A neural circuit from thalamic paraventricular nucleus via zona incerta to periaqueductal gray for the facilitation of neuropathic pain

Top-down projections transmit a series of signals encoding pain sensation to the ventrolateral periaqueductal gray (vlPAG), where they converge with various incoming projections to regulate pain. Clarifying the upstream regulatory hierarchy of vlPAG can enhance our understanding of the neural circuitry involved in pain modulation. Here, we show that a in a mouse model of spared nerve injury (SNI), activation of a circuit arising from posterior paraventricular thalamic nucleus CaMKIIα-positive neurons (PVP^CaMKIIα) projects to gamma-aminobutyric acid neurons in the rostral zona incerta (ZIr^GABA) to facilitate the development of pain hypersensitivity behaviors. In turn, these ZIr^GABA neurons project to CaMKIIα-positive neurons in the vlPAG (vlPAG^CaMKIIα), a well-known neuronal population involved in pain descending modulation. In vivo calcium signal recording and whole-cell electrophysiological recordings reveal that the PVP^CaMKIIα→ZIr^GABA→vlPAG^CaMKIIα circuit is activated in SNI models of persistent pain. Inhibition of this circuit using chemogenetics or optogenetics can alleviate the mechanical pain behaviors. Our study indicates that the PVP^CaMKIIα→ZIr^GABA→vlPAG^CaMKIIα circuit is involved in the facilitation of neuropathic pain. This previously unrecognized circuit could be explored as a potential target for neuropathic pain treatment.