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 DOI: 10.1258/002367797780600198

1997 31: 116Lab AnimTrevor Poole

Happy animals make good science  

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What is This? 

- Apr 1, 1997Version of Record >>

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Happy animals make good science

Trevor PooleUniversities Federation for Animal Welfare, 8 Hamilton Close, Potters Bar, Hertfordshire EN6 3QD, UK

SummaryIn this paper the question is posed whether it is not only better for the animal to be happy, butwhether its state of mind may also have the potential to influence the scientific resultsderived from it. To ensure good science, the animal should have a normal physiology andbehaviour, apart from specific adverse effects under investigation. There is a growing body ofevidence from a wide variety of sources to show that animals whose well-being iscompromised are often physiologically and immunologically abnormal and that experimentsusing them may reach unreliable conclusions. On scientific, as well as ethical grounds,therefore, the psychological well-being of laboratory animals should be an important concernfor veterinarians, animal technicians and scientists.

Keywords Well-being; laboratory animals; endocrine; immune response; handling;experimental method

What are happy animals?Most people who have worked closely withanimals or who keep them as pets are awareif they are suffering or unwell; the signs maybe small but we become aware that all is notwell. Colloquially, we will say to ourcolleagues 'that animal is not happy'. Thesigns which tell us that there is somethingwrong are changes in the behaviour whichwe have come to expect from the individual,for example, we may find it sitting huddledin a comer, failing to greet us or lackinginterest in events taking place around it. Ifthe behavioural change persists, we takeaction and may even call in veterinaryadvice.

Happiness and unhappiness, or distress,refer to states of mind of the animal; theycannot be measured directly but the wholeconcept of animal welfare is based on thebelief that higher animals, like us, are able toexperience pain and pleasure. The best wayto decide whether an animal is happy ordistressed is by observing its behaviour. On

Corespondence to: Trevor Poole

Accepted 6 September 1996

this basis, I will define a 'happy animal' asone which is alert and busy (shows a widerepertoire of behaviour), is able to rest in arelaxed manner, is confident (outward goingand does not display fear towards trivial non-threatening stimuli) and does not showabnormal behaviour. It is, of course, impor-tant to be familiar with the particular.animal's character to make these judge-ments. Some individuals are naturallyextrovert and active, while others are quietand lethargic. In the laboratory, those of uswho care for animals like to think that ourcharges are happy and that any procedureswhich have to be performed on them causethem the absolute minimum of distress.

In this article the question is posedwhether it is not only better for the animal tobe happy, but whether its state of mind mayalso have the potential to influence thescientific results which are derived from it.The most obvious cases of unhappiness willoccur when animals are sick or injured andsymptoms will vary from mild to severe.Generally, with modem laboratory practicethis source of distress has virtually beeneliminated. We take it for granted that

LaboratoryAnimals (1997) 31,116-124

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Happy animals make good science

scientists do not work with animals whichare ill or injured. Nor do laboratory animalslack essential physical needs, such as food,water or suitable climatic conditions. Thereremain, however, a variety of potentialcauses of distress, such as social problemswith aggressive cage mates, overcrowding, orsocial isolation. There are also features of thephysical environment, such as loud orsudden noises, including ultrasound whichcan be perceived by rodents, dogs and smallerprimates, which might also be sources ofdistress. Finally, there are the attitudes andsometimes inexpert manipulations by staff.Mammals, particularly become distressed ifthey are badly handled, especially when theyare restrained by personnel unfamiliar tothem. This may be a common occurrence, asthe experimenter is not usually the personin day-to-day care. A factor which isincreasingly being recognized as a sourceof unhappiness, is the failure of the captiveenvironment to meet the animal'sbehavioural needs and assure its psycho-logical well-being. It is becoming apparentthat captive mammals can be bored or resortto abnormal behflviour if their environmentis not sufficiently complex and interesting tothem (Wemelsfelder 1990, Poole 1988).

