Multilayer brain network analysis in mice reveals ketamine-induced reorganization of brain- wide fluctuations and gut-brain axis
Fengkai He, Xiaojun Xu, Y Y Zhu, Jiahui Lu, Jie Liu, Dongyong Guo, An Liu, W L Bai, Xuyuan Zheng, Baolin Guo, Tiaotiao Liu
Communications Biology July 3, 2026 Peer reviewed DOI: 10.1038/s42003-026-10606-0 via OpenAlex
Summary
Ketamine treatment in a chronic social defeat stress model in male mice was found to reverse social avoidance and induce significant changes in brain network topology. The study developed a frequency-varying multilayer brain functional network framework that revealed frequency-specific hyperconnectivity and alterations in network integration. Notably, the lateral habenula exhibited an opposite response pattern compared to other regions. Additionally, changes in gut microbial features linked to ketamine were associated with global network topology.
Study at a glance
| Design | observational cohort |
|---|---|
| Sample size | 8 |
| Population | male C57BL/6 mice |
| Key finding | Ketamine reversed social avoidance and induced distinct reorganization of multilayer network topology in a chronic social defeat stress model. |
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.