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Model organisms

The ascent of mouse: advances in modelling human depression and anxiety

Nature Reviews Drug Discovery volume 4, pages 775790 (2005) | Download Citation

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Abstract

Psychiatry has proven to be among the least penetrable clinical disciplines for the development of satisfactory in vivo model systems for evaluating novel treatment approaches. However, mood and anxiety disorders remain poorly understood and inadequately treated. With the explosion in the use of genetically modified mice, enormous research efforts have been focused on developing mouse models of psychiatric disorders. The success of this approach is largely contingent on the usefulness of available behavioural models of depression- and anxiety-related behaviours in mice. Here, we assess the current status of research into developing appropriate tests for assessing such behaviours.

Key points

  • Depression and anxiety disorders are serious, growing medical problems that remain poorly understood and inadequately treated. However, psychiatry has proven to be among the least penetrable clinical disciplines for the development of satisfactory in vivo model systems for evaluating novel treatment approaches.

  • Although the rat has traditionally been the species of choice for assessing behavioural effects of manipulations relating to mental illness, there has been a recent explosion in the use of genetically modified mice and enormous research efforts have been focused on developing mouse models of psychiatric disorders.

  • The success of using genetically modified mice as models of psychiatric disorders is largely contingent on the utility of available behavioural models of depression- and anxiety-related behaviours. Here, we assess the current status of research aimed at developing such models.

  • There are several challenges facing the drug discovery industry as it endeavours to identify 'translational models' for anxiety and depression. The development of animal models of specific features of the disease, 'endophenotypes', which have a defined neurocircuitry or genetic basis, is emerging as a useful strategy.

  • Mouse models of depression largely rely on the reaction of the animal to stressful situations, although efforts are underway to develop models of specific features of the disease, such as anhedonia and cognitive dysfunction.

  • Popular tests for anxiety-like behaviours are often based on ethologically relevant behaviours, such as aversion to exposed, well-lit spaces.

  • The use of cognitive-based tasks that involve Pavlovian fear conditioning is one approach that is being used in both mouse and human situations to explain the neural substrates of fear and learning and memory in the brain.

  • Recent emphasis has been placed on developing mouse models of the childhood origins of anxiety and depression as childhood trauma and neglect exert a profound and pervasive influence on risk for depression and anxiety disorders.

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Acknowledgements

JFC is supported by a grant from the National Institutes of Mental Health/National Institute on Drug Abuse. AH is supported by the National Institute on Alcohol Abuse and Alcoholism intramural research programme and by the National Alliance for Research on Schizophrenia and Depression.

Author information

Affiliations

  1. Neuroscience Research, Novartis Institutes for BioMedical Research, Basel CH 4055, Switzerland, and Department of Pharmacology, School of Pharmacy, University College Cork, Ireland (from Jan 2006).

    • John F. Cryan
  2. Section on Behavioural Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Andrew Holmes

Authors

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  2. Search for Andrew Holmes in:

Competing interests

J.F.C. is an employee of Novartis Pharma AG.

Corresponding authors

Correspondence to John F. Cryan or Andrew Holmes.

Glossary

QUANTITATIVE TRAIT LOCUS ANALYSIS

Mapping the location of a genomic locus and estimating the percentage of its contribution (effect size) to the genetic basis of a specific behavioural phenotype that is genetically complex and continuous in a population.

PROGRESSIVE RATIO SCHEDULE

Requires an increase in operant responding for reward until a 'break-point' is reached. The break-point determines the maximal amount of effort made to procure the reward and therefore the subject's level of motivation.

INTRACRANIAL SELF-STIMULATION (ICSS)

A direct measure of brain reward function that works by mice pressing lever or turning a wheel to receive electrical intracranial self-stimulation of brain regions that are activated by natural reinforcers.

FLANKING GENES

DNA sequences on either side of a targeted gene mutation that derive from the embryonic donor mouse strain and could contain genes foreign to the host mouse that spuriously influence the behavioural phenotype of the host.

CONGENIC

A mutant line generated from repeated backcrossing to an inbred strain for ten generations or more.

GALVANIC SKIN CONDUCTANCE RESPONSES

A measure of electrical resistance used as a marker for changes in emotional arousal.

SIGNAL DETECTION TASK

Measures whether a subject perceives an ambiguous stimulus as being similar to an emotionally charged target stimulus.

CONSTITUTIVE MUTATION

A targeted mutation that prevents transcription of a gene of interest throughout development and adulthood in all cells where it is normally expressed.

TRANSLATIONAL MEDICINE

The testing of novel therapeutic strategies (in humans) that were developed through basic laboratory experimentation. Observations taken from the bedside-to-the-bench also constitute translational medicine.

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DOI

https://doi.org/10.1038/nrd1825

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