Asymmetric Lateral Habenula Function and Peripheral Neural Mechanisms in Regulating Itch-Evoked Scratching

Abstract

Scratch is an evolutionarily conserved behavior inextricably linked to itch. 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 lateral habenula (LHb) asymmetrically processes chloroquine (CQ)-evoked itch and scratching, with the left LHb being preferentially engaged by and negatively regulating scratching. Left LHb calcium activity increases when scratching is terminated, and activation of the left, but not the right, LHb neurons are sufficient to suppress itch-evoked scratching in an intensity-dependent manner.  In the periphery, MrgprD+ C-fiber afferents and PIEZO2 are required for scratching-evoked activation of the LHb and suppression of itch-evoked 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.

Keywords: Scratch, itch, lateral habenula, asymmetric function, sensory afferents, PIEZO2