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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?

  • Pharma & biotech companies developing innovative CNS therapeutics

  • Psychedelic developers seeking validated models and endpoints for regulatory submission

  • Translational research teams investigating neuroplasticity, inflammation, and biomarker integration

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

Our Validated Depression Models

Major Depressive Disorder (MDD) is not a single-entity 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.
Depression_models_ulysses-Neuroscience

Biomarker & 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)
  • Alamar NULISA-seq for exploratory biomarker discovery in rare and complex neurological disorders

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
  • Pinnacle Tethered Video-EEG

Validation of Ulysses Depression Models

Pharmacological Model – IFN-α in RAT

The IFN-α Rat Model is a robust and back-translational 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.

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

Innate Model – Wistar Kyoto Rat (WKY)

The Wistar Kyoto (WKY) Rat is a well-characterised 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

Forced Swimming Test

Synaptic Marker alterations in mPFC Synaptosomes

Publications

The Ulysses IFN-α model is featured in peer-reviewed publications by our clients:

The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

Link

Aarrestad, I. K., Cameron, L. P., Fenton, E. M., Casey, A. B., Rijsketic, D. R., Patel, S. D., … & Olson, D. E. (2025).

Nature Neuroscience, 1–13.

5-HT1B receptor activation produces rapid antidepressant-like effects in rodents

Link

Clark, E. A., Wang, L., Hanania, T., Kretschmannova, K., Bianchi, M., Jagger, E., … & Bristow, L. J. (2025).

Pharmacology Biochemistry and Behavior, 247, 173917.

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

Callaghan, C., Garrone, B., Milanese, C., Freeburn, A., Kealy, J., & Bianchi, M. (2025).

[submitted]

Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring

Link

Yennemadi, A. S., Jameson, G., Glass, M., De Pasquale, C., Keane, J., Bianchi, M., & Leisching, G. (2023).

Cellular Immunology, 390, 104741.

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

Link

McDonnell, C. W., Dunphy-Doherty, F., Rouine, J., Bianchi, M., Upton, N., Sokolowska, E., & Prenderville, J. A. (2021).

Frontiers in psychiatry, 11, 599588.

Ketamine supresses REM sleep and markedly increases EEG gamma oscillations in the Wistar Kyoto rat model of treatment-resistant depression

Link

Kantor, S., Lanigan, M., Giggins, L., Lione, L., Magomedova, L., de Lannoy, I., … & Duxon, M. (2023).

Behavioural Brain Research, 449, 114473.

Posters

Depression models and synaptic markers – IFN-alpha and WKY rats

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Enya Paschen, Connor Maltby, Priyadarshini Jayabal, Davide Selleri, Jessica Pinto, Massimiliano Bianchi

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