Multilayer brain network analysis in mice reveals ketamine-induced reorganization of brain- wide fluctuations and gut-brain axis

Depression involves disrupted communication across brain circuits, and ketamine can rapidly alleviate depressive symptoms. A new analytical framework, the frequency-varying multilayer brain functional network (FMBFN), was developed to examine how brain regions coordinate activity both within and across different frequency bands. Using local field potential recordings from eight brain regions in male mice subjected to chronic social defeat stress (a model of depression), the framework revealed that stress led to frequency-specific hyperconnectivity and altered network integration during social interaction. Ketamine reversed social avoidance and reorganized the multilayer network topology, with the lateral habenula showing a response pattern opposite to other regions. Exploratory analysis also linked ketamine-associated gut microbial changes to global network topology, suggesting possible gut-brain associations.

Study at a glance

Abstract

Depression involves dysregulation across distributed cortico-limbic circuits, and ketamine is notable for its rapid antidepressant effects. Although depression and ketamine treatment have been linked to altered brain network topology, how within-frequency and cross-frequency coupling are jointly reorganized at the brain-wide level remains unclear. Here, we developed a frequency-varying multilayer brain functional network (FMBFN) framework to analyze local field potential recordings from eight brain regions in male C57BL/6 mice. This framework integrates within- and cross-frequency coupling and extracts multi-scale network features to characterize brain network structure. Applying this approach in the chronic social defeat stress (CSDS) model, we found that CSDS was associated with frequency-specific hyperconnectivity and selective alterations in network integration during social interaction. Ketamine reversed social avoidance and induced the distinct reorganization of multilayer network topology, including region-specific nodal changes. Notably, the lateral habenula showed the response pattern opposite to that of the other recorded regions. As an exploratory cross-modal extension, we further examined gut microbial features and found that specific ketamine-associated microbial changes were linked to global network topology, suggesting candidate gut-brain association patterns. Together, these findings establish the FMBFN framework as a systems-level tool for characterizing brain-wide neural dynamics in psychiatric disorders and for linking network-level alterations to biological contexts.