Burn, 2008, What Is It Like To Be A Rat, Rat Sensory Perception and Its Implications For Experimental Design and Rat Welfare

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Applied Animal Behaviour Science 112 (2008) 132 www.elsevier.com/locate/applanim
Review
What is it like to be a rat? Rat sensory perception and its implications for experimental design and rat welfare
Charlotte C. Burn
Department of Clinical Veterinary Science, University of Bristol, Bristol BS40 5DU, UK Accepted 21 February 2008 Available online 10 April 2008
Abstract This review of rat sensory perception spans eight decades of work conducted across diverse research elds. It covers rat vision, audition, olfaction, gustation, and somatosensation, and describes how rat perception differs from and coincides with ours. As Nagels seminal work (1974) implies, we cannot truly know what it is like to be a rat, but we can identify and acknowledge their perceptual biases. These primarily nocturnal rodents are extremely sensitive to light, with articial lighting frequently causing retinal degeneration, and their vision extends into the ultraviolet. Their olfactory sensitivity and ultrasonic hearing means they are inuenced by environmental factors and conspecic signals that we cannot perceive. Rat and human gustation are similar, being opportunistic omnivores, yet this sense becomes largely redundant in the laboratory, where rodents typically consume a single homogenous diet. Rat somatosensation differs from ours in their thigmotactic tendencies and highly sensitive, specialised vibrissae. Knowledge of speciesspecic perceptual abilities can enhance experimental designs, target resources, and improve animal welfare. Furthermore, the sensory environment has inuences from neurone to behaviour, so it can not only affect the senses directly, but also behaviour, health, physiology, and neurophysiology. Research shows that environmental enrichment is necessary for normal visual, auditory, and somatosensory development. Laboratory rats are not quite the simple, convenient models they are sometimes taken for; although very adaptable, they are complex mammals existing in an environment they are not evolutionarily adapted for. Here, many important implications of rat perception are highlighted, and suggestions are made for rening experiments and housing. # 2008 Elsevier B.V. All rights reserved.
Keywords: Animal welfare; Communication; Olfaction; Perception; Rats; Renement; Vision
E-mail address: charlotte.burn@worcester.oxon.org. 0168-1591/$ see front matter # 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.applanim.2008.02.007
C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132
Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vision. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Sensitivity to light . . . . . . . . . . . . . . . . . . . . . 2.2. Colour vision . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Emitted light . . . . . . . . . . . . . . . . . . . 2.2.2. Colour in the environment . . . . . . . . . . 2.3. Periodicity . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Acuity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Audition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Audiogenic damage in the laboratory . . . . . . . . 3.2. Vocalisations and communication . . . . . . . . . . . 3.3. Perception of the human voice . . . . . . . . . . . . . 3.4. Sound recordings and playbacks. . . . . . . . . . . . 3.5. Echolocation . . . . . . . . . . . . . . . . . . . . . . . . . Olfaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Overview of rat olfactory communication . . . . . 4.2. Scent and reproduction . . . . . . . . . . . . . . . . . . 4.3. Olfactory modulation of aggression . . . . . . . . . 4.4. Communication about experiences . . . . . . . . . . 4.5. Communication about food . . . . . . . . . . . . . . . 4.6. Scents in the laboratory. . . . . . . . . . . . . . . . . . Gustation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Taste in the laboratory . . . . . . . . . . . . . . . . . . 5.2. Nutritional regulation . . . . . . . . . . . . . . . . . . . 5.3. Renement within the homecage . . . . . . . . . . . 5.3.1. Nutritional content . . . . . . . . . . . . . . . 5.3.2. Flavour . . . . . . . . . . . . . . . . . . . . . . . 5.3.3. Physical presentation . . . . . . . . . . . . . 5.4. Renement of experiments . . . . . . . . . . . . . . . Somatosensation . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Environmental enrichment and somatosensation . 6.2. Vibrissae and the laboratory environment . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3 5 6 6 7 8 8 9 9 10 11 11 12 12 12 13 13 14 15 15 16 17 17 18 18 18 19 19 20 21 21 21 22 22 22
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1. Introduction The stimuli that an animal can perceive depend on the available sensory apparatus, while the way stimuli are evaluated in terms of their biological relevance depends on the animals innate biases, cognitive abilities and experiences. Perception is therefore a subjective distortion of reality, differing between species and even between individuals within a species. Since rats and mice, which have similar perceptual abilities to each other, constitute over 80% of all research animals in the European Union (Commission of the European Communities, 2003), and they have been bred for research since the late 1800s (Krinke, 2000; Whishaw and Kolb, 2005), much
is known about their perceptual biases. However, the information is scattered through time and across different research elds, so it is not easily available to researchers, rat caretakers, and other rat specialists. The resulting lack of awareness can have serious implications, sometimes leading to poorly designed experiments and harming rat welfare. This review brings current information together, to help inform and rene rodent experiments and housing. The review concentrates on the laboratory rat, Rattus norvegicus, since summaries of mouse sensory perception are included within several other review papers (Sherwin, 2002; Olsson et al., 2003; Latham and Mason, 2004). Much of the information will also be true for mice and other rodents, but care should still be taken if extrapolating between species. The species natural ecology such as whether they are diurnal or nocturnal, social or solitary, arboreal, burrowing or terrestrial will profoundly affect their sensory perception. These ethological considerations are highly relevant in laboratory rats despite their domestication; adult laboratory rats retain so many of their wild instincts that, when released into a naturalistic habitat, their resulting community and behaviour rapidly resembles that of their wild relatives (Berdoy, 2002). This review is organised around the classic ve senses: vision, audition, olfaction, gustation and somatosensation. It should be remembered that these are actually not the only senses; indeed rats may even possess a magnetic compass, like mice (Muheim et al., 2006) and hamsters (Deutschlander et al., 2003), but most published information currently covers the aforementioned ve senses. For each sense, the rats sensory biases relative to humans are rst described, then some practical implications of its perception with respect to welfare and experimental design are discussed. This is an applied review, focussing on the known or suspected implications of each sense, and aiming to provide enough information to allow readers to extrapolate to their own situations. The review cannot be completely comprehensive, and it will become clear that in many cases, rat sensory perception is still poorly understood. 2. Vision An obvious difference between human and rat vision is that rats eyes are located on the sides of their heads, rather than the front. They therefore have a wider eld of view, but less binocular overlap than us: wild rats have a binocular overlap of 358, domestic rats 768, and humans 1058 (Heffner and Heffner, 1992a). Wild rats usually inhabit burrows or other enclosed environments, and tend to be nocturnal or crepuscular, so most of their activities occur under low-light conditions (e.g. Calhoun, 1963). Consequently, rats rely relatively little on vision, but they are dramatically more sensitive to dim light than we are, able to discriminate tiny increments in intensity, indiscernible to us, including discriminating total darkness from 0.107 lx (Campbell and Messing, 1969). Rats, especially albinos, have much poorer visual acuity (Lashley, 1938; Creel et al., 1970; Prusky et al., 2002) and narrower depth perception than humans (OSullivan and Spear, 1964; Routtenberg and Glickman, 1964). For example, human acuity can be around 30 cycles per degree (c/d, a measure of spatial resolution accounting for stimulus size and distance), while pigmented rats acuities are only 11.5 c/d and albino strains have even lower acuities of 0.5 c/d (Prusky et al., 2002). This presumably gives an extremely blurred image by human standards (Fig. 1, reprinted from Prusky et al., 2002). Poor acuity in rats is probably partly due to their eyes relatively small size, and partly because their eyes appear to have very limited abilities to focus light from different distances or angles compared with human eyes (Artal et al., 1998). Rats often bob their heads which may help them gain motion cues about the distance of objects (Legg and Lambert, 1990).
Fig. 1. Visual perception of rat strains in visual-based behavioral tasks, reprinted from Prusky et al. (2002) (with permission from Elsevier and the authors). The original image (top-left) has been blurred to model the perception of rats with acuities of 1.5 c/d (top-right; FisherNorway), 1.0 c/d (bottom-left; Dark Agouti, Long-Evans, wild) and 0.5 c/d (bottom-right; Fisher-344, SpragueDawley, Wistar) when the image subtends 108. This approximates the size of the image if it were used as a visual cue in a typical visuo-behavioral task (see Prusky et al., 2002 for details).
