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Cell. 2019 Jul 25;178(3):653-671.e19. doi: 10.1016/j.cell.2019.06.034.

A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward.

Author information

1
Departments of Anesthesiology, Division of Basic Research, Anatomy and Neurobiology, and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA.
2
Departments of Anesthesiology, Division of Basic Research, Anatomy and Neurobiology, and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
3
Departments of Anesthesiology, Division of Basic Research, Anatomy and Neurobiology, and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA; Neuroscience Program (DBBS), Washington University School of Medicine, St. Louis, MO, USA.
4
Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
5
Departments of Anesthesiology, Division of Basic Research, Anatomy and Neurobiology, and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO, USA; Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO, USA; Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.
6
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
7
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
8
Department of Pharmacology and Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
9
Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA; Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA.
10
Departments of Anesthesiology, Division of Basic Research, Anatomy and Neurobiology, and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA; Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mbruchas@uw.edu.

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

PMID:
31348890
DOI:
10.1016/j.cell.2019.06.034

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