Dynamics and Functional Role of Dopaminergic Neurons in the Ventral Tegmental Area during Itch Processing

Itchiness triggers a strong urge to engage in scratching behavior, which could lead to severe skin or tissue damage in patients with chronic itch. This process is dynamically modulated. However, the neural mechanisms underlying itch modulation remain largely unknown. Here, we report that dopaminergic (DA) neurons in the ventral tegmental area (VTA) play a critical role in modulating itch-induced scratching behavior. We found that the activity of VTA DA neurons was increased during pruritogen-induced scratching behavior in freely moving male mice. Consistently, individual VTA DA neurons mainly exhibited elevated neural activity during itch-induced scratching behavior as demonstrated by in vivo extracellular recording. In behavioral experiments, the transient suppression of VTA DA neurons with the optogenetic approach shortened the pruritogen-induced scratching train. Furthermore, the DA projection from the VTA to the lateral shell of the nucleus accumbens exhibited strong activation as measured with fiber photometry during itch-elicited scratching behavior. These results revealed the dynamic activity of VTA DA neurons during itch processing and demonstrated the modulatory role of the DA system in itch-induced scratching behavior. SIGNIFICANCE STATEMENT Itchiness is an unpleasant sensation that evokes a scratching response for relief. However, the neural mechanism underlying the modulation of itch-evoked scratching in the brain remains elusive. Here, by combining fiber photometry, extracellular recording, and optogenetic manipulation, we show that the dopaminergic neurons in the ventral tegmental area play a modulatory role in itch-evoked scratching behavior. These results reveal a potential target for suppressing excessive scratching responses in patients with chronic itch.