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 DOI: 10.1038/s42003-026-10606-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Male C57BL/6 mice |
| Intervention | Ketamine |
| Topics | Default mode network Esketamine Ketamine |
| Keywords | Habenula Local field potential Biological neural network Human brain Coupling piping Nerve net Modularity biology Association psychology Hippocampus Antidepressant Dynamic network analysis Depression economics Brain mapping Artificial neural network Exploratory analysis Deep brain stimulation Central nervous system |
| Key findings | Chronic social defeat stress induces frequency-specific hyperconnectivity and altered network integration in mouse brain networks, and ketamine reverses social avoidance while reorganizing multilayer network topology, with the lateral habenula showing an opposite response pattern to other recorded regions. |
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.