Regulation of itch-induced scratching by nucleus accumbens dopamine receptor expressing neurons

Scratching provides transient relief from itch, yet the neural circuit mechanisms that transform scratching into itch relief remain poorly understood. Midbrain dopaminergic neurons and their downstream targets in the lateral shell of the nucleus accumbens (NAc LaSh) are implicated in itch–scratch processing. Previous studies show that pharmacological manipulation of dopamine D1 and D2 receptors in the NAc LaSh alters scratching behavior, but the specific contributions of D1R- and D2R-expressing neurons during acute and chronic itch remain unclear. Here, we show that NAc LaSh D1R and D2R neurons bidirectionally regulate scratching behavior across itch states. NAc LaSh D1R neurons’ activity promotes scratching bouts, whereas NAc LaSh D2R neurons preferentially facilitate scratch termination. Anterograde viral tracing revealed distinct brain-wide projection patterns of NAc LaSh D1R and D2R neurons, which we functionally tested using projection-specific optogenetic manipulations. We found that NAc LaSh D2R neurons terminate scratching by inhibiting neurons in the lateral parabrachial nucleus (LPBN), a key hub for itch processing. Furthermore, dopamine levels in the NAc LaSh were elevated during chronic itch compared with acute itch, suggesting enhanced dopaminergic signaling contributes to persistent scratching. Together, these findings identify circuit mechanisms linking reward pathways to itch regulation.