Animal Models of Depression and Antidepressant Effects

Preclinical research into depression relies on validated animal paradigms that recapitulate core features of the disorder. Models such as olfactory bulbectomy, chronic unpredictable mild stress and learned helplessness generate behavioural hallmarks including anhedonia, behavioural despair and cognitive deficits. Pharmacological challenge in these paradigms establishes predictive validity, guiding the development of novel antidepressants. Outcome measures span a range of tests: forced-swim and tail-suspension assays index passive coping strategies; sucrose-preference probes hedonic capacity; open-field tasks reveal alterations in locomotion and anxiety. Advances in genetic and circuit-based models employ targeted manipulations of neurotrophic, monoaminergic and inflammatory pathways. For example, transgenic mice with altered brain-derived neurotrophic factor expression or microglial phenotype shifts in lipopolysaccharide-induced depression models have shed light on immune–neural interactions. More recently, focus has turned to oscillatory network dynamics, such as limbic gamma oscillations, revealing mechanistic links between disrupted rhythms and mood-like behaviours. Together, these approaches enhance our grasp of pathophysiology and foster translational pipelines for antidepressant discovery, with global significance for treatment-resistant depression and tailored therapeutic strategies.

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Animal Models of Depression and Antidepressant Effects publication trend

The graph below shows the total number of articles in animal models of depression and antidepressant effects across all publications each year (not limited to Nature Index journals).

Technical terms

Olfactory bulbectomy (OBX): Surgical removal of the olfactory bulbs to induce persistent depression-like behaviour in rodents.

Chronic unpredictable mild stress (CUMS): Exposure to a variable sequence of mild stressors to produce anhedonia and behavioural despair.

Forced-swim test: A behavioural assay measuring immobility in water as an index of behavioural despair.

Sucrose-preference test: Assessment of anhedonia through preference for a sweet solution over water.

Gamma oscillations: High-frequency neural rhythms (30–100 Hz) implicated in cognitive and mood regulation.

Brain-derived neurotrophic factor (BDNF): A neurotrophin that supports synaptic plasticity and is linked to antidepressant efficacy.

References

1. Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents. Neuron (2023).
2. Endogenous Omega (n)-3 Fatty Acids in Fat-1 Mice Attenuated Depression-Like Behavior, Imbalance between Microglial M1 and M2 Phenotypes, and Dysfunction of Neurotrophins Induced by Lipopolysaccharide Administration. Nutrients (2018).
3. Repeated Sulforaphane Treatment Reverses Depressive-like Behavior and Exerts Antioxidant Effects in the Olfactory Bulbectomy Model in Mice. Pharmaceuticals (2024).
4. Long‐term stability and characteristics of behavioral, biochemical, and molecular markers of three different rodent models for depression. Brain and Behavior (2019).