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Applied Animal Behaviour Science (2008) Volume 112: 1-32

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doi: 10.1016/j.applanim.2008.02.007

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Final Revision – NOT EDITED by the journal

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What is it like to be a rat? Rat sensory perception and its

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implications for experimental design and rat welfare

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Charlotte C. Burn

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Department of Clinical Veterinary Science, University of Bristol, Bristol BS40 5DU,

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UK

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Running title: Rat sensory perception and its implications

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Correspondence address: Department of Clinical Veterinary Science, University of

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Bristol, Bristol BS40 5DU, UK

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Abstract

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This review of rat sensory perception spans eight decades of work conducted across

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diverse research fields. It covers rat vision, audition, olfaction, gustation, and

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somatosensation, and describes how rat perception differs from and coincides with

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ours. As Nagel’s seminal work (1974) implies, we cannot truly know what it is like to

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be a rat, but we can identify and acknowledge their perceptual biases. These primarily

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nocturnal rodents are extremely sensitive to light, with artificial lighting frequently

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causing retinal degeneration, and their vision extends into the ultraviolet. Their

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olfactory sensitivity and ultrasonic hearing means they are influenced by

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environmental factors and conspecific signals that we cannot perceive. Rat and human

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gustation are similar, being opportunistic omnivores, yet this sense becomes largely

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redundant in the laboratory, where rodents typically consume a single homogenous

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diet. Rat somatosensation differs from ours in their thigmotactic tendencies and highly

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sensitive, specialised vibrissae. Knowledge of species-specific perceptual abilities can

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enhance experimental designs, target resources, and improve animal welfare.

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Furthermore, the sensory environment has influences from neurone to behaviour, so it

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can not only affect the senses directly, but also behaviour, health, physiology, and

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neurophysiology. Research shows that environmental enrichment is necessary for

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normal visual, auditory, and somatosensory development. Laboratory rats are not

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quite the simple, convenient models they are sometimes taken for; although very

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adaptable, they are complex mammals existing in an environment they are not

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evolutionarily adapted for. Here, many important implications of rat perception are

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highlighted, and suggestions are made for refining experiments and housing.

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Keywords: Animal Welfare; Communication; Olfaction; Perception; Rats;

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Refinement; Vision

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The stimuli that an animal can perceive depend on the available sensory apparatus,

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while the way stimuli are evaluated in terms of their biological relevance depends on

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the animal’s innate biases, cognitive abilities and experiences. Perception is therefore

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a subjective distortion of reality, differing between species and even between

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individuals within a species. Since rats and mice, which have similar perceptual

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abilities to each other, constitute over 80% of all research animals in the European

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Union (Commission of the European Communities, 2003), and they have been bred

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for research since the late 1800s (Krinke, 2000; Whishaw & Kolb, 2005), much is

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known about their perceptual biases. However, the information is scattered through

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time and across different research fields, so it is not easily available to researchers, rat

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caretakers, and other rat specialists. The resulting lack of awareness can have

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serious implications, sometimes leading to poorly designed experiments and harming

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rat welfare. This review brings current information together, to help inform and refine

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rodent experiments and housing.

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Introduction

The review concentrates on the laboratory rat, Rattus norvegicus, since

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summaries of mouse sensory perception are included within several other review

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papers (Sherwin, 2002; Olsson et al., 2003; Latham & Mason, 2004). Much of the

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information will also be true for mice and other rodents, but care should still be taken

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if extrapolating between species. The species’ natural ecology – such as whether they

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are diurnal or nocturnal, social or solitary, arboreal, burrowing or terrestrial – will

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profoundly affect their sensory perception. These ethological considerations are

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highly relevant in laboratory rats despite their domestication; adult laboratory rats

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retain so many of their wild instincts that, when released into a naturalistic habitat,

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their resulting community and behaviour rapidly resembles that of their wild relatives

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(Berdoy, 2002). This review is organised around the classic ‘five senses’: vision, audition,

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olfaction, gustation and somatosensation. It should be remembered that these are

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actually not the only senses; indeed rats may even possess a magnetic compass, like

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mice (Muheim et al., 2006) and hamsters (Deutschlander et al., 2003), but most

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published information currently covers the aforementioned five senses. For each

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sense, the rat’s sensory biases relative to humans are first described, then some

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practical implications of its perception with respect to welfare and experimental

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design are discussed. This is an applied review, focussing on the known or suspected

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implications of each sense, and aiming to provide enough information to allow readers

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to extrapolate to their own situations. The review cannot be completely

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comprehensive, and it will become clear that in many cases, rat sensory perception is

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still poorly understood.

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2

Vision

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An obvious difference between human and rat vision is that rats’ eyes are

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located on the sides of their heads, rather than the front. They therefore have a wider

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field of view, but less binocular overlap than us: wild rats have a binocular overlap of

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35o, domestic rats 76o, and humans 105o (Heffner & Heffner, 1992a).

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Wild rats usually inhabit burrows or other enclosed environments, and tend to

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be nocturnal or crepuscular, so most of their activities occur under low light

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conditions (e.g. Calhoun, 1963). Consequently, rats rely relatively little on vision, but

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they are dramatically more sensitive to dim light than we are, able to discriminate tiny

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increments in intensity, indiscernible to us, including discriminating ‘total

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darkness’ from 0.107 lux (Campbell & Messing, 1969).

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Rats, especially albinos, have much poorer visual acuity (Lashley, 1938; Creel

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et al., 1970; Prusky et al., 2002) and narrower depth perception than humans

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(O'Sullivan & Spear, 1964; Routtenberg & Glickman, 1964). For example, human

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acuity can be around 30 c/d (‘cycles per degree’ – a measure of spatial resolution

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accounting for stimulus size and distance), while pigmented rats’ acuities are only 1–

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1.5 c/d and albino strains have even lower acuities of 0.5 c/d (Prusky et al., 2002).

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This presumably gives an extremely blurred image by human standards (Figure 1,

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reprinted from Prusky and colleagues, 2002). Poor acuity in rats is probably partly

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due to their eyes’ relatively small size, and partly because their eyes appear to

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have very limited abilities to focus light from different distances or angles

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compared with human eyes (Artal et al., 1998). Rats often bob their heads which

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may help them gain motion cues about the distance of objects (Legg & Lambert,

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1990).

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Experiments in the 1930s suggested that, contrary to popular belief, rats possess

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colour vision (e.g. Munn & Collins, 1936; Walton & Bornemeier, 1938), which has

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recently been confirmed through electroretinograms and quantitative behavioural tests

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(Jacobs et al., 2001). Rod cells comprise 99% of rat photoreceptors, but rats also have

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two cone cell types (Szel & Rohlich, 1992). Around 93% of the cones respond

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maximally to blue–green light (around 510 nm), while the remaining 7% respond to

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ultraviolet (UV) (around 360 nm) (Jacobs et al., 2001; Akula et al., 2003). Cone

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responses are normally distributed, so rats actually perceive hues ranging from

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ultraviolet (400 nm) to orange-red (around 635 nm) (Jacobs et al., 2001), but they are

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most responsive to colours near their peak sensitivities (Jacobs et al., 2001; Akula et

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al., 2003).

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Flicker fusion thresholds (when emitted light flickers rapidly enough to appear

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constant) for rats are not yet known, but are relevant for their perception of video

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images and artificial lighting (D'Eath, 1998). Flicker fusion thresholds decrease with

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high light intensity, and increase with fatigue. Animals with high proportions of rod 5

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cells, like rats, generally have high flicker fusion thresholds, so rats might perceive

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videos, computer monitors, and some fluorescent lighting as flickering (Jarvis et al.,

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2003).

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Discussion of the implications of rat vision is separated according to sensitivity

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to light generally, colour vision, periodicity, and acuity.

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2.1

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The sensitivity of rats to light (Campbell & Messing, 1969) means that light levels

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comfortable for humans can rapidly cause retinal atrophy (reviewed in Schlingmann

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et al., 1993a; Schlingmann et al., 1993b) and cataract formation in rats (Rao, 1991).

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Albinos are particularly susceptible because they lack protective melanin in the iris

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and retinal epithelium, and the entire eyeball is slightly transparent (Schlingmann et

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al., 1993b). Consequently, even when the iris contracts in bright light, most of the

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light still enters the eye (Williams et al., 1985). In fact, albino rats may be the most

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susceptible of all laboratory animals to light-induced retinal degeneration (Bellhorn,

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1980).

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Sensitivity to light

To illustrate the relevant range of light intensities, the UK code of practice for

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the care and use of laboratory animals suggests that “350–400 lux at bench level is

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adequate for routine experimental and laboratory activities” (Home Office, 1989).

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Light intensities within cages are commonly between about 150 and 550 lux

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(Schlingmann et al., 1993c), but are higher in laboratory rooms, with upper limits

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approaching 10,000 lux due to current technological limitations (e.g. Light Therapy

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ProductsTM, 2006; Outside In Ltd., 2006). Humans can tolerate still higher intensities

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– outdoors on sunny days light often exceeds 50,000 lux, and only at this order of

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magnitude are discomfort and potential retinal damage likely in humans.

