Happy animals make good science

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

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

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

experimental method

What are happy animals? this basis, I will define a 'happy animal' as
one which is alert and busy (shows a wide
Most people who have worked closely with repertoire of behaviour), is able to rest in a
animals or who keep them as pets are aware relaxed manner, is confident (outward going
if they are suffering or unwell; the signs may and does not display fear towards trivial non-
be small but we become aware that all is not threatening stimuli) and does not show
well. Colloquially, we will say to our abnormal behaviour. It is, of course, impor-
colleagues 'that animal is not happy'. The tant to be familiar with the particular
signs which tell us that there is something .animal's character to make these judge-
wrong are changes in the behaviour which ments. Some individuals are naturally
we have come to expect from the individual, extrovert and active, while others are quiet
for example, we may find it sitting huddled and lethargic. In the laboratory, those of us
in a comer, failing to greet us or lacking who care for animals like to think that our
interest in events taking place around it. If charges are happy and that any procedures
the behavioural change persists, we take which have to be performed on them cause
action and may even call in veterinary them the absolute minimum of distress.
advice. In this article the question is posed
Happiness and unhappiness, or distress, whether it is not only better for the animal to
refer to states of mind of the animal; they be happy, but whether its state of mind may
cannot be measured directly but the whole also have the potential to influence the
concept of animal welfare is based on the scientific results which are derived from it.
belief that higher animals, like us, are able to The most obvious cases of unhappiness will
experience pain and pleasure. The best way occur when animals are sick or injured and
to decide whether an animal is happy or symptoms will vary from mild to severe.
distressed is by observing its behaviour. On Generally, with modem laboratory practice
this source of distress has virtually been
Corespondence to: Trevor Poole
eliminated. We take it for granted that

Accepted 6 September 1996 LaboratoryAnimals (1997) 31,116-124

Happy animals make good science 117

scientists do not work with animals which alleviation was the subject of the study, as in
are ill or injured. Nor do laboratory animals the case of testing an anti-depressant. What-
lack essential physical needs, such as food, ever the subject under investigation, all
water or suitable climatic conditions. There unnecessary stress should be minimized
remain, however, a variety of potential during the experiment to reduce the varia-
causes of distress, such as social problems bility of the results and thus the number of
with aggressive cage mates, overcrowding, or animals required. This requires, firstly, a
social isolation. There are also features of the thorough understanding of the animal and its
physical environment, such as loud or biology and, secondly, experiments which are
sudden noises, including ultrasound which well designed, statistically valid and appro-
can be perceived by rodents, dogs and smaller priate. Even in situations where the experi-
primates, which might also be sources of ment itself creates unhappiness for the
distress. Finally, there are the attitudes and animal, such as premature removal of young,
sometimes inexpert manipulations by staff. any effect may be diminished or even lost if
Mammals, particularly become distressed if the animal was not happy in the first
they are badly handled, especially when they instance. We can therefore conclude that, in
are restrained by personnel unfamiliar to all aspects, apart from unavoidable adverse
them. This may be a common occurrence, as effects of the experiment, the animal should
the experimenter is not usually the person be happy.
in day-to-day care. A factor which is Most scientists working with animals will
increasingly being recognized as a source make the assumptions that they will have
of unhappiness, is the failure of the captive normal blood pressure, heart rates, levels of
environment to meet the animal's stress hormones, immunological compe-
behavioural needs and assure its psycho- tence, digestion, appetite and behaviour. To
logical well-being. It is becoming apparent avoid confounding variables, experimental
that captive mammals can be bored or resort animals should have both normal physiology
to abnormal behflviour if their environment and behaviour. Some might argue that
is not sufficiently complex and interesting to behaviour is of less significance than phy-
them (Wemelsfelder 1990, Poole 1988). siology, but this is based on the erroneous
supposition that mind and body are separate
entities and that one will not influence the
What is good science?
other. Recent scientific work has shown how
The quality of experimental laboratory ani- the brain, behaviour, hormones and even the
mal science depends on three essential immune system, are all interdependent and
conditions being satisfied. Firstly, there that disturbances in one of these systems
should be an important problem for which an commonly influences one or all of the others
answer is sought, secondly, the experiment (see review article by Martin 1989 and Bohus
should yield unambiguous results which & Koolhaas 1991).In fact, behavioural
provide an answer to the problem and, changes are usually more sensitive indicators
finally, variables which are not under in- of distress than physiological ones. I shall
vestigation should be strictly controlled. I now consider some of the main factors which
shall take for granted the assumption that the may influence the psychological well-being
first two conditions have been met and only of laboratory animals.
be concerned with the third which, can also
have a direct bearing on the well-being of the
animals. Good laboratory animal science is Factors influencing psychological
based on normal, healthy subjects, unless the well-being
illness is itself the subject of investigation.
Scientific method assumes the absence of Social factors
confounding factors or uncontrolled vari- Laboratory mice are commonly kept in single
ables. Clearly, unhappiness might be a sex groups in stock cages. While females
confounding variable unless, for example, its generally tolerate such conditions, males
118 Poole

