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National Research Council (US) Committee on Recognition and Alleviation of Distress in Laboratory Animals. Recognition and Alleviation of Distress in Laboratory Animals. Washington (DC): National Academies Press (US); 2008.

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Recognition and Alleviation of Distress in Laboratory Animals.

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3Recognition and Assessment of Stress and Distress

INTRODUCTION

Recognition of distress in laboratory animals requires knowledge of what is normal for the species and strain used. Genetically modified animals should be evaluated in reference to the normality of their genotype.

Most vertebrate species routinely experience some type of distress either in natural settings (e.g., during a predator attack) or as part of normal development (e.g., following natural maternal separation in rhesus monkeys; Berman et al. 1994). The recognition of distress in laboratory animals, however, requires an understanding of what is “normal” for the species being studied. In this chapter we consider the use of behavioral and physiologic variables to recognize stress and distress.

Lab animals should behave according to species-specific normal behavioral, morphologic, and physiologic values (see Novak and Suomi 1988 and Snowdon and Savage 1989 for a discussion of psychological well-being in captive nonhuman primates). Species-specific normative ranges have been established for many parameters (e.g., hematocrit, blood glucose, body temperature, heart rate, blood pressure, respiration rate). Standardized growth curves and weight ranges can be obtained from laboratory animal suppliers for most species.

Recognition of stress and distress in laboratory animals requires an understanding of the species-, gender-, and age-specific norms, because the normal range of some of these variables may vary as a function of gender, age, physiological state, or genetic characteristics. Values outside normalcy, therefore, may or may not serve as clinical indicators of a disease state. Various transgenic and knockout mice that exhibit severe behavioral and physiological phenotypes appear abnormal relative to their control littermates, but are normal for their genotype. For example, it is appropriate to evaluate Huntington’s disease transgenic mice for signs of stress and distress only relative to their own “normal” behavior, taking into account their particular genetic makeup, their abnormal motor patterns, and reduced weight gain (Mangiarini et al. 1996).

BEHAVIORAL RECOGNITION OF STRESS AND DISTRESS

Normal Behavior

Many parameters have an effect on species-specific normal behavior and should be taken into consideration when behavioral characteristics are used to determine normalcy or the presence of stress and distress. Animals exhibit a variety of behavioral changes as part of the normal aging process. Males and females differ in the baseline values of many stress markers. Inbred murine strains differ in almost every behavioral, sensory, motor, and physiological trait studied and each inbred strain may respond to stress differently. Similar behavioral differences in response to stress have been observed in primates. Genetically engineered phenotypes need to be considered when assessing stress and distress in transgenic and knockout animals. The maternal environment and rearing experiences of the offspring affect their future responses to stress and distress. Special physiological states, such as impending parturition, are defined by state-specific behaviors. Housing conditions may also modify species-specific behavioral patterns. Behavioral normalcy is further characterized by the absence ofbizarre or atypical patterns of species-specific behavior. The presence of stereotypies usually implies suboptimal environments and possibly poor animal welfare.

The identification of species-typical behavior often comes from ethograms developed by researchers to describe the kinds of behavior that animals display in various settings (Bronson 1979; for more references see Additional References). While the use of species-typical behavior as a normative benchmark has considerable value (Latham and Mason 2004), it does have limitations. First, the full range of species-specific behaviors cannot be recreated (or allowed to be expressed) in the laboratory animal care facilities as some types of behavior observed in natural settings (e.g., severe aggression) are clearly undesirable from a laboratory management perspective. Second, species-typical behaviors are neither invariant nor universal, as both the frequency and the presence of such behaviors vary as a function of age, gender, physiological state, and genetic constitution. Third, rearing practices and housing environments may affect expected typical behavior.

