Motor Behavioral Deficits in the Cuprizone Model: Validity of the Rotarod Test Paradigm

Abstract

Multiple Sclerosis (MS) is a neuroinflammatory disorder, which is histopathologically characterized by multifocal inflammatory demyelinating lesions affecting both the central nervous system’s white and grey matter. Especially during the progressive phases of the disease, immunomodulatory treatment strategies lose their effectiveness. To develop novel progressive MS treatment options, pre-clinical animal models are indispensable. Among the various different models, the cuprizone de- and remyelination model is frequently used. While most studies determine tissue damage and repair at the histological and ultrastructural level, functional readouts are less commonly applied. Among the various overt functional deficits, gait and coordination abnormalities are commonly observed in MS patients. Motor behavior is mediated by a complex neural network that originates in the cortex and terminates in the skeletal muscles. Several methods exist to determine gait abnormalities in small rodents, including the rotarod testing paradigm. In this review article, we provide an overview of the validity and characteristics of the rotarod test in cuprizone-intoxicated mice.

Brain region dependent molecular signatures and myelin repair following chronic demyelination

“…The pronounced, persistent cellular deficits following acute and chronic cuprizone treatment led us to investigate whether they were accompanied by functional deficits in vivo . Most studies assessing behavioral deficits after cuprizone exposure have focused on the acute demyelination paradigm and motor function deficits and/or psychiatric effects such as social and anxiogenic behaviors ( Sen et al, 2019 ; Lubrich et al, 2022 ). Using a complex wheel running test, Hibbits et al (2009) showed impaired bilateral sensorimotor coordination in cuprizone-treated mice and function recovery upon remyelination following acute demyelination.…”

“…The functional outcome of cuprizone-induced CNS de/remyelination, particularly motor functional impairments, has been examined in multiple studies ( Lubrich et al, 2022 ). However, it is still unclear to what extent functional impairments recover upon remyelination, particularly in the context of chronic de/remyelination.…”

“…However, the molecular determinant of myelin repair of chronically demyelinating lesions remains poorly understood. Moreover, few studies have examined behavioral functional outcomes after chronic cuprizone-induced demyelination and during the recovery phase of myelin repair ( Sen et al, 2019 ; Lubrich et al, 2022 ).…”

Chronic alcohol exposure induces cerebral microbleeds by TGF-β1/Smad signaling pathway mediated remodeling of cerebral small vessels

“…The rotarod test, first proposed by Dunham and Miya, is used to assess motor coordination and balance abilities 35 . It has been widely used in assessing motor functions in cases of intracranial hemorrhage, multiple sclerosis, and traumatic brain injury [36][37][38] .Referring to the previous experimental protocols 39 , before the official test begins, let the mice undergo adaptive training on the rotating rod at a constant speed of 15 rpm for 15 minutes. During this period, if a mouse falls off, it will be put back on the rotating rod to continue training until it can walk steadily on it.…”

Evaluation of antiparkinsonian activity of water yam tuber (Dioscorea alata L.) extract on haloperidol-induced Parkinson’s disease in mice

“…The duration for when the mouse remained on and endured the rotarod and the rotating speed at which the mouse first fell were recorded. Usually, mice can maintain their balance unlimitedly (Lubrich et al, 2022).…”