Programming of the hypothalamo-pituitary-adrenal axis: serotonergic involvement

The ability of the early environment to programme the developing hypothalamo-pituitary-adrenal (HPA) axis has been reported in several animal species. There is considerable evidence that a similar process can occur in the human, and that long-term alterations in HPA function are associated with altered susceptibility to disease in later life. The phenotype of HPA function following early manipulation depends on the timing and intensity of the manipulation as well as the gender of the fetus/neonate. There is considerable interplay between the developing HPA and the reproductive axes and emerging evidence indicates that this interaction is modified by early environmental manipulation. Studies are rapidly unravelling the mechanisms that underlie developmental programming of the HPA axis. In this context, the serotonergic system has been identified as a primary system involved in this process. Understanding the mechanisms involved in neuroendocrine programming will facilitate the development of interventions aimed at reversing or ameliorating the impact of an adverse intrauterine environment.     

The hypothalamo-pituitary-adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome

The hypothalamo-pituitary-adrenal (HPA) axis plays a major role in the regulation of responses to stress. Human stress-related disorders such as chronic fatigue syndrome (CFS), fibromyalgia syndrome (FMS), chronic pelvic pain and post-traumatic stress disorder are characterized by alterations in HPA axis activity. However, the role of the HPA axis alterations in these stress-related disorders is not clear. Most studies have shown that the HPA axis is underactive in the stress-related disorders, but contradictory results have also been reported, which may be due to the patients selected for the study, the methods used for the investigation of the HPA axis, the stage of the syndrome when the tests have been done and the interpretation of the results. There is no structural abnormality in the endocrine organs which comprise the HPA axis, thus it seems that hypocortisolemia found in the patients with stress-related disorder is functional. It may be also an adaptive response of the body to chronic stress. In this review, tests used in the assessment of HPA axis function and the HPA axis alterations found in CFS and FMS are discussed in detail.     

Maternal separation in early life impairs tumor immunity in adulthood in the F344 rat

Neonatal stress alters the hypothalamic-pituitary-adrenal (HPA) axis in rodents, such that, when these animals are exposed to stress as adults they hypersecrete corticosterone. Given that glucocorticoids are immunosuppressive, we examined the impact of maternal separation on HPA axis reactivity, natural killer (NK) cytotoxicity, and tumor growth in Fischer 344 rats following chronic restraint stress in adulthood. Pups underwent a chronic stress protocol whereby they were separated from their dams for 3 h on postnatal days 1-21. In adulthood, corticosterone responses were assessed following exposure to chronic (6 days for 10 h) restraint stress. Rats allocated to the chronic stress condition were inoculated with MADB106 tumor cells on day 4 of the restraint protocol. Blood was assessed for NK cytotoxicity on the final day of the chronic restraint protocol, and tumor colonization was assessed 3 weeks thereafter. Maternal separation impaired developmental weight gain (P < 0.05), depressed NK cytotoxicity (P < 0.05), and increased tumor colonization in the presence of chronic restraint stress in adulthood (P < 0.00 l). These findings occurred independently of circulating plasma corticosterone as only adult stress exposure potentiated corticosterone responses (P < 0.05). Our findings indicate that maternal separation and chronic stress can impair NK cytotoxicity and hence tumor immunity, but these effects are not directly mediated by perturbations in HPA axis function.     

Involvement and role of the hypothalamo-pituitary-adrenal (HPA) stress axis in animal models of chronic pain and inflammation

Hypothalamo-pituitary-adrenal (HPA) axis changes have been reported in several disease states, including major depressive disorder, rheumatoid arthritis, multiple sclerosis and various other conditions associated with chronic pain. These observations suggest that stress and the HPA axis may play important roles in the pathology of these diseases. In order to contribute to a better understanding of the role that chronic stress may play in human pathology, this review article explores the involvement of the HPA axis in those animal models of chronic pain and inflammation that entail persistent rather than intermittent stress.     