Experiments in the 1930s suggested that, contrary to popular belief, rats possess colour vision (e.g. Munn and Collins, 1936; Walton and Bornemeier, 1938), which has recently been conrmed through electroretinograms and quantitative behavioural tests (Jacobs et al., 2001). Rod cells comprise 99% of rat photoreceptors, but rats also have two cone cell types (Szel and Rohlich, 1992). Around 93% of the cones respond maximally to blue-green light (around 510 nm), while the remaining 7% respond to ultraviolet (UV) (around 360 nm) (Jacobs et al., 2001; Akula et al., 2003). Cone responses are normally distributed, so rats actually perceive hues ranging from ultraviolet (400 nm) to orange-red (around 635 nm) (Jacobs et al., 2001), but they are most responsive to colours near their peak sensitivities (Jacobs et al., 2001; Akula et al., 2003). Flicker fusion thresholds (when emitted light ickers rapidly enough to appear constant) for rats are not yet known, but are relevant for their perception of video images and articial lighting (DEath, 1998). Flicker fusion thresholds decrease with high light intensity, and increase with fatigue. Animals with high proportions of rod cells, like rats, generally have high-icker fusion thresholds, so rats might perceive videos, computer monitors, and some uorescent lighting as ickering (Jarvis et al., 2003). Discussion of the implications of rat vision is separated according to sensitivity to light generally, colour vision, periodicity, and acuity.
2.1. Sensitivity to light The sensitivity of rats to light (Campbell and Messing, 1969) means that light levels comfortable for humans can rapidly cause retinal atrophy (reviewed in Schlingmann et al., 1993a,b) and cataract formation in rats (Rao, 1991). Albinos are particularly susceptible because they lack protective melanin in the iris and retinal epithelium, and the entire eyeball is slightly transparent (Schlingmann et al., 1993b). Consequently, even when the iris contracts in bright light, most of the light still enters the eye (Williams et al., 1985). In fact, albino rats may be the most susceptible of all laboratory animals to light-induced retinal degeneration (Bellhorn, 1980). To illustrate the relevant range of light intensities, the UK code of practice for the care and use of laboratory animals suggests that 350400 lx at bench level is adequate for routine experimental and laboratory activities (Home Ofce, 1989). Light intensities within cages are commonly between about 150 and 550 lx (Schlingmann et al., 1993c), but are higher in laboratory rooms, with upper limits approaching 10,000 lx due to current technological limitations (e.g. Light Therapy ProductsTM, 2006; Outside In Ltd., 2006). Humans can tolerate still higher intensitiesoutdoors on sunny days light often exceeds 50,000 lx, and only at this order of magnitude are discomfort and potential retinal damage likely in humans. Light intensities of only 65 lx can cause retinal degeneration in albino rats, even on a 12 h lightdark cycle (Semple-Rowland and Dawson, 1987). Half the photoreceptors were permanently damaged after just 3 days at 133 lx in albinos, but pigmented rats were less susceptible, with equivalent damage occurring at 950 lx (Williams et al., 1985). Rod cells are particularly vulnerable to light destruction, but cones often survive even after all rods have been destroyed (Cicerone, 1976; La Vail, 1976). Long-term cyclical light intensities of about 500 lx within an animal room can also cause cataracts in albino rats (Rao, 1991). These problems are worst in rats housed closest to the light source, usually those highest in the rack (Rao, 1991; Perez and Perentes, 1994). Surprisingly, some vision can remain after constant long-term light exposure, even when no intact photoreceptor cells can be observed (e.g. Lemmon and Anderson, 1979). This might be conferred by a few remaining cones that may be so sparse that they were undetectable by the quantitative techniques used (Cicerone, 1976; La Vail, 1976). Even so, under ordinary laboratory conditions, visual impairments can confound some tests. For example, in the Morris water maze a test of cognitive function rats with incidental light-induced retinal damage perform as poorly as rats with cognitive decits, both groups displaying difculties locating the platform (Osteen et al., 1995; Lindner et al., 1997). Also, in commonly used anxiety tests, such as open eld tests and lightdark boxes, visually impaired individuals might venture into the exposed/light areas more than fully sighted ones, through their lesser ability to discriminate light from dark, but this requires experimental conrmation. Therefore, light-induced retinopathy should be controlled for in such tests, or non-visual tests used alongside the established visual ones. Welfare problems might arise at even lower light levels than those causing retinal damage, because of motivation to hide, as well as to avoid ocular discomfort (Schlingmann et al., 1993c). Rats, especially albinos, reliably choose the lowest light intensities available, even when all the choices are very dim, appearing indistinguishable to humans (Campbell and Messing, 1969; Woodhouse and Greenfeld, 1985; Blom et al., 1995). Rats aversion to light was clearly demonstrated in a study showing that sleeping pigmented and albino rats awoke and moved to areas of lower illumination at thresholds of only 60 and 25 lx, respectively (Schlingmann et al., 1993c). Consistent with such behaviour, chromodacryorrhoea, an aversion-related secretion from the Harderian gland (e.g. Mason et al., 2004), increases with brighter light (Hugo et al., 1987).
There is clearly a conict between human workers needing adequate light to inspect rats, for example for signs of illness, and rats needing to avoid damaging or aversive light levels. Schlingmann et al. (1993a) therefore stressed the importance of providing shelters within cages, allowing rats some control over their light exposure. As described below, coloured shelters exist that allow humans to see rodents, while it supposedly appears dark to the rodents inside the shelter, although their efcacy requires conrmation. Light levels affect commonly used psychological tests, such as elevated plus-mazes in which exploration of the exposed arms is taken to indicate reduced anxiety; rats explore the exposed arms more in dim than bright light (Cardenas et al., 2001; Garcia et al., 2005). Moreover, some effects are only found under certain light conditions. For example, the anxiolytic effects of gentling only show in brightly lit open elds (Hirsjarvi and Valiaho, 1995), and some drug effects are inuenced by plus-maze illumination (Clenet et al., 2006). Therefore, some control and careful description of lighting conditions during these tests is necessary to account for its inuence on psychological measures. Surgery presents a difcult situation because good lighting is essential for delicate operations, but the anaesthetised, unblinking rat is unable to protect its eyes from that light. Care should therefore be taken, not only to keep the eyes hydrated, but also to protect them from prolonged bright light. Interestingly, the anaesthetic agent, halothane, prevents retinal degeneration (Keller et al., 2001); other anaesthetics have not yet been investigated. This protection is afforded under white, but not blue, light. Despite the above evidence that bright light is harmful to rats, this aspect of their biology is not always considered in some elds of research. An example is the use of rats as models for seasonal affective disorder in humans, exploring whether bright light therapy (up to 11,500 lx for 2 weeks) can cure depression in rats (e.g. Dilsaver and Majchrzak, 1988; Giroux et al., 1991; Humpel et al., 1992; Overstreet et al., 1995). Unsurprisingly, the depression was not cured, and the one study that considered the effects of light on rat vision discovered massive destruction of the albinos photoreceptors (Humpel et al., 1992). These examples illustrate how crucial knowledge of speciesspecic perception is for generating reasonable hypotheses and preventing animal suffering. 2.2. Colour vision Rats are not colour-blind (Muenzinger and Reynolds, 1936; Munn and Collins, 1936; Walton and Bornemeier, 1938; Lemmon and Anderson, 1979; Jacobs et al., 2001). However, relative to humans, they perform poorly when discriminating between colours of similar wavelengths (Walton, 1933), and they take longer to learn colour discriminations than light intensity ones (Jacobs et al., 2001). To discuss the implications of rats colour sensitivity, the implications for emitted light and that reected by objects in the environment will be dealt with separately, as their effects are quite distinct. 2.2.1. Emitted light Standard articial lighting rarely emits UV wavelengths (e.g. Bellhorn, 1980; Latham and Mason, 2004), since human cones are insensitive to it. To date, no studies have apparently investigated the effects of UV-decient light on rats. In some birds, UV light is important for their welfare (Moinard and Sherwin, 1999; Maddocks et al., 2001) and normal behaviour (Bennett and Cuthill, 1994), but laboratory mice appear to have, if anything, a slight aversion to it (C.M. Sherwin, personal communication). Also, high levels of UV can cause cataracts in mice (in
