ACC to dorsal medial striatum inputs modulate histaminergic itch sensation

Abstract

Itch is an unpleasant sensation that initiates scratching behavior. The itch–scratch reaction is a complex phenomenon that implicates supraspinal structures required for regulation of sensory, emotional, cognitive, and motivational aspects. However, the central mechanisms underlying the processing of itch and the interplay of the supraspinal regions and spinal cord in regulating itch–scratch processes are poorly understood. Here, we have shown that the neural projections from anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) constitute a critical circuit element for regulating itch-related behaviors in the brains of male C57BL/6J mice. Moreover, we demonstrate that ACC-DMS projections selectively modulate histaminergic, but not nonhistaminergic, itch-related behavior. Furthermore, photoactivation ofACC-DMSprojectionshasalsonosignificanteffectsonpainbehaviorinducedbythermal,mechanical,andchemicalstimuliexceptforarelief on inflammatory pain evoked by formalin and complete Freund’s adjuvant. We further demonstrate that the dorsal spinal cord exerts an inhibitoryeffectonitchsignalfromACC-DMSprojectionsthroughB5-Ineurons,whichrepresentapopulationofspinalinhibitoryinterneurons that mediate the inhibition of itch. Therefore, this study presents the first evidence that the ACC-DMS projections modulate histaminergic itch-related behavior and reveals an interplay between the supraspinal and spinal levels in histaminergic itch regulation.