HPA axis and sleep: identifying subtypes of major depression

It is increasingly acknowledged that the diagnosis of major depression encompasses patients who do not necessarily share the same disease biology. Though the diagnostic criteria allow the specification of different subtypes, e.g. melancholic and atypical features, a consensus still has to be reached with regard to the clinical symptoms that clearly delineate these subtypes. Beside clinical characteristics, biological markers may help to further improve identification of biologically distinct endophenotypes and, ultimately, to devise more specific treatment strategies. Alterations of the hypothalamus-pituitary-adrenal (HPA) axis and sleep architecture are not only commonly observed in patients with major depression, but the nature and extent of these alterations can help to identify distinct subtypes. Thus, a HPA overdrive, due to enhanced secretion of corticotropin-releasing hormone (CRH) and an impaired negative feedback via glucocorticoid receptors, seems to be most consistently observed in patients with melancholic features. These patients also show the clearest sleep-electroencephalogram (EEG) alterations, including disrupted sleep, low amounts of slow wave sleep (SWS), a short rapid eye movement (REM) latency and a high REM density. In contrast, patients with atypical features are characterized by reduced activity of the HPA axis and ascending noradrenergic neurons in the locus coeruleus. Though sleep-EEG alterations have been less thoroughly examined in these patients, there are data to suggest that SWS is not reduced and that REM sleep parameters are not consistently altered. While the atypical and melancholic subtypes of major depression may represent the extremes of a spectrum, the distinct clinical features provide an opportunity to further explore biological markers, as well as environmental factors, contributing to these clinical phenotypes. Moreover, dysregulations of the HPA axis and sleep-EEG alterations can also be induced in rodents, thereby allowing alignment of critical biological aspects of a human disease subtype with an animal model. Such "Translational Research" efforts should help to develop targeted therapies for distinct patient populations.     

In Search of HPA Axis Dysregulation in Child and Adolescent Depression

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system’s response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin-releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression.     

Stress, glucocorticoids and liquorice in human pregnancy: programmers of the offspring brain

A suboptimal prenatal environment may induce permanent changes in cells, organs and physiology that alter social, emotional and cognitive functioning, and increase the risk of cardiometabolic and mental disorders in subsequent life ("developmental programming"). Although animal studies have provided a wealth of data on programming and its mechanisms, including on the role of stress and its glucocorticoid mediators, empirical evidence of these mechanisms in humans is still scanty. We review the existing human evidence on the effects of prenatal maternal stress, anxiety and depression, glucocorticoids and intake of liquorice (which inhibits the placental barrier to maternal glucocorticoids) on offspring developmental outcomes including, for instance, alterations in psychophysiological and neurocognitive functioning and mental health. This work lays the foundations for biomarker discovery and affords opportunities for prevention and interventions to ameliorate adverse outcomes in humans.     

The central nucleus of the amygdala; a conduit for modulation of HPA axis responses to an immune challenge?

Physical stressors such as infection, inflammation and tissue injury elicit activation of the hypothalamic-pituitary-adrenal (HPA) axis. This response has significant implications for both immune and central nervous system function. Investigations in rats into the neural substrates responsible for HPA axis activation to an immune challenge have predominantly utilized an experimental paradigm involving the acute administration of the pro-inflammatory cytokine interleukin- 1β (IL-1β). It is well recognized that medial parvocellular corticotrophin-releasing factor cells of the paraventricular nucleus (mPVN CRF) are critical in generating HPA axis responses to an immune challenge but little is known about how peripheral immune signals can activate and/or modulate the mPVN CRF cells. Studies that have examined the afferent control of the mPVN CRF cell response to systemic IL-1β have centred largely on the inputs from brainstem catecholamine cells. However, other regulatory neuronal populations also merit attention and one such region is a component of the limbic system, the central nucleus of the amygdala (CeA). A large number of CeA cells are recruited following systemic IL-lβ administration and there is a significant body of work indicating that the CeA can influence HPA axis function. However, the contribution of the CeA to HPA axis responses to an immune challenge is only just beginning to be addressed. This review examines three aspects of HPA axis control by systemic IL-1β: (i) whether the CeA has a role in generating HPA axis responses to systemic IL-1β, (ii) the identity of the neural connections between the CeA and mPVN CRF cells that might be important to HPA axis responses and(iii) the mechanisms by which systemic IL-Iβ triggers the recruitment of CeA cells.     

Lactation and stress: protective effects of breast-feeding in humans

Whilst most research on breast-feeding has been designed to assess its importance for infant health or to find a human nutrient replacement for infant formula, the effects of breast-feeding on maternal health have received little scientific attention. In several animal studies lactation has been shown to be associated with a marked blunting of physiological and behavioral responses to physical and psychological stress. However, the literature on the effects of lactation on stress in humans remains limited. This review focuses primarily on recent findings on the effects of breast-feeding on neuroendocrine and behavioral responses to acute stress exposure in lactating women. The available data suggest that breast-feeding suppresses the hypothalamic-pituitary-adrenal (HPA) axis response to physical and psychosocial stress. However, lactation in women, in contrast to lactating rats, does not seem to result in a general restraint of the endocrine stress response during the whole period of lactation. Recent data strongly suggest that the blunted HPA axis response to stress in women seems to be counterbalanced if the acute stressor, at least when of a psychosocial nature, occurs later than 1 h after suckling. Further elucidation of the underlying psychobiological mechanisms involved in suppressed stress responses during lactation will no doubt lead to new insights into improved health sequelae of breast-feeding in women and to a better understanding of the psychobiology of human stress protection in general.     

