Stepwise engagement of cingulate ensembles underlies motivational decline in chronic pain.

Abstract

Chronic pain can progress from sensory hypersensitivity to impaired motivation, but the underlying circuit mechanisms remain unclear. Using whole-brain activity-dependent tagging, projection-specific perturbations, in vivo Ca2+ imaging, and single-unit recordings in male mice, we identify stage-dependent engagement of anterior cingulate cortex (ACC) circuits during neuropathic pain. ACC neurons projecting to the basolateral amygdala (BLA) are preferentially engaged early, respond to allodynic stimulation, and contribute to mechanical hypersensitivity, whereas neurons projecting to the lateral habenula (LHb) are engaged later and contribute to impaired effortful persistence. Within the ACC→LHb pathway, complementary functional classes represent momentary response vigor and slower session progression, with persistence-related coding preferentially disrupted after nerve injury. Anteromedial thalamic input is biased toward ACC→BLA neurons, while recurrent ACC-BLA-ACC signaling provides a candidate route to later ACC→LHb dysfunction. These findings reveal a temporally organized cingulate circuit framework for the sensory and effort-related consequences of persistent pain.