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The endocannabinoid system controls food intake via olfactory processes.

By February 9, 2014June 3rd, 2021No Comments
 2014 Feb 9. doi: 10.1038/nn.3647. [Epub ahead of print]

The endocannabinoid system controls food intake via olfactory processes.

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.
PMID:

24509429
[PubMed – as supplied by publisher] nature neuroscience

At a glance

Figures

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  1. CB1 receptor is expressed in centrifugal glutamatergic projections to the MOB.
    Figure 1
  2. Endocannabinoid signaling in the MOB is activated by fasting and promotes food intake by dampening glutamatergic transmission.
    Figure 2
  3. CB1 receptors on GCL-projecting feedback glutamatergic cortical neurons are necessary for fasting-induced hyperphagia.
    Figure 3
  4. CB1 receptors on GCL-projecting feedback glutamatergic cortical neurons are sufficient for fasting-induced hyperphagia.
    Figure 4
  5. Centrifugal glutamatergic transmission in the MOB mediates fasting-induced food intake and the hyperphagic effect of THC in C57BL/6N mice.
    Figure 5
  6. CB1 receptor activation decreases olfactory habituation in fasted mice.
    Figure 6
  7. CB1 receptor signaling in the MOB enhances olfactory detection in fasted mice and proportionally promotes food intake.
    Figure 7
  8. CB1 receptors control synaptic activity in the corticofugal system.
    Figure 8
  9. Expression of CB1 receptor mRNA in olfactory areas.
    Supplementary Fig. 1
  10. Tissue levels of anandamide
    Supplementary Fig. 2
  11. Trypan blue injection in the MOB.
    Supplementary Fig. 3
  12. CB1 receptor semi-quantification
    Supplementary Fig. 4
  13. Supplementary Fig. 5
  14. Activation of centrifugal glutamatergic transmission to the GCL/MOB by the Gq-DREADD approach.
    Supplementary Fig. 6
  15. Absolute exploration data of the olfactory habituation experiments depicted in Figure 6c and d of main text.
    Supplementary Fig. 7
  16. Supplementary Fig. 8
  17. The endocannabinoid system controls fasting-induced food intake via olfactory processes.
    Supplementary Fig. 9

right

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Author information

Primary authors

  1. These authors contributed equally to this work.

    • Edgar Soria-Gómez &
    • Luigi Bellocchio

  2. These authors jointly directed this work.

    • Pedro Grandes &
    • Giovanni Marsicano

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

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 financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Supplementary information

