VULNERABILITY OF THE DEVELOPING BRAIN AND PERINATAL EVENTS
Considerable advances in perinatal medicine have been associated with dramatic decrease in neonatal mortality. However, many hundreds of thousands of children will develop neurocognitive disabilities linked to several adverse perinatal events closely related to brain damages. Prematurity, intrauterine growth retardation, and perinatal brain insults occurring in term newborns are the main causes of abnormal neurodevelopment during infancy.
In 2010, preterm birth (<37 weeks of gestation) was the most common cause of death and disability in children <5 years of age.1 In the developed world, the rate of prematurity is increasing. Preterm birth results in the loss of 77 million Disability Adjusted Life Years,2 predominantly due to neurological damage. While the survival of preterm infants is increasing, morbidity associated with preterm birth remains mostly unchanged. Almost 10% of infants born very preterm (between 28 and 32 weeks of gestation) develop cerebral palsy, and ~35% have persistent cognitive and neuropsychiatric deficits. Although extreme prematurity (<28 weeks of gestation) induces the most severe problems, even moderate (32–34 weeks of gestation) or late (34–36 weeks of gestation) prematurity have significant adverse effects, including the need for special education, causing significant long-term educational and health care challenges.3 Currently, there is no treatment to prevent or mitigate these deficits. In addition to the emotional costs of these deficits to each individual, their families and society, lifetime costs of care for 1 child with cerebral palsy were estimated to be ~$1.3 million US dollars in 2003.4 Preterm birth typically occurs in the context of maternal/fetal inflammation or infection, exacerbated before/after birth by environmental insults including hypoxia/hyperoxia. Magnetic resonance imaging and postmortem studies show diffuse white and grey matter abnormalities collectively called encephalopathy of prematurity.5 Synaptic pruning and axonal growth,6,7 oligodendroglial lineage, and myelination8,9 are developmental processes involved in these developmental vulnerabilities.
Intrauterine Growth Restriction
Intrauterine growth restriction, a condition in which the fetus is unable to achieve its genetically determined size mainly as a consequence of placental insufficiency, is one of the most frequent complications of human pregnancy affecting more than 32 million newborns and 27% of all births in low- and middle-income countries10 in 2010. It increases risks of stillbirth, neonatal death and morbidity, and poor health in childhood and adult life.11,12 Furthermore, intrauterine growth retardation often requires a medically indicated preterm delivery, thereby exposing infants to risks linked to immaturity in addition to poor antenatal growth. Compared to infants with normal growth, those with intrauterine growth retardation are at a higher risk for death, metabolic and cardiovascular dysfunctions together with poor neurocognitive performances including cerebral palsy, intellectual disability, poor school performance, developmental-behavioral disorders, and a significant increase in the incidence of autism spectrum disorders.13–15 While the relationship between fetal growth restriction and subsequent neurodevelopmental impairment remains poorly understood, several preclinical models of intrauterine growth retardation have been associated with deficit of myelination and disturbance of oligodendroglial maturation, 2 key factors associated with neurocognitive handicaps both in rodents and in humans. An extensive dysregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia has been recently reported.16 Because neuroinflammation is commonly associated with delayed or arrested maturation of the developing white matter and with subsequent handicap, this dysregulation of microglial activation may be the missing link between intrauterine growth retardation and neurodevelopmental adverse outcomes (Figure 1).
