White matter atrophy and myelinated fiber disruption in a rat model of depression

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The monoaminergic hypothesis of depression posits that depression is caused by decreased monoamine function in the brain (Berton & Nestler, 2006). In clinical practice, monoamine‐based antidepressants remain the first‐line therapy for depression. Although antidepressants induce a rapid increase in the intrasynaptic levels of serotonin and/or norepinephrine, the onset of an appreciable clinical effect usually takes at least 3 to 4 weeks (Duman, Malberg, Nakagawa, & D'Sa, 2000; Manji, Drevets, & Charney, 2001; Wong & Licinio, 2001), which indicates that structural changes might occur within the depressed brain (Pittenger & Duman, 2008). This realization provides a strong impetus to search beyond monoaminergic systems to develop a better understanding of the neurobiology of depression and to consider these newly identified mechanisms in the search for novel antidepressant treatments (Berton & Nestler, 2006; Drevets, Price, & Furey, 2008; Manji et al., 2003)
Regarding structural changes in the depressed brain, several lines of evidence have indicated that white matter abnormalities may play a vital role in the pathophysiological mechanisms underlying depression. Previous structural magnetic resonance imaging (MRI) studies demonstrated smaller white matter volumes in diverse brain regions in depression, including the whole brain, the prefrontal cortex, the medial temporal lobe, the hippocampus, and the corpus callosum (Ballmaier et al., 2004; Bell‐McGinty et al., 2002; Berton & Nestler, 2006; Brambilla et al., 2004; Drevets et al., 2008; Frodl et al., 2008; Hashimoto et al., 2006; Manji et al., 2003; Steingard et al., 2002). Previous diffusion tensor imaging (DTI) and MRI investigations of depressed brains also showed decreased fractional anisotropy (FA) and increased white matter hyperintensities (WMHs), which indicate white matter lesions (WMLs) (Kieseppa et al., 2010; Ma et al., 2007; Taylor et al., 2004; Tham, Woon, Sum, Lee, & Sim, 2011). In clinical studies, WMLs usually represent demyelination, which is associated with the clinical severity and treatment responsiveness of depression (Iosifescu et al., 2006; Papakostas et al., 2005; Taylor et al., 2004). Therefore, WMLs could serve as diagnostic and treatment indicators in depressed patients (Dalby et al., 2010; Heiden et al., 2005; Kumar et al., 2004; Papakostas et al., 2005; Weber et al., 2010)
Advances in brain imaging techniques have revealed structural and functional white matter changes that are linked to depression. Brain neuroimaging changes, including increased WMHs and decreased FA, only provide a vague view of WMLs. To explore the pathological correlation of white matter imaging changes in depressed brains, this study was designed to quantitatively investigate changes in white matter and in the myelinated fibers in white matter in depressed brains. We hypothesized that white matter changes and myelinated fiber changes in the white matter may be involved in the pathological mechanism underlying depression. White matter and its myelinated fibers are difficult to visualize and quantify, although unbiased stereological techniques have been demonstrated as reliable and objective in quantitative studies of the morphological changes in myelinated fibers in the white matter (Li et al., 2009; Tang, Nyengaard, Pakkenberg, & Gundersen, 1997). Most morphological studies on brain changes in depression have utilized animal models of depression (Willner, Towell, Sampson, Sophokleous, & Muscat, 1987), in which a depressive‐like behavioral state is induced in rodents by exposing them to chronic unpredictable stress (CUS) (Willner et al., 1987; Willner, 2005). The rodent CUS model, one of the most valid and relevant models of depression (Willner et al., 1987; Willner, 2005; Banasr & Duman, 2008), consists of long‐term, daily exposure of animals to a series of mild and unpredictable stressors designed to prevent habituation (Willner, 2005).
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