Low-intensity focused ultrasound stimulation on the hippocampus improved CSDS-induced neuroinflammation through the Notch1 signaling pathway.

Exploring compensations for the limitations of current depression treatments holds significant social and clinical value. Low-intensity focused ultrasound (LIFU) is a promising emerging non-invasive therapy for the treatment of depression. Chronic social defeat stress (CSDS) is a validated rodent model of depression. In this study, we investigated the therapeutic effects of seven consecutive days of LIFU stimulation on the right hippocampus of CSDS mice. We observed that LIFU intervention significantly improved the behavioral performance of male CSDS mice in both the forced swim test and open field test, indicating alleviation of depression-like and anxiety-like behaviors. Mechanistically, this behavioral improvement was accompanied by a notable promotion of neurogenesis in the dentate gyrus (DG) of the hippocampus-a brain region critical for emotional regulation and stress response. Concurrently, in vivo experiments revealed that LIFU intervention induced a marked reduction in the protein levels of key components of the Notch1 signaling pathway (Notch1, Jagged1, and Hes1), as well as downstream pro-inflammatory mediators nuclear factor-κB (NF-κB) and interleukin-6 (IL-6). These findings suggest that LIFU suppresses neuroinflammation through inhibition of the Notch1 pathway, which may subsequently facilitate neurogenesis and drive behavioral recovery. Collectively, our results establish a mechanistic framework linking hippocampus-targeted LIFU stimulation, neuroinflammatory modulation, and neurogenesis, providing strong preclinical evidence for its translational potential as a novel therapeutic modality for mood disorders.