Eagleson Kathie L, Villaneuva Miranda, Southern Rebecca M, Levitt Pat
Department of Pediatrics and Program in Developmental Neuroscience and Neurogenetics, USA.
The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Neurobiol Stress. 2020 Sep 13;13:100251. doi: 10.1016/j.ynstr.2020.100251. eCollection 2020 Nov.
Exposure to early-life stress (ELS) increases risk for poor mental and physical health outcomes that emerge at different stages across the lifespan. Yet, how age interacts with ELS to impact the expression of specific phenotypes remains largely unknown. An established limited-bedding paradigm was used to induce ELS in mouse pups over the early postnatal period. Initial analyses focused on the hippocampus, based on documented sensitivity to ELS in humans and various animal models, and the large body of data reporting anatomical and physiological outcomes in this structure using this ELS paradigm. An unbiased discovery proteomics approach revealed distinct adaptations in the non-nuclear hippocampal proteome in male versus female offspring at two distinct developmental stages: juvenile and adult. Gene ontology and KEGG pathway analyses revealed significant enrichment in proteins associated with mitochondria and the oxidative phosphorylation (OXPHOS) pathway in response to ELS in female hippocampus only. To determine whether the protein adaptations to ELS reflected altered function, mitochondrial respiration (driven through complexes II-IV) and complex I activity were measured in isolated hippocampal mitochondria using a Seahorse X96 Flux analyzer and immunocapture ELISA, respectively. ELS had no effect on basal respiration in either sex at either age. In contrast, ELS increased OXPHOS capacity in juvenile males and females, and reduced OXPHOS capacity in adult females but not adult males. A similar pattern of ELS-induced changes was observed for complex I activity. These data suggest that initial adaptations in juvenile hippocampus due to ELS were not sustained in adults. Mitochondrial adaptations to ELS were also exhibited peripherally by liver. Overall, the temporal distinctions in mitochondrial responses to ELS show that ELS-generated adaptations and outcomes are complex over the lifespan. This may contribute to differences in the timing of appearance of mental and physical disturbances, as well as potential sex differences that influence only select outcomes.
早年生活应激（ELS）会增加在整个生命周期不同阶段出现的不良身心健康后果的风险。然而，年龄如何与ELS相互作用以影响特定表型的表达在很大程度上仍不清楚。我们采用一种既定的有限垫料范式在出生后早期诱导幼鼠发生ELS。基于人类和各种动物模型中已记录的对ELS的敏感性，以及大量使用该ELS范式报告该结构解剖和生理结果的数据，初步分析聚焦于海马体。一种无偏倚的发现蛋白质组学方法揭示了在两个不同发育阶段（幼年和成年）的雄性和雌性后代的非核海马蛋白质组中存在不同的适应性变化。基因本体论和KEGG通路分析显示，仅在雌性海马体中，与线粒体和氧化磷酸化（OXPHOS）通路相关的蛋白质有显著富集，这是对ELS的反应。为了确定蛋白质对ELS的适应性变化是否反映了功能改变，我们分别使用海马X96通量分析仪和免疫捕获ELISA在分离的海马线粒体中测量了线粒体呼吸（由复合物II - IV驱动）和复合物I活性。ELS对任何年龄的两性基础呼吸均无影响。相比之下，ELS增加了幼年雄性和雌性的OXPHOS能力，降低了成年雌性而非成年雄性的OXPHOS能力。对于复合物I活性，也观察到了类似的ELS诱导变化模式。这些数据表明，幼年海马体因ELS产生的初始适应性变化在成年后并未持续。肝脏也在外周表现出对ELS的线粒体适应性变化。总体而言，线粒体对ELS反应的时间差异表明，ELS产生的适应性变化和结果在整个生命周期中是复杂的。这可能导致心理和身体障碍出现时间的差异，以及仅影响特定结果的潜在性别差异。
