate early genes as a molecular switch for lasting vulnerability following pubertal stress in mice.
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早期基因作为小鼠青春期应激后持久脆弱性的分子开关。
DOI：
10.1101/2023.10.03.559350
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Morrison,KathleenE
中科院分区：
文献类型：
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作者：
Gautier,KarissaN;Higley,SamanthaL;Mendoza,JohnM;Morrison,KathleenE
为什么个体在压力后会遭受负面后果是一个复杂的现象，它由个体因素、生命周期中压力发生的时间以及在生命周期中何时测量后果决定。经历过不良童年经历的女性面临着持久的生物学后果的风险，包括情感和压力失调。我们已经证明，青春期逆境与围产期人类和小鼠的下丘脑-垂体-肾上腺轴糖皮质激素反应迟钝有关。在小鼠中，我们之前对下丘脑室旁核 (PVN) 的检查表明，青春期应激导致成年、怀孕小鼠 PVN 中 6 个即早基因 (IEG) 的基线 mRNA 表达上调。另外，我们表明，与妊娠相关的激素四氢孕酮对于在青春期应激小鼠中产生减弱的应激反应表型是必要且充分的。在当前的研究中，我们进一步研究了 IEG 在 PVN 中的潜在机制作用。我们发现，在青春期应激的成年雌性（而非雄性）小鼠中，PVN 内异孕酮足以重现先前在青春期应激的怀孕小鼠中观察到的基线 IEG mRNA 表达谱。我们还检查了青春期期间的基线 IEG mRNA 表达，发现 IEG 的发育轨迹显示出青春期压力对性别特异性的破坏。总而言之，这些数据表明，IEG 可能作为一个关键的分子开关，导致成年、青春期应激动物更容易受到负面结果的影响。产生脆弱性的因素如何在整个生命周期中结合起来是我们理解压力相关疾病病因的关键。
Why individuals suffer negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when in the lifespan the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted hypothalamic-pituitary-adrenal axis glucocorticoid response in peripartum humans and mice. In mice, our prior examination of the paraventricular nucleus (PVN) of the hypothalamus showed that pubertal stress led to an upregulation of baseline mRNA expression of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. In the current study, we further examined a potential mechanistic role for the IEGs in the PVN. We found that in pubertally stressed adult female, but not male, mice, intra-PVN allopregnanolone was sufficient to recapitulate the baseline IEG mRNA expression profile previously observed in pubertally stressed, pregnant mice. We also examined baseline IEG mRNA expression during adolescence, where we found that IEGs have developmental trajectories that showed sex-specific disruption by pubertal stress. Altogether, these data establish that IEGs may act as a key molecular switch involved in increased vulnerability to negative outcomes in adult, pubertally stressed animals. How the factors that produce vulnerability combine throughout the lifespan is key to our understanding of the etiology of stress-related disorders.