Developing Standardized Behavioral Tests for

Developing Standardized Behavioral Tests for Knockout and Mutant Mice

Richard E. Brown, Lianne Stanford, and Heather M. Schellinck Introduction

T

Richard E. Brown, Ph.D., is a Professor, Lianne Stanford, M. A., is a doctoral candidate, and Heather M. Schellinck, Ph.D., is a Senior Instructor in the Department of Psychology and Neuroscience Institute, Dalhousie University, Nova Scotia, Canada.

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Questions That Must Be Answered before Using a Behavioral Battery To conclude that differences in behavior between mutant and wild-type mice are due to genetic differences, one must control for the effects of confounding variables. The apparent effects of genetic manipulation on behavior may depend on factors other than those associated with the genetic differences in the subjects. Often there is not one best way to deal with these variables, thus we recommend that researchers ensure the inclusion of detailed information in the Methods sections of published papers. In particular, before testing mice in a standardized behavioral paradigm, a number of questions must be answered about the background of the animals and the conditions under which they are maintained (Table 1). First, what is the source of the animals? Animals from different breeding facilities may have been reared under different conditions and procedures, and investigators who purchase adult mice from different sources may not obtain consistent results due to such differences. Second, what is the health status of the animals? Strains of mice developed in facilities that are not specific pathogen free may contain parasites, bacteria, and viruses that can alter the health and behavior of the mice. For example, persistent viral infections disrupt learning, memory, and other behaviors in mice (Brot et al. 1997; Hotchin and Seegal 1977; Yayou et al. 1993), and these behavioral disruptions may continue for several months after antiviral therapy (Brot et al. 1997). Neonatal endotoxin exposure also influences the development of social behavior (Granger et al. 1996). Third, what are the physical housing conditions of the animals? Cage size, number of animals per cage, light:dark (LiD1) cycle, room temperature, and humidity all influence behavior. For example, cage size can alter activity levels (Poon et al. 1997), and social housing conditions may cause hormonal changes that influence behavior and physiology (Grimm et al. 1996). Because mice are nocturnal and thus more active in the dark, attention should be paid to the L:D 'Abbreviations used in this article: DNMTS, delayed nonmatching to sample; L:D, light:dark.

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he ability to produce transgenic, knockout, and mutant mice provides new animal models for the genetic analysis of behavior and its underlying neural mechanisms (Chen and Tonegawa 1997; Wehner et al. 1996). Knockout and transgenic mice have been developed as animal models for the study of human diseases such as Alzheimer's disease (Flood and Morley 1998; Nalbantoglu et al. 1997), Down's syndrome (Schuchmann et al. 1998; Tremml et al. 1998), Huntington's disease (Bates et al. 1997), schizophrenia (Mohn et al. 1999), and other neurobiologic disorders (Nelson and Young 1998). Transgenic mice can also be used to study the behavioral effects of altering specific neurochemical receptors such as for N-methyl-D-aspartate and a-amino-3-hydroxy-5-methyl-4-isoxasole-propionate (Sprengel and Single 1999), metabotropic glutamate (Galani et al. 1997), serotonin (Parks et al. 1998), or dopamine (Steiner et al. 1997). In many genetically altered mice, the most noticeable difference between the transgenic mouse and its background strain is a change in behavior. As indicated by Nelson and Young (1998, p. 453), however, "correlations among behavioral assessments of knockouts are difficult to make because no standardized behavioral tests are available." Crawley and Pay lor (1997) and Crawley (1999) list a number of behavioral test paradigms that can be used to test genetically altered mice, and Nelson and Young (1998) list a number of genetically altered mice that can be tested in these paradigms. Although early studies of transgenic, mutant, and knockout mice included very few behavioral tests, it is becoming more common to use a test battery approach when examining the behavioral phenotypes of these mice (Brunner et al. 1999). In this article, we review test batteries for examining sensory and motor behavior, species-typical behavior, learning and memory, and development and aging in transgenic mice. Before these test batteries are used, however, it is important to consider nongenetic variables such as animal housing and experience and procedural variables, which may interact with genetic differences to alter behavior. Behavioral genetic studies on mice have been conducted for more than 40 yr (Sprott and Staats 1975,1981). We have

not attempted a thorough review of all studies but have selected some recent representative studies to illustrate our points.

