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Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology University of Bristol Bristol BS1 3NY United Kingdom
Address all correspondence and requests for reprints to: David S. Jessop, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol BS1 3NY, United Kingdom. E-mail: david.jessop{at}bristol.ac.uk.
Stress is now recognized as a significant contributory factor in the cause and progression of many diseases (1, 2, 3). The sympathetic nervous system (SNS) and the hypothalamo-pituitary-adrenocortical (HPA) axis, the principal pathways that respond to stress, exert tonic inhibitory control over the immune system through multiple coordinated networks involving glucocorticoids, catecholamines, neuropeptides, and cytokines (4, 5, 6). Stress can result in a resetting of immune responses with consequent impaired ability of the organism to mount an effective defense after onset of infection or chronic inflammatory disease. The exacerbatory effects of stress on many inflammatory diseases are well documented, although the evidence is rather more anecdotal than scientific. Paradoxically, protective effects of stress on inflammation have been reported (7, 8). A major challenge in the field of psychoneuroimmunology lies in defining the highly complex interactions among the SNS, HPA axis, and immune system to elucidate the selective effects of stress on disease processes.
One very important aspect of this research is establishing the relationship between the effects of early life stress and predisposition to disease in adulthood. The group of Neumann and colleagues (9, 10) in Regensburg, Germany, has previously shown that in experimentally induced colitis, a rodent model of inflammatory bowel disease, mice subjected to chronic over-crowding and social defeat stress had increased severity of inflammation. This team has now developed a sophisticated paradigm of repeated maternal separation (MS) stress in neonatal mice, followed by chronic subordinate colony (CSC) stress in adulthood (11). The paper, published in this issue of Endocrinology, contains two key observations: 1) MS enhanced vulnerability to CSC, which is the first empirical demonstration of a relationship between early life stress and a maladaptation to chronic stress in adulthood; and 2) combined exposure to MS and CSC exacerbated the severity of colitis in adult rats, compared with the effects of MS or CSC alone, demonstrating that an adverse early life event can intensify the deleterious effects of chronic stress. The latter phenomenon was associated with an impaired ability to secrete corticosterone and also an increased secretion of proinflammatory cytokines interferon (IFN)-
, IL-6, and TNF. This has the potential to create a systemic proinflammatory milieu that may underlie the increased severity of disease.
Negative experiences in childhood can disrupt behavioral and physiological adaptive responses to subsequent acute stressors later in life and may increase the risk of developing inflammatory disorders (12). The paper by Veenema et al. (11) addresses important questions about the long-term effects of early life stress on subsequent chronic stress and inflammatory disease. The authors conclude that adverse early life experiences may make individuals more vulnerable to chronic stress later in life and consequently increase the risk of developing chronic inflammatory disease. But not all stressors elicit a negative response. Clearly it is important that children can mount a healthy, robust response to the many stressors encountered during their development, and it would be most undesirable (and evolutionarily highly unlikely) if all of these responses to acute stressors were to predispose toward serious illnesses in adulthood. One of the major questions arising from this field of research is, therefore, what defines a negative early childhood experience, compared with a healthy response to an environmental challenge, and once that distinction has been made, is there any way to intervene to mitigate or prevent long-term pathological consequences of a negative stress experience?
The answer may lie in the changes in corticosterone and proinflammatory cytokines IFN-, TNF, and IL-6, which the authors observed to be associated with increased inflammation in their colitis model. Corticosterone was decreased in MS-CSC mice, which consequently developed more severe inflammation, whereas IFN-, TNF, and IL-6 were all increased. Long-term alterations in neuroendocrine and cytokine responses have previously been reported subsequent to an acute stressor (13, 14). These changes may be associated with sensitization or desensitization of HPA axis activity, depending on whether the experimental paradigm is composed of homotypic or heterotypic stressors (15). Induction of an acute stress response either neonatally (16) or in adulthood (8, 17) can protect against the onset of inflammatory disease in mature rats, but protection is dependent on the timing of the stressor relative to induction of inflammation and whether plasma cytokine and corticosterone changes after the stressor exhibit a pro- or antiinflammatory profile (18). Thus, the type and severity, and also the timing of the stressor relative to the onset of disease, may be crucial in determining pathophysiological consequences. A negative stressor may be of the type and severity that precipitates an alteration in circulating glucocorticoids and cytokines with a bias toward a proinflammatory milieu. Therefore, it would be of great interest to measure HPA axis activity and cytokine profiles in MS mice throughout the 19-d period of CSC to determine whether there is an alteration in the balance of corticosterone and cytokine secretion. If there is, at which point does it begin to favor a proinflammatory environment, i.e. when do corticosterone levels begin to decline (and proinflammatory cytokines increase) and is this alteration in the pro- and antiinflammatory balance correlated with consequent severity of colitis?
