1. Medicine
  2. Neuroscience
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Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

  1. Alex Reichenbach
  2. Rachel E Clarke
  3. Romana Stark
  4. Sarah H Lockie
  5. Mathieu Mequinion
  6. Harry Dempsey
  7. Sasha Rawlinson
  8. Felicia Reed
  9. Tara Sepehrizadeh
  10. Michael DeVeer
  11. Astrid C Munder
  12. Juan Nunez-Iglesias
  13. David Spanswick
  14. Randall Mynatt
  15. Alexxai V Kravitz
  16. Christopher V Dayas
  17. Robyn Brown
  18. Zane B Andrews  Is a corresponding author
  1. Monash University, Australia
  2. Pennington Biomedical Research Center, United States
  3. Washington University in St. Louis, United States
  4. University of Newcastle, Australia
  5. University of Melbourne, Australia
Research Article
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Cite this article as: eLife 2022;11:e72668 doi: 10.7554/eLife.72668

Abstract

Agouti-related peptide (AgRP) neurons increase motivation for food, however whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat) in mice. We hypothesized that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 minutes in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-6, Figure 1 - Figure Supplement 1&2, Figure 6 - Figure Supplement 1

Article and author information

Author details

  1. Alex Reichenbach

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3520-8341
  2. Rachel E Clarke

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Romana Stark

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Sarah H Lockie

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Mathieu Mequinion

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Harry Dempsey

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5117-6995
  7. Sasha Rawlinson

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Felicia Reed

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Tara Sepehrizadeh

    Monash Biomedical Imaging Facility, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Michael DeVeer

    Monash Biomedical Imaging Facility, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Astrid C Munder

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Juan Nunez-Iglesias

    Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. David Spanswick

    Department of Physiology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  14. Randall Mynatt

    Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Baton Rouge, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Alexxai V Kravitz

    Departments of Psychiatry, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5983-0218
  16. Christopher V Dayas

    School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
    Competing interests
    The authors declare that no competing interests exist.
  17. Robyn Brown

    Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  18. Zane B Andrews

    Department of Physiology, Monash University, Clayton, Australia
    For correspondence
    zane.andrews@monash.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9097-7944

Funding

National Health and Medical Research Council (1126724)

  • Zane B Andrews

National Health and Medical Research Council (1154974)

  • Zane B Andrews

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were conducted in compliance with the Monash University Animal Ethics Committee guidelines (MARP 17855).

Reviewing Editor

  1. Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States

Publication history

  1. Received: July 30, 2021
  2. Accepted: January 11, 2022
  3. Accepted Manuscript published: January 12, 2022 (version 1)

Copyright

© 2022, Reichenbach et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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