Project

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Synaptic basis of eating disorders

Applicant Pascoli Vincent
Number 154737
Funding scheme Ambizione
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.02.2015 - 31.01.2018
Approved amount 599'053.00
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Keywords (5)

Synaptic plasticity; Obesity; Eating disorders; Addiction; Dopamine

Lay Summary (French)

Lead
Bases synaptiques des désordres alimentairesLe but du projet est de déterminer si les désordres alimentaires de type boulimie compulsive induisent des modifications des circuits de neurones (plasticité synaptique) identiques à ceux observés chez les rongeurs consommant des drogues d'abus et qui sont responsables des changements comportementaux qui caractérisent l'addiction.
Lay summary

L’augmentation mondiale de la prévalence de l’obésité pourrait être liée à une forme d’addiction à la nourriture dans certains désordres alimentaires. Cette hypothèse est essentiellement basée sur des observations cliniques du comportement humain vis-à-vis de certains types de nourriture et sur des mesures de la consommation compulsive des rongeurs exposés à une nourriture savoureuse, sucrée ou grasse. Ce type d’alimentation semble pouvoir activer le système de récompense, la cible privilégiée des drogues d’abus.

Cette hypothèse attractive n’a cependant pas été évaluée au niveau des mécanismes neuronaux sous-jacents. Les drogues d’abus, comme la cocaïne, activent de façon excessive le système de la dopamine pour induire des changements de la transmission entre les neurones. Cela représente le substrat cellulaire des adaptations comportementales persistantes qui caractérisent l’addiction. D’autres modifications des circuits de neurones et de leurs propriétés dans des régions cérébrales sensibles à la dopamine sont caractéristiques de la consommation de drogues.

Il a été démontré que la consommation de nourriture savoureuse agit sur le système de récompense et induit de façon répétée la libération de dopamine. C’est pourquoi, je propose d’évaluer chez la souris, l’influence de la consommation de nourriture anormalement savoureuse, grasse et sucrée sur la plasticité des circuits neuronaux de la récompense et sur les comportements compulsifs qui en résultent.

Ce projet de recherche va permettre de comprendre comment l’abondance de nourriture trop sucrée et trop grasse peut induire des changements pathologiques des circuits de neurones pouvant conduire certains individus à adopter un comportement d’addiction et éventuellement à l’obésité.
Direct link to Lay Summary Last update: 04.03.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Ribosomal Protein S6 Phosphorylation Is Involved in Novelty-Induced Locomotion, Synaptic Plasticity and mRNA Translation
Puighermanal Emma, Biever Anne, Pascoli Vincent, Melser Su, Pratlong Marine, Cutando Laura, Rialle Stephanie, Severac Dany, Boubaker-Vitre Jihane, Meyuhas Oded, Marsicano Giovanni, Lüscher Christian, Valjent Emmanuel (2017), Ribosomal Protein S6 Phosphorylation Is Involved in Novelty-Induced Locomotion, Synaptic Plasticity and mRNA Translation, in Frontiers in Molecular Neuroscience, 10, 419.
Mesolimbic dopamine neuron stimulation is sufficient for the progression to addiction
Pascoli Vincent (2016), Mesolimbic dopamine neuron stimulation is sufficient for the progression to addiction, in Médecine Science, 32(8-9)((8-9)), 692-698.
Accumbal D1R neurons projecting to lateral hypothalamus authorize feeding.
O’Connor EC Kremer Y Lefort S Harada M Pascoli V Rohner C Luscher C. (2015), Accumbal D1R neurons projecting to lateral hypothalamus authorize feeding., in Neuron, 88, 553-564.
Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology.
Creed M Pascoli V Luscher C (2015), Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology., in Science, 347(6222), 659-664.
Optogenetic dissection of neural circuitry: from synaptic causalities to blue prints for novel treatments of behavioral diseases.
Luscher C Pascoli V Creed M (2015), Optogenetic dissection of neural circuitry: from synaptic causalities to blue prints for novel treatments of behavioral diseases., in Curr. Opin. Neurobiol., 35, 95-100.
Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction.
Pascoli V* Terrier J Hiver A Luscher C (2015), Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction., in Neuron, 88, 1054-1066.
Cell-type specific insertion of GluA2-lacking AMPARs with cocaine exposure leading to sensitization, cue-induced seeking and incubation of craving.
Terrier J Luscher C Pascoli V, Cell-type specific insertion of GluA2-lacking AMPARs with cocaine exposure leading to sensitization, cue-induced seeking and incubation of craving., in Neuropsychopharmacology.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ECNP Congress Talk given at a conference Synaptic basis of cocaine addiction 02.09.2017 Paris, France Pascoli Vincent;
Gordon Research Conference, Excitatory synapses and Brain function Talk given at a conference Synaptic Correlates of Individual Vulnerability for Cocaine Addiction 28.05.2017 Les Diablerets, Switzerland Pascoli Vincent;
NeuroFrance Bordeaux 2017 Talk given at a conference Prefrontal cortex plasticity in mouse models of addiction 17.05.2017 Bordeaux, France Pascoli Vincent;
Giessbach meeting Talk given at a conference Compulsive behavior triggered by mesolimbic dopamine 07.05.2017 Giessbach, Switzerland Pascoli Vincent; Loureiro Michaël;
Giessbach Meeting 2016 Individual talk Compulsive Behavior triggered by mesolimbic dopamine 19.05.2016 Giessbach, Switzerland Pascoli Vincent;
The Assembly and Functions of Neuronal Circuits in Ascona (Switzerland) Poster Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction 27.09.2015 Ascona, Switzerland Pascoli Vincent;
OptoDBS meeting of Geneva (Switzerland) Poster Neuronal and behavioral determinants mediating transition to addiction. 07.05.2015 Geneva, Switzerland Pascoli Vincent;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Brain week Workshop 17.03.2015 Genève, Switzerland Pascoli Vincent;