What is good science?The quality of experimental laboratory ani-mal science depends on three essentialconditions being satisfied. Firstly, thereshould be an important problem for which ananswer is sought, secondly, the experimentshould yield unambiguous results whichprovide an answer to the problem and,finally, variables which are not under in-vestigation should be strictly controlled. Ishall take for granted the assumption that thefirst two conditions have been met and onlybe concerned with the third which, can alsohave a direct bearing on the well-being of theanimals. Good laboratory animal science isbased on normal, healthy subjects, unless theillness is itself the subject of investigation.Scientific method assumes the absence ofconfounding factors or uncontrolled vari-ables. Clearly, unhappiness might be aconfounding variable unless, for example, its

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alleviation was the subject of the study, as inthe case of testing an anti-depressant. What-ever the subject under investigation, allunnecessary stress should be minimizedduring the experiment to reduce the varia-bility of the results and thus the number ofanimals required. This requires, firstly, athorough understanding of the animal and itsbiology and, secondly, experiments which arewell designed, statistically valid and appro-priate. Even in situations where the experi-ment itself creates unhappiness for theanimal, such as premature removal of young,any effect may be diminished or even lost ifthe animal was not happy in the firstinstance. We can therefore conclude that, inall aspects, apart from unavoidable adverseeffects of the experiment, the animal shouldbe happy.

Most scientists working with animals willmake the assumptions that they will havenormal blood pressure, heart rates, levels ofstress hormones, immunological compe-tence, digestion, appetite and behaviour. Toavoid confounding variables, experimentalanimals should have both normal physiologyand behaviour. Some might argue thatbehaviour is of less significance than phy-siology, but this is based on the erroneoussupposition that mind and body are separateentities and that one will not influence theother. Recent scientific work has shown howthe brain, behaviour, hormones and even theimmune system, are all interdependent andthat disturbances in one of these systemscommonly influences one or all of the others(see review article by Martin 1989 and Bohus& Koolhaas 1991).In fact, behaviouralchanges are usually more sensitive indicatorsof distress than physiological ones. I shallnow consider some of the main factors whichmay influence the psychological well-beingof laboratory animals.

Factors influencing psychologicalwell-being

Social factorsLaboratory mice are commonly kept in singlesex groups in stock cages. While femalesgenerally tolerate such conditions, males

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fight and establish a hierarchy, but the typeof social structure depends on the number ofindividuals in the cage. Poole and Morgan(1973) found that, in small colonies of 3--4male CFW mice, the dominant's aggressionwas directed to few rivals and these sub-ordinates were highly intimidated and re-stricted in their movements about the cage.Five male mice however formed a linearhierarchy with each individual knowing itsplace and thus subordinates were able todevelop strategies to avoid conflict. In largercolonies of nine or more individuals thedominant was unable to control such a largenumber of subordinates, so that the socialstructure broke down after 3-5 days andanother dominant arose. This contrastedwith the situation in smaller groups of up tofive in number where, barring disturbance,aggression gradually decreased and wasminimal after 12-15 days. Physiological datafrom laboratory mice have shown that, instandard housing, subordinates exhibit high-er levels of stress and sex hormones thandominants (Hucklebridge et al. 1976, Bentonet al. 1978). In addition to experiencing fear,suffering injury and high levels of stresshormones, Beden and Brain (1984, 1985)found that the immunological response to anantigen (sheep red blood cell) was reduced insubordinate or defeated mice. Brayton andBrain (1973) found that crowding micelowered their resistance to a digenean para-site and Edwards and Dean (1977) alsoshowed that crowding affects the mouse'simmune response.

Age is another important considerationwhen housing male micej litter mates, unlesssignificantly disturbed will usually liveamicably together, as will members ofdifferent litters who have been groupedtogether from an early age. Clearly, whereverpossible, animals, should be kept in condi-tions where their social grouping leads to theminimum of aggression, and hence distress.