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Light intensities of only 65 lux can cause retinal degeneration in albino rats,

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even on a 12 h light-dark cycle (Semple-Rowland & Dawson, 1987). Half the

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photoreceptors were permanently damaged after just 3 days at 133 lux in albinos, but 6

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pigmented rats were less susceptible, with equivalent damage occurring at 950 lux

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(Williams et al., 1985). Rod cells are particularly vulnerable to light destruction, but

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cones often survive even after all rods have been destroyed (Cicerone, 1976; La Vail,

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1976). Long-term cyclical light intensities of about 500 lux within an animal room

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can also cause cataracts in albino rats (Rao, 1991). These problems are worst in rats

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housed closest to the light source, usually those highest in the rack (Rao, 1991; Perez

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& Perentes, 1994).

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Surprisingly, some vision can remain after constant long-term light exposure,

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even when no intact photoreceptor cells can be observed (e.g. Lemmon & Anderson,

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1979). This might be conferred by a few remaining cones that may be so sparse that

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they were undetectable by the quantitative techniques used (Cicerone, 1976; La Vail,

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1976). Even so, under ‘ordinary’ laboratory conditions, visual impairments can

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confound some tests. For example, in the Morris water maze – a test of cognitive

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function – rats with incidental light-induced retinal damage perform as poorly as rats

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with cognitive deficits, both groups displaying difficulties locating the platform

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(Osteen et al., 1995; Lindner et al., 1997). Also, in commonly used ‘anxiety’ tests,

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such as open field tests and light-dark boxes, visually impaired individuals might

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venture into the exposed/light areas more than fully sighted ones, through their lesser

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ability to discriminate light from dark, but this requires experimental confirmation.

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Therefore, light-induced retinopathy should be controlled for in such tests, or non-

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visual tests used alongside the established visual ones.

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Welfare problems might arise at even lower light levels than those causing

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retinal damage, because of motivation to hide, as well as to avoid ocular discomfort

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(Schlingmann et al., 1993c). Rats, especially albinos, reliably choose the lowest light

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intensities available, even when all the choices are very dim, appearing

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indistinguishable to humans (Campbell & Messing, 1969; Woodhouse & Greenfeld,

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1985; Blom et al., 1995). Rats’ aversion to light was clearly demonstrated in a study

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showing that sleeping pigmented and albino rats awoke and moved to areas of lower 7

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illumination at thresholds of only 60 and 25 lux, respectively (Schlingmann et al.,

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1993c). Consistent with such behaviour, chromodacryorrhoea, an aversion-related

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secretion from the Harderian gland (e.g. Mason et al., 2004), increases with brighter

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light (Hugo et al., 1987).

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There is clearly a conflict between human workers needing adequate light to

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inspect rats, for example for signs of illness, and rats needing to avoid damaging or

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aversive light levels. Schlingmann (1993a) therefore stresses the importance of

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providing shelters within cages, allowing rats some control over their light exposure.

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As described below, coloured shelters exist that allow humans to see rodents, while it

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supposedly appears dark to the rodents inside the shelter, although their efficacy

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requires confirmation.

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Light levels affect commonly used psychological tests, such as elevated plus-

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mazes in which exploration of the exposed arms is taken to indicate reduced anxiety;

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rats explore the exposed arms more in dim than bright light (Cardenas et al., 2001;

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Garcia et al., 2005). Moreover, some effects are only found under certain light

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conditions. For example, the anxiolytic effects of gentling only emerge in brightly lit

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open fields (Hirsjarvi & Valiaho, 1995), and some drug effects are influenced by plus

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maze illumination (Clenet et al., 2006). Therefore, some control and careful

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description of lighting conditions during these tests is necessary to account for its

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influence on psychological measures.

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Surgery presents a difficult situation because good lighting is essential for

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delicate operations, but the anaesthetised, unblinking rat is unable to protect its eyes

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from that light. Care should therefore be taken, not only to keep the eyes hydrated, but

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also to protect them from prolonged bright light. Interestingly, the anaesthetic agent,

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halothane, prevents retinal degeneration (Keller et al., 2001); other anaesthetics have

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not yet been investigated. This protection is afforded under white, but not blue, light.

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Despite the above evidence that bright light is harmful to rats, this aspect of

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their biology is not always considered in some fields of research. An example is the

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use of rats as models for seasonal affective disorder in humans, exploring whether

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bright light therapy (up to 11,500 lux for 2 weeks) can cure depression in rats (e.g.

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Dilsaver & Majchrzak, 1988; Giroux et al., 1991; Humpel et al., 1992; Overstreet et

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al., 1995). Unsurprisingly, the depression was not cured, and the one study that

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considered the effects of light on rat vision discovered massive destruction of the

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albinos’ photoreceptors (Humpel et al., 1992). These examples illustrate how crucial

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knowledge of species-specific perception is for generating reasonable hypotheses and

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preventing animal suffering.

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2.2

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Rats are not colour-blind (Muenzinger & Reynolds, 1936; Munn & Collins, 1936;

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Walton & Bornemeier, 1938; Lemmon & Anderson, 1979; Jacobs et al., 2001).

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However, relative to humans, they perform poorly when discriminating between

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colours of similar wavelengths (Walton, 1933), and they take longer to learn colour

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discriminations than light intensity ones (Jacobs et al., 2001).

Colour vision

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To discuss the implications of rats’ colour sensitivity, the implications for

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emitted light and that reflected by objects in the environment will be dealt with

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separately, as their effects are quite distinct.

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2.2.1

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Standard artificial lighting rarely emits UV wavelengths (e.g. Bellhorn, 1980; Latham

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& Mason, 2004), since human cones are insensitive to it. To date, no studies have

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apparently investigated the effects of UV-deficient light on rats. In some birds, UV

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light is important for their welfare (Moinard & Sherwin, 1999; Maddocks et al., 2001)

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and normal behaviour (Bennett & Cuthill, 1994), but laboratory mice appear to have,

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if anything, a slight aversion to it (C. M. Sherwin, personal communication). Also,

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high levels of UV can cause cataracts in mice (in Bellhorn, 1980), and can affect

Emitted light

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reproductive and circadian rhythms in rats (reviewed in Brainard et al., 1994). In fact,

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the colour composition of artificial light can have large effects. In rats, blue light

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(around 490 nm) causes most retinal degeneration (reviewed in Schlingmann et al.,

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1993b), and also more disruption to fertility (Tong & Goh, 2000) than any other

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wavelengths tested; UV light was not included in these studies, but is of a shorter

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wavelength than blue light so may be more harmful.

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At the opposite end of the spectrum, dim red light is sometimes used to observe

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nocturnal behaviour in rats, because it is on the upper edge of the wavelengths visible

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as colour to them (Jacobs et al., 2001). However, rats’ rod cells are stimulated by

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similar wavelengths to human rod cells, including red light (Akula et al., 2003). This

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means that, provided some rod cells remain intact, rats can see red light, even if only

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as light and dark contrast. This may not be a problem in experiments if rats are

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habituated to it, since moonlight would provide illumination in the wild. As an

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alternative to red light, sodium lamps, which emit very narrow peaks of yellow–

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orange (589 and 589.6 nm) light, can be used (McLennan & Taylor-Jeffs, 2004). Not

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only is it more visible to humans than red light, but there were no long-term

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differences between the activity levels of mice when illuminated by this lamp or in

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darkness. However, in studies unequivocally requiring rats to behave as if in pitch

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darkness, infra-red light and the necessary viewing equipment should be used.

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It is also worth noting that most video equipment and computer monitors, which

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create images using emitted light, include no UV emissions and the colour balance is

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optimised for human vision (D'Eath, 1998). Even in black-and-white images and light

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from white artificial light bulbs, ‘white’ is composed of red, green and blue light

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adjusted for humans, and so would not appear as white to rats. Therefore, any such

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images presented to species with different colour sensitivities, particularly UV-

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sensitive animals, could lack important information.

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2.2.2

Colour in the environment

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Caution is required when presenting images to rats in discrimination tests, even if the

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cues reflect rather than emit light. Different inks have different spectral properties that

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may be invisible to the human eye, and some might even reflect UV. Moreover,

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different pigments might differ in their olfactory qualities, which could be more

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salient to rats than their visual qualities. Even if this does not harm the experimental

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purpose, it can make standardisation between experiments difficult.

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Outside experimental situations, there are also some relevant implications of

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rodent colour vision within the homecage. In recent years, manufacturers of rodent

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environmental enrichments have produced transparent shelters in various colours (e.g.

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Robbins, 2004; Datesand Ltd, 2005). The idea behind them is that, while rodents -

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supposedly blind to the shelter’s colour - perceive themselves as being sheltered in a

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dark environment, human carers can inspect them without disturbing them. However,

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these shelters seem not to have been independently evaluated for their efficacy. Red

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transparent material might make a suitable shelter, being the least visible colour to

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rats (Jacobs et al., 2001), but as explained earlier, it would still stimulate rod cells and

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possibly some cones. The colour of the homecage itself might also affect rats. Sherwin and Glen

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(2003) housed mice in different coloured cages and found that they had significantly

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different preferences for cage-colours. Moreover, the colour affected their food-to-

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body mass conversion rates and their elevated plus-maze anxiety. Assuming these

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effects were due to the colours directly (rather than the scents, tastes, or textures of the

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dyes used), this study shows that environmental colour can have surprisingly strong

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effects on mouse behaviour and physiology, and so possibly that of rats too.