Awards

Title Year
Pfizer Price 2015

Abstract

Synaptic basis of eating disorders 1. AbstractVincent Pascoli, Dept of Basic Neuroscience, Faculty of Medecine, University of Geneva, Geneva.Background: For some eating disorders, addiction to food has been proposed to underlie the epidemic increase in the prevalence of obesity1,2. Evidence for food addiction has mainly come from rodent models of binge eating3, where it is proposed that highly palatable food, similar to drugs of abuse, hijack the reward system to cause addiction. While appealing, this hypothesis has not been tested at the level of the underlying neural mechanisms. Addictive drugs cause a surge of dopamine, which drives synaptic plasticity in the reward system4,5. Indeed, drug-evoked synaptic plasticity of excitatory transmission onto Nucleus Accumbens (NAc) neurons, which receive dopamine inputs from the Ventral Tegmental Area (VTA), has been specifically linked to drug-adaptive behaviour5-7. Moreover, in the medial Prefrontal Cortex (mPFC, structure that projects to the NAc), hypoexcitability and synaptic alteration of pyramidal neurons are observed only in drug-addicted animals8,9. Excessive stimulation of dopamine receptors seems therefore to be a key trigger in circuit remodeling leading to addiction10. Interestingly, food consumption is rewarding and can repeatedly evoke dopamine transients11. With the support of an Ambizione fellowship, I now propose to branch out from my previous work to test whether highly palatable food can drive dopamine-dependent synaptic circuit adaptations. I hypothesize that excessive stimulation of the dopamine D1 receptor in the NAc and in upstream structures (e.g mPFC) by binge eating of sweet and high caloric food will induce a remodeling of the reward circuit (i.e. synaptic plasticity) that eventually leads to compulsive food consumption (binge eating associated to bulimia nervosa).To test these hypotheses I propose the following specific aims:Aim 1: To set up a model of compulsive consumption of highly palatable food.a. Test the binge eating model and compare it with cocaine self-administrationb. Quantify addiction criteria (compulsivity, resistance to punishment and loss of intake controlc. Select mice showing addiction-related behaviour for high palatable foodAim 2: Evaluate synaptic adaptations in dopaminoceptive neurons.a. Identify dopaminoceptive neurons relevant for food reward circuitb. Characterize synaptic plasticity in rodent model of food addiction ex vivo c. Determine the induction and expression mechanisms of food-evoked synaptic plasticityAim 3: Establish links between adapted synapses and food addicted-behaviours.a. Evaluate the role of dopamine D1R in behavioural alterationsb. Use pathway specific interventions to act on behavioural adaptationc. Compare cocaine and food addiction at the adaptive circuit levelMethods: To tackle the questions raised, I will first adapt the behavioural drug-addiction model in mice to a binge-eating paradigm that models eating disorders. Then, to specifically investigate the role of D1R in the circuit remodeling, a mouse line expressing both D1rD1a-td-tomato and D1-CRE will be created. This will allow stereotactic delivery of either optogenetic effectors to control circuit activity and to activate specific inputs, or anterograde/retrograde tracers to characterize connections between D1R-expressing neurons located in different parts of the reward circuit. Whole cell electrophysiological recording will be performed to evaluate long-lasting changes (synaptic plasticity) evoked by compulsive feeding. Finally, using optogenetic tools to control neurons activity in behaving mice I will test the causality between circuit remodeling and food addiction, which will establish an independent line of research.Expected value: My research project will test the idea that availability of highly palatable and caloric food overstimulates D1R in the reward circuit to trigger addiction-related neuroadaptations. A successful completion of the present proposal will represent a launch pad for an independent career addressing the role of the reward system in food addiction and eventually obesity.References:1.Volkow, N. D., Wang, G.-J., Tomasi, D. & Baler, R. D. The Addictive Dimensionality of Obesity. BPS 73, 811-818 (2013).2.Smith, D. G. & Robbins, T. W. The Neurobiological Underpinnings of Obesity andBinge Eating: A Rationale for Adopting the FoodAddiction Model. BPS 73, 804-810 (2013).3.De Jong, J. W., Vanderschuren, L. J. M. J. & Adan, R. A. H. Towards an Animal Model of Food Addiction. Obes Facts 5, 180-195 (2012).4.Lüscher, C. & Malenka, R. C. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69, 650-663 (2011).5.Pierce, R. C. & Wolf, M. E. Psychostimulant-Induced Neuroadaptations in Nucleus Accumbens AMPA Receptor Transmission. Cold Spring Harbor Perspectives in Medicine 3, a012021-a012021 (2013).6.Pascoli, V., Turiault, M. & Lüscher, C. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature 481, 71-75 (2011).7.Lee, B. R. et al. Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nature Publishing Group (2013).8.Chen, B. T. et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 1-6 (2013).9.Kasanetz, F. et al. Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Molecular Psychiatry 18, 729-737 (2012).10.Baik, J.-H. Dopamine signaling in reward-related behaviors. 1-16 (2013). 11.Rada, P., Avena, N. M. & Hoebel, B. G. Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience 134, 737-744 (2005).
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