ReviewWhat's wrong with my mouse model?: Advances and strategies in animal modeling of anxiety and depression
Introduction
Stress underlies anxiety and affective disorders [8], [12], [102], [130], [151], [152], [366]. Human anxiety is associated with excessive worries, and its formalized disorders include generalized anxiety, panic, social and separation anxiety, agoraphobia, post-traumatic stress and obsessive–compulsive (OCD) disorders [202], [261], [331], [354]. Unipolar and bipolar depression constitute another common group of stress disorders with a wide spectrum of syndromes (depressed mood, anhedonia, sleep disturbances, negative thinking and suicidality) and unclear pathogenesis [79], [165], [368].
In her recent book “What's wrong with my mouse?” Crawley [73] comprehensively evaluated current animal models of anxiety and depression, which have also been discussed in detail in several recent reviews [20], [78], [79], [195], [257], [337]. While researchers’ confidence in these models varies [69], [338], they are indispensable for screening psychotropic drugs [109], [288], [346], [368], phenotyping gene-targeted and transgenic animals [73], [108], [345], testing neurobiological hypotheses and finding candidate genes for human disorders [65], [119], [195], [280].
Traditional anxiety models include exploration-based paradigms (e.g., open field, holeboard, elevated plus maze, light–dark box, mirrored chamber, social interaction tests) and conditioned or unconditioned threat responses [1], [105], [108], [134], [160], [205], [264], [298]; Table 1. Popular experimental models of depression include “despair” paradigms (such as Porsolt's forced swim, tail suspension tests and learned helplessness), as well as olfactory bulbectomy, maternal/social deprivation and “anhedonic” chronic mild stress [15], [64], [80], [81], [82], [90], [226], [232], [233], [363], [364], [365]. With the growing popularity of these tests in neuroscience, drug development and genetics research [76], [103], [115], [207], [240], [251], [314], [316], [345], [348], it is timely to re-examine the current situation with animal models of anxiety and depression. The present review aims to discuss further challenges and outline strategic perspectives of research in this field.
Section snippets
State of the art: moving from Hall and Montgomery
In general, there are as many methodological and conceptual problems with animal experimental models of stress, as exist detailed protocols and useful recommendations on how to overcome these problems [20], [75], [76], [77], [116], [297], [330]. Certain features of human behavior and cognition cannot be fully reproduced in animals, which complicates potential translation of human symptoms into animal tests [78], [207], [368]. Animal paradigms often fail to reproduce complex multi-syndromal
Current discussions
Several important discussions in the field will be commented on here. First, while some authors stress stringent standardization of experimental conditions [350], [358], [359], others question its utility [369], [370]. Although substantial inter-laboratory variability has been reported in the literature [70], [358], [360], other studies have shown that some behaviors and their patterning either remain stable in varying environmental conditions [184], [359], [367], or vary despite
Deeper into anxiety and depression
Importantly, anxiety and depression, as both dramatic and debilitating multi-facetic psychiatric illnesses, demonstrate marked overlap and co-occurrence [113], [260], [261], [262], [263], [331]. Many of their symptoms are similar, and mild anxiety can be difficult to distinguish from mild depression. Depression is common in anxiety patients and anxiety is often reported in depressed patients, both being predictors of poor outcome [260], [263]. Over the past several decades, there has been
Expanding beyond anxiety and depression: focus on obsessions, compulsions and impulsivity
The emerging link between clinical anxiety, depression and some other brain disorders prompts the need in animal models that specifically address this aspect of pathogenesis, and extend beyond anxiety and depression domains [112]. For example, given high comorbidity of anxiety and autism, the possibility to study this phenomenon in animal models of autism based on social interaction is particularly interesting [74], [167], [249], [250], [293], [312], and is also relevant to social anxiety
Modeling other relevant brain disorders
In addition to modeling emotional and behavioral disorders, there are several other related psychiatric conditions that merit further scrutiny. For example, anxiety is often seen in serotonin syndrome [122], [168], and may be an interesting target for experimental modeling. Serotonin syndrome is a serious disorder, commonly observed in humans with increased serotonergic tone due to antidepressant therapy [96], [120], [122]. A similar phenomenon has been reported in animals with
“Hybridizing” animal models
In addition to targeting specific domains, some models can simultaneously be relevant to several disorders, or their subtypes. Conceptualized as “hybrid models” [180], these models are particularly interesting from the animal modeling point of view. For example, the forced swim paradigm is a test of depression, but can also induce post-swim anxiety (serving as its model). Despite early claims of specificity to depression, this paradigm may also be used as a test of anxiety, due to sensitivity
Concluding remarks: reinforcing the “mouse psychiatry”
The 1973 Nobel Prize to von Frisch, Lorentz, and Tinbergen marked a major success of behavioral analysis, and we should continue work in this direction, promoting the ideas of in-depth behavioral dissection of complex phenotypes and translating animal data into clinical research. While some authors recommend concentrating on a few models with high face and construct validity, care should be taken to heed famous warning [194] that the dangers are not in working with models, but in working with
Acknowledgement
This study was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH/NIH, USA).
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