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The effects of cerebellar hemorrhage on the development of the postnatal cerebellum

University of British Columbia

With the improvement in neuroimaging technology and the increase in survival of preterm infants, the detection of abnormalities in the cerebellum has become increasingly common. Human and animal studies suggest that the preterm cerebellum is particularly vulnerable to damage because of its dramatic growth and complex developmental processes. Cerebellar hemorrhage (CBH) is the most frequently detected cerebellar lesion in premature infants and often leads to long-term neurological sequela, such as motor, affective and cognitive dysfunction. However, how CBH affects the development and function of the cerebellum remains largely unknown. Therefore, our study focuses on developing a mouse model of CBH to determine the anatomical, behavioural, and molecular phenotypes resulting from the hemorrhage in the developing cerebellum. To induce hemorrhage in the fourth ventricle and germinal matrix of the cerebellum, we injected bacterial collagenase, which breaks down surrounding blood vessel walls, into the fourth ventricle of postnatal (P) day two mice. Controls were injected with saline. We then performed various anatomical, behavioural and molecular assessments to detect any changes in the morphology and function of the cerebellum and to unravel the mechanisms of injury and neuroprotection activated as a result of CBH. In our model, we found a delay in cerebellar development, reduction in granule cell and interneuron density, and persistent neurobehavioural abnormalities similar to the abnormalities found in premature infants with CBH. Furthermore, we found a significant upregulation of neurotrophic factor expression and of genes in the sonic hedgehog pathway, which indicate the activation of endogenous neuroprotective mechanisms. Thus, our study provides a novel preclinical model of CBH that can be used to understand the pathophysiology of the disease and for the development and evaluation of preventive therapies and post-hemorrhagic treatments.

Text

2013-05-29

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44519

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/