  1. Age: Many young mammals engage in high levels of social play whereas adults rarely do. Thus, play may be normal for young animals but not necessarily so for adults (Ruppenthal et al. 1974; Vanderschuren et al. 1997). All animals display physiological, behavioral, and cognitive changes as they age. Some of these changes, for example changes in coat/ hair appearance and locomotor ability, are overt and easily recognizable. Many laboratory animals display an age-related decline in exploratory activity, which is sometimes correlated to weight gain (as observed, for example, in mice of various strains; Ingram 2000; Ingram et al. 1981). In addition, a number of neurosensory, cardiovascular, endocrine, gastrointestinal, musculoskeletal, and reproductive changes occur with aging, some of which cannot be directly observed in the living animal. Such age-related changes (e.g., hearing and vision deficits) have been documented for a number of murine strains (Hawkins et al. 1985; for more references see Additional References), while cognitive deficits have been reported in aging mice and rats. It is postulated that some of these changes may be gender- and strain-related (Decker et al. 1988; Fischer et al. 1992; Frick et al. 2000). Changes in pain sensitivity and in emotional behavior that may have direct implications for stress and distress have also been reported in aging animals (Berry et al. 2007; Lamberty and Gower 1992).
  2. Gender: Female mammals generally care for infants, whereas the extent of male involvement varies across species. Thus, species-typical behavior may be gender-biased. Moreover, gender-related differences in stress markers can be profound and occur in all vertebrate species. For example, female rats and mice exhibit marked elevations in basal and stress-induced corticosterone release relative to males, although these are buffered by high levels of corticosteroid-binding globulin, thus making free corticosterone levels similar in both sexes (McCormick et al. 1995). Absolute corticosteroid levels in females fluctuate in relation to the stage of estrus, presumably affected by circulating levels of estrogens (Figueiredo et al. 2002). Thus, assessment of HPA activity as a measure of stress (see below) needs to account for the gender of the animal and the type of steroid measurement (i.e., total [plasma] or free [saliva]). Males and females also appear to differ in other aspects of their stress response(s); for example, while females have greater anhedonic and HPA axis responses to chronic mild stress than males, they score lower on tests of behavioral depression caused by chronic stress exposure (Dalla et al. 2005).
  3. Genetic traits: Genetic variability among many animal species complicates our understanding of the effects of stress and distress in laboratory animals. Multiple studies in the mouse have shown that generalizations even across a single species can be problematic. Selective breeding has produced hundreds of inbred mouse strains, providing extensive genetic and phenotypic variability (Beck et al. 2000; Silver 1995). A mouse strain is classified as inbred after 20 inbreedings (that is, 20 generations of brother × sister or offspring × parent matings), at which point its members are virtually genetically identical because at the 20th or subsequent generations all animals are traceable to a single breeding pair. One cannot assume that mice from different inbred strains are alike (or even similar), perform identically, or experience and react uniformly to stimuli—stressful or otherwise. In fact, inbred strains of mice differ in almost every behavioral, sensory, motor, and physiological trait studied to date, such as anxiety, learning and memory, brain structure and size, visual acuity, acoustic startle, exploratory behavior, alcohol sensitivity, depression, pain sensitivity, and motor coordination (Crawley et al. 1997; for more references see Additional References). What is typical for one strain—for example, high levels of play behavior or social interaction (Moy et al. 2004) or novelty seeking and exploratory behavior (Bolivar et al. 2000; Kliethermes and Crabbe 2006)—may not be characteristic of another.
    For these reasons different inbred murine strains respond to stress differently and thus may well experience distress in different ways. Indeed, a number of behavioral studies provide evidence that strain differences in distress susceptibility are likely. For instance, inbred strains differ in performance on anxiety, depression, and fear learning assays (Balogh and Wehner 2003; for more references see Additional References). Correlating behavioral performance across such matrices can provide some indication of basic genetic differences among strains in response to stressful situations (Ducottet and Belzung 2005). When exposed to a month of unpredictable mild stress (e.g., cage tilting, damp bedding, lights on for a short period during the dark phase) most strains groom themselves less resulting in poor fur condition, while only a few display heightened aggression levels (Mineur et al. 2003). In general, inbred strain differences appear in the stress-induced hyperthermia model (Bouwknecht and Paylor 2002; van Bogaert et al. 2006) and in stress-invoked autonomic responses (body temperature and heart rate), although the latter are also a function of the intensity of the insult applied (van Bogaert et al. 2006). Behavioral differences have also been observed in primates. High reactor monkeys1 are much less likely to explore a novel stimulus than low reactors (Suomi 2004). Moreover, because even within genetically diverse species individual animals will vary on many dimensions, high levels of exploration may be the norm for some but not for others.
  4. Transgenic and knockout mouse models: Many genetic mouse models have intentional or incidental behavioral and/or physiological phenotypes relevant to stress. Disturbances in genes associated with brain stress-regulatory systems can elicit stress hyposensitivity (e.g., deletion of the corticotrophin-releasing hormone [CRH] gene; Muglia et al. 1995) or stress hypersensitivity (e.g., overexpression of CRH; Stenzel-Poore et al. 1994). Moreover, there are any number of transgenic/knockout phenotypes that affect behavioral or physiological indices of stress without producing overt stress or distress. For example, deletion of the S6 kinase gene produces a remarkably small animal, not because of the animal’s “failure to thrive” but rather because absence of this powerful cell-size regulator results in a smaller size of otherwise healthy cells (Thomas 2002). Thus, expressed phenotypes need to be considered when assessing stress and/or distress in genetically engineered animal models because their presence may be even more difficult to recognize and diagnose in these animals than in their control littermates.
