Team
NSA
Team manager: Mouledous Lionel & Guiard Bruno
Presentation
The acute stress response is a physiological reaction that prepares individuals to face harmful or even traumatic events. This response is accompanied by a constellation of reflexive survival behaviors and neuronal responses which can, under some circumstances, become dysregulated. Prolonged dysregulation can promote functional impairment leading to stress-related disorders such as post-traumatic stress disorder (PTSD), major depression (MD), or one of several anxiety pathologies (often comorbid). Currently available treatments for these neuropsychiatric disorders are, for most, monoamine uptake inhibitors, in particular serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. Despite their efficacy, these pharmacological compounds show important limitations notably a slow action onset and adverse side-effects
Against this backdrop, our research aims to develop relevant animal model of stress that mimic human psychiatric disorders, to characterize factors involved in behavioral, neurochemical and neuronal plasticity phenomena triggered by acute or chronic stress, and to identify new therapeutic targets and strategies for the treatment of PTSD or MD
Project 1
In this project, two main axes will be explored.
1) N/OFQ as a mediator of stress-induced alterations in hippocampal function and related memory deficits using three preclinical models i.e., prolonged exposure to corticosterone, chronic restraint stress and neuropathic pain induced by sciatic nerve injury. The main objectives will be (i) to map in detail the changes occurring in the hippocampus at the level of NOP receptor expression and N/OFQ release; (ii) to establish the behavioral consequences on memory of NOP receptor blockade in different hippocampal neuronal populations; (iii) to analyze alterations in neuronal activity and hippocampal networks associated with chronic stress and manipulation of the N/OFQ system. The results could open up new therapeutic perspectives for improving cognitive deficits linked to neuropsychiatric disorders associated with chronic stress.
2) N/OFQ system as a therapeutic target in post-traumatic stress disorder. We have recently shown that acute blockade of the N/OFQ system prevents resignation after traumatic stress in mice. Thus, it can be proposed that early administration of NOP antagonists would have the unique ability to block the development of some symptoms of PTSD. Our objective is to validate this hypothesis in a mouse model of the disease by studying the effect of early administration of NOP antagonists on symptoms such as extinction deficit, hypervigilance, social and general anxiety and hyperalgesia. We will also identify the neurobiological mechanisms of this therapeutic effect using genetic tools. Finally, our longer-term objective is to initiate a translational approach by studying plasma N/OFQ levels in cohorts of patients suffering from stress-related disorders.
Project 2
Serotonergic psychedelics are a broad category of drugs that have inspired new hope for treating brain disorders. Among these compounds, tryptamine derivatives such as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a structural analogue of dimethyltryptamine (DMT, the psychoactive ingredient of ayahuasca) and 4-hydroxy-N,N-dimethyltryptamine (psilocin) are gaining growing interest. In vivo, preclinical studies have highlighted their therapeutic potential but the paucity of controlled clinical studies does not allow to draw any definitive conclusions. The role of the serotonergic system and the respective contribution of the 5-HT1A and 5-HT2A receptors in the beneficial effects of these substances represents an important gap that has to be solved. Moreover, a number of studies endorses the view that the hallucinogenic effects of psychedelics are required for their antidepressant effects but this notion has been recently challenged. Finally, the influence of the context of administration on the trajectory of their behavioral effects represents another exciting question in the field of psychedelics. This project will therefore address these important questions. We first propose to determine whether the hallucinogenic effect of the 2 tryptamine derivatives 5-MeO-DMT and psilocin is required for their anxiolytic/antidepressant-like effects and to what extent the 5-HT1A/5-HT2A receptors contribute to their expected beneficial effects. We will also explore the possibility that the trajectory of anxiolytic/antidepressant-like effects of these psychedelics in the CORT mouse model of depression depends on the context of administration as a result of the modulation of the excitatory/inhibitory balance, notably underpinned by the perineuronal nets (PNNs) surrounding inhibitory GABAergic interneurons.
Project 3
Backed by the NSA team, the joint CNRS-ReST Therapeutics laboratory “TransNMDA” was launched in November 2024 to enable better interactions between academic and industrial players. Its research theme represents an extension of our team in the sense that the objective will be to identify new NMDA receptor ligands -with different binding affinities for GluN2C/GluN2D subunits – for the diagnosis and treatment of stress-related disorders. In this framework, the task of the NSA team will be the evaluation of these drug candidates in preclinical models. This CNRS joint laboratory composed of chemists, pharmacologists and clinicians will enrich our research activities and give them a clinical perspective.
– Xu X, Barriot R, Voisin B, Arrowsmith TJ, Usher B, Gutierrez C, Han X, Pagès C, Redder P, Blower TR, Neyrolles O, Genevaux P. Robert C, D’Oliveira da Silva F, Seminara F, Martinelli C, Farrugia F, Sturaro C, Pacary E, Rampon C, Ruzza C, Moulédous L. Nociceptin/OrphaninFQ Receptor Modulates the Maturation of Adult-Born Neurons in the Mouse Dentate Gyrus Under Physiological Conditions and in a Chronic Stress Model. Mol Neurobiol. 2025 May 26. doi: 10.1007/s12035-025-05062-6.
– D’Oliveira da Silva F, Robert C, Lardant E, Pizzano C, Bruchas MR, Guiard BP, Chauveau F, Moulédous L. Targeting Nociceptin/Orphanin FQ receptor to rescue cognitive symptoms in a mouse neuroendocrine model of chronic stress. Mol Psychiatry. 2024 Mar;29(3):718-729. doi: 10.1038/s41380-023-02363-x.
– Martin H, Bullich S, Martinat M, Chataigner M, Di Miceli M, Simon V, Clark S, Butler J, Schell M, Chopra S, Chaouloff F, Kleinridders A, Cota D, De Deurwaerdere P, Pénicaud L, Layé S, Guiard BP, Fioramonti X. Insulin modulates emotional behavior through a serotonin-dependent mechanism. Mol Psychiatry. 2024 Jun;29(6):1610-1619. doi: 10.1038/s41380-022-01812-3.
– Coutens B, Lejards C, Bouisset G, Verret L, Rampon C, Guiard BP. Enriched environmental exposure reduces the onset of action of the serotonin norepinephrin reuptake inhibitor venlafaxine through its effect on parvalbumin interneurons plasticity in mice. Transl Psychiatry. 2023 Jun 26;13(1):227. doi: 10.1038/s41398-023-02519-x.
– D’Oliveira da Silva F, Azevedo Neto J, Sturaro C, Guarino A, Robert C, Gavioli EC, Calo G, Mouledous L, Ruzza C. The NOP antagonist BTRX-246040 increases stress resilience in mice without affecting adult neurogenesis in the hippocampus. Neuropharmacology. 2022 Jul 1;212:109077. doi: 10.1016/j.neuropharm.2022.109077.
Affiliation
