Regulation of Circadian Rhythm Disruption in Mice via Transcranial Low-Intensity Focused Ultrasound Stimulation...

Circadian rhythm disruption (CRD) is a critical contributor to sleep, metabolic, and neuropsychiatric disorders. Ultrasound (US) stimulation represents a non-invasive neuromodulatory modality, yet its impact on CRD remains unexplored. This study is the first to propose and systematically assess the effects of transcranial low-intensity focused ultrasound (LIFU) stimulation targeting the suprachiasmatic nucleus (SCN) in a chronic jet lag mouse model. Circadian and anxiety-related behaviors were evaluated through spontaneous locomotor activity monitoring and open field testing. Plasma melatonin and cortisol levels were quantified via ELISA, and neuronal activity in the SCN, dorsomedial hypothalamus (DMH), and subparaventricular zone (SPZ) was assessed using c-Fos immunofluorescence. Results revealed that US stimulation markedly reduced the phase difference in the US-SCN group to -2.6 h, in contrast to -7.15 h in the CJL group, indicating enhanced circadian alignment with the normal control group in the US-SCN. In the US-SCN group, melatonin and cortisol levels significantly decreased from 214.70 $~\pm ~$ 3.54 pg/mL and 217.21 $~\pm ~$ 5.62 pg/mL to 172.45 $~\pm ~$ 10.16 pg/mL (p = 0.001) and 187.35 $~\pm ~$ 2.57 pg/mL (p = 0.002), respectively. Additionally, anxiety-like behaviors were alleviated in the US-SCN group, as evidenced by a 61.40% increase in the time spent exploring the center zone. Neuronal activity in the SCN, DMH, and SPZ was significantly enhanced. Histological analysis confirmed no tissue damage following LIFU stimulation, demonstrating its safety. LIFU stimulation of the SCN effectively alleviates CRD. This non-invasive approach offers a promising therapeutic strategy for CRD and advancing neuromodulation-based chronotherapy.