  5. Rearing and postnatal separation: In most mammals, the early environment of the young animal is defined by the presence of its mother; therefore maternal characteristics can have a profound impact on the future behavior of adult offspring. There is ample scientific evidence that maternal environment can be an important epigenetic determinant of physiology and behavior, and should be considered as a variable for assessment of stress and distress. Offspring are generally reared with their mothers and may also be reared in larger social groups that include other offspring as well as adult males and females. Some species- or strain-typical behaviors, such as cross fostering, in which the offspring of one species are reared by the parents of another species or of the same species but a different strain, are more susceptible to parent-related environmental manipulations. The extent to which cross fostering may produce distress in the offspring depends on the degree to which parental care varies across the two species (or strains) in question. In birds, cross fostering can be relatively benign (e.g., rearing of green finches’ offspring by canaries; Guettinger 1979). In other cases, however, cross fostering may complicate the assessment of stress and distress, as cross-fostered rats, mice, and goats frequently exhibit behaviors more similar to the adoptive mother strains (Ahmadiyeh et al. 2004; Anisman et al. 1998; Kendrick et al. 2001). In rats, female offspring of dams bred for high licking and grooming that have been reared with their biological mothers will themselves provide extensive maternal care of their own pups. In contrast, if female offspring of high licking and grooming dams are instead cross fostered with low licking and grooming (i.e., “poor”) mothers, they will subsequently provide little maternal care to their own offspring, resulting in behavioral and physiological changes that persist into adulthood (Francis et al. 1999). Recent research into the effects of maternal behavior on such developmental traits as DNA methylation, an epigenetic mechanism that alters gene expression, has shown that maternal environmental programming (for example, high or low grooming) affects the glucocorticoid receptor gene and possibly the responses of the offspring to stress. Offspring of high grooming mothers (or those cross fostered to them) appeared less responsive to stressful stimuli and had increased expression of these receptors in the hippocampus compared to those raised by low grooming dams (Fish et al. 2004; Weaver et al. 2004). Microarray analysis has shown that more than 900 genes of the hippocampal transcriptome are stably regulated by maternal care (Weaver et al. 2006).
    In species such as primates, however, infants may be nursery-reared because of the infant’s illness, the mother’s failure to care for the infant, or demands of the experimental protocol. The two most common nursery rearing procedures for macaques are peer rearing (i.e., rearing infants together 24 hours a day) and surrogate peer rearing (i.e., rearing infants on inanimate surrogate mothers 24 hours a day with 1-2 hours of daily peer exposure in a playroom setting). Both conditions commence shortly after an animal’s birth before a strong attachment has been formed to the mother, and thus infants show little in the way of separation anxiety.
    From a developmental perspective, peer rearing appears to confer the greater risk for distress and social maladjustment. Peer-reared monkeys typically show higher levels of mutual clinging and greater fear responses than surrogate-peer-reared monkeys early in life and have difficulty adapting to larger social groups as juveniles (Ruppenthal et al. 1991). Peer rearing has also been associated with impaired immune responses (Coe et al. 1989; Lubach et al. 1995) and, when combined with repeated separations, appears to promote heightened aggressiveness, impaired impulse control, alcohol abuse, and low levels of 5-hydroxyindoleacetic acid (a serotonin metabolite) in cerebrospinal fluid (Ichise et al. 2006). Although less studied, surrogate-peer-reared monkeys appear to behave more like normally reared monkeys. Indeed, a large comparison study of surrogate-peer-reared monkeys (n=506) to normally reared monkeys (n=1,187) failed to detect any differences in growth, health, survival, reproduction, and maternal abilities between the two groups (Sackett et al. 2002). But because some individuals reared in either condition may be more vulnerable to the development of abnormal behavior than normally reared monkeys, careful observation and ongoing assessments would help guide colony management decisions regarding group composition and enrichment strategies.
    A different kind of early rearing experience involves separation from the mother or other attachment figure (e.g., other peers) after a strong attachment has been formed. Such separations may occur both for research purposes or to facilitate weaning. Depending on such variables as the timing of the separation, the nature of the separation environment, and the primate species, separation can induce high levels of stress in infants expressed by vocalizations and heightened activity (Bayart et al. 1990; Jordan et al. 1985; Laudenslager et al. 1990; Levine et al. 1993). It can also alter HPA activity (Levine 2005; Levine and Mody 2003; Parker et al. 2006; Vogt et al. 1980) and immune responses (Laudenslager et al. 1982). Reactions are often stronger when the infant is separated both from its mother and the environment in which it was raised compared to when only the mother is removed from the infant, but this effect can vary by species (Laudenslager et al. 1990). These signs generally disappear when infants are reunited with their mothers or their attachment figures, although neuroendocrine responses may be altered.
  6. Physiological state: Many species (such as dogs, sows, rabbits, and mice) need to build nests just before parturition, whereas others do not engage in such behavior (Arey 1997; Broida and Svare 1982; Crawley 2000; Kunkele 1992).
  7. Housing: Environmental conditions can modify species-specific behavioral patterns. Adults housed in same sex groups cannot show some aspects of the species-typical physiological repertoire (e.g., mating or parental behavior). Housing conditions (such as cage types and environmental enrichment) affect the amount of time that mice spend engaging in distinct behavioral patterns, as reported by Olsson and Sherwin who, using videorecording, showed that mice in furnished cages (i.e., cages with nesting material, running wheels, nest box, and chew box) “spent less time resting, bar-chewing and bar-circling and more time on exploratory/locomotor behaviors” (Olsson and Sherwin 2006, p. 392). Lack of environmental stimulation or social deprivation adversely impacts normal brain function in rats, such as attenuation of the prepulse inhibition (PPI) behavior elicited by startling events, and is accompanied by underlying neurochemical changes such as enhanced dopamine activity (Würbel 2001). Based on significantly fewer instances of abnormal behaviors (i.e., stereotypies) encountered in wild-caught animals vs. their captive-bred controls, the argument for a neuro-protective effect of early environmental enrichment against future abnormal behaviors has been made (Lewis et al. 2006). Moreover, studies have shown that dendritic anatomy in young rats was altered in response to a brief 4-day exposure to a complex environment (Wallace et al. 1992) and so was the hippocampus of adult mice in comparison to controls (Kempermann et al. 2002; for more discussion on enrichment see Chapter 4).

