Early Life Stress Restricts Translational Reactivity in CA3 Neurons Associated With Altered Stress Responses in Adulthood
Early Life Stress Restricts Translational Reactivity in CA3 Neurons Associated With Altered Stress Responses in Adulthood
复制标题
DOI：
10.3389/fnbeh.2019.00157
复制
发表时间：
2019-07-11
影响因子：
3
通讯作者：
McEwen, Bruce S.
中科院分区：
文献类型：
--
作者：
Marrocco, Jordan;Gray, Jason D.;McEwen, Bruce S.
早期的生活经历会影响大脑的结构和功能，并有助于成年后的行为内表型。这些经历对基因表达的表观遗传控制会影响涉及情绪、认知功能和下丘脑-垂体-肾上腺（HPA）轴调节的离散大脑区域。在啮齿动物中，急性束缚应激会增加海马区（包括 CA3 锥体神经元）中抑制性组蛋白 H3 赖氨酸 9 三甲基化 (H3K9me3) 的表达。这些 CA3 神经元对于认知功能和情绪调节以及糖皮质激素 (CORT) 分泌的激活至关重要。 CA3 神经元在生命早期应激 (ELS) 以及成年期慢性应激后也表现出结构和功能的变化。使用有限的垫料和筑巢材料诱导慢性 ELS 的方案，然后在成年后进行急性游泳应激 (AS)，我们发现有 ELS 病史的小鼠对 AS 表现出迟钝的 CORT 反应，尽管在应激后表现出与对照小鼠相似的早期基因激活。我们发现，ELS 诱导基线时 CA3 亚区中抑制性 H3K9me3 组蛋白标记的表达持续增加，随后在 AS 后减少。相比之下，AS 诱导对照小鼠的这一标记短暂增加。使用翻译核糖体亲和纯化（TRAP）方法分离CA3翻译mRNA，我们发现表观遗传基因家族、GABA/谷氨酸家族和糖皮质激素受体结合基因的基因表达在AS对照小鼠中短暂降低，并且在ELS小鼠中表现出持续降低。在大多数情况下，ELS 小鼠中的 AS 不会引起基因表达变化。对对照和 ELS 小鼠中受 AS 影响的基因进行严格筛选后发现，与对照相比，ELS 小鼠的基因表达变化显着减少。在 ELS 小鼠中，只有 18 个基因被 AS 选择性调节，涵盖昼夜节律、炎症反应、阿片受体等途径，以及糖皮质激素受体结合家族中包含的更多基因。因此，ELS在应激敏感的CA3神经元中编程对应激的有限翻译反应，导致基因表达的持续变化，其中一些模仿对照小鼠中AS的瞬时效应，同时在操作中保留对AS的立即早期基因反应。
Early life experiences program brain structure and function and contribute to behavioral endophenotypes in adulthood. Epigenetic control of gene expression by those experiences affect discrete brain regions involved in mood, cognitive function and regulation of hypothalamic-pituitary-adrenal (HPA) axis. In rodents, acute restraint stress increases the expression of the repressive histone H3 lysine 9 tri-methylation (H3K9me3) in hippocampal fields, including the CA3 pyramidal neurons. These CA3 neurons are crucially involved in cognitive function and mood regulation as well as activation of glucocorticoid (CORT) secretion. CA3 neurons also exhibit structural and functional changes after early-life stress (ELS) as well as after chronic stress in adulthood. Using a protocol of chronic ELS induced by limited bedding and nesting material followed by acute-swim stress (AS) in adulthood, we show that mice with a history of ELS display a blunted CORT response to AS, despite exhibiting activation of immediate early genes after stress similar to that found in control mice. We find that ELS induced persistently increased expression of the repressive H3K9me3 histone mark in the CA3 subfield at baseline that was subsequently decreased following AS. In contrast, AS induced a transient increase of this mark in control mice. Using translating ribosome affinity purification (TRAP) method to isolate CA3 translating mRNAs, we found that expression of genes of the epigenetic gene family, GABA/glutamate family, and glucocorticoid receptors binding genes were decreased transiently in control mice by AS and showed a persistent reduction in ELS mice. In most cases, AS in ELS mice did not induce gene expression changes. A stringent filtering of genes affected by AS in control and ELS mice revealed a noteworthy decrease in gene expression change in ELS mice compared to control. Only 18 genes were selectively regulated by AS in ELS mice and encompassed pathways such as circadian rhythm, inflammatory response, opioid receptors, and more genes included in the glucocorticoid receptor binding family. Thus, ELS programs a restricted translational response to stress in stress-sensitive CA3 neurons leading to persistent changes in gene expression, some of which mimic the transient effects of AS in control mice, while leaving in operation the immediate early gene response to AS.