There has been a tendency to believe thatisolation in the form of single housing isdistressing for other mammals, as it is forhumans. However, it has been found thatisolated male mice have hormonal profilessimilar to dominants (Brain 1975, Huckle-bridge et al. 1976, Brain & Benton 1977,

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Benton et al. 1978, Brain 1990), so thatsingly-housed mice do not suffer from 'iso-lation stress'. This finding is compatible withthe fact that mice are territorial in the wildand thus actively repel other males. How-ever, providing a simulation of the wild inthe laboratory may actually be deleteriousbecause Bishop and Chevins (1988) foundthat territorial male mice placed in an arenahad high levels of stress hormones, presum-ably associated with the defence of theirterritories. While access to social compa-nions benefits many species of laboratoryanimals, some solitary species, may have tobe kept alone because of their aggressivetendencies, for example, male rabbits andferretsj this is particularly common in caseswhere males have bred or been exposed tomembers of the opposite sex, or females haveinfant young. Even individuals of socialspecies must have adequate space to avoidone another and thus minimize any conflict.

Bohus and Koolhaas (1991) reviewed theliterature on psycho-immunology and cameto the conclusion that social stress is onlylikely to impair immune function signifi-cantly when the animal is unable to exertsome control over the situation by develop-ing a coping strategy. Inability to escape froman attacker and chronic overcrowding areclear examples of situations which animalsare unable to control.

It is important to remember that a rat isnot simply a scaled-up mouse. Rats are muchmore sociable than mice and consequentlyseem likely to suffer more when isolated,although Brain and Benton (1979) could findno evidence of isolation stress in this species.However, young rats show very active socialplay which involves both chasing and wrest-ling (Poole & Fish 1975, 1976), so they needadequate space to do this. During theirdevelopmental stage, rats acquire skills andexperience; adult rats reared in deprivedconditions are not only less intelligent, butalso have smaller brains than those from richand stimulating environments (Renner &Rosenzweig 1978). They are thus less normal,but this does not necessarily mean that theyare less happy.

Beynen (19921 reviewed literature whichindicated that control rats in the same room

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as the experimentals showed raised levels ofcorticosteroids, as compared to controls inanother room. This suggests that some rats(and therefore possibly other animals) may beable to communicate their feelings to otherindividuals either by vocalizations or pher-omones and that situations which causedistress may also upset others within therange of these forms of communication.

Mendoza et a1. (1991)found that squirrelmonkeys showed differences in levels ofcorticosteroids which related to their sex andsocial grouping. Females showed higherlevels when kept singly, with a single femalecompanion, or with a male. Three femaleshoused together appeared to be the minimumsocial group which would reduce the levels ofcorticosteroids to a normallevelj this num-ber also showed much higher levels ofreproductive cycling as compared to thesmaller groups or females paired with a male.Likewise male squirrel monkeys showedlower levels of corticosteroids when housedwith male companions. The practical im-plication for husbandry and breeding is thatthe minimum breeding group should consistof two males and three females.

Both mammals and some birds have aperiod of life when they acquire knowledgeof the world and are able to test its proper-ties while protected by a vigilant mother orfamily group. The developmental environ-ment determines, to a large extent the kindof situations with which they are able tocope when they reach adulthood. Duringchildhood they practise skills and motorcoordinations which will be of benefit inlater life. Many mammals play fight whenyoung and thus practise the strategies ofattack and defence which they will needwhen faced with real rivals. They showextraordinary curiosity and inventivenessand thus learn the properties of objects andother organisms in their environment.Mammals enjoy play and experimentation inthe sense that it is self-rewarding, so thatthey should be provided with a stimulatingand complex developmental environment.Likewise, the presence of a mother isimportant because it allows the young toexpress their wide repertoire of play andcuriosity without fear.