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2.3

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Rats tend to be most active at dusk and dawn, although their circadian rhythms are

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relatively flexible (e.g. Calhoun, 1963). Because we are diurnal, many rodent

Periodicity

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experiments are carried out in the light, so much of our knowledge of this species

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comes from individuals awakened during their resting period, and tested under much

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brighter conditions than they would voluntarily experience. The implications of this

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can be profound, but time-shifted experiments are still rare in some fields. The brain

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state changes radically between sleep and activity, with whole populations of neurons

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shifting between activity and inactivity (Hobson, 2005; Saper et al., 2005). The time

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of testing can strongly influence the variables of interest in experiments. For example,

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during the light phase, rats’ cardiovascular responses to various stressors are more

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pronounced (Schnecko et al., 1998), and they show less exploratory behaviour in an

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elevated plus-maze than in the dark phase (Andrade et al., 2003).

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For most experiments, rats will be in a wakeful state provided they have

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sufficient time to awaken, but little published information is available on how long

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rodents require to fully awaken (i.e. be in the same state as during the active phase).

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Any conclusions drawn from light phase studies of rats as human models could suffer

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from interpretive problems, because it is unclear whether the observed state would

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reflect a similar state in our light (active) phase or our (dark) resting phase.

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Time shifted experiments and husbandry can be made possible by using red or

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sodium illumination as described above, and also by feeding rats only during the

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phase when we wish them to be active (cited in Saper et al., 2005); a situation that

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sometimes occurs in the wild (Calhoun, 1963).

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2.4

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As described above, rats have very poor acuity (Figure 1). Their image resolution is at

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least 20 times poorer than ours (Artal et al., 1998). Note though that the studies

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investigating rat visual acuity (Lashley, 1938; Creel et al., 1970; Artal et al., 1998;

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Robinson et al., 2001; Prusky et al., 2002) have used laboratory rats, whose acuity

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might have been further reduced by their artificially lit environments.

Acuity

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Apart from the damaging effects of light itself, several other factors can affect

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rat vision, including the early environment. Complete lack of light impairs rats’ visual

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development (Fagiolini et al., 1994), but providing environmental enrichment to these

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dark-reared animals can eliminate this effect (Bartoletti et al., 2004). In mice,

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enriched environments during rearing accelerate visual development and improve

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adult acuity (Prusky et al., 2000; Cancedda et al., 2004).

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Also, diet has a large influence on vision (Berson, 2000). For example, caloric

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restriction can prevent cataracts (e.g. Wolf et al., 2000), and antioxidant intake and

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consumption of certain vitamins can prevent retinal damage (Li et al., 1985; Berson,

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2000). Dietary composition is discussed in more detail in the Gustation section of this

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paper.

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The research implications of rats’ poor visual acuity depends on the experiment

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in question, but if visual cues are used they should be relatively large and high

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contrast, but not too bright as to be aversive. Also, visual cues may not be as salient to

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rats as cues in other modalities. Few experiments have tested this directly, but rats do

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remember auditory associations for longer than equivalent visual ones (Wallace et al.,

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1980), and can more rapidly learn discriminations using multimodal stimuli (floor

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surfaces differing in appearance, smell, and texture Dymond, 1995; Dymond et al.,

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1996) or olfactory or tactile cues (Birrell & Brown, 2000). However, vision is often

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the most appropriate sense for guiding rats in water mazes (Prusky & Douglas, 2005),

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for comparison with past studies, and for certain models of human activities.

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Sound can be described in terms including its frequency, intensity, timbre (frequency

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spectrum) and envelope (shape of sound pressure through time). While young

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humans hear frequencies from about 0.02 kHz to 20 kHz (Moore, 2003), hearing in

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rats is shifted upwards to include the ultrasonic range (Kelly & Masterton, 1977). The

Audition

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lowest frequency rats have been reported to hear is 0.25 kHz and the highest is 80 kHz

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(Kelly & Masterton, 1977; Heffner & Heffner, 1992b; Heffner et al., 1994). They can

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also detect lower sound frequencies (Petounis et al., 1977), probably through contact

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with vibrating surfaces, and can even perceive low frequency sounds using their

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vibrissae (Neimark et al., 2003) (see the section on Somatosensation). Auditory sensitivity decreases near the extremes of the detectable frequencies,

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so sounds at the lower and higher extremes must be louder before rats can detect

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them. The rat’s peak sensitivity is estimated to lie between about 8 and 50 kHz (Kelly

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& Masterton, 1977; Heffner & Heffner, 1992b), although estimates vary, probably

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due to factors including strain, age, and background noise. Even whether the

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homecages of rats are barren or environmentally enriched can greatly affect hearing

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sensitivity; auditory neurone performance is vastly improved by environmental

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enrichment (Engineer et al., 2004).

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The implications of rat auditory perception include what sound characteristics

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are harmful, vocal communication between rats, perception of the human voice, and

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experimental use of sound cues. There has also been debate about whether rats can

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echolocate.

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3.1

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Interactions between sound intensity and frequency (Fleshler, 1965; Voipio et al.,

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1998; Björk et al., 2000) make it difficult to determine detection- and safety-

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thresholds for sound intensities. The decibel (dB) scale is logarithmic, so even small

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numerical increases represent large increases in the actual intensity. European

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Union legislation (2003) states that advice and hearing-protection must be provided

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for human workers frequently exposed to sounds of 80 dB or more. Above about 150

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dB, auditory damage is inevitable with most perceivable sounds (Gamble, 1982).

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Equivalent thresholds are unknown for rats, but young rats are more sensitive to

Audiogenic damage in the laboratory

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sounds than older ones, and permanent audiogenic damage is most likely in pups

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between about 12 and 22 days of age (Voipio, 1997).

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In the laboratory, audible sounds as loud as 80–90 dB have been recorded; and

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50–75 dB for ultrasound (Milligan et al., 1993), so conceivably, audiogenic damage

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could occur in both humans and rats. Husbandry procedures cause the loudest sounds,

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especially if metallic equipment is involved (Gamble & Clough, 1976; Milligan et al.,

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1993; Sales et al., 1999). Filling metal food hoppers made 80 dB of (mostly

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ultrasonic) sound, which would occur about once a week for the rats’ lifetimes (Sales

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et al., 1999). This was measured from a distance of 50 cm, approximately the furthest

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that a caged rat could get from the sound.

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Many apparently silent activities or devices actually produce high levels of

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ultrasound (Sales et al., 1988; Sales et al., 1999). Examples include computer

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monitors, making 68–84 dB of broadband ultrasound (Sales et al., 1988), and some

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fluorescent lighting (G. J. Mason personal communication, and personal observation).

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Cage washers, hoses, running taps, squeaky chairs, and rotating glass stoppers (Sales

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et al., 1988) produce both ultrasound and audible sound, as do some air-flow hoods

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worn to prevent allergy in human workers (Picciotto et al., 1999). Similarly, standard

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fire alarms produce loud high and low frequency sounds, which laboratory animals

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cannot escape, so laboratories can be fitted with fire alarms that only emit sound

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audible to humans but not rodents (Home Office, 1989); although note that even

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frequencies below rats’ audible range can affect them (Petounis et al., 1977).

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Whether common laboratory sounds affect rodent welfare has not been

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investigated directly, but loud noises generally can trigger seizures, reduce fertility,

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and cause diverse metabolic changes (Sales et al., 1988; Milligan et al., 1993).

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Repeated short bursts of 2 kHz sound at 120 dB caused ‘behavioural despair’ in rats

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(Bulduk & Canbeyli, 2004). Longer-lasting sounds can also affect animals, although

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that has apparently not been tested in rats. In pigs, 90 dB prolonged or intermittent

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broadband noise increased cortisol, ACTH, noradrenaline:adrenaline ratios and time

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lying down, and decreased growth and social interactions (Otten et al., 2004).

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Conceivably then, a fluorescent light emitting loud ultrasound could cause significant

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stress in rats housed near it. The envelopes and timbres of sounds also determine how aversive or damaging

395 396

they are. Noise-type sounds, e.g. white noise or the sound of tearing paper, cause

397

stronger fear reactions in rats than equivalent harmonic or pure tones, or audible rat

398

vocalisations (Voipio, 1997). Sudden sounds are probably also more startling than

399

those with gradual onsets. It should be noted that avoidance of sound occurs at still

400

lower thresholds than those causing startle reactions (in Fleshler, 1965), or physical

401

damage.

