Molecular and Systems Pharmacology Graduate Program, Emory University, Atlanta, GA, USA.
Neuroscience Graduate Program, Emory University, Atlanta, GA, USA.
Neuropsychopharmacology. 2019 Jun;44(7):1207-1215. doi: 10.1038/s41386-019-0321-z. Epub 2019 Jan 23.
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.
慢性青春期应激在青春期结束和成年期以性别特异性的方式改变行为。尽管已经记录了慢性青春期应激的长期行为后果，但潜在的机制仍不完全清楚。在这项研究中，我们证明了慢性青春期应激史改变了成年应激反应，如皮质酮浓度所示，即慢性青春期应激史导致对新的急性应激源的反应迟钝。为了开始解决潜在的机制基础，我们评估了慢性青春期应激对全球 DNA 甲基化的影响程度。在有慢性青春期应激史的雌性中，明显观察到海马体的全基因组甲基化减少；因此，慢性青春期应激可能改变了成年雄性和雌性大鼠整个海马体的全球转录。此外，由于急性应激可以刺激基因组反应，我们评估了暴露于急性新应激源后的转录组，以确定慢性青春期应激史在多大程度上改变了雄性和雌性对急性应激源的成年转录反应。除了全球甲基化减少外，慢性青春期应激还导致成年海马体中的基因表达出现不同的模式，这些模式因性别而异。此外，性别和慢性青春期应激史都影响了成年期对急性新应激源的转录反应，这表明慢性青春期应激在基因转录水平上既有潜在的影响，也有功能上的影响。通路分析表明，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，并为未来的研究提供了候选机制。总的来说，这些研究表明，青春期应激暴露具有性别特异性和持久的影响，在女性中比在男性中更为明显。
