A Novel Gut-Brain Pathway Underlying Early Life Stress

The interaction between the gut microbiome and the brain profoundly affects the brain’s physiology, influencing mood and behavior. Yet, mechanisms linking gut microbes to brain responses to adverse childhood experiences (ACE) remain largely unexplored. The proposal research addresses this gap by investigating how specific gut bacterial genera, particularly Roseburia, influence social behavior through modifications in glial cell plasticity and whether interventions can reverse stress-induced dysregulation of the gut microbiome and behavior. Using a mouse model, we will simulate early-life stress (ELS) via limited bedding and nesting (LBN), which reduces social reward behaviors and diminishes Roseburia populations. In Aim 1, we will examine how Roseburia inoculation in the gut affects astrocyte morphology and mitochondrial function in the orbitofrontal cortex, a region crucial for social behavior. Roseburia strains will be inoculated into adolescent mice through oral gavage reared under LBN or standard conditions, with mitochondrial functional assessments using an astrocyte-specific MitoGFP tracker. We will also perform 3- dimensional morphometric (3D Morph) modeling to elucidate astrocyte structural plasticity in the OFC. In Aim 2, we will explore how favorable environmental factors, such as enriching toys and cross-fostering, affect gut microbiome profiles, and social rewards with outcomes diverging based on sex and environmental factors. We will use advanced multi-omic (metagenomics and metabolomic) profiling of the colonic substructures of mice raised in LBN or standard environments and exposed to favorable environmental interventions. Overall, this study seeks to provide significant insights into novel gut-brain interactions and develop effective interventions to mitigate the long-term effects of ELS.