The hypothalamic–neurohypophysial system regulates the hypothalamic–pituitary–adrenal axis under stress: An old concept revisited
Introduction
In its natural habitat, Rattus norvegicus is frequently confronted with potentially harmful situations, such as encounters with dominant conspecifics and predators [144] or natural disasters. The ability to cope with such threatening situations made rats one of the most successful mammals throughout evolution as well as excellent experimental subjects for the analysis of the neuroendocrine mechanisms underlying the stress response. Two neuroendocrine protection systems, the sympatho-adrenergic system (SAS) and the hypothalamic–pituitary–adrenal (HPA) axis mediate a bi-directional brain–body communication during aversive encounters and orchestrate the individual’s adaptation to potentially harmful or even life-threatening situations (Fig. 1). In sudden aversive encounters, animals show an alarm reaction, which includes non-specific immediate behavioural responses (e.g., startle) followed by specific behavioural responses (e.g., fight, flight). In parallel, a variety of physiological parameters are changed (e.g., increase in blood pressure, tachycardia) that, together with the behavioural responses, prepare the animals for a successful control of the threat by active coping strategies. Alarm reactions are primarily linked to a stimulated SAS and involve an activation of brainstem nuclei, the vagal nerve and the medulla of the adrenal gland. Such events lead to the release of noradrenaline and adrenaline into the blood. In contrast, when aversively perceived encounters cannot be controlled by fight or flight, animals show passive coping strategies that are primarily associated with an activation of the HPA axis [23], [22], [74]. The resulting hormonal changes cause adaptive redirection of both energy (e.g., direction of oxygen and nutrients to the brain, gluconeogenesis, lipolysis, inhibition of growth, and reproductive systems, containment of inflammatory responses) and behaviour (e.g., increased arousal, vigilance and cognition, suppression of feeding and reproductive behaviour). Severe, uncontrollable and long-lasting aversive events may lead to a sustained activation of the HPA axis. This maladaptive response is thought to be causally linked to a variety of human psychiatric disorders, including anxiety disorders and depression (for reviews see [23], [22], [62], [99]). Detailed knowledge about the regulation of HPA axis activity during physiological and pathological conditions might lead to the development of novel therapeutic strategies for the treatment of psychopathologies.
Originally, vasopressin (AVP) originating from magnocellular neurones of the hypothalamic–neurohypophysial system (HNS) was regarded as the major modulator of the HPA axis. Today, however, it is generally accepted that parvocellular neurones of the hypothalamic paraventricular nucleus (PVN) trigger corticotropin (ACTH) secretion via the release of corticotropin-releasing hormone (CRH) and AVP. As a consequence, less attention was paid to the contribution of the HNS to the HPA axis regulation. The aim of this article is to reinforce and extend this regulatory concept and to provide new evidence for its support. In this context, we will briefly review the literature published since the seminal publications establishing the control of ACTH secretion by AVP (for review see [6]). We focus on studies performed in male rats as the preferred experimental subjects in neuroendocrine research. It is not our intention to provide a full coverage of the individual players in the neuroendocrine ‘stress game.’ Instead, we will refer the interested reader to more specialised review articles.
In the first part of this manuscript, we shall define the terms stress, stressor and adaptive response, followed by a focused description of the HPA axis and the HNS. We will then outline whether the HNS is activated during stress and how it might affect the activity of the HPA axis in situations with controllable aversive events. We will conclude with a discussion of the HNS contribution to pathological alterations in HPA axis activity.
Section snippets
What is stress?
Under certain circumstances, prolonged and repeated exposure to unavoidable aversive situations leads to a dysregulation of the HPA axis. Consequences are pathological changes, such as thymus weight loss, ulceration of the stomach, and proliferation of adrenal tissue. Hans Selye was the first to describe this non-specific response in the 1930s as the general adaptive syndrome [136] or stress syndrome, which is independent from a specific stimulus configuration. He introduced this syndrome as a
General features of the HPA axis
Both, beneficial and deleterious effects of stress are thought to involve the action of corticosterone/cortisol secreted from the adrenal glands into the blood. This secretion is primarily controlled by the adrenocorticotropic hormone/corticotropin (ACTH), which is secreted into the general blood circulation from corticotrope cells of the anterior pituitary gland. The nature and significance of the chemical factors, which regulate the secretion of ACTH, have been a matter of discussion for
General features of the HNS
Since the pioneering studies of Ernst Scharrer [132], [133] and Wolfgang Bargmann [9], [10], the HNS became the foundation stone of neuroendocrine research. The HNS is composed of magnocellular neurones of the PVN and the supraoptic nucleus (SON) that synthesise AVP and another structurally related nonapeptide, oxytocin (OXT). The magnocellular neurones of the PVN and SON almost exclusively project through the Zona interna of the median eminence to the posterior pituitary, where they terminate
Activation of the HNS during stress
With the discovery that parvocellular PVN neurones comprise the central component of the HPA axis, the assumption of a significant contribution of the HNS to the regulation of ACTH secretion appeared less likely. Obviously, the attractiveness of the parvocellular pathway outweighed the experimental evidence for an involvement of the HNS, which derived, amongst others, from measurements of stress-related changes in plasma concentrations, particularly of OXT. Several studies demonstrated that a
Regulation of HNS activity during stress
Among the regulatory principles that control the electrical and secretory activity of HNS neurones, auto-feedback loops of AVP and OXT have attracted particular interest. This is reflected by an extensive literature dealing with this subject (e.g. [110], [156], [89]). It has been reported that AVP both positively and negatively controls its peripheral release depending upon the ‘basal’ electrical activity of the individual neurone [87], [47]. In contrast, OXT seems to exert a pronounced
Involvement of the HNS in HPA axis regulation
We have demonstrated that: (1) defined stressors trigger the release of AVP and OXT within SON and PVN in a stressor-specific manner and (2) this release need not necessarily occur simultaneously from dendrites within the two nuclei and axon terminals into the blood. The question remains whether the activation of the HNS and HPA axis is coincident but unrelated, or whether the two neuroendocrine systems interact during stress. Animal models with chronically depleted magnocellular AVP synthesis
Involvement of the HNS in HPA axis dysregulation
Chronic AVP overexpression both under basal conditions and during stressor exposure associated with HPA axis hyper-reactivity would be a useful model for studying the involvement of magnocellular AVP neurones in HPA axis regulation. An animal model of extremes in trait anxiety, comorbid depression-like behaviour and hyperactive HPA axis would fulfil this criterion. For more than a decade, Wistar rats have been bred for either high (HAB) or low (LAB) anxiety-related behaviour on the elevated
Conclusion
In the past decade, a variety of studies unequivocally demonstrated that the HNS significantly contributes to the regulation of the HPA axis. The present review re-instates this old concept and extends it by the Janus—faced effects AVP and OXT exert on the HPA axis following their release from dendrites and somata within the hypothalamic SON and PVN on the one hand (inhibition of ACTH secretion) and their secretion from axons and axon terminals on the other (stimulation of ACTH secretion).
Acknowledgments
The authors are indebted to Dr. Thomas F.W. Horn and Andrea Rudloff (Magdeburg, Germany) as well as N. Singewald and P. Salchner (Innsbruck, Austria) for helping with the immunohistochemical figures. The authors thank Colin H. Brown (Edinburgh, UK) for critical reading the manuscript. The work reported in this paper was partially supported by Deutsche Forschungsgemeinschaft (M.E.).
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