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

In a rat model of treatment-resistant depression (Wistar-Kyoto rats exposed to chronic mild stress), brain scans revealed metabolic and structural changes distinct from non-depressed controls. Magnetic resonance spectroscopy showed reduced glutamate, glutamine, and taurine in the prefrontal cortex and decreased glutamine and choline compounds in the hippocampus, along with increased myo-inositol in the prefrontal cortex. Diffusion tensor imaging indicated higher mean diffusivity in both regions, consistent with demyelination or axonal loss, and lower fractional anisotropy in the hippocampus, suggesting compromised white-matter integrity. These findings mirror depression- and stress-related brain changes in humans, supporting the model's use for testing novel treatments like rTMS and psychedelics.

Study at a glance

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).