402

Ultrasound detectors (e.g. bat detectors), which represent ultrasounds in a form

403

that humans can hear or visualise, would be useful as standard pieces of laboratory

404

equipment to regularly check whether ultrasound of certain frequencies is being

405

emitted in the animal rooms and to test experimental set-ups. Few experimenters

406

would choose to carry out experiments during loud building work, for example,

407

because of potential effects on the animals’ performances, and the same

408

meticulousness should apply to ultrasound. Indeed, background noise levels during

409

behavioural experiments do affect the apparent learning abilities of rats, with louder

410

white noise leading to faster completion of a maze task (Prior, 2006). Moreover, even

411

loud infrasound affects rat behaviour, reducing their activity and triggering sleep

412

(Petounis et al., 1977).

413

3.2

414

As well as audible ‘squeaks’, rats produce at least three types of ultrasonic

415

vocalisations. Firstly, juvenile rats produce a 40–50 kHz vocalisation (Noirot, 1968),

416

which together with olfactory cues, causes pup-retrieval by the mother (e.g. Allin &

417

Banks, 1972; Farrell & Alberts, 2002).

Vocalisations and communication

16

418

The second ultrasonic vocalisation is the ‘22 kHz long-call’, which occurs

419

mainly in aversive situations and might therefore indicate negative affect (Knutson et

420

al., 2002). Examples of such situations include social defeat (Van der Poel & Miczek,

421

1991), exposure to cat odour (Blanchard et al., 1991), administration of naloxone or

422

lithium chloride (Burgdorf et al., 2001), arthritic pain without analgesia (Calvino et

423

al., 1996), acute pain (Jourdan et al., 1995), acoustic startle (Kaltwasser, 1990) and

424

electric shocks (Kaltwasser, 1991). However, male rats make a similar vocalisation

425

after ejaculation (Van der Poel & Miczek, 1991), so this call might occur in two

426

subtly different forms, or might not reliably indicate negative affect.

427

The third ultrasonic vocalisation is the ‘50 kHz chirp’, which is apparently

428

associated with positive events (Knutson et al., 2002), and has even been suggested as

429

a form of laughter (Panksepp & Burgdorf, 2000). It occurs in anticipation of positive

430

social contact (Knutson et al., 1998; Brudzynski & Pniak, 2002), rewarding ‘tickling’

431

by humans (Panksepp & Burgdorf, 2000; Burgdorf & Panksepp, 2001; Panksepp,

432

2006), amphetamine or morphine administration (Knutson et al., 1999), and feeding

433

or rewarding electrical stimulation of the brain (Burgdorf et al., 2000), and also during

434

play (Knutson et al., 1998; Brudzynski & Pniak, 2002; Burn, 2006). However, again,

435

this vocalisation does not reliably indicate positive affect because it occurs in some

436

aversive situations, e.g. during morphine withdrawal (Vivian & Miczek, 1991),

437

aggression (Sales, 1972), and in certain painful situations (Hawkins et al., 2005).

438

Surprisingly little work has investigated the audible squeak. There may in fact

439

be several different types of squeak, because subjectively there is variation in the

440

quality of sounds produced (O. H. P. Burman, personal communication; personal

441

observation). Pups and their mothers make audible squeaks in the nest (e.g. Voipio,

442

1997), but this may be different from squeaking in other contexts. Squeaks occur

443

during nociception as they persist even when central nervous system analgesics are

444

given, which might suggest that they are detached from the emotional experience of

445

pain (Jourdan et al., 1995). They also occur during playing and fighting (Voipio, 17

446

1997; Burn et al., 2006a), and sometimes during handling, especially alongside

447

struggling behaviour (van Driel et al., 2004; Burn, 2006). They generally seem to

448

indicate negative affect, but do not necessarily occur alongside the 22 kHz long-call,

449

so there must be some qualitative or quantitative difference between the motivations

450

behind the two call types.

451

All of these vocalisations could have practical implications. Procedures or

452

environments that cause rats to vocalise could affect the behaviour and physiology of

453

all neighbouring rats within audible range. For example, playbacks of 22 kHz long-

454

calls caused freezing and decreased activity (Sales, 1991; Brudzynski & Chiu, 1995)

455

and increased latencies to emerge into an arena (Burman et al., 2007). Playbacks of

456

audible squeaks also caused conspecifics to orientate towards the speaker and

457

occasionally to squeak themselves (Voipio, 1997).

458

3.3

459

An awareness that rats can hear our voices is important, because of affects on

460

experimental results and rat welfare. Rats can hear and discriminate many elements of

461

the human voice (e.g. Pons, 2006), and pet rats can learn to respond to verbal

462

commands (e.g. Fox, 1997). In fact, rats can distinguish between some languages

463

(Toro et al., 2003), so the pitches, rhythms and accents of different human workers

464

could be at least partly responsible for rats being able to distinguish between

465

individual humans (McCall et al., 1969; Morlock et al., 1971; Davis et al., 1997; van

466

Driel & Talling, 2005). Shouting causes stress responses in farm animals

467

(Hemsworth, 2003), so this may also be true for laboratory rats, especially because

468

when humans speak with more emotional content, the higher-pitched and ultrasonic

469

content of our speech increases (Mason, 1969).

470

3.4

471

By default, most standard recording devices and speakers include no ultrasound, so

472

specialised equipment is necessary, such as ‘tweeter’ speakers and ultrasonic

Perception of the human voice

Sound recordings and playbacks

18

473

microphones (Björk et al., 2000). White noise, although aversive to rats (Voipio,

474

1997), is commonly used to standardise background noise in experiments, but

475

different speakers differ in their ultrasonic output, so comparisons across studies

476

might sometimes be invalid. Even a study that specifically investigated how

477

background noise affected rat behaviour in a maze, neither mentioned their ultrasonic

478

hearing abilities, nor used specialist equipment to produce the experimental white

479

noise (Prior, 2006), indicating that awareness of these auditory issues may be lacking

480

in some fields.

481

3.5

Echolocation There has been some debate about whether rats can echolocate (e.g. Rosenzweig

482 483

et al., 1955; Riley & Rosenzweig, 1957; Kaltwasser & Schnitzler, 1981; Forsman &

484

Malmquist, 1988). Blind rats can use self-generated sounds, reflected off solid

485

objects, to guide them in mazes (Rosenzweig et al., 1955; Riley & Rosenzweig,

486

1957). Also, sighted rats in darkness can discriminate between shelves close enough

487

to jump to and those too far away, but not if they are deafened (Chase, 1980). Some

488

studies described quiet ultrasonic ‘clicks’ (Chase, 1980; Graver et al., 2004), which

489

were produced more in darkness than in light, more before rats jumped to the platform

490

than after, and the decision to jump was faster in rats that clicked more (Graver et al.,

491

2004). However, rats seem not to have anything like the specialised echolocation

492

abilities of mammals such as bats or cetaceans. Indeed, some blind and blindfolded

493

humans can ‘echolocate’ using reflected sound, similar to rats (in Riley &

494

Rosenzweig, 1957), but there is no evidence that either species can use sound to build

495

up a detailed picture of their environment, as bats or cetaceans can.

496

4

497

Rats rely heavily on olfaction (e.g. Doty, 1986). They can quickly associate olfactory

498

cues with food rewards (Le Magnen, 1999a; Birrell & Brown, 2000), with this ability

499

even making them a suitable alternative to ‘sniffer’ dogs for locating contraband

Olfaction

19

500

substances (Otto et al., 2002). Rats can locate the direction of odorants, without

501

moving their heads, three orders of magnitude more quickly than we can (Rajan et al.,

502

2006). It is sometimes stated that albinism dampens olfaction, because albinos show

503

weaker avoidance of garlic than pigmented rats do (Keeler, 1942), but of course they

504

might simply be less averse to the scent. Humans are unusual mammals because a much smaller proportion of our

505 506

genome is devoted to olfaction, than other species (Gilad et al., 2003; Emes et al.,

507

2004; Rat Genome Sequencing Project Consortium, 2004; Quignon et al., 2005), and

508

our vomeronasal organ is vestigial or non-existent (e.g. Brennan & Keverne, 2004). In

509

contrast, rats not only possess main olfactory epithelia, but also well-developed

510

vomeronasal organs. Although the two systems overlap (reviewed in Shepherd, 2006),

511

the vomeronasal organ seems specialised for instinctive recognition of pheromones

512

and evolutionarily relevant compounds (Dulac, 1997; Holy et al., 2000; Brennan &

513

Keverne, 2004), while the olfactory epithelium is specialised for learned associations

514

between volatile scents and their implications (Dulac, 1997). The vomeronasal system

515

detects relatively non-volatile compounds, requiring the rat to lick or imbibe some

516

compounds before it can detect them (Brennan & Keverne, 2004). Here ‘olfaction’

517

includes both systems, because in most cases the specific odorant or detection

518

mechanism is currently unknown. The focus is on olfactory communication, but some

519

significant scents within laboratory environments are also discussed.