Table 1 Background questions that must be answered before using a behavioral test battery

cycle under which animals are housed and whether this L:D cycle is a natural or reversed day:night cycle. Routine cleaning of animal rooms and cage changes can also disrupt behavior (Milligan et al. 1993; Saibaba et al. 1996). Fourth, what type of food, water, and medications are given to the animals? The type and amount of food provided to the animals may alter their behavior; for example, dietary restriction alters motor behavior (Duan and Mattson 1999) and levels of constituents such as lineolate in the diet influence activity, emotionality, and cognitive performance (Umezawa et al. 1999). Are the animals given tap, distilled, or specially treated water? Are medications added to the water or food? The routine administration of medications such as tetracycline to animals may influence social behavior in adults (Barnett and Sandford 1982) and behavioral development (Seo et al. 1993). Fifth, what litter size and sex composition are used? Litter size and sex composition affect development (Laviola and Terranova 1998; Tanaka 1998). Should litter size be adjusted if one strain produces significantly more pups per litter than another strain? Should the number of pups in litters be increased or decreased to match for litter size, and what effects does manipulation of litter size have on behavior? Sexual differentiation in utero can be modulated by the sex ratio of the litter, resulting in changes in sexually dimorphic behaviors (Vandenbergh and Huggett 1995; Vom Saal 1981). Sixth, what effects does maternal care have on behavior? Maternal care influences neural and behavioral development (Caldji et al. 1998; Liu et al. 1997), and there are strain differences in maternal care patterns (Brown et al. 1999b; 164

Seventh, what are the social experiences from weaning to adulthood that can affect behavior? Housing in single-sex littermate groups, single-sex mixed litter groups, or mixed sex groups can affect social behavior (Hahn and Schanz 1996; Harshfield and Grim 1997; Koolhaas et al. 1997; Young et al. 1997). Comparison of inbred strains of mice reared under different social conditions is an important procedure for dissociating genetic and social experiences in determining behavior (Hoffmann et al. 1993). Social isolation induces physiologic and behavioral abnormalities in mice (Brain 1975; Hall 1998; Morse et al. 1993), whereas housing mice in all male groups leads to the formation of dominance hierarchies. Male mice housed in groups may develop dominance hierarchies, resulting in increased corticosteroid and opioid release and decreased LH and folliclestimulating hormone levels in subordinate males (Bronson and Eleftheriou 1965; Bronson et al. 1973; Miczek et al. 1982). Dominant and subordinate animals differ in locomotor activity, swimming, and anxiety measures (Ferrari et al. 1998; Hilakivi-Clarke and Lister 1992), and these differences may have significant effects on performance in tests of learning and memory (Dubrovina et al. 1997). When animals are group housed, individuals are often identified using ear tags, ear punching, or toe clipping. If a stressful procedure such as toe clipping is to be used, the effect of this procedure on future performance should be considered (Schellinck and Anand 1999). Eighth, should animals receive environmental enrichment? Environmental enrichment facilitates neural and cognitive development (Boehm et al. 1996; Soffie et al. 1999) and reduces anxiety (Chapillon et al. 1999). The effects of environmental enrichment may be age and strain specific (Soffie et al. 1999; van de Weerd et al. 1994). Environmental enrichment may enable the same strains of mice to perform better in tests of learning and memory, have greater dendritic arborization, and have longer axons (Greenough and Volkmar 1973). Current North American animal care standards advocate the use of shelters, chewing blocks, and nesting material to reduce animal stress (NRC 1996; Wolfensohn and Lloyd 1998); and although the use of nesting material as environmental enrichment does not appear to ILAR Journal


1. What is the source of the animals? 2. What is the health status of the animals? 3. What are the physical housing conditions? • Cage size? • Number of animals per cage? • Light:dark cycle? • Temperature? • Humidity? 4. What type of food, water, and medications are provided? • Brand and amount of food? • Tap, distilled, or specially treated water? • Medications? 5. What are the litter size and sex composition? • To cull or not to cull? 6. What are the effects of maternal care? • Cross-fostering? • Age at weaning? 7. What are the social experiences from weaning to adulthood? • Isolation vs. social rearing? 8. Should animals receive environmental enrichment?

