Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression

Abstract

Animal models of psychiatric disorders are usually discussed with regard to three criteria first elaborated by Willner; face, predictive and construct validity. Here, we draw the history of these concepts and then try to redraw and refine these criteria, using the framework of the diathesis model of depression that has been proposed by several authors. We thus propose a set of five major criteria (with sub-categories for some of them); homological validity (including species validity and strain validity), pathogenic validity (including ontopathogenic validity and triggering validity), mechanistic validity, face validity (including ethological and biomarker validity) and predictive validity (including induction and remission validity). Homological validity requires that an adequate species and strain be chosen: considering species validity, primates will be considered to have a higher score than drosophila, and considering strains, a high stress reactivity in a strain scores higher than a low stress reactivity in another strain. Pathological validity corresponds to the fact that, in order to shape pathological characteristics, the organism has been manipulated both during the developmental period (for example, maternal separation: ontopathogenic validity) and during adulthood (for example, stress: triggering validity). Mechanistic validity corresponds to the fact that the cognitive (for example, cognitive bias) or biological mechanisms (such as dysfunction of the hormonal stress axis regulation) underlying the disorder are identical in both humans and animals. Face validity corresponds to the observable behavioral (ethological validity) or biological (biomarker validity) outcomes: for example anhedonic behavior (ethological validity) or elevated corticosterone (biomarker validity). Finally, predictive validity corresponds to the identity of the relationship between the triggering factor and the outcome (induction validity) and between the effects of the treatments on the two organisms (remission validity). The relevance of this framework is then discussed regarding various animal models of depression.

Differential susceptibility of BALB/c, C57BL/6N, and CF1 mice to photoperiod changes

“…It would be of interest to incorporate rhythm changes into translationally relevant rodent models, 11 given that changes in sleep (e.g., delayed onset, non-restful sleep, early morning awakening, and daytime fatigue) are among the most characteristic symptoms of depression. 31 Temperature rhythm itself is a robust parameter, 32 which, when combined with activity rhythms, may prove useful for characterizing desynchronization.…”

“…[8][9][10] Translational research calls for animal models that employ known etiological and risk factors that can result in measurable behavioral and/or physiological changes, preferably mimicking those of the human disease of interest. 11 Mice have been extensively used in behavioral research both to predict psychoactive properties of molecular entities in research and development of drug discovery programs and to understand the pathophysiology of central nervous system (CNS) disorders. 12,13 Despite differences in endogenous periods among species, rodent models are suitable for studying the effects of rhythm disruption on behavior and physiology.…”

Neural substrates of cognitive bias and anxiogenesis

“…The proposed criteria for validation of animal models for anxiety and depression studies [5] define a paradigm better suited for this type of focused research. By providing face validity, predictive validity, and construct validity, this paradigm has a potential to better connect the studies of cognitive bias with those focused on susceptibility or resilience.…”

“…Varying definitions and techniques of inducing stress, difficulties in connecting animal and human behavior to specific neuronal pathway and the nature of evolving diagnostic criteria present additional challenges. Use of clearly defined criteria for testing and characterizing anxiety and depression-related behaviors in animal models have also been proposed [5].…”

Time to recognize zebrafish ‘affective’ behavior

“…The use of larval and adult zebrafish in high-throughput models is one of the most promising strategies to increase our understanding of complex psychiatric disorders (Lessman, 2011;Rihel & Schier, 2012). However, this goal is not possible without careful examination of behavioral responses (face validity) to known psychiatric states and treatments (predictive validity), identifying neural pathways (construct validity), individual risk factors and mechanisms of resilience (population validity), evaluating evolutionarily conserved traits (homological validity), testing replicability/reliability of zebrafish models (internal validity), and analyzing their external validity); see (Willner, 1986;van der Staay et al, 2009;Belzung & Lemoine, 2011) for discussion of valid animal behavioral models.…”