520

4.1

521

Rat olfactory communication is well-developed, yet remains little understood by

522

humans. Much communication is mediated through urine, but rats have many scent

523

glands, including the sebaceous, preputial, clitoral, perineal, salivary, anal, plantar,

524

and Harderian glands. Through scent, rats can gain information about each others’

525

gender (Alberts & Galef, 1973; Moore, 1985; Brown, 1992; Garcia-Brull et al., 1993),

526

reproductive state (Gawienowski et al., 1975; Manzo et al., 2002; Zala et al., 2004),

Overview of rat olfactory communication

20

527

genetic relatedness (Wills, 1983; Hurst et al., 2005), dominance (Krames et al., 1969),

528

health status (Zala et al., 2004), and individual identity (Hopp et al., 1985; Gheusi et

529

al., 1997). Rats also recognise familiar conspecifics using olfaction (Burman &

530

Mendl, 2003), not through a shared ‘colony scent’, but through remembering

531

individual odours (Alberts & Galef, 1973; Carr et al., 1976). These odours can be

532

determined genetically or be acquired from the environment (Schellinck et al., 1991;

533

Schellinck & Brown, 2000; Hurst et al., 2005). Laboratory rats may not be completely isolated from conspecifics even when

534 535

individually housed, because scents from neighbouring cages, or experimental

536

apparatus and instruments can influence them (unless they are in individually

537

ventilated cages). These scents can profoundly affect rats, as described below,

538

although it should be mentioned that isolation itself also affects these social animals

539

(e.g. Day et al., 1982; Hurst et al., 1997; Sharp et al., 2002; Westenbroek et al., 2005).

540

4.2

541

Much sexual behaviour in rodents is olfactorily mediated. The ‘Bruce effect’,

542

whereby female mice abort their offspring upon encountering the volatile scent of

543

unfamiliar males (Bruce & Parrott, 1960), seems not to occur in rats. However, the

544

‘Whitten effect’, in which volatile male scents trigger oestrus in females (Whitten,

545

1959), and the ‘Lee–Boot effect’, when females housed without males show

546

suppressed, irregular oestrus cycles (Van Der Lee & Boot, 1956) do occur relatively

547

weakly in rats. In rats and mice, male odour accelerates the onset of puberty in

548

females, in a phenomenon labelled the ‘Vandenbergh effect’ (Vandenbergh, 1969,

549

1976).

550

Scent and reproduction

The scent of female rats, especially those in oestrus, stimulates male sexual

551

behaviour, but also urinary-marking (Manzo et al., 2002) and competitive aggression

552

(Alberts & Galef, 1973). It is possible therefore, that housing males where they can

553

smell females could affect their physiology and behaviour, affecting research, and 21

554

might affect their welfare either way. The vomeronasal system, probably responsible

555

for detecting these scents, habituates to stimuli less easily than most sensory systems

556

(Holy et al., 2000), so the effects might be persistent. However, since the vomeronasal

557

organ requires direct physical contact to detect some pheromones (Brennan &

558

Keverne, 2004), the problem might only exist if the scent is volatile. Other important scents here include those mediating the mother–pup

559 560

relationship. For example, diodecyl proprionate, a pup preputial gland pheromone,

561

induces maternal licking (Brouettelahlou et al., 1991). Mother rats produce various

562

odours aiding pup survival, including those guiding pups to the nipples, and those

563

deposited in the bedding that reduce pup activity, keeping them in the nest (Porter &

564

Winberg, 1999). Also, pregnant females release a non-volatile pheromone that

565

prevents infanticide by cohabiting males (Mennella & Moltz, 1988). Perhaps it is the

566

removal of these scents that increases the likelihood of pups being cannibalised when

567

rats’ cages are cleaned within the first few days of birth (Burn & Mason, in press).

568

4.3

569

Aggression in male rodents can be triggered by novel (usually male) scents, so rats

570

rendered anosmic show little aggression in resident–intruder tests (Alberts & Galef,

571

1973). Habituation to familiar or self-scents plays a large role in reducing aggression

572

between familiar or related individuals. For example, aggression is reduced between

573

more familiar individuals (Alberts & Galef, 1973; Garcia-Brull et al., 1993) and

574

between more closely related individuals (Nevison et al., 2003). Some inbred mouse

575

strains cannot discriminate between familiar and unfamiliar conspecific odours,

576

resulting in reduced aggression (Nevison et al., 2003). This could also be true for rats.

577

In fact, unfamiliar male scents not only stimulate aggression, but also defensive

578

behaviour in subordinate males encountering dominant male odours. Rats defeated by

579

an alpha-male, subsequently show avoidance and fear behaviour upon encountering

580

the scent of other alpha-males (Williams & Groux, 1993; Williams, 1999).

Olfactory modulation of aggression

22

581

This said, while cage-cleaning – which removes scent marks – provokes

582

aggression in male mice (Gray & Hurst, 1995; Van Loo et al., 2000), in familiar rats it

583

merely provokes non-aggressive skirmishing (Burn et al., 2006a; Burn et al., 2006b);

584

perhaps for this reason cage-cleaning frequency seemingly has no long-term effects

585

on male rat welfare.

586

When unfamiliar rats are to be housed together, exposing them to each other’s

587

scents for a few days before allowing physical contact may prevent aggression (e.g.

588

Bulla, 1999). Alternatively, aggression can sometimes be prevented by masking

589

unfamiliar conspecifics using another unfamiliar, neutral scent. In rats evidence is

590

anecdotal, but in a controlled study of mice, chocolate or sheep’s wool odours reduced

591

resident–intruder aggression (Kemble et al., 1995).

592

Finally, it is worth mentioning that odour-mediated aggression does not only

593

occur between males. For example, mother rats able to smell their own pups show

594

aggression towards intruders – neither visual, tactile, nor auditory cues from the pups

595

elicit this aggression (Ferreira & Hansen, 1986).

596

4.4

597

Rats are generally attracted to areas smelling of conspecifics (e.g. Galef & Heiber,

598

1976; Mackay-Sim & Laing, 1980), but scents released during negative or positive

599

experiences, can make those areas aversive or more attractive, respectively.

600

Communication about experiences

Rats produce ‘alarm’ odour when they experience electric shocks (Mackay-Sim

601

& Laing, 1980; Abel & Bilitzke, 1990; Williams & Groux, 1993; Kiyokawa et al.,

602

2004), transport between rooms (Beynen, 1992), and the events and disturbances

603

accompanying carbon dioxide euthanasia (Ware & Mason, 2003). They probably also

604

produce it in forced-swim tests (Abel & Bilitzke, 1990), but no unstressed controls

605

were used so rats may simply have been responding to odours left by an unfamiliar

606

male. Alarm odour is more powerful with more severe stressors (Mackay-Sim &

607

Laing, 1980). The molecule(s) involved have not yet been identified, but a candidate 23

608

is 2-heptanone; more of this is present in urine from stressed rats, but diazepam during

609

the stressor does not reduce the amount produced (Gutiérrez-García et al., 2006).

610

In recipients, alarm odour increases freezing behaviour (Williams, 1999;

611

Kikusui et al., 2001), activity (Mackay-Sim & Laing, 1980; Abel & Bilitzke, 1990;

612

Kikusui et al., 2001; Ware & Mason, 2003), body temperature (Kikusui et al., 2001),

613

hypothalamic–pituitary–adrenal activity (Takahashi et al., 1990; but see Mackay-Sim

614

& Laing, 1980), urination (Stevens & Koster, 1972), and latency to approach rewards

615

(Mackay-Sim & Laing, 1981; Ware & Mason, 2003). It also causes avoidance

616

compared with the scent of unstressed conspecifics (Mackay-Sim & Laing, 1980).

617

Experience can affect responses to alarm odour, with rats avoiding the odour of

618

shocked rats more if they have experienced shock themselves, but not necessarily if

619

they have experienced defeat by an alpha-male (Williams & Groux, 1993).

620

A somewhat separate body of literature describes ‘frustration’ or ‘non-reward’

621

odour, produced when anticipated rewards are withheld (Collerain & Ludvigson,

622

1972; Ludvigson et al., 1985; Taylor & Ludvigson, 1987). Again this odour causes

623

avoidance, but unlike alarm odour, no fear responses to it have been reported. It seems

624

not to exist in urine (Collerain & Ludvigson, 1972), unlike alarm odour (Mackay-Sim

625

& Laing, 1981), but both are also produced from other bodily sources yet to be

626

identified (Mackay-Sim & Laing, 1981; Weaver et al., 1982).

627

Rats probably also produce a ‘reward’ odour, although this has mainly been

628

tested against non-reward situations (i.e. frustration odour), with no neutral rat odour

629

control. Nevertheless, a rat’s trail is more attractive if laid down after the rat receives

630

a reward than before (Galef & Buckley, 1996), and when it perceives a signal that

631

reliably predicts reward (Ludvigson et al., 1985). However, the attraction of rats to

632

reward odour is much weaker than the avoidance of frustration odour, when compared

633

against the same ‘no odour’ control (Taylor & Ludvigson, 1980).