Neonatal Stroke and Perinatal Asphyxia in Term Infants
Perinatal/neonatal arterial stroke is a cerebrovascular event occurring around the time of birth, with pathological or radiological evidence of focal arterial infarction mainly affecting the middle cerebral arterial territory, with an incidence of 1/2800 to 1/5000 live births.17,18 Perinatal stroke results in a spectrum of developmental disturbances including neuroinflammation leading to behavioral disorders associated with white matter injury, identified as cerebral palsy, more common in men than in women.19
Neonatal hypoxic-ischemic encephalopathy after birth asphyxia is a major cause of death or long-term disability in term neonates, affecting about 1–4 per 1000 live births. The incidence and consequences of hypoxic-ischemic encephalopathy are even more common and severe in less privileged settings, affecting about 1 million infants worldwide20 every year. In recent years, therapeutic hypothermia became the standard of care to improve outcome after perinatal hypoxic-ischemic insults. Despite hypothermia and state-of-the-art neonatal intensive care, 45%–50% of the children with moderate or severe hypoxic-ischemic encephalopathy (ie, 3000–15,000 infants/y in Europe) still die or suffer from long-term neurodevelopmental impairment.21
BRAIN DEVELOPMENT AND MICROGLIAL CELLS
Microglial Cells Origin and Fate
Microglia are permanent macrophages in the central nervous system (CNS) that play fundamental roles in brain homeostasis, neuronal expansion, and circuitry during brain development and plasticity in adulthood.22 Brain invasion from the embryonic yolk sac is highly regulated as reviewed by Tay et al.23 Precursors of microglia born in the yolk sac at early embryonic stages follow tangential and radial migration pathways to colonize all CNS regions, including the barrels in rodents with close interaction with thalamocortical synapses after birth.24 In addition to this crosstalk between microglia and neurons, maturation of yolk sac–derived microglia is dependent on specific signaling pathways involving purinergic receptors and cell surface protein Csf-1R, but also transforming growth factor β, a critical factor for mediating microglial survival and phenotypic differentiation in adults. The expression of several markers (including Iba1, CD45, major histocompatibility complex class II, and others) of microglial function was found to be changed during aging and CNS disease.25,26
Physiological Roles of Microglia During Brain Development
Microglia are the key mediators of brain physiological functions and microglial reactivity should not only be interpreted according to their neurotoxic effects but also to their alternative neuroprotective functions27 (Figure 2). Microglia also play central multifaceted physiological roles during normal development in neuronal proliferation, programmed neuronal cell death, angiogenesis, synaptogenesis and pruning, and influence oligodendroglial survival and maturation.28 Dysfunction of these normal physiological functions of microglia can result in developmental disorders that are traditionally viewed only as neuronal dysfunctions. Mutating or deleting microglia very often leads to the development or worsening of a brain disease.27 Conversely, tissue damage or cellular stress is also a potent inducer of innate immunity and therefore microglial activation, aiming at restoring cellular function in challenged conditions.29 The very partial and probably partly wrong view of cytotoxic cell lines should be strongly revised in the near future using detailed analysis of the causal relationship between microglial function and neuronal fate, and a better understanding of all aspects of the microglia response to brain injury. These diverse roles make microglia critical modulators of brain development and injury, and targeting their phenotype/activation states could be a key therapeutic strategy in brain injury.
Microglia Activation and Perinatal Brain Damage
In addition to their physiological roles in brain function, microglia play a key role in the development and long-term consequences of injury in the developing brain of perinatal origin. Microglial activation is a hallmark of most neurological disorders related to perinatal noxious events, and microglia can acquire diverse and complex functional states with effects on cytotoxicity and cell death—or on regeneration and repair—depending on the nature and severity of the injury.30–32 These innate immune cells can acquire distinct but dynamic phenotype/activation states in response to stimuli such as maternal/fetal inflammation or infection that allow them to either produce neurotoxic products and disrupt normal developmental processes or support repair and regeneration33 (Figure 2). In clinical studies and preclinical models of perinatal brain injuries, microglia activation is consistently observed and strongly associated with poor outcome.16,34–39 In addition, infants suffering from perinatal brain injury leading to cerebral palsy are often exposed to systemic inflammation associated with invasive medical procedures and are at risk of sepsis, factors also known to activate microglia.40 Systemic inflammation has also been shown to sensitize the developing brain to a secondary hypoxic or excitatory insult.41 Using a collection of postmortem brain cases (preterm infants who died in the early postnatal period compared to age-matched control fetuses), it has been possible to establish a strong correlation between accumulation of activated microglia, oligodendroglial maturation blockade, and axonal transport impairment.34,42
Limiting the cytotoxic activation of microglia while promoting repair appears to be a relevant strategy to protect the brain from injury.43,44 While an increasing number of mechanisms involved in the regulation of microglial activation have been reported in adult CNS disorders, few data are available regarding the regulators of microglial phenotypes. Recent studies demonstrated that microglia are not mature before term in humans and day 14 in rodents, allowing to study the regulation of microglial phenotypes in rodents at a relevant time period for neonatal neuroprotection in premature infants.45,46 In a mouse model that recapitulates the key features of encephalopathy of prematurity, 3 distinct pathways were found to play key roles in microglia activation: microglia expression of N-methyl-d-aspartate (NMDA) receptors,47 massive down-regulation of the wingless integration site/β-catenin pathway in microglial cells, and inflammation-induced sustained expression of postsynaptic protein 95 on the microglial membrane.48 The wingless integration site/β-catenin pathway and postsynaptic protein 95 expression were further shown to be highly correlated with magnetic resonance imaging–based white matter abnormalities in human preterm neonates.