Bellhorn, 1980), and can affect reproductive and circadian rhythms in rats (reviewed in Brainard et al., 1994). In fact, the colour composition of articial light can have large effects. In rats, blue light (around 490 nm) caused more retinal degeneration (reviewed in Schlingmann et al., 1993b), and also more disruption to fertility (Tong and Goh, 2000) than any other wavelengths tested; UV light was not included in these studies, but is of a shorter wavelength than blue light so may be more harmful. At the opposite end of the spectrum, dim red light is sometimes used to observe nocturnal behaviour in rats, because it is on the upper edge of the wavelengths visible as colour to them (Jacobs et al., 2001). However, rats rod cells are stimulated by similar wavelengths to human rod cells, including red light (Akula et al., 2003). This means that, provided some rod cells remain intact, rats can see red light, even if only as light and dark contrast. This may not be a problem in experiments if rats are habituated to it, since moonlight would provide illumination in the wild. As an alternative to red light, sodium lamps, which emit very narrow peaks of yellow-orange (589 and 589.6 nm) light, can be used (McLennan and Taylor-Jeffs, 2004). Not only is it more visible to humans than red light, but also there were no signicant long-term differences between the activity levels of mice when illuminated by this lamp or in darkness. However, in studies unequivocally requiring rats to behave as if in pitch darkness, infrared light and the necessary viewing equipment should be used. It is also worth noting that most video equipment and computer monitors, which create images using emitted light, include no UV emissions and the colour balance is optimised for human vision (DEath, 1998). Even in black-and-white images and light from white articial light bulbs, white is composed of red, green and blue light adjusted for humans, and so would not appear as white to rats. Therefore, any such images presented to species with different colour sensitivities, particularly UV-sensitive animals, could lack important information. 2.2.2. Colour in the environment Caution is required when presenting images to rats in discrimination tests, even if the cues reect rather than emit light. Different inks have different spectral properties that may be invisible to the human eye, and some might even reect UV. Moreover, different pigments might differ in their olfactory qualities, which could be more salient to rats than their visual qualities. Even if this does not harm the experimental purpose, it can make standardisation between experiments difcult. Outside experimental situations, there are also some relevant implications of rodent colour vision within the homecage. In recent years, manufacturers of rodent environmental enrichments have produced transparent shelters in various colours (e.g. Robbins, 2004; Datesand Ltd., 2005). The idea behind them is that, while rodents supposedly blind to the shelters colour perceive themselves as being sheltered in a dark environment, human carers can inspect them without disturbing them. However, these shelters seem not to have been independently evaluated for their efcacy. Red transparent material might make a suitable shelter, being the least visible colour to rats (Jacobs et al., 2001), but as explained earlier, it would still stimulate rod cells and possibly some cones. The colour of the homecage itself might also affect rats. Sherwin and Glen (2003) housed mice in different coloured cages and found that they had signicantly different preferences for cagecolours. Moreover, the colour affected their food-to-body mass conversion rates and their elevated plus-maze anxiety. Assuming these effects were due to the colours directly (rather than the scents, tastes, or textures of the dyes used), this study shows that environmental colour can have surprisingly strong effects on mouse behaviour and physiology, and so possibly that of rats too.
2.3. Periodicity Rats tend to be most active at dusk and dawn, although their circadian rhythms are relatively exible (e.g. Calhoun, 1963). Because we are diurnal, many rodent experiments are carried out in the light, so much of our knowledge of this species comes from individuals awakened during their resting period, and tested under much brighter conditions than they would voluntarily experience. The implications of this can be profound, but time-shifted experiments are still rare in some elds. The brain state changes radically between sleep and activity, with whole populations of neurons shifting between activity and inactivity (Hobson, 2005; Saper et al., 2005). The time of testing can strongly inuence the variables of interest in experiments. For example, during the light phase, rats cardiovascular responses to various stressors are more pronounced (Schnecko et al., 1998), and they show less exploratory behaviour in an elevated plus-maze than in the dark phase (Andrade et al., 2003). For most experiments, rats will be in a wakeful state provided they have sufcient time to awaken, but little published information is available on how long rodents require to fully awaken (i.e. be in the same state as during the active phase). Any conclusions drawn from light phase studies of rats as human models could suffer from interpretive problems, because it is unclear whether the observed state would reect a similar state in our light (active) phase or our (dark) resting phase. Time-shifted experiments and husbandry can be made possible by using red or sodium illumination as described above, and also by feeding rats only during the phase when we wish them to be active (cited in Saper et al., 2005); a situation that sometimes occurs in the wild (Calhoun, 1963). 2.4. Acuity As described above, rats have very poor acuity (Fig. 1). Their image resolution is at least 20 times poorer than ours (Artal et al., 1998). Note though that the studies investigating rat visual acuity (Lashley, 1938; Creel et al., 1970; Artal et al., 1998; Robinson et al., 2001; Prusky et al., 2002) have used laboratory rats, whose acuity might have been further reduced by their articially lit environments. Apart from the damaging effects of light itself, several other factors can affect rat vision, including the early environment. Complete lack of light impairs rats visual development (Fagiolini et al., 1994), but providing environmental enrichment to these dark-reared animals can eliminate this effect (Bartoletti et al., 2004). In mice, enriched environments during rearing accelerate visual development and improve adult acuity (Prusky et al., 2000; Cancedda et al., 2004). Also, diet has a large inuence on vision (Berson, 2000). For example, caloric restriction can prevent cataracts (e.g. Wolf et al., 2000), and antioxidant intake and consumption of certain vitamins can prevent retinal damage (Li et al., 1985; Berson, 2000). Dietary composition is discussed in more detail in Section 5. The research implications of rats poor visual acuity depends on the experiment in question, but if visual cues are used they should be relatively large and high contrast, but not too bright as to be aversive. Also, visual cues may not be as salient to rats as cues in other modalities. Few experiments have tested this directly, but rats do remember auditory associations for longer than equivalent visual ones (Wallace et al., 1980), and can more rapidly learn discriminations using multimodal stimuli (oor surfaces differing in appearance, smell, and texture: Dymond, 1995;
Dymond et al., 1996) or olfactory or tactile cues (Birrell and Brown, 2000). However, vision is often the most appropriate sense for guiding rats in water mazes (Prusky and Douglas, 2005), for comparison with past studies, and for certain models of human activities. 3. Audition Sound can be described in terms including its frequency, intensity, timbre (frequency spectrum) and envelope (shape of sound pressure through time). While young humans hear frequencies from about 0.02 to 20 kHz (Moore, 2003), hearing in rats is shifted upwards to include the ultrasonic range (Kelly and Masterton, 1977). The lowest frequency rats have been reported to hear is 0.25 kHz and the highest is 80 kHz (Kelly and Masterton, 1977; Heffner and Heffner, 1992b; Heffner et al., 1994). They can also detect lower sound frequencies (Petounis et al., 1977), probably through contact with vibrating surfaces, and can even perceive lowfrequency sounds using their vibrissae (Neimark et al., 2003) (see Section 6). Auditory sensitivity decreases near the extremes of the detectable frequencies, so sounds at the lower and higher extremes must be louder before rats can detect them. The rats peak sensitivity is estimated to lie between about 8 and 50 kHz (Kelly and Masterton, 1977; Heffner and Heffner, 1992b), although estimates vary, probably due to factors including strain, age, and background noise. Even whether the homecages of rats are barren or environmentally enriched can greatly affect hearing sensitivity; auditory neurone performance is vastly improved by environmental enrichment (Engineer et al., 2004). The implications of rat auditory perception include what sound characteristics are harmful, vocal communication between rats, perception of the human voice, and experimental use of sound cues. There has also been debate about whether rats can echolocate. 