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The Endocannabinoid System

Controls Food Intake via Olfactory

ProcessesEdgar Soria-Gómez, Luigi Bellocchio, Leire Reguero, Gabriel Lepousez, Claire Martin, Mounir Bendahmane, Sabine

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 MarsicanoBioNB 4110March 24, 2014

Presented by: Rachel Au and Iha Kaul

Nature Neuroscience

• Founded in May 1998, as subset of the journal Nature

• Impact factor: 15. 251

o Ranked 6th among 251 journals in Neuroscience

• Nature Publishing Group

European Research

Council• An independent body that funds

investigator-driven frontier research in

the EU

• Launched in Feb 2007 by a common

action of the Commission, the

Parliament, and the Council of the

European Union

• Created to provide a new source and

philosophy for competitive funding,

based on peer-reviewed excellence

The Agenda

1. Major Authors

2. Background Information

3. Experiment

a. Distribution of CB1 receptors in the olfactory

system

b. Necessity and sufficiency of CB1 receptors in

the MOB for hyperphagia

c. Circuitry of CB1 and cannabinoid control on

olfaction and feeding

4. Discussion and Implications

Researchers

• Many authors collaborated on this paper, so

we will highlight the important contributors:

• These authors contributed equally to this

work: o Edgar Soria-Gomez

o Luigi Bellocchio

• These authors jointly directed this work: o Pedro Grandes

o Giovanni Marsicano

Edgar Soria-Gomez, PhD.

• PostDoc Position at French

Institute of Health and

Medicine, Neurocentre

Magendie U862

• Universidad Nacional

Autonoma de Mexico

o Neuroscience PhD. Biomedical

Science

o Mexico, Mexico city

http://neurocentre-magendie.academia.edu/edgarsoria

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Luigi Bellocchio, PhD. • PostDoc in Cannabinoid

signaling group, Department of

Biochemistry and Molecular

Biology at Complutense

University, Madrid, Spain

• Magendie Institute, Bordeaux

o Neuroscience PhD.

o Thesis work on role of

endocannabinoid system in food

intake under Dr. Giovanni

Marsicano

http://www.bbm1.ucm.es/cannabis/manuelguzmanequipo_en.htm

Pedro Grandes, PhD.

• Professor of

Anatomy and Human

Embryology in the

Department of

Neurosciences at the

UPV/EHU (University

of the Basque

Country)

• Leioa, Spain

http://www.actualidaduniversitaria.com/2011/12/un-estudio-demuestra-que-la-modulacio%CC%81n-del-sistema-endocannabinoide-puede-ser-efectiva-contra-el-

estre%CC%81s/

Giovanni Marsicano, PhD.

• University of Bordeaux,

Neurocentre Magendie

U862, Bordeaux,

France

• PhD, PostDoc at Max-

Planck Institute Munich

• CR1 level at the

Neurocentre Magendiehttp://www.neurocentre-magendie.fr/NCM_Pages/Equipes/UK_acc_eq_perso_dynamic.php?team=

Marsicano

Overview of the Study• Hunger triggers a set of mechanisms that encourage

feeding, one of which includes increasing sensory

perceptions such as sense of smell.

• CB1 cannabinoid receptors control a circuit that connects the

olfactory bulb to the olfactory cortex.

• Hunger triggers CB1 receptors to activate the olfactory

circuit making it more responsive.

• ⇒ Increased sensitivity to smell during hunger explains food

intake and attraction to food.

Key Terms

• glutamatergic CB1 receptors - CB1 receptors that are

found on neurons that release glutamate

• CB1 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

cannabinoid that is often found in marijuana

Components of the

Olfactory System

http://images.flatworldknowledge.com/stangor/stangor-

fig04_020.jpg

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Connectivity of the

Olfactory System

Squire et al., 2013; Holy, 2010

CB1 Plasticity

Kauer and Malenka, 2007

Past Research

• the endocannabinoid system is an important component of the

central regulation of energy balance, and cannabinoid intoxication

increases food intake (DiPatrizio & Piomelli, 2012; Pagotto et al.,

2006)

• the use of CB1 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

Purpose

To determine the mechanisms in which hunger arouses sensory perceptions, particularly olfaction, and induces increased food intake.

Hypothesis

Cannabinoid activation of glutamatergic type-1 cannabinoid (CB1) receptors control excitatory neurotransmission from centrifugal feedback projections of cortical glutamatergic neurons to the olfactory bulb to determine the efficiency of olfactory processes and food intake in fasted mice.

Test Subjects• Wild-type C57BL/6N mice were used, dark brown mice that are

genetically identical, were used

• All experiments involving mutant mice were littermates, except in

experiments depicted in Figure 4b, where mice were originated

from independent breedings

• male mice, aged 2-5 months, were maintained under standard

conditions with food and water ad libitum

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CB1 receptor expression in

glutamatergic projections to the MOB

Figure 1. a-f: CB1 receptor is expressed in centrifugal glutamatergic

projections to the MOB

CB1 receptor expression in

glutamatergic projections to the MOB

Figure 1. j,k: CB1 receptor is expressed in centrifugal glutamatergic

projections to the MOB

CB1 in the MOB is necessary for

hyperphagia after fasting

Figure 2. a-c: Endocannabinoid signalling in the MOB is activated by

fasting and promotes food intake by dampening glutamatergic

transmission

CB1 in the MOB is necessary for

hyperphagia after fasting

Figure 2. d: Endocannabinoid signalling in the MOB is activated by

fasting and promotes food intake by dampening glutamatergic

transmission

CB1 in the MOB is sufficient for

hyperphagia after fasting

Figure 3: CB1 receptors on GCL-projecting feedback glutamatergic

cortical neurons are necessary for fasting-induced hyperphagie

CB1 in the MOB is sufficient for

hyperphagia after fasting

Figure 4. a,b: CB1 receptors on GCL-projecting feedback

glutamatergic cortical neurons are sufficient for fasting-induced

hyperphagia

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CB1 in the MOB is sufficient for

