TY - JOUR
T1 - Combined fetal inflammation and postnatal hypoxia causes myelin deficits and autism-like behavior in a rat model of diffuse white matter injury
AU - van Tilborg, Erik
AU - Achterberg, E. J.Marijke
AU - van Kammen, Caren M.
AU - van der Toorn, Annette
AU - Groenendaal, Floris
AU - Dijkhuizen, Rick M.
AU - Heijnen, Cobi J.
AU - Vanderschuren, Louk J.M.J.
AU - Benders, Manon N.J.L.
AU - Nijboer, Cora H.A.
N1 - Funding Information:
We would like to thank M. van den Berg, K. Amarouchi and B. Hornix for their excellent technical assistance in this study. This work was funded by the Wilhelmina Children's Hospital Research Fund.
Funding Information:
We would like to thank M. van den Berg, K. Amarouchi and B. Hornix for their excellent technical assistance in this study. This work was funded by the Wilhelmina Children’s Hospital Research Fund.
Publisher Copyright:
© 2017 The Authors GLIA Published by Wiley Periodicals, Inc.
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - astrocytes
KW - autism-like behavior
KW - microglia
KW - oligodendrocytes
KW - preterm birth
UR - http://www.scopus.com/inward/record.url?scp=85030126723&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030126723&partnerID=8YFLogxK
U2 - 10.1002/glia.23216
DO - 10.1002/glia.23216
M3 - Article
C2 - 28925578
AN - SCOPUS:85030126723
SN - 0894-1491
VL - 66
SP - 78
EP - 93
JO - Glia
JF - Glia
IS - 1
ER -