The cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of cuprizone and discuss the molecular and enzymatic mechanisms by which cuprizone induces metabolic stress, oligodendrocyte apoptosis, myelin degeneration and eventually axonal and neuronal pathology. In addition, we describe the dual effector function of the immune system which tightly controls demyelination by effective induction of oligodendrocyte apoptosis, but in contrast also paves the way for fast and efficient remyelination by the secretion of neurotrophic factors and the clearance of cellular and myelinic debris. Finally, we discuss the many clinical symptoms that can be observed following cuprizone treatment, and how these strengthened the cuprizone model as a useful tool to study human multiple sclerosis, schizophrenia and epilepsy.
Objectives Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. Results First, we demonstrated that TNF ΔARE mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNF ΔARE mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation. Conclusions These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA.
At present, resting state functional MRI (rsfMRI) is increasingly used in human neuropathological research. The present study aims at implementing rsfMRI in mice, a species that holds the widest variety of neurological disease models. Moreover, by acquiring rsfMRI data with a comparable protocol for anesthesia, scanning and analysis, in both rats and mice we were able to compare findings obtained in both species. The outcome of rsfMRI is different for rats and mice and depends strongly on the applied number of components in the Independent Component Analysis (ICA). The most important difference was the appearance of unilateral cortical components for the mouse resting state data compared to bilateral rat cortical networks. Furthermore, a higher number of components was needed for the ICA analysis to separate different cortical regions in mice as compared to rats.
With diffusion tensor imaging, the diffusion of water molecules through brain structures is quantified by parameters, which are estimated assuming monoexponential diffusion-weighted signal attenuation. The estimated diffusion parameters, however, depend on the diffusion weighting strength, the b-value, which hampers the interpretation and comparison of various diffusion tensor imaging studies. In this study, a likelihood ratio test is used to show that the diffusion kurtosis imaging model provides a more accurate parameterization of both the Gaussian and non-Gaussian diffusion component compared with diffusion tensor imaging. As a result, the diffusion kurtosis imaging model provides a b-value-independent estimation of the widely used diffusion tensor parameters as demonstrated with diffusionweighted rat data, which was acquired with eight different b-values, uniformly distributed in a range of [0,2800 sec/mm 2 ]. In addition, the diffusion parameter values are significantly increased in comparison to the values estimated with the diffusion tensor imaging model in all major rat brain structures. As incorrectly assuming additive Gaussian noise on the diffusionweighted data will result in an overestimated degree of nonGaussian diffusion and a b-value-dependent underestimation of diffusivity measures, a Rician noise model was used in this study. Diffusion tensor magnetic resonance imaging (DTI) is an important medical imaging modality in neuroscience research, because it allows the study of the complex network of myelinated axons, in vivo and noninvasively (1,2). In DTI, the diffusion of water molecules through brain structures is mathematically described by a second order 3D diffusion tensor (DT). It is generally accepted that the first eigenvector of the tensor, corresponding to the direction of maximal diffusion, is aligned with the underlying fiber structures. Furthermore, the diffusion is often quantified with diffusion parameters (i.e., fractional anisotropy (FA) and mean (MD), radial (D ⊥ ) and axial (D ) diffusivity), which provide insight in the organization, structural integrity, and development of white matter (WM) structures of the normal and pathological brain (3-9).In DTI, the diffusion of water molecules along a certain gradient direction is assumed to occur in an unrestricted environment. Consequently, the molecules' probability of diffusing from one location to another in a given time is described by a Gaussian distribution of which the standard deviation relates to the apparent diffusion coefficient (ADC). As a result, the normalized diffusion-weighted signal that is measured along a certain axis can be described by a monoexponential function; the exponent equals the ADC, weighted by the diffusion weighting strength that is given by the b-value. Several DTI studies, however, reported that the estimation of diffusion parameters depends on the b-value that is used during data acquisition. Therefore, the comparison and interpretation of various DTI studies are hampered. Jones and Basser (10) and Ande...
Although MRI is the gold standard for the diagnosis and monitoring of multiple sclerosis (MS), current conventional MRI techniques often fail to detect cortical alterations and provide little information about gliosis, axonal damage and myelin status of lesioned areas. Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) provide sensitive and complementary measures of the neural tissue microstructure. Additionally, specific white matter tract integrity (WMTI) metrics modelling the diffusion in white matter were recently derived. In the current study we used the well-characterized cuprizone mouse model of central nervous system demyelination to assess the temporal evolution of diffusion tensor (DT), diffusion kurtosis tensor (DK) and WMTI-derived metrics following acute inflammatory demyelination and spontaneous remyelination. While DT-derived metrics were unable to detect cuprizone induced cortical alterations, the mean kurtosis (MK) and radial kurtosis (RK) were found decreased under cuprizone administration, as compared to age-matched controls, in both the motor and somatosensory cortices. The MK remained decreased in the motor cortices at the end of the recovery period, reflecting long lasting impairment of myelination. In white matter, DT, DK and WMTI-derived metrics enabled the detection of cuprizone induced changes differentially according to the stage and the severity of the lesion. More specifically, MK, RK and the axonal water fraction (AWF) were the most sensitive for the detection of cuprizone induced changes in the genu of the corpus callosum, a region less affected by cuprizone administration. Additionally, microgliosis was associated with an increase of MK and RK during the acute inflammatory demyelination phase. In regions undergoing severe demyelination, namely the body and splenium of the corpus callosum, DT-derived metrics, notably the mean diffusion (MD) and radial diffusion (RD), were among the best discriminators between cuprizone and control groups, hence highlighting their ability to detect both acute and long lasting changes. Interestingly, WMTI-derived metrics showed the aptitude to distinguish between the different stage of the disease. Both the intra-axonal diffusivity (Da) and the AWF were found to be decreased in the cuprizone treated group, Da specifically decreased during the acute inflammatory demyelinating phase whereas the AWF decrease was associated to the spontaneous remyelination and the recovery period. Altogether our results demonstrate that DKI is sensitive to alterations of cortical areas and provides, along with WMTI metrics, information that is complementary to DT-derived metrics for the characterization of demyelination in both white and grey matter and subsequent inflammatory processes associated with a demyelinating event.
L1 is a neural cell adhesion molecule mainly involved in axon guidance and neuronal migration during brain development. Mutations in the human L1 gene give rise to a complex clinical picture, with mental retardation, neurologic abnormalities and a variable degree of hydrocephalus. Recently, a transgenic mouse model with a targeted null mutation in the L1 gene was generated. These knockout (KO) mice show hypoplasia of the corticospinal tract. Here we have performed further studies of these KO mice including magnetic resonance imaging of the brain, neuropathological analysis and behavioral testing. The ventricular system was shown to be abnormal with dilatation of the lateral ventricles and the 4th ventricle, and an altered shape of the Sylvius aqueduct. Additionally, the cerebellar vermis of the KO mice is hypoplastic. Their exploratory behavior is characterized by stereotype peripheral circling reminiscent of that of rodents with induced cerebellar lesions.
Our study underscores the importance of elastin fragmentation in the vessel wall as an accelerator of atherosclerosis with enhanced inflammation and increased neovascularization, thereby promoting the development of unstable plaques that eventually may rupture. The present mouse model offers the opportunity to further investigate the role of key factors involved in plaque destabilization and potential targets for therapeutic interventions.
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