Developmental window of vulnerability to white matter injury driven by sublethal intermittent hypoxemia

In the developing brain, the death of immature oligodendrocytes (OLs) has been proposed to explain a developmental window for vulnerability to white matter injury (WMI). However, in neonatal mice, chronic sublethal intermittent hypoxia (IH) recapitulates the phenotype of diffuse WMI without affecting cellular viability. This work determines whether, in neonatal mice, a developmental window of WMI vulnerability exists in the absence of OLs lineage cellular death.

Neonatal sublethal IH recapitulates the phenotype of diffuse WMI only when IH stress coincides with the developmental stage of primary white matter myelination. This signifies a contribution of cell-nonlethal mechanisms in defining the developmental window of vulnerability to diffuse WMI. Impact: The key message of our work is that the developmental window of vulnerability to the WMI driven by intermittent hypoxemia exists even in the absence of excessive OLs and other cells death. This is an important finding because the existence of the developmental window of vulnerability to WMI has been explained by a lethal-selective sensitivity of immature OLs to hypoxic and ischemic stress, which coincided with their differentiation. Thus, our study expands mechanistic explanation of a developmental window of sensitivity to WMI by showing the existence of cell-nonlethal pathways responsible for this biological phenomenon.

Neonatal mice were exposed to cell-nonlethal early or late IH stress. The presence or absence of WMI phenotype in their adulthood was defined by the extent of sensorimotor deficit and diffuse cerebral hypomyelination. A separate cohort of mice was examined for markers of cellular degeneration and OLs maturation.

Compared to normoxic littermates, only mice exposed to early IH stress demonstrated arrested OLs maturation, diffuse cerebral hypomyelination, and sensorimotor deficit. No cellular death associated with IH was detected. Conclusions: Neonatal sublethal IH recapitulates the phenotype of diffuse WMI only when IH stress coincides with the developmental stage of primary white matter myelination. This signifies a contribution of cell-nonlethal mechanisms in defining the developmental window of vulnerability to diffuse WMI. Impact: The key message of our work is that the developmental window of vulnerability to the WMI driven by intermittent hypoxemia exists even in the absence of excessive OLs and other cells death. This is an important finding because the existence of the developmental window of vulnerability to WMI has been explained by a lethal-selective sensitivity of immature OLs to hypoxic and ischemic stress, which coincided with their differentiation. Thus, our study expands mechanistic explanation of a developmental window of sensitivity to WMI by showing the existence of cell-nonlethal pathways responsible for this biological phenomenon.