Willner, P. The chronic mild stress (CMS) model of depression: History, evaluation and usage. Neurobiol. Stress 6, 78–93 (2017).
Hollis, F. & Kabbaj, M. Social defeat as an animal model for depression. ILAR J. 55, 221–232 (2014).
Rygula, R. et al. Citalopram counteracts depressive-like symptoms evoked by chronic social stress in rats. Behav. Pharmacol. 17, 19–29 (2006).
Vialou, V. et al. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci 13, 745–752 (2010).
Venzala, E., García-García, A. L., Elizalde, N., Delagrange, P. & Tordera, R. M. Chronic social defeat stress model: Behavioral features, antidepressant action, and interaction with biological risk factors. Psychopharmacology 224, 313–325 (2012).
Iijima, M., Ito, A., Kurosu, S. & Chaki, S. Pharmacological characterization of repeated corticosterone injection-induced depression model in rats. Brain Res. 1359, 75–80 (2010).
Rainer, Q. et al. Beneficial behavioural and neurogenic effects of agomelatine in a model of depression/anxiety. Int. J. Neuropsychopharmacol. 15, 321–335 (2012).
Sallie, F. N. et al. Neurobehavioral and molecular changes in a rodent model of ACTH-induced HPA axis dysfunction. Brain Res. https://doi.org/10.1016/j.brainres.2024.148913 (2024).
Zoratto, F. et al. Consumption of the prebiotic-rich chicory taproot contrasts the cognitive and motivational consequences of chronic corticosterone exposure and modulates gut microbiota composition in mice. Biol. Psychiatry Glob. Open Sci. https://doi.org/10.1016/j.bpsgos.2025.100520 (2025).
Wang, D. et al. Behavioural and neurochemical features of olfactory bulbectomized rats resembling depression with comorbid anxiety. Behav. Brain Res. 178, 262–273 (2007).
Ho, Y. J., Chen, K. H., Tai, M. Y. & Tsai, Y. F. MK-801 suppresses muricidal behavior but not locomotion in olfactory bulbectomized rats: Involvement of NMDA receptors. Pharmacol. Biochem. Behav. 77, 641–646 (2004).
Okamoto, K. & Aoki, K. Development of a strain of spontaneously hypertensive rats. Jpn. Circ. J. 27, 282–293 (1963).
Nam, H., Clinton, S. M., Jackson, N. L. & Kerman, I. A. Learned helplessness and social avoidance in the Wistar-Kyoto rat. Front. Behav. Neurosci. 8, 109 (2014).
Part~, W. P. Open field, learned helplessness, conditioned defensive burying, and forced-swim lests in WKY rats. Physiol. Behav. 55(33), 433–439 (1994).
Will, C. C., Aird, F. & Redei, E. E. Selectively bred Wistar-Kyoto rats: An animal model of depression and hyper-responsiveness to antidepressants. Mol. Psychiatry 8, 925–932 (2003).
Aleksandrova, L. R., Wang, Y. T. & Phillips, A. G. Evaluation of the Wistar-Kyoto rat model of depression and the role of synaptic plasticity in depression and antidepressant response. Neurosci. Biobehav. Rev. 105, 1–23 (2019).
Gormley, S., Rouine, J., McIntosh, A., Kerskens, C. & Harkin, A. Glial fibrillary acidic protein (GFAP) immunoreactivity correlates with cortical perfusion parameters determined by bolus tracking arterial spin labelling (bt-ASL) magnetic resonance (MR) imaging in the Wistar Kyoto rat. Physiol. Behav. 160, 66–79 (2016).
Cominski, T. P., Jiao, X., Catuzzi, J. E., Stewart, A. L. & Pang, K. C. H. The role of the hippocampus in avoidance learning and anxiety vulnerability. Front. Behav. Neurosci. 8, 273 (2014).
Papp, M. & Willner, P. Models of affective illness: Chronic mild stress in the rat. Curr. Protoc. https://doi.org/10.1002/cpz1.712 (2023).
Strekalova, T. et al. Chronic mild stress paradigm as a rat model of depression: Facts, artifacts, and future perspectives. Psychopharmacology 239, 663–693 (2022).
Paré, W. P. & Redei, E. Depressive behavior and stress ulcer in Wistar Kyoto rats. J. Physiol. (Paris) 87, 229–238 (1993).
Redei, E., Pare, W. P., Aird, F. & Kluczynski, J. Strain differences in hypothalamic-pituitary-adrenal activity and stress ulcer. Am. J. Physiol. https://doi.org/10.1152/ajpregu.1994.266.2.R353 (1994).
