title: Behavioural changes observed in demyelination model shares similarities with white matter abnormalities in humans.
abstract: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Further to the symptoms resulting from demyelination, new studies point to the involvement of neuroinflammation and white matter abnormalities in psychiatric disorders and neurodegenerative diseases. Cuprizone, a model of MS, produces consistent demyelination and elicits behavioural, morphological and inflammatory changes in animals that share some similarities with those observed in humans. In this study, we used the cuprizone model in Lewis rats to evaluate clinical signs triggered by the demyelination process which could be comparable with the symptoms seen in white matter abnormalities in human beings. To induce the demyelination process, 0.6% cuprizone was added to the Lewis rats' diet for 4 weeks. We proceeded with behavioural, morphological and immunological analyses. Animals fed with cuprizone exhibited behavioural changes: higher scores in the neurotoxicity test, reduced exploratory and locomotion behaviour, and also an increase of permanency in the closed arm of the elevated plus maze test, were observed. In these analyses, the animals showed motor coordination impairment and anxiety-like behaviour. Demyelination also triggered changes in discrimination of objects identified by an increase in the time spent close to a familiar object. These behavioural alterations were associated with a significant increase in the levels of TNF-alpha and corticosterone, consistent with the activation of microglia and astrocytes. Taken together, the results of this work show the cuprizone/Lewis rat model demyelination as an attractive paradigm for studying the correlation between white matter abnormalities and behaviour.
authors.affiliation: Programa Interdisciplinar em Ciências da Saúde, Universidade Federal de São Paulo - UNIFESP, Av. Ana Costa, 95, Santos, SP 11060-001, Brazil; Departamento de Biociências, Universidade Federal de São Paulo - UNIFESP, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil.
authors.forename: Nathalia
authors.initials: N
authors.lastname: Serra-de-Oliveira
authors.affiliation: Departamento de Biociências, Universidade Federal de São Paulo - UNIFESP, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil.
authors.forename: Sabine Nunes
authors.initials: SN
authors.lastname: Boilesen
authors.affiliation: Departamento de Biociências, Universidade Federal de São Paulo - UNIFESP, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Prado de França Carvalho
authors.affiliation: Departamento de Biociências, Universidade Federal de São Paulo - UNIFESP, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: LeSueur-Maluf
authors.affiliation: Laboratório de Imunologia & Alergia Experimental - LIAE, Faculdade de Ciências Médicas - FCM, Universidade Estadual de Campinas - UNICAMP, Rua Tessália Vieira de Camargo, 126, CEP 13083-887, Cidade Universitária "Zeferino Vaz", Campinas, SP, Brazil.
authors.forename: Ricardo de Lima
authors.initials: Rde L
authors.lastname: Zollner
authors.affiliation: Departamento de Biociências, Universidade Federal de São Paulo - UNIFESP, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil.
authors.forename: Regina Célia
authors.initials: RC
authors.lastname: Spadari
authors.affiliation: Departamento de Biociências, Universidade Federal de São Paulo - UNIFESP, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil.
authors.forename: Carla Cristina
authors.initials: CC
authors.lastname: Medalha
authors.affiliation: Departamento de Biociências, Universidade Federal de São Paulo - UNIFESP, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil. Electronic address: glaucia.castro@unifesp.br.
authors.forename: Gláucia
authors.initials: G
authors.lastname: Monteiro de Castro
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D003337:Corpus Callosum / Q000473:pathology*; D003471:Cuprizone / Q000633:toxicity; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism; D006801:Humans; D008297:Male; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000473:pathology* / Q000523:psychology*; D009186:Myelin Sheath / Q000473:pathology*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D066127:White Matter / Q000473:pathology*
chemical_list: D003471:Cuprizone
keywords: Behaviour; Cognition; Cuprizone; Neuroinflammation; White matter