Timed fetal inflammation and postnatal hypoxia cause cortical white matter injury, interneuron imbalances, and behavioral deficits in a double-hit rat model of encephalopathy of prematurity.

Autor: Brandt MJV; Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Lundlaan 6, 3584 EA, Utrecht, the Netherlands., Kosmeijer CM; Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Lundlaan 6, 3584 EA, Utrecht, the Netherlands., Achterberg EJM; Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584 CM, Utrecht, the Netherlands., de Theije CGM; Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Lundlaan 6, 3584 EA, Utrecht, the Netherlands., Nijboer CH; Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Lundlaan 6, 3584 EA, Utrecht, the Netherlands.
Jazyk: angličtina
Zdroj: Brain, behavior, & immunity - health [Brain Behav Immun Health] 2024 Jul 05; Vol. 40, pp. 100817. Date of Electronic Publication: 2024 Jul 05 (Print Publication: 2024).
DOI: 10.1016/j.bbih.2024.100817
Abstrakt: Extreme preterm birth-associated adversities are a major risk factor for aberrant brain development, known as encephalopathy of prematurity (EoP), which can lead to long-term neurodevelopmental impairments. Although progress in clinical care for preterm infants has markedly improved perinatal outcomes, there are currently no curative treatment options available to combat EoP. EoP has a multifactorial etiology, including but not limited to pre- or postnatal immune activation and oxygen fluctuations. Elucidating the underlying mechanisms of EoP and determining the efficacy of potential therapies relies on valid, clinically translatable experimental models that reflect the neurodevelopmental and pathophysiological hallmarks of EoP. Here, we expand on our double-hit rat model that can be used to study EoP disease mechanisms and therapeutic options in a preclinical setting. Pregnant Wistar dams were intraperitoneally injected with 10 μg/kg LPS on embryonic day (E)20 and offspring was subjected to hypoxia (140 min, 8% O 2 ) at postnatal day 4. Rats exposed to fetal inflammation and postnatal hypoxia (FIPH) showed neurodevelopmental impairments, such as reduced nest-seeking ability, ultrasonic vocalizations, social engagement, and working memory, and increased anxiety and sensitivity. Impairments in myelination, oligodendrocyte maturation and interneuron development were examined as hallmarks for EoP, in different layers and coordinates of the cortex using histological and molecular techniques. Myelin density and complexity was decreased in the cortex, which partially coincided with a decrease in mature oligodendrocytes. Furthermore, interneuron populations (GAD67+ and PVALB+) were affected. To determine if the timing of inducing fetal inflammation affected the severity of EoP hallmarks in the cortex, multiple timepoints of fetal inflammation were compared. Inflammation at E20 combined with postnatal hypoxia gave the most severe EoP phenotype in the cortex. In conclusion, we present a double-hit rat model which displays various behavioral, anatomical and molecular hallmarks of EoP, including diffuse white matter injury. This double-hit model can be used to investigate pathophysiological mechanisms and potential therapies for EoP.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2024 The Authors.)
Databáze: MEDLINE
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