Solberg, L. C., Olson, S. L., Turek, F. W. & Redei, E. Altered Hormone Levels and Circadian Rhythm of Activity in the WKY Rat, a Putative Animal Model of Depression Experimental Protocol. vol. 47 www.ajpregu.org.
Loizeau, V. et al. Behavioural characteristics and sex differences of a treatment-resistant depression model: Chronic mild stress in the Wistar-Kyoto rat. Behav. Brain Res. https://doi.org/10.1016/j.bbr.2023.114712 (2024).
Willner, P. & Belzung, C. Treatment-resistant depression: Are animal models of depression fit for purpose?. Psychopharmacology 232, 3473–3495 (2015).
Willner, P. et al. Validation of chronic mild stress in the Wistar-Kyoto rat as an animal model of treatment-resistant depression. Behav. Pharmacol. 30, 239–250 (2019).
Hashimoto, K. Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective. Psychiatry Clin. Neurosci. 73, 613–627 (2019).
Berlim, M. T., Van Den Eynde, F., Tovar-Perdomo, S. & Daskalakis, Z. J. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: A systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol. Med. 44, 225–239 (2014).
Pettorruso, M. et al. Comparing fast-acting interventions for treatment-resistant depression: An explorative study of accelerated HF-rTMS versus intranasal esketamine. Brain Stimul 16, 1041–1043 (2023).
Weiner, R. D. & Reti, I. M. Key updates in the clinical application of electroconvulsive therapy. Int. Rev. Psychiatry 29, 54–62 (2017).
Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).
Holtzheimer, P. E. et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry 4, 839–849 (2017).
Bergfeld, I. O. et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry 73, 456–464 (2016).
Falowski, S. M. et al. An evaluation of neuroplasticity and behavior after deep brain stimulation of the nucleus accumbens in an animal model of depression. Neurosurgery 69, 1281–1290 (2011).
Kyeremanteng, C. et al. Effects of electroconvulsive seizures on depression-related behavior, memory and neurochemical changes in Wistar and Wistar-Kyoto rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 54, 170–178 (2014).
Tizabi, Y., Bhatti, B. H., Manaye, K. F., Das, J. R. & Akinfiresoye, L. Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats. Neuroscience 213, 72–80 (2012).
Cerri, C. et al. Timing matters: Inverted U-shaped efficacy of dose distribution in translational neuromodulation for treatment-resistant depression. Brain Stimul. 19, 102976 (2025).
Redei, E. E., Solberg, L. C. & Kluczynski, J. M. Paradoxical hormonal and behavioral responses to hypothyroid and hyperthyroid states in the Wistar-Kyoto rat. Neuropsychopharmacology https://doi.org/10.1016/S0893-133X(00)00229-3 (2001).
Ne Durand, M. et al. Strain-dependent neurochemical and neuroendocrine effects of Desipramine, but not Fluoxetine or Imipramine, in Spontaneously Hypertensive and Wistar-Kyoto rats. Neuropharmacology https://doi.org/10.1016/S0028-3908(00)00088-5 (2000).
Cusick, J. A., Wellman, C. L. & Demas, G. E. Maternal stress and the maternal microbiome have sex-specific effects on offspring development and aggressive behavior in Siberian hamsters (Phodopus sungorus). Horm. Behav. https://doi.org/10.1016/j.yhbeh.2022.105146 (2022).
Rittenhouse, P. A., López-Rubalcava, C., Stanwood, G. D. & Lucki, I. Amplified behavioral and endocrine responses to forced swim stress in the Wistar-Kyoto rat. Psychoneuroendocrinology https://doi.org/10.1016/S0306-4530(01)00052-X (2002).
De La Garza, R. & Mahoney, J. J. A distinct neurochemical profile in WKY rats at baseline and in response to acute stress: Implications for animal models of anxiety and depression. Brain Res. 1021, 209–218 (2004).
Malkesman, O. & Weller, A. Two different putative genetic animal models of childhood depression-a review. Prog. Neurobiol. 88, 153–169 (2009).
Villanueva, R. Neurobiology of major depressive disorder. Neural Plast. https://doi.org/10.1155/2013/873278 (2013).
Scholl, J. L., Renner, K. J., Forster, G. L. & Tejani-Butt, S. Central monoamine levels differ between rat strains used in studies of depressive behavior. Brain Res. 1355, 41–51 (2010).
