Interactive reportBehavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests1
Introduction
Targeted gene mutation technology represents a powerful new tool for biomedical research. When the targeted gene is expressed in the brain, the behavioral phenotype of the mutant mice may reveal genetic mechanisms underlying normal behaviors, and may increase our knowledge of genetic factors in neuropsychiatric disorders. Transgenic mice have a new gene, or an additional copy of an existing gene, added to the genome. Knockout mice have a targeted gene deletion, such that no product of the mutated gene is synthesized in the null mutants. The methods for developing the mutation, and breeding strategies to generate null mutants in the F2 and subsequent generations, are extensively described in this volume and elsewhere 11, 54, 76.
Approximately 100 different genes expressed in the central nervous system have been targeted and phenotyped in transgenic and knockout mice to date 4, 11, 52, 54, 68. Reported behavioral phenotypes include aberrant social, reproductive, and parental behaviors, aggression, feeding disorders, learning and memory impairments, anxiety-like behaviors, and altered responses to antidepressants, antipsychotics, ethanol, and psychostimulant drugs of abuse. Experimental design is presently being optimized for thorough evaluation of behavioral phenotyping in mutant mice. This review is designed to suggest general methods that have been validated in our laboratory and others. Specific protocols for individual behavioral tasks can be found in the original publications referenced throughout the text, and in several recent reviews 11, 16, 19, 20, 34, 38, 54, 74.
Section snippets
The mice
After the mutation has been successfully introduced, and the gene product shown to be correctly overexpressed or absent, the first chimeras are mated with wildtype mice. A Mendelian distribution of F2 offspring is predicted. The strain of mouse used for the embryonic stem cells, for the donor blastulas, and for the breeding, can greatly affect the behavioral phenotype. For example, some 129 substrains (e.g. 129/J and 129/SvJ) have an incomplete or missing corpus callosum [42], and perform
Preliminary observations
A series of carefully conducted preliminary observations of general health, home cage behaviors, sensory abilities, and motor functions is first conducted for each mouse to avoid spurious false positives. If an animal has a major health problem or a gross motor defect it will be unable to perform many behavioral tasks for reasons not necessarily specific to the mutation. If an animal is blind or deaf, specific behavioral tests can be designed around the sensory deficit, such as olfactory
Specific behavioral tasks to test discrete hypotheses
Targeted gene mutation is designed to address specific hypotheses about the behavioral role of a gene. The set of specific behavioral tasks to be used for behavioral phenotyping is designed around the hypothesis. Genes for neuropeptides in the hypothalamus might be analyzed in tests of feeding behaviors, sexual behaviors, and stress-related behaviors. Signalling genes expressed in the hippocampus might be analyzed in tests of spatial learning and memory. Genes for serotonin receptor subtypes
Conclusions
In the opinion of this author, the present technology for the generation of mutant mice is most useful for modeling the symptoms of single gene mutation human hereditary diseases. Behavioral phenotypes identified for transgenic and knockout mice may lead to important medical applications. When the mutation is designed to mimic the genetic mutation in a human hereditary disease, the mouse behavioral phenotype can serve to evaluate the efficacy of new pharmacological and gene therapy treatments 4
References (77)
- et al.
Quantitative trait loci contributing to phencyclidine-induced and amphetamine-induced locomotor behavior in inbred mice
Neuropsychopharmacol.
(1996) - et al.
Atm-deficient mice: A paradigm of Ataxia–Telangiectasia
Cell
(1996) - et al.
A defect in nurturing in mice lacking the immediate early gene fosB
Cell
(1996) - et al.
Difference in pup care V-pup ultrasonic emissions and pup care behavior
Physiol. and Behavior
(1985) Neuropharmacological specificity of a simple animal model for the behavioral actions of benzodiazepines
Pharmacol. Biochem. and Behavior
(1981)Unusual behavioral phenotypes of inbred mouse strains
Trends Neurosci.
(1996)- et al.
Biological actions of cholecystokinin
Peptides
(1994) - et al.
Baseline exploratory activity predicts anxiolytic responsiveness to diazepam in five mouse strains
Brain Res. Bull.
(1982) - et al.
A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice
Hormones and Behavior
(1997) - et al.
Radial-maze performance and structural variation of the hippocampus in mice: a correlation with mossy fibre distribution
Brain Res.
(1987)
Gene-targeting studies of mammalian behavior: is it the mutation of the background genotype?
Trends Neurosci.
Startle response models of sensorimotor gating and habituation deficits in schizophrenia
Brain Res. Bull.
Learning impairment in transgenic mice with central overexpression of corticotropin-releasing factor
Neurosci.
Targeted disruption of the melanocortin-4 receptor results in obesity in mice
Cell
Murine models of brain aging and age-related neurodegenerative diseases
Behav. Brain Res.
Transgenic models of neurodegenerative diseases
Curr. Opin. Neurobiol.
Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1
Cell
Neurobiological mechanisms controlling aggression: Preclinical developments for pharmacotherapeutic interventions
Neurosci. Biobehavioral Reviews
Cocaine reward and locomotor activity in C57BL/6J and 129/SvJ inbred mice and their F1 cross
Pharmacol. Biochem. Behav.
Spatial localisation does not depend on the presence of local cues
Learning and Motivation
Behavior in mice with targeted disruption of single genes
Neurosci. Biobehavioral Reviews
A gene influencing active avoidance performance in mice
Physiol. and Behavior
Genetic influences in opioid analgesic sensitivity in mice
Brain Res.
Subregion- and cell type-restricted gene knockout in mouse brain
Cell
Masculine sexual behavior is disrupted in male and female mice lacking a functional estrogen receptor α gene
Hormones and Behavior
Mouse models of human disease. Part I: Techniques and resources for genetic analysis in mice
Genes and Develop.
Voluntary consumption of ethanol in 15 inbred mouse strains
Psychopharmacol.
Applications of gene therapy to the CNS
Human Mol. Genetics
Quantitative trait loci mapping of three loci controlling morphine preference using inbred mouse strains
Nature Genetics
Post-training administration of GABAergic antagonists enhances retention of aversively motivated tasks
Psychopharmacol.
Quantitative trait loci analysis affecting contextual conditioning in mice
Nature Genetics
Transgenic modeling of neuropsychiatric disorders
Mol. Psychiatry
Genetic determinants of sensitivity to diazepam in inbred mice
Behavioral Neurosci.
Behavioral phenotypes of inbred strains of mice
Psychopharmacol.
The effect of narcotics and narcotic antagonists on the tail-flick response in spinal mice
J. Pharm. Pharmacol.
Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y
Science
Cited by (665)
A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury
2024, Brain, Behavior, and ImmunityReduction in GABAB on glia induce Alzheimer's disease related changes
2023, Brain, Behavior, and ImmunityTailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion disease
2023, Neurobiology of DiseaseCannabidiol (CBD) treatment improves spatial memory in 14-month-old female TAU58/2 transgenic mice
2022, Behavioural Brain ResearchTest, rinse, repeat: A review of carryover effects in rodent behavioral assays
2022, Neuroscience and Biobehavioral Reviews
- 1
Published on the World Wide Web on 2 December 1998.