Info

Environmental Stressor

Immune Stressor

HPA Axis

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Sympathetic Nervous System

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t

Adrenal Medulla

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t

Brain Noradrenergic Systems

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Brain Dopaminergic Systems

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Î*

Brain Serotonergic Systems

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t

Brain Tryptophan

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*In some cases only.

*In some cases only.

not every specific aspect of sickness is necessarily adaptive at any given time.

Considering sickness behaviour as a relatively nonspecific behavioural defence strategy provides a rationale for interpreting the many non-immunological triggers that elicit something closely resembling sickness behaviour. For example, it has been shown that in the young of many species, maternal separation elicits a profile of behavioural change that in the past was considered to reflect despair [60]. This pattern of behaviour closely resembles sickness behaviour, including decreased activity, reduced social behaviour and induction of a crouched posture. Moreover, in common with other stressors, maternal separation activates the hypothalamo-pituitary adrenocortical (HPA) axis. Based on these observations, Hennessy and colleagues suggested that maternal separation induces "stress-induced sickness behaviour" [60],

Others have shown that over-training (i.e., excessive exercise) in athletes is associated with both increases in cytokines and a sickness behaviour profile, possibly because the musculoskeletal stress induces an inflammatory response [61]. Over-training is also associated with activation of the HPA axis, indicative of stress. It has been suggested that this over-training syndrome is a protective state that occurs during stress [61]. Given the various ways in which sickness behaviour can be induced, this profile of behavioural changes may be more than a response to immune activation, and may be a behavioural profile that can be elicited in many circumstances, especially stressful ones.

The presence of sickness-like behavioural profiles in maternal separation and over-training probably applies to other forms of stress. Most humans would consider that being sick is stressful. The behavioural similarities are obvious. Under stress, animals may eat less, be less interested in sexual activity, in exploring their environment, etc. Thus from a behavioural perspective, sickness can be considered a form of stress.

The parallels go beyond behaviour. Dunn et al. showed that infection with influenza virus induced a pattern of physiological responses that closely resembled responses to environmental stressors in activating the HPA axis, and certain neurochemical systems in the brain (noradrenergic and serotonergic) long associated with stress [62] (see Table III). Moreover, the responses to influenza virus resembled very closely those to peripheral (and intracerebral) administration of IL-1 and LPS [63],

The similarities between the physiological responses to IL-1, LPS and viral infection and environmental stressors are extensive [64], so that such agents have sometimes been referred to as "immune stressors". Both induce a profound activation of the HPA axis, elevating secretion of corticotropin-releasing factor (CRF) from the hypothalamus, resulting in secretion of adrenocorticotropin (ACTH) from the pituitary, and glucocorticoids from the adrenal cortex.

Moreover, the sympathoadrenal system is also activated by immune challenges, elevating circulating concentrations of the catecholamines, noradrenaline and adrenaline, although to a lesser extent than most environmental stressors. In addition, the responses within the brain are similar. In all cases, there is a widespread activation of cerebral noradrenergic systems, although the ventral (hypothalamic) system is activated by pathogens, IL-1 and LPS to a greater extent than with environmental stressors. In all cases, there is also an increase in brain tryptophan and serotonin metabolism. Cerebral CRF systems other than those associated with ACTH secretion also appear to be activated. The only major difference between immune challenges and environmental stress is in brain dopaminergic systems, which are activated less frequently during immune challenges (although they are affected by LPS, but minimally by IL-1), and in patterns distinct from those observed with environmental stressors, which tend to affect mesocortical and mes-olimbic projections preferentially [64]. Thus an immune challenge can be regarded as a stressor from a physiological as well as a behavioural perspective, and it may be that sickness behaviour is but one example of a broad category of stress-related physiological changes.

