INVESTIGATING ASTROCYTE METABOLISM IN A MOUSE MODEL OF ACUTE STRESS

Stress is a major risk factor for psychiatric disorders, which affect 14% of people worldwide. Chronic stress alters brain metabolism via corticosterone release, increasing glucose uptake and lactate release in the hippocampus and amygdala, key brain areas controlling emotional regulation. Stress also affects the number and morphology of principal glial cell types – astrocytes and microglia. Astrocytes metabolically support neurons during high energy demand, whereas microglia modulate stress-related neuroinflammatory responses. Despite these established roles, the contribution of glial metabolism in shaping responses to acute stress (AS) and the impact of AS on brain energy metabolism remain unclear. Here, we employed a restraint paradigm (2hr/day, 3 days) to investigate the effects of AS on mitochondrial respiration and glia metabolism in the hippocampus and amygdala and to determine whether AS-induced transcriptional alterations represent compensatory responses to mitochondrial dysfunction. In parallel, we assessed how exposure to acute versus chronic cortisol, the primary stress-related corticosteroid in humans, modulates cytokine release in hiPSC‑derived ioMicroglia (bit.bio). Elevated Plus Maze testing at days 1, 7, 14, and 21 post‑AS revealed strongest anxiogenic phenotype at day 1, which served as the time-point for metabolic analyses. AS animals showed unchanged basal mitochondrial respiration, with increased and decreased ATP production in the amygdala and dorsal hippocampus, respectively. Transcriptomic profiling of glia-enriched populations focused on glycolysis, Krebs cycle, and lactate metabolism. Cortisol-treated ioMicroglia showed no differences in cytokine release across acute and chronic conditions. Our findings highlight stress-sensitive metabolic pathways that may contribute to psychiatric disorder‑associated metabolic dysfunction.