Carlieretal. 1982). Should pups be cross-fostered to "good" mothers if their own mothers fail to care for them? How does one determine whether strain differences are due to the effects of maternal environment (pre- and postnatal) or to genetic differences between strains (Carlier et al. 1983)? Comparison of the behavior of pups reared by mothers of their own strain and pups cross-fostered to mothers of other strains provides a mechanism for dissociating the effects of postnatal maternal care from the putative effects of genetics on behavior (van Abeelen 1980), but this paradigm does not control for prenatal maternal influences on behavior (Carlier et al. 1999). The age at which animals are weaned can also influence behavior. Animals weaned 3 days earlier than normal or weaned at lower than the normal weight are more likely to develop behavioral stereotypy (Wuerbel and Stauffacher 1997).

alter behavior in mice (van de Weerd et al. 1997), the use of such materials for environmental enrichment should be noted.

Procedural Questions for Designing Behavioral Studies

Table 2 Procedural questions for designing behavioral studies 1. 2. 3. 4. 5. 6. 7. 8. 9.

What control strains should be used? At what age should mice be tested? Should both males and females be tested? What time of the day:night cycle should mice be tested? How many tests should be given to each animal, and how many subjects per group should be tested? How many different test paradigms should be used? How should mice be handled before and during testing? What apparatus should be used for each test? What is the testing room environment?


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Third, should both sexes be tested? Sex differences should be considered as males and females may be differentially affected by gene mutations. For example, male and female ddY mice differ in the performance of spatial learning tasks but not in avoidance learning (Mishima et al. 1986), and delta-168 transgenic mice show sex-linked changes in locomotor activity and learning (Douhet et al. 1997). Genotype-by-sex interactions also have been found in tests of anxiety in 5-HT1A receptor knockout mice (Ramboz et al. 1998). Fourth, what time of the day:night cycle should mice be tested? Behavior may be influenced by the time of testing during the L:D cycle (Miyamoto et al. 1986; Rosenwasser et al. 1979; Sandman et al. 1971; Stephens et al. 1967). For example, Kriegsfeld et al. (1999) found that nitric oxide synthase knockout mice had deficits in motor coordination when tested in the dark phase of the L:D cycle but not when tested in the light phase. They state, "Even though rodents are nocturnal animals, most behavioral studies, including learning, are conducted during the light period. Our findings emphasize the importance of examining the diurnal variations, especially in gene knockout research" (p. 314). Fifth, how many tests should be given to each animal and how many subjects per group should be tested? Because transgenic and knockout mice are expensive and difficult to maintain, only a few may be available. Before testing each mouse multiple times, one should consider whether repeated testing affects the animal and whether there is a test order interaction. How many mice should there be in each group so that adequate statistical power is reached? As more advanced statistical and multivariate analyses are being used in animal behavior studies, one must provide sample sizes adequate to attain the power level determined for the effect sizes observed (Belknap 1998). In general, mice should be tested with groups in excess of 10, but this recommendation is dependent on the effect size estimated and the desired power value (Keppel 1991). The problem of experimental design, sample size, and power in genetic experiments is discussed by Wahlsten (1999). Sixth, how many different test paradigms should be used? The number of tests to use with each strain and which tests to use have been discussed by Crawley and Pay lor (1997) and is discussed below (see Tests for Sensory and Motor Deficits 165


