Abstract
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.
Highlights
Alterations in cortical layering, cellular organization, and functionality were recently identified as pathological hallmarks characterizing diseases like multiple sclerosis (MS)1 3 Vol.:(0123456789)Brain Structure and Function (2018) 223:3091–3106 following demyelinating and inflammatory lesion formation (He et al 2009; Deppe et al 2014)
To assess how demyelination affects the spread and dynamic properties of neuronal network activity, we investigated acute brain slices preserving the bulk of auditory thalamocortical axonal connections (Agmon and Connors 1992; Broicher et al 2010), focusing on the primary auditory cortex (A1) as a model system
Our results show that myelin loss profoundly affects spatiotemporal patterns of neuronal activation and signal propagation in the mouse auditory cortex
Summary
Alterations in cortical layering, cellular organization, and functionality were recently identified as pathological hallmarks characterizing diseases like multiple sclerosis (MS)1 3 Vol.:(0123456789)Brain Structure and Function (2018) 223:3091–3106 following demyelinating and inflammatory lesion formation (He et al 2009; Deppe et al 2014). Alterations in cortical layering, cellular organization, and functionality were recently identified as pathological hallmarks characterizing diseases like multiple sclerosis (MS). Time points and location of lesioning define the symptoms and deficits that can be observed both in patients and animal models (Dubois-Dalcq et al 2005; Crawford et al 2009b; Rodgers et al 2013; Deshmukh et al 2013; Cerina et al 2017). Recent findings obtained from structural and functional MRI studies in MS patients pointed out that altered memory, cognition, or locomotion was associated with grey matter damage in terms of atrophy but was accompanied by a profound reorganization of network topology. Disappearance of myelin, changes in axonal thickness, and the tightness of wrapping myelin sheets can result in altered excitability, modified stimulus propagation, and cell death (Nave and Werner 2014; Calabrese et al 2015), with important consequences for neuronal network functionality and topology (Crawford et al 2009a; Ehling et al 2011; Hamada and Kole 2015; Cerina et al 2017)
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