Motor skill sequence (MOSS), a highly sensitive tool to characterise and quantify deficits of central motor coordination in mice

Aim: So far, it remains difficult to reliably detect a behavioural equivalent of central motor coordination in mice. A highly sensitive functional readout parameter is desirable specifically with regard to the development of new medical treatments in neurological diseases. We therefore introduce a novel murine motor test, the motor skill sequence (MOSS), which is designed to detect latent deficits in motor performance. The test is evaluated in the cuprizone mouse model of multiple sclerosis (MS), where the copper chelator cuprizone induces reversible demyelination predominantly of the corpus callosum, and in the widely use subchronic MPTP mouse model of Parkinson's disease (PD).

Methods: MOSS analyses voluntary running wheel activity of a sequence of two different types of running wheels. In a first step of MOSS, mice are habituated to a training wheel composed of regular crossbars till maximal wheel running performance was achieved. Subsequently, animals are exposed to a wheel with irregularly spaced crossbars demanding high-level motor coordination. This two-step approach minimizes a contribution of cardio-pulmonary and musculo-sceletal training to any improvement of motor performance on the complex wheel.

Results: Demyelinated animals under cuprizone diet showed reduced running performance on both wheel types. In contrast, remyelinated animals after cuprizone withdrawal did not exhibit any functional impairment on the training wheels. Latent motor skill deficits were however revealed on the complex wheels, although clearly ameliorated as compared to acutely demyelinated mice.

MPTP-treated animals displayed clear central motor deficits on the complex wheels, as indicated by a reduced maximum speed and running distance, although all mice had shown equal improvement of running performance during the learning phase on the regular wheel.

Conclusion: Our results demonstrate that central motor deficits of cuprizone-induced demyelination and after remyelination can be detectd by MOSS in a quantitative manner. Also in the in the MPTP mouse model of PD MOSS is capable of unmasking latent motor deficits with high sensitivity. With its features of fully automated data collection and high sensitivity, MOSS meets all criteria for an in vivo screening approach for potential therapeutic strategies, not only in mice models of PD or MS but also for assessing central motor deficits and respective therapeutic effects in models of other neurological diseases.