Nicotine exposure in adolescence triggers the activation and subsequent damage of microglia in the dentate gyrus and promotes depression later in life.

Adolescence is a critical period of neuroplasticity during which the brain can be affected by various harmful factors such as nicotine. Nicotine abuse in adolescence can promote depression in adulthood, but the underlying mechanisms are still unknown. The decline of microglia in the hippocampus, triggered by over-activation of microglia, is thought to be an important mechanism for the progression of depression. Since nicotine can also activate microglia, we speculate that the depression-like behavior triggered by nicotine exposure in adolescents may be related to the dynamic changes of microglia in the hippocampus. Our results show that 12 days of nicotine exposure during adolescence, followed by 28 days of nicotine withdrawal, triggered depression-like behavior and impaired neurogenesis in the hippocampus of adult mice, accompanied by a significant decrease of microglia in the dentate gyrus, which might be due to pyroptosis triggered by their early activation and proliferation. Pre-treatment with minocycline before the start of nicotine stimulation, which suppressed the initial activation of microglia, simultaneously prevented the depression-like behavior and the impairment of neurogenesis and microglia in the dentate gyrus. Restoration of microglia function by injection of an innate immune system stimulant, lipopolysaccharide (LPS, 100 μg/kg), reversed the depression-like behavior and decreased neurogenesis induced by nicotine exposure in adolescents. These results demonstrate a novel role of microglia in depression-like behavior induced by adolescent nicotine exposure and suggest that enhancing the function of microglia in the hippocampus may be a potential strategy for the treatment of depression induced by adolescent nicotine exposure.