Learning more about the nature of an early life stressor, in particular the neuroendocrine-immune fingerprint of compounds secreted in response to specific stressors, may go some way toward predicting the long-term consequences of a stressful episode on inflammation. In a separate but related context, Straub and Besedovsky (19) proposed the hypothesis that a relatively minor and transient infection may perturb the major systems that maintain homeostasis such that immune, nervous, and endocrine coordinates are reset at a level that can sensitize susceptible subjects to future immune challenge and predispose to chronic inflammatory diseases. Given that infections can simulate stress by activating the HPA axis and SNS as well as the immune system (20, 21), this hypothesis may be extended to fit stressful events in early life, with similar consequences for disease onset and progression. Identification of children subjected to severe stressful episodes, in conjunction with other information such as hereditary risk factors for conditions such as arthritis or asthma, would enable them to be monitored later in life for early markers of inflammation, offering the scenario of therapeutic intervention at the earliest opportunity.
Although not measured by Veenema et al. (11), their paper has implications for the role of central neurotransmitters in chronic inflammatory disease. Increased levels of anxiety were observed in adult mice after MS or CSC. In another study, rats subjected to MS exhibited altered responses to social defeat stress in adulthood along with alterations in central levels of serotonin (22). Anxiety and depression have been associated with major dysfunctions in serotonergic and catecholaminergic pathways within the central nervous system. Evidence has emerged that manipulation of these neurotransmitters within the brain can have profound effects on the development of inflammation in a rat model of arthritis (23) and in patients with rheumatoid arthritis (24). Therefore, it would be of some interest to measure changes in neurotransmitters within the brains of MS-CSC mice to determine any correlation between neurotransmitter levels and subsequent severity of colitis. Studies of this nature on coordinated neuroendocrine and neurotransmitter responses to early life stress may lead to a better understanding of how central neurotransmitters can influence peripheral inflammatory processes, a field of research that barely existed 10 yr ago.
One further important issue highlighted by Veenema et al. (11) is their proposal that the MS-CSC mice with decreased corticosterone secretion may represent a suitable model to study human illnesses associated with chronic hypocortisolism such as chronic fatigue syndrome, fibromyalgia, posttraumatic stress disorder and chronic pain (although the literature on hypocortisolism in these conditions is by no means consistent). Elevated corticotrophin-releasing factor mRNA in the paraventricular nucleus of the hypothalamus in MS-CSC mice is consistent with reports of increased corticotrophin-releasing factor production in posttraumatic stress disorder (25). Research into these syndromes in humans has been limited by the lack of a reliable animal model. The MS-CSC mouse model of hypocortisolemia may serve as an appropriate model to study the complex neuroendocrinology underlying these hypocortisolemic disorders and may permit testing of therapeutic interventions such as glucocorticoid replacement or receptor antagonists to normalize cortisol secretion.
Finally, one major difficulty in relating early life stress to risk of disease in humans is that it is very difficult to identify and quantify the nature and intensity of the stressor in childhood other than in extreme cases and draw any meaningful etiological relationships with probability of illness in adulthood. Most data relating adult illness to early childhood events derive from retrospective studies, and predictive data from longitudinal programs following children into adulthood are rare. The usefulness of animal studies in this area is that they can provide us with well-defined models of early life stress, which can be extrapolated to guide our design of testable hypotheses and protocols for prospective stress studies in humans.
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Received March 6, 2008.
Accepted for publication March 7, 2008.
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