Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Ramat HaGolan St 65, 4077625, Ariel, Israel.
Dr. Miriam and Sheldon G. Adelson School of Medicine, Ariel University, Ariel, Israel.
Mol Psychiatry. 2023 Sep;28(9):3816-3828. doi: 10.1038/s41380-023-02273-y. Epub 2023 Oct 16.
Maternal care is critical for epigenetic programming during postnatal brain development. Stress is recognized as a critical factor that may affect maternal behavior, yet owing to high heterogeneity in stress response, its impact varies among individuals. We aimed here to understand the connection between inborn stress vulnerability, maternal care, and early epigenetic programming using mouse populations that exhibit opposite poles of the behavioral spectrum (social dominance [Dom] and submissiveness [Sub]) and differential response to stress. In contrast to stress-resilient Dom dams, stress-vulnerable Sub dams exhibit significantly lower maternal attachment, serum oxytocin, and colonic Lactobacillus reuteri populations. Sub offspring showed a reduced hippocampal expression of key methylation genes at postnatal day (PND) 7 and a lack of developmentally-dependent increase in 5-methylcytosine (5-mC) at PND 21. In addition, Sub pups exhibit significant hypermethylation of gene promoters connected with glutamatergic synapses and behavioral responses. We were able to reverse the submissive endophenotype through cross-fostering Sub pups with Dom dams (Sub/D). Thus, Sub/D pups exhibited elevated hippocampal expression of DNMT3A at PND 7 and increased 5-mC levels at PND 21. Furthermore, adult Sub/D offspring exhibited increased sociability, social dominance, and hippocampal glutamate and monoamine levels resembling the neurochemical profile of Dom mice. We postulate that maternal inborn stress vulnerability governs epigenetic patterning sculpted by maternal care and intestinal microbiome diversity during early developmental stages and shapes the array of gene expression patterns that may dictate neuronal architecture with a long-lasting impact on stress sensitivity and the social behavior of offspring.
母体照护对于产后大脑发育中的表观遗传编程至关重要。压力被认为是一个关键因素，可能会影响母体行为，但由于压力反应的高度异质性，其影响在个体之间存在差异。我们旨在使用表现出行为谱两极（社会支配地位[Dom]和顺从地位[Sub]）和对压力有不同反应的小鼠群体，理解先天压力易感性、母体照护和早期表观遗传编程之间的联系。与具有压力抗性的 Dom 母鼠不同，具有压力易感性的 Sub 母鼠表现出明显较低的母性依恋、血清催产素和结肠罗伊氏乳杆菌种群。Sub 后代在产后第 7 天表现出关键甲基化基因表达减少，并且在第 21 天没有表现出与发育相关的 5-甲基胞嘧啶（5-mC）增加。此外，Sub 幼鼠表现出与谷氨酸能突触和行为反应相关的基因启动子的显著高甲基化。我们能够通过将 Sub 幼鼠与 Dom 母鼠交叉寄养（Sub/D）来逆转顺从的表型。因此，Sub/D 幼鼠在产后第 7 天表现出 DNMT3A 的海马表达增加，并且在第 21 天增加了 5-mC 水平。此外，成年 Sub/D 后代表现出社交能力、社会支配地位以及海马谷氨酸和单胺水平增加，类似于 Dom 小鼠的神经化学特征。我们假设母体先天压力易感性控制着由母体照护和早期发育阶段肠道微生物组多样性塑造的表观遗传模式，并塑造了一系列可能决定神经元结构的基因表达模式，对压力敏感性和后代的社会行为产生持久影响。
