Neuropathic pain drives time-dependent reorganization of naturalistic movement and corticostriatal circuits
Journal:
bioRxiv
Published Date:
Oct 8, 2026
Abstract
Chronic pain fundamentally alters sensorimotor behavior and naturalistic movement, leading to debilitating changes in quality of life. While human neuroimaging studies suggest that chronic pain leads to functional changes in the dorsal striatum (DStr), a region imperative for shaping action selection and movement patterns, most preclinical studies have focused on ventral striatums role in reward and motivation, leaving critical questions about DStr circuitry and chronic pain-related behavior unresolved. Furthermore, the reliance on standard evoked reflexive assays misses the persistent, complex behavioral adaptations most relevant to patient wellbeing. Here, we combine machine learning for detailed, automated behavioral characterization with in vivo fiber photometry and ex vivo synaptic physiology in the spared nerve injury (SNI) mouse model of chronic pain. Through this longitudinal approach, we identified specific functional changes in DStr circuitry that define distinct temporal stages of chronic pain progression. At 3 weeks post-injury, a critical "transition phase", patch clamp recordings revealed transiently depressing synaptic inputs from primary sensory cortex (S1) to D2-expressing spiny projection neurons (SPNs). Concurrently, unsupervised machine learning demonstrated that behavioral syntax, the structure and sequencing of movement, diverged most sharply during this 3-week window. Conversely, by the late chronic phase at 12 weeks, longitudinal photometry revealed a profound reorganization of D1-SPNs around naturalistic behaviors like grooming and rearing. These findings uncover a pathway-specific corticostriatal mechanism for pain chronification, identifying the DStr as a key mediator of pain-induced movement reorganization and highlighting the 3-week transition phase as a critical therapeutic window to intervene in the progression of chronic pain.