Jiao, X., Paré, W. P. & Tejani-Butt, S. Strain differences in the distribution of dopamine transporter sites in rat brain. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 913–919 (2003).
Jiao, X., Paré, W. P. & Tejani-Butt, S. M. Antidepressant drug induced alterations in binding to central dopamine transporter sites in the Wistar Kyoto rat strain. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 30–41 (2006).
Novick, A., Yaroslavsky, I. & Tejani-Butt, S. Strain differences in the expression of dopamine D1 receptors in Wistar-Kyoto (WKY) and Wistar rats. Life Sci. 83, 74–78 (2008).
Guan, J. et al. Early life stress increases brain glutamate and induces neurobehavioral manifestations in rats. ACS Chem. Neurosci. 11, 4169–4178 (2020).
Kaadt, E., Hedemann, N. K., Damgaard, C. K., Müller, H. K. & Elfving, B. From microRNA to protein, linking the neurotrophic hypothesis of depression to the Wistar-Kyoto rat. Neurosci. Appl. https://doi.org/10.1016/j.nsa.2023.101131 (2023).
Kin, K. et al. Hippocampal neurogenesis of Wistar Kyoto rats is congenitally impaired and correlated with stress resistance. Behav. Brain Res. 329, 148–156 (2017).
Filatova, E. V., Shadrina, M. I. & Slominsky, P. A. Major depression: One brain, one disease, one set of intertwined processes. Cells 10, 1283 (2021).
Karege, F. et al. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. https://doi.org/10.1016/s0165-1781(02)00005-7 (2002).
Pandey, G. N. et al. Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 645–651 (2010).
Nagasawa, M., Otsuka, T., Yasuo, S. & Furuse, M. Chronic imipramine treatment differentially alters the brain and plasma amino acid metabolism in Wistar and Wistar Kyoto rats. Eur. J. Pharmacol. 762, 127–135 (2015).
Li, Q. et al. Partial resistance to citalopram in a Wistar-Kyoto rat model of depression: An evaluation using resting-state functional MRI and graph analysis. J. Psychiatr. Res. 151, 242–251 (2022).
Zou, Q. H. et al. An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: Fractional ALFF. J Neurosci Methods 172, 137–141 (2008).
Di, X. et al. The influence of the amplitude of low-frequency fluctuations on resting-state functional connectivity. Front. Hum. Neurosci. 7, 118 (2013).
Dingess, P. M. et al. Structural and functional plasticity within the nucleus accumbens and prefrontal cortex associated with time-dependent increases in food cue-seeking behavior. Neuropsychopharmacology 42, 2354–2364 (2017).
Yin, S. et al. Intervention-induced enhancement in intrinsic brain activity in healthy older adults. Sci. Rep. https://doi.org/10.1038/srep07309 (2014).
Tao, J. et al. Tai Chi Chuan and Baduanjin mind-body training changes resting-state low-frequency fluctuations in the frontal lobe of older adults: A resting-state fMRI study. Front. Hum. Neurosci. 11, 1–10 (2017).
Lan, M. J. et al. Resting-state amplitude of low-frequency fluctuation is associated with suicidal ideation. Depress. Anxiety 36, 433–441 (2019).
Frodl, T. et al. Hippocampal changes in patients with a first episode of major depression. Am. J. Psychiatry https://doi.org/10.1176/appi.ajp.159.7.1112 (2002).
Tura, A. & Goya-Maldonado, R. Brain connectivity in major depressive disorder: A precision component of treatment modalities?. Transl. Psychiatry 13, 196 (2023).
Hou, X. et al. Neural activity in adults with major depressive disorder differs from that in healthy individuals: A resting-state functional magnetic resonance imaging study. Front. Psychiatry https://doi.org/10.3389/fpsyt.2022.1028518 (2022).
Tomasi, D. & Volkow, N. D. Functional connectivity hubs in the human brain. Neuroimage 57, 908–917 (2011).
Kropf, E., Syan, S. K., Minuzzi, L. & Frey, B. N. From anatomy to function: The role of the somatosensory cortex in emotional regulation. Braz. J. Psychiatry 41, 261–269 (2019).
Yoshii, T. et al. Validation of Wistar-Kyoto rats kept in solitary housing as an animal model for depression using voxel-based morphometry. Sci. Rep. https://doi.org/10.1038/s41598-024-53103-2 (2024).
Wise, T. et al. Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis. Mol. Psychiatry 22, 1455–1463 (2017).
