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Functional Magnetic Resonance Imaging of Rats with Experimental Autoimmune Encephalomyelitis Reveals Brain Cortex Remodeling.


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Article

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Authors

Peruzzotti-Jametti, Luca  ORCID logo  https://orcid.org/0000-0002-9396-5607
Rigolio, Roberta 
Fiorini, Silvia 
Bontempi, Pietro 

Abstract

UNLABELLED: Cortical reorganization occurring in multiple sclerosis (MS) patients is thought to play a key role in limiting the effect of structural tissue damage. Conversely, its exhaustion may contribute to the irreversible disability that accumulates with disease progression. Several aspects of MS-related cortical reorganization, including the overall functional effect and likely modulation by therapies, still remain to be elucidated. The aim of this work was to assess the extent of functional cortical reorganization and its brain structural/pathological correlates in Dark Agouti rats with experimental autoimmune encephalomyelitis (EAE), a widely accepted preclinical model of chronic MS. Morphological and functional MRI (fMRI) were performed before disease induction and during the relapsing and chronic phases of EAE. During somatosensory stimulation of the right forepaw, fMRI demonstrated that cortical reorganization occurs in both relapsing and chronic phases of EAE with increased activated volume and decreased laterality index versus baseline values. Voxel-based morphometry demonstrated gray matter (GM) atrophy in the cerebral cortex, and both GM and white matter atrophy were assessed by ex vivo pathology of the sensorimotor cortex and corpus callosum. Neuroinflammation persisted in the relapsing and chronic phases, with dendritic spine density in the layer IV sensory neurons inversely correlating with the number of cluster of differentiation 45-positive inflammatory lesions. Our work provides an innovative experimental platform that may be pivotal for the comprehension of key mechanisms responsible for the accumulation of irreversible brain damage and for the development of innovative therapies to reduce disability in EAE/MS. SIGNIFICANCE STATEMENT: Since the early 2000s, functional MRI (fMRI) has demonstrated profound modifications in the recruitment of cortical areas during motor, cognitive, and sensory tasks in multiple sclerosis (MS) patients. Experimental autoimmune encephalomyelitis (EAE) represents a reliable model of the chronic-progressive variant of MS. fMRI studies in EAE have not been performed extensively up to now. This paper reports fMRI studies in a rat model of MS with somatosensory stimulation of the forepaw. We demonstrated modifications in the recruitment of cortical areas consistent with data from MS patients. To the best of our knowledge, this is the first report of cortical remodeling in a preclinical in vivo model of MS.

Description

Keywords

brain plasticity, cortical reorganization, experimental autoimmune encephalomyelitis, functional magnetic resonance imaging, multiple sclerosis, neuroimmunology, Afferent Pathways, Animals, Cerebral Cortex, Corpus Callosum, Cytokines, Dendrites, Disease Models, Animal, Electric Stimulation, Encephalomyelitis, Autoimmune, Experimental, Hindlimb, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Nerve Tissue Proteins, Neurons, Oxygen, Rats

Journal Title

J Neurosci

Conference Name

Journal ISSN

0270-6474
1529-2401

Volume Title

35

Publisher

Society for Neuroscience
Sponsorship
Wellcome Trust (105795/Z/14/Z)
European Research Council (260511)
Wellcome Trust (097922/Z/11/B)
This work was supported by grants from the National Multiple Sclerosis Society (NMSS; RG-4001-A1 to SP), the Italian Multiple Sclerosis Foundation (FISM; RG 2010/R/31 to SP and FISM Grant 10/12/F14/2011 to PM), the Italian Ministry of Health (GR08/7 to SP), the European Research Council (ERC) 2010-SIG (RG 260511-SEM_SEM to SP), the European Community (EC) 7th Framework Programme (FP7/2007-2013; RG 280772-iONE to SP), The Evelyn Trust (RG 69865 to SP), The Bascule Charitable Trust (RG 75149 to SP). LPJ is supported by a Wellcome Trust Research Training Fellowship (RRZA/057).