Melatonin Potentiates Running Induced Neurogenesis in the Dentate Gyrus of Adult C3H/HeN mice

Impairment of hippocampus neurogenesis has been associated with neurodegenerative and psychiatric disorders such as Alzheimer's disease and major depression. By studying mechanisms regulating the distinct phases of neurogenesis, including proliferation of progenitor cells, selective survival, and functional integration of new neurons, we can gain insight into the pathology and treatment of these disorders. In laboratory rodents, environmental enrichments, e.g. running wheel (RW) activity can stimulate adult neurogenesis in the dentate gyrus (van Praag, et al. 1999). The pineal hormone melatonin, via activation of the MT1 and MT2 G-protein coupled receptors modulates sleep and circadian rhythms which are altered in major depression (Dubocovich et al., 2005). It has been reported that melatonin enhances neurogenesis by modulating cell survival (Ramirez-Rodiguez et al., 2009). Therefore we hypothesized that melatonin can potentiate neurogenesis induced by RW activity in adult mice.;To assess the role of melatonin treatment on RW induced cell proliferation and survival, single housed C3H/HeN mice (3--4 month old) in a 12/12 hr light/dark cycle with access to fixed wheels (FW) or RW were treated with vehicle (VEH: 0.01% ethanol) or melatonin: (0.02 mg/ml in VEH) via drinking water ad libitum for 12 days. Six injections of bromodeoxyuridine (BrdU 75mg/kg, ip) were given at 12 hr intervals started on day 9. Brains were collected on day 12 to assess alterations in cell proliferation or on day 40 to determine cell survival. In the survival group, wheel activity was continued after the 12 days but treatments were removed. One in six hippocampal coronal sections (50 um) collected for immunohistochemistry. Cell proliferation and survival were quantified by determining the number of BrdU-labeled cells in the inner granular cell layer across six sections of dentate gyrus. RW activity increased cell proliferation by 65.9% (p<0.0001 by two way ANOVA). Melatonin treatment did not affect cell proliferation in the FW and RW groups. RW activity increased cell survival by 210% (p<0.0001 by two way ANOVA). Melatonin treatment did not affect cell survival in the FW group but increased the RW induced cell survival by 47.3% compared to VEH treatment (p<0.05 Bonferroni posttests). The phenotype of surviving neuron is confirmed by BrdU and NeuN colocalization. Our data indicate a role for melatonin in increasing the survival of new hippocampal neuron whose formation is induced by RW activity. This capacity of melatonin is selective for the survival phase of neurogenesis because no effect was observed in the cell proliferation phase. We conclude that melatonin increases RW induced neurogenesis by increasing cell survival without modulating cell proliferation in the dentate gyrus. This positive response to melatonin requires RW activity suggesting a novel role of melatonin regulating neurogenesis.