Arnone, D. et al. Computational meta-analysis of statistical parametric maps in major depression. Hum. Brain Mapp. 37, 1393–1404 (2016).
Lin, A. et al. Minimum reporting standards for in vivo magnetic resonance spectroscopy (MRSinMRS): Experts’ consensus recommendations. NMR Biomed. 34(5), e4484 (2021).
Zhao, Y. J. et al. Brain grey matter abnormalities in medication-free patients with major depressive disorder: A meta-analysis. Psychol. Med. 44, 2927–2937 (2014).
Kang, Y. et al. The effect of inflammation markers on cortical thinning in major depressive disorder: A possible mediator of depression and cortical changes. J. Affect. Disord. 348, 229–237 (2024).
Chen, J. et al. Causal structural covariance network identifies progressive gray matter atrophy in adolescents with major depressive disorder. Psychol Med 55, e249 (2012).
Zhang, Y. et al. Revealing complexity: segmentation of hippocampal subfields in adolescents with major depressive disorder reveals specific links to cognitive dysfunctions. Eur. Psychiatry 68(1), e5 (2025).
Moriguchi, S. et al. Glutamatergic neurometabolite levels in major depressive disorder: A systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol. Psychiatry 24, 952–964 (2019).
Hemanth Kumar, B. S., Mishra, S. K., Rana, P., Singh, S. & Khushu, S. Neurodegenerative evidences during early onset of depression in CMS rats as detected by proton magnetic resonance spectroscopy at 7 T. Behav. Brain Res. 232, 53–59 (2012).
Cherix, A. et al. Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine. eLife 9, e50631 (2020).
Pavlova, I. & Ruda-Kucerova, J. Brain metabolic derangements examined using 1H MRS and their (in)consistency among different rodent models of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 127, 110808 (2023).
Schür, R. R. et al. Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies. Hum. Brain Mapp. 37, 3337–3352 (2016).
Lebel, C. et al. Prepartum and postpartum maternal depressive symptoms are related to children’s brain structure in preschool. Biol. Psychiatry 80, 859–868 (2016).
Harris, A. D. & MacMillan, E. L. MRS in neuroinflammation. In Advances in Magnetic Resonance Technology and Applications Vol. Vol. 9 (eds Laule, C. & D., P. J.) 79–116 (Academic Press, 2023).
Jung, C. et al. Magnetic resonance imaging of neuroinflammation in chronic pain: A role for astrogliosis?. Pain 161, 1555–1564 (2020).
Patel, N. C., Cecil, K. M., Strakowski, S. M., Adler, C. M. & DelBello, M. P. Neurochemical alterations in adolescent bipolar depression: A proton magnetic resonance spectroscopy pilot study of the prefrontal cortex. J. Child Adolesc. Psychopharmacol. 18, 623–627 (2008).
Drago, T. et al. A comprehensive regional neurochemical theory in depression: A protocol for the systematic review and meta-analysis of 1H-MRS studies in major depressive disorder. Syst. Rev. 7(1), 158 (2018).
Lirng, J. F. et al. Increased myo-inositol level in dorsolateral prefrontal cortex in migraine patients with major depression. Cephalalgia 35, 702–709 (2015).
Kumar, A. et al. Frontal white matter biochemical abnormalities in late-life major depression detected with proton magnetic resonance spectroscopy. Am. J. Psychiatry https://doi.org/10.1176/appi.ajp.159.4.630 (2002).
Kim, S. Y. et al. Reversal of myo-inositol metabolic level in the left dorsolateral prefrontal cortex of rats exposed to forced swimming test following desipramine treatment: An in vivo localized (1)H-MRS study at 4.7 T. Magn. Reson. Imaging 28, 1461–1467 (2010).
Li, C. X. et al. Cerebral metabolic changes in a depression-like rat model of chronic forced swimming studied by ex vivo high resolution 1H magnetic resonance spectroscopy. Neurochem. Res. 33, 2342–2349 (2008).
Kim, S., Hong, K. B., Kim, S., Suh, H. J. & Jo, K. Creatine and taurine mixtures alleviate depressive-like behaviour in Drosophila melanogaster and mice via regulating Akt and ERK/BDNF pathways. Sci. Rep. 10(1), 11370 (2020).
Rajkowska, G. & Stockmeier, C. Astrocyte pathology in major depressive disorder: Insights from human postmortem brain tissue. Curr. Drug Targets. 14, 1225–1236 (2013).