Behavioral normalcy is further characterized by the absence of bizarre or atypical patterns of species-specific behavior. Examples of abnormal behavior include excessive barbering observed in mice (Garner et al. 2004; Morton 2002), regurgitation/rumination and coprophagy seen in apes (Nash et al. 1999), or more serious self-injurious behaviors exhibited by rhesus monkeys (Novak 2003). Sometimes, such behaviors represent normal social patterns. For example, coprophagy associated with mother rearing occurs not only in laboratory-housed apes (Nash et al. 1999) but also in the wild where it is postulated to contribute to the reclaiming of unused resources from the feces (Krief et al. 2004). In other cases, however, such patterns are a sign of well-defined diseases or disorders, as, for example, excessive tremors observed in transgenic mice with Huntington’s disease (Mangiarini et al. 1996). In yet other instances, abnormal behavioral patterns, such as stereotypies, may result from suboptimal housing environments (Bayne et al. 1992, 2002; Hubrecht et al. 1992; Mason 1991).

Stereotypic behavior is characterized by highly repetitive and ritualistic actions, the function of which is largely unknown. Environments that elicit or enhance stereotypies not as part of defined pathophysiology or disease models are typically suboptimal (Berkson and Mason 1964; for more references see Additional References). Stereotypies vary across species and appear at different times of day and under different conditions (Mason and Mendl 1997). Classic whole-body stereotypies include circling, pacing (dogs, primates), wall bouncing (dogs), and somersaulting and bar chewing (rodents), whereas self- or other-animal-directed stereotypies often involve the limbs or face and include such patterns as digit sucking, paw licking, and overgrooming (Bayne and Novak 1998; for more references see Additional References).

Although there is yet inadequate research on the relationship between distress and stereotypy, a recent meta-analysis of studies linking stereotypy to animal welfare suggests that some stereotypies may function to regulate arousal and possibly reduce distress as “do-it-yourself enrichment” strategies to alleviate the effect of a suboptimal environment (see Mason and Latham 2004). Overall, however, the presence of stereotypies should be a cause for concern because animals that exhibit such behavioral patterns may not only have experienced some stress or distress in the past but also live in environments that promote or sustain these abnormal behaviors. Moreover, as a study by Krohn and colleagues has shown, stereotypies are probably underreported as they may occur during the night when staff are not present, or cease when staff enter a room (Krohn et al. 1999). If, in fact, the presence of stereotypies is being investigated, then more sophisticated methods such as closed-circuit television or videorecording, or simpler diagnostics such as partially reversed light cycles, would enable staff to observe nocturnal animals during their most active periods in order to document instances of abnormal behavior (Hubrecht 1997).

Abnormal Behavior and Clinical Signs

Recognition of distress should be derived from intimate knowledge of the species’ or strain’s normal behavior and may be based on (1) clinical signsand/or (2) significant deviation from the expected behavioral repertoire. Some clinical signs (e.g., changes in temperature, respiration, feeding behavior) indicate an abrupt onset of distress while others (e.g., weight loss) develop over a longer period of time and may serve as warnings. A thorough clinical examination with references to baseline effects of age, gender, genotype, etc., is necessary to establish the presence of distress, while an abrupt and marked change in behavior lasting more than a few days may also indicate a disease state. While the presence of stereotypiesis undesirable, the relationship between stereotypic behavior and distress remains largely unknown. Preventing the development of stereotyped behavior by providing species-specific appropriate environments is likely to result in improved welfare.

Assuming that an animal’s behavior has been well characterized, indications of distress may include certain clinical signs or marked change from the individual animal’s usual behavioral repertoire (Morton and Griffiths 1985; see score sheet examples in Appendix). An abrupt and marked change in behavior lasting more than a few days may also indicate the presence of a disease state in addition to distress, particularly if these changes occur in conjunction with severe reductions in normal daily activities such as feeding behavior, sexual behavior, maternal behavior, or attention to threat. Conversely, animals may exhibit increased activity associated with unusual motions (e.g., head rubbing) or unusually high levels of certain behaviors (e.g., scratching). Even marked changes in behavior, however, must be evaluated in context. For example, females usually exhibit decreased activity the first day following parturition, an expected behavior.

Clinical Signs of Distress

Clinical examination to establish the presence of distress should focus on, but not be limited to, the following: signs of abnormal respiration (shallow, labored, or rapid); assessment of grooming and hair coat (piloerected or greasy, possibly reflecting reduced grooming); examination of the eyes (runny, glassy, or unfocused); examination of motor postures (hunching or cowering in the corner of the cage, lying on one’s side, lack of movement with loss of muscle tone); absence of alertness or quiescence (inattention to ongoing stimuli); changes in body weight; the ability or failure to produce urine or feces; unusual features of urine (volume, smell, and color) or feces (quantity, consistency, and color); the presence of vomit; the status of the animal’s appetite and water intake; and intense or frequent vocalizations (Bennett et al. 1998; Fortman et al. 2002; Fox et al. 2002). It is appropriate to evaluate some of these signs in context, as, for example, rapid breathing could result from vigorous activities such as playing or running on the wheel, lying down may occur as part of social grooming (e.g., among macaques), weight loss is often associated with advanced age, and some mammals raise their hair (piloerection) while eating. In addition, clinical evaluation and diagnosis should consider species, age, gender, physiological state, and genetic variables (Bennett et al. 1998).

While some of the clinical signs described above (e.g., respiratory changes, changes in fecal material and/or in urine) are more relevant to the acute onset of a distressful state, other measures may serve as potential early warning signs of distress (e.g., rapid body weight changes in the absence of dietary modifications). Significant and unexpected changes in weight in either direction may be indicators of altered endocrinological, immunological, or neurological parameters. Indeed, the relatively sudden loss of 25% body weight of a nonhuman primate is one of the parameters used to determine humane endpoints in primate research (Association of Primate Veterinarians 2008).

This view should not be applied to caloric restriction research protocols where animals may be subject to controlled diets that reduce their weight by as much as 15-20% (Heiderstadt et al. 2000). Such protocols are widely used in gerontology research where diet has been shown to slow aging, extend lifespan, and reduce the incidence of age-related diseases in rodents (Goto et al. 2002; for more references see Additional References), while beneficial effects have also been observed in nonhuman primates (Ingram et al. 2007). Moreover, sensory-motor function and learning studies may use caloric or water restriction as a motivational tool (Heiderstadt et al. 2000; Smith and Metz 2005). In these studies regular monitoring of body weight is essential to ensure that animals either do not fall below an accepted weight range or, in the case of young animals, gain the appropriate body weight for their age.

