Cuprizone Demyelination of the Corpus Callosum in Mice Correlates with Altered Social Interaction and Impaired Bilateral Sensorimotor Coordination

Abstract

For studies of remyelination in demyelinating diseases, the cuprizone model of CC (corpus callosum) demyelination has experimental advantages that include overall size, proximity to neural stem cells of the subventricular zone, and correlation with a lesion predilection site in multiple sclerosis. In addition, cuprizone treatment can be ended to allow more direct analysis of remyelination than with viral or autoimmune models. However, CC demyelination lacks a useful functional correlate in rodents for longitudinal analysis throughout the course of demyelination and remyelination. In the present study, we tested two distinct behavioural measurements in mice fed 0.2% cuprizone. Running on a ‘complex' wheel with varied rung intervals requires integration between cerebral hemispheres for rapid bilateral sensorimotor coordination. Maximum running velocity on the ‘complex' wheel decreased during acute (6 week) and chronic (12 week) cuprizone demyelination. Running velocity on the complex wheel distinguished treated (for 6 weeks) from non-treated mice, even after a 6-week recovery period for spontaneous remyelination. A second behavioural assessment was a resident–intruder test of social interaction. The frequency of interactive behaviours increased among resident mice after acute or chronic demyelination. Differences in both sensorimotor coordination and social interaction correlated with demonstrated CC demyelination. The wheel assay is applicable for longitudinal studies. The resident–intruder assay provides a complementary assessment of a distinct modality at a specific time point. These behavioural measurements are sufficiently robust for small cohorts as a non-invasive assessment of demyelination to facilitate analysis of subsequent remyelination. These measurements may also identify CC involvement in other mouse models of central nervous system injuries and disorders.

Beneficial Effects of Minocycline on Cuprizone Induced Cortical Demyelination

“…When motor coordination and balance were tested, the cuprizone fed mice had more difficulties in walking along the narrow 11 mm wooden beam. These results are consistent with recent reports of motor coordination deficits in cuprizone induced demyelination [38][39][40]. Furthermore, mice fed with cuprizone and treated with minocycline demonstrated an improved motor coordination than cuprizone fed and sham treated mice as the time to tranverse the narrow beam was shorter after 5 and 6 weeks of cuprizone feeding.…”

Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin‐forming oligodendrocytes during CNS remyelination

“…Interestingly, the impaired motor performance in the TG2 2/2 mice coincides with reduced PLP mRNA expression in the CC of those animals, suggesting that myelination of the CC is essential for motor performance. Indeed, demyelination of the CC has been shown to correlate with modified motor function (Hibbits et al, 2009), perhaps as a consequence of reduced transfer of visual information between the cerebral hemispheres (De Bleecker et al, 2005). To exclude that the impaired motor performance of the TG2 2/2 mice as observed is due to reduced mitochondrial complex enzyme activity in the heart resulting in less energy (i.e., ATP) production as suggested by others (Birckbichler et al, 1981;Mastroberardino et al, 2006), we studied in the hearts of both mice types the activity of mitochondrial Complex II and IV enzymes, i.e., SDH and COX, respectively.…”

Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging, Histopathology, and Behavior

“…41–43 Running wheels were placed in home cages equipped with an optical sensor to detect wheel revolutions and determine the daily maximal running velocity using Activity Monitoring Software (Lafayette Instruments, Lafayette, IN) over a 3-week period. A regular “training” wheel with evenly spaced rungs was in the cages for 1 week to reduce variability in running behavior.…”