Marrocco Jordan, Gray Jason D, Kogan Joshua F, Einhorn Nathan R, O'Cinneide Emma M, Rubin Todd G, Carroll Thomas S, Schmidt Eric F, McEwen Bruce S
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, United States.
Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, United States.
Front Behav Neurosci. 2019 Jul 11;13:157. doi: 10.3389/fnbeh.2019.00157. eCollection 2019.
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.
早期生活经历塑造大脑结构和功能，并影响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参与情绪、认知功能以及下丘脑 - 垂体 - 肾上腺（HPA）轴调节的离散脑区。在啮齿动物中，急性束缚应激会增加海马区包括CA3锥体神经元在内的抑制性组蛋白H3赖氨酸9三甲基化（H3K9me3）的表达。这些CA3神经元在认知功能、情绪调节以及糖皮质激素（CORT）分泌激活中起关键作用。CA3神经元在早期生活应激（ELS）以及成年后的慢性应激后也会表现出结构和功能变化。通过使用有限垫料和筑巢材料诱导慢性ELS，随后在成年期施加急性游泳应激（AS）的方案，我们发现有ELS史的小鼠对AS的CORT反应减弱，尽管在应激后与对照小鼠一样表现出即刻早期基因的激活。我们发现，ELS诱导基线时CA3亚区抑制性H3K9me3组蛋白标记的表达持续增加，随后在AS后降低。相比之下，AS在对照小鼠中诱导该标记的短暂增加。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/谷氨酸家族以及糖皮质激素受体结合基因的基因表达在对照小鼠中因AS而短暂降低，在ELS小鼠中则持续降低。在大多数情况下，ELS小鼠中的AS并未诱导基因表达变化。对对照和ELS小鼠中受AS影响的基因进行严格筛选发现，与对照相比，ELS小鼠中基因表达变化显著减少。在ELS小鼠中只有18个基因被AS选择性调节，包括昼夜节律、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的更多基因。因此，ELS在应激敏感的CA3神经元中对应激编程了一种受限的翻译反应，导致基因表达持续变化，其中一些模仿了对照小鼠中AS的短暂效应，同时保留了对AS的即刻早期基因反应。