Microglia and Tertiary Phase Injury
Microglia are important in the acute phase of brain injury. In addition, microglia are also long lived; in the human brain their lifespan is estimated to be up to 20 years6 and in the mouse for their entire lives. This observation is highly relevant, because after brain injury, the number and function microglia are altered for many months and even years in humans and nonhuman primates,49 and also in adulthood in experimental models of cerebral palsy-related perinatal brain injury.50–53
There is increasing evidence showing that child survivors with neurodevelopmental delays have experienced proinflammatory events leading to brain damage and subsequent late neurodegeneration, commonly called tertiary phase lesions. Interestingly, in survivors of traumatic brain injury, persistent and late microglial neuroinflammation have also been described as potential mechanisms.6 In addition to clinical observations of increased serum proinflammatory cytokines, the heightened responses to endotoxin challenges in 7-year-old children with cerebral palsy confirm the enduring effects of early life brain injury during childhood.54 Consistently cerebral palsy has been shown to be an independent risk factor for adult stroke,55 dementia-associated neurocognitive impairments,56 and neuropsychiatric disorders such as depression in later life.57 As a result, there are many ongoing translational projects testing dedicated delayed start therapy to target microglial activation resolution.
MICROGLIA ACTIVITY, PERINATAL STRESS, AND GLUCOCORTICOSTEROIDS
Microglial functional phenotypes are regulated by fine-tuned autocrine and paracrine pathways. These have been well studied in the acute phase across various models of injury and stress.58 Glucocorticosteroids are classically described as anti-inflammatory and immunosuppressive agents, but they also have proinflammatory properties and could potentiate the inflammatory response both at the central and peripheral levels.59–61 The proinflammatory effects of glucocorticosteroids are long lasting, and early life stress is able to shift the immune response toward a proinflammatory phenotype later in life.62 Interestingly, this study evidenced a direct effect of early stress exposure on microglia reactivity and maturation.
The mechanisms responsible for these effects are not yet well understood. However, an important role could be played by nuclear glucocorticosteroid receptors. Analysis of magnetically cell-sorted mice microglia reveals evidence of a disrupted glucocorticosteroid receptor/Cytosine-Cytosine-Adenosine-Adenosine-Thymidine enhancer-binding protein beta (CEBPB) axis, with 120 dysregulated genes specifically in adulthood but not early after birth.48 Activation of the glucocorticosteroid receptor-CEBPB axis is necessary for the control and regulation of the proinflammatory and anti-inflammatory balance in macrophages and microglia.63–65 A loss of CEBPB expression could increase brain injury severity.66 Glucocorticosteroid receptor–mediated neuroinflammatory processes are specific to microglia (unobserved in astrocytes) in the adult brain. The impact of early life stress on adult brain functions via glucocorticosteroid receptor–dependent pathways is supported by other paradigms, including maternal separation, chronic pain, and human neuropsychiatric disorders.67
Hippocampal glucocorticosteroid receptor expression was found to undergo epigenetic regulation influenced by early parental care.68 A recent study evidenced a relationship between glucocorticosteroid receptor methylation and inflammation at the central level.69 Rats exposed to maternal separation showed a higher methylation of hippocampal glucocorticosteroid receptor linked to an increase in the inflammatory response after sevoflurane administration.
Because microglia are the resident immune cells of the brain, we could hypothesize that stress conditions or high levels of glucocorticosteroids can induce epigenetic modifications of glucocorticosteroid receptors in microglia cells, too. The change in glucocorticosteroid receptor expression could therefore shift the microglia response toward the proinflammatory phenotype observed in premature infants and in animal models of fetal growth restriction. In this context, defining strategies to prevent exposure of the developing brain to high proinflammatory levels of glucocorticosteroids could be of crucial interest.
ANESTHETICS, VULNERABILITY OF THE DEVELOPING BRAIN, AND MICROGLIA REACTIVITY
Because brain maturation is highly dependent on microglial maturation, synaptic pruning and axonal growth, and myelination, perinatal brain insult and overall, perinatal stress, could have the effect of disrupting these complex processes with long-lasting impact on the brain.70 It is well known that neurotoxicity associated with anesthetics and surgery could also have a substantial impact on early brain development, possibly through glial cells including microglia and astrocytes.71
Isoflurane exposure has been reported to induce microglial activation and apoptosis in the neonatal piglet brain.72 In another model, Gui et al73 reported that surgery associated with sevoflurane anesthesia in neonatal rats induced neuroinflammation, and was found to be associated with a decreased level of glial-derived neurotrophic factor, a reduction of hippocampal neurogenesis, and cognitive impairment. Conversely, other preclinical studies demonstrated neuroprotective and beneficial behavioral effects conferred by isoflurane exposure of rats subjected to hypoxia-ischemia through pre/postconditioning mechanisms.74,75 In addition, the microglial resting state was shown to be linked to the 2-pore domain K+ channel tandem of P domains in a weak inwardly rectifying K+ channel-related halothane-inhibited K+ channel, also involved in normal neuroimmune regulation.76 Unlike most other 2-pore domain channels, tandem of P domains in a weak inwardly rectifying K+ channel-related halothane-inhibited K+ channel is blocked by most gaseous anesthetics including halothane, isoflurane, and sevoflurane, leading to a dysregulation of microglial phenotypes.
