School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, United States.
School of Arts & Sciences, Health Psychology Program, Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, United States.
Brain Behav Immun. 2020 Jan;83:44-55. doi: 10.1016/j.bbi.2019.08.192. Epub 2019 Sep 4.
Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of 'positive' maternal experiences on the placenta and fetus remain unclear. In animal models of early life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic writers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1β were elevated 3 h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic writers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.
妊娠期间的不良经历会诱导胎盘编程，影响胎儿及其发育轨迹。然而，“积极”的母体经历对胎盘和胎儿的影响尚不清楚。在早期生活应激的动物模型中，环境富集（EE）改善了甚至预防了与大脑和行为相关的损伤。在这里，我们使用大鼠的母体免疫激活（MIA）模型，测试 EE 是否减弱了母体、胎盘和/或胎儿对炎症挑战的反应，从而提供了一种防止胎儿编程的机制。此外，我们评估了终生 EE 暴露对后代发育的影响，并研究了一组可能抵御 MIA 挑战的基因和表观遗传书写器。在我们的模型中，母体血浆皮质酮和白细胞介素-1β在 MIA 后 3 小时升高，验证了母体的炎症反应。胎盘酶 Hsd11b2 和 Hsd11b2/Hsd11b1 的同时减少证明了发育编程的证据，这表明糖皮质激素代谢紊乱。认为对挑战的 Hsd11b2 减少会导致胎儿暴露于过量的糖皮质激素和改变糖皮质激素受体表达，从而增加生命后期行为损伤的易感性。EE 减轻了 MIA 对胎盘而非母体的糖皮质激素影响。环境经验和性别也导致胎盘和胎脑中的表观遗传书写器持续变化。MIA 后，雄性和雌性幼小动物的社交辨别能力受损。终生 EE 减轻了这些损伤，此外还减轻了与 MIA 相关的中央 Fkbp5 和 Oprm1 的性别特异性中断。这些数据首次提供了 EE 在应激暴露期间保护胎盘功能的证据，强调了在整个怀孕期间解决母婴健康和福祉的重要性。未来的工作必须评估 EE 使用的关键时期，以确定产后 EE 体验是否必要，或者单独的产前暴露是否足以提供保护。