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Early weaning is undoubtedly stressful formammals because of the upset caused bylosing their mothers. The problem is furtherexacerbated by the sudden loss of maternalantibody. This immune deficiency is tem-porary until the young independent animaldevelops its own fully functioning immunesystem. However, the temporary immuno-deficiency may be enhanced by stress result-ing from separation and immuno-suppressionhas been recorded from both adult pigs(Blecha& Kelley 1981,Blecha et a1. 1983)andprimates (Reite 1987)which had been re-moved from their mothers unnaturally early.For example, Reite showed that the separa-tion of young Macaca nemestrina for 2 weeksat the age of 6 months still had an effect onthe immune system in the form of areduction in T-cell proliferation in responseto a mitogen 6 years later. Early separationfrom the mother, is commonly practised bythe breeders of non-human primates, so thatthe young not only develop abnormal beha-viour (Goosen 1989)but may also suffer fromreduced immunological competence asadults, and thus, would be unsatisfactory asexperimental animals.

The phYSical environmentThere is increasing evidence that a number ofphysical environmental factors which influ-ence an animal's psychology may also affectits immune system. Unpleasant events, suchas inescapable electric shock, increase theincidence of tumours in rats (Keller et a1.1981).However, not all stress is deleteriousand some may even be beneficial. Forexample Marsh et a1. (1963)found thatcynomolgus monkeys (Macaca fascicularis)trained over a 24-h period to avoid electricshocks increased resistance to polio virusinfection. Similarly, mice which had beentrained to avoid electric shocks showedgreater resistance to malaria than controlsnot subjected to the training. What seems tobe important in these animals is not theshock itself but the degree of control whichthe animal is able to exert to avoid it.

Mice conditioned to drink saccharinesolution followed by an immuno-suppressivedrug (cyclophosphamide) were subsequently

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found to have a suppressed immune systemwhen drinking saccharine alone. This indi-cates that the immune response may actuallybe susceptible to Pavlovian conditioning(Kelley et a1. 1984, 1985).

Differences in levels of stress hormonesalso relate to the animal's ability to controlevents. Rats were subjected to an electricshock from the grid on which they walked.Where the rat could prevent the grid frombecoming electrified by pressing a lever,corticosteroid levels were much lower thanin controls which were shocked but had noway of switching it off.

There are also marked species differencesin responsiveness to stressors, even whenthey are closely related, for example rhesus,bonnet and cynomolgus macaques showmarked differences in hormonal responses toroutine procedures (Clark et a1. 1988).Mendoza and Mason (1984)compared thephysiology of titi (Callicebusl and squirrelmonkeys (Saimiri). The former are notor-iously difficult to keep in the laboratorywhereas squirrel monkeys readily adapt tocaptivity. The two species show very differ-ent endocrinological responses to stress.Interestingly, Callicebus shows very limitedcorticosteroid response to stress compared toSaimiri and the authors suggest that thecapacity to show a high level of cortico-steroids relates to the lifestyles of thetwo species. Saimiri is an active, mobileand highly exploratory species.whereas Cal-licebus has a small home range, is mono-gamous and leads a rather quiet life. Thus inkeeping species in captivity it is important toconsider their ability to adapt to an artificialenvironment which is far removed from theirnatural way of life. The titi monkey is clearlyunhappy in captivity and has only a limitedability to cope with a profound change fromits natural environment.

Mild unpredictable stressors (such as waterdeprivation, continuous illumination, cagetilt, living in a soiled cage, or loud noises)have been shown to influence the appetite ofrats and mice for sweet substances (Willneret a1. 1987, Monleon et a1. 1995). Theseuncontrolled variables, which may be asso-ciated with poor husbandry, could seriouslycompromise experiments using a food re-

Poole

ward. Exposure to bright light, often resultingfrom cages being high on a rack, can also beaversive to nocturnal rodents and can induceretinal degeneration, prenatal mortality anddecreased growth rates in various strains ofrats and mice (Clough 19841.Schlingmann eta1. (1993) showed that rats show avoidancebehaviour to light intensities as low as20-25 lux, which is well below the thresholdfor retinal degeneration (60 lux). In manyinstances experiments on rats and mice arecarried out during the daytime and in brightlight, when the animals would normally beasleep. This would seem certain to causethem some distress but, as far as I am aware,no one has investigated whether such con-ditions may add to any stress caused by theexperiment.