fight and establish a hierarchy, but the type Benton et al. 1978, Brain 1990), so that
of social structure depends on the number of singly-housed mice do not suffer from 'iso-
individuals in the cage. Poole and Morgan lation stress'. This finding is compatible with
(1973) found that, in small colonies of 3--4 the fact that mice are territorial in the wild
male CFW mice, the dominant's aggression and thus actively repel other males. How-
was directed to few rivals and these sub- ever, providing a simulation of the wild in
ordinates were highly intimidated and re- the laboratory may actually be deleterious
stricted in their movements about the cage. because Bishop and Chevins (1988) found
Five male mice however formed a linear that territorial male mice placed in an arena
hierarchy with each individual knowing its had high levels of stress hormones, presum-
place and thus subordinates were able to ably associated with the defence of their
develop strategies to avoid conflict. In larger territories. While access to social compa-
colonies of nine or more individuals the nions benefits many species of laboratory
dominant was unable to control such a large animals, some solitary species, may have to
number of subordinates, so that the social be kept alone because of their aggressive
structure broke down after 3-5 days and tendencies, for example, male rabbits and
another dominant arose. This contrasted ferretsj this is particularly common in cases
with the situation in smaller groups of up to where males have bred or been exposed to
five in number where, barring disturbance, members of the opposite sex, or females have
aggression gradually decreased and was infant young. Even individuals of social
minimal after 12-15 days. Physiological data species must have adequate space to avoid
from laboratory mice have shown that, in one another and thus minimize any conflict.
standard housing, subordinates exhibit high- Bohus and Koolhaas (1991) reviewed the
er levels of stress and sex hormones than literature on psycho-immunology and came
dominants (Hucklebridge et al. 1976, Benton to the conclusion that social stress is only
et al. 1978). In addition to experiencing fear, likely to impair immune function signifi-
suffering injury and high levels of stress cantly when the animal is unable to exert
hormones, Beden and Brain (1984, 1985) some control over the situation by develop-
found that the immunological response to an ing a coping strategy. Inability to escape from
antigen (sheep red blood cell) was reduced in an attacker and chronic overcrowding are
subordinate or defeated mice. Brayton and clear examples of situations which animals
Brain (1973) found that crowding mice are unable to control.
lowered their resistance to a digenean para- It is important to remember that a rat is
site and Edwards and Dean (1977) also not simply a scaled-up mouse. Rats are much
showed that crowding affects the mouse's more sociable than mice and consequently
immune response. seem likely to suffer more when isolated,
Age is another important consideration although Brain and Benton (1979) could find
when housing male micej litter mates, unless no evidence of isolation stress in this species.
significantly disturbed will usually live However, young rats show very active social
amicably together, as will members of play which involves both chasing and wrest-
different litters who have been grouped ling (Poole & Fish 1975, 1976), so they need
together from an early age. Clearly, wherever adequate space to do this. During their
possible, animals, should be kept in condi- developmental stage, rats acquire skills and
tions where their social grouping leads to the experience; adult rats reared in deprived
minimum of aggression, and hence distress. conditions are not only less intelligent, but
There has been a tendency to believe that also have smaller brains than those from rich
isolation in the form of single housing is and stimulating environments (Renner &
distressing for other mammals, as it is for Rosenzweig 1978). They are thus less normal,
humans. However, it has been found that but this does not necessarily mean that they
isolated male mice have hormonal profiles are less happy.
similar to dominants (Brain 1975, Huckle- Beynen (19921 reviewed literature which
bridge et al. 1976, Brain & Benton 1977, indicated that control rats in the same room
Happy animals make good science 119

