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<p>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 <sup>1</sup>H-MRS or DTI—we compared WKY/CMS rats with non-depressed controls, quantifying brain metabolism by <sup>1</sup>H-MRS and assessing structural alterations with T2-weighted MRI and 30-direction DTI. In WKY/CMS rats, <sup>1</sup>H-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&#xa0;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).</p>

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Neuroimaging insights from Wistar-Kyoto rats under chronic mild stress: morphological and metabolic brain correlates of treatment-resistant depression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Gianmauro Palombelli,
  • Valentina Zecca,
  • Marta Boffa,
  • Carola Cerri,
  • Taljinder Singh,
  • Luisa De Risio,
  • Mauro Pettorruso,
  • Francesca Zoratto,
  • Rossella Canese

摘要

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).