Cuprizone‐induced demyelination in CNP::GFP transgenic mice

Abstract

Cuprizone (bis-cyclohexanone oxaldihydrazone) was previously shown to induce demyelination in white matter enriched brain structures. In the present study we used the cuprizone demyelination model in transgenic mice expressing the enhanced green fluorescent protein (GFP) under the 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) promoter. The use of these particular transgenic mice allows easy detection of cells belonging to the entire oligodendroglial (OLG) lineage, ranging from OLG precursors to mature myelinating OLGs. We were able to evaluate the precise extent of oligodendroglial cell damage and recovery within the murine adult central nervous system (CNS) after inducing demyelination by acute cuprizone intoxication. A generalized loss of GFP+ cells was observed after cuprizone exposure and correlated with a decline in myelin basic protein (MBP) expression. OLGs were depleted in many brain areas that were previously thought to be unaffected by cuprizone treatment. Thus, in addition to the well-known cuprizone effects on the medial corpus callosum, we also found a loss of GFP+ cells in most brain structures, particularly in the caudatus putamen, cortex, anterior commissure, olfactory bulb, hippocampus, optic chiasm, brainstem, and cingulum. Loss of GFP+ cells was accompanied by extensive astrogliosis and microglial activation, although neurons were not affected. Interestingly, cuprizone-treated animals showed both activation of GFAP expression and a higher proliferation rate in subventricular zone cells. A week after cuprizone removal from the diet, GFP+ oligodendroglial cells began repopulating the damaged structures. GFP expression precedes that of MBP and allows OLG detection before myelin restoration.

Zfp488 promotes oligodendrocyte differentiation of neural progenitor cells in adult mice after demyelination

“…Although these cells labeled for different markers the transduction efficiency was similar in both conditions. The deficiency of ZsGreen1 positive cell migration into the olfactory bulb through the rostral migratory stream could be explained by the extreme demyelinating milieu 54, and poor oligodendrogenesis in the olfactory bulb 55, of this cuprizone demyelination mouse model. In addition, Zfp488 transduced Olig2 positive cells were always localized to the white matter tract at both the peak of demyelination and 6 weeks after recovery (i.e.…”

Towards improved animal models of neonatal white matter injury associated with cerebral palsy

“…For example, WMI induced by HI triggers a rapid several-fold expansion in resident populations of OPCs in subcortical white matter (Segovia et al, 2008). Death and depletion of SVZ progenitors followed by robust cellular expansion of the SVZ in the repair phase of injury is a common feature following acute HIE, chronic neonatal hypoxia and toxin-induced lesions of the subcortical white matter (Fagel et al, 2006;Levison et al, 2001;Ness et al, 2001;Silvestroff et al, 2010;Yang and Levison, 2006). Although OPCs make up only ~5% of SVZ progenitors in the healthy brain, this population expands substantially upon WMI and SVZ-derived OPCs migrate to regions of WMI (Menn et al, 2006).…”

Demyelination reduces brain parenchymal stiffness quantified in vivo by magnetic resonance elastography

“…The copper chelator cuprizone was used as demyelination model and fed to susceptible mouse strains (C57BL/6 mice) resulting in progressive demyelination in several brain regions, particularly in the corpus callosum (9)(10)(11). We show in this particular model that the degree and the time kinetics of the induced disruption of extra-axonal tissue integrity (i.e., extensive demyelination and distinctive extracellular matrix (ECM) degradation) lead to a decrease of viscoelasticity in the corpus callosum.…”