as the experimentals showed raised levels of Early weaning is undoubtedly stressful for
corticosteroids, as compared to controls in mammals because of the upset caused by
another room. This suggests that some rats losing their mothers. The problem is further
(and therefore possibly other animals) may be exacerbated by the sudden loss of maternal
able to communicate their feelings to other antibody. This immune deficiency is tem-
individuals either by vocalizations or pher- porary until the young independent animal
omones and that situations which cause develops its own fully functioning immune
distress may also upset others within the system. However, the temporary immuno-
range of these forms of communication. deficiency may be enhanced by stress result-
Mendoza et a1. (1991)found that squirrel ing from separation and immuno-suppression
monkeys showed differences in levels of has been recorded from both adult pigs
corticosteroids which related to their sex and (Blecha & Kelley 1981, Blecha et a1. 1983)and
social grouping. Females showed higher primates (Reite 1987)which had been re-
levels when kept singly, with a single female moved from their mothers unnaturally early.
companion, or with a male. Three females For example, Reite showed that the separa-
housed together appeared to be the minimum tion of young Macaca nemestrina for 2 weeks
social group which would reduce the levels of at the age of 6 months still had an effect on
corticosteroids to a normallevelj this num- the immune system in the form of a
ber also showed much higher levels of reduction in T-cell proliferation in response
reproductive cycling as compared to the to a mitogen 6 years later. Early separation
smaller groups or females paired with a male. from the mother, is commonly practised by
Likewise male squirrel monkeys showed the breeders of non-human primates, so that
lower levels of corticosteroids when housed the young not only develop abnormal beha-
with male companions. The practical im- viour (Goosen 1989)but may also suffer from
plication for husbandry and breeding is that reduced immunological competence as
the minimum breeding group should consist adults, and thus, would be unsatisfactory as
of two males and three females. experimental animals.
Both mammals and some birds have a
period of life when they acquire knowledge
of the world and are able to test its proper- The phYSical environment
ties while protected by a vigilant mother or There is increasing evidence that a number of
family group. The developmental environ- physical environmental factors which influ-
ment determines, to a large extent the kind ence an animal's psychology may also affect
of situations with which they are able to its immune system. Unpleasant events, such
cope when they reach adulthood. During as inescapable electric shock, increase the
childhood they practise skills and motor incidence of tumours in rats (Keller et a1.
coordinations which will be of benefit in 1981).However, not all stress is deleterious
later life. Many mammals play fight when and some may even be beneficial. For
young and thus practise the strategies of example Marsh et a1. (1963)found that
attack and defence which they will need cynomolgus monkeys (Macaca fascicularis)
when faced with real rivals. They show trained over a 24-h period to avoid electric
extraordinary curiosity and inventiveness shocks increased resistance to polio virus
and thus learn the properties of objects and infection. Similarly, mice which had been
other organisms in their environment. trained to avoid electric shocks showed
Mammals enjoy play and experimentation in greater resistance to malaria than controls
the sense that it is self-rewarding, so that not subjected to the training. What seems to
they should be provided with a stimulating be important in these animals is not the
and complex developmental environment. shock itself but the degree of control which
Likewise, the presence of a mother is the animal is able to exert to avoid it.
important because it allows the young to Mice conditioned to drink saccharine
express their wide repertoire of play and solution followed by an immuno-suppressive
curiosity without fear. drug (cyclophosphamide) were subsequently
120 Poole

