Thèse le Rôle des Psychédéliques dans la Plasticité Neuronale et le Metabolisme H/F - Doctorat.Gouv.Fr

Établissement : Université Paris Cité École doctorale : Cerveau, cognition, comportement Laboratoire de recherche : Institut de Psychiatrie et Neurosciences de Paris Direction de la thèse : Diana ZALA ORCID 0000000200528011 Début de la thèse : 2026-10-01 Date limite de candidature : 2026-06-01T23:59:59 Les psychédéliques suscitent un regain d'intérêt en raison de leur potentiel thérapeutique dans le traitement de troubles psychiatriques tels que la dépression et l'anxiété. Leur mécanisme d'action, principalement médié par le récepteur sérotoninergique 5-HT2A, implique une plasticité neuronale ainsi qu'un remodelage du cytosquelette.
Cependant, leurs effets au niveau présynaptique restent mal compris, en partie en raison des défis techniques liés à l'étude des boutons synaptiques, qui nécessitent des techniques d'imagerie avancées. Des études récentes montrent que le LSD induit des changements protéomiques distincts, suggérant une adaptation métabolique.
Nos travaux antérieurs ont montré que l'activation du récepteur cannabinoïde de type 1 (CB1) active la voie RhoA/ROCK, provoquant une contractilité cellulaire qui entraîne une rétraction axonale ainsi qu'une réorganisation des vésicules synaptiques. Ce processus dépend de l'ATP d'origine glycolytique et s'accompagne d'une réduction de la respiration mitochondriale.
Nous postulons qu'à l'inverse, les psychédéliques induisent un remodelage opposé du cytosquelette en relâchant les forces contractiles, favorisant ainsi la croissance axonale et synaptique ainsi que la polymérisation de l'actine. Comme pour les cannabinoïdes, ce remodelage nécessite une adaptation métabolique pour soutenir cette plasticité.
Ce projet vise à : (1) quantifier les effets des psychédéliques sur la dynamique des cônes de croissance et des boutons synaptiques, (2)
caractériser les voies de signalisation en aval, (3) analyser les changements métaboliques associés.

The neuropsychological properties of psychedelics such as LSD are being reevaluated in a so called renaissance' following 50 years of abandonment of interest driven more by political ideologies than by scientific evidences (Sessa 2018). Their promise in treating various psychiatric disorders such as depression and anxiety, combined with their lack of addiction, and long-term side-effect present them as relevant therapeutic opportunity (Chi and Gold 2020). Acting primarily as agonists of the serotonergic 5-HT2A receptor, their long-term effects involve neuronal structural plasticity and cytoskeletal reorganization (Cameron et al. 2023). Despite this renewed interest in psychedelics, little research has been conducted on their effects at the presynaptic level. This lack of research is partly due to the difficulty of analyzing presynaptic components, mainly because of technical challenges. Indeed, the relatively small size of synaptic boutons compared to dendritic spines requires the use of more advanced super-resolution imaging techniques. Chronic exposure to LSD in human brain organoids is accompanied by changes in the proteome with a distinct signature. As expected, these changes are linked to various proteins involved in neuronal plasticity, but interestingly, they also favor an increase in glycolytic proteins while being associated with a reduction in mitochondrial proteins involved in oxidative phosphorylation (N. Costa et al. 2024). This suggests that LSD may induce a metabolic shift toward glycolysis, implying a link between structural and metabolic plasticity.
Our team has previously demonstrated that cannabinoids, which are psychoactive compounds acting on the CB1 receptor, induce the activation of the RhoA/Rock pathway, leading to the downstream actomyosin contractility (Roland et al. 2014). These cellular contractile forces induce axonal retraction of the growth cone, which is an important aspect of the cannabinoides biology during development (Roland et al. 2014). In mature neurons, however, they induce a reorganization of synaptic vesicles, leading to the inhibition of synaptic vesicle release upon CB1 receptor activation (McFadden et al. 2024). Intriguingly, we have also shown that axonal retraction is locally fueled by glycolytic, rather than mitochondrial, ATP (Santos et al. 2023), and that RhoA/ROCK activation results in a decrease in mitochondrial respiration (Santos et al. 2023)

We hypothesize that, similar to the action of cannabinoids, psychedelics exert an actin-cytoskeleton remodeling but with opposites effects by releasing tonic contractile forces, thereby promoting axonal and synaptic growth as well as actin polymerization. However, similar to cannabinoids, this cytoskeletal remodeling requires a metabolic preadaptation to energetically sustain such plasticity.
This project proposes to:
Quantify the structural effects induced by psychedelics on growth cone dynamics and synaptic boutons
Characterize the downstream signaling pathways
Characterize the associated metabolic changes induced by psychedelics.
We have previously established and/or developed specialized experimental approaches to address the different aims of this study. Our research model consists of primary cortical neurons from rats at various developmental stages.
Axonal growth cone dynamics induced by psychedelics in developing neurons will be recorded using time-lapse video microscopy in neurons expressing LifeAct-mCherry.
Presynaptic activity will be recorded in mature neurons expressing the synaptophysin-pHluorin probe (sypH2).
3D-STORM super-resolution microscopy will be used to quantify and localize synaptic vesicle distribution within presynaptic boutons, along with cytoskeleton components (F-actin, Homer, Bassoon).
NanoPAINT with QD-CTB will be employed to track synaptic topology remodeling during psychedelic treatments.
A Seahorse Analyzer, which simultaneously records glycolytic flux and mitochondrial respiration, will be used to analyze the acute and sub-acute effects of psychedelics.
In these experimental approaches, we will use diverse pharmacological tools, including:
- 5-HT2A receptor ligands: agonists (DOI, LSD, psilocin) and antagonists (ketanserin);
- Modulators of small GTPases: inhibitors/activators of RhoA, Rac, and Cdc42 pathways;
- Metabolic modulators: drugs targeting mitochondrial respiration and glycolysis.

Étudiant motivé dans le domaine de la recherche en neurobiologie cellulaire, avec des compétences en culture cellulaire et en microscopie phononique. Prérequis : connaissances de base en analyse d'images, programmation Python et en statistiques.