Stress, the HPA axis, and nonhuman primate well-being: A review

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Abstract

Numerous stressors are routinely encountered by wild-living primates (e.g., food scarcity, predation, aggressive interactions, and parasitism). Although many of these stressors are eliminated in laboratory environments, other stressors may be present in that access to space and social partners is often restricted. Stress affects many physiological systems including the hypothalamic–pituitary–adrenocortical (HPA) axis, which is the focus of this review. The glucocorticoid, cortisol, is the ultimate output of this system in nonhuman primates, and levels of this hormone are used as an index of stress. Researchers can measure cortisol from several sampling matrices that include blood, saliva, urine, faeces, and hair. A comparison of the advantages and disadvantages of each sampling matrix is provided to aid researchers in selecting an optimal strategy for their research. Stress and its relationship to welfare have been examined in nonhuman primates using two complimentary approaches: comparing baseline cortisol levels under different conditions, or determining the reactivity of the system through exposure to a stressor. Much of this work is focused on colony management practices and developmental models of abnormal behaviour. Certain colony practices are known to increase stress at least temporarily. Both blood sampling and relocation are examples of this effect, and efforts have been made to reduce some of the more stressful aspects of these procedures. In contrast, other colony management practices such as social housing and environmental enrichment are hypothesized to reduce stress. Testing this hypothesis by comparing baseline cortisol levels has not proved useful, probably due to “floor” effects; however, social buffering studies have shown the powerful role of social housing in mitigating reactions of nonhuman primates to stressful events. Models of abnormal behaviour come from two sources: experimentally induced alterations in early experience (e.g., nursery rearing), and the spontaneous development of behavioural pathology (e.g., self-injurious behaviour). Investigators have often assumed that abnormal behaviour is a marker for stress and thus such monkeys are predicted to have higher cortisol levels than controls. However, an emerging finding is that monkeys with abnormal behaviour are more likely to show a pattern of lowered cortisol concentrations which may reflect either an altered set point or a blunting of the stress response system. These findings parallel human clinical studies demonstrating that neuropsychiatric disorders may be associated with either increased or decreased activity of the HPA system, depending on the aetiology and manifestation of the disorder and their potential influence in provoking allostatic shifts in system functioning.

Introduction

It is commonly assumed that laboratory environments are stressful for nonhuman primates, in part because of spatial and social constraints. For example, rhesus monkeys typically live in large socially complex troops with large home ranges whereas in the laboratory, they are often maintained in relatively smaller environments with limited companionship (usually pair housing). However, life in nature is also stressful. Free-ranging rhesus monkeys routinely experience stressful situations that include severe aggression during the breeding season, dominance interactions, disease, parasitism, predation, and food shortages leading to food competition (Aureli et al., 1999, Beehner et al., 2005, Sapolsky, 1987). Thus, stress is a ubiquitous feature of primate life whether in the laboratory or in the wild. The goals of this article are to briefly review the concept of stress, examine and evaluate the various ways to measure stress with a specific focus on the hypothalamic–pituitary–adrenocortical (HPA) axis, and identify possible relationships between stress and well-being in laboratory housed nonhuman primates.

Stress can be defined as a perturbation of an organism's physiological and/or behavioural homeostasis as a result of exposure to certain events or situations (termed stressors). Perturbations can occur in response to rewarding events (called eustress); however, researchers have focused much more intensively on perturbations resulting from aversive events (called distress) (Selye, 1975). What constitutes an “aversive” event for an animal is often determined by how we assess the event, since self-report by nonhuman primates is not possible.

In many instances, the perturbation (hereafter referred to as the stress response) is brief and homeostasis is restored. In other instances, the stressor may be chronic and homeostasis is not restored, producing physiological dysregulation (i.e., recurring stress responses). Alternatively, a persistent challenge to homeostasis may, over time, lead to allostasis, which is a readjustment of the physiological system in which the homeostatic baseline has been shifted to account for the changing conditions (e.g., increased basal cortisol levels in the absence of a stressor) (Sterling and Eyer, 1988). But allostasis may inflict its own cost in terms of increased energy demands on the organism. This increased cost or demand (sometimes conceptualized as “wear and tear” on the body) has been termed allostatic load (McEwen, 1998, Stewart, 2006).

