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Drug-evoked synaptic plasticity of excitatory and inhibitory transmission in mouse models of addiction

English title Drug-evoked synaptic plasticity of excitatory and inhibitory transmission in mouse models of addiction
Applicant Lüscher Christian
Number 149985
Funding scheme Project funding (Div. I-III)
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 01.10.2013 - 30.09.2016
Approved amount 942'783.00
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Keywords (5)

Plasticity; Cocaine; Dopamine; Synapse; Addiction

Lay Summary (French)

Lead
Les avancées récentes des neurosciences ont conduit à envisager l'addiction comme un dérèglement des mécanismes d'apprentissage et de la mémorisation qui pousse à la consommation compulsive. Ce changement comportemental est sous-tendu par une malléabilité excessive dela communication entre les cellules nerveuses, en d’autres mots une plasticité synaptique évoquée par les drogues.
Lay summary
Notre laboratoire vise à identifier les mécanismes cellulaires sous-jacents à ces formes d'apprentissages pathologiques.
Basé sur nos précédentes découvertes, nous avons postulé que "la plasticité synaptique suscité par des drogues " est le corrélât neuronal qui peut mener à l'addiction.

Avec le projet actuel, nous étendons ce concept à la large partie du striatum, incluant aussi la transmission inhibitrice et surtout visons à concevoir des stratégies d'inversions pour restaurer la transmission normal avec l'espoir que cela effacera le comportement adaptatif par les drogues.

Les résultats de notre étude renforcera le lien de causalité entre la plasticité synaptique altérée et le comportement addictif avec des implications translationnelles évidentes.

Ce nouveau paradigme ouvre de nouvelles perspectives à explorer dans le domaine de la prévention et du traitement de l’addiction. 

