Context-dependent brain connectivity reorganization following chronic antibiotic exposure during social behavior

Introduction The gut microbiome influences brain function, but how chronic antibiotic exposure affects neural network organization during social behavior remains unclear. We investigated the effects of microbiome disruption on brain metabolism and functional connectivity. Methods Male C57BL/6J mice received chronic broad-spectrum antibiotics ( n = 10) or served as controls ( n = 10). Mice experienced three social contexts: isolation, familiar-mouse interaction, and novel-mouse interaction. Following each 10-min session, [ 18 F]fluorodeoxyglucose positron emission tomography was performed. Functional connectivity was assessed across 74 brain regions. Results Despite preserved social discrimination, antibiotic-treated mice showed reduced limbic metabolism in the anterior cingulate, hypothalamus, and amygdala across contexts, with increased sensory cortical metabolism during novel interactions. The greatest network reorganization occurred during familiar interaction, with 48 connectivity gains and 2 losses, primarily involving thalamo-limbic, brainstem-limbic, and striato-limbic circuits. Antibiotic-treated mice also showed higher degree centrality but lower small-worldness and greater connectivity fluctuations. Discussion Chronic antibiotic exposure induces context-dependent brain network reorganization while preserving social behavior. Increased connectivity may compensate for reduced limbic metabolism but is associated with reduced network efficiency and stability, suggesting that microbiome disruption sustains behavior through energetically unstable neural networks.