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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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”.
The authors declare no competing financial interests.
Integrated supplementary information
(a) Representative coronal pictures of fluorescent in situ hybridization (FISH) of CB1 receptor 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).
(a) and (b) 2-AG in the hypothalamus and cerebellum of free-fed (Control) and 24-h fasted C57BL/6-N mice. Source data
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
(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). Source data
(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. Source data
Supplementary Figure 6 Activation of centrifugal glutamatergic transmission to the GCL/MOB by the Gq-DREADD approach.
(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. Source data
Supplementary Figure 7 Absolute exploration data of the olfactory habituation experiments depicted in Figure 6c and d of main text.
(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). Source data
(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). Source data
Supplementary Figure 9 The endocannabinoid system controls fasting-induced food intake via olfactory processes.
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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Soria-Gómez, E., Bellocchio, L., Reguero, L. et al. The endocannabinoid system controls food intake via olfactory processes. Nat Neurosci 17, 407–415 (2014). https://doi.org/10.1038/nn.3647
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