While the effects of anesthetics on neurodegeneration and behavioral deficits are well documented,77–80 less data about their effect on neuroinflammation and microglial activation in the developing brain are currently available. A proinflammatory effect of anesthetic exposure, including isoflurane, on the neonatal brain has previously been reported in rodents81–84 but anti-inflammatory effects or the absence of effects were also reported.85,86 It is therefore unclear whether this type of microglial activation induced by anesthetic gas is damaging or reflects the activation of an endogenous protective response.87
Propofol has been shown to alleviate microglial activation after experimental brain trauma in the adult brain through inhibition of nicotinamide adenine dinucleotide phosphate oxidase.88 In vitro, lipopolysaccharide-induced proinflammatory cytokine and proinflammatory enzyme expression were found to be down-regulated by propofol, via inhibiting the NMDA receptor, attenuating Ca2+ accumulation, and inhibiting Ca2+/Calmodulin-dependent protein kinase II, extracellular signal-regulated channel 1/2, and nuclear factor kappa-light chain enhancer of activated B cells phosphorylation.89 The same authors also demonstrated that this inhibitory effect involved an upregulation of suppressor cytokines signaling via suppression of microRNA-15590 expression.
Ketamine, a NMDA receptor antagonist used in pediatric anesthesia, given as a single neonatal exposure to mice led to alteration in cortical integration of γ-aminobutyric acid–mediated interneurons, short-term NMDA receptor cortical developmental profile impairments and induced long-term sex-dependent impairments in mice.91,92
Dexmedetomidine is an attractive drug to providing neuroprotection in the developing brain during anesthesia. When tested at doses similar to those used in pediatric and obstetric medicine (ie, 1–5 mg/kg), it provided protection against the neurotoxic effects of both sepsis in adult rats and sevoflurane anesthesia in the developing brain, reducing excessive microglial proinflammatory response by suppressing the toll-like receptor 4/nuclear factor kappa-light chain enhancer of activated B cells pathway.93,94 The neuroprotective properties of this α2-adrenoreceptor agonist on neurogenesis and neuronal plasticity have also been assessed by measuring the differentiation and proliferation of neuronal precursors in the dentate gyrus in a rat model of neonatal oxidative stress–induced brain injury.95
Glial cells differentially express opioid receptors and are thought to be functionally modulated by the activation of these receptors, possibly playing a role in the development of morphine tolerance in the context of neuropathic pain.96 Morphine is known to induce microglial activation, which in turn participates in antinociceptive tolerance in the spinal cord.97 Consistently, microglial inhibitors have been found to prevent (but not reverse) neuropathic pain.98 Chronic opioid exposure has been shown to induce glial activation, that in turn could increase tolerance and opioid-induced hyperalgesia.46 Using large-scale RNA sequencing study in neurons and glia and in situ hybridization experiments, Corder et al99 demonstrated that microglia do not express μ-opioid receptors. They also reported that μ-opioid receptors-knockout mice show intact morphine-induced microglial activation, but do not develop opioid-induced hyperalgesia. The molecular mechanisms underlying the activation of microglia during chronic morphine exposure should therefore occur through the μ-opioid receptor–independent pathway, presumably through toll-like receptor 4, which is able to bind damaged-associated molecular patterns released from neurons or by binding morphine itself. However, the crosstalk between opioids and microglia in the developing brain needs to be further studied.
Finally, crosstalk between microglial cells and neurons is now known to participate in pain control. Differences in the phenotypes of microglial activation between man and woman and between neonates and adults, in response to nerve injury, have recently been described,100 but with limited clinical implications to date.
Neuroinflammation is a very common feature in almost all types of brain injuries. Some uncertainty persists regarding the role of microglial activation as a trigger or a consequence of perinatal brain damage. However, inflammation during pregnancy and the neonatal period is a major risk factor for neurodevelopmental impairment and neuropsychiatric disorders. Microglia cells are the primary effector cells of inflammation in the brain, and their phenotypes might be implicated in synaptic and network dysfunctions in response to abnormal perinatal events associated with these diseases, which could be potentiated by a secondary anesthesia/surgery event. While microglial cells could be considered as key targets in both vulnerability and neuroprotection, further preclinical experiments are still needed to better understand crosstalk between anesthesia and neuroinflammation in the developing brain.
The authors thank Audrey Toulotte-Aebi for editing the manuscript.
Name: Olivier Baud, MD, PhD.
Contribution: This author helped write the first 3 parts of the review, and revised and approved the actual version of the manuscript.
Name: Marie Saint-Faust, MD.
Contribution: This author helped write the last part, and revised and approved the actual version of the manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
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