Although the IFN molecule is large a

Although the IFN-α molecule is large, a small fraction of systemically administered IFN-α penetrates the brain in areas where the blood brain barrier is more permeable (Biddle, 2006; Pan et al., 1997). In addition, IFN-α treatment increased the expression of endogenous IFN-α in the hippocampus (data not shown). Therefore, both exogenously administered and locally produced IFN-α can be involved in activating IFNAR signaling in the brain. Although IFN-α treatment inhibited hippocampal neurogenesis and caused depressive behaviors, it is still unclear whether decreased neurogenesis directly affects mood and emotional regulation. New neurons have electrophysiological features that are distinct from those of mature granule cells and play a critical role in the plasticity of hippocampal circuitry (Nakashiba et al., 2012; Schmidt-Hieber et al., 2004), which is considered to be important for tbtu to environmental changes and stress coping (Eisch and Petrik, 2012). However, because ablation of hippocampal neurogenesis does not always cause depressive-like symptoms (Jayatissa et al., 2010), it is controversial whether new neurons participate in mood or emotional control (Eisch and Petrik, 2012). Impaired social behavior coincides with depression-like behaviors in some mouse lines, such as heat shock factor 1 knockout (Uchida et al., 2011) and RGS2 mutant (Lifschytz et al., 2012) mice. However, little is known about the neuronal circuits responsible for depression-like and/or social behaviors. Further studies are needed to understand how IFN treatment affects sociability. Some proinflammatory cytokines, including IL-1 and IL-6, induce the secretion of glucocorticoid (Dunn, 2000), a negative regulator of adult hippocampal neurogenesis. IFN-α also induces glucocorticoid secretion by stimulating the release of corticotropin-releasing hormone in the hypothalamus, followed by activation of the HPA axis (Gisslinger et al., 1993). Moreover, hippocampal neurogenesis negatively regulates the HPA axis, thereby reducing stress responses (Snyder et al., 2011). Because excessive activation of the HPA axis is thought to play a role in depression (Nestler et al., 2002), it is possible that the decreased neurogenesis caused by IFN-α (Figures 1 and 5) leads to depression via HPA axis dysregulation. Thus, although the precise relationships among depression, neurogenesis, and the HPA axis remain unclear, their interactions could amplify the depression-promoting effects of IFN-α.
Experimental Procedures
Author Contributions
Acknowledgments
Introduction The skin is a highly regenerative organ containing distinct populations of adult precursors that serve to maintain this regenerative capacity. One of these is a SOX2-positive dermal precursor that resides in hair follicles and that can regenerate the dermis and induce hair follicle morphogenesis (Biernaskie et al., 2009; Fernandes et al., 2004). When these cells (termed skin-derived precursors, or SKPs) are expanded in culture, they differentiate into mesenchymal cell types like smooth muscle cells, adipocytes, and dermal fibroblasts (Biernaskie et al., 2009; Lavoie et al., 2009; Steinbach et al., 2011; Toma et al., 2001, 2005) and peripheral neural cells such as Schwann cells (Biernaskie et al., 2007; Hunt et al., 2008; McKenzie et al., 2006). This differentiation repertoire is reminiscent of embryonic neural crest precursors and, consistent with this, SKPs exhibit many neural crest precursor-like properties (Fernandes et al., 2004). However, lineage tracing recently showed that SKPs isolated from facial skin come from the neural crest, while SKPs from dorsal skin derive instead from a somite origin (Jinno et al., 2010), as does the rest of the dorsal dermis (Mauger, 1972). In spite of these different origins, dorsal and facial SKPs are very similar at the transcriptome level (Jinno et al., 2010).