Behavioral Signs of Distress

It has been suggested that abnormal behavior, such as stereotypies, is a marker for distress (Dawkins 1990). It remains unclear at this time whether any or all abnormal behaviors qualify as indicators of distress. Several alternative (and largely speculative) hypotheses attempt to explain the occurrence of stereotypic behavior in animals (Mason and Latham 2004; Tiefenbacher et al. 2005). Among these, the stimulation hypothesis suggests that when sensory motor input is low, possibly due to existing (i.e., nonstimulating, poor) housing arrangements, animals engage in stereotypic behavior to self-provide increased sensory-motor input (Sherwin 1998). For example, when cage size constrains normal movements, some animals may respond by developing stereotyped pacing in order to satisfy their need for activity (Draper and Bernstein 1963). The habit hypothesis suggests that although stereotypic behavior may have originally arisen in response to stress or distress, it persists as a habit uncoupled from the situation that originally produced it (Dantzer 1986; Mason 1991). Those who favor the arousal reduction hypothesis suggest that stereotypic behavior may serve to calm the animal and thereby avoid distress (reviewed in Mason 1991). Research shows that in some humans and nonhuman primates, even more serious forms of abnormal and self-injurious behavior may function to reduce arousal (Tiefenbacher et al. 2005). The arousal reduction hypothesis is consistent with the view that while an underlying stress or distress state may have initially caused abnormal behavior, eliminating the behavior may be neither desirable nor possible because the stereotypy may sometimes prevent the onset of distress.

Preventing the development of stereotyped behavior by providing the animals with species-specific appropriate environments is obviously desirable and likely to result in improved welfare, especially as enrichment “therapy” may reduce but will not cure the abnormal behavior (van Praag et al. 2000; Wolfer et al. 2004). Although recent studies suggest that stereotypical animals may experience psychological distress due to a putative common mechanism between stereotypy, schizophrenia, and autism, the relationship between stereotypic behavior and distress remains largely unknown and is in need of further study (Garner 2006; Garner and Mason 2002; Garner et al. 2003; Mason 2006).

Behavioral Signs of Stress

As mentioned in Chapter 2, stress is ubiquitous, it can occur in both pleasurable and aversive situations, and its physiological parameters are well established. Our knowledge of the behavioral correlates of stress, however, is considerably smaller. The behavioral changes observed in a stressed animal (as opposed to a distressed one) may be more subtle and variable, depending on the environmental conditions in which the behavior is being evaluated. In addition to recognizing an animal’s normal patterns of behavior, the observer must be well trained and knowledgeable about the normal species-specific behavior in the context of species, strain, gender, and physiological state. Types of behavior commonly explored to investigate the presence of stress include open-field activity, movements in an elevated plus maze, changes in innate behaviors (e.g., movement, grooming, feeding, sexual behavior), defensive behaviors (to external threats), and avoidance/escape (Beck and Luine 2002; for more references see Additional References).

PHYSIOLOGIC MEASURES OF STRESS AND DISTRESS

Endocrinological Parameters

One of the primary endocrinological systems involved in the stress response is the hypothalamic-pituitary-adrenal (HPA) axis, which reacts to stress by releasing glucocorticoids. Glucocorticoid levels can be used as indicators for the impact and strength of a stressor, with two caveats: (1) they cannot inform as to the type of stressor (positive or aversive) that stimulates the HPA and (2) most sampling procedures are themselves stressful to the animals, thereby confounding the measurements. Therefore, the assessment of distress based on glucocorticoid levels has limitations, especially under the unproven assumption that a certain glucocorticoid concentration indicates the presence of distress. Furthermore, stress or distress may exist without the concomitant activation of the HPA axis.

Glucocorticosteroids

The hypothalamic-pituitary-adrenal (HPA) axis, often referred to as the “stress response system”, plays an important role in an organism’s reaction to stressors. In response to a stressful situation the hypothalamic paraventricular nucleus synthesizes corticotrophin-releasing hormone (CRH), which is released into the median eminence and travels to the anterior pituitary where it causes the release of adrenocorticotropic hormone (ACTH) into the circulatory system. ACTH then acts selectively on specific receptors in the adrenal cortex, resulting in the release of glucocorticoids (cortisol or corticosterone), which mobilize energy stores in response to the perceived stress. When the stressor is removed or otherwise adapted to, glucocorticoids bound to receptors in the hypothalamus and pituitary initiate negative feedback that causes a decrease in the production and release of CRH and ACTH, thus terminating the hormonal response and completing the negative feedback loop (Meaney et al. 1996; Miller and O’Callaghan 2002). It should be noted that the HPA axis affects many hormonal and neural systems and plays a role in modulating the immune system.

Both positive and negative stimuli activate the HPA axis with short-and long-lasting effects. For example, exposure to novel stimuli may elicit exploratory behavior and brief activation of the HPA axis. In contrast, prolonged or repeated stressors, such as social separation of young from their mother, generally elicit strong protest reactions and activation of the HPA axis (Levine 2005; Levine and Mody 2003; Vogt et al. 1980). In the first instance, homeostasis is quickly restored, whereas in the latter case animals may be subjected to chronic HPA changes associated with neuroendocrine stress resistance that persists even after animals are returned to their mother (Parker et al. 2006).

Glucocorticoid levels (usually corticosterone in rodents, cortisol in other species) are used as indicators of the strength and impact of a stressor. Meaningful interpretation of these values, however, presents significant challenges. Glucocorticoids are typically measured in blood serum or plasma but can also be quantified in saliva, urine, feces, and hair (Abelson et al. 2005; for more references see Additional References).

