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

2 doi: 10.1016/j.applanim.2008.02.007

3 Final Revision – NOT EDITED by the journal

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

5 implications for experimental design and rat welfare

6 Charlotte C. Burn

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

8 UK

9 Running title: Rat sensory perception and its implications

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17 Correspondence address: Department of Clinical Veterinary Science, University of

18 Bristol, Bristol BS40 5DU, UK

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19 Abstract

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

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

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

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

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

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

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

27 olfactory sensitivity and ultrasonic hearing means they are influenced by

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

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

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

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

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

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

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

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

36 neurophysiology. Research shows that environmental enrichment is necessary for

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

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

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

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

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

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

44 Refinement; Vision

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48 1 Introduction

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

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

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

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

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

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

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

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

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

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

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

60 serious implications, sometimes leading to poorly designed experiments and harming

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

62 rodent experiments and housing.

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

64 summaries of mouse sensory perception are included within several other review

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

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

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

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

69 profoundly affect their sensory perception. These ethological considerations are

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

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

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

73 (Berdoy, 2002).

74 This review is organised around the classic ‘five senses’: vision, audition,

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

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

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

78 published information currently covers the aforementioned five senses. For each

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

80 practical implications of its perception with respect to welfare and experimental

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

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

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

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

85 still poorly understood.

86 2 Vision

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

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

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

90 35o, domestic rats 76o, and humans 105o (Heffner & Heffner, 1992a).

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

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

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

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

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

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

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

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

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

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

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

102 1.5 c/d and albino strains have even lower acuities of 0.5 c/d (Prusky et al., 2002).

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

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

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

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

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

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

109 1990).

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

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

112 recently been confirmed through electroretinograms and quantitative behavioural tests

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

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

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

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

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

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

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

120 al., 2003).

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

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

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

124 high light intensity, and increase with fatigue. Animals with high proportions of rod
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125 cells, like rats, generally have high flicker fusion thresholds, so rats might perceive

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

127 2003).

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

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

130 2.1 Sensitivity to light

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

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

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

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

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

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

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

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

139 1980).

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

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

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

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

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

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

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

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

148 magnitude are discomfort and potential retinal damage likely in humans.

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

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

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

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

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

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

155 1976). Long-term cyclical light intensities of about 500 lux within an animal room

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

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

158 & Perentes, 1994).

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

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

161 1979). This might be conferred by a few remaining cones that may be so sparse that

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

163 1976). Even so, under ‘ordinary’ laboratory conditions, visual impairments can

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

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

166 with cognitive deficits, both groups displaying difficulties locating the platform

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

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

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

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

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

172 visual tests used alongside the established visual ones.

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

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

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

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

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

178 1985; Blom et al., 1995). Rats’ aversion to light was clearly demonstrated in a study

179 showing that sleeping pigmented and albino rats awoke and moved to areas of lower
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180 illumination at thresholds of only 60 and 25 lux, respectively (Schlingmann et al.,

181 1993c). Consistent with such behaviour, chromodacryorrhoea, an aversion-related

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

183 light (Hugo et al., 1987).

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

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

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

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

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

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

190 requires confirmation.

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

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

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

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

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

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

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

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

199 influence on psychological measures.

200 Surgery presents a difficult situation because good lighting is essential for

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

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

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

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

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

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

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

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

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

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

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

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

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

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

215 preventing animal suffering.

216 2.2 Colour vision

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

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

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

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

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

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

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

224 separately, as their effects are quite distinct.

225 2.2.1 Emitted light

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

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

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

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

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

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

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

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

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

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

236 1993b), and also more disruption to fertility (Tong & Goh, 2000) than any other

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

238 wavelength than blue light so may be more harmful.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

258 sensitive animals, could lack important information.

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259 2.2.2 Colour in the environment

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

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

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

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

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

265 purpose, it can make standardisation between experiments difficult.

266 Outside experimental situations, there are also some relevant implications of

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

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

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

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

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

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

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

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

275 possibly some cones.

276 The colour of the homecage itself might also affect rats. Sherwin and Glen

277 (2003) housed mice in different coloured cages and found that they had significantly

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

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

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

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

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

283 2.3 Periodicity

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

305 sometimes occurs in the wild (Calhoun, 1963).

