title: The effect of hemorrhage on the development of the postnatal mouse cerebellum.
abstract: Recent studies have shown that hemorrhagic injury in the preterm cerebellum leads to long-term neurological sequelae, such as motor, affective, and cognitive dysfunction. How cerebellar hemorrhage (CBH) affects the development and function of the cerebellum is largely unknown. Our study focuses on developing a mouse model of CBH to determine the anatomical, behavioral, and molecular phenotypes resulting from a hemorrhagic insult to the developing cerebellum. To induce CBH in the postnatal mouse cerebellum, we injected bacterial collagenase, which breaks down surrounding blood vessel walls, into the fourth ventricle at postnatal day two. We found a reduction in cerebellar size during postnatal growth, a decrease in granule cells, and persistent neurobehavioural abnormalities similar to abnormalities reported in preterm infants with CBH. We further investigated the molecular pathways that may be perturbed due to postnatal CBH and found a significant upregulation of genes in the inflammatory and sonic hedgehog pathway. These results point to an activation of endogenous mechanisms of injury and neuroprotection in response to postnatal CBH. Our study provides a preclinical model of CBH that may be used to understand the pathophysiology of preterm CBH and for potential development of preventive therapies and treatments.
authors.affiliation: University of British Columbia, Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, 950W. 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Ji Young Janice
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: University of British Columbia, Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, 950W. 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Gloria K
authors.initials: GK
authors.lastname: Mak
authors.affiliation: University of British Columbia, Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, 950W. 28th Avenue, Vancouver, BC V5Z 4H4, Canada. Electronic address: dang@cmmt.ubc.ca.
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldowitz
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001804:Blood Transfusion, Autologous / Q000009:adverse effects; D020201:Brain Hemorrhage, Traumatic / Q000209:etiology / Q000473:pathology*; D002452:Cell Count; D002531:Cerebellum / Q000254:growth & development* / Q000473:pathology*; D017364:Collagenases / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016207:Cytokines; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017364:Collagenases
keywords: Behavioral phenotype; Cerebellar development; Cerebellar granule cells; Gene expression; Mouse model; Preterm brain injury; Preterm cerebellar hemorrhage