Sex-specific and strain-dependent effects of early life adversity on behavioral and epigenetic outcomes.
Sex-specific and strain-dependent effects of early life adversity on behavioral and epigenetic outcomes.
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DOI：
10.3389/fpsyt.2013.00078
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发表时间：
2013
影响因子：
4.7
通讯作者：
Champagne FA
中科院分区：
文献类型：
--
作者：
Kundakovic M;Lim S;Gudsnuk K;Champagne FA
早期生活的逆境可能会对精神病理学的出现产生重大的长期影响。母婴互动的中断是早期生活逆境的一种形式，尤其可能对发育中的大脑产生深远的编程影响。然而，尽管来自人类和动物研究的证据越来越多，但与逆境相关的神经行为变化的确切机制途径尚未阐明。机制研究的一个途径是探索与早期生活经历相关的表观遗传变化。在目前的研究中，我们研究了出生后母体分离（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，我们包括两种不同的小鼠品系（C57 BL/6 J和Balb/cJ）和雄性和雌性后代，以确定应变和/或性别相关的差异反应MS。我们发现了两个应变特异性和性别依赖性的影响MS在青春期早期的后代开放领域的探索，蔗糖偏好和社会行为的措施。皮质和海马的糖皮质激素受体（Nr 3c 1）和脑源性神经营养因子（BDNF）基因的mRNA水平的分析表明，减少海马BDNF表达的母分离C57 BL/6 J女性和增加皮质BDNF表达的母分离的男性和女性Balb/cJ后代。Nr 3c 1和BDNF（IV和IX）CpG甲基化分析表明，在母系分离的C57 BL/6 J雄性中，海马Nr 3c 1甲基化增加，在雄性和雌性母系分离的Balb/c小鼠中，海马BDNF IX甲基化增加。总的来说，虽然效应大小是适度的，这些研究结果表明，在确定神经行为和表观遗传结果，可能会导致对晚年疾病的差异脆弱性，早期生活逆境，遗传背景和性别之间的复杂的相互作用。
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.