3.1. Audiogenic damage in the laboratory Interactions between sound intensity and frequency (Fleshler, 1965; Voipio et al., 1998; Bjork et al., 2000) make it difcult to determine detection- and safety-thresholds for sound intensities. The decibel (dB) scale is logarithmic, so even small numerical increases represent large increases in the actual intensity. European Union legislation (2003) states that advice and hearingprotection must be provided for human workers frequently exposed to sounds of 80 dB or more. Above about 150 dB, auditory damage is inevitable with most perceivable sounds (Gamble, 1982). Equivalent thresholds are unknown for rats, but young rats are more sensitive to sounds than older ones, and permanent audiogenic damage is most likely in pups between about 12 and 22 days of age (Voipio, 1997). In the laboratory, audible sounds as loud as 8090 dB have been recorded; 5075 dB for ultrasound (Milligan et al., 1993), so conceivably, audiogenic damage could occur in both humans and rats. Husbandry procedures cause the loudest sounds, especially if metallic equipment is involved or if the work is performed in a hurried manner (Gamble and Clough, 1976; Milligan et al., 1993; Sales et al., 1999; Voipio et al., 2006). Filling metal food hoppers made 8090 dB of (mostly ultrasonic) sound, which would occur about once a week for the rats lifetimes (Sales et al., 1999; Voipio et al., 2006). This was measured from a distance of 50 cm, approximately the furthest that a caged rat could get from the sound. Many apparently silent activities or devices actually produce high levels of ultrasound (Sales et al., 1988, 1999). Examples include computer monitors, making 6884 dB of broadband ultrasound (Sales et al., 1988), and some uorescent lighting (G.J. Mason personal
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communication and personal observation). Cage washers, hoses, running taps, squeaky chairs, and rotating glass stoppers (Sales et al., 1988) produce both ultrasound and audible sound, as do some air-ow hoods worn to prevent allergy in human workers (Picciotto et al., 1999). Similarly, standard re alarms produce loud high- and low-frequency sounds, which laboratory animals cannot escape, so laboratories can be tted with re alarms that only emit sound audible to humans but not rodents (Home Ofce, 1989); although note that even frequencies below rats audible range can affect them (Petounis et al., 1977). Whether common laboratory sounds affect rodent welfare has not been investigated directly, but loud noises generally can trigger seizures, reduce fertility, and cause diverse metabolic changes (Sales et al., 1988; Milligan et al., 1993). Repeated short bursts of 2 kHz sound at 120 dB caused behavioural despair in rats (Bulduk and Canbeyli, 2004). Longer lasting sounds can also affect animals, although that has apparently not been tested in rats. In pigs, 90 dB prolonged or intermittent broadband noise increased cortisol, ACTH, noradrenaline:adrenaline ratios and time lying down, and decreased growth and social interactions (Otten et al., 2004). Conceivably then, a uorescent light emitting loud ultrasound could cause signicant stress in rats housed near it. The envelopes and timbres of sounds also determine how aversive or damaging they are. Noise-type sounds, e.g. white noise or the sound of tearing paper, cause stronger fear reactions in rats than equivalent harmonic or pure tones, or audible rat vocalisations (Voipio, 1997). Sudden sounds are probably also more startling than those with gradual onsets. It should be noted that avoidance of sound occurs at still lower thresholds than those causing startle reactions (in Fleshler, 1965), or physical damage. Ultrasound detectors (e.g. bat detectors), which represent ultrasounds in a form that humans can hear or visualise, would be useful as standard pieces of laboratory equipment to regularly check whether ultrasound of certain frequencies is being emitted in the animal rooms and to test experimental setups. Few experimenters would choose to carry out experiments during loud building work, for example, because of potential effects on the animals performances, and the same meticulousness should apply to ultrasound. Indeed, background noise levels during behavioural experiments do affect the apparent learning abilities of rats, with louder white noise leading to faster completion of a maze task (Prior, 2006). Moreover, even loud infrasound affects rat behaviour, reducing their activity and triggering sleep (Petounis et al., 1977). 3.2. Vocalisations and communication As well as audible squeaks, rats produce at least three types of ultrasonic vocalisations. First, juvenile rats produce a 4050 kHz vocalisation (Noirot, 1968), which together with olfactory cues, causes pup retrieval by the mother (e.g. Allin and Banks, 1972; Farrell and Alberts, 2002). The second ultrasonic vocalisation is the 22 kHz long-call, which occurs mainly in aversive situations and might therefore indicate negative affect (Knutson et al., 2002). Examples of such situations include social defeat (Van der Poel and Miczek, 1991), exposure to cat odour (Blanchard et al., 1991), administration of naloxone or lithium chloride (Burgdorf et al., 2001), arthritic pain without analgesia (Calvino et al., 1996), acute pain (Jourdan et al., 1995), acoustic startle (Kaltwasser, 1990) and electric shocks (Kaltwasser, 1991). However, male rats make a similar vocalisation after ejaculation (Van der Poel and Miczek, 1991), so this call might occur in two subtly different forms, or might not reliably indicate negative affect. The third ultrasonic vocalisation is the 50 kHz chirp, which is apparently associated with positive events (Knutson et al., 2002), and has even been suggested as a form of laughter (Panksepp and Burgdorf, 2000). It occurs in anticipation of positive social contact (Knutson et al.,
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1998; Brudzynski and Pniak, 2002), rewarding tickling by humans (Panksepp and Burgdorf, 2000; Burgdorf and Panksepp, 2001; Panksepp, 2006), amphetamine or morphine administration (Knutson et al., 1999), and feeding or rewarding electrical stimulation of the brain (Burgdorf et al., 2000), and also during play (Knutson et al., 1998; Brudzynski and Pniak, 2002; Burn, 2006). However, again, this vocalisation does not reliably indicate positive affect because it occurs in some aversive situations, e.g. during morphine withdrawal (Vivian and Miczek, 1991), aggression (Sales, 1972), and in certain painful situations (Hawkins et al., 2005). Surprisingly little work has investigated the audible squeak. There may in fact be several different types of squeak, because subjectively there is variation in the quality of sounds produced (O.H.P. Burman, personal communication; personal observation). Pups and their mothers make audible squeaks in the nest (e.g. Voipio, 1997), but this may be different from squeaking in other contexts. Squeaks occur during nociception but they persist even when central nervous system analgesics are given, which might suggest that they are detached from the emotional experience of pain (Jourdan et al., 1995). They also occur during playing and ghting (Voipio, 1997; Burn et al., 2006a), and sometimes during handling, especially alongside struggling behaviour (van Driel et al., 2004; Burn, 2006). They generally seem to indicate negative affect, but do not necessarily occur alongside the 22 kHz long-call, so there must be some qualitative or quantitative difference between the motivations behind the two call types. All of these vocalisations could have practical implications. Procedures or environments that cause rats to vocalise could affect the behaviour and physiology of all neighbouring rats within audible range. For example, playbacks of 22 kHz long-calls caused freezing and decreased activity (Sales, 1991; Brudzynski and Chiu, 1995) and increased latencies to emerge into an arena (Burman et al., 2007). Playbacks of audible squeaks also caused conspecics to orientate towards the speaker and occasionally to squeak themselves (Voipio, 1997). 3.3. Perception of the human voice An awareness that rats can hear our voices is important, because of affects on experimental results and rat welfare. Rats can hear and discriminate many elements of the human voice (e.g. Pons, 2006), and pet rats can learn to respond to verbal commands (e.g. Fox, 1997). In fact, rats can distinguish between some languages (Toro et al., 2003), so the pitches, rhythms and accents of different human workers could be at least partly responsible for rats being able to distinguish between individual humans (McCall et al., 1969; Morlock et al., 1971; Davis et al., 1997; van Driel and Talling, 2005). Shouting causes stress responses in farm animals (Hemsworth, 2003), so this may also be true for laboratory rats, especially because when humans speak with more emotional content, the higher pitched and ultrasonic content of our speech increases (Mason, 1969). 3.4. Sound recordings and playbacks By default, most standard recording devices and speakers include no ultrasound, so specialised equipment is necessary, such as tweeter speakers and ultrasonic microphones (Bjork et al., 2000). White noise, although aversive to rats (Voipio, 1997), is commonly used to standardise background noise in experiments, but different speakers differ in their ultrasonic output, so comparisons across studies might sometimes be invalid. Even a study that specically investigated how background noise affected rat behaviour in a maze, neither mentioned their ultrasonic hearing abilities, nor used specialist equipment to produce the experimental white noise (Prior, 2006), indicating that awareness of these auditory issues may be lacking in some elds.
