DEPRESSION MODELS IN RODENTS
A Translational Triad of Validated Rodent Models for Depression
At Ulysses Neuroscience Ltd., we offer a robust and translational preclinical platform for the investigation of Major Depressive Disorder (MDD) and treatment-resistant depression (TRD). Our internationally recognised scientific leadership in depression research is grounded in over two decades of neuropharmacology innovation and cutting-edge model development from our founder. With facilities in Ireland (HPRA accredited) and North America (AAALAC accredited), we deliver high-quality, reproducible, and ethically conducted in vivo studies tailored to our clients’ drug discovery needs. What sets us apart is our integrated translational approach: we combine validated behavioural endpoints with molecular biomarkers and advanced sampling strategies, generating data with direct clinical relevance. Our platform bridges the gap between animal models and human studies, accelerating the path from compound to clinic.
WHO WILL FIND THIS PLATFORM USEFUL?
The Ulysses Triade of Depression Models
Major Depressive Disorder (MDD) is not a singleentity disease, but a heterogeneous condition with multiple biological origins and clinical presentations. To address this complexity, we have established a triad of validated rodent models, each capturing a distinct mechanistic pathway associated with depression:
1. PHARMACOLOGICAL MODEL - IFN-α in Rat:
mimics inflammation-driven depression using systemic interferon-alpha treatment.
2. INNATE MODEL - Wistar Kyoto (WKY) Rat:
an inbred rat strain with natural depressive traits and no response to SSRIs.
3. PSYCOSOCIAL STRESS MODEL - Chronic Social Defeat (CSD) in Mouse:
a behavioural paradigm replicating the impact of chronic social stress.
The Ulysses Triade of Depression Models
Biomarker and Sampling Platforms
Ulysses is uniquely equipped to perform multiplexed biomarker analyses in tissues and fluids, alongside advanced cellular and histological profiling, using:
• Luminex 200
• MESO QuickPlex SQ 120MM
• Li-Cor Odyssey CLx
• Flow cytometry for neurogenesis and immune cell populations
• Histology, including Golgi staining and immunohistochemistry (IHC)
EEG as Translational Biomarker
We incorporate high-resolution EEG telemetry and wireless platforms in rats and mice, supporting:
• Pharmacodynamic profiling
• Sleep architecture and vigilance state analysis
• Electrophysiological biomarkers including gamma power, spectral shifts, and REM suppression
Available technologies include:
• Pinnacle Wireless Video-EEG
• DSI Telemetry
• Tainitec "TaiNi" head-mounted systems
• ASSR paradigms for auditory processing and cortical synchrony
VALIDATION OVERVIEW OF ULYSSES DEPRESSION MODELS
PHARMACOLOGICAL MODEL
IFN-α IN RAT
The IFN-α Rat Model is a robust and backtranslational pharmacological model of inflammation-associated depression. It is based on the repeated systemic administration of human interferon-alpha 2a (IFN-α2a), a cytokine known to induce depressive symptoms in patients treated for certain forms of hepatitis or cancer. Initially designed to explore neuroimmune mechanisms of mood disorders, the model has also proven ideal for evaluating compounds targeting neuronal plasticity, neuroinflammation, and rapid-acting antidepressant pathways, including psychedelics and neuroplastogens. The model has been fully validated at Ulysses Neuroscience Ltd. and has become one of the most widely used and scientifically supported preclinical models of depression on the market, with over 25 internal studies conducted since 2019 in collaboration with leading biotech and pharmaceutical companies./p>
KEY FEATURES
• High reproducibility across multiple behavioural domains
• Sensitive to chronic fluoxetine (SSRI), but not to acute dosing
• Robust response to ketamine (NMDA antagonist), 24h post administration
• Validated with psilocybin (5-HT₂A agonist) and non-hallucinogenic analogues
• Responsive to dual-action agents with anti-inflammatory and neuroplastogen effects
• Characterised by central and peripheral biomarker alterations
Experimental design of the Ulysses IFN-α rat model.
The Ulysses IFN-α model is featured in peer-reviewed publications by our clients:
• Aarrestad, I. K., Cameron, L. P., Fenton, E. M., Casey, A. B., Rijsketic, D. R., Patel, S. D., ... & Olson, D. E. (2025). The psychoplastogen
tabernanthalog induces neuroplasticity without proximate immediate early gene activation. Nature Neuroscience, 1–13.
• Clark, E. A., Wang, L., Hanania, T., Kretschmannova, K., Bianchi, M., Jagger, E., ... & Bristow, L. J. (2025). 5-HT1B receptor activation
produces rapid antidepressant-like effects in rodents. Pharmacology Biochemistry and Behavior, 247, 173917.
• Callaghan, C., Garrone, B., Milanese, C., Freeburn, A., Kealy, J., & Bianchi, M. (2025). Interferon-alpha administration in the rat as
a back-translational model of depression: Behavioral and molecular effects of chronic treatment with fluoxetine and Glycogen
Synthase Kinase-3β (GSK3β) inhibitors. [submitted]
• Yennemadi, A. S., Jameson, G., Glass, M., De Pasquale, C., Keane, J., Bianchi, M., & Leisching, G. (2023). Chronic IFNα treatment
induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring. Cellular Immunology, 390, 104741.
Behavioural and Molecular Effects of Chronic Fluoxetine in the IFN-α Rat Model of Depression.
