There are some models of sleep deprivation such

There are some models of sleep deprivation, such as acute or chronic, total or selective sleep deprivation, sleep restriction, or sleep fragmentation. Modifed multiple platform method (MMPM) in our study causes a particularly strong reduction in REM sleep, breaks the sleep continuity. Previous studies proved that it suppresses all phases of sleep (Grahnstedt and Ursin, 1985), including non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, particularly causes a strong reduction in REM sleep (Mueller et al., 2008). A study showed that MMPM abolishes paradoxical sleep completely during the deprivation period, but also results in significant decreases in slow wave sleep (−31%) (Machado et al.,2004). Sleep deprivation induced neuroinflammation has been studied, mostly focusing on IL-1β and TNF-α. Chronic sleep restriction for 1 and 3 successive days significantly increases IL-1β mRNA expression in the hippocampus (Zielinski et al., 2014). In another study, chronic sleep fragmentation selectively increases expression of TNF-α in cortex; TNF-α double receptor knockout or treatment with a TNF-α neutralizing antibody abrogates sleep fragmentation-induced learning deficits and increased sleep propensity (Ruiz et al., 2012). 72 h REM sleep deprivation increases the plasma levels of proinflammatory cytokines (IL-1, IL-1β, IL-6, IL-17A, and TNF-α), as well as an anti-inflammatory cytokine (IL-10), after 7 days of recovery, IL-17A still remains high (Yehuda et al., 2009). IL-1 suppresses hippocampal neurogenesis in model of chronic isolation and acute or chronic stress (Ben Menachem-Zidon et al., 2008, Goshen et al., 2008, Koo and Duman, 2008). REM sleep deprivation suppresses cell proliferation by the presence of elevated corticosterone and IL-1β signaling (Mueller et al., 2014). However, how IL-17 changes and takes effect after sleep deprivation in central nervous system remains unknown. IL-17A was involved in LPS-induced neuroinflammation and cognitive impairment in aged rats via microglial activation (Sun et al., 2015). It has been proven that IL-17 is a negative regulator of adult hippocampal neurogenesis in the DG of hippocampus under physiological conditions. Absence of IL-17 enhanced synaptic function, reduced expression of inflammatory cytokines, increased expression of proneuronal genes in neuronal progenitor cells, and significantly improved neurogenesis in the DG (Liu et al., 2014). An in vitro study indicated that IL-17 blocks proliferation of neural stem calmodulin dependent protein kinase (NSCs), the effects of IL-17 on NSCs can be partially blocked by a p38MAPK inhibitor (Li et al., 2013). Our study indicates that acute REM sleep deprivation for 3 days increases IL-17 expression in the hippocampus, and significantly decreases BrdU+ cells in the DG. SOX-2 is the mark of neural progenitors. Fig. 2 in our study proved that hippocampal neural progenitor cells express IL-17RA and IL-17RC. Recombinant IL-17 (rIL-17) causes the production and release of CXCL1, CXCL2, CXCL5, CXCL8, CXCL10, CCL2 and CCL20 in different human cell types. CXCL1, CXCL5 and CXCL8 potentially mediate the biological function of IL-17 by attracting neutrophils in vivo (Zhu and Qian, 2012). In this study, the i.p. administration of exogenous rIL-17 has the same effect as sleep deprivation, demonstrating that IL-17 plays vital role in sleep deprivation induced antiproliferative effects. IL-17 (also known as IL-17A) is most homologous to IL-17F, they are both produced by Th17 cells. IL-17 and IL-17F trigger signaling by binding the heterodimeric IL-17RA and IL-17RC complex for host defense or pathogenesis of autoimmune diseases and other inflammatory disorders, activating NF-κB, MAPKs and C/EBP cascades in different cell types (Qian et al., 2010). The role of IL-17 signaling in sleep deprivation induced suppressed cell proliferation of hippocampus is not yet known. The mitogen activated protein kinase (MAPK) family is composed of ERK, JNK and p38MAPK, and the last two signaling pathways can be activated by intracellular and extracellular stresses, including environmental changes such as UV light, heat, and hyperosmotic conditions, and exposure to inflammatory cytokines (Hotamisligil and Davis, 2016). It has been reported that REM sleep deprivation decreases p-ERK1/2 levels in dorsal CA1. No reports about sleep deprivation induced changes of p38 MAPK in the hippocampus are available. P38 MAPK is important in the last step of the cell division because of regulating mitotic transit (Cha et al., 2007) and cytokinesis (Fujii et al., 2000, Fujii et al., 2000). P38α as the most abundant family member of p38, helps to couple cell proliferation and growth in response to certain damaging stimuli. In this study, the inhibitor SB203580 which blocks the p38 MAPK signaling pathway helps to increase new born cells in the DG without affecting IL-17 expression in the hippocampus, indicating that sleep deprivation-induced high expression of IL-17 in hippocampus activates p38 MAPK signing pathway by combing with its receptor IL-17RA and IL-17RC in hippocampal neural progenitor cell, and eventually contributes to suppressed proliferation of neural progenitor cells in adult hippocampal DG. In addition, it should not be neglected that sleep deprivation induces other proinflammatory factors like IL-1β and TNF-α, which may activate p38MAPK or be involved in suppressed neural progenitor cells proliferation.