Sirtuin 1 underlies depression-related behaviors by modulating the serotonin system in the dorsal raphe nucleus in female mice.

Major depressive disorder (MDD) is a primary driver of disability and greatly escalates the worldwide disease burden. Sirtuin 1 (Sirt1), a key regulator of cellular metabolism, is associated with genetic variations in MDD. We investigated how Sirt1 in serotonin (5-HT) neurons within the dorsal raphe nucleus (DRN) in mice affected behaviors associated with depression and susceptibility to stress. Our findings revealed that Sirt1 expression in the DRN was decreased when chronic unpredictable stress was induced in depressed female mice. Additionally, Sirt1 was co-localized with 5-HT neurons within the DRN, and its selective ablation in these neurons have induced depressive phenotypes in female mice but not in males. Adeno-associated virus-mediated knockdown of Sirt1 in adult female mice induced depressive behaviors, whereas Sirt1 overexpression eliminated these behaviors. Moreover, fiber-optic recordings showed a decrease in the neural excitability of 5-HT neurons and 5-HT levels in the DRN after Sirt1 knockdown. Furthermore, we observed that Sirt1 knockdown reduced the expression of tryptophan hydroxylase-2 (Tph2) and phosphorylation levels of extracellular signal-regulated kinase (ERK) and CAMP response element binding protein (CREB). Finally, variable molecular targets regarding immune responses and cytokine productions after Sirt1 knockdown were analyzed via high-throughput RNA-seq analysis of specimens from the DRN. The findings of this study emphasize the importance of Sirt1 for regulating depression-related behaviors in female mice by influencing the activity of 5-HT neurons in the DRN.