It has been hypothesized that neurogenesis

It has been hypothesized that neurogenesis in DG may play an important role in learning and memory and especially in spatial memory (Deng et al., 2010; Jessberger et al., 2009; Piatti et al., 2013). In the present study, mice with AQ treatment showed an increased percentage of spontaneous alternation in Y-maze task and an improved discrimination index in the test session of the novel object recognition task, suggesting that AQ administration enhances both short- and long-term learning and memory in mice. A previous study has shown that both faster acquisition and longer retention in the Morris water maze are associated with exercise-induced increase in adult hippocampal neurogenesis in mice (van Praag et al., 2005). Other studies also observed that mice with decreased adult hippocampal neurogenesis show impaired cognitive behaviors (Li et al., 2013; Lee et al., 2015). Interestingly, one placebo-controlled study reported that the intermittent preventive treatment of AQ improves the cognitive ability of semi-immune schoolchildren (Clarke et al., 2008). Therefore, we can speculate that AQ-induced cognitive enhancement may occur via a Nurr1-dependent modulation of adult hippocampal neurogenesis. While neuronal stem cells including neural stem cells (NSCs) in CNS and neural crest stem cells (NCSCs) in peripheral nervous system (PNS) have been successfully achieved to study developmental or degenerative neuronal disease with adequate cell types (Lee et al., 2009; Lafaille et al., 2012), still it is challenging to control transplanted cells in the specific region without various risks. Since adult neural stem cells were first identified in the mammalian cisapride Supplier (Ming and Song, 2005), the characterization of their functional properties allowed significant insights into the biology of stem cells and the mechanistic studies of brain disease (Tabar et al., 2005). This population of cells has been described as a reserve of endogenous stem cells with limited differentiation potential in comparison to other types of neuronal stem cells derived from embryonic stem cells (Lee et al., 2007; Kim et al., 2014). Current studies have shown that the direct regulation of cellular fate is possible through the manipulation of environmental conditions (Najm et al., 2015). In addition, more advanced technologies, including pharmacological approaches, have been reported to increase our ability to control cell activity, including its differentiation and cellular functions (Kim and Lee, 2013) both in vitro and after in vivo transplantation. Moreover, it has been suggested that promoting the differentiation of endogenous neural stem cells, rather than introducing exogenous cells, might be a more effective strategy to modulate adult hippocampal neurogenesis. Here we showed that activation of Nurr1 induces hippocampal neurogenesis in the mouse brain by stimulating neural stem cells. Furthermore, the direct stimulation of neural stem cells exerted by AQ is a viable pharmacological approach to regulate gene activation and to control the differentiation of NPCs into neuronal cells. Indeed, the observation that this endogenous stem cell activation enhances cognitive functions suggests that novel concept for pharmacological regulation of endogenous NSC control for future studies related to stem cell regulation and memory failure diseases. However, there were reports that the discrepancies in the duration of cell maturation and the amount of new granule cells after stimulation of NPCs in DG between two different species; rat and mice (Snyder et al., 2009; Ray and Gage, 2006). Since we compared the in vivo results using C57BL/6 mice with in vitro results using NPCs derived from fisher 344 rats, there may be a discrepancy in effectiveness of AQ on neuronal maturation between two different species. Thus, conclusion based on comparison between two different species should be limited to adult hippocampal neurogenesis. Further in vitro studies using mice adult hippocampal NPCs are needed to further elucidate the effects of pharmacological stimulation of Nurr1 on adult hippocampal neurogenesis and cognitive functions.