Ketogenic diet attenuates neuroinflammation and restores hippocampal neurogenesis to improve CUMS induced depression-like behavior in mice.

The ketogenic diet (KD) has been proposed as a potential treatment for depression. However, the underlying mechanisms remain poorly understood. This study aimed to evaluate further the effects of KD on chronic unpredictable mild stress (CUMS)-induced depression in mice and investigate the underlying mechanisms. The results demonstrated that KD intervention significantly alleviated CUMS-induced depression-like behaviors, as evidenced by a decrease in immobility time in the forced swimming test and tail suspension test, an increase in distance traveled in the open field test, and a greater preference for sucrose in the sucrose preference test. KD alleviated neuroinflammation by reducing the levels of glial cell activation markers Iba-1 and GFAP, inhibiting the expression of inflammatory factors IL-1β, TNF-α, and COX-2, and suppressing the overactivation of the TLR4/MyD88/NF-κB signaling pathway. Furthermore, KD increased the number of DCX-, BrdU-, and PSD95-positive cells in the hippocampus and enhanced the BDNF/TrkB/CREB and Wnt/β-catenin signaling pathways, thereby promoting hippocampal neurogenesis. These findings suggested that KD alleviated CUMS-induced depression-like behaviors in mice by reducing neuroinflammation, enhancing neurotrophic signaling, and promoting hippocampal neurogenesis, thereby providing a mechanistic basis for its potential as a novel dietary antidepressant therapy.