We have previously shown that high runner (HR) mice (from a line genetically selected for increased wheel-running behavior) have distinct, genetically based, neurobiological phenotypes as compared with non-selected control (C) mice. However, developmental programming effects during early life, including maternal care and parent-of-origin-dependent expression of imprinted genes, can also contribute to variation in physical activity. Here, we used cross-fostering to address two questions. First, do HR mice have altered DNA methylation profiles of imprinted genes in the brain compared to C mice? Second, does maternal upbringing further modify the DNA methylation status of these imprinted genes? To address these questions, we cross-fostered all offspring at birth to create four experimental groups: C pups to other C dams, HR pups to other HR dams, C pups to HR dams, and HR pups to C dams. Bisulfite sequencing of 16 imprinted genes in the cortex and hippocampus revealed that the HR line had altered DNA methylation patterns of the paternally imprinted genes, Rasgrf1 and Zdbf2, as compared with the C line. Both fostering between the HR and C lines and sex modified the DNA methylation profiles for the paternally expressed genes Mest, Peg3, Igf2, Snrpn, and Impact. Ig-DMR, a gene with multiple paternal and maternal imprinted clusters, was also affected by maternal upbringing and sex. Our results suggest that differential methylation patterns of imprinted genes in the brain could contribute to evolutionary increases in wheel-running behavior and are also dependent on maternal upbringing and sex.

我们之前已经证明，与未选择的对照 (C) 小鼠相比，高跑者 (HR) 小鼠（来自基因选择的增加轮跑行为的品系）具有独特的、基于遗传的神经生物学表型。然而，生命早期的发育规划效应，包括母亲护理和印记基因的父母来源依赖性表达，也可能导致身体活动的变化。在这里，我们使用交叉培养来解决两个问题。首先，与 C 小鼠相比，HR 小鼠大脑中印迹基因的 DNA 甲基化谱是否发生了改变？其次，母亲的教养是否会进一步改变这些印记基因的DNA甲基化状态？为了解决这些问题，我们在出生时交叉培养所有后代，创建四个实验组：C 幼崽到其他 C 水坝，HR 幼崽到其他 HR 水坝，C 幼崽到 HR 水坝，HR 幼崽到 C 水坝。对皮层和海马中 16 个印记基因的亚硫酸氢盐测序显示，与 C 系相比，HR 系改变了父系印记基因Rasgrf1和Zdbf2的 DNA 甲基化模式。 HR 系和 C 系之间的培育和性别均改变了父系表达基因Mest 、 Peg3 、 Igf2 、 Snrpn和Impact 的DNA 甲基化谱。 Ig-DMR是一种具有多个父本和母本印记簇的基因，也受到母亲的教养和性别的影响。我们的结果表明，大脑中印记基因的差异甲基化模式可能有助于轮子运行行为的进化增加，并且还取决于母亲的教养和性别。