Low-intensity focused ultrasound stimulation on the hippocampus improved CSDS-induced neuroinflammation through the Notch1 signaling pathway
Yi Luo, Kaixuan Luo, Xiaofan Zhang, Xiangjun Feng, Lei Lei, Shu Cheng, Fanyuan Meng, Xuan Xu, Moxian Chen, Lijuan Ao
Journal of Affective Disorders 2025 · 10.1016/j.jad.2025.119793
Abstract
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.
Abstract via europepmc.
Exposures
Exposure 1: LIFU, right hippocampus
Target: hippocampus — “right hippocampus”
Device: not reported
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,000 | ✓✓✓ |
| Pulse duration (ms) | 0.125 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 800 | ✓✓✓ |
| Duty cycle (%) | 10pulse duration × PRF gives 10% | ✓✓✓ |
| Sonication duration (s) | 1 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Pressure, domain unspecified (kPa) | 134 | ✓✓✓⚑ |
Daily 15 min sessions for 7 consecutive days; 1 s sonication, 4 s inter-stimulus interval, 1 MHz, PRF 800 Hz, DC 10 %, tone burst duration 0.125 ms, acoustic pressure 0.134 MPa.
Flags from extraction
n_subjects— Main CSDS+LIFU group n = 10; a prophase c-Fos experiment also had a LIFU group of n = 3 (text lists Sham group n = 3 twice), so total exposed may be 13. Figure 4 legend gives CSDS + LIFU n = 9.exposures[0].unspecified_domain.pressure_kpa— Pressure given as acoustic pressure 0.134 MPa; hydrophone calibration mentioned but domain not stated.exposures[0].device— No transducer maker or model named (signal generator, amplifier and hydrophone are named).anaesthesia— Anaesthesia state during sonication not stated.direction_of_effect— Mixed readouts: c-Fos increased, depression-like behaviour and inflammatory markers reduced.