Unlike the systemic FoxO1 knockout mice, mice lacking brain FoxO1 survive through adulthood, thus nestin-directed brain FoxO1 deletion provides a useful model to identify behaviors that involve complex neuronal circuits. Mice lacking brain FoxO1 consistently displayed an anxiolytic behavioral phenotype, which in males only required a partial depletion of FoxO1, indicating that FoxO1 has a prominent role in regulating anxiety-like behaviors. This interesting finding is in accordance with the well-known effect of serotonin on anxiety and the anxiolytic effect of most monoamine reuptake inhibitor antidepressants (69). A somewhat surprising observation from this study is that mice lacking brain FoxO1 appear to have a depression-like behavioral phenotype. A significant difference from the matching wild-type mice suggests that the results represent a FoxO1-specific behavioral alteration. Since mood is a complex behavior regulated diversely in brain by monoamines and neurotrophins in a temporal 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
