Measuring normal and pathological anxiety-like behaviour in mice: a review

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Abstract

Measuring anxiety-like behaviour in mice has been mostly undertaken using a few classical animal models of anxiety such as the elevated plus-maze, the light/dark choice or the open-field tests. All these procedures are based upon the exposure of subjects to unfamiliar aversive places. Anxiety can also be elicited by a range of threats such as predator exposure. Furthermore, the concepts of ‘state’ and ‘trait’ anxiety have been proposed to differentiate anxiety that the subject experiences at a particular moment of time and that is increased by the presence of an anxiogenic stimulus, and anxiety that does not vary from moment to moment and is considered to be an ‘enduring feature of an individual’. Thus, when assessing the behaviour of mice, it is necessary to increase the range of behavioural paradigms used, including animal models of ‘state’ and ‘trait’ anxiety. In the last few years, many mice with targeted mutations have been generated. Among them some have been proposed as animal models of pathological anxiety, since they display high level of anxiety-related behaviours in classical tests. However, it is important to emphasise that such mice are animal models of a single gene dysfunction, rather than models of anxiety, per se. Inbred strains of mice, such as the BALB/c line, which exhibits spontaneously elevated anxiety appear to be a more suitable model of pathological anxiety.

Introduction

The discovery of benzodiazepines (BZs) in the early sixties and their considerable commercial success in the treatment of anxiety has fueled the development of numerous animal models of anxiety. Unfortunately, because BZs were the only anxiolytic agents marketed at that time, the predictive validity of these initial models has been mainly based on their ability to detect the pharmacological action of BZs. This became evident in the early eighties, when non-BZ anxiolytics, such as the 5-HT1A receptor partial agonist buspirone, were found inactive in some anxiety tests, in particular conflict procedures. At that time, unconditioned conflict tests such as the elevated plus-maze were developed. Later, a second difficulty appeared, when it became evident that anxiety is not a unitary phenomenon but could be divided in various forms including ‘state’ and ‘trait’ anxiety, ‘normal’ and ‘pathological’ anxiety. These various forms have been shown to be differentially sensitive to pharmacological challenge. Therefore, when measuring anxiety in animals, it would be useful to have information on the type of anxiety processes which may be involved in a given test. These models are now extensively used not only to predict the clinical efficacy of pharmacological treatments, but also to phenotype the behaviour of transgenic or knockout mice.

The aim of the present paper is to consider animal models of both ‘normal’ and ‘pathological’ anxiety. Therefore, we will first give a tentative definition of anxiety, and review the validity criteria of animal models, before presenting animal models of ‘normal’ and ‘pathological’ anxiety. Only animal models using mice as subjects will be considered.

Section snippets

Tentative definition of anxiety

Fear and anxiety are here, respectively, defined as the response of a subject to real or potential threats that may impair its homeostasis. This response may include physiological (increase in heart rate, blood pressure etc.), as well as behavioural (inhibition of ongoing behaviours, scanning, avoidance of the source of danger, etc.) parameters. When this response is excessive or maladaptive, it involves ‘pathological’ anxiety. On a clinical level, the DSM IV [25] describes various forms of

Validity criteria of an animal model

What is an animal model of a human behavior? According to McKinney, animal models are ‘experimental preparations developed in one species for the purpose of studying phenomena occurring in another species’ [57]. Kaplan [45] added that a model may be valid if it has the same structure as the human behavior or pathology, that is whenever a relation holds between two elements of the animal model, a corresponding relation may hold between the corresponding elements of the human behavior.

Other

‘Normal’ anxiety and ‘pathological’ anxiety

Two rather opposite conceptions have been proposed as to the relationship between the ‘normal’ and ‘pathological’ state of a subject. In fact, pathology can be described either as a quantitative variation of a normal state, or as a qualitative variation. According to the first conception, ‘pathological’ anxiety might be considered as an excess of ‘normal’ anxiety. The second conception of the relationship between normality and pathology proposes that there is a qualitative, rather than a

Mouse models of anxiety

Over the past three decades, a bewildering diversity of tests has been developed which claim face, construct and/or predictive validity as animal models of anxiety disorders (for review, see [73], [89]). While most of these procedures use rats as subjects, a few of them have been validated with mice. Most of them involve exposure of subjects to external (e.g. cues earlier paired with footshock, bright light, predator) or internal (e.g. drug states) stimuli that are assumed to be capable of

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