Disruption of Sonic Hedgehog Signaling Accelerates Age-Related Neurogenesis Decline and Abolishes Stroke-Induced Neurogenesis and Leads to Increased Anxiety Behavior in Stroke Mice

Sonic Hedgehog (SHH) signaling has a critical role in mediating developmental neurogenesis and has been implicated in adult subventricular (SVZ) neurogenesis. However, the precise role of Smoothened (SMO) receptor–mediated SHH signaling in adult neurogenesis during aging especially in hippocampal subgranular zone (SGZ) neurogenesis remains undefined. Additionally, our previous study showed that stimulation of SHH signaling post-stroke leads to increased neurogenesis and improved behavioral functions after stroke. However, it is not clear whether SHH signaling in neural stem cells (NSCs) is required for stroke-induced neurogenesis and functional recovery post-stroke. In this study, using conditional knockout (cKO) of SHH signaling receptor Smo gene in NSCs, we show a decreased neurogenesis at both SVZ and SGZ in young-adult mice and an accelerated depletion of neurogenic cells in the process of aging suggesting that SHH signaling is critical in maintaining neurogenesis during aging. Behavior studies revealed that compromised neurogenesis in Smo cKO mice leads to increased anxiety/depression-like behaviors without affecting general locomotor function or spatial and fear-related learning. Importantly, we also show that NSCs with a cKO of SHH signaling abolishes stroke-induced neurogenesis in Smo cKO mice. Compared to control mice, Smo cKO mice also show delayed motor function recovery and increased anxiety level after stroke. Our data highlights the essential role of Smo function in regulating adult neurogenesis and emotional behaviors during both aging and CNS injury such as stroke.