One of the fundamental issues in neuroscience is how somatosensory information is processed in the spinal cord, and how maladaptive changes in the spinal circuitry can give rise to chronic pain and itch.! The overall goal of this application is to map the spinal circuits that transmit the light touch modalities that drive mechanical/touch-evoked itch. The discovery that NPY::Cre inhibitory interneurons in the dorsal spinal cord have a selective role in gating mechanical itch has opened up a new avenue for mapping the spinal circuitry for mechanical itch and light touch. Using an innovative genetic epistasis screen, the Goulding lab has recently identified a class of excitatory neurons, the Y1 INs, which are required for the development of mechanical itch. These cells express the neuropeptide Y receptor NPY1R. The experiments in this proposal will use cutting-edge intersectional genetic approaches, combined with rabies virus-based tracings, molecular neuroanatomy, electrophysiological recordings and behavioral testing, to characterize the morphology, cellular properties and connectivity of the Y1 INs, and to define the functional contribution they make to the processing of light touch information. This study will assess the cellular interactions between the Y1 INs and inhibitory NPY::Cre INs, in order to precisely define the inhibitory mechanisms by which the NPY::Cre INs gate mechanical itch and light touch. It will also examine the role that NPY peptide signaling plays in regulating mechanical itch and Y1 IN excitability. Finally, additional genetic epistasis screens will be used to identify other neuronal cell types that are part of the mechanical itch/light touch transduction pathway. These analyses, in addition to providing the first comprehensive analysis of a newly identified spinal pathway for mechanical itch that is distinct from the chemical itch pathway, will provide new insights into the cellular logic of the dorsal horn circuits that process and transmit light touch information.
Developing effective treatments for chronic itch is a major medical challenge. This proposal will identify and functionally dissect the neural circuits in the dorsal spinal cord that transmit and gate mechanical itch, identifying for the first time the excitatory pathway that drives this form of itch and the inhibitory mechanisms that regulate transmission within this pathway. These studies will reveal how changes to the spinal circuitry lead to itch being evoked by innocuous light touch stimuli, and they will generate fundamental biological insights that can be used to develop treatments for chronic itch.
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