Behavioural phenotypes in the cuprizone model of central nervous system demyelination

[Display omitted] •Behavioural tests using the CPZ model focus mainly on motor, anxiety and cognition but not other common clinical symptoms in MS like pain or fatigue.•Most histological correlations associated with behavioural deficits were found to be inappropriate.•CPZ-feeding alone may be a useful tool to model some behavioural aspects of demyelinating diseases but it should not be regarded as a model of MS per se. The feeding of cuprizone (CPZ) to animals has been extensively used to model the processes of demyelination and remyelination, with many papers adopting a narrative linked to demyelinating conditions like multiple sclerosis (MS), the aetiology of which is unknown. However, no current animal model faithfully replicates the myriad of symptoms seen in the clinical condition of MS. CPZ ingestion causes mitochondrial and endoplasmic reticulum stress and subsequent apoptosis of oligodendrocytes leads to central nervous system demyelination and glial cell activation. Although there are a wide variety of behavioural tests available for characterizing the functional deficits in animal models of disease, including that of CPZ-induced deficits, they have focused on a narrow subset of outcomes such as motor performance, cognition, and anxiety. The literature has not been systematically reviewed in relation to these or other symptoms associated with clinical MS. This paper reviews these tests and makes recommendations as to which are the most important in order to better understand the role of this model in examining aspects of demyelinating diseases like MS.