Project Details
Projekt
Brain-Gut crosstalk in anxiety disorders: Multi-Omics and interference strategies to uncover the developmental mechanisms of susceptibility and resilience
Subject Area
Molecular and Cellular Neurology and Neuropathology
Cell Biology
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 561671523
This study investigates the mechanisms underlying susceptibility and resilience to anxiety disorders induced by stress dysregulation of the brain-gut-microbiota axis. Anxiety disorders affect 10-33% of adults at some time in their lives, posing significant public health concerns. The study focuses on how individual differences in response to stress may predispose some to anxiety while others remain unaffected. Central to this investigation is the brain-gutmicrobiota axis, a bidirectional communication pathway between brain and microbiota which influences stress responses and psychiatric outcomes. Stress in early life, particularly during puberty, appears critical in shaping long-term anxiety risk. This project aims to identify early and long-lasting molecular and cellular changes along the brain-gut-microbiota axis in mice subjected to a Moderate Pubertal 2-Hit Stress (MP2XS) protocol. The MP2XS protocol simulates human stress exposure, with pubertal stress leaving a lasting imprint that causes susceptibility or resilience, revealed upon a second adult stress event. Anxiety is often triggered by stressful events in adulthood, such as the death of a loved one, loss of employment, violent incidents, and confinement, such as that experienced during pandemics. Initial findings highlight the importance of the habenulo-interpeduncular system (HIPS), specifically the Otx2-positive subcircuit (HIPOPS), in mediating stress-induced anxiety. Dysbiosis, an imbalance in the gut microbiota, may further exacerbates psychiatric risk by affecting gut-brain communication. Chronic stress during puberty is known to induce brain and microbiota dysregulations that are implicated in long-term anxiety. Our MP2XS protocol induces HIPOPS hyperactivity and metabolic changes indicative of gut microbiota dysbiosis. This proposal integrates electrophysiological, transcriptomic, metagenomic, and metabolomic approaches to unravel the temporal activation of brain-gut and gut-brain circuits conferring susceptibility or resilience to anxiety. Partner collaborations will elucidate HIPOPS-related neuronal plasticity, microbiota-induced metabolic shifts, and the role of brain-gut-microbiota axis, including the vagal and sympathetic pathways. Machine learning will be employed to develop predictive models of anxiety risk, validated in mouse and human studies, aiming to translate findings into clinical applications. The outcomes of this project will define brain-gut-microbiota axis’s role in anxiety regulation and identify potential predictive markers and therapeutic targets. By dissecting the molecular, neural, and microbial pathways involved in stress-induced anxiety, this research aims to develop preventative and therapeutic strategies to prevent susceptibility and enhance resilience and mental health.
DFG Programme
Research Grants
International Connection
France, Switzerland
Cooperation Partners
Dr. Fabien D' Autreaux; Dr. Virginie Mansuy-Aubert; Professor Dr. Michel Vignes
