As has been observed in studies in other systems, FoxO1 and FoxO3a have divergent physiological effects despite their physical and functional relatedness (45-47). Findings in this study provides new evidence that the two major FoxO subtypes also exhibit distinct physiological effects in brain, where they preferentially regulate behaviors related to anxiety and mood. Detailed studies in the context of FoxO brain distribution, preferential regulation by serotonin and neurotrophins, and selective molecular targets of each FoxO may be useful in addressing their differential roles in brain. On the other hand, the common regulation of FoxOs by serotonin and antidepressant may add a level of complexity to the physiological consequence when all subtypes of FoxOs are regulated simultaneously by a neuromodulator. Using genetic mouse model that carries more than one FoxO mutant may help further identify the common as well as the divergent functions of FoxOs in brain.