24

634

The release of alarm odour means that rat welfare and experimental aims might

635

be compromised if neighbouring conspecifics are distressed by illness, injury, or

636

experimental procedures (Beynen, 1992). Any of these odours can bias rats’ decisions

637

in choice tests (Collerain & Ludvigson, 1972; Aoyama & Okaichi, 1994; Mitchell et

638

al., 1999), increase ‘baseline’ stress in subsequently tested rats or supposed control

639

ones (Beynen, 1992; Kikusui et al., 2001), and alter behaviour in tests such as swim

640

tests (Abel & Bilitzke, 1990), and open field or novelty tests (Mackay-Sim & Laing,

641

1981; Takahashi et al., 1990; Ware & Mason, 2003). There has apparently been no evaluation of effective ways to clean experimental

642 643

apparatus; various cleaning agents are used, which probably vary in efficacy and may

644

have intrinsic odours that affect rats. Alcohol is commonly used, but in pigs, its

645

volatile components can reduce cortisol levels in open field tests (Thodberg et al.,

646

2006).

647

4.5

648

Rats can learn about specific foods from conspecific odours. Carbon disulphide,

649

present in rats’ breath (Galef et al., 1988), causes rats to strongly prefer novel foods

650

eaten by their cagemates versus other novel foods (e.g. Strupp & Levitsky, 1984). The

651

preferences can persist for at least 30 days, even without opportunity to sample the

652

foods during that time (Galef & Whiskin, 2003b).

653

Communication about food

Aversion to novel foods can be caused by the ‘poisoned partner effect’ (Lavin et

654

al., 1980). Here if a novel food is eaten by a rat, which then encounters the odour of a

655

poisoned conspecific, the healthy rat will subsequently avoid the novel food, even if

656

the poisoned rat did not eat it (Stierhoff & Lavin, 1982). Strangely, the healthy rat

657

only avoids food that it itself has eaten, rather than that eaten by the poisoned rat, and

658

therefore not necessarily the poisonous food (Galef et al., 1990). In fact, exactly as

659

described above, the healthy rat actually prefers novel foods after smelling them on

660

the poisoned rat’s breath (Galef et al., 1990). 25

661

Lactating rats also avoid novel foods ingested just before their pups become ill,

662

because of an odour released by pups with gastrointestinal illness (Gemberling, 1984).

663

The odour causes no aversion in males or nulliparous females, and is not released by

664

pups stressed in other ways, so it seems more specific than the poisoned partner

665

effect.

666

4.6

667

Most of the scents relevant to laboratory rats are those within the cage itself. Apart

668

from those produced by conspecifics or food, others could include detergent residues,

669

bedding materials, and microbial products from the breakdown of food or excreta.

670

Cage-cleaning abruptly changes the olfactory environment, which might contribute to

671

post-cleaning changes in rat behaviour and physiology (Burn et al., 2006a). Also, like

672

gerbils, rats might more accurately discriminate scents in a test arena on days when

673

their cages are clean rather than soiled (Dagg et al., 1971).

Scents in the laboratory

674

Another salient source of smell for laboratory rodents might be their human

675

handlers. Rats respond differently towards different humans (McCall et al., 1969;

676

Morlock et al., 1971; Davis et al., 1997; van Driel & Talling, 2005), mostly because

677

of differences in odour (McCall et al., 1969). People smell different due to genetic

678

factors and environmental ones, such as diet, smoking, perfume, soap, and deodorant.

679

Regular rodent handlers may also be ‘marked’ with odours from previously handled

680

rodents, sometimes including reward or alarm odours.

681

Additionally, rats might fear humans carrying scents from their pets, especially

682

if the pet is a predatory species. Rats innately fear predator odours, including cats and

683

mustelids (reviewed in Blanchard et al., 2003), but apparently not dogs. Rats cannot

684

easily habituate to predator odours (Blanchard et al., 1998), showing increased

685

corticosterone, freezing and vigilance, elevated plus-maze anxiety and endogenous

686

opioid analgesia, and suppressed electric-prod burying, and impaired working

687

memory (Williams, 1999; Blanchard et al., 2003). Predator odours also elicit fear26

688

related fast-waves and reduce cell-proliferation in the dentate gyrus (Heale et al.,

689

1994; Tanapat et al., 2001).

690

It is even possible that rats would instinctively fear human odour – wild rats

691

usually avoid close human contact, and any such fear of humans might have escaped

692

our notice, of course, it would require a controlled experiment not involving human

693

presence.

694

Many odours from synthetic products used in laboratories could affect rodents.

695

While several reviews compare the efficacy of detergents for cleaning animal cages

696

(e.g. Heuschele, 1995), none discuss their potential olfactory impacts on the animals.

697

Yet, some organic solvents (e.g. xylene, toluene, diethyl ether, and methyl

698

methacrylate) cause avoidance and fast-waves in the dentate gyrus, just as predator

699

odours do (Heale et al., 1994). These solvents constitute many everyday substances,

700

including some inks, glues, and paints; indeed, identification-marking rodents with

701

inks or dyes can affect their anxiety profiles (Burn et al., in press) and cause them to

702

become submissive to unmarked cagemates (Lacey et al., 2007).

703

Many odorants that smell subjectively pleasant to humans, often therefore being

704

present in perfumed products or human diets, can also influence hypothalamo-

705

pituitary-adrenal activity and immune responsiveness, positively or negatively

706

(Komori et al., 2003). Rose oil (de Almeida et al., 2004) and ‘green odour’, trans-2-

707

hexenal (Nakashima et al., 2004), are anxiolytic to rats. Citrus oils are analgesic

708

(Aloisi et al., 2002), but can have complex effects on rodent anxiety (Komori et al.,

709

2003; Ceccarelli et al., 2004). In rat pups, peppermint increases mortality and

710

decreases activity (Pappas et al., 1982), and rats avoid the scent of garlic (Keeler,

711

1942) and rosemary (R. M. J. Deacon, personal communication). Many of these

712

effects could inadvertently introduce variation between experiments, but some could

713

be used as non-nutritive environmental enrichments or rewards. Also, anxiolytic

27

714

scents could be easily administered to rats in mildly stressful situations (de Almeida et

715

al., 2004; Nakashima et al., 2004).

716

5

717

Like us, rats are opportunistic omnivores; their ecological niche is characterised by

718

sampling diverse food substances and remembering their nutritional consequences

719

(e.g. Capaldi, 1996). They rapidly learn aversions to harmful novel foods, which can

720

be a problem in pest control situations when they ingest sub-lethal quantities of bait.

721

Rats, particularly wild strains, are neophobic, being reluctant to consume novel food

722

(Galef & Whiskin, 2003a). They initially sample only small amounts of novel food (if

723

any at all), but if it proves safe, they later readily consume it, often in preference to

724

more familiar foods (Calhoun, 1963). Under natural conditions, this cautious but

725

explorative behaviour might help them obtain a full nutritional complement, reducing

726

reliance on any one food type, while avoiding poisoning.

727

Gustation

Rats detect similar taste dimensions to humans, i.e. sweetness (carbohydrates

728

and artificial sweeteners), saltiness (sodium salts), sourness (hydrogen ions),

729

bitterness (quinine, caffeine, most natural toxins, and some others) (Grill & Norgren,

730

1978), and umami (amino acids, such as glutamate) (e.g. Smith & Margolskee, 2001).

731

As with humans, sweetness and umami are rewarding, bitterness is usually aversive,

732

and saltiness and sourness are only pleasant at low concentrations (Grill & Norgren,

733

1978; Berridge, 2000). They also initially strongly avoid capsaicin, the ‘hot’ taste of

734

chilli, but often consume it readily once it becomes familiar (Jensen et al., 2003).

735

However, rats do not perceive certain artificial sweeteners as being ‘sweet’ (Sclafani

736

& Abrams, 1986; Dess, 1993; Sclafani & Clare, 2004), and they may have separate

737

receptors for sugars and starch (Sclafani, 1987). Their bitterness thresholds for some

738

compounds differ from ours (Glendinning, 1994; Mueller et al., 2005), allowing

739

denatonium benzoate – which tastes less bitter to rats than to humans and some other

740

animals – to be added to baits to prevent its consumption by non-target species 28

741

(Hansen et al., 1993). There are also some strain and sex differences in rat gustation

742

(Boakes et al., 2000; Clarke et al., 2001).

743

In fact, ‘flavour’ involves not only gustation, but also olfaction and tactile

744

sensations (Smith & Margolskee, 2001). For completeness, these senses are not

745

separated here when discussing the practical implications of rat gustatory biases.

746

5.1

747

Laboratory rodents usually have no opportunity to sample different foods, typically

748

being fed a palatable, dry, nutritionally complete diet, in powder form or as pellets.

749

These diets are easily stored, inexpensive, and require little preparation (Lane-Petter,

750

1975), and they aid standardisation between experiments. Laboratory rats will also

751

taste their mothers’ milk, bodily secretions from themselves or conspecifics (if

752

socially housed), their cage surfaces, and perhaps human hands or gloves, and

753

bedding material (if provided). Hence, scope for learning taste–nutrient associations is

754

very limited, rendering the gustatory sense largely redundant in laboratories.