The neuroendocrinology of posttraumatic stress disorder: new directions

Studies of the hypothalamic-pituitary-adrenal (HPA) axis in persons with posttraumatic stress disorder (PTSD) have produced variable findings. This review focuses on the factors likely to have affected the outcome of these studies, including population characteristics and experimental design. Also discussed is a possible role for the adrenal neurosteroid dehydroepiandrosterone (DHEA) as a mediator of HPA axis adaptation to extreme stress and the psychiatric symptoms associated with PTSD. The antiglucocorticoid properties of DHEA may contribute to an upregulation of HPA axis responses as well as mitigate possible deleterious effects of high cortisol levels on the brain in some PTSD subpopulations. The neuromodulatory effects of DHEA and its metabolite DHEAS at gamma-aminobutyric acid and N-methyl-D-aspartate receptors in the brain may contribute to psychiatric symptoms associated with PTSD. The possible importance of other neurohormone systems in modulating HPA axis and symptom responses to traumatic stress is also discussed. Understanding the complex interactions of these stress-responsive neurosteroid and peptide systems may help explain the variability in patterns of HPA axis adaptation, brain changes, and psychiatric symptoms observed in PTSD and lead to better targeting of preventive and therapeutic interventions.     

Effect of Interleukin-1beta on Pituitary-Adrenal Responses and Body Weight in Neonatal Rats: Interaction with Maternal Deprivation

The hypothalamic-pituitary-adrenal (HPA) axis of the infant rat is normally hyporesponsive during postnatal days (pnd) four to fourteen. This interval is termed the stress hyporesponsive period (SHRP). The HPA axis, however, does respond to selective stimuli, such as interleukin-1beta (IL-1beta) during this period. Furthermore, maternal deprivation has been shown to alter the system so that it is responsive to mild stimuli. The present studies examined the interaction between 24 h of maternal deprivation and intraperitoneal administration of recombinant human (rh) IL-1beta (4 μg/kg) at 3 ages (i.e., pnd 6, 12, 18) during or after the SHRP. The results demonstrate that maternal deprivation modifies the response of the HPA axis induced by IL-1beta in an age-dependent fashion: 1) a greater response at pnd 6; 2) a quicker response at pnd 12; and 3) a suppressed response pattern at pnd 18. Moreover, these responses across ages differ as a function of maternal contact postinjection: 1) deprivation augments the ACTH and CORT response and maternal contact postinjection further augments this response at pnd 6; 2) deprivation increases the ACTH and CORT response to vehicle and the CORT response to IL-1beta in 12 day-old pups and the mother has a modest inhibitory effect; and 3) at pnd 18 deprivation leads to lower ACTH concentrations, but higher overall CORT levels and maternal contact postinjection effectively suppresses both the ACTH and CORT response to IL-1. These differences in the HPA response do not appear to be due to differences in the immune response. Plasma concentrations of endogenous rat IL-1beta determined 1 and 2 h after injection of rhIL-1beta were not modified by deprivation and were reduced at pnd 18 compared to pnd 6 and 12 in NDEP pups. Finally, IL-1beta reduced food intake, as reflected by a decrease in body weight, in deprived pups at all 3 ages. The findings in the present experiments suggest that there are additional pathways through which IL-1beta can act on the CNS to activate the HPA axis besides direct action at the hypothalamus.     

Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorders

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.     

产前母亲心理压力对儿童心理行为发展影响的研究述评

产前母亲心理压力对儿童心理行为发展有着重要的影响。大量的研究证据表明,产前母亲的心理应激,对后代的情感或认知发展会产生消极的影响,如容易出现注意力缺陷/活动过度、焦虑、语言迟缓等问题。这种影响的潜在机制之一是下丘脑-垂体-肾上腺（HPA）轴的变化,另一个机制可能是,母亲压力或焦虑引起交感-肾上腺系统高度激活。关于产前母亲心理压力对儿童心理行为发展影响的研究,在方法学上存在一定的缺陷,也还有一些未明确的问题,如产前压力的敏感期、性别特异性效应等。未来这一领域应该开发更多的研究途径。已有的证据足以表明,应该积极开展关于预防、干预和支持性方案方面的研究,以减轻妊娠期的压力或焦虑及其对儿童发展的不利影响。     

背景应激对静息态下大脑自发神经活动的影响

本研究试图探究背景应激对应激相关大脑自发神经活动的影响。使用日常应激水平作为背景应激的量化指标。同时，使用静息态fMRI技术，采集了个体在静息态下的大脑自发神经活动，并使用局部一致性（ReHo）作为指标。结果发现，背景应激越高的个体，右侧海马（扩展到丘脑和脑干）静息态下局部一致性水平越高。结果提示，经历了高背景应激的个体会表现出边缘系统脑区的自发神经活动的持续活跃状态。     

