Targeting the Medial Prefrontal Cortex with Transcranial Focused Ultrasound Alleviates Adolescent Sleep-Deprivation-Induced Persistent Postsurgical Pain in Adulthood.

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 (mPFCGlu) 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 mPFCGlu 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 mPFCGlu hypoactivity and normalizes aberrant network-level gamma oscillations and spike-gamma phase locking. Collectively, our findings suggest that adolescent SD precipitates adult PPSP via mPFCGlu 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.