Blood sampling requires venipuncture and possibly other stressful procedures such as handling, transport, capture, restraint, needle stick(s), and sedation. Unless animals are habituated to blood sampling, the method itself can activate the HPA axis thereby confounding assay results. A less stressful sampling method involves measuring glucocorticoid levels in hair. Hair samples are obtained by shaving hair from a particular region (usually the nape of the neck) and then shaving the hair once again after a defined period of regrowth (for a discussion of the method in primates see Davenport et al. 2006). Although this procedure requires the animals’ habituation, restraint, or sedation, unlike venipuncture the stress caused by hair collection does not confound the measurement. Similarly, saliva collection may impact animals less if they have been habituated to the process (Lutz et al. 2000). Urine and feces are collected after excretion from the body and so probably have the least impact, unless animals are not habituated to the special metabolic cages used for sample collection.

The type of sample obtained and the time frame it reflects may also influence results. Blood and saliva yield an index of stress at one brief moment in time (point samples) and are, therefore, influenced by circadian variation (Windle et al. 1998b), making it crucial that samples be collected at the same time each day (e.g., at the nadir of the rhythm). In contrast, urine and feces yield an index of stress reactivity over hours or possibly several days (steady-state samples) and are, therefore, less vulnerable to circadian variation. To date, only hair can provide a chronic index of stress covering a period of several months or more. Assessment of cortisol in hair is presumably unaffected by circadian variation and can be obtained at any time of day.

The above information is relevant for understanding and interpreting what might be revealed about stress and distress by examining the activation of the HPA axis. The two most likely ways to assess distress are to (1) examine differences in basal glucocorticoid levels and identify animals outside a “normal range” or (2) obtain glucocorticoid levels before and after the imposition of a stressor. The first approach is problematic because it assumes that a certain concentration of glucocorticoids indicates distress, although there is no scientific evidence to support this assumption. Moreover, as many sampling methods may themselves activate the stress response, there are no standardized ranges for basal glucocorticoid concentrations. The second approach is also problematic for two reasons: first, the putative relationship between the magnitude of change in glucocorticoid concentrations and distress has not been established; and second, both positive and aversive stimuli activate the HPA axis. Finally, the development of stress or distress is not necessarily associated with activation of the HPA axis, as hormonal changes are not necessarily present under all clearly stressful conditions. For example, animals that experience chronic neuropathic pain do not exhibit changes in circadian corticosteroid levels or oscillations in HPA responsivity to restraint, despite the presence of neuropathic pain markers (mechanical allodynia and hyperalgesia) and activation of central pain and stress circuits in the amygdala (Bomholt et al. 2005; Ulrich-Lai et al. 2006).

Other “Stress” Hormones

As is the case with the hormones of the HPA axis, stressors alter the secretion of other endocrine factors (e.g., prolactin, growth hormone, luteinizing hormone, α-melanocyte stimulating hormone [α-MSH], and oxytocin). Serum levels of these hormones can be effectively used to monitor the temporal dynamics of stress responses. While some (prolactin, α-MSH, oxytocin) increase during stress, others decrease (growth hormone, luteinizing hormone, prolactin), depending on the animal species and the physiological state in which stress occurs (Armario et al. 1984; for more references see Additional References). Due to the fact that these hormones are also released in response to other stimuli (e.g., suckling of young, ultradian or circadian variations), it is necessary to take into consideration and control for their normal patterns of secretion in order to accurately interpret their concentration levels. Moreover, their usefulness is subjected to the same limitations as discussed above, although chronic indwelling vascular catheters and automated blood collection systems may circumvent this limitation to some degree (Abelson et al. 2005; for more references see Additional References).

Neurological Parameters

Stressors activate the autonomic nervous system, specific brain areas, and various neurotransmitters, yet a cause and effect relationship has not yet been firmly established. Candidates for the role of a master integrator include the region of the amydgala and the neuropeptide corticotrophin-releasing factor.

The Autonomic Nervous System

Many different types of stressors cause the rapid activation of the sympathetic division of the autonomic nervous system (ANS) (Blanc et al. 1991; for more references see Additional References). This activation leads to increased cardiac output via increased heart rate and stroke volume; redistribution of blood flow from splanchnic, renal, and cutaneous vascular beds to active muscle; increased mobilization of nutrients; and increased heat production. Some stressors may also increase the activity of the parasympathetic division, affecting both core body temperature and the gastrointestinal system (e.g., disturbed intestinal absorption, gastric ulceration, colitis; Johnson et al. 2002; for more references see Additional References).

Direct monitoring of autonomic activity to assess the presence of distress in conscious animals is technically challenging, while indirect measures are somewhat easier to acquire (Li et al. 1997; Randall et al. 1994; Zhang and Thoren 1998). For example, telemetry in conscious, unrestrained animals is an effective method for the continuous monitoring of physiologic alterations in heart rate, respiration, blood pressure, ECG, and body temperature (Akutsu et al. 2002; for more references see Additional References). Once again, however, changes in these parameters do not necessarily indicate stress as they may result from nonstressful stimuli (e.g., circadian variations).

Neurotransmitters

Considerable effort has been directed at exploring the neurotransmitter systems and brain areas activated in response to stress as different insults activate separate but specific patterns of transmitters, modulators, and brain locations. An active area of investigation has been the identification of a basic core neural circuit that is activated by all stressors. A common approach has been to divide stressors into categories, hypothesizing that each category would activate a particular set of neural structures. The stressors are classified as either “processive” (i.e., stressors that require interpretation by higher brain structures) or “systemic” (i.e., stressors evoked by an immediate physiological threat; Herman and Cullinan 1997). However, the neural response has been heterogeneous for both these two as well as more narrowly defined categories. For example, Serrats and Sawchenko administered either lipopolysaccharide (LPS) or staphylococcal enterotoxin B (SEB) to rats in order to study brain activation patterns using c-fos induction as a measure of neural activity. Although both LPS and SEB activated some of the same brain structures, they produced distinctly different patterns of neural activation (Serrats and Sawchenko 2006).

