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Cerebral palsy is caused by injury or developmental disturbances to the immature brain and leads to substantial motor, cognitive, and learning deficits. In addition to developmental disruption associated with the initial insult to the immature brain, injury processes can persist for many months or years. We suggest that these tertiary mechanisms of damage might include persistent inflammation and epigenetic changes. We propose that these processes are implicit in prevention of endogenous repair and regeneration and predispose patients to development of future cognitive dysfunction and sensitisation to further injury. We suggest that treatment of tertiary mechanisms of damage might be possible by various means, including preventing the repressive effects of microglia and astrocyte over-activation, recapitulating developmentally permissive epigenetic conditions, and using cell therapies to stimulate repair and regeneration Recognition of tertiary mechanisms of damage might be the first step in a complex translational task to tailor safe and effective therapies that can be used to treat the already developmentally disrupted brain long after an insult.

Key Points Perinatal brain injuries result from a spectrum of conditions, including neonatal encephalopathy, arterial ischaemic stroke, prematurity, and systemic infections Depending on the timing and context, inflammation can prime the brain for injury or exert protective actions Pattern recognition receptors, such as Toll-like receptors on innate immune cells (microglia, mast cells and macrophages), are important participants in the early phases of injury, and can increase CNS vulnerability (sensitization) Inflammation during preterm labour and intensive care of premature infants affects the very immature brain during critical phases of brain development, with serious consequences for myelination and cortical development Understanding the involvement of inflammation in perinatal brain injury can aid identification of new strategies for prevention and treatment that could reduce neurological and neuropsychiatric morbidities in maturing infants Neuroinflammation during critical phases of brain development can increase the risk of neurological and neuropsychiatric disorders, even in adulthood. In this Review, Hagberg et al . review the mechanisms through which inflammation can exacerbate perinatal brain injury, and outline how understanding the interplay between inflammation and brain injury can aid the identification of new strategies to alleviate neurological and neuropsychiatric morbidity. Inflammation is increasingly recognized as being a critical contributor to both normal development and injury outcome in the immature brain. The focus of this Review is to highlight important differences in innate and adaptive immunity in immature versus adult brain, which support the notion that the consequences of inflammation will be entirely different depending on context and stage of CNS development. Perinatal brain injury can result from neonatal encephalopathy and perinatal arterial ischaemic stroke, usually at term, but also in preterm infants. Inflammation occurs before, during and after brain injury at term, and modulates vulnerability to and development of brain injury. Preterm birth, on the other hand, is often a result of exposure to inflammation at a very early developmental phase, which affects the brain not only during fetal life, but also over a protracted period of postnatal life in a neonatal intensive care setting, influencing critical phases of myelination and cortical plasticity. Neuroinflammation during the perinatal period can increase the risk of neurological and neuropsychiatric disease throughout childhood and adulthood, and is, therefore, of concern to the broader group of physicians who care for these individuals.

Microglia, the resident immune cells of the mammalian central nervous system (CNS), play a pivotal role in both physiological and pathological conditions such as the restoration of CNS integrity and the progression of neurodegenerative disorders. Extensive data have been published that describe neuroinflammation by microglial activation to have detrimental consequences on the developing and mature brain. On the other hand, a properly directed and limited inflammatory response is known to be a natural healing process after an insult in several other tissues. Thus, it is not surprising that research results illustrating benefits of neuroinflammation have been emerging over the past decade. Inflammation-mediated benefits for CNS outcomes include mechanisms such as neuroprotection, mobilization of neural precursors for repair, remyelination and axonal regeneration. Here, we review data that highlight the dual aspects of microglia with a focus on the developing brain, i.e. as aggressors potentiating damage and as helpers in the recovery process following CNS damage.

