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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.

Partner With Us

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

The Ulysses Triad of 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:

Pharmacological Model – IFN-α in Rat:
mimics inflammation-driven depression using systemic interferon-alpha treatment.
Innate Model – Wistar Kyoto (WKY) Rat:
an inbred rat strain with natural depressive traits and no response to SSRIs.
Psychosocial Stress Model – Chronic Social Defeat (CSD) in Mouse:
a behavioural paradigm replicating the impact of chronic social stress.

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)

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 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

EEG: Effects pf Psilocybin on sleep architecture

Figure provided by Tranpharmation.
Behavioural, Molecular, and EEG Effects in the WKY Rat Model of Treatment-Resistant Depression. Fluoxetine fails to reverse depressive-like behaviour or modulate synaptic markers in WKY rats, confirming the model’s treatment-resistant phenotype. In contrast, desipramine, ketamine, and psilocybin all rescue immobility in the Forced Swim Test (FST). However, ketamine and psilocybin produce stronger enhancements in synaptic protein expression in mPFC synaptosomes. EEG telemetry shows that psilocybin modulates sleep architecture, reducing REM sleep and increasing wakefulness, with patterns more closely resembling those of normal rats. Data are mean ± SEM. ANOVA followed by Fisher’s LSD post-hoc test, ***p < 0.001, **p < 0.01, *p < 0.05 vs. WKY-Vehicle. FST and Synaptic Markers: n = 4–6/group, EEG: n = 4/group

Innate Model – Wistar Kyoto Rat (WKY)

The Chronic Social Defeat (CSD) Mouse Model is a well-established paradigm of psychosocial stress-induced depression, widely used for studying stress susceptibility, resilience, and the underlying neurobiological 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

Social Preference Test

CSD in mice: Efficacy of Ketamine and Psilocybin

Figure provided by Transpharmation.
Chronic Social Defeat in Mice: Protocol, Classification, and Treatment Response. CSD induces a depression-like phenotype in a subset of mice, characterised by social avoidance in the Social Preference (SP) Test. Following a 10-day protocol of exposure to aggression, mice are classified as susceptible (SUS; SP < 100%) or resilient (RES; SP > 100%), based on their interaction with a CD-1 aggressor. Acute administration of ketamine (10 mg/kg, SC) reverses social avoidance in SUS mice and shows persistent efficacy up to 7 days post-treatment. Fluoxetine (10 mg/kg, SC) and desipramine (10 mg/kg, SC) are ineffective. Psilocybin (3 or 10 mg/kg, IP) also produces robust acute and sustained pro-social effects, supporting its long-lasting behavioural activity. Data are mean ± SEM. Mixed-effects ANOVA followed by Fisher’s LSD post-hoc test. (Left): **p < 0.01, ***p < 0.001 vs. CTRL+VEH (pre-treatment); ####p < 0.0001 vs. CTRL+VEH (post-treatment); (right) *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs. baseline; #p < 0.05 vs. 24h; n = 5–14 per group