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Emergence of compulsion in a mouse model of addiction

English title Emergence of compulsion in a mouse model of addiction
Applicant Lüscher Christian
Number 189188
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 01.10.2019 - 30.09.2023
Approved amount 1'397'665.00
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Keywords (2)

Optogenetics; Drug addiction

Lay Summary (French)

Lead
Dans ce projet, nous cherchons à identifier les circuits neuronaux qui sous-tendent la compulsion dans l'addiction.
Lay summary
L'addiction est une maladie dévastatrice sans traitement. Les observations cliniques et de nombreuses recherches ont démontré qu'il s'agit d'une maladie du comportement où les sujets prennent des décisions de manière compulsive malgré les conséquences négatives.

Les cellules neurales dans une partie du cerveau appelée striatum sont responsables de la prise de décision dans les conditions physiologiques. Nous étudions comment ces circuits sont modifiés lorsque la personne prend de la cocaïne. Etant donné que toutes les drogues qui entraînent une dépendance augmentent la dopamine dans le système de récompense, nous avons établi un nouveau modèle original de dépendance, dans lequel nous pouvons stimuler directement les cellules nerveuses qui produisent la dopamine.

Lors d'expériences préliminaires, nous avons constaté que certaines souris devenaient compulsives alors que d'autres non. Nous aimerions comprendre comment apparaît cette différence.
Direct link to Lay Summary Last update: 07.10.2019

Lay Summary (English)

Lead
In this project, we aim at identifying the neural circuits that underlie compulsion in addiction.
Lay summary
Drug addiction is a devastating disease without cure. Clinical observations and much research has demonstrated that addiction is a disease of pathological behavior where the subject compulsively makes decisions despite major negative consequences.

Neural cells in a part of the brain called striatum is responsible for decision making under physiological conditions. We now study how these circuits are altered when the individual takes cocaine. As all addictive drugs increase dopamine in the reward system, we have established a novel, original model of addiction where a mouse can directly stimulate the nerve cells that produce dopamine. 

In preliminary experiments we found that some mice become compulsive, while others do not. We would like to understand how this difference emerges.
Direct link to Lay Summary Last update: 07.10.2019

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
186266 Cellular determinants of subthalamic nucleus function 01.06.2019 Sinergia

Abstract

Background and rationale: Compulsion is a defining symptom of addiction that emerges in a fraction of drug users. Much clinical literature has established that even for highly addictive drugs, such as cocaine, only 20% of users will eventually develop a compulsive drug use with complete loss of control. We have implemented an original mouse model of drug addiction based on optogenetic dopamine neuron self-stimulation (oDASS) of the ventral tegmental area (VTA), which reproduces the bimodal distribution of compulsive behavior. We have further identified synaptic plasticity in the projection from the orbito-frontal cortex (OFC) to the dorsal striatum (DS) as the neural correlate of compulsion. Here we now ask the question what is different in the brain of a subject that drives the transition from recreational, controlled drug use towards compulsive consumption despite negative consequences. In other words we will examine how compulsion is induced and why only a subset of users are touched. We posit that life-experience shapes behavioral endophenotypes that predict enhanced addiction vulnerability, by facilitating synaptic plasticity in the prefrontal cortex (mPFC and OFC) that ultimately drives compulsion.We predict that synaptic alterations found in addicted mice are a result of staged forms of synaptic plasticity and neural activity starting in the nucleus accumbens (NAc) and eventually reaching the dorsal striatum (DS), following the spiralling anatomical connectivity of the midbrain-striatal system. We will focus on plasticity of the top-down control of the spiral by mPFC and OFC. The proposed project will harness advanced circuit investigation with cutting edge technology: machine learning assisted analysis of behavior and in vivo calcium imaging with single cell resolution, both of which are now established in the Lüscher lab. Much preliminary data provide proof of feasibility for all aims and proof of face validity for the oDASS. We are confident that our multidisciplinary approach at the frontiers of modern neurosciences carries the potential for groundbreaking results to answer this key question in addiction research. Unraveling the behavior and neural basis of individual vulnerability may impact current prevention strategies, spur investigations on related disorders and shape future therapies.In an attempt to experimentally falsify the above hypothesis, we propose the following aims: Aim1.Identify behavioral traits that have predictive value for addiction in the oDASS model.Aim2.Identify the locus and mechanism of induction of circuit adaptations driving compulsive oDASS. Aim3.Validate key results obtained with oDASS in a model of cocaine-self administration.Methods & expected results: Aim1: We will use a motion-sequencing (mo-seq) analysis to characterize spontaneous behavior and the effect of life experience manipulation (social isolation, selective serotonin reuptake inhibitor, SSRI, treatment) to search for syllables that correlate with the development of compulsive behavior in our bona-fide addiction model. Aim2: We will characterize mPFC and OFC afferents and efferents using anatomical, electrophysiological as well as functional calcium imaging approaches in vitro and in vivo with the goal to identify the induction mechanism of plasticity in the neurons that drive the compulsion. Aim3: We will test efficient circuit interventions on a model of cocaine self-administration to confirm the face validity of oDASS. Impact: Individual vulnerability is a key observation in addiction, which can only be understood by dissecting the underlying molecular, cellular and systems mechanisms. The present project with its ambitious implementation of cutting edge technology of modern neurosciences may yield results that address this fundamental question. Identifying the behavioral and cellular markers predicting the transition to addiction will provide the framework to test their implication in human addicts. Last but not least, by identifying the circuit alterations underlying compulsive drug use, our results may inspire novel prevention strategies and rational addiction treatments.
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