755

Taste in the laboratory

For other sensory modalities, sensory deprivation reduces the volume and

756

functioning of the associated brain regions. For example, the visual cortices of rats

757

reared in darkness are permanently underdeveloped (Fagiolini et al., 1994), while

758

sensory deprivation only temporarily limits olfactory bulb (Cummings et al., 1997)

759

and barrel cortex development (Polley et al., 2004; but see Rema et al., 2003).

760

However, despite rats frequently being used as models in taste research, precisely

761

because their gustatory perception is supposedly similar to ours, the effects of

762

gustatory deprivation on the brain and behaviour are apparently unknown. The effects

763

may be minimal if taste is tightly genetically controlled, but alternatively, lack of

764

gustatory experience could, for example, exaggerate rats’ neophobia or diminish their

765

gustatory learning abilities.

29

766

5.2

767

It is unclear whether rats can appropriately self-regulate their nutritional intake, given

768

the opportunity. Most discrepancies between findings are probably due to differences

769

between the diets offered to rats (Naim et al., 1985; Sclafani, 1987; Prats et al., 1989),

770

and circadian variations in intake patterns (Larue-Achagiotis et al., 1992). Rats

771

generally do select foods appropriate for their changing nutritional needs, but like

772

humans, they are biased towards sugary or fatty foods. They are consequently also

773

prone to obesity if offered palatable, calorific diets (Naim et al., 1985; Sclafani, 1987;

774

Prats et al., 1989).

775

Nutritional regulation

Because laboratory rodent diets are homogenous, they allow no qualitative

776

nutritional regulation. Generally, this is unproblematic because the diets have

777

sustained rodent populations for many decades, without apparent negative effects on

778

breeding, health, or longevity. However, although special formulations are available,

779

many widely used diets cover all age and sex categories: oestrus females, weanling

780

pups, and elderly males alike. Moreover, they are often common to rats and mice.

781

Thus, within this diversity, individuals might sometimes have different nutritional

782

requirements from that provided. In standardising diets to this extent, we might

783

inadvertently increase, rather than decrease, variation in rodents’ internal nutritional

784

states because they have no opportunity to regulate them.

785

Some dietary supplements can enhance laboratory rat health, calling into

786

question the completeness of homogenous diets. For example, blueberries, high in

787

antioxidants, prevent cognitive deficits in aging rats (Casadesus et al., 2004), and as

788

mentioned previously, other dietary supplements prevent retinal damage (Li et al.,

789

1985). Also, in hamsters, supplementation with seeds and rabbit chow increased pup

790

growth, and reduced cannibalism by the mothers (Day et al., 2002).

30

791

5.3

Refinement within the homecage

792

Palatable diets may provide rats with ‘enjoyment’ (Lane-Petter, 1975) or hedonic

793

experiences, with palatable and unpalatable foods eliciting distinctive behavioural

794

expressions that are homologous to human gustatory expressions (Berridge, 2000).

795

Most welfare efforts concentrate on reducing negative welfare, but facilitating

796

positive welfare, such as pleasure from food or foraging, should not be neglected (e.g.

797

Balcombe, 2005). Food-related environmental enrichments might be particularly

798

relevant for generalists, like rats, because their natural ecology incorporates diverse

799

food types, varying through time and space. However, the idea of food-related

800

enrichment has been little explored for laboratory rats, and yet it could improve their

801

welfare (Johnson & Patterson Kane, 2003), provided obesity is avoided (e.g. Mattson,

802

2005). There are three main aspects of food that could be varied for enrichment

803

purposes: nutritional content, flavour, and physical presentation.

804

5.3.1

805

Providing rodents with very nutritionally diverse diets may be undesirable for

806

practical reasons (Lane-Petter, 1975; Key, 2004), and because they encourage obesity

807

(Mattson, 2005), and may increase variation. Nevertheless, offering some opportunity

808

to nutritionally self-regulate could be beneficial, as suggested above. In some animal

809

facilities, seeds and nuts are scattered onto rats’ bedding; rats become very active

810

upon hearing them being scattered in neighbouring cages, and continue foraging for

811

many hours (Key, 2004). Since the seeds would constitute only a very small

812

proportion of the diet, they are unlikely to impact heavily on nutritional regulation,

813

but could allow some relevant gustatory stimulation and regular hedonic experiences.

814

Proper evaluation of the effects is necessary however; the most relevant study so far

815

seems to be one, mentioned earlier, when seed supplements enhanced hamster pup

816

growth and decreased cannibalism (Day et al., 2002).

Nutritional content

31

817

5.3.2

818

Even without nutritional value, gustatory enrichment could be achieved; providing

819

daily non-nutritional pina-colada flavour treats to breeding mice increased the number

820

of pups weaned (Inglis et al., 2004), suggesting that the hedonistic aspects alone of

821

scatter-feeding are beneficial.

822

Flavour

Domesticated rats value variety, and will substitute a preferred food that has

823

been their sole diet for several days for a less preferred, newly available food (Galef

824

& Whiskin, 2003a, 2005). They also consume more food if provided as a succession

825

of varied ‘meals’ rather than homogenous meals (Treit et al., 1983; Clifton et al.,

826

1987; Le Magnen, 1999b). These preferences exist even when foods differ primarily

827

in flavour not nutritional value, such as when cinnamon, cocoa, ‘all spice’, or

828

marjoram are added to normal chow (as in the above five studies). These additives

829

presumably have negligible bioactivity, being common non-nutritive components of

830

human diets, but confirmation in rats is required. The above studies suggest that

831

obesity might be a risk because of the increased food consumption, but they were all

832

relatively short-term, so rats might down-regulate their intake of variable food over

833

time. Le Magnen (1999b) found that if ‘variable days’ were alternated with

834

‘homogenous days’, rats ate less food than normal on homogenous days, perhaps

835

compensating for over-eating on variable days.

836

5.3.3

837

Finally, enrichment might be achieved through varying dietary presentation. Soft ‘wet

838

mash’ (chow soaked in water) is often used to help sick or weak rats gain weight, and

839

usually any healthy cage-mates also prefer the mash to freely available pellets.

840

However, it is an impractical enrichment for healthy rats, being messy and

841

encouraging microbial growth (Lane-Petter, 1975). Occasionally scattering chow

842

pellets within the cage allows rats to eat in their natural posture, holding the pellet in

Physical presentation

32

843

their forepaws (Bruce, 1965), and they more readily consume these pellets than those

844

in the hopper (personal observation). Captive rats also ‘contra-freeload’, choosing food that requires handling and

845 846

preparation, even when prepared food is available (Carder & Berkowitz, 1970). This

847

may be because most of a wild rat’s time and effort would be devoted to foraging

848

(Johnson & Patterson Kane, 2003). Scattering small food items, such as the

849

aforementioned seed mixes or chow pellets, in bedding allows rats to forage, which

850

may be rewarding in itself. Scatter-feeding rarely triggers competitive aggression

851

because the food is spatially distributed. Commercially available rodent puzzle-

852

feeders are also available, although they are uncommon in laboratories and are not

853

always easily sourced.

854

5.4

855

The generalist feeding habits of rats can be exploited in research, improving

856

experiments ethically, enhancing rats’ cooperation, and reducing interference from

857

stress. Drugs and inoculants are often delivered by gavage, a tube inserted via the

858

mouth into the stomach, which can be technically difficult, and causes stress,

859

respiratory distress, and occasionally even death (Balcombe et al., 2004). However,

860

substances can be successfully delivered within palatable vehicles that rats will

861

voluntarily consume, provided there is no interference with the active ingredient.

862

Fruit- or beef-flavoured gelatine is commonly used but some rats only reluctantly

863

consume it, so it can be worth trying several alternatives (Hawkins et al., 2004).

864

Another example is to use small amounts of chocolate (Huang-Brown & Guhad,

865

2002). Taste aversion can develop if the vehicle becomes associated with illness, but

866

giving rats prior experience with the unadulterated food can prevent this. Some

867

substances can also be microencapsulated and added to chow for long-term studies

868

(Melnick et al., 1987; Dieter et al., 1993; Yuan et al., 1993).

Refinement of experiments

33

869

Preferred rewards can often be used to motivate rats to perform tasks in

870

experiments, rather than using punishments or prior deprivation. Deprivation is a

871

powerful motivator, but can undesirably affect behaviour, physiology,

872

neurochemistry, and drug efficacy (Slawecki & Roth, 2005). Moreover, it is

873

sometimes unnecessary, because undeprived rats will often work – albeit to a limited

874

extent – for preferred rewards, including commercially available reward pellets,

875

sucrose solution (Slawecki & Roth, 2005), or breakfast cereals (e.g. Ellis, 1984). Prats

876

and colleagues (1989) found that rats did not readily consume cheese, chocolate or

877

fruit-candy, and instead preferred other foods offered, including banana, cookies,

878

standard chow pellets, and liver pâté. Large quantities of dairy products (DiBattista,

879

1990) and chocolate (Huang-Brown & Guhad, 2002) should be avoided as they harm

880

rodent health. Undeprived rats are particularly motivated to earn rewards if

881

experiments coincide with their active period (Hyman & Rawson, 2001), with a

882

shifted light cycle enabling practical working hours (see the section on Vision).

