Environmental Enrichment-Induced Recovery of Neuronal and Glial Maturation Following Perinatal Hypoxia

本研究旨在阐明环境富集（environmental enrichment， EE）诱导围产期缺氧恢复的机制。早产引起的脑损伤会导致慢性神经发育障碍，如智力障碍、运动缺陷和行为障碍。早产儿出生时呼吸系统不发达，在神经元成熟、突触形成和广泛胶质形成的关键发育时期暴露于缺氧条件下。这种氧合失败易导致早产儿脑白质和灰质发育异常。啮齿类动物和人类不同的神经发育时间允许出生后啮齿动物缺氧范式，模拟人类早产。在这个模型中，一种促进恢复的干预措施是将动物安置在情感表达中。通过简单地增加认知、身体和社会刺激水平，暴露于围产期缺氧的小鼠恢复了正常的皮层间神经元成熟和皮层下白质髓鞘形成，恢复了空间记忆，并改善了运动协调。这些发现支持了一个重要的假设，即情感表达通过促进神经元和神经胶质的成熟来促进围产期缺氧后的恢复。然而，尚不清楚情感表达是否会影响皮质锥体神经元及其半球间连接轴突，这些神经元对复杂的认知行为、学习和协调运动至关重要。为了确定EE是否能挽救围产期缺氧后皮层锥体神经元的成熟，形态学和电生理特性将被检查。然后，评估巨轴突髓鞘形成和传导速度，以确定EE是否能在围产期缺氧后恢复胼胝体轴突功能。最后，将检查少突胶质细胞mRNA翻译的变化，以确定EE是否恢复了参与轴突代谢支持的少突胶质细胞基因的翻译。这项研究将为ee诱导围产期缺氧恢复的机制提供重要的见解，并有助于为早产儿制定更有针对性和更有效的治疗方案。

This proposal aims to elucidate mechanisms of environmental enrichment (EE)-induced recovery from perinatal hypoxia. Brain damage induced by premature birth causes chronic neurodevelopmental impairments such as intellectual disabilities, locomotor deficits and behavioral disorders. Premature infants are born with an underdeveloped respiratory system, exposing them to hypoxic conditions during a critical developmental period of neuronal maturation, synapse formation, and extensive gliogenesis. This oxygenation failure predisposes preterm infants to dysmaturation of cerebral white and gray matter. The divergent neurodevelopmental timeline of rodents and humans allows for a postnatal rodent hypoxia paradigm that models human preterm birth. One intervention that enhances recovery in this model is housing animals in EE. By simply increasing levels of cognitive, physical, and social stimulation, mice exposed to perinatal hypoxia recover normal cortical interneuron maturation and subcortical white matter myelination, restore spatial memory, and improve locomotor coordination. These findings support the overarching hypothesis that EE promotes recovery after perinatal hypoxia by enhancing neuronal and glial maturation. However, it is unknown whether EE affects cortical pyramidal neurons and their interhemispheric commissural axons, which are essential for complex cognitive behaviors, learning, and coordinated movement. To determine if EE rescues cortical pyramidal neuron maturation following perinatal hypoxia, morphological and electrophysiological properties will be examined. Then, colossal axon myelination and conduction velocity will be assessed to determine if EE rescues callosal axon function following perinatal hypoxia. Finally, changes in oligodendrocyte mRNA translation will be examined to determine if EE restores translation of oligodendrocyte genes involved in metabolic support of axons. This study will provide crucial insight into the mechanisms of EE-induced recovery from perinatal hypoxia, and aid in the development of more targeted and effective treatment options for preterm infants.