Thalamocortical-auditory network alterations following cuprizone‐induced demyelination

Ghaffarian, Nikoo; Mesgari, Masoud; Cerina, Manuela; Göbel, Kerstin; Budde, Thomas; Speckmann, Erwin‐Josef; Meuth, Sven G.; Gorji, Ali

doi:10.1186/s12974-016-0629-0

Cited by 20 publications

(14 citation statements)

References 57 publications

(61 reference statements)

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“…Reorganization of white matter pathways has been described as a potential mechanism to explain these effects [3,57]. This explanation is supported by the results of our correlation analyses between FA values and PLP signal (Table 1) and by reduced excitability at maximal myelin loss probably due to lack of stimulus propagation [33,44]. Interestingly, the cuprizone diet leads to a transitory period of hyperexcitability in early phases of remyelination associated with altered activity in the several network regions in vitro [11] and in vivo and affects white and gray matter regions differently [71].…”

Section: Discussionsupporting

confidence: 85%

Myelination- and immune-mediated MR-based brain network correlates

Cerina

Gallus

Koirala

et al. 2020

J Neuroinflammation

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Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammatory and neurodegenerative processes. Despite demyelination being a hallmark of the disease, how it relates to neurodegeneration has still not been completely unraveled, and research is still ongoing into how these processes can be tracked non-invasively. Magnetic resonance imaging (MRI) derived brain network characteristics, which closely mirror disease processes and relate to functional impairment, recently became important variables for characterizing immune-mediated neurodegeneration; however, their histopathological basis remains unclear. Methods: In order to determine the MRI-derived correlates of myelin dynamics and to test if brain network characteristics derived from diffusion tensor imaging reflect microstructural tissue reorganization, we took advantage of the cuprizone model of general demyelination in mice and performed longitudinal histological and imaging analyses with behavioral tests. By introducing cuprizone into the diet, we induced targeted and consistent demyelination of oligodendrocytes, over a period of 5 weeks. Subsequent myelin synthesis was enabled by reintroduction of normal food. Results: Using specific immune-histological markers, we demonstrated that 2 weeks of cuprizone diet induced a 52% reduction of myelin content in the corpus callosum (CC) and a 35% reduction in the neocortex. An extended cuprizone diet increased myelin loss in the CC, while remyelination commenced in the neocortex. These histologically determined dynamics were reflected by MRI measurements from diffusion tensor imaging. Demyelination was associated with decreased fractional anisotropy (FA) values and increased modularity and clustering at the network level. MRI-derived modularization of the brain network and FA reduction in key anatomical regions, including the hippocampus, thalamus, and analyzed cortical areas, were closely related to impaired memory function and anxiety-like behavior.

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Section: Discussionsupporting

confidence: 85%

Myelination- and immune-mediated MR-based brain network correlates

Cerina

Gallus

Koirala

et al. 2020

J Neuroinflammation

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“…Reorganization of white matter pathways has been described as a potential mechanism to explain these effects (Ayache et al, 2015;Kerschensteiner et al, 2004). This explanation is supported by the results of our correlation analyses between FA values and PLP signal (Table 1), and by reduced excitability at maximal myelin loss probably due to lack of stimulus propagation (Ghaffarian et al, 2016;Hamada and Kole, 2015). Interestingly, the cuprizone diet leads to a transitory period of hyperexcitability in early phases of remyelination associated with altered activity in the several network regions in vitro (Cerina et al, 2018) and in vivo and affects white and grey matter regions differently (Narayanan et al, 2018).…”