A further interesting aspect is the relationship between clinical depression and sickness behaviour. Several authors have noted that the profile of behaviour seen in patients with major depression parallels that of sickness behaviour [65-67]. The cardinal symptoms of depression are depressed mood, and anhedonia (the inability to take pleasure in normally pleasurable activities). In fact, depression has been likened to a chronic state of stress. Behaviourally, depression can be associated with decreases in activity, decreased feeding, decreased sexual activity, decreased interest in a variety of activities and altered sleep patterns, behavioural changes that parallel sickness behaviour. Moreover, there are marked parallels in behaviour during stress and depression [68], In addition, a majority (about two-thirds) of severely depressed patients exhibit a hyperactive or hyper-responsive HPA axis, and there is important evidence for a hyperactivity of brain noradrenergic systems, which are activated in stress [68,69],

Very specific parallels have been drawn between depression and the actions of LPS and IL-1 [65,66], This has led to a cytokine hypothesis of depression which postulates that increased cytokine production from a variety of causes can induce the symptoms of depression [66], Consistent with this, increased circulating concentrations of certain cytokines have been observed in depressed patients. However, the parallels between LPS- and IL-1-induced sickness behaviour are imperfect. Depressed patients often exhibit hyperphagia, rather than hypophagia, and the sleep abnormalities in depressed patients are more commonly the inability to sleep than the increased duration of slow-wave sleep observed with IL-1 and LPS [70], Moreover, plasma cytokines are not elevated in all depressed patients, just as the HPA axis is not elevated in all depressed patients. It is entirely possible that some chronic diseases induce depression and elevate cytokines, and that in some cases the cytokines contribute to the depression. However, it is clear that cytokines are not the sole cause of depression. Nevertheless, there are clear parallels, both behaviourally and physiologically between stress, sickness and depression.

Clearly there are multiple parallels between immune and environmental stressors. An apparent difference between the stress induced by infection and environmental stressors is that the activation of a cytokine response is part of the immune system's response to an unrecognised antigen. However, over-training also appears to increases circulating concentrations of cytokines [61 ] and through activation of an acute phase response [60], maternal separation may also do so. This observation is consistent with evidence that restraint and footshock elevate the circulating concentrations of certain cytokines (especially IL-6) [71-74]. Such changes in plasma cytokines do not appear to be responsible for the physiological and behavioural changes [75]. A possible explanation for the plasma cytokine (e.g., IL-6) response induced during stress could be that it primes the immune system for a response that may be needed when individuals are under stress, or that it reflects such a priming. By adopting an appropriate behavioural profile and increasing cytokine secretion, the organism may be better prepared to counter pathogens.

This suggestion is congruent with evidence that meal intake activates the mucosal immune system. Hansen et al. have shown that meal consumption results in increased levels of neutrophils and granulocytes and reduced levels of lymphocytes [76]. These authors suggested that these changes reflect cell migration that supports immune responses in the gut. Based on these findings, one could speculate that because the consumption of a meal puts the organism at risk of pathogen exposure, an immune system response to eating minimizes the threat of pathogens ingested during the meal. Similarly, studies have shown that acute restraint produces both a stress response and immunoenhancement, as measured by increased leukocyte trafficking [77,78]. Thus it can be speculated that behaviours that induce an acute stress response may facilitate immune responding. Indeed, Dhabhar [78] speculated that "a hormonal alarm signal released by the brain upon detecting a stressor, may "prepare" the immune system for potential challenges (wounding or infection) which may arise due to the actions of the stress-inducing agent (e.g., a predatory or attacker)" (p. 789). Perhaps the stress-related increases in certain cytokines are such a signal.

The information reviewed above suggests that it may well be that the behavioural responses induced by pathogens are adaptive responses serving to facilitate survival as originally described by Hart [2]. Given the arguments that events like maternal separation, excessive exercise and depression can induce sickness-like behaviour, we may need to extend our thinking about sickness behaviour beyond Hart's original analysis. Stress elicits a behavioural profile resembling sickness behaviour, and increases the secretion of certain cytokines. Thus it is suggested that the immune system is sensitive to the behaviours of the organism, and perhaps can be activated in a manner that minimizes the possible deleterious effects of these behaviours. For example, it can be speculated that mucosal immune activation after a meal minimizes possible deleterious effects of eating, and "sickness behaviour" during maternal separation might prevent activities that result in an immunological challenge. The behavioural changes induced by immune activation likely facilitate survival and they may do so as part of a general, nonspecific response to stressors, immunological or otherwise, that serves to protect the animal.

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