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3.5. Echolocation There has been some debate about whether rats can echolocate (e.g. Rosenzweig et al., 1955; Riley and Rosenzweig, 1957; Kaltwasser and Schnitzler, 1981; Forsman and Malmquist, 1988). Blind rats can use self-generated sounds, reected off solid objects, to guide them in mazes (Rosenzweig et al., 1955; Riley and Rosenzweig, 1957). Also, sighted rats in darkness can discriminate between shelves close enough to jump to and those too far away, but not if they are deafened (Chase, 1980). Some studies described quiet ultrasonic clicks (Chase, 1980; Graver et al., 2004), which were produced more in darkness than in light, more before rats jumped to the platform than after, and the decision to jump was faster in rats that clicked more (Graver et al., 2004). However, rats seem not to have anything like the specialised echolocation abilities of mammals such as bats or cetaceans. Indeed, some blind and blindfolded humans can echolocate using reected sound, similar to rats (in Riley and Rosenzweig, 1957), but there is no evidence that either species can use sound to build up a detailed picture of their environment, as bats or cetaceans can. 4. Olfaction Rats rely heavily on olfaction (e.g. Doty, 1986). They can quickly associate olfactory cues with food rewards (Le Magnen, 1999a; Birrell and Brown, 2000), with this ability even making them a suitable alternative to sniffer dogs for locating contraband substances (Otto et al., 2002). Rats can locate the direction of odorants, without moving their heads, three orders of magnitude more quickly than we can (Rajan et al., 2006). It is sometimes stated that albinism dampens olfaction, because albinos show weaker avoidance of garlic than pigmented rats do (Keeler, 1942), but of course they might simply be less averse to the scent. Humans are unusual mammals because a much smaller proportion of our genome is devoted to olfaction, than other species (Gilad et al., 2003; Emes et al., 2004; Rat Genome Sequencing Project Consortium, 2004; Quignon et al., 2005), and our vomeronasal organ is vestigial or nonexistent (e.g. Brennan and Keverne, 2004). In contrast, rats not only possess main olfactory epithelia, but also well-developed vomeronasal organs. Although the two systems overlap (reviewed in Shepherd, 2006), the vomeronasal organ seems specialised for instinctive recognition of pheromones and evolutionarily relevant compounds (Dulac, 1997; Holy et al., 2000; Brennan and Keverne, 2004), while the olfactory epithelium is specialised for learned associations between volatile scents and their implications (Dulac, 1997). The vomeronasal system detects relatively non-volatile compounds, requiring the rat to lick or imbibe some compounds before it can detect them (Brennan and Keverne, 2004). Here olfaction includes both systems, because in most cases the specic odorant or detection mechanism is currently unknown. The focus is on olfactory communication, but some signicant scents within laboratory environments are also discussed. 4.1. Overview of rat olfactory communication Rat olfactory communication is well developed, yet remains little understood by humans. Much communication is mediated through urine, but rats have many scent glands, including the sebaceous, preputial, clitoral, perineal, salivary, anal, plantar, and Harderian glands. Through scent, rats can gain information about each others gender (Alberts and Galef, 1973; Moore, 1985; Brown, 1992; Garcia-Brull et al., 1993), reproductive state (Gawienowski et al., 1975;
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Manzo et al., 2002; Zala et al., 2004), genetic relatedness (Wills, 1983; Hurst et al., 2005), dominance (Krames et al., 1969), health status (Zala et al., 2004), and individual identity (Hopp et al., 1985; Gheusi et al., 1997). Rats also recognise familiar conspecics using olfaction (Burman and Mendl, 2003), not through a shared colony scent, but through remembering individual odours (Alberts and Galef, 1973; Carr et al., 1976). These odours can be determined genetically or be acquired from the environment (Schellinck et al., 1991; Schellinck and Brown, 2000; Hurst et al., 2005). Laboratory rats may not be completely isolated from conspecics even when individually housed, because scents from neighbouring cages, or experimental apparatus and instruments can inuence them (unless they are in individually ventilated cages). These scents can profoundly affect rats, as described below, although it should be mentioned that isolation itself also affects these social animals (e.g. Day et al., 1982; Hurst et al., 1997; Sharp et al., 2002; Westenbroek et al., 2005). 4.2. Scent and reproduction Much sexual behaviour in rodents is olfactorily mediated. The Bruce effect, whereby female mice abort their offspring upon encountering the volatile scent of unfamiliar males (Bruce and Parrott, 1960), seems not to occur in rats. However, the Whitten effect, in which volatile male scents trigger oestrus in females (Whitten, 1959), and the LeeBoot effect, when females housed without males show suppressed, irregular oestrus cycles (Van Der Lee and Boot, 1956) do occur relatively weakly in rats. In rats and mice, male odour accelerates the onset of puberty in females, in a phenomenon labelled the Vandenbergh effect (Vandenbergh, 1969, 1976). The scent of female rats, especially those in oestrus, stimulates not only male sexual behaviour, but also urinary-marking (Manzo et al., 2002) and competitive aggression (Alberts and Galef, 1973). It is possible therefore, that housing males where they can smell females could affect their physiology and behaviour, affecting research, and might affect their welfare either way. The vomeronasal system, probably responsible for detecting these scents, habituates to stimuli less easily than most sensory systems (Holy et al., 2000), so the effects might be persistent. However, since the vomeronasal organ requires direct physical contact to detect some pheromones (Brennan and Keverne, 2004), the problem might only exist if the scent is volatile. Other important scents here include those mediating the motherpup relationship. For example, diodecyl proprionate, a pup preputial gland pheromone, induces maternal licking (Brouettelahlou et al., 1991). Mother rats produce various odours aiding pup survival, including those guiding pups to the nipples, and those deposited in the bedding that reduce pup activity, keeping them in the nest (Porter and Winberg, 1999). Also, pregnant females release a nonvolatile pheromone that prevents infanticide by cohabiting males (Mennella and Moltz, 1988). Perhaps it is the removal of these scents that increases the likelihood of pups being cannibalised when rats cages are cleaned within the rst few days of birth (Burn and Mason, in press). 4.3. Olfactory modulation of aggression Aggression in male rodents can be triggered by novel (usually male) scents, so rats rendered anosmic show little aggression in residentintruder tests (Alberts and Galef, 1973). Habituation to familiar or self-scents plays a large role in reducing aggression between familiar or related individuals. For example, aggression is reduced between more familiar individuals (Alberts and Galef, 1973; Garcia-Brull et al., 1993) and between more closely related individuals (Nevison et al.,
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2003). Some inbred mouse strains cannot discriminate between familiar and unfamiliar conspecic odours, resulting in reduced aggression (Nevison et al., 2003). This could also be true for rats. In fact, unfamiliar male scents not only stimulate aggression, but also defensive behaviour in subordinate males encountering dominant male odours. Rats defeated by an alpha-male, subsequently show avoidance and fear behaviour upon encountering the scent of other alphamales (Williams and Groux, 1993; Williams, 1999). This said, while cage-cleaning which removes scent marks provokes aggression in male mice (Gray and Hurst, 1995; Van Loo et al., 2000), in familiar rats it merely provokes nonaggressive skirmishing (Burn et al., 2006a,b); perhaps for this reason cage-cleaning frequency seemingly has no long-term effects on male rat welfare. When unfamiliar rats are to be housed together, exposing them to each others scents for a few days before allowing physical contact may prevent aggression (e.g. Bulla, 1999). Alternatively, aggression can sometimes be prevented by masking unfamiliar conspecics using another unfamiliar, neutral scent. In rats evidence is anecdotal, but in a controlled study of mice, chocolate or sheeps wool odours reduced residentintruder aggression (Kemble et al., 1995). Finally, it is worth mentioning that odour-mediated aggression does not only occur between males. For example, mother rats able to smell their own pups show aggression towards intrudersneither visual, tactile, nor auditory cues from the pups elicit this aggression (Ferreira and Hansen, 1986). 4.4. Communication about experiences Rats are generally attracted to areas smelling of conspecics (e.g. Galef and Heiber, 1976; Mackay-Sim and Laing, 1980), but scents released during negative or positive experiences, can make those areas aversive or more attractive, respectively. Rats produce alarm odour when they experience electric shocks (Mackay-Sim and Laing, 1980; Abel and Bilitzke, 1990; Williams and Groux, 1993; Kiyokawa et al., 2004), transport between rooms (Beynen, 1992), and the events and disturbances accompanying carbon dioxide euthanasia (Ware and Mason, 2003). They probably also produce it in forced-swim tests (Abel and Bilitzke, 1990), but no unstressed controls were used so rats may simply have been responding to odours left by an unfamiliar male. Alarm odour is more powerful with more severe stressors (Mackay-Sim and Laing, 1980). The molecule(s) involved have not yet been identied, but a candidate is 2-heptanone; more of this is present in urine from stressed rats, but diazepam during the stressor does not reduce the amount produced (Gutierrez-Garca et al., 2006). In recipients, alarm odour increases freezing behaviour (Williams, 1999; Kikusui et al., 2001), activity (Mackay-Sim and Laing, 1980; Abel and Bilitzke, 1990; Kikusui et al., 2001; Ware and Mason, 2003), body temperature (Kikusui et al., 2001), hypothalamicpituitaryadrenal activity (Takahashi et al., 1990; but see Mackay-Sim and Laing, 1980), urination (Stevens and Koster, 1972), and latency to approach rewards (Mackay-Sim and Laing, 1981; Ware and Mason, 2003). It also causes avoidance compared with the scent of unstressed conspecics (Mackay-Sim and Laing, 1980). Experience can affect responses to alarm odour, with rats avoiding the odour of shocked rats more if they have experienced shock themselves, but not necessarily if they have experienced defeat by an alpha-male (Williams and Groux, 1993). A somewhat separate body of literature describes frustration or non-reward odour, produced when anticipated rewards are withheld (Collerain and Ludvigson, 1972; Ludvigson et al., 1985; Taylor and Ludvigson, 1987). Again this odour causes avoidance, but unlike alarm odour, no fear responses to it have been reported. It seems not to exist in urine (Collerain and Ludvigson, 1972),