In addition to the background questions listed in Table 1, a number of procedural questions must be answered when designing behavioral experiments with transgenic and mutant mice (Table 2). First, when a genetically altered mouse is tested, what control strains should be used? Genetically engineered mice may differ from their background strains in physiologic, endocrine, and neural functions and in the development of these functions (Gassmann and Hennett 1998; Nelson 1997; Shastry 1995). Of the variety of different background strains used in the development of knockout and mutant mice, some (e.g., the 129Sv strain) have substrains that show behavioral differences (Simpson et al. 1997; Balogh et al. 1999). For example, the 129/SvJ strain has agerelated visual pathology (Hengemihle et al. 1999). Every attempt should be made to use the appropriate control strain whenever the animals are bred as homozygous knockouts. If a single control strain is not available, then all parent strains must be used because there are large differences in behavior, physiology, and anatomy between inbred strains. When heterozygotic mice are bred to achieve knockout (-/-), homozygous (+/+), and heterozygous (+/-) strains, littermates are appropriate controls provided they are from an appropriate hybrid cross (Banbury Conference 1997; Frankel 1998; Lathe 1996). The use of littermate controls is often recommended (Banbury Conference 1997; Frankel 1998; Zorrilla 1997). Some information on appropriate control strains is given by Fox and Witham (1997) and on the Jackson Laboratory website (WWW.JAX.ORG). Second, at what age should mice be tested: during infancy, adolescence, adulthood or old age? Mice are weaned at about 21 days of age and can be mated as early as 28 days of age, but there are strain and sex differences in reproductive performance and longevity (Fox and Witham 1997).

Relatively small differences in the age at testing can result in different behavioral results (Hascoet et al. 1999; Strohle et al. 1998) because neural development and sexual differentiation of the brain continues until puberty (Andersen et al. 1997). With knockout mice, the longevity of the strain is greatly affected by the targeted gene. The lack of some genes can be lethal at birth, cause animals to have a shortened life span, decrease reproductive viability, or increase the time course of development (Miyamoto 1997; Nishii et al. 1998; Yagi et al. 1998). In determining the age at which the animals should be tested, one must consider the rationale behind the test. Animals may perform differently at different ages, so it may also be necessary to test both young and old animals (Miyamoto et al. 1986).

Tests for Sensory and Motor Deficits Many strains of congenic, inbred, and mutant mice suffer from sensory and/or motor deficits that alter their behavior. Mice may suffer from retinal degeneration and perform poorly in tests requiring visual acuity (Hengemihle et al. 1999; Provencio et al. 1994). Some strains of mice such as DBA/2 and C57BL/6J (B6) become deaf at an early age and therefore perform poorly in tests requiring auditory discrimination (Erway et al. 1993; Steel 1995). Other strains may have disrupted olfactory sensitivity (Feron and Baudoin 1998), somatosensory deficits (Wilkinson et al. 1996), or abnormal pain thresholds (Mogil and Belknap 1997; Onaivi et al. 1995). In each of these cases, poor performance in behavioral tests may be due to sensory rather than cognitive deficits. An example of a test battery for measuring sensory and motor abilities is given in Table 3. Strains of mice such as staggerer, lurcher, weaver, dystonia musculorium mutants, and dopamine 1A receptor-deficient mice suffer from locomotor abnormalities that may affect movement and grooming (Bolivar et al. 1996a,b; Coscia and 166

Table 3 Example of a sensory-motor test battery 1. Visual cliff (Zhong et al. 1996) 2. Auditory startle response (Golub et al. 1994; Koch and Schnitzler1997) 3. Odor orientation/discrimination test (Sundbergetal. 1982) 4. Locomotion in the open field test (Markowska et al. 1998; Moechars et al. 1998) 5. Motor learning and balance in the roto-rod test (Lalonde et al. 1996; Le Marec and Lalonde 1997) 6. Pain sensitivity in the hot plate or tail-flick test (Rubinstein et al. 1996)

Fentress 1993; Cromwell et al. 1998; Lalonde et al. 1994, 1996; Strazielle and Lalonde 1998). These motor deficits may affect performance in behavioral tasks, particularly when time is measured as the dependent variable. For these reasons, tests of sensory and motor performance should be conducted on transgenic and knockout mice to ensure that abnormal responses, particularly in learning and memory tasks, are not due to noncognitive sensory-motor abnormalities.