883

Neophobia can be eliminated by providing the palatable incentive in the homecages of

884

rats several days before experiments.

885

Finally, food must often be withheld overnight before surgery or intraperitoneal

886

injections. This deprivation causes weight loss, and reduced hepatic weight and blood

887

glucose, and potentially, emotional distress from hunger. However, providing sugar

888

cubes to the rats can prevent these problems, while gastrointestinal volume is still

889

reduced, as required (Levine & Saltzman, 1998).

890

6

891

Rat somatosensation could be considered from many different angles. Here, the focus

892

is on that relating to the ability of rats to explore and interact with their environments.

893

In the rat somatosensory cortex, the vibrissae (sensory whiskers), nose and mouth,

894

forepaws, and sinus hairs on its wrists, are particularly well-represented. In fact, the

895

forepaws are represented twice each, and the whiskers and sinus hairs have

Somatosensation

34

896

specialised granular aggregates devoted to them (Hermer-Vazquez et al., 2005). In

897

general, rat and human somatosensation seem similar, but there are two main

898

differences that noticeably affect rat behaviour. Firstly, rats’ vibrissae are extremely

899

sensitive (Arabzadeh et al., 2005), being comparable to primate fingertips (Carvell &

900

Simons, 1990). Rats can whisk them independently of each other across surfaces to

901

make fine tactile discriminations (Guic-Robles et al., 1989; Carvell & Simons, 1990).

902

In a study investigating rats’ numerical competencies, subjects could not discriminate

903

between two, three or four tactile stimuli delivered to the body, but they succeeded

904

when the stimuli were delivered to a single vibrissal hair (Davis et al., 1989). The

905

vibrissae also detect differences in mechanical resonant frequencies, with the shorter

906

anterior vibrissae detecting higher frequencies than the longer posterior ones

907

(Neimark et al., 2003).

908

The second obvious difference from humans relates to thigmotaxis; the bias of

909

rats towards maintaining physical contact with vertical surfaces. In fact, thigmotaxis

910

underlies many tests of ‘anxiety’ (Treit & Fundytus, 1988), because when rats

911

perceive environments as threatening, they stay closer to vertical surfaces, such as the

912

boundaries of open field arenas, or the closed arms of elevated plus-mazes. The

913

thigmotactic bias may not be strictly somatosensory, perhaps also incorporating visual

914

preferences for avoiding light exposure. Rats that lack vibrissae on one side prefer to

915

maintain wall-contact on their intact side, suggesting the vibrissae play a role (Meyer

916

& Meyer, 1992). The implications of rat somatosensation include the impact of environmental

917 918

enrichment on rat somatosensory development generally, and implications of the

919

vibrissal sense for experiments and housing.

920

6.1

921

Environmental enrichment profoundly affects the somatosensory and barrel cortices.

922

In rats kept in enriched rather than barren environments, the primary somatosensory

Environmental enrichment and somatosensation

35

923

cortex representing the forepaws becomes 1.5 times larger (Xerri et al., 1996; Coq &

924

Xerri, 1998, 2001). The barren cages in these studies contained bedding, exerting their

925

effect despite rats being able to dig with their forepaws, so the difference might be

926

even more pronounced in rats housed on wire floors. Environmental enrichment

927

seemingly does not enhance textural discrimination abilities, but it does increase the

928

rate of learning such discriminations (Bourgeon et al., 2004). Enrichment can also

929

counteract age-related declines in hind-paw representation in the somatosensory

930

cortex, which is otherwise associated with impaired walking in aged rats (Godde et

931

al., 2002). Finally, in naturalistic environments, the representation of each whisker in

932

the barrel cortex becomes dramatically more well-defined compared with standard

933

cages (Polley et al., 2004).

934

The above studies combined several enrichment types, including social

935

contact, foraging opportunities, structural features and novelty, so it is unclear what

936

relative contributions were made by each enrichment type. It is lack of tactile contact

937

with conspecifics that apparently leads to the self-biting and tail manipulation seen in

938

isolated rats (Day et al., 1982; Hurst et al., 1997).

939

6.2

940

The sensitivity of the vibrissal sense (Davis et al., 1989; Guic-Robles et al., 1989;

941

Carvell & Simons, 1990; Arabzadeh et al., 2005) is probably under exploited in

942

learning tasks, where less salient visual cues are currently more widely used

943

(Dymond, 1995; Dymond et al., 1996; Birrell & Brown, 2000). However, laboratory

944

rats can sometimes lack vibrissae for various reasons, including ‘barbering’, when

945

hairs and often whiskers are removed by conspecifics (Garner et al., 2004). This

946

occurs in rats, albeit to a much lesser extent than in mice (Bresnahan et al., 1983;

947

Wilson et al., 1995). Other rats may lack whiskers due to their strain; some nude

948

rodent strains have no whiskers at all (e.g. Sundberg et al., 2000), but most have short,

949

kinked whiskers, giving a limited sensory range (e.g. Festing et al., 1978; Moemeka et

Vibrissae and the laboratory environment

36

950

al., 1998). Nude strains also lack the sensitive guard hairs otherwise dispersed through

951

the coat, and which would convey proprioceptive information. Both vibrissal absence and barrel cortex impairment through lack of

952 953

environmental enrichment (as described above), could have practical consequences.

954

Rats lacking vibrissae show impaired orientation towards tactile stimuli, and –

955

provided they have environmental enrichment – compensate by orienting towards

956

visual stimuli more than controls (Symons & Tees, 1990). Whiskers also aid

957

swimming, enabling animals to keep their heads above water (Ahl, 1986; Meyer &

958

Meyer, 1992), and consequently, rats lacking vibrissal sensation can drown in water

959

mazes and swim tests (Hughes et al., 1978).

960

Finally, vibrissae are important in social interactions, with whiskerless rats

961

being unable to avoid bites to their faces during fighting (Blanchard et al., 1977a;

962

Blanchard et al., 1977b). Because aggression between familiar rats is uncommon

963

(Burn et al., 2006b), whiskerless rats need not be socially isolated, except in cases

964

where aggression is observed. However, whiskerless rats may be injured if introduced

965

to unfamiliar conspecifics, when fighting is more likely.

966

7

967

It is impossible for us to know what it is like to be a `rat` (Nagel, 1974), but

968

knowledge of their sensory biases allows us to imagine what it might be like, as a

969

human, to have those biases within a laboratory rat’s environment. This insight, while

970

imperfect, could help predict how rats might be affected by different situations,

971

improving our experimental design and their welfare. In summing up then, an overall

972

theoretical picture of a rat’s perception of the laboratory could be as follows.

973

Summary

The rat’s sensitive eyes, shunning the intense artificial light, provide it with a

974

hazy view in predominantly grey, ultra-violet and green hues. From within its cage, it

975

hears the chirps, squeaks and whines of its neighbours, gaining information that we 37

976

cannot hear unaided and are yet to understand. Background noise consists of the low

977

babbles and hisses of distinctively scented humans, and the unregulated drones and

978

blasts of ultrasonic sounds. Scents provide visceral warnings and enticements, induce

979

new motivations, and inform the rat about social possibilities outside the cage. The

980

environment wafts a succession of scents, from pleasant, calming fragrances to the

981

innately alarming odours of intangible predators. The rat tastes little apart from its

982

dry, satiating homogenous diet. Its vibrissae provide a protective, finely tuned force-

983

field to feel the details of the cage surfaces; with the rat perceiving security from close

984

contact with the solid walls.

985

8

986

Conclusion Knowledge of the sensory gulfs and similarities between ourselves and this

987

commonly used research animal can improve science and enhance rat welfare. More

988

work is still necessary to understand rat perception, and even more so for less well-

989

researched species. The aim of this review is to make current knowledge accessible to

990

researchers, rat caretakers and rodent specialists, in the hope that it will enable

991

tangible improvements in experimental design and rat welfare.

992

Acknowledgements

993

Many thanks to Georgia Mason for her detailed comments and encouragement,

994

and also to Robert Deacon, Mark Ungless, Jennifer Bizley, and Alex Weir for their

995

comments.

996

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997 998 999 1000 1001 1002 1003

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Figure 1

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Visual perception of rat strains in visual-based behavioral tasks, reprinted from

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Prusky and colleagues (2002) (with permission from Elsevier and the authors). The

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original image (top-left) has been blurred to model the perception of rats with acuities

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of 1.5 c/d (top-right; Fisher–Norway), 1.0 c/d (bottom-left; Dark Agouti, Long-Evans,

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wild) and 0.5 c/d (bottom-right; Fisher-344, Sprague–Dawley, Wistar) when the

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image subtends 10 degrees. This approximates the size of the image if it were used as

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a visual cue in a typical visuo-behavioural task (see Prusky et al., 2002 for details).

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What is it like to be a rat

This review of rat sensory perception spans eight decades of work conducted across diverse research fields. It covers rat vision, audition, olfaction, gustation, and somatosensation, and describes how rat perception differs from and coincides with ours. As Nagel's seminal work (1974) implies, we cannot truly know what it is ...

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