Asymmetric lateral habenula function and peripheral neural mechanisms in regulating itch-evoked scratching

Itch is an aversive sensory experience inextricably linked to a desire to scratch.^1,2 While recent progress has advanced our understanding of itch sensation and transmission, the neural mechanisms underlying how scratching is sensed and controlled remain largely elusive. Here, we show that the left lateral habenula (LHb), which responds to negatively valent somatosensory stimuli,^3,4,5,6,7,8 preferentially engages and negatively regulates chloroquine (CQ)-evoked itch and scratching. Calcium activity in left LHb neurons increases when scratching is terminated, and their activation is sufficient to suppress itch-evoked scratching in an intensity-dependent manner. Peripheral MrgprD⁺ C-fiber afferents and PIEZO2 are required for scratching-evoked LHb activation and its suppression of scratching behaviors. Collectively, this work establishes a pathway that controls itch-evoked scratching from the periphery to the brain and reveals a novel left-right asymmetry of mammalian LHb functionality.