Chronic administration of fluoxetine (10 mg/kg, PO; once a day for 14 days) reverses IFN-α-induced behavioural deficits in the Forced Swim Test (FST), Sucrose Preference Test (SPT), and Elevated Plus Maze (EPM), indicating antidepressant and anxiolytic-like effects. Fluoxetine also normalises peripheral and central IL-6 and BDNF levels, enhances hippocampal neurogenesis, and restores synaptic marker expression in the mPFC. Additionally, fluoxetine modulates the GSK3β pathway in the hippocampus, further supporting its neuroplastic and anti-inflammatory action. Data are mean ± SEM. ANOVA followed by Fisher’s LSD post-hoc test, ***p < 0.001, **p < 0.01, *p < 0.05 vs. Saline-Vehicle. FST: n = 12/group, SPT: n = 6–7/group, EPM: n = 10–14/group, IL-6 and BDNF: n = 4–8/group, Neurogenesis: n = 8–10/group, Synaptic markers: n = 5–8/group, GSK3β: n = 4/group
Behavioural and Molecular Effects of A Single Ketamine Administration in the IFN-α Rat Model of Depression.
Behavioural Effect of Psilocybin in the IFN-α Rat Model of Depression.
A single subcutaneous dose of psilocybin (1 mg/kg) reverses IFN-α-induced immobility in the Forced Swim Test (FST) at 24h, indicating rapid antidepressant-like activity. This result is part of our broader platform for testing 5-HT₂A agonists, including multiple proprietary compounds assessed in the IFN-α model. Ongoing molecular studies are further characterising synaptic mechanisms of action. Data are mean ± SEM. ANOVA followed by Fisher’s LSD post-hoc test, ***p < 0.001 vs. Saline-Vehicle, n = 4–6/group.
INNATE MODEL
WISTAR KYOTO RAT (WKY)
The Wistar Kyoto (WKY) Rat is a wellcharacterised inbred strain that naturally exhibits depressive-like behaviours, including social withdrawal, anhedonia, and anxiety-like traits. This model requires no external manipulation and offers strong relevance for studying innate vulnerability to depression and treatment resistant pathways. At Ulysses Neuroscience Ltd., the WKY model has been implemented in multiple client-sponsored studies to investigate neuroplastogens and psychedelic agents. Our datasets include comprehensive characterisation of the Forced Swim Test (FST), EEG endpoints, and neuroplasticity-related biomarkers.
KEY FEATURES
• Innate depressive-like traits without the need for external manipulation
• Resistant to fluoxetine (SSRI), but responsive to desipramine (TCA)
• Decreased SV2a, PSD-95, and spinophilin (brain)
• Altered social behaviour in female urine sniffing and social interaction tests
• Reduced 55 kHz ultrasonic vocalisations (USVs)
• Disrupted sleep architecture (EEG)
• Suitable for testing rapid-acting antidepressants, neuroplastogens, psychedelics, and
non-hallucinogenic analogues
The Ulysses IFN-α model is featured in peer-reviewed publications by our clients:
• McDonnell, C. W., Dunphy-Doherty, F., Rouine, J., Bianchi, M., Upton, N., Sokolowska, E., & Prenderville, J. A. (2021). The
antidepressant-like effects of a clinically relevant dose of ketamine are accompanied by biphasic alterations in working memory
in the Wistar Kyoto rat model of depression. Frontiers in psychiatry, 11, 599588.
• Kantor, S., Lanigan, M., Giggins, L., Lione, L., Magomedova, L., de Lannoy, I., ... & Duxon, M. (2023). Ketamine supresses REM sleep
and markedly increases EEG gamma oscillations in the Wistar Kyoto rat model of treatment-resistant depression. Behavioural
Brain Research, 449, 114473.
PSYCHOSOCIAL STRESS MODEL
CHRONIC SOCIAL DEFEAT (CSD)
The Chronic Social Defeat (CSD) Mouse Model is a well-established paradigm of sychosocial stress-induced depression, widely used for studying stress susceptibility, resilience, and the underlyingneurobiological mechanisms of mood disorders. At Ulysses Neuroscience Ltd., the CSD model has been adapted and implemented in alignment with translational needs. This model involves repeated exposure of a test mouse to an aggressive conspecific, leading to long-lasting alterations in social behaviour, emotional reactivity, and stress physiology. It is particularly valuable for profiling novel antidepressant treatments and dissecting stress-related pathophysiology. Our current implementation focuses on clear behavioural stratification (susceptible vs. resilient animals) and is now expanding to include biomarker discovery and molecular profiling in brain and plasma samples.
KEY FEATURES
• Ethologically valid model of psychosocial stress-induced depression
• Repeated exposure to social defeat induces long-lasting behavioural changes
• Altered social interaction in susceptible mice
• Suitable for stratification into stress-resilient and stress-susceptible phenotypes
• Responsive to chronic fluoxetine treatment (SSRI)
• Ongoing profiling of neuroinflammatory and neuroplasticity-related biomarkers
• Ideal for assessing pro-resilience compounds, rapid-acting antidepressants, and neuroplastogens
CSD in mice - Protocol
Why Partner with Ulysses
- Unique triad of robust and complementary depression models (IFN-α, WKY, CSD)
- Biomarker-integrated behavioural, molecular and EEG endpoints
- Proven track record of high-quality, reproducible data
- Flexible study designs, shared-risk models, and co-development
opportunities
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