Species-typical Behavior: The Mouse Ethogram Genetic manipulation may alter species-typical behaviors in mice, and test batteries should be able to detect these changes. Ethologic descriptions of species-typical behavior use an "ethogram," which is a complete inventory of the behavior repertoire of a species (Tinbergen 1951, p. 7) in terms of qualitatively and quantitatively measured "behavioural units." Each behavioral study thus begins with a description of the units of behavior to be recorded, which are often grouped into functional categories such as locomotor, reproductive, and aggressive (Grant and Mackintosh 1963). Eisenberg (1968) has provided an ethogram for mouse behavior that describes the behavior observed in adult mice in isolation and in social encounters (Table 4). Ethologic analyses have been used to study locomotor behavior (Carter et al. 1999; Crabbe 1986; Paulus et al. 1999), grooming (Drago et al. 1999), exploration (Elias et al. 1975), fear (Brown et al. 1999c; Trullas and Skolnick 1993), anxiety and defensive behavior (Griebel et al. 1996), sexual behavior (McGill and Tucker 1964), aggression (Schneider et al. 1992), and parental behavior (Ward 1980) in mice. Strain differences in fearfulness and anxiety should be studied because emotional responses interfere with the expression of other behaviors and can affect performance in learning and memory tasks (Markowska et al. 1998; Parks et al. 1998; Smith etal. 1998; Strohle et al. 1998). For example, serotonin 5-HT1A receptor knockout mice show increased anxiety (Ramboz et al. 1998), and dopamine D3 receptor knockout mice show reduced anxiety levels (Steiner et al. IIAR Journal


and Species-typical Behavior: The Mouse Ethogram). Because many behavioral tests are designed for rats, one must consider species differences in size and in behavior when adapting these tests for use with mice. The size and sensitivity of the apparatus and even the behavioral measures scored may have to be altered to adapt behavioral tests designed for rats for use with mice (Crawley and Paylor 1997). Seventh, how should mice be handled during testing? How the animals are handled before and during testing is important. Test behavior may be influenced by habituation to handling and the method of retrieving the subject (Barry 1957). For example, whether mice are picked up by the tail, carried in a container, or allowed to move themselves into transport container may influence their behavior. Eighth, what test apparatus should be used? Its size, material, and method of cleaning may all influence the test results. Using a rat apparatus to test mice is often not appropriate inasmuch as the activity levels of mice make it difficult for them to perform tasks that are easy for rats (Crawley and Paylor 1997). Additionally, cleaning the apparatus in a manner that will eliminate odor trails is especially important because odor may provide cues that alter the behavior of the subjects (Roullet et al. 1993). Ninth, what is the testing room environment? Animals tested in an open laboratory are subject to distractions from visual, auditory, and olfactory stimuli. Extraneous stimuli such as odors from perfume or chemicals and noise from equipment, both audible and ultrasonic, may interfere with the behavior of the animal (Sales et al. 1988). Testing in a purpose-built behavioral test room shields animals from these distracting stimuli; however, even under controlled conditions, there are effects of the laboratory environment on behavior (Crabbe et al. 1999).

Table 4 Behavioral categories in the mouse ethogram* Individual behavior patterns 1. Sleep and resting 2. Locomotion 3. Grooming: care of the body surface and comfort movements 4. Ingestion of food 5. Gathering food and caching 6. Digging 7. Nest building 8. Exploration and foraging 9. Fear, anxiety, and defensive behavior

a

Adapted from Eisenberg JF. 1968. Behavior patterns. In: King JA, editor. Biology of Peromyscus (Rodentia). Washington DC: American Society of Mammologists. p 451-494.

