br Experimental Procedures br Acknowledgments br Introductio

Experimental Procedures
Acknowledgments
Introduction New neurons are continuously generated in the hippocampal dentate gyrus (DG) throughout life in mammals, including rodents (Altman and Das, 1965; Kaplan and Hinds, 1977; Kuhn et al., 1996), nonhuman primates (Gould et al., 1999; Kornack and Rakic, 1999), and humans (Eriksson et al., 1998; Manganas et al., 2007). In the DG, neural stem HMBA Linker Supplier (NSCs) residing in the subgranular zone (SGZ), a thin cell layer between the granule cell layer (GCL) and the dentate hilus, generate transit-amplifying intermediate progenitors that give rise to new neurons (Gage, 2002; Zhao et al., 2008). The newly generated neurons then migrate into the GCL, where they differentiate into mature granule cells to be integrated into the hippocampal circuitry (Mathews et al., 2010; Toni et al., 2007; van Praag et al., 2002). Evidence suggests that neurogenesis in this region plays a role in emotional regulation (Eisch and Petrik, 2012; Samuels and Hen, 2011). Decreased neurogenesis in the adult DG is implicated in the pathophysiology of depression, a common psychiatric disorder. Clinical imaging studies demonstrated reduced volume and altered metabolism in the hippocampus of depressed patients (Block et al., 2009; Campbell et al., 2004; Gilbertson et al., 2002; Huang et al., 2010). Hippocampal neurogenesis is downregulated in animal models of depression induced by exposure to chronic psychosocial stress (Jacobs et al., 2000; Kempermann and Kronenberg, 2003). Conversely, chronic treatment with antidepressants enhances hippocampal neurogenesis (Anacker et al., 2011; Malberg et al., 2000; Pechnick et al., 2011), which is required for the behavioral effects of these drugs in mice (Santarelli et al., 2003). However, the relationship between neurogenesis suppression and depressive symptoms remains elusive (Airan et al., 2007; David et al., 2009; Lucassen et al., 2010). Animal models of depression induced by a single ligand and its receptor would be useful for investigating these mechanisms in vivo using genetic approaches. Interferon-α (IFN-α), a proinflammatory cytokine with potent antiviral, antiproliferative, and immunoregulatory effects, has been widely used to treat chronic viral hepatitis and several types of malignancy (Deutsch and Hadziyannis, 2008; Papatheodoridis et al., 2008; Tagliaferri et al., 2005). However, long-term IFN-α treatment frequently triggers a variety of neuropsychiatric symptoms (Dieperink et al., 2000). Depression is the most common and serious side effect, affecting approximately 30%–45% of patients receiving IFN-α treatment, resulting in occasional discontinuation of the therapy (Bonaccorso et al., 2001; Lieb et al., 2006). Despite its clinical importance, the mechanism underlying IFN-α-induced depression is still not well understood. We previously reported that repeated IFN-α treatment suppresses cell proliferation in the SGZ of adult rats (Kaneko et al., 2006). However, little is known about how peripheral IFN-α affects brain function. Because a small fraction of peripheral IFN-α gains access to the brain (Greig et al., 1988; Smith et al., 1985), hippocampal neurogenesis can be directly affected by the increased IFN-α signaling in the brain (Wang et al., 2008). However, it is also possible that IFN-α affects brain function via secondary effectors such as humoral or cellular components of the peripheral immune system (Hayley et al., 2013; Orsal et al., 2008). Here, we analyzed the effects of IFN-α treatment on neurogenesis and depressive behaviors using two types of interferon-α receptor (IFNAR) knockout (KO) mouse lines: a systemic KO (IFNAR; Müller et al., 1994) and a conditional KO in NSCs and their progenies (IFNAR:Nes-Cre; Detje et al., 2009). Our findings suggest that peripherally administered IFN-α directly suppresses the neurogenic function of NSCs and increases depression-like behaviors.