School of Psychological Sciences and University of Haifa Center for Brain and Behavior Research, Haifa, Israel.
Integrated Brain and Behavior Research Center, University of Haifa, Haifa, Israel.
Stress. 2023 Jan;26(1):2201325. doi: 10.1080/10253890.2023.2201325.
Stress during development affects maternal behavior and offspring phenotypes. Stress in adolescence is particularly consequential on brain development and maturation, and is implicated in several psychiatric disorders. We previously showed that pre-reproductive stress (PRS) in female adolescent rats affects behavior and corticotropin releasing hormone receptor 1 (CRHR1) expression in first- (F1) and second- (F2) generation offspring. We further showed that offspring phenotypes are partially reversed by post-stress treatment with fluoxetine (FLX) or the CRHR1 antagonist NBI27914 (NBI). Epigenetic processes, such as DNA methylation, are implicated in the stress response and interact with maternal care quality across generations. Here, we asked whether PRS and FLX or NBI exposure would affect maternal care and global DNA methylation in the brains of exposed dams and their adult F1 and paternally-derived F2 offspring. We found that PRS decreased self-care while increasing pup-care behaviors. PRS also increased DNA methylation in the amygdala of dams and their F1 male offspring, but decreased it in F2 females. Drug treatment had no effect on maternal care, but affected DNA methylation patterns in F0 and F1 generations. Furthermore, PRS altered the expression of DNA methylating enzymes in brain, blood and oocytes. Finally, maternal care variables differentially predicted methylation levels in PRS and control offspring. Thus, the effects of adolescent stress are long-lasting and impact methylation levels across three generations. Combined with our findings of epigenetic changes in PRS-exposed oocytes, the present data imply that biological changes and social mechanisms act in concert to influence adult offspring phenotypes.
发育过程中的压力会影响母体行为和后代表型。青春期的压力对大脑发育和成熟尤其重要，并与几种精神疾病有关。我们之前曾表明，雌性青春期大鼠的生殖前压力（PRS）会影响第一代（F1）和第二代（F2）后代的行为和促肾上腺皮质激素释放激素受体 1（CRHR1）表达。我们进一步表明，应激后用氟西汀（FLX）或 CRHR1 拮抗剂 NBI27914（NBI）处理可部分逆转后代表型。表观遗传过程，如 DNA 甲基化，与应激反应有关，并与跨代的母体照顾质量相互作用。在这里，我们想知道 PRS 和 FLX 或 NBI 暴露是否会影响暴露母鼠及其成年 F1 和父系衍生 F2 后代大脑中的母性行为和全脑 DNA 甲基化。我们发现 PRS 减少了自我护理，同时增加了对幼崽的护理行为。PRS 还增加了母鼠及其 F1 雄性后代杏仁核中的 DNA 甲基化，但降低了 F2 雌性中的 DNA 甲基化。药物治疗对母性行为没有影响，但影响了 F0 和 F1 代的 DNA 甲基化模式。此外，PRS 改变了大脑、血液和卵母细胞中 DNA 甲基化酶的表达。最后，母体护理变量差异预测了 PRS 和对照后代的甲基化水平。因此，青春期压力的影响是持久的，并影响了三代的甲基化水平。结合我们在 PRS 暴露卵母细胞中发现的表观遗传变化，本数据表明，生物变化和社会机制协同作用，影响成年后代的表型。
