Environmental Enrichment Ameliorates Perinatal Brain Injury and Promotes Functional White Matter Recovery
Open AccessThe premise for this study is the utilization of a non-invasive approach to attenuate the effects of perinatal injury (perinatal hypoxia, HX) on the developing brain. Hypoxic damage to the brain sustained as a consequence of preterm birth is associated with permanent neurodevelopmental disabilities. This oxygenation failure predisposes preterm infants to diffuse white matter (WM) injury - a debilitating condition involving maturational delays in the HX-sensitive oligodendrocyte (OL) population, disturbances in myelination, and gross reductions in WM volume, which in turn lead to major cognitive and behavioral impairments seen throughout life. Yet, in light of the complexity and ever-rising rates of preterm brain injury, there remains no viable approach to attenuate the impact of HX on developing WM.It is well established that the environment in which premature babies and children are reared has profound effects on functional and behavioral outcomes. Previous studies demonstrated that the environment affects both neural plasticity and functional recovery after brain injury. Furthermore, social, family, and environmental factors contribute to improve cognitive outcome of premature children. To this end, we used a pre-clinical model of perinatal brain injury, and asked whether modulation of the neonatal environment could be used to enhance the endogenous repair of the developing WM and restore behavioral function. To elucidate the influence of environmental input on WM recovery after HX, we employed environmental enrichment (EE) during critical neurodevelopmental periods. EE refers to a complex domain that emulates the natural environment and challenges an animal to continuously adapt to its surroundings. Modeled from previous research, our EE paradigm houses mice in large cages filled with novel toys, a running wheel, and an increased number of cage mates. We determined the effects of EE on normal and injured mice by studying OL production and development, and WM-associated behavior. We find that early, prolonged EE selectively enhances endogenous repair of the developing WM by promoting oligodendroglial maturation, myelination, and functional recuperation after perinatal brain injury. These effects require increased exposure to socialization, physical activity, and cognitive enhancement of surroundings - a complete enriched environment. Importantly, functional recovery requires de novo oligodendrogenesis, suggesting that myelin plasticity induced by noninvasive modulation of the neonatal environment can be targeted as a therapeutic strategy for preterm birth. The intersection of WM development and disease is a maturational period primed for plasticity and functional regeneration induced by exogenous environmental stimuli. Environmental experience promotes structural changes in myelin, resulting in the modulation of neural circuits and therefore elaboration of our phenotypes in response to experiential input. In early life, this myelin plasticity and remodeling can reduce neurodevelopmental disability in children born preterm. Nevertheless, our understanding and clinical implementation of environmental influence on measurable patterns of developmental myelination, especially after injury, is still rudimentary.
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