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.

PROJECT NARRATIVE Mechanisms of Oligodendrocyte and Axonal Abnormalities After Perinatal Brain Injury PI: Vittorio Gallo, PhD Diffuse white matter injury (DWMI) is the major form of brain injury found in premature infants, and is associated with a broad range of motor, cognitive, behavioral and learning disabilities. Oligodendrocytes (OLs) are a major target of DWMI and defects in their development cause myelin abnormalities found in premature infants. We have shown that OL progenitors (OPCs) play a major role in WM recovery in an animal model of premature brain injury. We will determine whether protracted WM immaturity caused by premature brain injury arises from dysregulation of OPC proliferation and differentiation, and from axonal abnormalities.