Social isolation impairs remyelination in mice through modulation of IL‐6

Abstract

Recent studies have revealed that social experience affects myelination. These findings have important implications for disorders that feature abnormal myelination, such as multiple sclerosis (MS), as previous studies have shown that psychosocial stress exacerbates the pathobiology of MS. However, most studies have focused on psychosocial stress during the demyelination phase of MS and have not investigated the effects of social experience on remyelination. Thus, the current study sought to determine whether social experience can alter remyelination after myelin depletion. Myelin in the mouse medial prefrontal cortex was depleted with cuprizone, and the effects of subsequent social isolation on remyelination were evaluated. Remyelination was severely impaired in socially isolated mice. Social isolation also increased IL-6 levels in the medial prefrontal cortex, and administration of an IL-6 inhibitor (ND = 0.01-0.03 μg for 0.25 ng/ml IL-6) ameliorated remyelination impairments. Consistent with this result, IL-6 administration (ED = 0.02-0.06 ng/ml) disturbed remyelination. In addition, neuron-oligodendrocyte coculture experiments showed that IL-6 treatment (ED ≤ 0.02 ng/ml) markedly impeded myelination, which was recovered with IL-6 inhibitor administration (ND = 0.01-0.03 μg for 0.25 ng/ml IL-6). This study provides the first direct evidence, to our knowledge, that social experience influences remyelination via modulation of IL-6 expression. These findings indicate that psychosocial stress may disturb remyelination through regulation of IL-6 expression in patients with such demyelinating diseases that involve remyelination as MS.-Makinodan, M., Ikawa, D., Miyamoto, Y., Yamauchi, J., Yamamuro, K., Yamashita, Y., Toritsuka, M., Kimoto, S., Okumura, K., Yamauchi, T., Fukami, S., Yoshino, H., Wanaka, A., Kishimoto, T. Social isolation impairs remyelination in mice through modulation of IL-6.

Effects of cross-rearing with social peers on myelination in the medial prefrontal cortex of a mouse model with autism spectrum disorder

“…Because BTBR mice are generally considered genetic models of ASD ( McFarlane et al, 2008 ), hypomyelination in mPFC could occur due to genetic mechanisms. The elevated expression of proinflammatory cytokines such as interleukin-6 in the brains of BTBR mice ( Wei et al, 2016 ) may cause hypomyelination, as shown in our previous study ( Makinodan et al, 2016 ). If so, myelin in the motor cortex of BTBR mice should also be thinner than that in the motor cortex of C57BL/6J mice.…”

Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain

“…Remyelination is a regenerative process by which myelin sheaths are restored to demyelinated axons ( Franklin and Ffrench-Constant, 2008 ). Ample evidence indicates that a reduced inflammatory burden favors remyelination ( Cantuti-Castelvetri et al, 2018 ; Karamita et al, 2017 ; Lan et al, 2018 ; Makinodan et al, 2016 ; Vela et al, 2002 ). Given that SCD1 inhibition and deficiency suppressed the inflammatory status of phagocytes after prolonged myelin incubation, we reasoned that abrogation of SCD1 activity could be a therapeutic target to promote remyelination.…”

A Novel Neighbor Housing Environment Enhances Social Interaction and Rescues Cognitive Deficits from Social Isolation in Adolescence

“…The authors suggest a brain region-specific effectiveness of enriched physical environment in remediating brain impairment of isolated mice, with a complete reversal of hippocampal structural impairments and cognitive dysfunctions, but without mitigation of mPFC pathological changes or associated anxiety and social interaction defects [12]. Re-socialization with other group housed conspecifics after adolescent social isolation, however, can restore the impaired social interaction and hypomyelination in the medial prefrontal cortex [20], suggesting a social component is necessary for complete restoration of typical behavioral responses following social isolation. The goal of our neighbor housing is to minimize the adverse effects a single housing environment can induce on behavior and physiological changes in the brain during adolescence and to minimize the chance for harm that can occur in group housing conditions.…”

“…Investigations of the structural and molecular changes in the brain associated with adolescent social isolation have identified reduced neuronal excitability in the dentate gyrus [17,18], and white matter structural changes in the prefrontal cortex [19,20]. Mice that were socially isolated two weeks after weaning displayed cognitive and behavioral dysfunction that was associated with alterations in the white matter tracts of the prefrontal cortex [19].…”