1997). For these reasons, tests of fearfulness or anxiety should be conducted on transgenic and knockout mice to ensure that abnormal behavioral scores are not due to noncognitive anxiety factors. The emotional/defensive behavior test battery (Table 5) is an example of an ethologic test battery.

Learning and Memory Test Battery Many tests have been devised to test learning and memory in mice (Crawley and Paylor 1997; Wehner et al. 1996). For example, the Hebb-Williams maze has been used as a general test of animal intelligence (Brown and Stanford 1997; Meunier et al. 1986), and the habituation test has been used as a nonassociative test of learning (Platel and Porsolt 1982).

Table 5 Example of a species-typical emotional/ defensive behavior test battery 1. 2. 3. 4. 5. 6. 7. 8.

Locomotion/exploration in the open field (Crawley 1985) Elevated plus maze (Lister 1987) Elevated zero maze (Brown et al. 1999a) Light:dark box (Crawley 1985) Holeboard test (File and Wardill 1975) Social interaction test (Olivier and van Dalen 1982) Social conflict test (Vogel et al. 1971) Exploratory/defensive behavior in the visible burrow system (Blanchard et al. 1990)


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Many behavioral paradigms have been used to examine the contribution of each of the five neural systems implicated in learning and memory function in rodents. Although primarily used with rats, these paradigms are being adapted for use with transgenic and knockout mice (Bach et al. 1995; Silva et al. 1992). One example of a learning and memory test battery that is based on these different memory systems is presented in Table 6. We are in the process of refining this test battery (Brown et al. 1998b). Hippocampal functioning has typically been examined with tests of spatial learning such as the Morris water maze (Upchurch and Wehner 1988) and the radial arm maze (McDonald and White 1993). Learning the water maze, however, may depend on the amygdala as well as the hippocampus inasmuch as swimming in an opaque pool may arouse anxiety (McNaughton 1991). The win-shift paradigm in the radial arm maze can be used as a paradigm to test hippocampally based spatial learning in mice (McDonald and White 1993).

Table 6 Example of a learning and memory test battery based on multiple memory systems 1. 2. 3. 4. 5. 6. 7.

8. 9.

Habituation (Platel and Porsolt 1982) Hebb-Williams maze (Meunier et al. 1986) Morris water maze (Upchurch and Wehner 1988) Win-shift task on the 8-arm radial maze (McDonald and White 1993) Conditioned fear response (Fanselow 1994) Step down passive avoidance (Mondadori and Weiskrantz 1993) Cued discrimination task of the 8-arm radial maze (Ammassari-Teule et al. 1993; McDonald and White 1993) Object exploration and memory (Messier 1997) Delayed nonmatching to sample (Zhu et al. 1995)

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Social behavior patterns 1. Initial contact-social investigation 2. Contact promoting and sexual behavior 3. Approach, flight, attack, and other agonistic patterns 4. Miscellaneous behaviors seen in a social context 5. Parental behavior

One advantage of the Hebb-Williams test is that it has a series of graded problems so that the same animals can be compared on easy and difficult problems in the same apparatus (Stanford et al. 1998, 1999). Although the neurobiologic basis for learning and memory is far from understood, at least five different neural systems have been proposed to underlie these different memory systems. Damage to one of these structures disrupts some memory systems but leaves others intact (Squire 1987). The five neural systems most widely studied include the hippocampus, amygdala, dorsal striatum, rhinal cortex, and cerebellum. None of these neural systems is a unitary entity. The hippocampus is a complex structure involving many components (Shepherd 1994). The amygdala is composed of at least four independent units (Swanson and Petrovich 1998), and the dorsal striatum is part of the basal ganglia complex (White 1997). The rhinal cortex is part of the temporal lobe (Aggleton and Saunders 1997), and the cerebellum has a number of components and connections to other brain areas (Lavond et al. 1993).

