From psychiatric disorders to animal models: a bidirectional and dimensional approach

Psychiatric genetics research is bidirectional in nature, with human and animal studies becoming more closely integrated as techniques for genetic manipulations allow for more subtle exploration of disease phenotypes. This synergy highlights the importance of considering the way in which we approach the genotype-phenotype relationship. In particular, the nosologic divide of psychiatric illness, although clinically relevant, is not directly translatable in animal models. For instance, mice will never fully recapitulate the broad criteria for many psychiatric disorders; additionally, mice will never have guilty ruminations, suicidal thoughts, or rapid speech. Instead, animal models have been and continue to provide a means to explore dimensions of psychiatric disorders to identify neural circuits and mechanisms underlying disease-relevant phenotypes. The genetic investigation of psychiatric illness can yield the greatest insights if efforts continue to identify and use biologically valid phenotypes across species. This review discusses the progress to date and the future efforts that will enhance translation between human and animal studies, including the identification of intermediate phenotypes that can be studied across species and the importance of refined modeling of human disease-associated genetic variation in mice and other animal models.