Abstract
Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these.
Highlights
The present review will focus on four causes of Perinatal brain injuries (PBIs) that are highly prevalent both in westernized and emerging countries: (i) encephalopathy associated with fetal growth restriction (EoFGR); (ii) encephalopathy of prematurity (EoP); (iii) neonatal encephalopathy of term neonates (NE), and; (iv) neonatal stroke (NS) that can occur both in preterm and term neonates
This study revealed that this MG subset produced factors, including IGF-1, that are necessary for myelination and neurogenesis
Future studies will need to address the precise roles of MG in these disorders by systematically ablating these cells in relevant animal models, despite the complexity to achieve this goal in newborn animals as described above
Summary
Perinatal brain injuries (PBIs) represent a number of entities of different origins that are each responsible for causing neurodevelopmental disorders (NDDs). It is unknown if MG from the first wave are phenotypically, developmentally and functionally different to MG from the first wave Another important point to note, is that the invasion and proliferation of MG in human [43], mouse [44], and sheep (Shearer and Fleiss, unpublished observations) occurs via the subventricular zones, with MG accumulating and sitting adjacent to oligodendrocyte progenitor cells (OPCs). MG pass through three temporally regulated stages of development: early MG, pre-MG, and adult MG (Figure 1) Each of these three stages are marked by changes in gene expression, morphology, and the specific roles that these cells undertake [36,45,46,47]. Species is another significant factor in the expression profile of MG [66] and a focus on understanding changes the core across-species markers will improve the translational potential of work on MG
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