Exercise protects myelinated fibers of white matter in a rat model of depression

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Depression, a common psychiatric disorder with a lifetime prevalence of 10–20% worldwide (Berton & Nestler, 2006; Moussavi et al., 2007), ranks as the leading cause of disability globally due to its high morbidity, recurrence, and association with suicide (Krishnan & Nestler, 2008; Whiteford et al., 2013; Wong & Licinio, 2001). Therefore, understanding the mechanisms of depression and exploring the potential therapeutic targets against depression are crucial.
Several past preliminary studies found that alterations of the white matter, both in size and morphology, were associated with a diagnosis of depression (Nobuhara et al., 2004; Nobuhara et al., 2006; Taylor et al., 2004) and depression outcomes (Alexopoulos, Kiosses, Choi, Murphy, & Lim, 2002; Bae et al., 2006; Taylor et al., 2004). In fact, the white matter atrophy reported in patients with depression was accompanied by high white matter hyperintensities (WMH) on magnetic resonance imaging (MRI), which most likely represents white matter fiber dysmyelination (Aizenstein et al., 2011; Dalby et al., 2010), as well as by low fractional anisotropy (FA) on diffusion tensor imaging (DTI), which most likely represents decreased integrity of myelinated fibers in the white matter (Liu et al., 2016; Xiao, He, McWhinnie, & Yao, 2015). Furthermore, lesions of myelinated fibers in the white matter were positively correlated with the severity of depression (Iosifescu et al., 2005), and subjects with severe damage to myelinated fibers of the white matter had a poor response to antidepressants (Papakostas et al., 2005; Tham, Woon, Sum, Lee, & Sim, 2011), indicating that the myelinated fibers of the white matter may not only participate in the pathomechanism of depression but also play an extremely important role in the mechanism of antidepressant therapy.
The antidepressive effects of exercise, a nonpharmacological treatment characterized by its safety and nontoxic side effects, have been of interest in the past few years. Cross‐sectional studies have consistently found that regular physical activity was associated with a greater reduction in depressive symptoms (Blumenthal et al., 2007; Bridle, Spanjers, Patel, Atherton, & Lamb, 2012; Camacho, Roberts, Lazarus, Kaplan, & Cohen, 1991; Cooney, Dwan, & Mead, 2014; Hassmen, Koivula, & Uutela, 2000; Ruuskanen & Ruoppila, 1995; Schuch et al., 2015; Stephens, 1988). In rodents, regular exercise was also shown to improve depressive behavior in animal models of depression, such as chronic unpredictable stress (CUS) (Kim et al., 2015; Kiuchi, Lee, & Mikami, 2012; Wen et al., 2014). All of these studies showed the beneficial effects of regular physical exercise on depression, but the precise mechanism underlying the antidepressant action of exercise is still unclear. Several human neuroimaging studies have reported that exercise could induce a reduction in the volume of high WMH and promote regeneration in white matter suggestive of alterations in myelin architecture (Scholz, Klein, Behrens, & Johansen‐Berg, 2009; Tseng et al., 2013; Voss et al., 2013), with similar findings demonstrated in rodents (Sampaio‐Baptista et al., 2013). These studies have amply demonstrated the protective effects of exercise on myelinated fibers of white matter in the brain. However, whether the remodeling of the myelinated fibers in white matter is crucial to the relief of depression and whether the antidepressant effects of exercise are dependent on changes in white matter myelination are unknown. To address clarify these scientific questions, we designed the following experiment.
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