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unlike alarm odour (Mackay-Sim and Laing, 1981), but both are also produced from other bodily sources yet to be identied (Mackay-Sim and Laing, 1981; Weaver et al., 1982). Rats probably also produce a reward odour, although this has mainly been tested against nonreward situations (i.e. frustration odour), with no neutral rat odour control. Nevertheless, a rats trail is more attractive if laid down after the rat receives a reward than before (Galef and Buckley, 1996), and when it perceives a signal that reliably predicts reward (Ludvigson et al., 1985). However, the attraction of rats to reward odour is much weaker than the avoidance of frustration odour, when compared against the same no odour control (Taylor and Ludvigson, 1980). The release of alarm odour means that rat welfare and experimental aims might be compromised if neighbouring conspecics are distressed by illness, injury, or experimental procedures (Beynen, 1992). Any of these odours can bias rats decisions in choice tests (Collerain and Ludvigson, 1972; Aoyama and Okaichi, 1994; Mitchell et al., 1999), increase baseline stress in subsequently tested rats or supposed control ones (Beynen, 1992; Kikusui et al., 2001), and alter behaviour in tests such as swim tests (Abel and Bilitzke, 1990), and open eld or novelty tests (Mackay-Sim and Laing, 1981; Takahashi et al., 1990; Ware and Mason, 2003). There has apparently been no evaluation of effective ways to clean experimental apparatus; various cleaning agents are used, which probably vary in efcacy and may have intrinsic odours that affect rats. Alcohol is commonly used, but in pigs, its volatile components can reduce cortisol levels in open eld tests (Thodberg et al., 2006). 4.5. Communication about food Rats can learn about specic foods from conspecic odours. Carbon disulphide, present in rats breath (Galef et al., 1988), causes rats to strongly prefer novel foods eaten by their cagemates versus other novel foods (e.g. Strupp and Levitsky, 1984). The preferences can persist for at least 30 days, even without opportunity to sample the foods during that time (Galef and Whiskin, 2003b). Aversion to novel foods can be caused by the poisoned partner effect (Lavin et al., 1980). Here if a novel food is eaten by a rat, which then encounters the odour of a poisoned conspecic, the healthy rat will subsequently avoid the novel food, even if the poisoned rat did not eat it (Stierhoff and Lavin, 1982). Strangely, the healthy rat only avoids food that it itself has eaten, rather than that eaten by the poisoned rat, and therefore not necessarily the poisonous food (Galef et al., 1990). In fact, exactly as described above, the healthy rat actually prefers novel food after smelling it on the poisoned rats breath (Galef et al., 1990). Lactating rats also avoid novel foods ingested just before their pups become ill, because of an odour released by pups with gastrointestinal illness (Gemberling, 1984). The odour causes no aversion in males or nulliparous females, and is not released by pups stressed in other ways, so it seems more specic than the poisoned partner effect. 4.6. Scents in the laboratory Most of the scents relevant to laboratory rats are those within the cage itself. Apart from those produced by conspecics or food, others could include detergent residues, bedding materials, and microbial products from the breakdown of food or excreta. Cage-cleaning abruptly changes the olfactory environment, which might contribute to post-cleaning changes in rat behaviour and physiology (Burn et al., 2006a). Also, like gerbils, rats might more accurately discriminate scents in a test arena on days when their cages are clean rather than soiled (Dagg et al., 1971).
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Another salient source of smell for laboratory rodents might be their human handlers. Rats respond differently towards different humans (McCall et al., 1969; Morlock et al., 1971; Davis et al., 1997; van Driel and Talling, 2005), mostly because of differences in odour (McCall et al., 1969). People smell different due to genetic factors and environmental ones, such as diet, smoking, perfume, soap, and deodorant. Regular rodent handlers may also be marked with odours from previously handled rodents, sometimes including reward or alarm odours. Additionally, rats might fear humans carrying scents from their pets, especially if the pet is a predatory species. Rats innately fear predator odours, including cats and mustelids (reviewed in Blanchard et al., 2003), but apparently not dogs. Rats cannot easily habituate to predator odours (Blanchard et al., 1998), showing increased corticosterone, freezing and vigilance, elevated plusmaze anxiety and endogenous opioid analgesia, and suppressed electric-prod burying, and impaired working memory (Williams, 1999; Blanchard et al., 2003). Predator odours also elicit fear-related fast-waves and reduce cell-proliferation in the dentate gyrus (Heale et al., 1994; Tanapat et al., 2001). It is even possible that rats would instinctively fear human odourwild rats usually avoid close human contact, and any such fear of humans might have escaped our notice because, of course, it would require a controlled experiment not involving human presence. Many odours from synthetic products used in laboratories could affect rodents. While several reviews compare the efcacy of detergents for cleaning animal cages (e.g. Heuschele, 1995), none discuss their potential olfactory impacts on the animals. Yet, some organic solvents (e.g. xylene, toluene, diethyl ether, and methyl methacrylate) cause avoidance and fast-waves in the dentate gyrus, just as predator odours do (Heale et al., 1994). These solvents constitute many everyday substances, including some inks, glues, and paints; indeed, identication-marking rodents with inks or dyes can affect their anxiety proles (Burn et al., 2008) and cause them to become submissive to unmarked cagemates (Lacey et al., 2007). Many odorants that smell subjectively pleasant to humans, often therefore being present in perfumed products or human diets, can also inuence hypothalamo-pituitaryadrenal activity and immune responsiveness, positively or negatively (Komori et al., 2003). Rose oil (de Almeida et al., 2004) and green odour, trans-2-hexenal (Nakashima et al., 2004), are anxiolytic to rats. Citrus oils are analgesic (Aloisi et al., 2002), but can have complex effects on rodent anxiety (Komori et al., 2003; Ceccarelli et al., 2004). In rat pups, peppermint increases mortality and decreases activity (Pappas et al., 1982), and rats avoid the scent of garlic (Keeler, 1942) and rosemary (R.M.J. Deacon, personal communication). Many of these effects could inadvertently introduce variation between experiments, but some could be used as non-nutritive environmental enrichments or rewards. Also, anxiolytic scents could be easily administered to rats in mildly stressful situations (de Almeida et al., 2004; Nakashima et al., 2004). 5. Gustation Like us, rats are opportunistic omnivores; their ecological niche is characterised by sampling diverse food substances and remembering their nutritional consequences (e.g. Capaldi, 1996). They rapidly learn aversions to harmful novel foods, which can be a problem in pest control situations when they ingest sub-lethal quantities of bait. Rats, particularly wild strains, are neophobic, being reluctant to consume novel food (Galef and Whiskin, 2003a). They initially sample only small amounts of novel food (if any at all), but if it proves safe, they later readily consume it, often in preference to more familiar foods (Calhoun, 1963). Under natural
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conditions, this cautious but explorative behaviour might help them obtain a full nutritional complement, reducing reliance on any one food type, while avoiding poisoning. Rats detect similar taste dimensions to humans, i.e. sweetness (carbohydrates and articial sweeteners), saltiness (sodium salts), sourness (hydrogen ions), bitterness (quinine, caffeine, most natural toxins, and some others) (Grill and Norgren, 1978), and umami (amino acids, such as glutamate) (e.g. Smith and Margolskee, 2001). As with humans, sweetness and umami are rewarding, bitterness is usually aversive, and saltiness and sourness are only pleasant at low concentrations (Grill and Norgren, 1978; Berridge, 2000). They also initially strongly avoid capsaicin, the hot taste of chilli, but often consume it readily once it becomes familiar (Jensen et al., 2003). However, rats do not perceive certain articial sweeteners as being sweet (Sclafani and Abrams, 1986; Dess, 1993; Sclafani and Clare, 2004), and they may have separate receptors for sugars and starch (Sclafani, 1987). Their bitterness thresholds for some compounds differ from ours (Glendinning, 1994; Mueller et al., 2005), allowing denatonium benzoate which tastes less bitter to rats than to humans and some other animals to be added to baits to prevent its consumption by non-target species (Hansen et al., 1993). There are also some strain and sex differences in rat gustation (Boakes et al., 2000; Clarke et al., 2001). In fact, avour involves not only gustation, but also olfaction and tactile sensations (Smith and Margolskee, 2001). For completeness, these senses are not separated here when discussing the practical implications of rat gustatory biases. 5.1. Taste in the laboratory Laboratory rodents usually have no opportunity to sample different foods, typically being fed a palatable, dry, nutritionally complete diet, in powder form or as pellets. These diets are easily stored, inexpensive, and require little preparation (Lane-Petter, 1975), and they aid standardisation between experiments. Laboratory rats will also taste their mothers milk, bodily secretions from themselves or conspecics (if socially housed), their cage surfaces, and perhaps human hands or gloves, and bedding material (if provided). Hence, scope for learning tastenutrient associations is very limited, rendering the gustatory sense largely redundant in laboratories. For other sensory modalities, sensory deprivation reduces the volume and functioning of the associated brain regions. For example, the visual cortices of rats reared in darkness are permanently underdeveloped (Fagiolini et al., 1994), while sensory deprivation only temporarily limits olfactory bulb (Cummings et al., 1997) and barrel cortex development (Polley et al., 2004; but see Rema et al., 2003). However, despite rats frequently being used as models in taste research, precisely because their gustatory perception is supposedly similar to ours, the effects of gustatory deprivation on the brain and behaviour are apparently unknown. The effects may be minimal if taste is tightly genetically controlled, but alternatively, lack of gustatory experience could, for example, exaggerate rats neophobia or diminish their gustatory learning abilities. 5.2. Nutritional regulation It is unclear whether rats can appropriately self-regulate their nutritional intake, given the opportunity. Most discrepancies between ndings are probably due to differences between the diets offered to rats (Naim et al., 1985; Sclafani, 1987; Prats et al., 1989), and circadian variations in intake patterns (Larue-Achagiotis et al., 1992). Rats generally do select foods appropriate for their changing nutritional needs, but like humans, they are biased towards sugary or fatty foods.