306 2.4 Acuity

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

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

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

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

311 might have been further reduced by their artificially lit environments.

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

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

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

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

316 enriched environments during rearing accelerate visual development and improve

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

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

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

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

321 2000). Dietary composition is discussed in more detail in the Gustation section of this

322 paper.

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

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

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

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

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

328 1980), and can more rapidly learn discriminations using multimodal stimuli (floor

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

330 1996) or olfactory or tactile cues (Birrell & Brown, 2000). However, vision is often

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

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

333 3 Audition

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

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

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

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

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

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

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

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

342 vibrissae (Neimark et al., 2003) (see the section on Somatosensation).

343 Auditory sensitivity decreases near the extremes of the detectable frequencies,

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

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

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

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

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

349 sensitivity; auditory neurone performance is vastly improved by environmental

350 enrichment (Engineer et al., 2004).

351 The implications of rat auditory perception include what sound characteristics

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

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

354 echolocate.

355 3.1 Audiogenic damage in the laboratory

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

357 1998; Björk et al., 2000) make it difficult to determine detection- and safety-

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

359 numerical increases represent large increases in the actual intensity. European

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

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

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

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

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

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

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

367 50–75 dB for ultrasound (Milligan et al., 1993), so conceivably, audiogenic damage

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

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

370 1993; Sales et al., 1999). Filling metal food hoppers made 80 dB of (mostly

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

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

373 that a caged rat could get from the sound.

374 Many apparently silent activities or devices actually produce high levels of

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

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

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

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

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

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

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

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

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

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

385 Whether common laboratory sounds affect rodent welfare has not been

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

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

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

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

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

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

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

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

394 stress in rats housed near it.

395 The envelopes and timbres of sounds also determine how aversive or damaging

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 Vocalisations and communication

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).

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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 Perception of the human voice

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 Sound recordings and playbacks

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

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

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

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

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 Olfaction

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
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.

505 Humans are unusual mammals because a much smaller proportion of our

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 Overview of rat olfactory communication

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),

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).

534 Laboratory rats may not be completely isolated from conspecifics even when

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 Scent and reproduction

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 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.

559 Other important scents here include those mediating the mother–pup

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 Olfactory modulation of aggression

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).

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 Communication about experiences

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 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).

642 There has apparently been no evaluation of effective ways to clean experimental

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 Communication about food

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 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 Scents in the laboratory

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).

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 fear-

26
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 Gustation

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 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 Taste in the laboratory

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 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 Nutritional regulation

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 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 Nutritional content

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).

31
817 5.3.2 Flavour

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 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 Physical presentation

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

32
843 their forepaws (Bruce, 1965), and they more readily consume these pellets than those

844 in the hopper (personal observation).

845 Captive rats also ‘contra-freeload’, choosing food that requires handling and

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 Refinement of experiments

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).

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 Somatosensation

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
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).

917 The implications of rat somatosensation include the impact of environmental

918 enrichment on rat somatosensory development generally, and implications of the

919 vibrissal sense for experiments and housing.

920 6.1 Environmental enrichment and somatosensation

921 Environmental enrichment profoundly affects the somatosensory and barrel cortices.

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

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 Vibrissae and the laboratory environment

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

36
950 al., 1998). Nude strains also lack the sensitive guard hairs otherwise dispersed through

951 the coat, and which would convey proprioceptive information.

952 Both vibrissal absence and barrel cortex impairment through lack of

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 Summary

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 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 Conclusion

986 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.

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1773
1774

54
1775 Figure 1

1776 Visual perception of rat strains in visual-based behavioral tasks, reprinted from

1777 Prusky and colleagues (2002) (with permission from Elsevier and the authors). The

1778 original image (top-left) has been blurred to model the perception of rats with acuities

1779 of 1.5 c/d (top-right; Fisher–Norway), 1.0 c/d (bottom-left; Dark Agouti, Long-Evans,

1780 wild) and 0.5 c/d (bottom-right; Fisher-344, Sprague–Dawley, Wistar) when the

1781 image subtends 10 degrees. This approximates the size of the image if it were used as

1782 a visual cue in a typical visuo-behavioural task (see Prusky et al., 2002 for details).

1783

1784

55