Measurement and meaning of salivary cortisol: a focus on health and disease in children

Measurement of salivary cortisol can provide important information about hypothalamic-pituitary-adrenal (HPA) axis activity under normal conditions and in response to stress. However, there are many variables relating to the measurement of cortisol in saliva which may introduce error and therefore may render difficult the comparison and interpretation of data between, and within, laboratories. This review addresses the effects of gender, age, time and location of sampling, units of measurement, assay conditions and compliance with the protocol, all of which have the potential to impact upon the precision, accuracy and reliability of salivary cortisol measurements in the literature. Some of these factors are applicable to both adults and children, but the measurement of salivary cortisol in children introduces aspects of unique variability which demand special attention. The specific focus of this review is upon the somewhat neglected area of methodological variability of salivary cortisol measurement in children. In addition to these methodological issues, the review highlights the use of salivary cortisol measurements to provide information about HPA axis dysfunction associated with psycho- and patho-physiological conditions in children. Novel applications for salivary cortisol measurements in future research into HPA axis activity in children are also discussed.     

创伤后应激障碍患者的HPA轴功能变化的时间序列特征

已知创伤后应激障碍(posttraumatic stress disorder, PTSD)患者表现出HPA轴(hypothalamic-pituitary- adrenocortical axis)功能异常, 而皮质醇是反映PTSD患者HPA轴功能的重要生物标记。近期的研究结果提示, PTSD患者的皮质醇水平变化可能有明显的时间序列特征, 即应激事件发生后先升高, 后下降至正常水平之下。这一特征受到生物标记的时间特性, 患者病程, 应激源类型和强度, 伴生疾病等因素的干扰和掩蔽。未来研究应进一步采用长期追踪设计, 控制干扰因素的影响, 结合急性应激和慢性应激生物标记来综合验证PTSD患者皮质醇水平变化的时间序列特征|并利用该特征预测PTSD的发生、发展, 以便及时进行干预|考虑皮质醇的代谢、拮抗等机制, 结合多种生物标记综合评估、诊断PTSD患者的HPA轴功能活性。     

Does physical activity reduce risk for Alzheimer's disease through interaction with the stress neuroendocrine system?

Lack of physical activity (PA) is a risk factor for Alzheimer's disease (AD), and PA interventions are believed to provide an effective non-pharmacological approach for attenuating the symptoms of this disease. However, the mechanism of action of these positive effects is currently unknown. It is possible that the benefits may be at least partially mediated by the effects on the neuroendocrine stress system. Chronic stress can lead to dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, leading to aberrant basal and circadian patterns of cortisol secretion and a cascade of negative downstream events. These factors have been linked not only to reduced cognitive function but also increased levels of amyloid-β plaques and protein tau "tangles" (the neuropathological hallmarks of AD) in the non-demented mouse models of this disease. However, there is evidence that PA can have restorative effects on the stress neuroendocrine system and related risk factors relevant to AD. We explore the possibility that PA can positively impact upon AD by restoring normative HPA axis function, with consequent downstream effects upon underlying neuropathology and associated cognitive function. We conclude with suggestions for future research to test this hypothesis in patients with AD.     

Maternal stress in pregnancy and its effect on the human foetus: an overview of research findings

There is evidence from human studies that anxiety or stress during pregnancy can affect birth outcome, causing babies to be born earlier and possibly smaller for gestational age. There is also some suggestive evidence for longer-term behavioural problems. Animal studies indicate that antenatal stress does have a long-term effect on the behaviour of the offspring, including a hyper-responsive hypothalamo-pituitary -adrenal axis. The human foetus can mount an independent stress response from mid-gestation. Two possible mechanisms have been demonstrated by which maternal stress or anxiety may affect the human foetus, the passage of cortisol across the placenta, and an impairment of blood flow through the maternal uterine arteries.     

Glutamate-mediated neuroplasticity in a limbic input to the hypothalamus

Emotionally-salient stressors are processed by cortical and limbic circuits that provide important regulatory input to the hypothalamic-pituitary-adrenal (HPA) axis. However, exposure to chronic or severe stress may cause disregulation of the axis and a variety of physiological and psychological symptoms. The mechanisms that underlie stress-induced alterations in HPA axis function are not well characterized, but one possibility is that severe stress causes plastic changes in limbic inputs to the hypothalamus. We examined plasticity within the bed nucleus of stria terminalis (BNST) and the hypothalamic paraventricular nucleus (PVN) with a stimulating electrode in the BNST and a recording electrode in the PVN. High-frequency BNST stimulation produced long-lasting suppression of evoked field potentials recorded from the PVN, and this effect was blocked by administration of MK-801. Accordingly, rapid glutamate-mediated neuroplasticity in the BNST to PVN neurocircuitry may contribute to plasticity in limbic regulation of the HPA axis.