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They are consequently also prone to obesity if offered palatable, caloric diets (Naim et al., 1985; Sclafani, 1987; Prats et al., 1989). Because laboratory rodent diets are homogenous, they allow no qualitative nutritional regulation. Generally, this is unproblematic because the diets have sustained rodent populations for many decades, without apparent negative effects on breeding, health, or longevity. However, although special formulations are available, many widely used diets cover all age and sex categories: oestrus females, weanling pups, and elderly males alike. Moreover, they are often common to rats and mice. Thus, within this diversity, individuals might sometimes have different nutritional requirements from that provided. In standardising diets to this extent, we might inadvertently increase, rather than decrease, variation in rodents internal nutritional states because they have no opportunity to regulate them. Some dietary supplements can enhance laboratory rat health, calling into question the completeness of homogenous diets. For example, blueberries, high in antioxidants, prevent cognitive decits in aging rats (Casadesus et al., 2004), and as mentioned previously, other dietary supplements prevent retinal damage (Li et al., 1985). Also, in hamsters, supplementation with seeds and rabbit chow increased pup growth, and reduced cannibalism by the mothers (Day et al., 2002). 5.3. Renement within the homecage Palatable diets may provide rats with enjoyment (Lane-Petter, 1975) or hedonic experiences, with palatable and unpalatable foods eliciting distinctive behavioural expressions that are homologous to human gustatory expressions (Berridge, 2000). Most welfare efforts concentrate on reducing negative welfare, but facilitating positive welfare, such as pleasure from food or foraging, should not be neglected (e.g. Balcombe, 2005). Food-related environmental enrichments might be particularly relevant for generalists, like rats, because their natural ecology incorporates diverse food types, varying through time and space. However, the idea of food-related enrichment has been little explored for laboratory rats, and yet it could improve their welfare (Johnson and Patterson Kane, 2003), provided obesity is avoided (e.g. Mattson, 2005). There are three main aspects of food that could be varied for enrichment purposes: nutritional content, avour, and physical presentation. 5.3.1. Nutritional content Providing rodents with very nutritionally diverse diets may be undesirable for practical reasons (Lane-Petter, 1975; Key, 2004), and because they encourage obesity (Mattson, 2005), and may increase variation. Nevertheless, offering some opportunity to nutritionally self-regulate could be benecial, as suggested above. In some animal facilities, seeds and nuts are scattered onto rats bedding; rats become very active upon hearing them being scattered in neighbouring cages, and continue foraging for many hours (Key, 2004). Since the seeds would constitute only a very small proportion of the diet, they are unlikely to impact heavily on nutritional regulation, but could allow some relevant gustatory stimulation and regular hedonic experiences. Proper evaluation of the effects is necessary however; the most relevant study so far seems to be one, mentioned earlier, when seed supplements enhanced hamster pup growth and decreased cannibalism (Day et al., 2002). 5.3.2. Flavour Even without nutritional value, gustatory enrichment could be achieved; providing daily non-nutritional pina-colada avour treats to breeding mice increased the number of pups
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weaned (Inglis et al., 2004), suggesting that the hedonistic aspects alone of scatter-feeding are benecial. Domesticated rats value variety, and will substitute a preferred food that has been their sole diet for several days for a less preferred, newly available food (Galef and Whiskin, 2003a, 2005). They also consume more food if provided as a succession of varied meals rather than homogenous meals (Treit et al., 1983; Clifton et al., 1987; Le Magnen, 1999b). These preferences exist even when foods differ primarily in avour not nutritional value, such as when cinnamon, cocoa, all spice, or marjoram are added to normal chow (as in the above ve studies). These additives presumably have negligible bioactivity, being common non-nutritive components of human diets, but conrmation in rats is required. The above studies suggest that obesity might be a risk because of the increased food consumption, but they were all relatively short-term, so rats might down-regulate their intake of variable food over time. Le Magnen (1999b) found that if variable days were alternated with homogenous days, rats ate less food than normal on homogenous days, perhaps compensating for over-eating on variable days. 5.3.3. Physical presentation Finally, enrichment might be achieved through varying dietary presentation. Soft wet mash (chow soaked in water) is often used to help sick or weak rats gain weight, and usually any healthy cagemates also prefer the mash to freely available pellets. However, it is an impractical enrichment for healthy rats, being messy and encouraging microbial growth (Lane-Petter, 1975). Occasionally scattering chow pellets within the cage allows rats to eat in their natural posture, holding the pellet in their forepaws (Bruce, 1965), and they more readily consume these pellets than those in the hopper (personal observation). Captive rats also contra-freeload, choosing food that requires handling and preparation, even when prepared food is available (Carder and Berkowitz, 1970). This may be because most of a wild rats time and effort would be devoted to foraging (Johnson and Patterson Kane, 2003). Scattering small food items, such as the aforementioned seed mixes or chow pellets, in bedding allows rats to forage, which may be rewarding in itself. Scatter-feeding rarely triggers competitive aggression because the food is spatially distributed. Commercially available rodent puzzle-feeders are also available, although they are uncommon in laboratories and are not always easily sourced. 5.4. Renement of experiments The generalist feeding habits of rats can be exploited in research, improving experiments ethically, enhancing rats cooperation, and reducing interference from stress. Drugs and inoculants are often delivered by gavage, a tube inserted via the mouth into the stomach, which can be technically difcult, and causes stress, respiratory distress, and occasionally even death (Balcombe et al., 2004). However, substances can be successfully delivered within palatable vehicles that rats will voluntarily consume, provided there is no interference with the active ingredient. Fruit- or beef-avoured gelatine is commonly used but some rats only reluctantly consume it, so it can be worth trying several alternatives (Hawkins et al., 2004). Another example is to use small amounts of chocolate (Huang-Brown and Guhad, 2002). Taste aversion can develop if the vehicle becomes associated with illness, but giving rats prior experience with the unadulterated food can prevent this. Some substances can also be microencapsulated and added to chow for long-term studies (Melnick et al., 1987; Dieter et al., 1993; Yuan et al., 1993).
