Fewer studies have explored the function of FoxOs in the brain and its link to neuropsychiatric diseases. In neuronal tissues, FoxO3a induces the expression of the proapoptotic Bcl-2 interactive mediator (Bim) (26, 48-52). Ischemia in the brain has been shown to elevate the level of active FoxO3a (49, 53, 54). Neurotrophins, such as BDNF, activate signaling pathways leading to phosphorylation and inactivation of FoxOs (48, 55, 56). More recently, a study in C. elegans (57) revealed that activation of serotonin receptors led to inhibition of FoxO transcriptional activity via activation of Akt, which appeared to be an important mechanism in stress modulation in worms. Additionally, we have also reported that FoxO3a transcriptional activity in mouse brain is inhibited by the mood stabilizer lithium (58). We therefore hypothesized that FoxO is an important mediator of behaviors normally regulated by neuromodulators. In this study, we sought to test this hypothesis by examining the regulation of mouse brain FoxO1 and FoxO3a by serotonin and antidepressant and by testing anxiety- and mood-relevant behaviors in mice lacking FoxO1 or FoxO3a.
