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Bonus of Excellence - The emergence of a circuit model for addiction

English title Bonus of Excellence - The emergence of a circuit model for addiction
Applicant Lüscher Christian
Number 170266
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 01.10.2016 - 30.09.2019
Approved amount 1'008'000.00
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Keywords (3)

cocaine; synapses; addiction

Lay Summary (French)

Lead
Drogues, synapses et circuits: vers un nouveau modèle de l'addiction.
Lay summary

Ce projet a pour but la compréhension des réseaux dans le cerveau qui contrôle le comportement motivé. L'idée est alors de tester comment les drogues addictives comme la cocaïne et l'héroïne changent leur fonction.

De nombreux travaux de notre laboratoire et d'autres indiquent maintenant que le processus de la maladie commence par une forte activation du système de récompense en libérant des quantités excessives de dopamine. Dans un deuxième temps, cela modifie la communication entre les cellules nerveuses. Ce processus est appelé la plasticité synaptique.

Notre recherche pourra ouvrir des portes à de nouvelles approches translationnelles, car la plasticité synaptique induite pas les drogues est réversible. Nous établissons des protocoles de stimulation électrique appropriés pour rétablir la communication normale et effacer le comportement adaptatif liée à la drogue.

Direct link to Lay Summary Last update: 24.10.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Aberrant habit formation in the Sapap3-knockout mouse model of obsessive-compulsive disorder
Hadjas Lotfi C., Lüscher Christian, Simmler Linda D. (2019), Aberrant habit formation in the Sapap3-knockout mouse model of obsessive-compulsive disorder, in Scientific Reports, 9(1), 12061-12061.
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.
The Molecular Basis of Drug Addiction: Linking Epigenetic to Synaptic and Circuit Mechanisms
Nestler Eric J., Lüscher Christian (2019), The Molecular Basis of Drug Addiction: Linking Epigenetic to Synaptic and Circuit Mechanisms, in Neuron, 102(1), 48-59.
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.
Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement
CorreJulie, van ZessenRuud, LoureiroMichaël, PatriarchiTommaso, TianLin, PascoliVincent, LüscherChristian (2018), Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement, in eLife, 1.
Homeostatic Plasticity in the Hippocampus Facilitates Memory Extinction
Mendez Pablo, Stefanelli Thomas, Flores Carmen E., Muller Dominique, Lüscher Christian (2018), Homeostatic Plasticity in the Hippocampus Facilitates Memory Extinction, in Cell Reports, 22(6), 1451-1461.
Temporally precise labeling and control of neuromodulatory circuits in the mammalian brain
Lee Dongmin, Creed Meaghan, Jung Kanghoon, Stefanelli Thomas, Wendler Daniel J, Oh Won Chan, Mignocchi Neymi Layne, Lüscher Christian, Kwon Hyung-Bae (2017), Temporally precise labeling and control of neuromodulatory circuits in the mammalian brain, in Nature Methods, 14(5), 495-503.

Associated projects

Number Title Start Funding scheme
149985 Drug-evoked synaptic plasticity of excitatory and inhibitory transmission in mouse models of addiction 01.10.2013 Project funding (Div. I-III)
149985 Drug-evoked synaptic plasticity of excitatory and inhibitory transmission in mouse models of addiction 01.10.2013 Project funding (Div. I-III)
186266 Cellular determinants of subthalamic nucleus function 01.06.2019 Sinergia
154411 Dopamine receptor-associated proteins (DRAPs): From D1 and D2 receptor proteomes to brain functions 01.10.2014 Sinergia

Abstract

We hypothesize that addiction constitutes a syndrome of reinforcement and negative affect that is driven by drug-evoked plasticity at specific synapses in the mesolimbic dopamine system. Here we will focus on the ventral pallidum, which, according to our preliminary data, may constitute a hub integrating reinforcement and aversion. Identification and characterization of drug-evoked synaptic plasticity may enable to design stimulation protocols to restore normal transmission at identified synapses, which may erase specific adaptive behaviors, in the quest to establishing links of causalities. We will test this hypothesis by carrying out the following aims:1.We will characterize cocaine evoked synaptic plasticity in the VP, a downstream target of D1 and D2R expressing medium spiny neurons of the nucleus accumbens. 2. We will monitor behavioral sensitization and hedonic taste perception and motivation as adaptive behaviors reflecting incentive saliency and negative affect.3. We will establish reversal protocols to establish links of causality between changes in synaptic plasticity and drug-adaptive behavior. A successfully completion of the present project will constitute an important step forward in the establishment of a comprehensive circuit model of drug addiction, which will open the door for novel, rational therapeutic strategies, such as deep brain stimulation.
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