Supplementary Figures

  1. Supplementary Figure 1: Expression of CB1 receptor mRNA in olfactory areas. (425 KB)
    (a) Representative coronal pictures of fluorescent in situ hybridization (FISH) of CB1receptor mRNA expression (red) in the MOB. (b-f) Detailed analysis of CB1 receptor mRNA in different layers of the MOB. In wild-type mice (n=3), CB1 mRNA (green) is co-expressed with mRNA coding for tyrosine hydroxylase (TH, red, b) and GAD 65 (red, c) in the glomerular layer (GL, white arrows), but very sparse co-localization with GAD 65 was found in the granular cell layer (GCL, white arrows, d). No co-expression with the vesicular glutamate transporter 1 (VGluT1) was detected in any layer (e,f). Note that CB1 mRNA expression is not changed in Glu-CB1–/– mice (n=3) and it is absent in CB1–/– mice (n=3).
  2. Supplementary Figure 2: Tissue levels of anandamide (53 KB)
    (a) and (b) 2-AG in the hypothalamus and cerebellum of free-fed (Control) and 24-h fasted C57BL/6-N mice.
  3. Supplementary Figure 3: Trypan blue injection in the MOB. (181 KB)
    The volume and rate of injection was exactly the same as for intra-MOB pharmacological treatments. Note the restriction of diffusion to the granule cell layer of the MOB. GCL, granule cell layer; GL, glomerular layer; MCL, mitral cell layer
  4. Supplementary Figure 4: CB1 receptor semi-quantification (31 KB)
    (a) in the IPL of CB1-flox AAV-Ctrl (AAV-Ctrl) and AON/APC-CB1–/– mice (CB1-flox AAV-Cre). (b) Correlation between the levels of CB1 protein expression in the IPL and food intake in CB1-flox-AAV-Ctrl (black symbols) and AON/APC-CB1–/– mice (blue symbols).
  5. Supplementary Figure 5: (167 KB)
    (a,b) Expression of the CB1 receptor protein in the AON (a) and the hippocampus (b) of wild-type (WT, n=3), Stop-CB1 (n=3), CB1-RS (n=3) and Glu-CB1-RS mice (n=3). Note the absence of CB1 receptor protein in Stop-CB1 mice and its complete rescue in global CB1-RS mice. According to the low levels of CB1 receptors on cortical glutamatergic neurons, Glu-CB1-RS mice display only slightly above-background staining. The presence of abundant CB1 receptor protein in the inner molecular layer of the dentate gyrus (b) and in the GCL/MOB (compare with Figure 4a of main text) confirms the presence of abundant receptors at terminals of hippocampal mossy cells, and at terminals of centrifugal feedback projections of olfactory cortical areas. (c) Percentage of increase in food intake of CB1-RS, Glu-CB1-RS and AON-CB1-RS mice as compared to respective Stop-CB1 mice.
  6. Supplementary Figure 6: Activation of centrifugal glutamatergic transmission to the GCL/MOB by the Gq-DREADD approach. (251 KB)
    (a) Representative coronal pictures of the anterior olfactory nucleus (AON) and the main olfactory bulb (MOB) from mice injected in the AON with rAAV CaMK-DREAAD-mCherry. Due to the expression of DREADD-mCherry exclusively at somatic level, the fluorescent signal is detected only in the AON and not in the MOB, where infected neurons project (compare with Figure 5c of main text). (b) Phospo-CREB immunohistochemistry in mice injected with rAAV CaMK-DREAAD in the AON and injected with saline (veh) or 1 mg/kg of CNO 30 minutes before sacrifice. Note the activation of both MOB and AON (dotted lines) following DREADD stimulation with CNO. (c) Food intake in control mice injected with rAAV CaMK-mCherry in the AON (AON-mCherry) after administration of saline (VEH) or 1mg/kg CNO.
  7. Supplementary Figure 7: Absolute exploration data of the olfactory habituation experiments depicted in Figure 6c and d of main text. (82 KB)
    (a,b) The inhibitory effect of THC on olfactory habituation is abolished in Glu-CB1–/– mice (a) and by local intra-MOB injection of DCS (b).
  8. Supplementary Figure 8: (66 KB)
    (a) Food intake and AUC of odor detection threshold values after different doses of THC or (b) URB597. Note that positive correlations between food intake and olfactory detection were found only with the hyperphagic doses of THC (1mg/kg) and URB597 (10mg/kg).
  9. Supplementary Figure 9: The endocannabinoid system controls fasting-induced food intakevia olfactory processes. (135 KB)
    Schematic representation of the putative mechanisms mediating the (endo)cannabinoids effects on olfactory circuits of fasted mice. Under basal conditions (left picture), low endocannabinoid activation of CB1 receptors on centrifugal terminals contributes maintaining a certain level of activity of inhibitory granule cells (orange cloud) in the GCL/MOB, thereby likely providing basal levels of olfactory activity (small nose purple cloud) and food intake (small food in the thought balloon). Upon fasting (right picture), increased endocannabinoids (green cloud) or THC administration activate CB1 receptors in the GCL/MOB leading to a decrease of centrifugal glutamatergic transmission (blue lines) and eventually to a reduction of GABAergic activity in the GCL. The final impact of these changes is an enhancement of olfactory detection (large nose purple cloud) and hyperphagia (large food in thought balloon). This phenomenon is likely triggered by orexigenic signals associated with fasting (brown arrows). GCL, granule cell layer; GL, glomerular layer; MCL, mitral cell layer; OSN, olfactory sensory neurons.

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