Circuit mechanisms of itch modulation: from physiology to pathology

Abstract

Itch is a distinct somatosensation, evoked by chemical and mechanical pruritogens or psychosomatic factors. It detects harmful sensory stimuli and triggers scratching to remove irritants from the skin. However, chronic itch, which lasts longer than six weeks, is not protective and can severely impair quality of life, often accompanying stress and anxiety. The current prognosis of patients with chronic itch is poor, primarily because we have an incomplete understanding of the neural circuits involved in itch sensation. Over the past three decades, we have gained substantial knowledge about peripheral mechanisms of itch, but an understanding of the underlying brain circuits is still scarce. To address this, we employed advanced neural circuits dissecting techniques such as viral tracing, chemogenetics, optogenetics, and fiber photometry to investigate how the brain modulates itch under negative states, such as pain, or stress, and positive experiences such as reward or pleasure. My thesis is divided into three parts, each focusing on a distinct modulatory mechanism: i. Pain-Induced Suppression of Itch: We investigated the circuitry between the parabrachial nucleus (PBN) and the rostral ventromedial medulla (RVM). While pain is known to suppress itch, the underlying brain circuitry was unclear. We found that sustained pain activates PBNTacr1 neurons, which connect monosynaptically with RVMTacr1 neurons. Chemogenetic activation of these neurons reduces scratching behavior, whereas inhibiting them blocks the pain-induced suppression of itch. RVM neurons project to various brain regions and the spinal cord to modulate itch signalling. ii. Stress modulation of itch: Using TRAP2 mice, which express tamoxifen-inducible Cre recombinase under the c-Fos promoter, we identified stress-sensitive neurons in the lateral hypothalamic area (LHA). The activation of these neurons suppresses acute and chronic itch, while inhibition increases it. Mapping their projections revealed that connections from LHA to the periaqueductal gray (PAG) are specifically involved in stress-related itch modulation. Interestingly, chronic itch causes an increase in the excitability of the stress-sensitive neurons of the LHA. iii. Reward Circuits and Itch: We focused on the D1R-expressing neurons in the lateral shell of the nucleus accumbens (NAc) to determine the role of the dopaminergic system in itch modulation. D1R neuronal activity increases at the start of scratching, and its activity positively correlates with scratching duration. Both acute and chronic itch are processed similarly in the reward circuitry, with scratching linked to dopamine release. Notably, dopamine levels rise during scratching; once a certain change in dopamine concentration is reached, scratching stops. We observed higher dopamine levels in the NAc during chronic itch, which may contribute to the persistent itch-scratch cycle, as the dopamine levels fail to reach the change in dopamine concentration needed to terminate scratching. Together, our findings provide new insights into understanding the neural circuits involved in itch modulation. These insights could guide the development of more effective treatments for chronic itch.