and spatial-dependent manner (70, 71), we speculate that several factors may contribute to this differential mood/anxiety-related effect of FoxO1. Noticeably, unlike FoxO3a, the distribution of FoxO1 in the brain is mostly confined to a few brain areas, including dentate gyrus and ventral CA3 area of the hippocampus, the amygdalohippocampal region, the piriform cortex, the striatum, the caudate putamen, and the nucleus accumbens (64). Serotonin regulates mood and anxiety by activating, as well as desensitizing many types of serotonin receptors located in different brain regions (72, 73). BDNF, on the other hand, differentially regulates mood and anxiety in selective brain regions (71, 74, 75). Serotonin and BDNF also interact with each other to achieve enhanced regulation of mood and anxiety (76, 77). The localization of FoxO1 may determine its selective regulation by either BDNF or serotonin in a brain region-specific manner. However, a conclusion cannot be reached until the regulation of brain FoxO1 by neuromodulators is further investigated in detail. On the other hand, the findings in this study may also suggest that maintaining FoxO1 transcriptional activity in brain is necessary to stabilize mood and prevent depression developed under environmental changes, such as stress. A limitation of this study was that
