Chronic itch (pruritis) is a widespread condition that severely diminishes quality of life. However, there are few effective treatments for chronic itch, in part because the neural basis for itch remains poorly understood. Thus, the long-term goal of our research is to gain a better understanding of how itch is encoded in the nervous system at the level of specific neural circuits with the view of developing more effective therapies for pruritis. We previously discovered that the transcription factor Bhlhb5 is required for the surviva of a subset of inhibitory interneurons in the spinal cord (which are here termed B5-I neurons) that are required for normal itch sensation;mice lacking these spinal interneurons suffer from persistent pathological itch. These findings imply that B5-I neurons function to inhibit itch;however, the evidence is merely correlative. In this application we propose to use intersectional genetic strategies to manipulate the activity of B5-I neurons in order to establish cause-and-effect relationships between the activity of B5-I neurons and scratching behavior in mice. Here we propose to test this hypothesis through 3 specific aims: 1) Characterize the Bhlhb5-flpO knockin mouse, a key tool for our dual intersection strategy, and use this mouse together with the Ptf1a-cre line to genetically define B5-I neurons. 2) Investigate the functional response properties of B5-I neurons to natural stimulation of the skin and to confirm the ability of pharmacogenetic approaches to specifically manipulate their activity. 3) Use exocytogenetic and pharmacogenetic approaches to delineate function of B5-I neurons in vivo for itch-mediated scratching behavior. Results from these experiments will begin decoding the neural circuits that underlie itch by enabling us to visualize, characterize, and functionally manipulate B5-I neurons in vitro and in vivo. Moreover, the insight gleaned may have major clinical implications for people that suffer from chronic itch.

Public Health Relevance

Chronic itch (pruritis) is a pervasive health problem for which effective therapies are greatly needed. Our previous studies provided correlative evidence linking the loss of specific neural subtype in the spinal cord with pathological itch in mice. Here we propose to use cutting-edge molecular genetic techniques to label, characterize and manipulate the activity of this key population of neurons with the long term goal of understanding of how itch is encoded in the nervous system at the level of specific neural circuits, thereby identifying therapeutic targets for pruritis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MOSS-D (81))
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Tseng, Hung H
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University of Pittsburgh
Schools of Medicine
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Hachisuka, Junichi; Omori, Yu; Chiang, Michael C et al. (2018) Wind-up in lamina I spinoparabrachial neurons: a role for reverberatory circuits. Pain 159:1484-1493
Hachisuka, Junichi; Chiang, Michael C; Ross, Sarah E (2018) Itch and neuropathic itch. Pain 159:603-609
Cai, Xiaoyun; Huang, Huizhen; Kuzirian, Marissa S et al. (2016) Generation of a KOR-Cre knockin mouse strain to study cells involved in kappa opioid signaling. Genesis 54:29-37
Hachisuka, Junichi; Baumbauer, Kyle M; Omori, Yu et al. (2016) Semi-intact ex vivo approach to investigate spinal somatosensory circuits. Elife 5:
Snyder, Lindsey M; Kuzirian, Marissa S; Ross, Sarah E (2016) An Unexpected Role for TRPV4 in Serotonin-Mediated Itch. J Invest Dermatol 136:7-9
Huang, Huizhen; Kuzirian, Marissa S; Cai, Xiaoyun et al. (2016) Generation of a NK1R-CreER knockin mouse strain to study cells involved in Neurokinin 1 Receptor signaling. Genesis 54:593-601
Cai, Xiaoyun; Kardon, Adam P; Snyder, Lindsey M et al. (2016) Bhlhb5::flpo allele uncovers a requirement for Bhlhb5 for the development of the dorsal cochlear nucleus. Dev Biol 414:149-60
Saloman, Jami L; Scheff, Nicole N; Snyder, Lindsey M et al. (2016) Gi-DREADD Expression in Peripheral Nerves Produces Ligand-Dependent Analgesia, as well as Ligand-Independent Functional Changes in Sensory Neurons. J Neurosci 36:10769-10781
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Kardon, Adam P; Polgár, Erika; Hachisuka, Junichi et al. (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82:573-86

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