Cognitive disturbances in the cuprizone model of multiple sclerosis
File(s)
OA Location
Author(s)
Type
Journal Article
Abstract
Cognitive problems frequently accompany neurological manifestations of multiple sclerosis (MS). However, during screening of preclinical candidates, assessments of behaviour in mouse models of MS typically focus on locomotor activity. In the present study, we analysed cognitive behaviour of 9 to 10‐week‐old female C57Bl/6J mice orally administered with the toxin cuprizone that induces demyelination, a characteristic feature of MS. Animals received 400 mg/kg cuprizone daily for 2 or 4 weeks, and their performance was compared with that of vehicle‐treated mice. Cuprizone‐treated animals showed multiple deficits in short touchscreen‐based operant tasks: they responded more slowly to visual stimuli, rewards and made more errors in a simple rule‐learning task. In contextual/cued fear conditioning experiments, cuprizone‐treated mice showed significantly lower levels of contextual freezing than vehicle‐treated mice. Diffusion tensor imaging showed treatment‐dependent changes in fractional anisotropy as well as in axial and mean diffusivities in different white matter areas. Lower values of fractional anisotropy and axial diffusivity in cuprizone‐treated mice indicated developing demyelination and/or axonal damage. Several diffusion tensor imaging measurements correlated with learning parameters. Our results show that translational touchscreen operant tests and fear conditioning paradigms can reliably detect cognitive consequences of cuprizone treatment. The suggested experimental approach enables screening novel MS drug candidates in longitudinal experiments for their ability to improve pathological changes in brain structure and reverse cognitive deficits.
Date Issued
2021-01-01
Date Acceptance
2020-04-29
Citation
Genes, Brain and Behavior, 2021, 20 (1)
ISSN
1601-183X
Publisher
Wiley
Journal / Book Title
Genes, Brain and Behavior
Volume
20
Issue
1
Copyright Statement
© 2020 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor
UK DRI Ltd
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000535030500001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Behavioral Sciences
Neurosciences
Neurosciences & Neurology
diffusion tensor imaging
fear conditioning
learning
MRI
multiple sclerosis
touchscreen
WHITE-MATTER PATHOLOGY
INDUCED DEMYELINATION
BEHAVIORAL-CHANGES
CORPUS-CALLOSUM
MOUSE MODEL
NEUROBIOLOGICAL CHANGES
NLRP3 INFLAMMASOME
AXONAL DAMAGE
EFFECT SIZE
MICE
Publication Status
Published
Article Number
ARTN e12663
Date Publish Online
2020-05-06