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 DOI: 10.1038/s41598-026-45121-z (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Wistar-Kyoto rats exposed to chronic mild stress (WKY/CMS) and non-depressed controls |
| Topics | Depression |
| Citations | 1 |
| Key points | The WKY/CMS rat model shows reduced glutamate, glutamine, and taurine in the prefrontal cortex and decreased glutamine and choline compounds in the hippocampus, along with increased mean diffusivity in both regions and reduced fractional anisotropy in the hippocampus, consistent with depression-related metabolic and microstructural changes. |
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).
Comparable studies
Other preclinical and animal studies on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... | 2011 | Animal experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons | 2023 | Preclinical study | |
| Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress | 2017 | Preclinical animal study |