ABSTRACT: Biphasic functional regulation in hippocampus of rat with chronic cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid artery
Project description:Carotid artery disease is frequent and can result in chronic modest hypoperfusion of the brain causing cognitive impairments even if classified asymptomatic without a transient ischemic attack or stroke. Paracrine Interleukin 6 (IL 6) improves functional outcome after stroke. However, in carotid artery disease it might have adverse long-term effects. With this exploratory study, we investigated the effect of paracrine IL 6 on cerebral remodeling in early stages after asymptomatic carotid artery occlusion. Therewith we aimed to distinguish IL 6 dependent targets with beneficial effects for long-term outcome from factors causing the detrimental long-term effects of IL 6. To mimic a human asymptomatic carotid artery disease, we used a mouse model of unilateral common carotid artery (CCA) occlusion. We developed a mouse model for inducible paracrine cerebral IL 6 expression (Cx30-Cre-ERT2;FLEX IL6) and induced IL 6 two days after CCA occlusion. We studied the effects of paracrine IL 6 after CCA occlusion on neuronal connectivity using diffusion tensor imaging and on local proteome regulations of the hypo-perfused striatum and contralateral motor cortex using mass spectrometry of laser capture micro-dissected tissues. Paracrine IL-6 induced cerebral remodeling leading to increased inter-hemispheric connectivity and changes in motor system connectivity. We identified changes in local protein abundance which might have adverse effects on functional outcome such as upregulation of Synuclein gamma (Sncg) or downregulation of Proline Dehydrogenase 1 (Prodh). However, we also identified changes in local protein abundance having potentially beneficial effects such as upregulation of Caprin1 or downregulation of GABA transporter 1 (Gat1).
Project description:Chronic cerebral hypoperfusion is manifested in various CNS diseases accompanied by cognitive impairment, such as dementia, however the precise mechanism of chronic cerebral hypoperfusion-induced cognitive impairment remains unknown. Recently, transient receptor potential ankyrin 1 (TRPA1), activated by oxidative stress, was reported to be involved in the cerebrovascular diseases, therefore we investigated the pathophysiological role of TRPA1 in chronic cerebral hypoperfusion using a mouse bilateral common carotid artery stenosis (BCAS) model. Early cognitive impairment and white matter injury was induced by BCAS in TRPA1-knockout (TRPA1-KO) but not wild-type (WT) mice. For further investigation into the involvement of TRPA1 in chronic cerebral hypoperfusion, we conducted RNA sequence (RNAseq) in the corpus callosum from sham- and BCAS-operated WT and TRPA1-KO mice.
Project description:profiling gene transcription in a mouse model of permanent focal cerebral ischemia that was induced by middle cerebral artery occlusion (MCAO)
Project description:To investigate the effect of stroke on the trasnscriptome of intestinal muscularis macrophages, mice underwent permanent middle cerebral artery occlusion (pMCAO) or sham surgery for 24 hours
Project description:To investigate the effect of stroke on the transcriptome of intestinal epithelial cells, mice underwent permanent middle cerebral artery occlusion (pMCAO) or sham surgery for 24 hours
Project description:To investigate the effect of stroke on the trasnscriptome of intestinal lamina propria macrophages, mice underwent permanent middle cerebral artery occlusion (pMCAO) or sham surgery for 24 hours
Project description:Genetic deletion of transmembrane prolyl-4-hydroxylase (P4H-TM) in mice leads to increased inflammatory microgliosis and neutrophil infiltration in the cortex after permanent midle cerebral artery occlusion (pMCAO)
Project description:Chronic cerebral hypoperfusion (CCH) is a well-known risk factor for vascular dementia and other neurodegenerative disease, for which there are currently no effective medications available. MicroRNA (miRNA) are noncoding RNAS mediating post-translational silencing of genes, and has been extensively studied for their involvement in neurodegenerative disease. However, little is known about their roles in vascular dementia (VaD). In this work, a bilateral common carotid arteries occlusion (2-VO) surgery in rats was employed to induced CCH related cognitive dysfunction. Four months later, the hippocampi were dissected from 2-VO and sham operated rats for high-throughput profiling of miRNAs. Twelve differentially expressed miRNAs were identified according to a cutoff of |log2(Fold Change)|≥1 and p＜0.05. GO analysis of target genes revealed that the most relevant biological processes included the regulatory region nucleic acid binding, histone acetyltransferase binding, organic acid transmembrane transporter activity, L-amino acid transmembrane transporter activity. The cellular structure mainly included histone deacetylation complexes, endosomes, Golgi membranes, etc. And the involved molecular processes mainly included axon development, organ morphogenesis, macromolecular modification, regulation of neuron projection development, neuron development. This study provides a framework for understanding the alternations in hippocampus miRNA profiles underwent hypoxia insult.
Project description:To analyze gene expression we isolated total mRNA from the core, periinfarct and contralateral cortex of 60 sprague-dawley rats after 24 hours or 3 days of permanent middle cerebral artery occlusion (pMCAo). Also ipsilateral and contralateral cortex was obtained from sham-operated and healthy animals. A total of 44 microarrays were performed with RNA pooled from 3 independent animals. For each experimental condition the total n number is of 12. Microarray analysis of different areas of the rat brain (core, periinfarct and contralateral cortex) after 24h and 3days of permanent ischemia
