Strain-Specific Trajectories of Behavioural, Neuroinflammatory, and Microbiota Changes under Chronic Stress in Rats with Contrast Levels of Nervous System Excitability

Objectives: Chronic stress can trigger neuroinflammation and gut microbiota alterations, contributing to post-stress disorders. Individual differences in stress responses, shaped by genetic and physiological factors, require better characterization. We aimed to investigate the long-term effects of chronic stress in rats selectively bred for high and low nervous system excitability. Methods: Adult male rats from two strains selectively bred for high (HT) and low (LT) excitability thresholds of the nervous system underwent a 15-day chronic emotional-pain stress protocol. Behavioral assessments (elevated plus maze), cytokine levels (TNF, IL-1β, IL-6, IL-10) in the hippocampus and amygdala measured by ELISA, glial fibrillary acidic protein (GFAP+) cell counts obtained via immunohistochemistry in the prefrontal cortex, hippocampus, and amygdala, and gut microbiota profiling (16S rRNA sequencing) were conducted on days 7 and 24 post-stress. Results: By day 24, LT rats exhibited reduced exploratory behavior, elevated proinflammatory cytokines, and decreased GFAP+ cells across multiple brain regions. In contrast, HT rats exhibited an anxiety-like phenotype even in controls but showed increased exploratory activity after stress, without signs of brain inflammation; GFAP+ reduction was limited to the hippocampus. Microbiota composition remained stable in LT rats but changed transiently in HT rats. Conclusion: Two distinct stress response patterns emerged: delayed neuroinflammatory and behavioral dysregulation with rigid microbiota in LT rats, vs. primarily behavioral changes with transient microbiota shifts in HT rats. These findings highlight the need to consider genetic excitability traits when modeling stress-related disorders and exploring potential therapeutic strategies.