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Metabolic-sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

Alex Reichenbach, Rachel E Clarke, Romana Stark, Sarah Haas Lockie, Mathieu Mequinion, Felicia Reed, Sasha Rawlinson, Harry Dempsey, Tara Sepehrizadeh, Michael DeVeer, Astrid C Munder, Juan Nunez-Iglesias, David C. Spanswick, Randall Mynatt, Alexxai V. Kravitz, Christopher V. Dayas, Robyn Brown, View ORCID ProfileZane B. Andrews
doi: https://doi.org/10.1101/2021.03.22.436393
Alex Reichenbach
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
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Rachel E Clarke
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
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Romana Stark
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
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Sarah Haas Lockie
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
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Mathieu Mequinion
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
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Felicia Reed
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
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Sasha Rawlinson
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
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Harry Dempsey
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
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Tara Sepehrizadeh
2Monash Biomedical Imaging Facility, Monash University, Clayton 3800, Victoria, Australia
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Michael DeVeer
2Monash Biomedical Imaging Facility, Monash University, Clayton 3800, Victoria, Australia
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Astrid C Munder
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
3Florey Institute of Neuroscience & Mental Health, Parkville 3052, Victoria, Australia
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Juan Nunez-Iglesias
5Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, Victoria, Australia
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David C. Spanswick
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
9Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
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Randall Mynatt
6Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA
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Alexxai V. Kravitz
8Departments of Psychiatry, Anesthesiology, and Neuroscience, Washington University in St Louis, St Louis, MO, US
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Christopher V. Dayas
7School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, NSW, Australia
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Robyn Brown
3Florey Institute of Neuroscience & Mental Health, Parkville 3052, Victoria, Australia
4Department of Biochemistry and Pharmacology, University of Melbourne, Parkville 3010, Victoria, Australia
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Zane B. Andrews
1Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton 3800, Victoria, Australia
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  • ORCID record for Zane B. Andrews
  • For correspondence: Zane.Andrews@monash.edu
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ABSTRACT

Hunger increases the motivation of an organism to seek out and consume highly palatable energy dense foods. While hunger-sensing Agouti-related peptide (AgRP) neurons influence this process, whether metabolic detection of homeostatic state via metabolic sensing in AgRP neurons potentiates motivation through the midbrain dopamine system is unexplored. Here, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat), a metabolic enzyme regulating glucose and fatty acid oxidation, as a model of impaired metabolic-sensing in AgRP neurons. We then tested the hypothesis that appropriate metabolic-sensing in AgRP neurons is required to increase food reward motivation by modulating accumbal or striatal dopamine release. Electrophysiological studies confirm that Crat deletion in AgRP neurons (KO) impairs normal ex vivo glucose-sensing, and in vivo photometry experiments show that AgRP neurons in KO mice do not exhibit normal responses to repeated palatable food presentation and consumption, highlighting that this model is appropriate to test the hypothesis. Fiber photometry experiments, using the dopamine sensor GRAB-DA, revealed that impaired metabolic-sensing reduces acute dopamine release (seconds) in the nucleus accumbens, but not the dorsal striatum, to palatable food consumption and during operant responding. Positron electron tomography (PET) methods indicated that impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ∼30 minutes in the dorsal striatum but not the ventral striatum, suggesting a role for AgRP neurons to restrict a long term post-ingestive dopamine response in the dorsal striatum. Finally, impaired metabolic-sensing in AgRP neurons suppresses motivated operant responding for sucrose rewards. Notably, these behavioural effects are potentiated in the hungry state and therefore highlight that metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 22, 2021.
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Metabolic-sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum
Alex Reichenbach, Rachel E Clarke, Romana Stark, Sarah Haas Lockie, Mathieu Mequinion, Felicia Reed, Sasha Rawlinson, Harry Dempsey, Tara Sepehrizadeh, Michael DeVeer, Astrid C Munder, Juan Nunez-Iglesias, David C. Spanswick, Randall Mynatt, Alexxai V. Kravitz, Christopher V. Dayas, Robyn Brown, Zane B. Andrews
bioRxiv 2021.03.22.436393; doi: https://doi.org/10.1101/2021.03.22.436393
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Metabolic-sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum
Alex Reichenbach, Rachel E Clarke, Romana Stark, Sarah Haas Lockie, Mathieu Mequinion, Felicia Reed, Sasha Rawlinson, Harry Dempsey, Tara Sepehrizadeh, Michael DeVeer, Astrid C Munder, Juan Nunez-Iglesias, David C. Spanswick, Randall Mynatt, Alexxai V. Kravitz, Christopher V. Dayas, Robyn Brown, Zane B. Andrews
bioRxiv 2021.03.22.436393; doi: https://doi.org/10.1101/2021.03.22.436393

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