New frontiers in animal research of psychiatric illness

Abstract

Alterations in neurodevelopment are thought to modify risk of numerous psychiatric disorders, including schizophrenia, autism, ADHD, mood and anxiety disorders, and substance abuse. However, little is known about the cellular and molecular changes that guide these neurodevelopmental changes and how they contribute to mental illness. In this review, we suggest that elucidating this process in humans requires the use of model organisms. Furthermore, we advocate that such translational work should focus on the role that genes and/or environmental factors play in the development of circuits that regulate specific physiological and behavioral outcomes in adulthood. This emphasis on circuit development, as a fundamental unit for understanding behavior, is distinct from current approaches of modeling psychiatric illnesses in animals in two important ways. First, it proposes to replace the diagnostic and statistical manual of mental disorders (DSM) diagnostic system with measurable endophenotypes as the basis for modeling human psychopathology in animals. We argue that a major difficulty in establishing valid animal models lies in their reliance on the DSM/International Classification of Diseases conceptual framework, and suggest that the Research Domain Criteria project, recently proposed by the NIMH, provides a more suitable system to model human psychopathology in animals. Second, this proposal emphasizes the developmental origin of many (though clearly not all) psychiatric illnesses, an issue that is often glossed over in current animal models of mental illness. We suggest that animal models are essential to elucidate the mechanisms by which neurodevelopmental changes program complex behavior in adulthood. A better understanding of this issue, in animals, is the key for defining human psychopathology, and the development of earlier and more effective interventions for mental illness.

Fig. 1

Animal work should play a central role in the development of more effective interventions for mental illness. Advances in sequencing technologies provide a growing list of candidate genes implicated in mental illness (step 1). Genes implicated in mental illness are used to define endophenotypes (step 2) that segregate with the genetic biomarker. Endophenotypes should also inform about pathophysiology (step 3) and help guide interventions (step 4) with improved clinical outcome (step 5). Work in animals plays a central role in the transition along steps 1–5. This includes characterization of neurodevelopmental pathways by which genes identified in step 2 affect brain function and adult behavior. Such work identifies additional genes implicated in these behavioral changes (step 6), helps define possible endophenotypes (step 7), informs about pathological changes (step 8), and helps in the development of novel diagnostic and interventional strategies (step 9).