Department of Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
Neuropsychopharmacology. 2022 Aug;47(9):1620-1632. doi: 10.1038/s41386-022-01270-z. Epub 2022 Jan 31.
Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine. In utero exposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin-associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally, Mag and Mbp expression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.
许多孕妇会出现抑郁症状，通常会接受选择性 5-羟色胺再摄取抑制剂（SSRI）类抗抑郁药治疗，如氟西汀。胎儿期暴露于 SSRI 与产妇抑郁症状与大脑和行为的性别特异性影响有关。然而，对于这些性别差异背后的神经生物学机制的了解是有限的。此外，大多数关于发育性 SSRI 暴露的动物研究都忽略了母体逆境的影响。因此，我们使用与抑郁症相关的大鼠模型，研究了围产期氟西汀暴露对雄性和雌性幼年后代前额叶皮质和基底外侧杏仁核的分子影响；这些是皮质边缘回路的关键区域。围产期氟西汀增强了前额叶皮质中的髓鞘相关基因表达，而在基底外侧杏仁核中则抑制了它。SSRI 暴露和母体逆境相互作用会影响髓鞘相关糖蛋白（Mag）和髓鞘碱性蛋白（Mbp）等基因的表达。我们推测，髓鞘改变反映了大脑成熟的改变。此外，这些影响在雄性中比在雌性中更强，类似于已知的行为结果。最后，Mag 和 Mbp 的表达与 DNA 甲基化相关，突出了表观遗传调控作为发育性氟西汀诱导的髓鞘改变的潜在机制。