Numerous test batteries exist for analyzing the development of behavioral reflexes (Fox 1965; Kodama 1993; Rogers et al. 1997), sensory-motor development (Heuze et al. 1997; Noel 1989; Roubertoux et al. 1985, 1992), locomotor behavior (Brown et al. 1999a), grooming (Bolivar et al. 1996a), swimming (Bolivar et al. 1996b), exploration (Tremml et al. 1998), anxiety and fear (Ramboz et al. 1998), ultrasonic vocalizations (Bolivar and Brown 1994; Hahn et al. 1987), and social behavior (Williams and Scott 1954). Test batteries used for studying behavioral development include the Collaborative Behavioral Teratology Study Battery, the Cincinnati Psychoteratogenicity Screening Test Battery, and the Functional Observational Battery. The Collaborative Behavioral Teratology Study Battery (Vorhees 1983,1985) was created to assess the reliability and sensitivity of several behavioral tests when conducted under identical protocols in different laboratories or in the same laboratory over time. This battery employs tests of developmental landmarks (e.g., eye opening, incisor eruption, vaginal opening, testes descent) and six behavioral tests (negative geotaxis, olfactory discrimination, auditory startle habituation, figure8 maze activity, visual discrimination learning, and activity). The Cincinnati Psychoteratogenicity Screening Test Battery (Vorhees 1985) was designed to be a comprehensive, reliable, and practical screening battery. It includes tests of physical landmarks (e.g., upper and lower incisor eruption, eye opening, vaginal patency), surface righting, negative geotaxis, swimming ontogeny, pivoting locomotion, olfactory orientation, auditory startle, activity, spontaneous alternation, maze learning, and active and passive avoidance. The Functional Observational Battery (Moser 1989,1990; Tilson and Moser 1992) uses 31 behavioral tests to assess behavioral development. Although these test batteries were developed for toxicologic studies they can be adapted to study behavioral development in transgenic mice. Both physical and behavioral development should be assessed in a developmental test battery. In Table 7, an example of a developmental test battery is shown, which includes tests that examine the sensory and motor development of mice and their locomotion, exploration, and fear responses (Bolivar and Brown 1994; Brown et al. 1998a, 1999a). These tests begin at birth, and animals are tested daily until they reach each developmental milestone, as described by Fox (1965) and Bolivar and Brown (1994).

Behavioral Development The genetic basis of neural and behavioral development is important for understanding the interaction between genes and environment in determining behavior (Bateson 1987, 1998; Gottlieb 1998). Likewise, the study of behavioral development is an important tool for genetic analysis in mice (Roubertoux et al. 1992). Analysis of behavioral development in mutant mice is also important for understanding the ontogeny of neurodevelopmental disorders (Bolivar and Brown 1994; Coscia and Fentress 1993; Greenough 1986; Lyons and Wahlsten 1988; van Ableen and Kalkhoven 1970). 168

Aging Mice Test batteries are important for measuring the behavioral changes associated with aging (Jucker and Ingram 1997). Sensory-motor, species-typical, and learning and memory test batteries can be used with aging animals, or composite test batteries can be developed that use subsets of the other test batteries (Giuliani et al. 1994; Markowska et al. 1998; Miyamoto 1997). Genetically defined mouse models are important for the study of aging (Sprott 1997), and an ILAR Journal


