psiloNOVA: the new bridges by psilocybin to treat depression, from gut to brain

Objectif

The psiloNOVA project aims (i) to investigate the acute and sustained modulatory effects of psilocybin on gut-brain and hypothalamic-pituitary-interrenal (HPI) (HPA-like) axes; (ii) to evaluate the promotion of neuroplasticity, neuroprotection, and immune regulation; and (iii) to identify molecular and cellular markers that define antidepressant responses in a depressive-like state zebrafish model. Using transgenic zebrafish, the project will integrate molecular profiling, along with high-resolution imaging approaches to evaluate serotonergic and stress-related signaling, synaptogenesis, neuroprotection and remodeling of the myenteric plexus, as well as immunomodulation and microglial/enteric muscularis macrophage dynamics after a single dose. psiloNOVA is highly relevant to the MSCA Work Programme by addressing an urgent societal challenge, such as Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD), through cutting-edge and interdisciplinary research that will advance European excellence and reference in neuroscience and psychopharmacology. The interdisciplinary methods designed and chosen to answer our objectives will provide the first multilevel mechanistic evidence of psilocybin’s sustained antidepressant effects, bridging central and enteric nervous system regulation. The results will expand studies on psychedelic compounds with potential therapeutic applications, promoting more effective and well-tolerated responses. Additionally, the outcomes will better define the precise markers associated with antidepressant responses triggered by psilocybin.