Stress, Dopamine, Wnt signaling, And Myelin Loss

Dopamine is related to major aspects of behavior, and abnormal regulation of the dopamine system is linked to depression and other mental disorders. Mice with knocked out dopamine receptors display increased anxiety and depression when confronted with chronic stress. Loss of myelin occurs with multiple sclerosis, and this study shows that chronic stress causes myelin loss in wild-type mice, while the dopamine receptor mutant mice have lower baseline (starting) levels of myelin, but in these mutant mice, myelin levels are not further decreased by stress.  Wnt signaling, which is abnormally regulated in different forms of cancer, is downregulated in the brains of stressed mice; this effect is reversed by lithium treatment (lithium can upregulate Wnt signaling), which normalizes myelin and behavior in stressed wild-type mice.  However, this effect of lithium did not occur in dopamine receptor-mutant mice.  This links the dopamine system with Wnt signaling affecting myelin levels and behavior in mice; the possibility exists that the same association occurs in humans. Stress has previously been linked to multiple sclerosis – with inflammation being one possible mechanism – but the dopamine pathway is another possibility, one that requires further consideration and study. Abstract:

Dopaminergic systems play a major role in reward-related behavior and dysregulation of dopamine (DA) systems can cause several mental disorders, including depression. We previously reported that dopamine D2 receptor knockout (D2R-/-) mice display increased anxiety and depression-like behaviors upon chronic stress. Here, we observed that chronic stress caused myelin loss in wild-type (WT) mice, while the myelin level in D2R-/- mice, which was already lower than that in WT mice, was not affected upon stress. Fewer mature oligodendrocytes (OLs) were observed in the corpus callosum of stressed WT mice, while in D2R-/- mice, both the control and stressed group displayed a decrease in the number of mature OLs. We observed a decrease in the number of active β-catenin (ABC)-expressing and TCF4-expressing cells among OL lineage cells in the corpus callosum of stressed WT mice, while such regulation was not found in D2R-/- mice. Administration of lithium normalized the behavioral impairments and myelin damage induced by chronic stress in WT mice, and restored the number of ABC-positive and TCF4-positive OLs, while such effect was not found in D2R-/- mice. Together, our findings indicate that chronic stress induces myelin loss through the Wnt/β-catenin signaling pathway in association with DA signaling through D2R.