The role of HCAR1 on oligodendrocyte proliferation and survival after neonatal hypoxia ischemia in mice

Neonatal cerebral hypoxia-ischemia (HI) is a leading cause of death and disability in infants. It is characterized by insufficient supply of blood and oxygen to the brain, resulting in cell death and tissue loss. The only current treatment of neonatal HI is hypothermia, a treatment that is only effective for moderate HI insults, and not beneficial for more than 30% of surviving babies. In addition, many of the survivors still experience long-term neurological effects such as cerebral palsy, epilepsy, and cognitive disabilities. New treatments that can reduce the brain injury and improve tissue regeneration after HI are therefore needed. The oligodendrocytes and their myelin are highly vulnerable to hypoxia ischemia and other forms of brain injury. Myelin insulates the nerve fibers and is crucial for effective action potential propagation and neuronal health. HI leads to oligodendrocyte death and damage and consequently demyelination of the axons. An important goal for brain tissue repair after injury is therefore to be able to stimulate the production of new oligodendrocytes to remyelinate the axons. Our group and others have previously shown that lactate can support myelination and cell proliferation in the brain, an effect that was attributed to its metabolic properties. New studies suggest that lactate exert some of its protective effects through the newly discovered Hydroxycarboxylic acid receptor 1 (HCAR1), but in vivo studies are scarce. The purpose of this study was to investigate whether this lactate receptor is involved in oligodendrocyte survival and proliferation after brain injury, and to find out which cell types express HCAR1 in the mouse brain. This study revealed HCAR1 expression in oligodendrocytes in the corpus callosum of mouse brain sections. HCAR1 was also detected in the subventricular zone, neocortex, and the granular cell layer of the dentate gyrus of the hippocampus, indicating that HCAR1 is expressed in a variety of other cells. By using a mouse model for cerebral HI, this study showed that mice lacking HCAR1 have a reduced number of proliferated oligodendrocytes after HI compared with wild type (WT) mice. When investigating loss of mature oligodendrocytes however, a similar reduction of oligodendrocytes was detected in both genotypes after injury. These data suggest that HCAR1 is important for oligodendrocyte proliferation, but not oligodendrocyte survival, after HI. In the long term, these findings could contribute to increase o