hyperphagia after fasting

Figure 4. c,d: CB1 receptors on GCL-projecting feedback

glutamatergic cortical neurons are sufficient for fasting-induced

hyperphagia

CB1 controls feeding via olfactory

corticofugal circuits

Figure 5. a,b: Centrifugal glutamatergic transmission in the MOB

mediates fasting-induced food intake and the hyperphagic effect of

THC in C57BL/6N mice

CB1 controls feeding via olfactory

corticofugal circuits

Figure 5. c: Centrifugal glutamatergic transmission in the MOB

mediates fasting-induced food intake and the hyperphagic effect of

THC in C57BL/6N mice

CB1 controls feeding via olfactory

corticofugal circuits

Figure 5. d,e: Centrifugal glutamatergic transmission in the MOB

mediates fasting-induced food intake and the hyperphagic effect of

THC in C57BL/6N mice

CB1 signalling in the MOB couples

olfaction to feeding

Figure 6: CB1 receptor activation decreases olfactory habituation in

fasted mice

CB1 signalling in the MOB couples

olfaction to feeding

Figure 7. a,b,g,h:

CB1 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

C57BL/6N

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CB1 signalling in the MOB couples

olfaction to feeding

Figure 7. c-f: CB1

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

C57BL/6N

Cannabinoids modulate synaptic

activity in the MOB

Figure 8. a,b: CB1 receptors control synaptic activity in the

corticofugal system

Cannabinoids modulate synaptic

activity in the MOB

Figure 8. c,d: CB1 receptors control synaptic activity in the

corticofugal system

Cannabinoids modulate synaptic

activity in the MOB

Figure 8. e-g: CB1 receptors control synaptic activity in the

corticofugal system

The endocannabinoid system controls

fasting-induced food intake via olfactory

processes

Supplementary Figure 9. Schematic representation of the putative

mechanisms mediating the (endo) cannabinoids effects on olfactory

circuits of fasted mice.

Discussion and

Implication of Results• CB1 cannabinoid receptors control a circuit that connects the

olfactory bulb to the olfactory cortex

• Electrophysiological in vivo recordings revealed that

cannabinoids can decrease glutamatergic centrifugal activity

• Hyperphagic doses of exogenous cannabinoids are able to

modulate both olfactory habituation and odor detection.

However, the lack of clear correlations between habituation

and successive food intake in individual mice suggests that

this pharmacological effect might be unrelated to

cannabinoid control of food intake, and instead is related to

olfaction (Detection of low concentration odors was decreased

in Glu-CB1 KO mice)

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Continued...• c-Fos expression study showed the inhibitory effect of CB1

receptor signaling on glu transmission led to decreased

activity in granule cells of the MOB

• Optogenetic electrophysiological recordings demonstrate

that cannabinoids decrease local potentials induced by

centrifugal glu activity onto Inhibitory feedforward granule

cells, which dis-inhibits the mitral cells.

• There may be extensions of this research in studying the

involvement of olfactory processess to different modalities

of stimulated food intake like exposure to palatable food, or

deprevation of specific nutrients or hormonal treatments

Discussion Questions1. What is the connectivity of the AON/APC to the olfactory bulb, and

what are the different cell layers and connectivities of the olfactory

bulb? Describe which cells are excitatory or inhibitory in this circuit.

Make sure to include the epithelial cells, glomeruli, mitral cells, granule

cells, and any others

2. How do CB1 receptors affect glutamate transmission?

3. Describe the effect of THC on the activation of the GCL and how this

affects food intake.

4. How did the authors directly test the effect of cannabinoid signalling on

glutamatergic transmission from the AON/APC to the MOB? What

about this method made it a direct test?

5. In the discussion, the authors mention the possible effect that THC has

on memory processes, and how this might alter odour detection. Do

you think THC’s effect on memory affected the results? Why or why

not?

References

Bellocchio, L. et al. (2010). Bimodal control of stimulated food intake by the endocannabinoid system. Nat. Neurosci. 13: 281-283.

DiPatrizio, NC., Piomelli, D. (2012). The thrifty lipids: endocannabinoids and the neural control of energy conservation. Trends Neurosci. 35: 403-411.

Holy, T. (2010). “Yes! We’re all individuals!”:redundancy in neuronal circuits. Natur Neuroscience. 13: 1306-1307.Kauer, JA., Malenka, RC. (2007) Synaptic plasticity and addiction. Nature Reviews Neuroscience. 8: 844-858. Pagotto, U., Marsciano, G., Cota, D., Lutz, B., Pasquali, R. (2006). The emerging role of the endocannabinoid system in

endocrine regulation and energy balance. Endocr. Rev. 27: 73-100.Soria-Gómez et al. (2013). The endocannabinoid system controls food intake via olfactory processes. Nature Neuroscience.

17(3): 407-415.Squire et al. (2013) Fundamental Neuroscience 4th ed. Elsevier Inc: Waltham, MA. 526.Tart, CT. (1970). Marijuana intoxication common experiences. Nature. 225: 701-704.Wang, ZH., Sun, L., Heinbockel, T. (2012). Cannabinoid receptor-mediated regulation of neuronal activity and signalling in

glomeruli of the main olfactory bulb. J. Neurosci. 32: 8475-8479.