A Novel Murine Multi-Hit Model of Perinatal Acute Diffuse White Matter Injury Recapitulates Major Features of Human Disease

Abstract

The selection of an appropriate animal model is key to the production of results with optimal relevance to human disease. Particularly in the case of perinatal brain injury, a dearth of affected human neonatal tissue available for research purposes increases the reliance on animal models for insight into disease mechanisms. Improvements in obstetric and neonatal care in the past 20 years have caused the pathologic hallmarks of perinatal white matter injury (WMI) to evolve away from cystic necrotic lesions and toward diffuse regions of reactive gliosis and persistent myelin disruption. Therefore, updated animal models are needed that recapitulate the key features of contemporary disease. Here, we report a murine model of acute diffuse perinatal WMI induced through a two-hit inflammatory–hypoxic injury paradigm. Consistent with diffuse human perinatal white matter injury (dWMI), our model did not show the formation of cystic lesions. Corresponding to cellular outcomes of dWMI, our injury protocol produced reactive microgliosis and astrogliosis, disrupted oligodendrocyte maturation, and disrupted myelination.. Functionally, we observed sensorimotor and cognitive deficits in affected mice. In conclusion, we report a novel murine model of dWMI that induces a pattern of brain injury mirroring multiple key aspects of the contemporary human clinical disease scenario.

Silencing neuroinflammatory reactive astrocyte activating factors ameliorates disease outcomes in perinatal white matter injury

“…Based on these findings, we aimed to examine the effect of silencing Tnf, Il1a , and C1q on WMI disease outcomes during early development. Using an established rodent model of perinatal WMI recently published by our group, we quantified myelination in the corpus callosum at postnatal day 11 (9 days post injury, dpi) in Tnf, Il1a, C1q triple knockout (TKO) mice in comparison with wildtype (WT) C57Bl/6 mice (Figure 1A) [15]. We observed the expected myelination defects in injured wildtype mice.…”

“…Motor coordination and balance were tested in injured and healthy WT and TKO mice at 28 days post injury (28dpi) using the rotarod. The rotarod test was performed as in Renz et al 2022 [15]. Briefly, on the first day, the mice were trained to remain on the wheel at 5rpm for five minutes.…”

“…The two-hit acute diffuse perinatal white matter injury was induced, according to Renz et al [15]. Briefly, following random assignment to an injured or an uninjured group.…”

“…Our rodent model of perinatal white matter injury results in functional deficits that mirror the sensorimotor and cognitive disabilities observed in humans affected by WMI [15]. Given reduced myelination defects in TKO mice, we also aimed to investigate whether the absence of TNFα, IL1α, and C1q could rescue behavioral outcomes in our WMI model.…”

Neuroinflammatory reactive astrocyte formation correlates with adverse outcomes in perinatal white matter injury

“…Motor coordination and balance were tested in injured and healthy WT and TKO mice at 28 days postinjury (28 dpi) using the rotarod. The rotarod test was performed as in Renz et al (2022). Briefly, on the first day, the mice were trained to remain on the wheel at 5 rpm for 5 min.…”