NP-4 Functional Restoration of the Brain:White Matter Matters

The brain white matter is composed of bundles of myelinated axons.Myelin provides critical supports for axons such as insulation and energy metabolism.Disruption of CNS myelin occurs in numerous neurological and psychiatric disorders.Remyelination is therefore a key to restore brain functions in such neuropsychiatric disorders.Myelin in the central nervous system is formed by oligodendrocytes,which arise from oligodendrocyte precursor cells(OPCs).Mature oligodendrocytes in the CNS lose their capability to remyelinate axons.In response to myelin loss,only OPCs are capable of generating new oligodendrocytes to remyelinate axons.OPCs are widely distributed in the adult CNS,accounting for 5%~8%of the total brain cell population.We observed that a sublethal episode of ischemia increased tolerance of neurons and astrocytes but aggravated death of OPCs to subsequent ischemic and hypoxic insults.OPCs are therefore considered the most vulnerable cells in the brain.To understand the vulnerability of OPCs,we examined responses of oligodendrocytes to metabolic stresses.Lactate is the primary energy substrate that is distributed through monocarboxylate transporters(MCTs)between brain cells to maintain energy metabolism and pH homeostasis.We found that MCT1,a primary MCT in oligodendrocyte,is significantly upregulated in response to ischemic preconditioning.Under hypoxic conditions,neurons export lactate through MCT2 to maintain an intracellular pH homeostasis,while oligodendrocytes increase importation of extracellular lactate due to their upregulated MCT1 leading to intracellular acidosis.We further obtained evidence to show that acidosis resulting from ischemic preconditioning primes OPCs to express high levels of the death gene Bcl-2/E1B-19K-interacting protein 3(BNIP3)in response to subsequent ischemic insults.Inhibition of BNIP3 by RNAi or necrostatin-1 and knocking out of the BNIP3 gene robustly reduced death of OPCs and preserve white matter integrity.Using an in vitro co-culture model of remyelination with neurons and oligodendrocytes prepared from neural stem cells,we found that pre-myelinating NG2-positive OPCs are able to make contact with axons and initiate remyelination.This is a short time-course and requires activation and M2 polarization of microglia.In conclusion,functional restoration of the brain relies not only on reestablishment of the neural networks,but also on appropriate remyelination of the axons.Since oligodendrocytes are the most vulnerable cells in the brain,strategies to protect oligodendrocytes and enhance remyelination shall help restore the brain functions and reduce demyelination-associated postinjury symptoms such as depression and dementia.