found to have a suppressed immune system ward. Exposure to bright light, often resulting
when drinking saccharine alone. This indi- from cages being high on a rack, can also be
cates that the immune response may actually aversive to nocturnal rodents and can induce
be susceptible to Pavlovian conditioning retinal degeneration, prenatal mortality and
(Kelley et a1. 1984, 1985). decreased growth rates in various strains of
Differences in levels of stress hormones rats and mice (Clough 19841.Schlingmann et
also relate to the animal's ability to control a1. (1993) showed that rats show avoidance
events. Rats were subjected to an electric behaviour to light intensities as low as
shock from the grid on which they walked. 20-25 lux, which is well below the threshold
Where the rat could prevent the grid from for retinal degeneration (60 lux). In many
becoming electrified by pressing a lever, instances experiments on rats and mice are
corticosteroid levels were much lower than carried out during the daytime and in bright
in controls which were shocked but had no light, when the animals would normally be
way of switching it off. asleep. This would seem certain to cause
There are also marked species differences them some distress but, as far as I am aware,
in responsiveness to stressors, even when no one has investigated whether such con-
they are closely related, for example rhesus, ditions may add to any stress caused by the
bonnet and cynomolgus macaques show experiment.
marked differences in hormonal responses to The environment may also contain stres-
routine procedures (Clark et a1. 1988). sors of which we are unaware. An obvious
Mendoza and Mason (1984) compared the example is noise which is in the ultrasonic
physiology of titi (Callicebusl and squirrel range and can be perceived by and is known
monkeys (Saimiri). The former are notor- to influence the behaviour of rodents. I recall
iously difficult to keep in the laboratory entering an experimental laboratory where
whereas squirrel monkeys readily adapt to drugs were tested on rodents. It contained
captivity. The two species show very differ- five computers with visual display units.
ent endocrinological responses to stress. Such equipment emits a high pitched ultra-
Interestingly, Callicebus shows very limited sonic scream which is almost indistinguish-
corticosteroid response to stress compared to able from the fear cry of a rat (Sales et a1.
Saimiri and the authors suggest that the 1988). Three computer visual display units
capacity to show a high level of cortico- (VDUs) were switched on when I entered the
steroids relates to the lifestyles of the laboratory and, when I asked whether the
two species. Saimiri is an active, mobile computers were switched off during experi-
and highly exploratory species.whereas Cal- ments, the scientists were obviously sur-
licebus has a small home range, is mono- prised by my question and unaware of the
gamous and leads a rather quiet life. Thus in possibility that VDUs might affect experi-
keeping species in captivity it is important to mental results!
consider their ability to adapt to an artificial Some of the most stressful events in every
environment which is far removed from their day husbandry result from changes in envir-
natural way of life. The titi monkey is clearly onment. Animals may be placed in unfami-
unhappy in captivity and has only a limited liar/ clean cages and, for mammals which
ability to cope with a profound change from scent mark their home range, this may be
its natural environment. highly disturbing. For example, rodents often
Mild unpredictable stressors (such as water fight when moved to another cage. Even
deprivation, continuous illumination, cage more stressful is the situation where an
tilt, living in a soiled cage, or loud noises) animal is moved from its home cage to an
have been shown to influence the appetite of unfamiliar one and then subjected to an
rats and mice for sweet substances (Willner experiment. It is good practice to allow
et a1. 1987, Monleon et a1. 1995). These plenty of time for the animal to acclimatize
uncontrolled variables, which may be asso- to its new situation, not only on welfare
ciated with poor husbandry, could seriously grounds but also because the experimental
compromise experiments using a food re- results may be influenced. For example
Happy animals make good science 121