Section: Discussionsupporting

confidence: 86%

Myelination- and immune mediated MR-based brain network correlates

Cerina

Gallus

Koirala³

et al. 2020

Preprint

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Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammatory and neurodegenerative processes. Despite demyelination being a hallmark of the disease, how it relates to neurodegeneration has still not been completely unraveled, and research is still ongoing into how these processes can be tracked non-invasively. Magnetic resonance imaging (MRI) derived brain network characteristics, which closely mirror disease processes and relate to functional impairment, recently became important variables for characterizing immune-mediated neurodegeneration, however their histopathological basis remains unclear. Methods: In order to determine the MRI-derived correlates of myelin dynamics and to test if brain network characteristics derived from diffusion tensor imaging reflect microstructural tissue reorganization, we took advantage of the cuprizone model of general demyelination in mice and performed longitudinal histological and imaging analyses with behavioral tests. By introducing cuprizone into the diet, we induced targeted and consistent demyelination of oligodendrocytes, over a period of 5 weeks. Subsequent myelin synthesis was enabled by reintroduction of normal food. Results: Using specific immune-histological markers, we demonstrated that two weeks of cuprizone diet induced a 52% reduction of myelin content in the corpus callosum (CC) and a 35% reduction in the neocortex. An extended cuprizone diet increased myelin loss in the CC, while remyelination commenced in the neocortex. These histologically determined dynamics were reflected by MRI measurements from diffusion tensor imaging. Demyelination was associated with decreased fractional anisotropy (FA) values and increased modularity and clustering at the network level. MRI-derived modularization of the brain network and FA reduction in key anatomical regions, including the hippocampus, thalamus and analyzed cortical areas, were closely related to impaired memory function and anxiety-like behavior. Conclusion: Network specific remyelination, shown by histology and MRI metrics, determined amelioration of functional performance and neuropsychiatric symptoms. Taken together, we illustrate the histological basis for the MRI-driven network responses to demyelination, where increased modularity leads to evolving damage and abnormal behavior in MS. Quantitative information about in vivo myelination processes is mirrored by diffusion based imaging of microstructural integrity and network characteristics.

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“…Moreover, disruption of energy production, redistribution ion channels, and axonal degeneration and loss may alter information processing and excitability (Crawford et al 2009a , b ). In this respect, transient changes in excitability were already suggested to be the initial event leading to long-lasting deficits and neurodegeneration following loss of myelin in other disease models (Sutor et al 2000 ; Busche et al 2008 ; Ghaffarian et al 2016 ). In fact, it is known that myelin synthetized following demyelination, especially when the synthesis is triggered by removal of cuprizone treatment, is characterized by regionalization (Brousse et al 2015 ), thinner sheaths (Zendedel et al 2013 ), altered distribution of Nodes of Ranvier (Crawford et al 2009b ), and reduced tightness between the wrapped sheathing (Stidworthy et al 2006 ; Praet et al 2014 ).…”

Section: Discussionmentioning

confidence: 96%

Protective potential of dimethyl fumarate in a mouse model of thalamocortical demyelination

et al. 2018

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Alterations in cortical cellular organization, network functionality, as well as cognitive and locomotor deficits were recently suggested to be pathological hallmarks in multiple sclerosis and corresponding animal models as they might occur following demyelination. To investigate functional changes following demyelination in a well-defined, topographically organized neuronal network, in vitro and in vivo, we focused on the primary auditory cortex (A1) of mice in the cuprizone model of general de- and remyelination. Following myelin loss in this model system, the spatiotemporal propagation of incoming stimuli in A1 was altered and the hierarchical activation of supra- and infragranular cortical layers was lost suggesting a profound effect exerted on neuronal network level. In addition, the response latency in field potential recordings and voltage-sensitive dye imaging was increased following demyelination. These alterations were accompanied by a loss of auditory discrimination abilities in freely behaving animals, a reduction of the nuclear factor-erythroid 2-related factor-2 (Nrf-2) protein in the nucleus in histological staining and persisted during remyelination. To find new strategies to restore demyelination-induced network alteration in addition to the ongoing remyelination, we tested the cytoprotective potential of dimethyl fumarate (DMF). Therapeutic treatment with DMF during remyelination significantly modified spatiotemporal stimulus propagation in the cortex, reduced the cognitive impairment, and prevented the demyelination-induced decrease in nuclear Nrf-2. These results indicate the involvement of anti-oxidative mechanisms in regulating spatiotemporal cortical response pattern following changes in myelination and point to DMF as therapeutic compound for intervention.

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Thalamocortical-auditory network alterations following cuprizone‐induced demyelination

Cited by 20 publications

References 57 publications

Myelination- and immune-mediated MR-based brain network correlates

Myelination- and immune-mediated MR-based brain network correlates

Myelination- and immune mediated MR-based brain network correlates

Protective potential of dimethyl fumarate in a mouse model of thalamocortical demyelination

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