By disease model we mean more than a useful tool for probing abnormal neurobiology and behavior. Disease models should be derived from plausible risk factors or causative agents of human disease or else exhibit a significant degree of neural or behavioral pathology that corresponds convincingly to human disease. Animal models of neuropsychiatric disorders have been generated through diverse means, including selective breeding, genetic engineering, brain lesions, and environmental manipulations (). Optogenetic manipulations of specific circuits21
promise a useful new approach.
Approaches to constructing animal models of neuropsychiatric disorders
Given these diverse approaches and the challenges of validation, it is useful for the scientific community to share criteria for judging whether a particular disease model is “good enough” to warrant further investments. A longstanding framework posits three types of validators: construct, face, and predictive validity. This framework would benefit from greater agreement on how stringently to judge validators. Too often validity is asserted in published papers rather than systematically discussed in terms of strengths and weaknesses.
refers to the disease relevance of the methods by which a model is constructed. In the ideal situation, researchers would achieve construct validity by recreating in an animal the etiologic processes that cause a disease in humans and thus replicate neural and behavioral features of the illness22
. A straightforward way of accomplishing this would be knocking into a mouse a known disease-causing (Mendelian) genetic mutation or, with somewhat less certainty, inserting a highly—but not fully—penetrant genetic variant that markedly increases vulnerability for a human disease. However, this is currently not possible for most mental illnesses since such disease-causing genes have not been established with certainty and most disorders exhibit highly complex genetic architecture23
. Moreover, most reported genetic associations represent common variants of small effect, which makes their utility for animal models highly questionable (Box 2
In addition to genetic manipulation, disease models can be generated by altering the expression or function of particular proteins, biochemical pathways, or neural circuits hypothesized to play a role in disease pathogenesis (). The challenge for interpreting such approaches, in the absence of relevant human genetic evidence, is whether they represent legitimate disease models rather than interesting phenocopies. There is an important chasm between the claim that disruption of some biochemical pathway regulates behavior vs. the claim that it models a particular human disorder with useful implications for pathophysiology or treatment development.
Construct validity might also be achieved through exposure of an animal to a well-validated environmental risk factor or known disease-causing agent. An example would be a pathogenic prion inducing Creutzfeldt-Jakob disease in rodents23
. However, beyond this straightforward case, there is much room for disagreement in selecting thresholds for construct validity of environmental insults given their frequent lack of specificity: virtually all environmental contributions to mental illness, such as stress or childhood adversity25
, are associated with multiple disorders and most often normal outcomes.
Given the pleomorphic effects of genes in the brain, the shallow and phenomenological nature of current disease classification for mental disorders7
, and the still evolving understanding of how disease-associated genes correlate with disease phenotypes23
, it is critical to be circumspect about when construct validity is achieved and, if so, how best to use the resulting model.
signifies that a model recapitulates important anatomical, biochemical, neuropathological, or behavioral features of a human disease. As stated earlier, however, there are few if any neurobiological abnormalities known with certainty to be hallmarks or biomarkers of common mental illnesses. Consequently, behavioral features reminiscent of a human disorder are still required to achieve face validity. Unfortunately, it is not likely that any animal model of a neuropsychiatric disorder would recapitulate all of the behavioral features observed in humans or even that single behaviors will precisely model the human situation. Moreover, the diagnosis of a given disorder can be highly variable and inexact (see Box 1
). Thus, judgments of face validity will often be contested, putting the onus on authors to make explicit arguments for and against face validity in a proposed animal model.
Predictive (or pharmacological) validity
signifies that a model responds to treatments in a way that predicts the effects of those treatments in humans. For neuropsychiatric disorders, however, predictive validity is a highly vexed concept. As stated earlier, the targets of the major classes of drugs that treat neuropsychiatric disorders were identified post hoc
by studying the mechanism of action of drugs identified by serendipity4
. In order to discover new drugs, several behavioral screens were developed (see Supplementary Tables 2–4
) that used the animal nervous system as a black box, with behavior as its readout, to detect drugs that act in similar fashion to existing reference compounds. These screens were not developed as mechanistic models of drug action, nor have they been shown to reflect either the pathophysiological processes of human disease or the therapeutic mechanism of action of the reference compounds. These screens also may not detect potential efficacy of compounds that interact with distinct molecular targets. A frequent failing of the literature is the use of such screens as if they were based on validated pathophysiological models.