The beneficial effects of calorie restriction (CR) have been described at organismal and cellular levels in multiple organs, including the brain1. However, our understanding of the causal mediators is relatively poorly understood, particularly in the context of improved memory. We have shown that the orexigenic gut hormone, acyl-ghrelin (AG)2, increases adult hippocampal neurogenesis (AHN) and improves memory in adult rats3. Here, we have studied the role of AG and it’s receptor, the growth hormone secretagogue receptor (Ghsr), as possible causal factors in mediating the beneficial effects of CR on AHN and memory. Using the Ghsr-eGFP reporter mouse we found that Ghsr expression was enriched in the dentate gyrus (DG) of the hippocampus, where it was expressed in mature granule neurones in apposition to type II neural stem (NSC) cells. Ghsr expression was not observed in Sox2+ or nestin+ NSCs, Ki67+ proliferating cells, DCX+ immature neurons or in S100B+ astrocytes. These data suggest that Ghsr may facilitate AHN within the DG. Treatment of wild-type and Ghsr-/- mice4 with AG (7 days i.v, 48μg/day, n=3 per group) induced expression of hippocampal gene transcripts that support cognition and neurogenesis in a Ghsr dependent manner. Genome-wide microarray identified 1,106 AG/Ghsr-regulated transcripts (P<0.05 and >1.5 fold change). RT-qPCR validated the AG mediated up-regulation of transcripts associated with neurogenesis (Gadd45b, P = 0.0314) and plasticity (c-Fos, P = 0.0213; analysed by unpaired two-tailed t test, vs saline). Next, we analysed whether AG and CR were able to similarly induce expression of the immediate early genes, Egr1 and c-Fos in Ghsr-eGFP+ and Ghsr-eGFP- neurones within the DG. We raised AG levels directly via injection (10μg/kg i.p), indirectly via CR (16h overnight fast), or with both injection and CR (n=4-5 per group). Expression of Egr1 was increased in the DG after CR (P<0.05), direct AG injection (P<0.05), and after the combination of CR and exogenous treatment with AG (P<0.001). Notably, there was an increase in Ghsr-GFP+ cells expressing c-Fos in the DG following AG treatment (P<0.05; analysed by 1-way ANOVA with Tukey post hoc testing; vs saline). Finally, given the CR mediated increase in proneurogenic Egr15 we analysed the impact of 14-days of CR on AHN and hippocampal dependent memory in wild-type and Ghsr-/- mice (n=12 per group). Our data show that CR (70% of ad-lib controls) increased AHN in wild-type (P = 0.048) but not Ghsr-/- mice (P = 0.888). Furthermore, CR wild-type (P = 0.0121) but not Ghsr-/- mice (P = 0.1837) displayed improved contextual fear memory (analysed by 2-way ANOVA with Tukey post hoc testing; vs ad-libitum). Together, these findings demonstrate a previously unknown function for Ghsr in mediating the beneficial effects of CR on enhancing AHN and memory.