Background Fever during pregnancy is a relatively common and most often trivial event. However, under specific conditions, it could affect significantly fetal brain development. Few studies, with inconsistent results, investigated whether fever, regardless the pathogen, could represent a risk factor for neurodevelopmental disorders (NDD) in the offspring. We aimed to explore further this question by performing a systematic review and meta-analysis. Methods Peer-reviewed studies exploring the occurrence of NDD in offspring after a fetal exposure to maternal fever were included. We specifically considered the impact of fever severity and duration, taking into consideration some confounding variables such as the use of antipyretic during pregnancy, the trimester in which the fever arose, the maternal age or smoking at time of gestation. MEDLINE, EMBASE, PsycINFO, Cochrane and Web of Science were searched without language restriction. PRISMA recommendations were followed. Odds ratio (OR) were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using random-effects meta-regression analysis. (PROSPERO CRD42020182801). Results We finally considered ten studies gathering a total of 10,304 children with NDD. Among them, 1394 were exposed to fever during pregnancy. The selected studies were divided into 5 case–control studies and 5 cohort studies. Maternal exposure to fever during pregnancy increased the risk of NDD in offspring with an OR of 1.24 [95% CI: 1.12–1.38]. Secondary analysis revealed an increased risk for NDD when fever occurred during the first trimester of gestation [OR 1.13–95% CI: 1.02–1.26]. Limitations We excluded studies that considered infections with no evidence of fever. Another potential limitation may be the possible heterogeneity between study designs (cohorts and case–control). Conclusion Additional evidence supported the association between fever during pregnancy and increased risk for NDD in offspring. Careful monitoring should be considered for children born from mothers with a febrile episode during pregnancy (specifically during the first trimester).

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.

Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk–associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53. Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17. However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.

Traumatic brain injury (TBI) results in white matter injury (WMI) that is associated with neurological deficits. Neuroinflammation originating from microglial activation may participate in WMI and associated disorders. To date, there is little information on the time courses of these events after mild TBI. Therefore we investigated (i) neuroinflammation, (ii) WMI and (iii) behavioral disorders between 6 hours and 3 months after mild TBI. For that purpose, we used experimental mild TBI in mice induced by a controlled cortical impact. (i) For neuroinflammation, IL-1b protein as well as microglial phenotypes, by gene expression for 12 microglial activation markers on isolated CD11b+ cells from brains, were studied after TBI. IL-1b protein was increased at 6 hours and 1 day. TBI induced a mixed population of microglial phenotypes with both pro-inflammatory, anti-inflammatory and immunomodulatory markers from 6 hours to 3 days post-injury. At 7 days, microglial activation was completely resolved. (ii) Three myelin proteins were assessed after TBI on ipsi- and contralateral corpus callosum, as this structure is enriched in white matter. TBI led to an increase in 2',3'-cyclic-nucleotide 3'-phosphodiesterase, a marker of immature and mature oligodendrocyte, at 2 days post-injury; a bilateral demyelination, evaluated by myelin basic protein, from 7 days to 3 months post-injury; and an increase in myelin oligodendrocyte glycoprotein at 6 hours and 3 days post-injury. Transmission electron microscopy study revealed various myelin sheath abnormalities within the corpus callosum at 3 months post-TBI. (iii) TBI led to sensorimotor deficits at 3 days post-TBI, and late cognitive flexibility disorder evidenced by the reversal learning task of the Barnes maze 3 months after injury. These data give an overall invaluable overview of time course of neuroinflammation that could be involved in demyelination and late cognitive disorder over a time-scale of 3 months in a model of mild TBI. This model could help to validate a pharmacological strategy to prevent post-traumatic WMI and behavioral disorders following mild TBI.

