Targeting the Medial Prefrontal Cortex with Transcranial Focused Ultrasound Alleviates Adolescent...

Adolescent sleep deprivation (SD) increases latent vulnerability to pain, a major risk factor for persistent postsurgical pain (PPSP) in adulthood, yet the underlying mechanisms remain unclear. Given the limitations of current pharmacological treatments, noninvasive transcranial focused ultrasound (TFUS) offers a promising neuromodulatory alternative; however, its therapeutic efficacy for PPSP remains unknown. Here, we utilized a mouse model of adolescent SD followed by an adult plantar incision to elucidate how early sleep loss drives long-term PPSP and to systematically investigate the therapeutic potential and underlying mechanisms of TFUS. By integrating resting-state functional magnetic resonance imaging, chemogenetics, and behavioral assays, we demonstrated that medial prefrontal cortex glutamatergic (mPFC^Glu) hypoactivity mediates this SD-driven PPSP development. To evaluate TFUS intervention, we first screened various stimulation paradigms and identified that 200-Hz pulse repetition frequency TFUS optimally activated mPFC^Glu neurons and effectively alleviated PPSP. Mechanistically, guided by single-nucleus RNA sequencing, we found that TFUS activates the mechanosensitive transient receptor potential channel 5 (TRPC5) to promote Homer1-dependent glutamatergic synaptic plasticity. This molecular cascade subsequently ameliorates mPFC^Glu hypoactivity and normalizes aberrant network-level gamma oscillations and spike-gamma phase locking. Collectively, our findings suggest that adolescent SD precipitates adult PPSP via mPFC^Glu dysfunction and that TFUS alleviates this condition through an integrated pathway linking molecular mechanosensation to network rhythm recovery. These results offer a novel therapeutic paradigm and provide a mechanistic foundation for developing noninvasive TFUS strategies to manage PPSP in vulnerable patients.