Research indicates that there are few, if any, transmitters and modulators that are not activated in some region of the brain by some stressor. Mono-aminergic circuits, such as noradrenergic neurons, projecting from the locus coeruleus (Aston-Jones et al. 1996), serotonergic neurons projecting from the dorsal raphe nucleus (Lowry 2002), and dopaminergic neurons projecting from the ventral tegmental area (Pezze and Feldon 2004) are particularly stress-responsive. Research on neuropeptides has focused on CRH (Nemeroff and Vale 2005), endogenous opioids (Ribeiro et al. 2005), and neuropeptide Y (Heilig 2004). CRH may be the key central integrator of the stress response as CRH-containing neurons in the paraventricular nucleus of the hypothalamus are the primary common path in the neural regulation of both the HPA and autonomic responses to stressors. In addition, CRH is found in the central amygdaloid nucleus, an important node in regulating behavioral alterations in response to fear (see below for additional information on the fear response).

A somewhat different experimental approach to elucidate the interaction between stressors, neurotransmitters, the brain, and behavioral patterns has been to identify the neural circuit that mediates a specific behavior. For example, the neural circuitry involved in fear conditioning is well known. When a neutral stimulus, such as a light or a tone, is followed closely by an aversive stimulus such as a foot shock, it elicits a fear response. The association between the neutral and aversive stimuli is formed in the basal and lateral nuclei of the amygdala via an N-methyl D-aspartate (NMDA)-dependent long-term potentiation (LTP)-like process. The information is subsequently transmitted via the central nucleus of the amygdala to the proximate mediators of the particular behavioral and physiological constituents of fear (Davis and Whalen 2001) as, for example, to hypothalamic nuclei that regulate respiration. However, many of the fear-modulating factors alter the activity in structures that project to the top of the central nucleus of the amygdala (Sotres-Bayon et al. 2006), underscoring the amygdala as the key integrative site for fear.

In contrast, much remains to be learned about the neural control of defense responses to threat. For example, depending on circumstances, external threats such as the presence of a predator may result in flight, freezing, or other defensive behaviors. While the involvement of the midbrain periaqueductal gray is well known (Keay and Bandler 2002), inactivation of the brain areas typically responding to a threat from a predator reduces the defense response(s) elicited by predator odor or exposure (Blanchard et al. 2005; Canteras 2002), which may differentially impact predator defense and shock stimuli responses.

Immunological Parameters

The relationship between stress, distress, and the immune system is very complex. Acute stress usually activates innate immune responses (i.e., nonspecific immunity), but it may either increase or inhibit adaptive immunity. On the other hand, chronic stressors suppress adaptive immune responses. Activation of various types of immunity-related cells may be used as an indicator of immune system-stress interaction.

Signaling pathways link the brain with the immune system thereby allowing stress and distress to influence immune function. Immune system cells such as lymphocytes and macrophages express receptors for a variety of hormones and neurotransmitters, while the spleen and thymus are innervated by the autonomic nervous system (Felten et al. 1985; Sanders et al. 2001). The complex nature of these influences, however, does not permit simple generalizations such as “stress/distress suppresses immune function”. The immune responses elicited depend on the type, duration, and intensity of the stressor; the species, strain, age, and gender of the animal(s); and the aspect of immunity examined.

Acute Stress/Distress and Immunity

The principles that determine whether acute stressors inhibit or potentiate adaptive immunity are currently unknown. Nevertheless, adaptive immune responses that involve antigen recognition by T cells are invariably affected in acute stress. As Fleshner and colleagues have shown, rats stressed by inescapable tail shock failed to expand a subset of T cells and produced reduced quantities of IgM and IgG antibodies (Fleshner et al. 1995). In contrast, restraint at the time of immunization was shown to facilitate immunological memory due to elevated counts of memory and effector helper T cells (Dhabar and Viswanathan 2005).

In contrast, the innate immune response is most often enhanced in response to acute stress, including during stress conditions identical to those that interfere with specific immunity (Deak et al. 1999; Fleshner et al. 1998). A variety of stressors have been reported to increase macrophage function and elevate levels of known pro-inflammatory mediators such as interleukin-1 and tumor necrosis factor (O’Connor et al. 2003). Acute phase protein levels are similarly elevated as these cytokines also initiate the acute phase response. In addition, acute stressors potentiate or even directly elicit the sickness response, a set of behavioral and physiological changes (including fever, increased sleep, reduced social interaction and physical activity) that occur during infection (Dantzer 2004; Maier and Watkins 1998).

Chronic Stress/Distress and Immunity

Chronic or repeated stress has been shown to suppress adaptive immunity (Tournier et al. 2001), but not much is known of its effects on innate immunity. Studies looking at the effects of stress on disease outcome rather than on immune responses have shown that stress can either increase or decrease disease severity depending on conditions and variables measured. Disease progression can be either inhibited or facilitated depending on the precise occurrence of the insult, as the timing of stressor exposure relative to disease onset is often critical (Johnson et al. 2006).

In addition to assays that measure T-cell proliferation, natural killer cell cytotoxicity, or B-cell activation and antibody production as indicators of adaptive immunity-stress interaction, one can also measure the capacity of polymorphonuclear cells to produce a respiratory burst in vitro. Research has shown that the functional capacity of leukocytes from stressed animals is suppressed, thus diminishing their “coping capacity” (as defined by the production of oxygen free radicals; McLaren et al. 2003).

