Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus

Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by environmental influences, and functionally implicated in behavioural responses to stress and antidepressants1-4. However, how adult-born neurons regulate dentate gyrus information processing to protect from stress-induced anxiety-like behaviour is unknown. Here we show in mice that neurogenesis confers resilience to chronic stress by inhibiting the activity of mature granule cells in the ventral dentate gyrus (vDG), a subregion that is implicated in mood regulation. We found that chemogenetic inhibition of adult-born neurons in the vDG promotes susceptibility to social defeat stress, whereas increasing neurogenesis confers resilience to chronic stress. By using in vivo calcium imaging to record neuronal activity from large cell populations in the vDG, we show that increased neurogenesis results in a decrease in the activity of stress-responsive cells that are active preferentially during attacks or while mice explore anxiogenic environments. These effects on dentate gyrus activity are necessary and sufficient for stress resilience, as direct silencing of the vDG confers resilience whereas excitation promotes susceptibility. Our results suggest that the activity of the vDG may be a key factor in determining individual levels of vulnerability to stress and related psychiatric disorders.