@article{d8f817a75c6444dfa31f7f2105a1fb7c,
title = "A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward",
abstract = "Nociceptin and its receptor are widely distributed throughout the brain in regions associated with reward behavior, yet how and when they act is unknown. Here, we dissected the role of a nociceptin peptide circuit in reward seeking. We generated a prepronociceptin (Pnoc)-Cre mouse line that revealed a unique subpopulation of paranigral ventral tegmental area (pnVTA) neurons enriched in prepronociceptin. Fiber photometry recordings during progressive ratio operant behavior revealed pnVTAPnoc neurons become most active when mice stop seeking natural rewards. Selective pnVTAPnoc neuron ablation, inhibition, and conditional VTA nociceptin receptor (NOPR) deletion increased operant responding, revealing that the pnVTAPnoc nucleus and VTA NOPR signaling are necessary for regulating reward motivation. Additionally, optogenetic and chemogenetic activation of this pnVTAPnoc nucleus caused avoidance and decreased motivation for rewards. These findings provide insight into neuromodulatory circuits that regulate motivated behaviors through identification of a previously unknown neuropeptide-containing pnVTA nucleus that limits motivation for rewards.",
keywords = "NOPR, motivation, neuropeptide, nociceptin, opioid, optogenetics, orphanin FQ, photometry, reward, ventral tegmental area",
author = "Parker, {Kyle E.} and Pedersen, {Christian E.} and Gomez, {Adrian M.} and Spangler, {Skylar M.} and Walicki, {Marie C.} and Feng, {Shelley Y.} and Stewart, {Sarah L.} and Otis, {James M.} and Ream Al-Hasani and McCall, {Jordan G.} and Kristina Sakers and Bhatti, {Dionnet L.} and Copits, {Bryan A.} and Gereau, {Robert W.} and Thomas Jhou and Kash, {Thomas J.} and Dougherty, {Joseph D.} and Stuber, {Garret D.} and Bruchas, {Michael R.}",
note = "Funding Information: We thank Dr. Ilya Monosov (Washington University) and Dr. Paul Philips (U. Washington) for helpful insights and discussion. This work was supported by Mallinckrodt Professorship, Hope Center for Neurological Studies (NIH P30 Blueprint Core for Viruses) and the NIH (R37DA033396 to M.R.B, R21DA034929 to M.R.B. R00DA038725 to R.A.H. 2T32DA007261-26, T32EB014856). The Dougherty lab is supported by NARSAD Independent Investigator grant from the Brain and Behavior Research Foundation and NIH (5U01MH109133, T32GM008151). Stuber lab is supported by NIH (R37DA032750 and R01DA038168 to G.D.S. and F32DA041184). Support was also provided by the Hope Center Viral Vectors Core and the Genome Technology Resource Center at Washington University in St. Louis (NIH P30CA91842 and UL1TR000448). K.E.P. C.E.P. and A.M.G. designed and performed experiments, collected and analyzed data, and wrote the manuscript. C.E.P. collected and analyzed photometry data. S.M.S. M.C.W. S.Y.F. and R.A.-H. performed experiments and collected data. J.M.O. J.G.M. and B.A.C designed and performed in vitro whole cell recordings. R.W.G. helped design and oversee cell recordings. K.S. and D.L.B. designed and performed TRAP experiments and RNA sequencing. J.D.D. helped design and oversee TRAP experiments. M.R.B. G.D.S. T.J.K. and T.J. facilitated resources for generation of the Pnoc-Cre mouse line. M.R.B. helped design, analyze, oversee experiments, provide resources, and write the manuscript. The authors declare no competing interests. Funding Information: We thank Dr. Ilya Monosov (Washington University) and Dr. Paul Philips (U. Washington) for helpful insights and discussion. This work was supported by Mallinckrodt Professorship, Hope Center for Neurological Studies ( NIH P30 Blueprint Core for Viruses ) and the NIH ( R37DA033396 to M.R.B, R21DA034929 to M.R.B., R00DA038725 to R.A.H., 2T32DA007261-26 , T32EB014856 ). The Dougherty lab is supported by NARSAD Independent Investigator grant from the Brain and Behavior Research Foundation and NIH ( 5U01MH109133 , T32GM008151 ). Stuber lab is supported by NIH ( R37DA032750 and R01DA038168 to G.D.S. and F32DA041184 ). Support was also provided by the Hope Center Viral Vectors Core and the Genome Technology Resource Center at Washington University in St. Louis ( NIH P30CA91842 and UL1TR000448 ). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = jul,
day = "25",
doi = "10.1016/j.cell.2019.06.034",
language = "English",
volume = "178",
pages = "653--671.e19",
journal = "Cell",
issn = "0092-8674",
number = "3",
}