Department of Psychology, Columbia University , New York, NY , USA.
Front Psychiatry. 2013 Aug 1;4:78. doi: 10.3389/fpsyt.2013.00078. eCollection 2013.
Early life adversity can have a significant long-term impact with implications for the emergence of psychopathology. Disruption to mother-infant interactions is a form of early life adversity that may, in particular, have profound programing effects on the developing brain. However, despite converging evidence from human and animal studies, the precise mechanistic pathways underlying adversity-associated neurobehavioral changes have yet to be elucidated. One approach to the study of mechanism is exploration of epigenetic changes associated with early life experience. In the current study, we examined the effects of postnatal maternal separation (MS) in mice and assessed the behavioral, brain gene expression, and epigenetic effects of this manipulation in offspring. Importantly, we included two different mouse strains (C57BL/6J and Balb/cJ) and both male and female offspring to determine strain- and/or sex-associated differential response to MS. We found both strain-specific and sex-dependent effects of MS in early adolescent offspring on measures of open-field exploration, sucrose preference, and social behavior. Analyses of cortical and hippocampal mRNA levels of the glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf) genes revealed decreased hippocampal Bdnf expression in maternally separated C57BL/6J females and increased cortical Bdnf expression in maternally separated male and female Balb/cJ offspring. Analyses of Nr3c1and Bdnf (IV and IX) CpG methylation indicated increased hippocampal Nr3c1 methylation in maternally separated C57BL/6J males and increased hippocampal Bdnf IX methylation in male and female maternally separated Balb/c mice. Overall, though effect sizes were modest, these findings suggest a complex interaction between early life adversity, genetic background, and sex in the determination of neurobehavioral and epigenetic outcomes that may account for differential vulnerability to later-life disorder.
早期生活逆境可能会产生重大的长期影响，对精神病理学的出现产生影响。母婴互动中断是一种早期生活逆境，它可能对发育中的大脑产生深远的编程影响。然而，尽管人类和动物研究的证据不断汇聚，与逆境相关的神经行为变化的确切机制途径尚未阐明。研究机制的一种方法是探索与早期生活经历相关的表观遗传变化。在当前的研究中，我们研究了产后母体分离（MS）对小鼠的影响，并评估了这种操作对后代的行为、大脑基因表达和表观遗传影响。重要的是，我们包括了两种不同的小鼠品系（C57BL/6J 和 Balb/cJ）以及雄性和雌性后代，以确定 MS 对不同品系和/或性别的差异反应。我们发现 MS 在早期青春期后代中对开阔场探索、蔗糖偏好和社会行为的测量既有品系特异性又有性别依赖性的影响。对皮质和海马中糖皮质激素受体（Nr3c1）和脑源性神经营养因子（Bdnf）基因的 mRNA 水平的分析表明，在 C57BL/6J 雌性的母源分离中，海马体中的 Bdnf 表达减少，而在母源分离的雄性和雌性 Balb/cJ 后代中，皮质中的 Bdnf 表达增加。对 Nr3c1 和 Bdnf（IV 和 IX）CpG 甲基化的分析表明，在 C57BL/6J 雄性的母源分离中，海马体中的 Nr3c1 甲基化增加，而在母源分离的雄性和雌性 Balb/c 小鼠中，Bdnf IX 甲基化增加。总体而言，尽管效应大小适中，但这些发现表明，早期生活逆境、遗传背景和性别的复杂相互作用决定了神经行为和表观遗传结果，这可能解释了对晚年障碍的不同易感性。
