ACC to dorsal medial striatum inputs modulate histaminergic itch sensation

Itch is an unpleasant sensation that initiates scratching behavior. Itch-scratch reaction is a complex phenomenon whose occurrence 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 identified 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 brain of male C57BL/6J mice. Moreover, we demonstrate that ACC-DMS projections selectively modulate histaminergic, but not nonhistaminergic itch-related behavior. And photoactivation of ACC-DMS projections has also no significant effects on pain behavior induced by thermal, mechanical and chemical stimuli except for a relief on inflammatory pain evoked by formalin and Complete Freund9s adjuvant (CFA). We further demonstrate that the dorsal spinal cord exerts an inhibitory effect on itch signal from ACC-DMS projections through B5-I neurons, which represent a population of spinal inhibitory interneurons that mediate the inhibition of itch. Thus, this study has presented the first evidence that the ACC-DMS projections modulate histaminergic itch-related behavior and revealed an interplay between the supraspinal and spinal levels in histaminergic itch regulation. Significance Statement This study reveals that the projections from anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) constitute a supraspinal circuit for modulation of histaminergic but not nonhistaminergic itch. Manipulation of ACC-DMS projections has no effect on acute pain sensation. And the dorsal spinal cord exerts an inhibitory effect on itch signal from ACC-DMS projections through B5-I neurons. Dissecting the supraspinal itch circuits is of great significance in the development of new therapies for the chronic itch-related intractable diseases.