The Endocannabinoid System Controls Food

4/1/2014
Nature Neuroscience
The Endocannabinoid System
Controls Food Intake via Olfactory
Processes
Edgar 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 Marsicano
BioNB 4110
March 24, 2014
Presented by: Rachel Au and Iha Kaul
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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
Researchers
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Many authors collaborated on this paper, so
we will highlight the important contributors:
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
Edgar Soria-Gomez, PhD.
• PostDoc Position at French
Institute of Health and
Medicine, Neurocentre
Magendie U862
These authors contributed equally to this
work:
o
o
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• 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
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Edgar Soria-Gomez
Luigi Bellocchio
http://neurocentre-magendie.academia.edu/edgarsoria
These authors jointly directed this work:
o
o
Pedro Grandes
Giovanni Marsicano
Universidad Nacional
Autonoma de Mexico
o
o
Neuroscience PhD. Biomedical
Science
Mexico, Mexico city
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4/1/2014
Luigi Bellocchio, PhD.
• PostDoc in Cannabinoid
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signaling group, Department of
Biochemistry and Molecular
Biology at Complutense
University, Madrid, Spain
Magendie Institute, Bordeaux
o
o
http://www.bbm1.ucm.es/cannabis/manuelguzmanequipo_e
n.htm
Neuroscience PhD.
Thesis work on role of
endocannabinoid system in food
intake under Dr. Giovanni
Marsicano
Giovanni Marsicano, PhD.
• University of Bordeaux,
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Neurocentre Magendie
U862, Bordeaux,
France
PhD, PostDoc at MaxPlanck Institute Munich
CR1 level at the
Neurocentre Magendie
http://www.neurocentremagendie.fr/NCM_Pages/Equipes/UK_acc_eq_perso_dynamic.php?team=
Marsicano
Key Terms
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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
Pedro Grandes, PhD.
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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-lamodulacio%CC%81n-del-sistema-endocannabinoide-puede-ser-efectiva-contra-elestre%CC%81s/
Overview of the Study
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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.
Components of the
Olfactory System
http://images.flatworldknowledge.com/stangor/stangorfig04_020.jpg
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Connectivity of the
Olfactory System
CB1 Plasticity
Squire et al., 2013; Holy, 2010
Kauer and Malenka, 2007
Purpose
Past Research
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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)
To determine the mechanisms in which hunger
arouses sensory perceptions, particularly
olfaction, and induces increased food intake.
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
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
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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
CB1 receptor expression in
glutamatergic projections to the MOB
Figure 1. a-f: CB1 receptor is expressed in centrifugal 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 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 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 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
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
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
CB1 signalling in the MOB couples
olfaction to feeding
Figure 6: CB1 receptor activation decreases olfactory habituation in
fasted mice
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
Cannabinoids modulate synaptic
activity in the MOB
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
Figure 8. a,b: CB1 receptors control synaptic activity in the
corticofugal system
Cannabinoids modulate synaptic
activity in the MOB
Cannabinoids modulate synaptic
activity in the MOB
Figure 8. c,d: 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.
Figure 8. e-g: CB1 receptors control synaptic activity in the
corticofugal system
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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 Questions
1. 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: 281283.
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.
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