Chronic adolescent stress alters behavior in a sex-specific manner at the end of adolescence and in adulthood. Although prolonged behavioral repercussions of chronic adolescent stress have been documented, the potential underlying mechanisms are incompletely understood. In this study we demonstrate that a history of chronic adolescent stress modified the adult stress response, as measured by corticosterone concentration, such that a history of chronic adolescent stress resulted in a blunted response to a novel acute stressor. In order to begin to address potential mechanistic underpinnings, we assessed the extent to which chronic adolescent stress impacted global DNA methylation. Reduced global hippocampal methylation was evident in females with a history of chronic adolescent stress; thus, it was possible that chronic adolescent stress altered global transcription in the whole hippocampi of adult male and female rats. In addition, because acute stress can stimulate a genomic response, we assessed the transcriptome following exposure to an acute novel stressor to determine the extent to which a history of chronic adolescent stress modifies the adult transcriptional response to an acute stressor in males and females. In addition to the reduction in global methylation, chronic adolescent stress resulted in distinct patterns of gene expression in the adult hippocampus that differentiated by sex. Furthermore, both sex and a history of chronic adolescent stress influenced the transcriptional response to an acute novel stressor in adulthood, suggesting both latent and functional effects of chronic adolescent stress at the level of gene transcription. Pathway analysis indicated that ESR1 and IFN-α may be particularly influential transcription factors mediating these transcriptional differences and suggest candidate mechanisms for future studies. Collectively, these studies demonstrate sex-specific and enduring effects of adolescent stress exposure that are more pronounced in females than in males.

中文翻译：

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慢性青少年应激会在成年后性别特异性地改变海马转录组。

慢性青春期应激会在青少年期末和成年期以性别特定的方式改变行为。尽管已记录了慢性青少年应激的长期行为影响，但潜在的潜在机制尚不完全清楚。在这项研究中，我们证明了慢性青春期应激的历史改变了成年人的应激反应（如皮质酮浓度），使得慢性青春期应激的历史导致对新型急性应激源的反应迟钝。为了开始解决潜在的机制基础，我们评估了慢性青少年应激影响全球DNA甲基化的程度。有慢性青春期应激史的女性明显降低了整体海马甲基化；因此，慢性青春期应激可能会改变成年雄性和雌性大鼠整个海马的整体转录。此外，由于急性应激会刺激基因组反应，因此我们评估了暴露于急性新型应激源后的转录组，以确定慢性青春期应激史改变了男性和女性对成人急性应激源的转录反应的程度。除了减少整体甲基化外，慢性青春期应激还会导致成年海马的基因表达模式出现性别差异。此外，性别和慢性青春期应激史都影响了成年后对急性新型应激源的转录反应，提示慢性青少年应激在基因转录水平上的潜在作用和功能作用。途径分析表明，ESR1和IFN-α可能是介导这些转录差异的特别有影响力的转录因子，并为今后的研究提供了可能的机制。这些研究共同表明，青春期压力暴露的性别特异性和持久性影响在女性中比在男性中更为明显。