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Preferred rewards can often be used to motivate rats to perform tasks in experiments, rather than using punishments or prior deprivation. Deprivation is a powerful motivator, but can undesirably affect behaviour, physiology, neurochemistry, and drug efcacy (Slawecki and Roth, 2005). Moreover, it is sometimes unnecessary, because undeprived rats will often work albeit to a limited extent for preferred rewards, including commercially available reward pellets, sucrose solution (Slawecki and Roth, 2005), or breakfast cereals (e.g. Ellis, 1984). Prats et al. (1989) found that rats did not readily consume cheese, chocolate or fruit-candy, and instead preferred other foods offered, including banana, cookies, standard chow pellets, and liver pate. Large quantities of dairy products (DiBattista, 1990) and chocolate (Huang-Brown and Guhad, 2002) should be avoided as they harm rodent health. Undeprived rats are particularly motivated to earn rewards if experiments coincide with their active period (Hyman and Rawson, 2001), with a shifted light cycle enabling practical working hours (see Section 2). Neophobia can be eliminated by providing the palatable incentive in the homecages of rats several days before experiments. Finally, food must often be withheld overnight before surgery or intraperitoneal injections. This deprivation causes weight loss, and reduced hepatic weight and blood glucose, and potentially, emotional distress from hunger. However, providing sugar cubes to the rats can prevent these problems, while gastrointestinal volume is still reduced, as required (Levine and Saltzman, 1998). 6. Somatosensation Rat somatosensation could be considered from many different angles. Here, the focus is on that relating to the ability of rats to explore and interact with their environments. In the rat somatosensory cortex, the vibrissae (sensory whiskers), nose and mouth, forepaws, and sinus hairs on the wrists, are particularly well represented. In fact, the forepaws are represented twice each, and the whiskers and sinus hairs have specialised granular aggregates devoted to them (HermerVazquez et al., 2005). In general, rat and human somatosensation seem similar, but there are two main differences that noticeably affect rat behaviour. First, rats vibrissae are extremely sensitive (Arabzadeh et al., 2005), being comparable to primate ngertips (Carvell and Simons, 1990). Rats can whisk them independently of each other across surfaces to make ne tactile discriminations (Guic-Robles et al., 1989; Carvell and Simons, 1990). In a study investigating rats numerical competencies, subjects could not discriminate between two, three or four tactile stimuli delivered to the body, but they succeeded when the stimuli were delivered to a single vibrissal hair (Davis et al., 1989). The vibrissae also detect differences in mechanical resonant frequencies, with the shorter anterior vibrissae detecting higher frequencies than the longer posterior ones (Neimark et al., 2003). The second obvious difference from humans relates to thigmotaxis; the bias of rats towards maintaining physical contact with vertical surfaces. In fact, thigmotaxis underlies many tests of anxiety (Treit and Fundytus, 1988), because when rats perceive environments as threatening, they stay closer to vertical surfaces, such as the boundaries of open eld arenas, or the closed arms of elevated plus-mazes. The thigmotactic bias may not be strictly somatosensory, perhaps also incorporating visual preferences for avoiding light exposure. Rats that lack vibrissae on one side prefer to maintain wall contact on their intact side, suggesting the vibrissae play a role (Meyer and Meyer, 1992). The implications of rat somatosensation include the impact of environmental enrichment on rat somatosensory development generally, and implications of the vibrissal sense for experiments and housing.
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6.1. Environmental enrichment and somatosensation Environmental enrichment profoundly affects the somatosensory and barrel cortices. In rats kept in enriched rather than barren environments, the primary somatosensory cortex representing the forepaws becomes 1.5 times larger (Xerri et al., 1996; Coq and Xerri, 1998, 2001). The barren cages in these studies contained bedding, exerting their effect despite rats being able to dig with their forepaws, so the difference might be even more pronounced in rats housed on wire oors. Environmental enrichment seemingly does not enhance textural discrimination abilities, but it does increase the rate of learning such discriminations (Bourgeon et al., 2004). Enrichment can also counteract age-related declines in hind-paw representation in the somatosensory cortex, which is otherwise associated with impaired walking in aged rats (Godde et al., 2002). Finally, in naturalistic environments, the representation of each whisker in the barrel cortex becomes dramatically more well dened compared with standard cages (Polley et al., 2004). The above studies combined several enrichment types, including social contact, foraging opportunities, structural features and novelty, so it is unclear what relative contributions were made by each enrichment type. It is lack of tactile contact with conspecics that apparently leads to the self-biting and tail manipulation seen in isolated rats (Day et al., 1982; Hurst et al., 1997). 6.2. Vibrissae and the laboratory environment The sensitivity of the vibrissal sense (Davis et al., 1989; Guic-Robles et al., 1989; Carvell and Simons, 1990; Arabzadeh et al., 2005) is probably under exploited in learning tasks, where less salient visual cues are currently more widely used (Dymond, 1995; Dymond et al., 1996; Birrell and Brown, 2000). However, laboratory rats can sometimes lack vibrissae for various reasons, including barbering, when hairs and often whiskers are removed by conspecics (Garner et al., 2004). This occurs in rats, albeit to a much lesser extent than in mice (Bresnahan et al., 1983; Wilson et al., 1995). Other rats may lack whiskers due to their strain; some nude rodent strains have no whiskers at all (e.g. Sundberg et al., 2000), but most have short, kinked whiskers, giving a limited sensory range (e.g. Festing et al., 1978; Moemeka et al., 1998). Nude strains also lack the sensitive guard hairs otherwise dispersed through the coat, and which would convey proprioceptive information. Both vibrissal absence and barrel cortex impairment through lack of environmental enrichment (as described above), could have practical consequences. Rats lacking vibrissae show impaired orientation towards tactile stimuli, and provided they have environmental enrichment compensate by orienting towards visual stimuli more than controls do (Symons and Tees, 1990). Whiskers also aid swimming, enabling animals to keep their heads above water (Ahl, 1986; Meyer and Meyer, 1992), and consequently, rats lacking vibrissal sensation can drown in water mazes and swim tests (Hughes et al., 1978). Finally, vibrissae are important in social interactions, with whiskerless rats being unable to avoid bites to their faces during ghting (Blanchard et al., 1977a,b). Because aggression between familiar rats is uncommon (Burn et al., 2006b), whiskerless rats need not be socially isolated, except in cases where aggression is observed. However, whiskerless rats may be injured if introduced to unfamiliar conspecics, when ghting is more likely. 7. Summary It is impossible for us to know what it is like to be a rat (Nagel, 1974), but knowledge of their sensory biases allows us to imagine what it might be like, as a human, to have those biases within
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a laboratory rats environment. This insight, while imperfect, could help predict how rats might be affected by different situations, improving our experimental design and their welfare. In summing up then, an overall theoretical picture of a rats perception of the laboratory could be as follows. The rats sensitive eyes, shunning the intense articial light, provide it with a hazy view in predominantly grey, ultraviolet and green hues. From within its cage, it hears the chirps, squeaks and whines of its neighbours, gaining information that we cannot hear unaided and are yet to understand. Background noise consists of the low babbles and hisses of distinctively scented humans, and the unregulated drones and blasts of ultrasonic sounds. Scents provide visceral warnings and enticements, induce new motivations, and inform the rat about social possibilities outside the cage. The environment wafts a succession of scents, from pleasant, calming fragrances to the innately alarming odours of intangible predators. The rat tastes little apart from its dry, satiating homogenous diet. Its vibrissae provide a protective, nely tuned force eld to feel the details of the cage surfaces; with the rat perceiving security from close contact with the solid walls. 8. Conclusion Knowledge of the sensory gulfs and similarities between ourselves and this commonly used research animal can improve science and enhance rat welfare. More work is still necessary to understand rat perception, and even more so for less well-researched species. The aim of this review is to make current knowledge accessible to researchers, rat caretakers and rodent specialists, in the hope that it will enable tangible improvements in experimental design and rat welfare. Acknowledgements Many thanks to Georgia Mason for her detailed comments and encouragement, and also to Robert Deacon, Mark Ungless, Jennifer Bizley, and Alex Weir for their comments. References
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Applied Animal Behaviour Science 112 (2008) 132 www.elsevier.com/locate/applanim

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

C.C. Burn / Applied Animal Behaviour Science 112 (2008) 132

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