Transcranial ultrasound stimulation relieves depression in mice with chronic restraint stress

Objective. Exhaustion of Serotonin (5-hydroxytryptamine, 5-HT) is a typical cause of the depression disorder's development and progression, including depression-like behaviors. Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique treating various neurodegenerative diseases. This study aims to investigate whether TUS ameliorates depression-like behaviors by restoring 5-HT levels. Methods. The depression model mice are established by chronic restraint stress (CRS). Ultrasound waves (FF = 1.1 MHz, PRF = 1000 Hz, TBD = 0.5 ms, SD = 1 s, ISI = 1 s, and DC = 50%) were delivered into the dorsal raphe nucleus (DRN) for 30 min per day for 2 weeks. Depression-like behavior changes are evaluated with the sucrose preference and tail suspension tests. Liquid chromatography-mass spectrometry is performed to quantitatively detect the concentration of 5-HT in the DRN to explore its potential mechanism. The effectiveness and safety of TUS were assessed by c-Fos immunofluorescence and hematoxylin and eosin (HE) staining, respectively. Results. Three weeks after CRS, 22 depressive mice models were screened by sucrose preference index (SPI). After 2 weeks of ultrasound stimulation of the DRN (DRN-TUS) in depressive mice, the SPI was increased (p = 0.1527) and the tail suspension immobility duration was significantly decreased (p = 0.0038) compared with the non-stimulated group. In addition, TUS significantly enhances the c-Fos (p = 0.05) positive cells' expression and the 5-HT level (p = 0.0079) in the DRN. Importantly, HE staining shows no brain tissue damage. Conclusion. These results indicate that DRN-TUS has safely and effectively improved depression-like behaviors including anhedonia and hopelessness, potentially by reversing the depletion of 5-TH. Significance TUS may provide a new perspective on depression therapy, possibly through restoring monoamine levels.