The environment may also contain stres-sors of which we are unaware. An obviousexample is noise which is in the ultrasonicrange and can be perceived by and is knownto influence the behaviour of rodents. I recallentering an experimental laboratory wheredrugs were tested on rodents. It containedfive computers with visual display units.Such equipment emits a high pitched ultra-sonic scream which is almost indistinguish-able from the fear cry of a rat (Sales et a1.1988).Three computer visual display units(VDUs) were switched on when I entered thelaboratory and, when I asked whether thecomputers were switched off during experi-ments, the scientists were obviously sur-prised by my question and unaware of thepossibility that VDUs might affect experi-mental results!

Some of the most stressful events in everyday husbandry result from changes in envir-onment. Animals may be placed in unfami-liar/ clean cages and, for mammals whichscent mark their home range, this may behighly disturbing. For example, rodents oftenfight when moved to another cage. Evenmore stressful is the situation where ananimal is moved from its home cage to anunfamiliar one and then subjected to anexperiment. It is good practice to allowplenty of time for the animal to acclimatizeto its new situation, not only on welfaregrounds but also because the experimentalresults may be influenced. For example

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Damon et a1. (1986) compared the nephro-toxic response of rats to implanted, refineduranium ore. They implanted group I rats andthen moved them to metabolism cages; groupII was allowed 21 days to acclimatize to themetabolism cage before implantation, whilegroup III were housed in polycarbonate cagesand implanted after 21 days, four beingretained without implantation, as controls.The surprising result was that, for group Irats 3-8 mg/kg proved toxic, while for theacclimatized experimental rats in groups IIand III, the toxic dose was 220-650 mg/kg.This example provides concrete data tosupport the practice of carrying out experi-ments in a familiar environment.

Handling and trainingAnother important consideration which canaffect their well-being, is the way in whichanimals are handled or restrained. Barclay eta1. (1988) found significant values of their'Disturbance Index' resulted from longerperiods of restraint lover 20 s) while Blecha eta1. (1982) showed that mice restrained in awire cone for 2 h, had increased levels ofcorticosteroids and that their immune re-sponse was suppressed.

Barclay et a1. (loc cit) found that miceshowed significant Disturbance Indexeswhen the handler had previously contactedcat urine. Mice exposed to a cat (Hamilton19741, or those which had been fighting, bothhad lower levels of resistance to tapewormsindicating a stress-induced immunosuppre-sion.

It is well known that restraint can behighly stressful to mammals (Cronin 1985,Lawrence 1991) and it may also lead tosuppression of the immune system (Ras-mussen et a1. 1957, Levine et a1. 1962). Inspite of this, in many laboratories monkeysare manhandled, restrained in crush cages oreven anaesthetized to carry out even trivialprocedures such as injections or blood sam-pling. Monkeys, like most mammals, caneasily be trained to cooperate in procedures.For example, rhesus monkeys trained toextend an arm for an injection showed amuch lower incidence of diarrhoea as com-pared with animals who were physically

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restrained IReinhardt 1990, 1992). Monkeysin zoos have been trained to perform a varietyof tasks, for example, female drills wereencouraged to present for artificial insemi-nation and a male to masturbate in a specialarea to facilitate the collection of sperm.Reinhardt (1991, 1992) also found that thehome cage is the best place to carry outvenipuncture on Macaca nemestrina andthat cortisol levels were lower in animalstrained to accept this procedure whencompared with individuals who were re-strained. Monkeys can also be trained to opentheir mouths for dental examination.

