Itch-specific brain circuit and dopaminergic gene polymorphisms influencing individual differences in itch perception

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Abstract Itch is a global health problem, affecting tens of millions of people. The brain plays a crucial role in itch perception; thus the specific circuit for itch processing in the brain has the potential to become a therapeutic target for itch in a wide range of pruritic diseases. Our understanding about the brain mechanism of itch has advanced in the past decades. Previous studies identified a key brain circuit related to itch, which includes the ascending pathway projecting from the thalamus to the posterior insular cortex (pIC) and networks originating from the pIC. In addition, dopamine was found to be a key neurotransmitter associated with itch. These achievements have also identified two important topics that must be understood to develop effective itch treatment targeting the brain. First, the brain circuit of itch is similar to that of pain, though itch and pain are clearly distinct sensations. An itch-specific ascending pathway and network have not yet been identified within the circuit (an itch-specific circuit). Second, there could be dopaminergic gene polymorphisms that determine individual differences in itch perception. If such polymorphisms are identified, brain imaging studies focusing on these genes can identify key loci regulating itch perception within the itch-specific circuit. This line of work will eventually enable us to develop brain-based, tailored itch treatment. To this end, it is crucial to identify an itch- specific circuit and dopaminergic gene polymorphisms influencing individual differences in itch perception. Our research proposal will address this significant gap. Aims 1 and 2 will use fMRI to determine an itch-specific ascending pathway and network by comparing brain activity between itch and pain stimuli. Aim 3 will use our novel method for quantitatively assessing genetic impacts on itch to identify dopaminergic gene polymorphisms that influence individual differences in itch perception. Success of our project will eventually lead to the development of brain-based tailored itch treatment, which will advance the treatment of chronic itch regardless of the underlying etiology.