Abstract
Diffuse white matter injury (WMI) is a serious problem in extremely preterm infants, and is associated with adverse neurodevelopmental outcome, including cognitive impairments and an increased risk of autism‐spectrum disorders. Important risk factors include fetal or perinatal inflammatory insults and fluctuating cerebral oxygenation. However, the exact mechanisms underlying diffuse WMI are not fully understood and no treatment options are currently available. The use of clinically relevant animal models is crucial to advance knowledge on the pathophysiology of diffuse WMI, allowing the definition of novel therapeutic targets. In the present study, we developed a multiple‐hit animal model of diffuse WMI by combining fetal inflammation and postnatal hypoxia in rats. We characterized the effects on white matter development and functional outcome by immunohistochemistry, MRI and behavioral paradigms. Combined fetal inflammation and postnatal hypoxia resulted in delayed cortical myelination, microglia activation and astrogliosis at P18, together with long‐term changes in oligodendrocyte maturation as observed in 10 week old animals. Furthermore, rats with WMI showed impaired motor performance, increased anxiety and signs of autism‐like behavior, i.e. reduced social play behavior and increased repetitive grooming. In conclusion, the combination of fetal inflammation and postnatal hypoxia in rats induces a pattern of brain injury and functional impairments that closely resembles the clinical situation of diffuse WMI. This animal model provides the opportunity to elucidate pathophysiological mechanisms underlying WMI, and can be used to develop novel treatment options for diffuse WMI in preterm infants.
Highlights
Whereas exposure to a single hit did not induce myelination deficits, rats exposed to both fetal inflammation and postnatal hypoxia displayed a pathology closely resembling that of preterm infants with diffuse white matter injury (WMI), including delayed myelination and impaired oligodendrocyte differentiation
To investigate how astrocyte reactivity may contribute to WMI pathology, we analyzed expression levels of several genes that previously have been associated with astrocyte-mediated myelination impairments
Reactive astrocytes have been associated with increased expression of BMP4 and Jagged1, two factors that inhibit OPC differentiation (Hammond et al, 2014; Reid et al, 2012; Wang et al, 2011)
Summary
Detected by MRI, affects the majority of WMI patients in neonatal intensive care units (Back & Miller, 2014). It has been proposed that exposure to multiple perinatal hits plays a crucial role in the etiology of WMI, with a first insult sensitizing the developing brain to subsequent insults that aggravate injury (Kaindl, Favrais, & Gressens, 2009; Van Steenwinckel et al, 2014) This notion is supported by clinical data indicating that exposure to multiple insults dramatically increases the risk of white matter abnormalities (Korzeniewski et al, 2014; Leviton et al, 2013). We investigated the pathology and outcome in a novel rat model of diffuse WMI in preterm infants, in which two clinically relevant perinatal hits, i.e. fetal inflammation and postnatal hypoxia, are combined during relevant stages of brain development. Functional outcome on several relevant modalities was investigated by behavioral paradigms for motor coordination, cognitive functioning, anxiety-like behavior and autism-like behavior
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