Abstract
Hypoxic damage to the developing brain due to preterm birth causes many anatomical changes, including damage to the periventricular white matter. This results in the loss of glial cells, significant disruptions in myelination, and thereby cognitive and behavioral disabilities seen throughout life. Encouragingly, these neurological morbidities can be improved by environmental factors; however, the underlying cellular mechanisms remain unknown. We found that early and continuous environmental enrichment selectively enhances endogenous repair of the developing white matter by promoting oligodendroglial maturation, myelination, and functional recovery after perinatal brain injury. These effects require increased exposure to socialization, physical activity, and cognitive enhancement of surroundings—a complete enriched environment. Using RNA-sequencing, we identified oligodendroglial-specific responses to hypoxic brain injury, and uncovered molecular mechanisms involved in enrichment-induced recovery. Together, these results indicate that myelin plasticity induced by modulation of the neonatal environment can be targeted as a therapeutic strategy for preterm birth.
Highlights
Hypoxic damage to the developing brain due to preterm birth causes many anatomical changes, including damage to the periventricular white matter
We characterized OL dynamics in the subcortical white matter (WM) (Fig. 1a) following HX-induced WM injury and EE-driven recovery. 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) enhanced green fluorescent protein (EGFP) mice—a widely used tool in which all OL lineage cells are fluorescently labeled28,29—were separated into four experimental groups: (1) Normoxic Standard (NX), which were reared in a standard laboratory environment; (2) Normoxic Enriched (NX-EE), which were placed into EE at P15, where they remained for the duration of the experiment; (3) Hypoxic Standard (HX), which were exposed to HX from postnatal day 3 (P3) to P11 (10.5 ± 0.5% oxygen), and raised thereafter in a standard environment; and (4) Hypoxic Enriched (HX-EE), which were exposed to HX from P3 to P11, and reared continuously in an enriched environment (Fig. 1b, c)
We first assessed the effects of HX on EGFP+NG2+-OPCs and EGFP+Ki67+-proliferating OPCs vs. NX controls, and found an increase in both cell types at P30 (HX vs. NX—OPCs: 6080 ± 167 cells/mm[3] vs. 4090 ± 241; proliferating OPCs: 5006 ± 279 vs. 3243 ± 110) (Fig. 1d–e; Supplementary Fig. 1a–f)
Summary
Hypoxic damage to the developing brain due to preterm birth causes many anatomical changes, including damage to the periventricular white matter. We found that early and continuous environmental enrichment selectively enhances endogenous repair of the developing white matter by promoting oligodendroglial maturation, myelination, and functional recovery after perinatal brain injury. These effects require increased exposure to socialization, physical activity, and cognitive enhancement of surroundings—a complete enriched environment. Using RNA-sequencing, we identified oligodendroglial-specific responses to hypoxic brain injury, and uncovered molecular mechanisms involved in enrichment-induced recovery Together, these results indicate that myelin plasticity induced by modulation of the neonatal environment can be targeted as a therapeutic strategy for preterm birth. Further investigation into specific candidate pathways and gene networks known to influence recovery will inform the development of new therapeutic strategies aimed at harnessing endogenous mechanisms of repair
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