Thèse Étude du Potentiel Thérapeutique de la Stimulation Cérébrale Profonde du Pallidum Ventral pour l'Alcoolodépendance. H/F - 38

Établissement : Université Grenoble Alpes
École doctorale : CSV- Chimie et Sciences du Vivant
Laboratoire de recherche : Grenoble Institut des Neurosciences
Direction de la thèse : Yvan VACHEZ ORCID 0000000150162751
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-04-09T23:59:59

L'addiction à l'alcool est une maladie caractérisée par une consommation compulsive malgré ses conséquences négatives. Les approches actuelles de stimulation cérébrale profonde (SCP) ciblant le noyau subthalamique (NST) montrent une efficacité limitée et des effets psychiatriques secondaires, en raison de la complexité de sa connectivité. Ce projet vise à identifier une nouvelle cible de SCP, spécifique à un circuit neuronal, en explorant le rôle de la voie reliant le pallidum ventral (PV) au NST ventromédian (NSTvm) dans la consommation compulsive d'alcool. Nos données préliminaires montrent que l'alcool diminue l'excitabilité du NSTvm. À l'aide d'un modèle de rat reproduisant l'usage compulsif d'éthanol, 1) nous déterminerons par electrophysiologie ex vivo (patch clamp) si l'activité de la voie PV-NST est exacerbée chez les individus compulifs; 2) nous testerons si l'inhibition chémogénétique de cette voie permet de réduire la consommation compulsive, 3) nous évaluerons si la SCP du PV permet également de réduire ces comportements pathologique. Ce projet apportera des connaissances clés sur les mécanismes neuronaux de l'addiction et ouvrira la voie à des thérapies de neuromodulation plus ciblées et plus sûres.

More than 300 million people suffer from Alcohol use disorder (AUD) worldwide, a pathology that encompasses a broad spectrum of health, social and economic problems with various degrees of severity1. The most severe form is frequently referred to as alcohol addiction, a chronic relapsing disease occurring in only a subset of vulnerable users2. It is notably characterized by compulsive alcohol use, that is the continuation of seeking and drinking alcohol despite having significant negative consequences3. While neuroscientists have identified a plethora of potential effectors involved in AUD, efficient therapeutic strategies and treatments are lacking, mainly due to the poor understanding of the psychobiological mechanisms underlying the shift from controlled to compulsive alcohol seeking and taking. At the neural system level, the subthalamic nucleus (STN) is pivotal for the control of compulsive behaviors4, mainly through its role in behavioral inhibition5. The ventromedial territory of the STN (vmSTN), considered as the limbic part of the STN, is of particular importance for the etiopathology of compulsive behaviors. Loss of vmSTN activity occludes cancelation of aberrant action13,14, and correlate with impulse control disorders in patients15. Conversely and importantly, increased activity of STN region has been described as protective against alcohol use relapse in patients16.
In this context, STN deep brain stimulation (STN-DBS) holds promise for addiction treatments6,7. However, the reported efficacy seems limited8 and deleterious psychiatric side effects are commonly observed9. This overall mixed outcome is likely due to the extreme small size of the STN and its high degree of connectivity. Indeed despite its smallness, the STN and more specifically the vmSTN receive connections from numerous structures, including key nuclei processing different limbic processes and motivation10. While STN-DBS cannot target a specific connection between one of these structures and the vmSTN, viral approaches with contemporary neuromodulation technics as optogenetic or chemogenetic permit this specificity in animal models. These approaches, combined with electrophysiology recordings also allows the investigation of transmission and plasticity of specific brain circuits11. Thus, we propose first to elucidate how alcohol use alters vmSTN circuits and how these adaptations drive the shift from controlled to compulsive alcohol use, the hallmark of alcohol addiction. Next, we aim at leveraging this characterization of vmSTN circuits adaptation by identifying a new DBS target.

Because a decrease of vmSTN activity appears to be potentially critical for compulsive alcohol use and because this decrease of activity can be driven by an imbalance of the excitation and inhibition activity from vmSTN inputs, the overall aims of this project are:

1) Test if alcohol use decreases the activity of the vmSTN and alter the excitation/inhibition in favor of inhibition
2) Identify the vmSTN input responsible for this imbalance and characterize the effects of alcohol use on this circuit activity
3) Elucidate if the neuromodulation of this circuit can reduce alcohol use, in particular compulsive use.
4) Test the therapeutic potential of DBS of this identified input to treat alcohol addiction.

Déterminer les mécanismes neurbiologiques, neuronaux et synpatiques de d'addiction à l'alcool, et cibler cés mécanismes avec la stimulation cérébrale profonde pour traiter l'addiction

Comportement sur rongeurs
Chirurgie stéréotaxique
Patch clamp
Stimulation cérébrale profonde
Chémogénétique