Women who have experienced adverse childhood events (ACEs) around puberty are at the greatest risk for neuropsychiatric disorders across the lifespan. This population is exceptionally vulnerable to neuropsychiatric disease presentation during the hormonally dynamic state of pregnancy. We previously established that chronic adversity around puberty in female mice significantly altered their HPA axis function specifically during pregnancy, modeling the effects of pubertal ACEs we also reported in women. We hypothesized that the pregnancy hormone, allopregnanolone, was involved in presentation of the blunted stress response phenotype by its interaction with the molecular programming that had occurred during pubertal adversity experience. Here, in adult mice previously stressed during puberty, allopregnanolone administration was sufficient to reproduce the decreased corticosterone response after acute stress. Examination of neuronal activation and the electrophysiological properties of CRF neurons in the paraventricular nucleus of the hypothalamus (PVN) found no significant changes in synaptic function that corresponded with the blunted HPA axis reactivity. However, at the chromatin level, utilization of ATAC-Seq profiling demonstrated a dramatic remodeling of DNA accessibility in the PVN following pubertal adversity. Altogether, these data establish a potential molecular mechanism whereby adversity during puberty can enact lasting transcriptional control that manifests only during a unique period of the lifespan where dynamic hormonal changes occur. These results highlight a biological process that may impart an increased risk for a highly vulnerable population, whereby pubertal programming of the PVN results in aberrant HPA axis responsiveness when exposed to the hormonal changes unique to pregnancy.

中文翻译：

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青春期逆境会改变怀孕大脑的染色质动态和压力回路。

在青春期经历过不良童年事件 (ACE) 的女性一生中患神经精神疾病的风险最大。该人群在怀孕期间荷尔蒙动态状态下特别容易出现神经精神疾病。我们之前确定，雌性小鼠青春期周围的慢性逆境显着改变了它们的 HPA 轴功能，特别是在怀孕期间，模拟了我们也在女性中报告的青春期 ACE 的影响。我们假设妊娠激素四氢孕酮通过与青春期逆境经历期间发生的分子编程相互作用，参与了应激反应迟钝表型的呈现。在这里，在青春期之前受到压力的成年小鼠中，给予四氢孕酮足以重现急性压力后皮质酮反应的降低。对下丘脑室旁核 (PVN) 中 CRF 神经元的神经元激活和电生理学特性的检查发现，与 HPA 轴反应性减弱相对应的突触功能没有显着变化。然而，在染色质水平上，ATAC-Seq 分析的利用表明，青春期逆境后 PVN 中 DNA 可及性发生了巨大的重塑。总而言之，这些数据建立了一种潜在的分子机制，青春期的逆境可以通过这种机制实施持久的转录控制，这种控制仅在生命周期中发生动态荷尔蒙变化的独特时期才会显现。这些结果强调了一个生物过程，可能会增加高度脆弱人群的风险，即当暴露于妊娠特有的激素变化时，PVN 的青春期编程会导致 HPA 轴反应异常。