The HPA axis is one of the many systems that are activated during exposure to stressful events. Because activation results in the production of cortisol, the primary glucocorticoid of human and nonhuman primates alike, the concentration of this hormone is often used as an index of the stress response (O’Connor et al., 2000). Two different approaches can be taken in assessing HPA axis activity. In the first approach, baseline samples of cortisol are collected to answer questions such as what is the relative “stressfulness” of different housing conditions. In this case, researchers measure cortisol levels in animals living under these different conditions without imposing the subjects to any physiological or behavioural challenge. Two key factors determine the validity of the data obtained from such studies. First, the animals must be well adapted to their respective living conditions for the comparison to be valid. Second, collection of the biological samples from which the cortisol will be measured must be minimally disruptive, otherwise the collection procedure itself may produce stress and skew the data (see discussion below on plasma/serum sampling). In the second approach, a stressor is imposed on the subjects to determine the HPA axis response to the challenge. Because nonhuman primate research is frequently limited with respect to availability of animals, stress response studies are often performed using a within-group design in which every subject contributes one or more baseline (i.e., pre-exposure) samples and one or more stress (i.e., during- or post-exposure) samples for cortisol measurement. The stressor may be relatively short, lasting for minutes (e.g., injections), an hour (e.g., exposure to novelty or brief separations from companions), or it may involve longer time periods of months or more in which the effects of exposure to an environmental change are examined (e.g., transfer from social to individual cage housing). Regardless of the time frame, the relevant comparison is how the cortisol levels in individual animals changed in response to the stressor.

One of the traditional ways of measuring the stress response has been to assay cortisol in plasma or serum, with the later advent of salivary measurement. These procedures are particularly useful for measuring the acute (minute by minute) response to a stressor. In recent years, however, researchers have focused on how organisms cope and adapt to long-term stressors. In animals, this effort is concentrated on improving welfare both by increasing the quality of captive environments for laboratory animals and by assessing the impact of ecological factors such as industrial pollutants on free-ranging animals. In humans, there is considerable interest in understanding the role of the HPA axis in the aetiology of neuropsychiatric disorders and in examining the effects of long-term stressors such as unemployment and ecological disasters (e.g., earthquakes and tsunamis) on HPA axis activity. The recently developed technique of measuring cortisol in hair has revolutionized our ability to assess long-term HPA activity and to use this information to evaluate the effects of chronic stress exposure (Davenport et al., 2006).

Section snippets

Methodological issues in measuring the HPA stress response

Cortisol can be obtained from many different fluid compartments and body excreta. Today laboratory scientists and field researchers have several options for measuring stress responses in nonhuman primates that include assaying cortisol in serum/plasma, saliva, urine, faeces, and hair. Each of these sampling matrices has advantages and disadvantages, and these must be considered in determining which sampling matrix is best for answering the research questions at hand, such as evaluating the

Stress and well-being in nonhuman primates

The stressfulness of the captive environment, as assessed through HPA axis activity, has been examined in many different contexts. However, much of the research has focused on colony management practices, enrichment, social experiences, and on the relationship between abnormal behaviour and HPA axis activity. Each of these areas differs in terms of the proposed hypotheses and predictions. As we will show below, the HPA axis is influenced by many different factors including variation in early

Stress assessment and colony health management

Given the widespread use of cortisol levels as an index of physiological stress, the question arises as to whether cortisol measurements have a role in routine colony management practices. An important objective of primate colony managers and veterinarians is to ensure that the animals under their care enjoy physical health and psychological well-being. The following criteria have been proposed for the assessment of overall health and well-being: (1) the primates are in good physical health for

General conclusions

The preceding discussion has revealed some of the complexities related to using the HPA axis as an index of stress or, conversely, well-being in nonhuman primates. We have summarized the various sample matrices and collection techniques that can be used to study the HPA system, thereby providing investigators with information that should be helpful in choosing the best methods for answering specific research questions. However, it is imperative that researchers keep in mind that this system is

Acknowledgement

The preparation of this review was supported by federal grants from the National Institutes of Health, USA (8R24OD011180-15 to MAN and RR000168 to the New England Primate Research Center).

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