4/1/2014 Nature Neuroscience The Endocannabinoid System • Founded in May 1998, as subset of the journal Controls Food Intake via Olfactory Nature Processes • Impact factor: 15. 251 Edgar Soria-Gómez, Luigi Bellocchio, Leire Reguero, Gabriel Lepousez, Claire Martin, Mounir Bendahmane, Sabine o Ranked 6th among 251 journals in Ruehle, Floor Remmers, Tiffany Desprez, Isabelle Matias, Theresa Wiesner, Astrid Cannich, Antoine Nissant, Aya Wadleigh, Hans-Christian Pape, Anna Paola Chiarlone, Carmelo Quarta, Daniéle Verrier, Peggy Vincent, Federico Massa, Beat Lutz, Manuel Guzmán, Hirac Gurden, Guillaume Ferreira, Pierre-Marie Lledo, Pedro Grandes & Giovanni Marsicano BioNB 4110 Neuroscience March 24, 2014 • Nature Publishing Group Presented by: Rachel Au and Iha Kaul European Research Council The Agenda • An independent body that funds 1. Major Authors investigator-driven frontier research in 2. Background Information the EU 3. Experiment • Launched in Feb 2007 by a common a. Distribution of CB1 receptors in the olfactory action of the Commission, the system Parliament, and the Council of the b. Necessity and sufficiency of CB1 receptors in European Union the MOB for hyperphagia • Created to provide a new source and c. Circuitry of CB1 and cannabinoid control on olfaction and feeding philosophy for competitive funding, 4. Discussion and Implications based on peer-reviewed excellence Researchers Edgar Soria-Gomez, PhD. • Many authors collaborated on this paper, so • PostDoc Position at French we will highlight the important contributors: Institute of Health and Medicine, Neurocentre • These authors contributed equally to this Magendie U862 work: • Universidad Nacional o Edgar Soria-Gomez o Luigi Bellocchio Autonoma de Mexico • These authors jointly directed this work: http://neurocentre-magendie.academia.edu/edgarsoria o Neuroscience PhD. Biomedical Science o Pedro Grandes o Mexico, Mexico city o Giovanni Marsicano 1
4/1/2014 Luigi Bellocchio, PhD. Pedro Grandes, PhD. • PostDoc in Cannabinoid • Professor of signaling group, Department of Anatomy and Human Biochemistry and Molecular Embryology in the Biology at Complutense Department of University, Madrid, Spain • Magendie Institute, Bordeaux Neurosciences at the UPV/EHU (University o Neuroscience PhD. of the Basque o Thesis work on role of Country) http://www.actualidaduniversitaria.com/2011/12/un-estudio-demuestra-que-la- modulacio%CC%81n-del-sistema-endocannabinoide-puede-ser-efectiva-contra-el- endocannabinoid system in food • Leioa, Spain http://www.bbm1.ucm.es/cannabis/manuelguzmanequipo_e estre%CC%81s/ n.htm intake under Dr. Giovanni Marsicano Giovanni Marsicano, PhD. Overview of the Study • Hunger triggers a set of mechanisms that encourage • University of Bordeaux, feeding , one of which includes increasing sensory Neurocentre Magendie perceptions such as sense of smell. U862, Bordeaux, • CB1 cannabinoid receptors control a circuit that connects the France • PhD, PostDoc at Max- olfactory bulb to the olfactory cortex. Planck Institute Munich • Hunger triggers CB1 receptors to activate the olfactory • CR1 level at the circuit making it more responsive. Neurocentre Magendie • ⇒ Increased sensitivity to smell during hunger explains food http://www.neurocentre- magendie.fr/NCM_Pages/Equipes/UK_acc_eq_perso_dynamic.php?team= Marsicano intake and attraction to food. Components of the Key Terms Olfactory System • glutamatergic CB 1 receptors - CB 1 receptors that are found on neurons that release glutamate • CB 1 receptors - type-1 cannabinoid receptors that are inhibitory on glutamatergic neurons • centrifugal glutamatergic neurons/projections - project from the brain/cortex outwards • NMDA receptors - excitatory receptors that induce glutamate release on glutamatergic neurons • hyperphagia - excessive hunger or increased appetite • hypophagia - reduction in feeding • THC - tetrahydrocannabinol, an exogenous http://images.flatworldknowledge.com/stangor/stangor- cannabinoid that is often found in marijuana fig04_020.jpg 2
