Modelling human anxiety and depression in mutant mice

Mood and anxiety disorders represent some of the most common and proliferating health problems worldwide, but are inadequately treated by existing therapeutic interventions. Valid animal models of anxiety and depression have a critical role to play in identifying novel therapeutic targets for these debilitating conditions. The emergence of techniques that allow genetic manipulation of specific molecules in mice has added a valuable new dimension to this field of research. In this chapter, we discuss some of the conceptual issues surrounding the use of mutant mice to study anxiety and depression, the behavioral tasks commonly used for assessment, and important caveats associated with the use of mutant mice. Anxietyrelated behavior is most commonly assayed in mice using tests based on exploratory approach/ avoid conflict (e.g., elevated plus maze, open field, light-dark exploration, and hyponeophagia), although a variety of alternatives exist (e.g., stress-induced hyperthermia, mouse defense test battery, Vogel conflict, shock-probe burying, four-plate test, marble burying, and separation-induced pup ultrasonic vocalizations). Mouse tests for depressionrelated behaviors include models based on “behavioral despair” (forced-swim test, tail-suspension test, and learned helplessness), as well as chronic mild stress, olfactory bulbectomy, and psychostimulant withdrawal. Various factors can confound performance and complicate interpretation of the behavior of mutant mice on anxiety- and depression-related tasks, including genetic background, abnormal motor and sensory phenotypes, previous test history, and variability in early life environment and parental behavior. In addition, lifelong constitutive mutations can recruit compensatory changes that occlude the normal function of a molecule in neural circuits mediating emotion-related behaviors. Mutant mice provide a particularly valuable approach to the study of anxiety disorders and depression and their treatment when used in conjunction with other techniques to generate converging lines of evidence regarding the role of a molecule in these circuits. When viewed as such, we believe that mutant mice will continue to foster the study of anxiety and depression.