ASSESSMENT OF DISTRESS

Clinical signs interpreted through relevant animal behavior and physiological states are the most reliable distress measures. Distress evaluation is crucial when research animals are purposefully exposed to stressful conditions or when animals appear distressed unexpectedly. The assessment andsubsequent interventions should involve researchers, veterinarians, andtechnicians and the team should continue its collaboration to develop an intervention strategy once the assessment is completed.

Assessment of distress varies in relation to the species, husbandry conditions, and experimental protocol employed as well as with each individual animal, and is most effectively achieved by the collection of multiple behavioral and physiological parameters and the use of a team approach that includes researchers, veterinarians, and animal caretakers/technicians. While the most reliable distress measures are the clinical signs previously described, identification and interpretation of these results depends on a solid foundation of knowledge of animal behavior and may likely require special training of relevant personnel.

Distress evaluation becomes crucial in two contexts: (1) when the research protocol calls for the animals’ exposure to stressful situations known to produce distress; and (2) when any animal unexpectedly shows signs of distress. In the first case, the experimental protocol approved by the Institutional Animal Care and Use Committee (IACUC) generally includes procedures and decision algorithms for distress management. The appropriate intervention will be informed by the stressor’s duration and intensity as well as some of the animal’s individual characteristics (e.g., species, age, gender). In the second case, additional assessments and monitoring may be necessary.

Once an animal has shown initial signs of distress, there should be immediate communication between the primary investigator, the veterinarian, and the animal care staff to determine whether the distress is related to the study (whether anticipated or unanticipated) or further investigation into its cause is required. The discussion should also include potential interventions (see Chapter 4) and their effects on the objectives of the research project, as they may introduce unknown variables into the study. Options may include removal of the animal from the study population or euthanasia, depending on the severity and prognosis of the distress insult. It is essential to maintain a collaborative relationship and dialogue between those responsible for the care and welfare of the animal throughout the assessment.

The next step is to identify the etiology or trigger of the distress episode by performing a thorough examination of the animal and its environment. The investigation should begin by obtaining information regarding the animal’s species, strain, age, gender, and reproductive status. An effective examination should account for species-related differences among natural behaviors, learning abilities, and levels of intelligence, in addition to the ways animals use their senses and communicate. Some species, strains, or breeds are predisposed to certain behavioral problems or have certain behavioral phenotypes, or an individual animal’s characteristics may affect both the development and alleviation of its distress.

Physical examination and appropriate diagnostic tests for all distressed animals can help determine whether an underlying medical condition is the primary cause of distress. A review of the medical and investigator records is an important part of the process, as background information and history may enable the veterinarian to determine whether preexisting medical conditions were resolved. An examination of colony records and interviews with animal care staff may help pinpoint possible environmental triggers. Other causes for consideration include husbandry and handling procedures, the behavior of other animals in the room, temperature variances, noises, vibrations, and odors, as well as any specific research-related (i.e., protocol specifications) or investigator-related (i.e., disturbance of housing routine) activities.

Clinical signs should initially be examined in a relatively undisturbed animal in order to assess the animal’s natural unprovoked behavior (e.g., appearance, behavior, posture, respiratory rate and pattern). The animal showing signs of distress is then observed more closely followed by gentle handling and examination to measure body weight, body condition and temperature, heart rate, dehydration, and alertness. For some parameters, the degree of change from the normal scale is a useful evaluation indicator, the assumption being that the greater the deviation from normalcy, the greater the impact. For example, an animal may lose 5, 10, 20, or even 40 percent of its body weight, or its temperature may rise (or fall) by several degrees above (or below) normal. Clinical assessments can also be supplemented by video records of the animal in the colony room or laboratory testing environment.

A team approach during assessment is crucial. The assessment of distress and subsequent interventions should involve researchers, veterinarians, and technicians, as they are often the first to observe signs of distress in individual animals. The team should similarly collaborate to develop an intervention strategy once the assessment is completed.

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      Page 38 While some (prolactin, α-MSH, oxytocin) increase during stress, others decrease (growth hormone, luteinizing hormone, prolactin), depending on the animal species and the physiological state in which stress occurs (Armario et al. 1984).

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      Page 39 Moreover, their usefulness is subjected to the same limitations as discussed above, although chronic indwelling vascular catheters and automated blood collection systems may circumvent this limitation to some degree (Abelson et al. 2005).

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      Page 39 Many different types of stressors cause the rapid activation of the sympathetic division of the autonomic nervous system (ANS) (Blanc et al. 1991).

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      Page 39 Some stressors may also increase the activity of the parasympathetic division affecting both core body temperature and the gastrointestinal system (e.g., disturbed intestinal absorption, gastric ulceration, colitis; Johnson et al. 2002).

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      Page 39 For example, telemetry in conscious, unrestrained animals is an effective method for the continuous monitoring of physiologic alterations in heart rate, respiration, blood pressure, ECG, and body temperature (Akutsu et al. 2002).

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Footnotes

1

It is now well established that there are marked individual differences in reactivity among nonhuman primates when animals are exposed to novel situations or to relatively minor changes in their social or physical environment. Some rhesus monkeys (~20%) respond to relatively mild environmental stressors with unusual behavioral disruption and physiological arousal including prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by plasma cortisol and adrenocorticotropic hormone (ACTH), increased cerebrospinal fluid levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol, heightened sympathetic nervous system activity as reflected in altered heart rate rhythms, and abnormal immune system response (Coe et al. 1989; Higley et al. 1991). The same stressors elicit only minor behavioral reactions and transient physiological responses in the remainder of the population (Suomi 2004).

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