Epidemiological studies have raised concerns about the risk of neurodevelopmental disorders (NDD) in children of patients with autoimmune or inflammatory disorders (AID). The pathophysiological pathways underlying this association are still unknown and little is known about the specific and distinct risk of each AID. To explore these questions, we investigated the association between the occurrences of several NDD in the offspring of mothers or fathers with different IDA. We conducted a meta-analysis— PROSPERO (CRD42020159250)—examining the risk of NDD in the offspring of mothers or fathers with AID. We performed specific analyses separately in fathers or mothers of NDD patients as well as subgroup analyses for each NDD and AID. We searched MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science Core Collection published until December 2021. From an initial pool of 2074 potentially relevant references, 14 studies were included, involving more than 1,400,000 AID and 10,000,000 control parents, 180,000 children with NDD and more than 14,000,000 control children. We found AID in mothers (Adjusted OR 1.27 [95% CI 1.03; 1.57] p  = 0.02, [I 2  = 65%, Tau 2  = 0.03 p  = 0.01] and adjusted OR 1.31 [95% CI 1.11; 1.55] p  = 0.001, [I 2  = 93%, Tau 2  = 0.13 p  = 0.001] and, although in a lesser extent, in fathers (adjusted OR 1.18 [95% CI 1.07; 1.30] p  = 0.01, [I 2  = 15.5%, Tau 2  = 0.002 p  = 0.47]) and adjusted OR 1.14 [95% CI 1.10; 1.17] p  < 0.0001, [I 2  = 0%, Tau 2  = 0 p  = 0.29]) to be associated with ASD and ADHD in the offspring. This difference in the strength of the association was found in the AID-specific analyses, suggesting that AID increase the risk of NDD by a shared mechanism but that a specific maternal route appears to represent an additional excess risk. Inflammatory bowel disease were not associated with an additional risk (neither in fathers nor in mothers) of NDD in offspring. Our results suggest that complex and multiple AID-specific pathophysiological mechanisms may underlie the association of AID and NDD in offspring. Further, comprehensive studies of the different AID and NDD are needed to draw definitive conclusions about the pathophysiological links between parental AID and NDD in children.

ABSTRACTDisabilities after brain injury in very preterm infants have mainly been attributed to noncystic periventricular white matter injury (PWMI). We analyzed spatiotemporal patterns of PWMI in the brains of 18 very preterm infants (25–29 postconceptional weeks [pcw]), 7 preterm infants (30–34 pcw), and 10 preterm controls without PWMI. In very preterm infants, we examined PWMI in detail in 2 axonal crossroad areas in the frontal lobeC1 (lateral to the lateral angle of the anterior horn of the lateral ventricle, at the exit of the internal capsule radiations) and C2 (above the corpus callosum and dorsal angle of the anterior horn). These brains had greater microglia-macrophage densities and activation but lesser astroglial reaction (glial fibrillary acidic protein and monocarboxylate transporter 1 expression) than in preterm cases with PWMI. In preterm infants, scattered necrotic foci were rimmed by axonal spheroids and ionized calcium binding adaptor molecule 1–positive macrophages. Diffuse lesions near these foci consisted primarily of hypertrophic and reactive astrocytes associated with fewer microglia. No differences in Olig2-positive preoligodendrocytes between noncystic PWMI and control cases were found. These data show that the growing axonal crossroad areas are highly vulnerable to PWMI in very preterm infants and highlight differences in glial activation patterns between very preterm and preterm infants.

A leading cause of preterm birth is the exposure to systemic inflammation (maternal/fetal infection), which leads to neuroinflammation and white matter injury (WMI). A wide range of cytokines and chemokines are expressed and upregulated in oligodendrocytes (OLs) in response to inflammation and numerous reports show that OLs express several receptors for immune related molecules, which enable them to sense inflammation and to react. However, the role of OL immune response in WMI is unclear. Here, we focus our study on toll-like receptor-3 (TLR3) that is activated by double-strand RNA (dsRNA) and promotes neuroinflammation. Despite its importance, its expression and role in OLs remain unclear. We used an in vivo mouse model, which mimics inflammation-mediated WMI of preterm born infants consisting of intraperitoneal injection of IL-1β from P1 to P5. In the IL-1β-treated animals, we observed the upregulation of Tlr3, IL-1β, IFN-β, Ccl2 , and Cxcl10 in both PDGFRα+ and O4+ sorted cells. This upregulation was higher in O4+ immature OLs (immOLs) as compared to PDGFRα+ OL precursor cells (OPCs), suggesting a different sensitivity to neuroinflammation. These observations were confirmed in OL primary cultures: cells treated with TLR3 agonist Poly(I:C) during differentiation showed a stronger upregulation of Ccl2 and Cxcl10 compared to cells treated during proliferation and led to decreased expression of myelin genes. Finally, OLs were able to modulate microglia phenotype and function depending on their maturation state as assessed by qPCR using validated markers for immunomodulatory, proinflammatory, and anti-inflammatory phenotypes and by phagocytosis and morphological analysis. These results show that during inflammation the response of OLs can play an autonomous role in blocking their own differentiation: in addition, the immune activation of OLs may play an important role in shaping the response of microglia during inflammation.