Most, if not all, laboratory mammals andbirds recognize humans as individuals andare nervous of strangers. When an experi-mental procedure is to be carried out it istherefore preferable that the handler shouldbe a person familiar to the animal, in whomit has confidence. An unfamiliar handler willundoubtedly cause the animal fear and stress.Wherever possible, laboratories should en-sure that the animal is familiar with those indirect contact with it during the experiment.Thus, the role of the animal technician is ofvital importance and should be appreciatedby the scientist (Biological Council 19921.

Kind and gentle handling make all thedifference to the animal. This is referred to as'stockmanship' in farming circles, where ithas been shown that a friendly stockman canincrease the milk yield of cows as comparedwith persons who treat them humanely butdo not form any relationship with theiranimals (Seabrook 1984). Atherosclerosis isreduced in rabbits handled in a consistentand friendly way as opposed to the moreusual laboratory procedure of simply pickingthem up and restraining them (Nerem et a1.1980). Good handling and friendly ap-proaches have been shown to lead to greatergrowth rates and reproductive success in pigs(Hemsworth & Barnett 1987). Insomeinstances experimental pigs with cathetersdid better than controls, probably becausethey received more attention from staff(Wiepkema 1990). Good handling and train-ing animals to cooperate, not only improvesthe quality of the relationship between carerand animal, but also allows the animal toexercise its intelligence. One of the major

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problems in experiments with consciousanimals is the fear or anxiety which thesubject experiences. If the experimentalanimal has been trained to cooperate and hasconfidence and trust in the handler it will bemuch less stressed and the experiment willbe much improved by the removal of thisunwanted variable. Thus a positive, caringattitude by staff not only improves the well-being of the animal but also makes it morewilling to cooperate in any procedures towhich it is subjected.

There are, of course sources of potentialstress even in the best run animal houses.Husbandry procedures themselves can dis-turb animals and, for example, the routineswhich occur regularly may affect animals inways which are not apparent. Line et al.(1989)found that during cage cleaning theheart rate of rhesus monkeys increased andremained significantly above normal for 2 hafterwards. Thus, there could be considerableeffects on, for example, drug metabolism,depending on the time of day in which theanimal was given the dose. Barclay et al.(1988)showed that the behaviour of rats wassignificantly disturbed when they were re-strained by an inexperienced handler ascompared to an experienced one.

One of the referees rightly pointed out thatthis paper seems to have a bias toward rats,mice and non-human primates; this iscorrect, but I do believe that it reflects thecoverage in the scientific literature. While itwould be surprising if other species ofmammal, and probably birds, were notaffected similarly, there is no doubt thatadditional information on other laboratoryanimals would be valuable.

ConclusionsHappy animals are busy, confident andbehave normally. They will not be in pain, ordistressed and should resist disease andreproduce successfully. I have given exam-ples which show that both the endocrinecondition and immunology of laboratoryanimals, which experimenters may assumeto be normal, can be compromised by socialconditions, developmental history and stres-sors in the animal unit or experimental

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laboratory. One of the most importantaspects of the life of laboratory animals aretheir relations with human handlers and caregivers on whom they are totally dependent.Good, kindly treatment and simple humanetraining are beneficial both in reducing stressand in producing animals which are con-fident, cooperative and easily handled; theywill also be the best subjects for scientificinvestigation. While it has to be acceptedthat no animal can live an entirely stress-freelife, what I have termed a happpy animal isreadily able to cope with the stressors towhich it is subjected. Unhappy animals haveto put up with distressing conditions beyondtheir control which result in behavioural andphysiological disabilities such as perma-nently raised levels of stress hormones orreduced concentrations of sex hormones anda compromised immune system; these un-controlled variables make them unsuitablesubjects for scientific studies. These findingsmake it obligatory for scientists to do every-thing practicable to ensure the happiness oflaboratory animals if the quality of theirresearch is to be beyond reproach.

Acknowledgment I am extremely grateful to DrE. D. Williamson for her very helpful comments onthis manuscript, however, I alone take responsibilityfor the opinions expressed therein.

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