Gestational environment programs adult depression-like behavior through methylation of the calcitonin gene-related peptide gene.
Gestational environment programs adult depression-like behavior through methylation of the calcitonin gene-related peptide gene.
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DOI：
10.1038/mp.2012.136
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发表时间：
2013-12
影响因子：
11
通讯作者：
Dulawa, S. C.
中科院分区：
文献类型：
--
作者：
Jiao, J.;Opal, M. D.;Dulawa, S. C.
早年暴露于特定的环境因素会增加成年后患上包括严重抑郁症在内的精神疾病的风险。然而，早期环境对成人情绪影响的分子途径和表观遗传机制仍然知之甚少。我们在Balb/CJ(CJ)和C57BL/6J(B6)小鼠品系中采用双向杂交和交叉培养相结合的设计，研究了不同的妊娠和养育条件对成年焦虑和抑郁样行为的影响。首先对由B6或CJ母鸡妊娠，然后由两个品系饲养的子代(F1)成年后的行为和全基因组海马区基因表达进行了评估。与CJ DAMs妊娠的成年杂交小鼠相比，B6 DAMs妊娠的成年杂交小鼠在强迫游泳和蔗糖偏好试验中抑郁样行为增加，海马区α-降钙素基因相关肽(α)转录产物表达增加，αCGRP启动子甲基化减少。成年期α降钙素基因相关蛋白的差异表达不是基因组印记造成的，B6和CJ线粒体DNA的差异也不是观察到的行为表型的原因。最后，成年杂交小鼠中枢注射降钙素基因相关肽可增加抑郁样行为，而α受体拮抗剂CGRP8-37则减少抑郁样行为。我们的发现表明，妊娠因素通过α降钙素基因甲基化影响成人抑郁样行为。
Early life exposure to specific environmental factors can increase risk for developing psychopathology including major depression in adulthood. However, the molecular pathways and epigenetic mechanisms that mediate the effects of early environments on adult mood remain poorly understood. We examined the effects of different gestational and rearing conditions on adult anxiety- and depression-like behavior using a combined reciprocal out-crossing and cross-fostering design in Balb/cJ (cJ) and C57BL/6J (B6) mouse strains. First filial (F1) hybrid offspring, which were gestated by B6 or cJ dams and then reared by either strain, were evaluated for behavior and whole-genome hippocampal gene expression during adulthood. Adult hybrid mice gestated by B6 dams showed increased depression-like behavior in the forced swim and sucrose preference tests, increased hippocampal expression of alpha calcitonin gene-related peptide (αCGRP) transcripts, and decreased methylation of the αCGRP promoter compared to those gestated by cJ dams. Differential expression of αCGRP in adulthood did not result from genomic imprinting, and differences between B6 and cJ mitochondrial DNA were not responsible for behavioral phenotypes observed. Lastly, central administration of αCGRP to adult hybrid mice increased depression-like behavior, while the CGRP1 receptor antagonist CGRP8–37 reduced depression-like behavior in the FST. Our findings suggest that gestational factors influence adult depression-like behavior through methylation of the αCGRP gene.
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