4/1/2014 Connectivity of the Olfactory System CB 1 Plasticity Squire et al., 2013; Holy, 2010 Kauer and Malenka, 2007 Purpose Past Research • the endocannabinoid system is an important component of the To determine the mechanisms in which hunger central regulation of energy balance, and cannabinoid intoxication increases food intake (DiPatrizio & Piomelli, 2012; Pagotto et al., arouses sensory perceptions, particularly 2006) olfaction, and induces increased food intake. • the use of CB 1 receptor KO from cortical glutamatergic neurons in the telencephalon revealed that (endo)cannabinoid-dependent control of excitatory neurotransmission from cortical glutamatergic neurons is necessary to promote fasting-induced food intake (Bellocchio et al., 2010) • cannabinoid drugs alter sensory perception, including olfaction (Tart, 1970; Wang et al., 2012), suggesting a potential link between these two effects of brain (endo)cannabinoid signalling Hypothesis Test Subjects • Wild-type C57BL/6N mice were used, dark brown mice that are Cannabinoid activation of glutamatergic type-1 genetically identical, were used • cannabinoid (CB 1 ) receptors control excitatory All experiments involving mutant mice were littermates, except in experiments depicted in Figure 4b, where mice were originated neurotransmission from centrifugal feedback from independent breedings • projections of cortical glutamatergic neurons male mice, aged 2-5 months, were maintained under standard conditions with food and water ad libitum to the olfactory bulb to determine the efficiency of olfactory processes and food intake in fasted mice. 3
4/1/2014 CB 1 receptor expression in CB 1 receptor expression in glutamatergic projections to the MOB glutamatergic projections to the MOB Figure 1. a-f: CB 1 receptor is expressed in centrifugal glutamatergic Figure 1. j,k: CB 1 receptor is expressed in centrifugal glutamatergic projections to the MOB projections to the MOB CB 1 in the MOB is necessary for CB 1 in the MOB is necessary for hyperphagia after fasting hyperphagia after fasting Figure 2. a-c: Endocannabinoid signalling in the MOB is activated by Figure 2. d: Endocannabinoid signalling in the MOB is activated by fasting and promotes food intake by dampening glutamatergic fasting and promotes food intake by dampening glutamatergic transmission transmission CB 1 in the MOB is sufficient for CB 1 in the MOB is sufficient for hyperphagia after fasting hyperphagia after fasting Figure 3: CB 1 receptors on GCL-projecting feedback glutamatergic Figure 4. a,b: CB 1 receptors on GCL-projecting feedback cortical neurons are necessary for fasting-induced hyperphagie glutamatergic cortical neurons are sufficient for fasting-induced hyperphagia 4
4/1/2014 CB 1 in the MOB is sufficient for CB 1 controls feeding via olfactory hyperphagia after fasting corticofugal circuits Figure 4. c,d: CB 1 receptors on GCL-projecting feedback Figure 5. a,b: Centrifugal glutamatergic transmission in the MOB glutamatergic cortical neurons are sufficient for fasting-induced mediates fasting-induced food intake and the hyperphagic effect of hyperphagia THC in C57BL/6N mice CB 1 controls feeding via olfactory CB 1 controls feeding via olfactory corticofugal circuits corticofugal circuits Figure 5. c: Centrifugal glutamatergic transmission in the MOB Figure 5. d,e: Centrifugal glutamatergic transmission in the MOB mediates fasting-induced food intake and the hyperphagic effect of mediates fasting-induced food intake and the hyperphagic effect of THC in C57BL/6N mice THC in C57BL/6N mice CB 1 signalling in the MOB couples CB 1 signalling in the MOB couples olfaction to feeding olfaction to feeding Figure 6: CB 1 receptor activation decreases olfactory habituation in Figure 7. a,b,g,h: fasted mice CB 1 receptor signalling in the MOB enhances olfactory detection in fasted mice and proportionally promotes food intake. Exploration of increasing concentrations of an odor under vehicle or THC treatment in 5
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