Review
Neuroendocrine mechanisms of innate states of attenuated responsiveness of the hypothalamo-pituitary adrenal axis to stress

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Abstract

Neuroendocrine responses to stress vary between sexes and reproductive states and are influenced by the type of stressor. Stress responses are attenuated in some physiological states, such as lactation and conditions of low visceral adipose tissue. Moreover, some individuals within a species characteristically display reduced stress responses. The neuroendocrine mechanisms for stress hyporesponsiveness are likely to include reduced synthesis and secretion of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus as a result of enhanced glucocorticoid negative feedback and/or reduced noradrenergic stimulatory input from the brain stem. A major limitation of research to date is the lack of direct measures of CRH and AVP secretion. Attenuated stress responsiveness is also commonly associated with reduced pituitary responsiveness to CRH and AVP. The possible roles of inhibitory central inputs to CRH and AVP neurons and of oxytocin and prolactin in attenuating the HPA axis responses to stress are unknown.

Introduction

Stress is a complicated physiological mechanism that embodies a range of integrative physiological and behavioral processes that occur when there is a real or perceived threat to homeostasis. While it is generally accepted that these processes are adaptive, designed to re-establish homeostasis and allow coping, it is also apparent that inadequate or excessive and/or prolonged activation of stress systems can disturb normal physiological and behavioral function. This can result in a range of adverse consequences such as depression, impaired cognition, cardiovascular disease, impaired immune function with increased vulnerability to disease, impaired growth and reproductive function, osteoporosis, diabetes, dementia and reduced life expectancy [22], [24], [220], [221], [236], [238]. Despite a vast literature on stress responses in a range of species, there is still much to be learned about the mechanisms of stress responses so that strategies can be developed to prevent and overcome stress-induced disorders.

Under some physiological conditions, responses to stress are naturally attenuated while still being adequate to allow adaptation to adverse threats to homeostasis. There are various physiological states where this occurs but one of the best known examples is seen in the female during late pregnancy and lactation. It is also apparent that stress responses vary between humans and animals with differing amounts of visceral adipose tissue. Lean individuals generally display reduced responses to stress. Furthermore, neuroendocrine and behavioral responses to stress often vary substantially between individuals, within the same species, such that some individuals inherently display reduced responsiveness of the stress systems, including the hypothalamo-pituitary adrenal (HPA) axis. An understanding of the neuroendocrine mechanisms that underlie natural physiological states of reduced stress responsiveness, defined here as stress hyporesponsiveness, will provide knowledge that could be utilized to generate physiological treatments for people at risk of illness due to chronic stress and/or disorders of the stress systems. This is conceptually attractive because the most effective mechanisms to suppress stress responses will undoubtedly be those that the body itself uses. In this review we explore some of the mechanisms of stress hyporesponsiveness in lactating females, lean individuals and individuals that display naturally attenuated neuroendocrine responses to stress. Our focus is upon the regulation of the HPA axis.

Section snippets

Physiological responses to stress

The intrinsic or extrinsic stimuli, whether real or perceived, that challenge homeostasis, are commonly termed stressors. Stressors are many and varied (e.g. psychological, physical, surgical trauma, strenuous exercise, undernutrition) and activate a range of physiological systems, the most commonly studied being the HPA axis (Fig. 1) and the sympathoadrenal system. Activation of the HPA axis results in stimulation of parvocellular neurons of the paraventricular nucleus (PVN) of the

Physiological states can influence stress responsiveness

Neuroendocrine responses to stress vary between sexes and in different physiological states. It is well established for various species that there are sex differences in responses of the HPA axis to stress and it has been proposed that these are due principally to the influence of the sex steroids [64]. Most research has been conducted with rodents where it has generally been found that females have higher basal circulating levels of cortisol [30], [97] and respond to stress with greater

Lactating females

It has been consistently found in many species that lactating females show attenuated neuroendocrine responses to stress [115], [235], [254] and alleviated anxiety-related behaviors [143], [235], [240]. Extensive studies in rats have revealed that there is alteration of both the basal and stress-induced activity of the HPA axis during lactation. Thus, in non-stressed lactating rats, concentrations of ACTH and corticosterone are elevated [53], [113], [212], [251], [266] due predominantly to a

Mechanisms for attenuated responsiveness of the HPA axis

The mechanisms for stress hyporesponsiveness in different physiological states are not well understood but there is good evidence for modification at each level of the HPA axis. Mechanistic studies have been carried out on lactating women and animals, but little has been done to determine the mechanisms of hyporesponsiveness in humans or animals with different levels of visceral adiposity or with naturally different responses to stress. It is evident that altered activity of the HPA axis may be

Conclusions and future directions

For an organism to survive and be healthy, the ability to elicit appropriate physiological and behavioral responses to stressful situations is paramount. If such responses are inadequate or excessive, physiological dysfunction occurs at various levels. An understanding of the mechanisms by which stress systems are regulated is essential in the development of strategies to overcome and prevent stress-induced disorders. Research in this area is complicated, however, by the fact that activation of

Acknowledgments

We thank Astrid Rivalland for her constructive feedback, provision of unpublished data and assistance with the figures and Kate, Molly and Sharon Tilbrook for assistance with proofing the manuscript.

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