Histopathological and functional Characterization of a neonatal mouse model of intraventricular hemorrhage

Abstract

Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is a major neurological problem of premature infants that leads to white matter injury and posthemorrhagic hydrocephalus. There is no optimal treatment for IVH-induced complications. Several animal models of IVH have been developed, but they have significant limitations. We employed a one-day-old C57BL/6 mouse (P1) and injected hemolyzed whole blood or saline into both cerebral ventricles under hypothermia-induced anesthesia. The blood was obtained from one of the C57BL/6 inbred mouse strains. We evaluated a range of parameters, including apoptosis, cerebral inflammation, myelination, ventricle size, and neurobehavioral functions. The weight gain was comparable between blood- and saline-injected mouse pups. The ventricle size and head dimensions were larger in blood-injected pups compared to saline controls at P21 through P60. We demonstrated greater apoptotic cell death, neuronal degeneration, and microglia infiltration in the periventricular white matter of blood-treated pups relative to controls at P3 and P7. Myelination was reduced, and astrogliosis was increased in blood-injected mice relative to saline controls at P21. Post-hemorrhagic hydrocephalus was noted in blood-treated mice at both P21 and P60. Neurobehavior evaluation revealed motor and cognitive deficits in blood-injected animals relative to controls at P60. A comparison between hemolyzed and non-hemolyzed whole blood-treated pups showed that the hemolyzed blood produced more consistent hydrocephalus and reduction in myelination compared to non-hemolyzed blood injections. The study provides comprehensive analyses of a novel model of IVH that can be employed to understand the mechanisms and develop therapeutic strategies for white matter injury and hydrocephalus in IVH survivors.