Cognitive deficits triggered by early life stress: The role of histone deacetylase 1.
Cognitive deficits triggered by early life stress: The role of histone deacetylase 1.
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DOI：
10.1016/j.nbd.2016.05.018
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发表时间：
2016-10
影响因子：
6.1
通讯作者：
Schmauss C
中科院分区：
文献类型：
--
作者：
Adler SM;Schmauss C
研究表明，组蛋白去乙酰化酶（HDAC）抑制剂可以逆转神经退行性疾病中发现的认知缺陷和与年龄相关的记忆衰退。然而，HDAC在应激诱导的认知缺陷中的作用尚未研究。在应激敏感的小鼠品系Balb/c中，早期生活应激触发了前脑新皮质中HDAC表达的持续降低，包括I类HDAC表达的降低。同样的老鼠在成年后表现出明显的认知缺陷，即工作记忆和注意力转移的缺陷。在这里，我们表明，这些小鼠也表现出减少关联HDAC 1与脑源性神经营养因子（BDNF）基因的启动子III，认知测试导致BDNF mRNA表达异常增加。药理学减少BDNF-原肌苷激酶B受体信号转导有效地逆转了认知缺陷，表明增强的转录激活的BDNF基因有助于他们的出现。与Balb/c小鼠相反，C57 Bl/6小鼠在幼仔暴露于早期生活压力期间由Balb/c寄养母亲抚养时仅发展注意力转移缺陷。在这些C57 Bl/6小鼠中，Bdnf启动子III处的HDAC 1水平没有改变，尽管它们在认知测试后表现出早期生长反应基因2（Egr 2）启动子处的HDAC 1水平降低和Egr 2 mRNA表达异常增加。因此，与HDAC抑制在神经退行性疾病中的有益作用相反，在不同可塑性相关基因的启动子处的HDAC 1水平降低使暴露于早期生活压力的动物在认知挑战时倾向于增强这些基因的表达，这是负面影响认知任务表现的作用。
Studies showed that histone deacetylase (HDAC) inhibitors can reverse cognitive deficits found in neurodegenerative disorders and age-related memory decline. However, the role of HDACs in stress-induced cognitive deficits has not been investigated. In the stress-susceptible mouse strain Balb/c, early life stress triggers a persistent decrease in HDAC expression in the forebrain neocortex, including reduced expression of class I HDACs. The same mice show pronounced cognitive deficits in adulthood, namely deficits in working memory and attention set-shifting. Here we show that these mice also exhibit reduced association of HDAC1 with promotor III of the brain-derived neurotrophic factor (Bdnf) gene, and that cognitive testing leads to abnormally increased Bdnf mRNA expression. A pharmacological reduction of Bdnf-tropomyosine kinase B receptor signaling effectively reverses the cognitive deficits, indicating that enhanced transcriptional activation of the Bdnf gene contributes to their emergence. In contrast to Balb/c mice, C57Bl/6 mice only develop attention set-shifting deficits when raised by Balb/c foster mothers during the time the pups are exposed to early life stress. HDAC1 levels at Bdnf promotor III are unaltered in such C57Bl/6 mice, although they exhibit decreased levels of HDAC1 at the promotor of the early-growth response gene 2 (Egr2) and abnormally increased Egr2 mRNA expression after cognitive testing. Hence, contrary to the beneficial effects of HDAC inhibition in neurodegenerative diseases, the reduced HDAC1 levels at promotors of distinct plasticity-associated genes predispose animals exposed to early life stress to enhanced expression of these genes upon cognitive challenge, an effect that negatively influences cognitive task performance.