The role of the amygdala in learning and memory is generally studied using tests of conditioned fear responses. In the context of conditioning, animals shocked in a distinct environment display conditioned fear behaviors (e.g., freezing) when they remember the association between the context and the shock (Fanselow 1990, 1994). In place avoidance conditioning, animals avoid the place associated with the shock (Siegfried and Frischknecht 1989). In active avoidance conditioning, mice learn to avoid the location/place associated with fear; and in passive avoidance conditioning, the mouse must learn to stay in the nonshock compartment and avoid entering the shock compartment (Delprato and Rusiniak 1991; Riekkinen et al. 1993; Schulteis and Koob 1993). The dorsal striatum (caudate/putamen) memory system is activated in operant conditioning tasks in which a stimulus associated with a specific motor response is reinforced. The cued win-stay radial maze task has been effective in dissociating deficiencies in the caudate/putamen from those in the amygdala and hippocampus. In this task, a light is used as the cue; and during each trial, the animal learns to enter the arm of the maze associated with the light/tone (Packard et al. 1989). The rhinal cortex appears to be involved in object recognition (Zhu et al. 1995). In rats, recognition memory in the delayed nonmatching to sample (DNMTS1) object recognition task is impaired by lesions of the rhinal cortex but not by lesions of the amygdala or hippocampus (Mumby and Pinel 1994; Mumby et al. 1992). This impairment difference suggests that the DNMTS object recognition task can be used to dissociate the role of the rhinal cortex, hippocampus, and amygdala in learning. When testing object recognition, it is necessary to ensure that there is an absence of all spatial and odor cues and that the objects have no biologic significance so that the spatial and emotional learning and memory systems are not activated. Mumby and Pinel (1994) have used an object recognition paradigm, and Winters et al. (2000) have developed an olfactory DNMTS task. The cerebellum controls coordinated motor learning tasks such as the conditioned eye-blink (Thompson 1986) and the vestibuloocular reflex (Ito 1984). Chen et al. (1996) have studied the conditioned eye-blink response in mutant mice with Purkinje cell degeneration.

Table 7 Example of a developmental test battery Physical development (Fox 1965) 1. Growth rate (body weight) 2. Age at eye opening 3. Age at pinna unfolding 4. Age at incisor eruption 5. Age at vaginal opening

example of a test battery for examining behavioral changes during aging in mice is shown in Table 8.

Summary and Conclusions In this article, we have examined some of the variables that must be considered in the development of behavioral test batteries and in the maintenance of animals being tested. Sample test batteries for sensory-motor abilities, speciestypical behaviors, learning and memory, behavioral development, and aging are presented. One of the problems, however, is that the development of such test batteries is idiosyncratic, and no standardized test batteries exist for mice. Future research projects should focus on the procedures for developing such a set of standardized test batteries, the psychonomic properties of these test batteries, and their practical application. The development of the SHIRPA test battery is a step in this direction (Rogers et al. 1999) (SHIRPA derives from SmithKline Beecham Pharmaceuticals of the Harwell MRC Mouse Genome Centre and Mammalian Genetics Unit of Imperial College School of Medicine at St. Mary's Royal London Hospital, St. Bartholomew's, and the Royal London School of Medicine). Tests batteries developed for neurotoxicology (Tilson 1987) might be adapted for use with transgenic mice, but there should be some theoretical basis for the inclusion of items in a test battery. We are developing test batteries for learning in memory in mice based on the theory of multiple memory Volume 4 1 , Number 3

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1. Sensory tasks • Visual cliff • Auditory startle • Olfactory discrimination 2. Motor tasks • Roto rod • Climbing • Activity in a running wheel 3. Exploration in an open field 4. Emotionality in an elevated plus maze 5. Spatial memory • Morris water maze • Radial arm maze 6. Fear conditioning 7. Object recognition memory 8. Social memory a

Adapted from Giuliani A, Ghirardi O, Caprioli A, di Serio S, Ramacci MT, Angelucci L. 1994. Multivariate analysis of behavioral aging highlights some unexpected features of complex systems organization. Behav Neural Biol 61:110-122; Markowska Al, Spangler EL, Ingram DK. 1998. Behavioral assessment of the senescence-accelerated mouse (SAM P8 and R1). Physiol Behav 37:909-913; Miyamoto M. 1997. Characteristics of age-related behavioral changes in senescence-accelerated mouse SAMP8 and SAMP10. Exp Gerontol 32:139-148.

systems (Brown et al. 1998a,b) and a developmental test battery (Brown et al. 1998a, 1999a) based on psychobiologic and neurodevelopmental theories of development (Cicchetti and Cannon 1999).

Acknowledgments We thank Melanie McFadyen for her help in preparing this paper. R.E.B. and H.M.S. were supported by research grants from the Natural Science and Engineering Research Council of Canada, and L.S. was supported by the K.M. Hunter Medical Research Council of Canada Doctoral Research Award.

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