Direct link to Lay Summary Last update: 16.12.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Social transmission of food safety depends on synaptic plasticity in the prefrontal cortex
Loureiro Michaël, Achargui Ridouane, Flakowski Jérôme, Van Zessen Ruud, Stefanelli Thomas, Pascoli Vincent, Lüscher Christian (2019), Social transmission of food safety depends on synaptic plasticity in the prefrontal cortex, in Science, 364(6444), 991-995.
Stochastic synaptic plasticity underlying compulsion in a model of addiction
Pascoli Vincent, Hiver Agnès, Van Zessen Ruud, Loureiro Michaël, Achargui Ridouane, Harada Masaya, Flakowski Jérôme, Lüscher Christian (2018), Stochastic synaptic plasticity underlying compulsion in a model of addiction, in Nature, 564(7736), 366-371.
[Mesolimbic dopamine neuron stimulation is sufficient for the progression to addiction].
Pascoli Vincent, Terrier Jean, Lüscher Christian (2016), [Mesolimbic dopamine neuron stimulation is sufficient for the progression to addiction]., in Medecine sciences : M/S, 32(8-9), 692-6.
Cell-Type Specific Insertion of GluA2-Lacking AMPARs with Cocaine Exposure Leading to Sensitization, Cue-Induced Seeking, and Incubation of Craving.
Terrier Jean, Lüscher Christian, Pascoli Vincent (2016), Cell-Type Specific Insertion of GluA2-Lacking AMPARs with Cocaine Exposure Leading to Sensitization, Cue-Induced Seeking, and Incubation of Craving., in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(7), 1779-89.
Hippocampal Somatostatin Interneurons Control the Size of Neuronal Memory Ensembles.
Stefanelli Thomas, Bertollini Cristina, Lüscher Christian, Muller Dominique, Mendez Pablo (2016), Hippocampal Somatostatin Interneurons Control the Size of Neuronal Memory Ensembles., in Neuron, 89(5), 1074-85.
Optogenetically inspired deep brain stimulation: linking basic with clinical research.
Lüscher Christian, Pollak Pierre (2016), Optogenetically inspired deep brain stimulation: linking basic with clinical research., in Swiss medical weekly, 146, 14278-14278.
SHANK3 controls maturation of social reward circuits in the VTA.
Bariselli Sebastiano, Tzanoulinou Stamatina, Glangetas Christelle, Prévost-Solié Clément, Pucci Luca, Viguié Joanna, Bezzi Paola, O'Connor Eoin C, Georges François, Lüscher Christian, Bellone Camilla (2016), SHANK3 controls maturation of social reward circuits in the VTA., in Nature neuroscience, 19(7), 926-34.
The Emergence of a Circuit Model for Addiction.
Lüscher Christian (2016), The Emergence of a Circuit Model for Addiction., in Annual review of neuroscience, 39, 257-76.
VTA Projection Neurons Releasing GABA and Glutamate in the Dentate Gyrus.
Ntamati Niels R, Lüscher Christian (2016), VTA Projection Neurons Releasing GABA and Glutamate in the Dentate Gyrus., in eNeuro, 3(4), /-/.
Accumbal D1R Neurons Projecting to Lateral Hypothalamus Authorize Feeding.
O'Connor Eoin C, Kremer Yves, Lefort Sandrine, Harada Masaya, Pascoli Vincent, Rohner Clément, Lüscher Christian (2015), Accumbal D1R Neurons Projecting to Lateral Hypothalamus Authorize Feeding., in Neuron, 88(3), 553-64.
Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology.
Creed Meaghan, Pascoli Vincent Jean, Lüscher Christian (2015), Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology., in Science (New York, N.Y.), 347(6222), 659-64.
Optogenetic dissection of neural circuitry: from synaptic causalities to blue prints for novel treatments of behavioral diseases.
Lüscher Christian, Pascoli Vincent, Creed Meaghan (2015), Optogenetic dissection of neural circuitry: from synaptic causalities to blue prints for novel treatments of behavioral diseases., in Current opinion in neurobiology, 35, 95-100.
Sufficiency of Mesolimbic Dopamine Neuron Stimulation for the Progression to Addiction.
Pascoli Vincent, Terrier Jean, Hiver Agnès, Lüscher Christian (2015), Sufficiency of Mesolimbic Dopamine Neuron Stimulation for the Progression to Addiction., in Neuron, 88(5), 1054-66.
Contrasting forms of cocaine-evoked plasticity control components of relapse.
Pascoli Vincent, Terrier Jean, Espallergues Julie, Valjent Emmanuel, O'Connor Eoin Cornelius, Lüscher Christian (2014), Contrasting forms of cocaine-evoked plasticity control components of relapse., in Nature, 509(7501), 459-64.
Firing modes of dopamine neurons drive bidirectional GIRK channel plasticity.
Lalive Arnaud L, Munoz Michaelanne B, Bellone Camilla, Slesinger Paul A, Lüscher Christian, Tan Kelly R (2014), Firing modes of dopamine neurons drive bidirectional GIRK channel plasticity., in The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(15), 5107-14.
Modality-specific thalamocortical inputs instruct the identity of postsynaptic L4 neurons.
Pouchelon Gabrielle, Gambino Frédéric, Bellone Camilla, Telley Ludovic, Vitali Ilaria, Lüscher Christian, Holtmaat Anthony, Jabaudon Denis (2014), Modality-specific thalamocortical inputs instruct the identity of postsynaptic L4 neurons., in Nature, 511(7510), 471-4.
Pathological circuit function underlying addiction and anxiety disorders.
Lüthi Andreas, Lüscher Christian (2014), Pathological circuit function underlying addiction and anxiety disorders., in Nature neuroscience, 17(12), 1635-43.
Retinal input directs the recruitment of inhibitory interneurons into thalamic visual circuits.
Golding Bruno, Pouchelon Gabrielle, Bellone Camilla, Murthy Sahana, Di Nardo Ariel A, Govindan Subashika, Ogawa Masahuro, Shimogori Tomomi, Lüscher Christian, Dayer Alexandre, Jabaudon Denis (2014), Retinal input directs the recruitment of inhibitory interneurons into thalamic visual circuits., in Neuron, 81(5), 1057-69.
Drug-evoked synaptic plasticity causing addictive behavior.
Lüscher Christian (2013), Drug-evoked synaptic plasticity causing addictive behavior., in The Journal of neuroscience : the official journal of the Society for Neuroscience, 33(45), 17641-6.
Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors.
Yuan Tifei, Mameli Manuel, O'Connor Eoin C, O' Connor Eoin C, Dey Partha Narayan, Verpelli Chiara, Sala Carlo, Perez-Otano Isabel, Lüscher Christian, Bellone Camilla (2013), Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors., in Neuron, 80(4), 1025-38.

