The impact of chronic unpredictable stress on cuprizone-induced demyelination and the occurrence of depressive-like behavior in C57BL/6 mice

Abstract

Objective To investigate whether cuprizone-induced demyelinating mice is more susceptible to developing depressive-like behaviors induced by chronic unpredictable stress (CUS), and to examine the underlying neuropathological changes. Methods C57BL/6 mice were randomly divided into four groups: control (n=10), stress (n=12), cuprizone (n=12) and cuprizone+ stress group (n=12). Mice in stress group were exposed to CUS for 3 weeks and mice in cuprizone group were fed with 0.3% cuprizone-containing food for 3 weeks. Mice in cuprizone+ stress group were exposed to both stress and cuprizone, and mice in control group were fed with normal food without exposure to stress. After 3 week exposure, they were subjected to behavioral tests including spontaneous activity, anxiety level and depressive-like behaviors and their brains were possessed for Western blot to test myelin marker MBP and astrocyte activation marker GFAP. Results CUS did not change the locomotor activity, anxiety levels and sucrose preference of cuprizone-induced demylinating mice, but did significantly increase their immobile time in forced swimming test (control (109.3±8.0)s, stress (111.3±21.8)s, cuprizone (90.5±8.9)s, cuprizone+ stress (155.0±9.1)s). Western blot revealed that CUS further decreased MBP expression (control (1.014±0.06), stress(1.088±0.104), cuprizone(0.436±0.071), cuproznie+ stress(0.150±0.041), (P<0.05)) and increased GFAP content (control (1.026±0.045), stress(0.846±0.078), cuprizone(1.736±0.215), cuprizone+ stress(2.428±0.314), (P<0.05)) in cuprizone-induced demyelinating mice. Conclusion Our findings suggest that demyelinating pathology increases individual susceptibility to chronic stress, which may induce depressive behaviors through damage of oligodendrocyte/myelin. Key words: Chronic unpredictable stress; Cuprizone; Demyelination; Myelin basic protein; Glial frillary acidic protein; Major depressive disorder