Manic switching from depression is affected by adult hippocampal neurogenesis

Many individuals who initially present with depression later develop manic or hypomanic episodes, yet the biological processes accompanying this delayed shift remain unclear. Here, we examined whether perturbation of the adult hippocampal neurogenic niche is associated with time-dependent shifts in mood-relevant behaviors. Using Nestin-CreER::Rosa26-FloxedSTOP-DTa (Nestin-DTa) mice, we induced partial ablation of Nestin-positive adult neural stem cells (aNSCs) in the hippocampus by tamoxifen administration and assessed phenotypes at 4 and 8 weeks post-ablation. Neurogenic-lineage populations in the dentate gyrus were quantified by immunohistochemistry using stage-specific markers. Partial aNSC ablation reduced the Nestin-positive pool and BrdU-labeled proliferation, followed by a compensatory expansion of proliferative progenitors and DCX-positive neuroblasts. At 4 weeks, Nestin-DTa mice exhibited anxiety-like behavior and increased forced-swim immobility. By 8 weeks, anxiety-like measures normalized, and mice displayed increased exploratory/locomotor activity and reduced forced-swim immobility, accompanied by sustained elevation of progenitor and immature neuronal compartments. These findings provide a tractable model in which disruption of the adult neurogenic niche is associated with a transition from depression-like behavior to a hyperactive, mania-like phenotype over time.