Mechanisms of Oligodendrocyte and Axonal Abnormalities After Perinatal Brain Injury

早产幸存者慢性残疾的一个主要原因是弥漫性白质损伤(DWMI)和 下髓鞘化症。WM的发育改变与不良后果直接相关，包括 脑性瘫痪、认知延迟和神经行为问题。弥漫性心肌梗死的细胞病理生理基础 而异常的髓鞘形成是复杂的，并没有完全被理解。WM胶质细胞，尤其是少突胶质细胞 (OL)及其祖细胞(OPC)容易受到早产时经常发生的损伤。我们有 以前使用了低氧(HX)诱导的全球WMI的动物模型来证明OPC显示 成熟延迟，导致髓鞘异常和WM功能改变。我们发现了少校 HX诱导的体部延迟髓鞘形成的细胞发育不良病理研究 骨痂，包括与OL分化减少相关的OPC增殖增强，并被破坏 髓鞘超微结构。我们最近对胼胝体(CC)中OL发育的分析表明：i) HX中OPC增殖状态延长和OL分化延迟是HIF1α变化的结果 组蛋白脱乙酰基酶Sirt1和SIRT2的依赖性表达和活性；ii)Hx降低 突触谷氨酸(Glu)从OPC上的皮质锥体神经元释放，正常情况下下调 OPC增殖，以及iii)HX损害SCWM的轴突完整性和功能，导致改变 轴突/髓鞘相互作用。基于这些结果，我们现在建议检验HX诱导的假设 OPC的内在(Sirt1和SIRT2)和外源性(突触)调节失调导致了旷日持久的WM不成熟 增殖和OL成熟，从而影响轴突的完整性和功能。首先，我们将确立 SIRT2在HX诱导的CC细胞OL延迟成熟中的作用其次，我们将定义 调节OPC增殖和延迟性OL的非细胞自主、谷氨酸介导的突触变化 HX后在CC内成熟。最后，我们将确定HX的影响和延迟的OL成熟在 CC的轴突完整性/功能。总之，这些研究不仅将阐明关键的细胞机制 HX诱导的WM成熟延迟，但也可能导致新的治疗方法的发展 旨在减少早产的长期神经后遗症。

A major cause of chronic disability in survivors of premature birth is diffuse white matter injury (DWMI) and hypomyelination. Altered development of the WM is directly associated with adverse outcomes, including cerebral palsy, cognitive delay and neurobehavioral problems. The cellular pathophysiology underlying DWMI and abnormal myelination is complex and not fully understood. WM glia, and particularly oligodendrocytes (OLs) and their progenitors (OPCs), are susceptible to injury that often occurs in premature birth. We have previously used an animal model of hypoxia (HX)-induced global WMI to demonstrate that OPCs display delayed maturation, which results in abnormal myelination and altered WM function. We have uncovered major aspects of the cellular dysmaturation pathology underlying HX-induced delayed myelination in corpus callosum, including enhanced OPC proliferation associated with decreased OL differentiation, and disrupted myelin ultrastructure. Our recent analysis of OL development in corpus callosum (CC) demonstrates that: i) the prolonged proliferative state of OPCs and delayed OL differentiation in HX is a result of changes in HIF1α- dependent expression and activity of the histone deacetylases Sirt1 and Sirt2, respectively; ii) HX reduces synaptic glutamate (Glu) release from cortical pyramidal neurons on OPCs, which normally downregulates OPC proliferation, and iii) HX compromises axonal integrity and function in SCWM, resulting in altered axon/myelin interactions. Based on these results, we now propose to test the hypothesis that HX-induced protracted WM immaturity arises from intrinsic (Sirt1 and Sirt2) and extrinsic (synaptic) dysregulation of OPC proliferation and OL maturation, thus affecting axonal integrity and function. Firstly, we will establish the role of Sirt2 as a crucial mediator of HX-induced delayed OL maturation in CC. Secondly, we will define the role of non-cell autonomous, glutamate-mediated synaptic changes in regulating OPC proliferation and delayed OL maturation in CC after HX. Finally, we will define the effects of HX and the role of delayed OL maturation on axonal integrity/function in CC. Together, these studies will not only shed light on crucial cellular mechanisms of HX-induced delay in WM maturation, but might also lead to the development of new therapeutic approaches aimed at lessening the long-term neurological sequelae of premature birth.