Currently, over 300 million people worldwide have depression, and the socioeconomic burden of this debilitating disorder is anticipated to increase markedly over the coming decades against a background of increasing global turmoil. Despite this impending crisis, we are still waiting for improved therapeutic options for this disorder to emerge, which has led to increasing criticism of the role and value of preclinical models of depression. In this Review, we examine this landscape, focusing firstly on issues related to the terminology used in this context and the myriad of preclinical approaches to modelling and assaying aspects of depression in rodents. We discuss the importance of sex as a biological variable and the controversial idea of intergenerational and transgenerational transmission of depressive-like traits. We then examine the technical strategies available to dissect these models and review emerging evidence for putative druggable disease mechanisms. Finally, we propose a brief framework for future research that makes optimal use of these models and will, we hope, accelerate the discovery of improved antidepressants.
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The authors gratefully acknowledge F. Freudenberg and A. O’Leary for their critical comments. D.A.S. is funded by European Community (EC) CORDIS (Community Research and Development Information Service) Framework Programme 7 (FP7) grant 602805; J.F.C. is employed by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI) through the Irish Government’s National Development Plan (grant no. 12/RC/2273). A.R. is funded by EC CORDIS FP7 grant 602805, Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) grant SFB1193 and EC Horizon 2020 Research and Innovation Framework Programme (H2020) grant 667302. A.G. is supported by a University of Sydney Research Fellowship and funded by H2020 grant MSCA-IF-2015 (DE-STRESS, Project ID: 704995). J.F.C. acknowledges research funding received from 4D Pharma, Alkermes, Cremo, Dupont Nutrition Biosciences, Mead Johnson Nutrition, Nutricia Danone and Suntory Wellness unrelated to the subject matter of this Review.
The authors declare no competing interests.
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- Homological validity
The relevance of the selected model, species and strain to the phenotype or condition under investigation.
- Pathogenic validity
The degree of alignment between species (including mouse versus human) in the process leading to the disease condition. Pathogenic validity can be further subdivided into ontopathogenic validity (which examines the influence of early environmental factors on vulnerability) and triggering validity (which refers to the similarity of factors that lead to pathology such as stress experienced in adulthood).
- Mechanistic validity
How closely the disease process or mechanism observed in the model aligns with the presumed clinical pathology.
- Convergent validity
An overall assessment of face, construct or predictive validities in terms of similarity to the condition under investigation.
- Discriminant validity
The specificity of face, construct or predictive validities to the condition under investigation; for example, decreased sucrose preference is observed in mouse models of depression but is not seen in mouse models of anxiety or schizophrenia.
- Internal validity
Consistency between the phenotype or model being studied, theories of the underlying disease process, biological and other related aspects of the disease; for example, decreased sucrose preference is consistent with decreased preference in the female urine sniffing test. Internal validity also refers to the robustness of the experimental design; for example, in terms of minimizing bias and blinding.
- External validity
Refers to applicability of the model or phenotype being studied to the disease and the disease population; it can also refer to the extent to which the effects of a specific inducing manipulation are reproducible across different laboratories.
- Model versus test
A model that comprises both an independent variable, known as the inducing manipulation, and a dependent variable that acts as a behavioural or neurochemical readout; a test simply comprises the latter variable.
- Forced swim test
This test involves placing rodents in a cylinder filled with water, which forces them to swim. Protocols differ between rats and mice, particularly in terms of test duration (over 2 days in rats, only 1 day in mice). Behaviours typically scored include immobility and climbing time.
- Tail suspension test
This test involves suspending mice above the ground by the tail for 6 min with immobility time scored for the full session or for the final 4 min. In contrast to the forced swim test, this assay avoids the potential confounding effects of hypothermia and does not depend on the rodent’s ability to swim.
- Learned helplessness
Protocols for this assay differ greatly between mice and rats but they both examine the latency to escape an uncontrollable aversive shock stimulus.
A state in which an individual is unable to appropriately manage stress, overreacts to negative stimuli and has poor self-control.
- Elevated plus maze
For this test, rodents are placed on an elevated, plus-shaped apparatus that has two arms without walls and two with walls that intersect in a centre area. A mouse is placed in the centre area and given free access to all four arms. The time spent and entries into each arm are used as indicators of anxiety-like behaviour. Another extractable measure from this test includes head-dipping from the open arms, which is considered a risk-assessment behaviour.
- Novelty-suppressed feeding test
For this test, rodents are food restricted for a period of time prior to being placed in an open field under a bright light. In the middle of the field is a small piece of chow. Latency to approach and eat the piece of chow is a measure of anxiety-like behaviour. This assay also tests the ability of rodents to deal with the conflict of an anxiogenic environment and the drive to seek a food reward.
In female mice, the oestrus cycle is 4–5 days and comprises four stages: proestrus, oestrus, metoestrus and dioestrus.
Olfactory chemical signals released by rodents that can influence conspecific behaviour.
- Ultrasonic vocalization
Ultrasonic vocalizations in mice are proxy readouts for vocal communication in humans; they are observed in a range of different contexts, including mother–infant relationships, juvenile interactions and sexual encounters between conspecifics.
The birth of new neurons, which primarily occurs in distinct sub-regions of the hippocampus and is consistently observed in rodents; debate continues in the human literature.
- Intracranial self-stimulation
This assay uses an operant chamber, in which rodents self-administer electrical stimulation via electrodes implanted into brain reward structures such as the ventral tegmental area, nucleus accumbens and the medial forebrain bundle. A rightward shift in stimulation threshold is usually indicative of a stimulus-induced decrease in reward function (that is, anhedonia), whereas a leftward shift reflects an increase in reward function.
- Operant chamber
Also known as a Skinner box, this is an apparatus in which an animal must depress a lever or activate a similar sensor to obtain a reward.
- Maternal immune activation
In this paradigm, pregnant dams are injected with a single dose of polyinosinic:polycytidylic acid or lipopolysaccharide.
A term used to describe the connectivity between two components of the CNS.
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Gururajan, A., Reif, A., Cryan, J.F. et al. The future of rodent models in depression research. Nat Rev Neurosci 20, 686–701 (2019). https://doi.org/10.1038/s41583-019-0221-6
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