Neuroimaging insights from Wistar-Kyoto rats under chronic mild stress: morphological and metabolic brain correlates of treatment-resistant depression.
Gianmauro Palombelli, Valentina Zecca, Marta Boffa, Carola Cerri, Taljinder Singh, Luisa De Risio, Mauro Pettorruso, Francesca Zoratto, Rossella Canese
Scientific reports March 27, 2026 Peer reviewed DOI: 10.1038/s41598-026-45121-z via PubMed
Summary
The Wistar-Kyoto rat exposed to chronic mild stress (WKY/CMS) serves as a model for treatment-resistant depression (TRD), showing limited response to standard antidepressants but sensitivity to effective interventions like esketamine and ECT. In WKY/CMS rats, brain metabolism analysis revealed reduced levels of glutamate, glutamine, and taurine, alongside increased myo-inositol in the prefrontal cortex. Additionally, structural imaging indicated compromised white-matter integrity in the hippocampus, highlighting metabolic and microstructural changes associated with depression.
Study at a glance
| Population | Wistar-Kyoto rats exposed to chronic mild stress |
|---|---|
| Key finding | WKY/CMS rats exhibit significant metabolic and microstructural alterations in the brain that are consistent with features of treatment-resistant depression. |
Abstract
Major depressive disorder is highly prevalent and disabling, and many patients do not respond to standard therapies, resulting in treatment-resistant depression (TRD). Progress in TRD requires preclinical models with poor response to conventional treatments. The Wistar-Kyoto rat exposed to chronic mild stress (WKY/CMS) offers a robust paradigm: it shows limited responsiveness to standard antidepressants yet remains sensitive to interventions effective in TRD (esketamine, ECT), making it well-suited to probe TRD mechanisms and evaluate candidate therapies. To extend the characterization of this model-previously unstudied with quantitative 1H-MRS or DTI-we compared WKY/CMS rats with non-depressed controls, quantifying brain metabolism by 1H-MRS and assessing structural alterations with T2-weighted MRI and 30-direction DTI. In WKY/CMS rats, 1H-MRS revealed reduced glutamate, glutamine, and taurine, and increased myo-inositol in the prefrontal cortex (PFC), along with decreases in glutamine, choline-containing compounds, and macromolecular signals at 0.9 and 1.4 ppm in the hippocampus (Hip). DTI revealed increased mean diffusivity in the PFC and Hip of WKY/CMS rats-consistent with demyelination and/or axonal loss-and reduced fractional anisotropy in the Hip, suggesting compromised white-matter integrity. Overall, the WKY/CMS profile reflects depression- and stress-related metabolic and microstructural changes, supporting translational studies and testing of interventions relevant to treatment resistance (e.g. rTMS, psychedelics).