Eagleson Kathie L, Levitt Pat
Division of Neurology, Developmental Neuroscience and Neurogenetics Program, Children's Hospital Los Angeles, The Saban Research Institute, Los Angeles, California 90027
Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California 90027.
eNeuro. 2025 Sep 26;12(9). doi: 10.1523/ENEURO.0172-25.2025. Print 2025 Sep.
The environment experienced by children, such as exposure to chronic early life adversity (ELA), increases lifespan brain disorder risk. The mechanisms that link ELA exposure to functional brain disruptions are not well understood. A limited-bedding and nesting paradigm, in which ELA is induced in mouse pups over the first postnatal week through disruption of maternal care, is characterized by limited resources, environment unpredictability, and disruption of reward and cognitive behaviors. Studies using this model demonstrated sex-selective alterations in hippocampal mitochondrial-associated proteins in response to ELA compared with care as usual (CAU). Further, oxidative phosphorylation (OXPHOS) capacity and complex I activity are increased in ELA juveniles, yet decreased in adults, with the impact of ELA moderated by sex in adults. Given that altered mitochondrial function is a key mediator in metabolic adaptations, the goal of the present study was to evaluate the possibility of reversing mitochondrial dysfunction and the anhedonia that accompanies ELA by addressing oxidative stress. Treatment with the antioxidant MitoQ began at weaning and extended to 3 months. Measures of complex I activity demonstrated full recovery in adults. Female-specific deficits in the sucrose preference task, which is a measure of rewarding behavior in rodents, also exhibited recovery, with preference for sucrose comparable with that of CAU mice. These data indicate that mitochondrial health is one component of responses to early life adversity that has lifespan implications, but with the capacity to recover normal functioning in adults.
儿童所经历的环境，如长期暴露于早期生活逆境（ELA）中，会增加其一生中患脑部疾病的风险。然而，将ELA暴露与大脑功能紊乱联系起来的机制尚不清楚。有限的筑巢和铺垫范式是指在出生后的第一周通过破坏母性照料在幼鼠中诱导ELA，其特点是资源有限、环境不可预测以及奖励和认知行为受到破坏。与常规照料（CAU）相比，使用该模型的研究表明，ELA会导致海马体线粒体相关蛋白出现性别选择性改变。此外，ELA幼年小鼠的氧化磷酸化（OXPHOS）能力和复合物I活性增加，但成年小鼠则降低，且成年小鼠中ELA的影响受性别调节。鉴于线粒体功能改变是代谢适应的关键调节因子，本研究的目的是通过解决氧化应激来评估逆转线粒体功能障碍以及ELA伴随的快感缺失的可能性。抗氧化剂MitoQ的治疗从断奶开始，持续3个月。复合物I活性的测量结果表明成年小鼠已完全恢复。蔗糖偏好任务是衡量啮齿动物奖励行为的指标，雌性小鼠在该任务中的特定缺陷也有所恢复，对蔗糖的偏好与CAU小鼠相当。这些数据表明，线粒体健康是对早期生活逆境反应的一个组成部分，这种反应会影响一生，但成年后有恢复正常功能的能力。
