Abstract

Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor–dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.

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Acknowledgements

We thank D. Gonzales, N. Aubailly and all of the personnel of the Animal Facility of the NeuroCentre Magendie for mouse care and genotyping, A. Desprez for help with the odor task set-up, D. Herrera and S. Rahayel (NutriBrain School 2012) for help with some experiments, all of the members of the Marsicano laboratory for useful discussions, A. Bacci, D. Cota, V. Deroche and M. Valley for critically reading the manuscript, and K. Deisseroth (Stanford University) and B.L. Roth (University of North Carolina) for providing the plasmids coding for ChR2 and DREADD, respectively. This work was supported by INSERM (G.M.), EU-Fp7 (REPROBESITY, HEALTH-F2-2008-223713, G.M.), European Research Council (ENDOFOOD, ERC-2010-StG-260515, G.M.), Fondation pour la Recherche Medicale (FRM-DRM-20101220445, G.M.), Region Aquitaine (G.M.), LABEX BRAIN (ANR-10-LABX-43), Fyssen Foundation (E.S.-G.), EMBO Post-doc Fellowship (L.B.), RTA, I.S. Carlos III (RD12/0028/0004, P.G.), Basque Country Government BCG IT764-13 (P.G.), University of the Basque Country UFI11/41 (P.G.), MINECO BFU2012-33334 (P.G.), Postdoctoral Specialization Contract from the University of the Basque Country UPV/EHU (L.R.), MINECO SAF2012-35759 (M.G.), Deutsche Forschungsgemeinschaft (SFB-TRR 58, B.L. and H.-C.P.), CONACyT (E.S.-G.). The Lledo laboratory is part of the École des Neurosciences de Paris Ile-de-France network, a member of the Bio-Psy Labex and is supported partially by “AG2R-La-Mondiale”.

Author information

Author notes

    • Edgar Soria-Gómez
    •  & Luigi Bellocchio

    These authors contributed equally to this work.

    • Pedro Grandes
    •  & Giovanni Marsicano

    These authors jointly directed this work.

Affiliations

  1. INSERM, U862 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France.

    • Edgar Soria-Gómez
    • , Tifany Desprez
    • , Isabelle Matias
    • , Theresa Wiesner
    • , Astrid Cannich
    • , Aya Wadleigh
    • , Daniéle Verrier
    • , Peggy Vincent
    • , Federico Massa
    •  & Giovanni Marsicano
  2. University of Bordeaux, NeuroCentre Magendie U862, Bordeaux, France.

    • Edgar Soria-Gómez
    • , Tifany Desprez
    • , Isabelle Matias
    • , Theresa Wiesner
    • , Astrid Cannich
    • , Aya Wadleigh
    • , Daniéle Verrier
    • , Peggy Vincent
    • , Federico Massa
    •  & Giovanni Marsicano
  3. Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University and CIBERNED, Madrid, Spain.

    • Luigi Bellocchio
    • , Anna Paola Chiarlone
    •  & Manuel Guzmán
  4. Department of Neurosciences, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain.

    • Leire Reguero
    •  & Pedro Grandes
  5. Laboratory for Perception and Memory, Institut Pasteur, Paris, France.

    • Gabriel Lepousez
    • , Antoine Nissant
    •  & Pierre-Marie Lledo
  6. CNRS UMR 3571, Paris, France.

    • Gabriel Lepousez
    • , Antoine Nissant
    •  & Pierre-Marie Lledo
  7. CNRS UMR 8165, IMNC, Univ. Paris Diderot & Sud, Orsay, France.

    • Claire Martin
    • , Mounir Bendahmane
    •  & Hirac Gurden
  8. Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

    • Sabine Ruehle
    • , Floor Remmers
    •  & Beat Lutz
  9. Institut fuer Physiologie I, Westfaelische Wilhelms-Universitaet, Muenster, Germany.

    • Hans-Christian Pape
  10. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

    • Carmelo Quarta
  11. INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, Bordeaux, France.

    • Guillaume Ferreira

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Contributions

E.S.-G., G.F., P.-M.L. and G.M. designed the experiments. E.S.-G., L.B., L.R., G.L., C.M., M.B., S.R., F.R., T.D., I.M., T.W., A.C., A.N., A.W., A.P.C., D.V. and P.V. performed the experiments. H.-C.P. provided reagents. E.S.-G., L.B., L.R., G.L., F.M., B.L., M.G., C.Q., H.G., G.F., P.-M.L., P.G. and G.M. analyzed the data. E.S.-G., and G.M. wrote the manuscript. All of the authors edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Giovanni Marsicano.

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https://doi.org/10.1038/nn.3647