Mechawar, N. & Savitz, J. Neuropathology of mood disorders: Do we see the stigmata of inflammation?. Transl. Psychiatry. https://doi.org/10.1038/tp.2016.212 (2016).
Gibbons, A. S., Brooks, L., Scarr, E. & Dean, B. AMPA receptor expression is increased post-mortem samples of the anterior cingulate from subjects with major depressive disorder. J. Affect. Disord. 136, 1232–1237 (2012).
Ramírez-Guerrero, S. et al. Taurine and astrocytes: A homeostatic and neuroprotective relationship. Front. Mol. Neurosci. https://doi.org/10.3389/fnmol.2022.937789 (2022).
Zhu, Y. et al. Taurine Alleviates Chronic Social Defeat Stress-Induced Depression by Protecting Cortical Neurons from Dendritic Spine Loss. Cell Mol Neurobiol 43, 827–840 (2023).
Zhou, H., Gao, Y., Dong, T., Wang, J. & Liu, Z. F. Magnetic resonance spectroscopy studies in children and adolescents with depression: A systematic review and meta-analysis. J. Affect. Disord. 389, 119747 (2025).
Rae, C. D. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochem. Res. 39, 1–36 (2014).
Kumar, A. et al. Frontal white matter biochemical abnormalities in late-life major depression detected with proton magnetic resonance spectroscopy. Am. J. Psychiatry. 159, 630–636 (2002).
Xie, X. et al. Altered neurometabolite levels in the brains of patients with depression: A systematic analysis of magnetic resonance spectroscopy studies. J. Affect. Disord. 328, 95–102 (2023).
Ebeid, M. A. et al. Cognitive effects of the GSK-3 inhibitor “lithium” in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy. Neurotoxicology 83, 77–88 (2021).
Cudalbu, C. et al. Contribution of macromolecules to brain 1H MR spectra: Experts’ consensus recommendations. NMR Biomed. 34, e4393 (2021).
Simicic, D. et al. In vivo macromolecule signals in rat brain 1 H-MR spectra at 9.4T: Parametrization, spline baseline estimation, and T2 relaxation times. Magn. Reson. Med. 86, 2384–2401 (2021).
Birch, R., Peet, A. C., Dehghani, H. & Wilson, M. Influence of macromolecule baseline on 1 H MR spectroscopic imaging reproducibility. Magn. Reson. Med. 77, 34–43 (2017).
Genovese, G. et al. Age-related differences in macromolecular resonances observed in ultra-short-TE STEAM MR spectra at 7T. Magn. Reson. Med. 92, 4–14 (2024).
Guo, W. B. et al. Altered white matter integrity of forebrain in treatment-resistant depression: A diffusion tensor imaging study with tract-based spatial statistics. Prog. Neuropsychopharmacol. Biol. Psychiatry 38, 201–206 (2012).
White, J. D. et al. Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning. Elife 9, 1–29 (2020).
Klok, M. P. C., van Eijndhoven, P., Argyelan, M., Schene, A. H. & Tendolkar, I. Structural brain characteristics in treatment-resistant depression: Review of magnetic resonance imaging studies. BJPsych Open. 5(4), 76 (2019).
Xu, Y. et al. Shared and distinct white matter alterations in major depression and bipolar disorder: A systematic review and meta-analysis. J. Integr. Neurosci. https://doi.org/10.31083/j.jin2309170 (2024).
Papp, M. Models of affective illness: Chronic mild stress in the rat. Curr. Protoc. Pharmacol. 5(1), 5–9 (2012).
Papp, M. et al. Rapid antidepressant effects of deep brain stimulation of the pre-frontal cortex in an animal model of treatment-resistant depression. J. Psychopharmacol. 32, 1133–1140 (2018).
Gottschalk, A., Scafidi, S. & Toung, T. J. K. Brain water as a function of age and weight in normal rats. PLoS One. https://doi.org/10.1371/journal.pone.0249384 (2021).
Canese, R. et al. Characterisation of in vivo ovarian cancer models by quantitative 1H magnetic resonance spectroscopy and diffusion-weighted imaging. NMR Biomed. 25, 632–642 (2012).
Provencher, S. W. In Vivo Proton NMR Spectra. (1993).
Öz, G. et al. Advanced single voxel 1H magnetic resonance spectroscopy techniques in humans: Experts’ consensus recommendations. NMR Biomed. 34, e4236 (2020).
Pang, Z. et al. MetaboAnalyst 5.0: Narrowing the gap between raw spectra and functional insights. Nucleic Acids Res. 49, W388–W396 (2021).