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A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
Systemic inflammation combined with neonatal cerebellar haemorrhage aggravates long-term structural and functional
Sophie Tremblay1, Alex Pai2, Lindsay Richter2
1Pediatrics, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada.
Insights
Combined early life cerebellar hemorrhage and inflammation in mice cause lasting motor and memory deficits, impacting cerebellar growth and white matter development.
Area of Science:
- Neuroscience
- Developmental Biology
- Pediatric Research
Background:
- Cerebellar injury is increasingly recognized in preterm infants, yet its specific neurodevelopmental effects are understudied.
- Preterm infants face stressors like cerebellar hemorrhage (CBH) and infection, linked to impairments.
Purpose of the Study:
- To investigate the neurodevelopmental consequences of combined cerebellar hemorrhage and inflammation.
- To establish a translational mouse model for studying these effects.
Main Methods:
- Developed a translational mouse model combining cerebellar hemorrhage (CBH) and early/late inflammatory states.
- Assessed short- and long-term structural and functional outcomes using MRI and behavioral tests.
Main Results:
- Early combined insults (CBH + early inflammation) caused motor delays, grasping deficits, and long-term memory impairment.
- Late inflammation with CBH led to poor fine motor function and memory deficits in adulthood.
- MRI revealed reduced cerebellar and hippocampal volumes, impaired white matter maturation, and persistent microgliosis.
Conclusions:
- Combined perinatal cerebellar insults lead to significant neurodevelopmental deficits.
- Findings highlight cerebellar hypoplasia, persistent inflammation, and altered white matter development as key outcomes.
Background:
Despite the increased recognition of cerebellar injury in survivors of preterm birth, the neurodevelopmental consequences of isolated cerebellar injury have been largely unexplored and our current understanding of the functional deficits requires further attention in order to translate knowledge to best practices. Preterm infants are exposed to multiple stressors during their postnatal development including perinatal cerebellar haemorrhage (CBH) and postnatal infection, two major risk factors for neurodevelopmental impairments.
Methods:
We developed a translational mouse model of CBH and/or inflammation to measure the short- and long-term outcomes in cerebellar structure and function.
Results:
Mice exposed to early combined insults of CBH and early inflammatory state (EIS) have a delay in grasping acquisition, neonatal motor deficits and deficient long-term memory. CBH combined with late inflammatory state (LIS) does not induce neonatal motor problems but leads to poor fine motor function and long-term memory deficits at adulthood. Early combined insults result in poor cerebellar growth from postnatal day 15 until adulthood shown by MRI, which are reflected in diminished volumes of cerebellar structures. There are also decreases in volumes of gray matter and hippocampus. Cerebellar microgliosis appears 24h after the combined insults and persists until postnatal day 15 in the cerebellar molecular layer and cerebellar nuclei in association with a disrupted patterning of myelin deposition, a delay of oligodendrocyte maturation and reduced white matter cerebellar volume.
Conclusions:
Together, these findings reveal poor outcomes in developing brains exposed to combined cerebellar perinatal insults in association with cerebellar hypoplasia, persistence of microgliosis and alterations of cerebellar white matter maturation and growth.
