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

本研究旨在阐明环境富集物(EE)诱导围产期缺氧恢复的机制。早产引起的大脑损伤会导致慢性神经发育障碍，如智力残疾、运动障碍和行为障碍。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期暴露在低氧条件下。这种氧合障碍使早产儿大脑白质和灰质发育不成熟。啮齿动物和人类不同的神经发育时间线允许对人类早产进行模拟的出生后啮齿动物缺氧范例。在这个模型中，一种促进恢复的干预措施是将动物安置在EE中。通过简单地增加认知、身体和社会刺激水平，暴露于围产期低氧的小鼠可以恢复正常的皮质神经元间成熟和皮质下白质髓鞘形成，恢复空间记忆，并改善运动协调。这些发现支持了最重要的假设，即EE通过促进神经元和神经胶质成熟来促进围产期缺氧后的恢复。然而，尚不清楚EE是否影响皮质锥体神经元及其半球间连合轴突，这是复杂的认知行为、学习和协调运动所必需的。为了确定EE是否挽救了围产期缺氧后皮质锥体神经元的成熟，我们将检测其形态和电生理特性。然后，将评估巨大轴突的髓鞘形成和传导速度，以确定EE是否能挽救围产期缺氧后的胼胝体轴突功能。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诱导从围产期缺氧中恢复的机制提供重要的见解，并有助于开发更有针对性和有效的早产儿治疗方案。

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.