Maternal Deprivation Enhances Contextual Fear Memory via Epigenetically Programming Second-Hit Stress-Induced Reelin Expression in Adult Rats.
Maternal Deprivation Enhances Contextual Fear Memory via Epigenetically Programming Second-Hit Stress-Induced Reelin Expression in Adult Rats.
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母性剥夺通过表观遗传编程成年大鼠第二次应激诱导的 Reelin 表达增强情境恐惧记忆
DOI：
10.1093/ijnp/pyy078
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发表时间：
2018-11-01
期刊：
影响因子：
--
通讯作者：
Zhao H
中科院分区：
文献类型：
--
作者：
Wang RH;Chen YF;Chen S;Hao B;Xue L;Wang XG;Shi YW;Zhao H
早期生活压力会增加患创伤后应激障碍的风险。然而，早期生活压力诱导的成年后创伤后应激障碍易感性的表观遗传机制尚不清楚。大鼠幼崽在出生后第1至14天每天暴露于母亲剥夺3小时，并在情境恐惧条件反射前7天使用DNA甲基转移酶抑制剂zebularine， l -蛋氨酸或载体治疗，情境恐惧条件反射被用作第二压力，并模仿成年后创伤后应激障碍的再体验症状。测定海马CA1中长时程增强、树突棘密度、DNA甲基转移酶mRNA、Reelin基因甲基化和Reelin蛋白表达。母性剥夺增强了成年期情境恐惧记忆。同时，母性剥夺降低了出生后22和90天海马CA1 DNA甲基转移酶mRNA和Reelin基因甲基化。成年期情境恐惧条件反射后海马CA1区Reelin蛋白表达增加。此外，与单独经历母性剥夺的大鼠相比，暴露于情境恐惧条件反射的大鼠在成年期情境恐惧条件反射后，海马长期增强和海马CA1区树突棘密度增加。Zebularine预处理导致成年大鼠情境恐惧记忆增强，Reelin基因低甲基化，Reelin蛋白表达增加，而l -蛋氨酸具有相反的作用。母性剥夺可以通过表观遗传编程二次应激诱导的Reelin表达，增强成年期情境恐惧记忆的易感性。这些发现为理解累积应力假说提供了一个新的框架。
Early-life stress increases the risk for posttraumatic stress disorder. However, the epigenetic mechanism of early-life stress-induced susceptibility to posttraumatic stress disorder in adulthood remains unclear. Rat pups were exposed to maternal deprivation during postnatal days 1 to 14 for 3 hours daily and treated with the DNA methyltransferase inhibitor zebularine, L-methionine, or vehicle 7 days before contextual fear conditioning, which was used as a second stress and to mimic the reexperiencing symptom of posttraumatic stress disorder in adulthood. Long-term potentiation, dendritic spine density, DNA methyltransferase mRNA, Reelin gene methylation, and Reelin protein expression in the hippocampal CA1 were measured. Maternal deprivation enhanced contextual fear memory in adulthood. Meanwhile, maternal deprivation decreased DNA methyltransferase mRNA and Reelin gene methylation in the hippocampal CA1 on postnatal days 22 and 90. Reelin protein expression was increased in the hippocampal CA1 following contextual fear conditioning in adulthood. Furthermore, compared with rats that experienced maternal deprivation alone, rats also exposed to contextual fear conditioning showed an enhanced induction of hippocampal long-term potentiation and increased dendritic spine density in the hippocampal CA1 following contextual fear conditioning in adulthood. Zebularine pretreatment led to an enhancement of contextual fear memory, hypomethylation of the Reelin gene, and increased Reelin protein expression in adult rats, while L-methionine had the opposite effects. Maternal deprivation can epigenetically program second-hit stress-induced Reelin expression and enhance the susceptibility to contextual fear memory in adulthood. These findings provide a new framework for understanding the cumulative stress hypothesis.
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影响因子：
11
作者：
Gray JD;Rubin TG;Hunter RG;McEwen BS
通讯作者：
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影响因子：
3.5
作者：
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影响因子：
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作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
2.7
作者：
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通讯作者：
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