Associated projects

Number Title Start Funding scheme
132729 Spiraling towards relapse: a network approach to addiction 01.10.2010 Project funding (Div. I-III)
170266 Bonus of Excellence - The emergence of a circuit model for addiction 01.10.2016 Project funding (Div. I-III)
136210 Dopamine receptor associated proteins (DRAPs): From molecular interactions to brain functions 01.10.2011 Sinergia
170266 Bonus of Excellence - The emergence of a circuit model for addiction 01.10.2016 Project funding (Div. I-III)

Abstract

Background: Drug addiction is defined by the compulsive use of a substance despite all negative consequences (WHO definition). The identification of the mechanisms that drive the transition from controlled recreational drug use to compulsive drug consumption and relapse even after prolonged abstinence remains a major challenge in the field of addiction research. During the last grant period, we have developed a model based on the hypothesis that the transition to compulsive drug use is mediated by specific forms of synaptic plasticity, which reshape neural circuits in the mesolimbic system and eventually lead to relapse. Addictive drugs target the ventral tegmental area (VTA) and cause a surge in extracellular dopamine (DA) levels. It is this mesolimbic DA that is permissive for synaptic alterations, which we and others have called “drug-evoked synaptic plasticity”. To understand the effects of addictive drugs on mesolimbic circuit function and ultimately behavior, drug-evoked synaptic plasticity at identified synapses throughout the mesolimbic system must be fully characterized. We must also know what the induction criteria are for plasticity and how it is expressed. An important prerequisite for this work is a comprehensive characterization of the functional anatomy of the mesolimbic system, which is topographically organized as a spiraling circuit between the midbrain and the striatum. Within this spiraling circuit, inhibitory neurons of the nucleus accumbens (NAc) back-project to midbrain neurons that are located more laterally than cells from which NAc neurons receive afferents. There are several such loops until midbrain neurons of the substantia nigra reach the dorsal striatum. Given this spiraling connectivity, the idea has been put forward that a gradual recruitment of more dorsal parts of the striatum may underlie the switch to compulsive drug use in addiction (4). However, synaptic mechanisms that allow for the recruitment of dorsal striatum following repeated drug exposure are not well understood. For example there is growing evidence that drug-adaptive changes also involve GABA transmission, yet the induction criteria and the expression mechanism of drug-evoked synaptic plasticity of inhibitory transmission remain elusive. With the goal to characterize drug-evoked plasticity necessary for addiction related behaviors, we propose the following hypothesis and related aims.Hypothesis: Exposure to addictive drugs evoke synaptic plasticity of both glutamate and GABA transmission in the mesolimbic system. This synaptic trace is not only responsible for the switch to compulsive drug consumption but may also trigger relapse, both of which define addiction. Aims: Using mouse models of addiction related behaviors we propose to:1. characterize the expression mechanism of the NMDA component of drug-evoked synaptic plasticity in DA neurons of the VTA.2. elucidate the molecular mechanisms of drug-evoked synaptic plasticity of GABA transmission at identified synapses in the VTA. 3. resolve the projection specificity of drug-evoked synaptic plasticity in D1R- and D2R-medium spiny neurons of the NAc. Research design: To achieve these aims, we will combine stereotaxic viral injections to express optogenetic effectors in mice that express a Cre-element in specific cell types, with in vitro, ex vivo and in vivo electrophysiology to expand the current description of the functional anatomy of the mesolimbic system. Using optogenetics with ex vivo electrophysiology in acute slices of the VTA and NAc we will investigate identified synapses and determine how exposure to addictive drugs modifies synaptic activity. Our experiments will integrate results ranging from the molecular level to the behavioral level. We will monitor the effects of our interventions looking at subcellular calcium transients and behavior in addiction relevant mouse models, such as cocaine self-administration and cue induced cocaine seeking.Expected value: A successful completion of the present project may narrow the search for mechanism leading to compulsion and relapse. Moreover our experiments with optogenetic effectors may guide the development of novel neuromodulatory protocols in humans to treat addiction (e.g. deep brain stimulation).
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