Damon et a1. (1986) compared the nephro- restrained IReinhardt 1990, 1992). Monkeys
toxic response of rats to implanted, refined in zoos have been trained to perform a variety
uranium ore. They implanted group I rats and of tasks, for example, female drills were
then moved them to metabolism cages; group encouraged to present for artificial insemi-
II was allowed 21 days to acclimatize to the nation and a male to masturbate in a special
metabolism cage before implantation, while area to facilitate the collection of sperm.
group III were housed in polycarbonate cages Reinhardt (1991, 1992) also found that the
and implanted after 21 days, four being home cage is the best place to carry out
retained without implantation, as controls. venipuncture on Macaca nemestrina and
The surprising result was that, for group I that cortisol levels were lower in animals
rats 3-8 mg/kg proved toxic, while for the trained to accept this procedure when
acclimatized experimental rats in groups II compared with individuals who were re-
and III, the toxic dose was 220-650 mg/kg. strained. Monkeys can also be trained to open
This example provides concrete data to their mouths for dental examination.
support the practice of carrying out experi- Most, if not all, laboratory mammals and
ments in a familiar environment. birds recognize humans as individuals and
are nervous of strangers. When an experi-
mental procedure is to be carried out it is
Handling and training therefore preferable that the handler should
Another important consideration which can be a person familiar to the animal, in whom
affect their well-being, is the way in which it has confidence. An unfamiliar handler will
animals are handled or restrained. Barclay et undoubtedly cause the animal fear and stress.
a1. (1988) found significant values of their Wherever possible, laboratories should en-
'Disturbance Index' resulted from longer sure that the animal is familiar with those in
periods of restraint lover 20 s) while Blecha et direct contact with it during the experiment.
a1. (1982) showed that mice restrained in a Thus, the role of the animal technician is of
wire cone for 2 h, had increased levels of vital importance and should be appreciated
corticosteroids and that their immune re- by the scientist (Biological Council 19921.
sponse was suppressed. Kind and gentle handling make all the
Barclay et a1. (loc cit) found that mice difference to the animal. This is referred to as
showed significant Disturbance Indexes 'stockmanship' in farming circles, where it
when the handler had previously contacted has been shown that a friendly stockman can
cat urine. Mice exposed to a cat (Hamilton increase the milk yield of cows as compared
19741, or those which had been fighting, both with persons who treat them humanely but
had lower levels of resistance to tapeworms do not form any relationship with their
indicating a stress-induced immunosuppre- animals (Seabrook 1984). Atherosclerosis is
sion. reduced in rabbits handled in a consistent
It is well known that restraint can be and friendly way as opposed to the more
highly stressful to mammals (Cronin 1985, usual laboratory procedure of simply picking
Lawrence 1991) and it may also lead to them up and restraining them (Nerem et a1.
suppression of the immune system (Ras- 1980). Good handling and friendly ap-
mussen et a1. 1957, Levine et a1. 1962). In proaches have been shown to lead to greater
spite of this, in many laboratories monkeys growth rates and reproductive success in pigs
are manhandled, restrained in crush cages or (Hemsworth & Barnett 1987). Insome
even anaesthetized to carry out even trivial instances experimental pigs with catheters
procedures such as injections or blood sam- did better than controls, probably because
pling. Monkeys, like most mammals, can they received more attention from staff
easily be trained to cooperate in procedures. (Wiepkema 1990). Good handling and train-
For example, rhesus monkeys trained to ing animals to cooperate, not only improves
extend an arm for an injection showed a the quality of the relationship between carer
much lower incidence of diarrhoea as com- and animal, but also allows the animal to
pared with animals who were physically exercise its intelligence. One of the major
122 Poole

problems in experiments with conscious laboratory. One of the most important

animals is the fear or anxiety which the aspects of the life of laboratory animals are
subject experiences. If the experimental their relations with human handlers and care
animal has been trained to cooperate and has givers on whom they are totally dependent.
confidence and trust in the handler it will be Good, kindly treatment and simple humane
much less stressed and the experiment will training are beneficial both in reducing stress
be much improved by the removal of this and in producing animals which are con-
unwanted variable. Thus a positive, caring fident, cooperative and easily handled; they
attitude by staff not only improves the well- will also be the best subjects for scientific
being of the animal but also makes it more investigation. While it has to be accepted
willing to cooperate in any procedures to that no animal can live an entirely stress-free
which it is subjected. life, what I have termed a happpy animal is
There are, of course sources of potential readily able to cope with the stressors to
stress even in the best run animal houses. which it is subjected. Unhappy animals have
Husbandry procedures themselves can dis- to put up with distressing conditions beyond
turb animals and, for example, the routines their control which result in behavioural and
which occur regularly may affect animals in physiological disabilities such as perma-
ways which are not apparent. Line et al. nently raised levels of stress hormones or
(1989) found that during cage cleaning the reduced concentrations of sex hormones and
heart rate of rhesus monkeys increased and a compromised immune system; these un-
remained significantly above normal for 2 h controlled variables make them unsuitable
afterwards. Thus, there could be considerable subjects for scientific studies. These findings
effects on, for example, drug metabolism, make it obligatory for scientists to do every-
depending on the time of day in which the thing practicable to ensure the happiness of
animal was given the dose. Barclay et al. laboratory animals if the quality of their
(1988) showed that the behaviour of rats was research is to be beyond reproach.
significantly disturbed when they were re-
strained by an inexperienced handler as Acknowledgment I am extremely grateful to Dr
compared to an experienced one. E. D. Williamson for her very helpful comments on
this manuscript, however, I alone take responsibility
One of the referees rightly pointed out that
for the opinions expressed therein.
this paper seems to have a bias toward rats,
mice and non-human primates; this is
correct, but I do believe that it reflects the References
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