br Material methods br Results br Discussion br

Material & methods
Results
Discussion
Acknowledgements We thank Melissa Carballosa-Gautam in the Miami Project to Cure Paralysis Imaging Core. This design, experimentation, data analysis and manuscript writing was supported by the Miami Project to Cure Paralysis; NIH/NINDS (DJL: NS049545 and NS30291); and an NH&MRC fellowship (AMT: 628344).
Introduction Neurogenesis is a process characterized by the generation of neurons from neural precursor cells (NPCs) (Kintner, 2002; Kaslin et al., 2008). Two main ccr5 inhibitor regions where the neurogenesis persistently takes place throughout adulthood have been described (Ming and Song, 2005; Zhao et al., 2008). Many studies have shown adult neurogenesis, generation and differentiation of neurons from NPCs occurring in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) (Goritz and Frisen, 2012). Interestingly, adult hippocampal neurogenesis is responsible for the regulation of cognitive functions, including learning and memory. Increasing evidence supports the hypothesis that NPCs-derived newborn neurons may play a key role in long- and short-term spatial memory as well as in object recognition memory (Deng et al., 2010; Jessberger et al., 2009; Piatti et al., 2013). Thus, increasing adult hippocampal neurogenesis by stimulating NPCs has been suggested as a viable strategy for the enhancement of cognitive functions. Nurr1 (or Nr4a2) is a nuclear receptor acting as an intracellular transcription factor and it is considered to be important for the development of NPCs (Kim et al., 2002, 2007; Bae et al., 2009; Hong et al., 2014; Rodriguez-Traver et al., 2015; Zetterstrom et al., 1997; Vergano-Vera et al., 2015; Wagner et al., 1999; Park et al., 2008; Shim et al., 2007; Saucedo-Cardenas et al., 1998; Castillo et al., 1998). Previous studies manipulating the Nurr1 gene have demonstrated that Nurr1 plays key roles in both the proliferation and differentiation of mouse embryonic stem cells (Kim et al., 2002; Hong et al., 2014), mouse embryonic olfactory bulb stem cells (Vergano-Vera et al., 2015) and rat NPCs of the ventral midbrain, striatum, cortex, lateral ganglionic eminence, SVZ and white matter (Kim et al., 2007; Bae et al., 2009; Wagner et al., 1999; Park et al., 2008; Shim et al., 2007). Consistent with in vitro studies, Nurr1 was shown to be required for maintaining the development of NPCs in vivo. Indeed, Nurr1 knockout mice showed reduced differentiation of NPCs into neurons in the ventral midbrain, including the substantia nigra and the ventral tegmental area (Zetterstrom et al., 1997; Saucedo-Cardenas et al., 1998; Castillo et al., 1998), while transplanted Nurr1-engineered NPCs exhibited an enhanced differentiation of neurons in the striatum (Kim et al., 2002; Shim et al., 2007). In particular, several studies have focused on the role played by Nurr1 in promoting neurogenesis from dopaminergic precursors. However, to date, the role of Nurr1 in the generation of neurons from adult hippocampal NPCs has not been thoroughly examined. In addition to the role played by Nurr1 on the development of NPCs in the Central Nervous System (CNS), recent studies suggest that Nurr1 may be involved in the regulation of cognitive functions (Hawk et al., 2012; Hawk and Abel, 2011; Colón-Cesario et al., 2006). Indeed, both Nurr1 knock-down and heterozygous mice showed an impairment of hippocampus-dependent memory (Colón-Cesario et al., 2006; Rojas et al., 2007) and Nurr1 mRNA expression was increased in the hippocampus following acquisition of hippocampal-dependent learning task (Pena de Ortiz et al., 2000). Despite the fact that the underlying mechanism was not directly examined, it has been suggested that Nurr1 may play an important role in both neurogenesis and the deficits of spatial memory observed in juvenile mice (Ibi et al., 2008). Nurr1 was considered as an orphan nuclear receptor (Wang et al., 2003; Law et al., 1992) until a very recent study identified a selective and potent agonist for Nurr1: an anti-malarial drug amodiaquine (AQ) which stimulates Nurr1\'s transcriptional function via a direct interaction with its ligand-binding domain (Moon et al., 2015). To date, effects of AQ on adult hippocampal neurogenesis have not been investigated. Taking advantage of AQ\'s agonistic effect on the activation of Nurr1, we examined whether Nurr1 can regulate cognitive functions via the induction of adult hippocampal neurogenesis.