Glucocorticoid receptor signaling in leukocytes after early life adversity

2019 ◽  
Vol 32 (3) ◽  
pp. 853-863 ◽  
Author(s):  
Martha M. C. Elwenspoek ◽  
Xenia Hengesch ◽  
Fleur A. D. Leenen ◽  
Krystel Sias ◽  
Sara Beatriz Fernandes ◽  
...  
Keyword(s):  
Immune System ◽  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Early Life ◽  
Promoter Region ◽  
Target Genes ◽  
Early Life Adversity ◽  
Time Points ◽  
Biological Parents ◽  
Separation From Parents

AbstractEarly life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA axis. Because the immune system and the HPA axis are tightly intertwined around the glucocorticoid receptor (GR), we examined peripheral GR functionality in the EpiPath cohort among participants who either had been exposed to ELA (separation from parents and/or institutionalization followed by adoption; n = 40) or had been reared by their biological parents (n = 72).Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA.Our results suggest that peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered GR response to the perturbed HPA axis and glucocorticoid (GC) profile, although we are limited in our measures of GR activity and time points.

Stress Hormone System and Epigenetics in Depression

2017 ◽  
Vol 41 (S1) ◽  
pp. S19-S19
Author(s):  
V. O’Keane ◽  
C. Farrell ◽  
K. Doolin ◽  
J. Chai ◽  
N. O’leary ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Target Genes ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Mrna Levels ◽  
Early Life Adversity ◽  
Generational Transmission ◽  
T Cell Receptor Gene ◽  
Competing Interest ◽  
Hormone System

BackgroundExposure to early life adversity (ELA) has been identified as a major risk factor in the development of major depressive disorder (MDD). It is hypothesized that a mediating mechanism may be environmentally induced alterations in gene function. In our REDEEM (Research in depression: endocrinology, epigenetics and neuroimaging) project we are examining possible epigenetic difference in some previously investigated target genes relevant to depression. To this end, methylation of the following genes were measured: NR3C1 (HPA axis), SLC6A4 (serotonin neurotransmitter function), and CD3ɛ (T cell receptor gene). We also looked at possible trans-generational transmission of epigenetic markers in a mother-baby sample.MethodsDNA was isolated from depressed patients and controls and babies and a portion of the above genes, encompassing our regions of interest, were amplified by PCR. Percentage methylation levels were measured by pyrosequencing. mRNA was also measured for some gene products to see if function was related to methylation. HPA axis function was measured with serial saliva samples throughout the day.Resultsto date: Methylation was increased in the CD3ɛ promoter in depressed subjects relative to controls. In the total group, those exposed to ELA had significantly increased methylation at this site. Levels of CD3ɛ mRNA levels were inversely related to methylation. There were some relationships between maternal ELA and baby methylation at the sites examined.ConclusionsConsistent with an allostatic model of ELA damage, our findings suggest an alteration in epigenetic function in acquired immunity and the HPA axis, mediated by ELA. Findings will be discussed.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals The differential calibration of the HPA axis as a function of trauma versus adversity: A systematic review and p-curve meta-analyses

2021 ◽  
Author(s):  
Niki H. Kamkar ◽  
Cassandra J Lowe ◽  
J. Bruce Morton
Keyword(s):  
Hpa Axis ◽  
Early Life ◽  
Life Experiences ◽  
Curve Analysis ◽  
Early Life Adversity ◽  
Cortisol Reactivity ◽  
Evidential Value ◽  
Dsm 5 ◽  
Meta Analyses ◽  
The Relationship

Although there is an abundance of evidence linking the function of the hypothalamic-pituitary-adrenal (HPA) axis to adverse early-life experiences, the precise nature of the association remains unclear. Some evidence suggests early-life adversity leads to cortisol hyper-reactivity, while other evidence suggests adversity leads to cortisol hypo-reactivity. Here, we distinguish between trauma and adversity, and use p-curves to interrogate the conflicting literature. In Study 1, trauma was operationalized according to DSM-5 criteria; the p-curve analysis included 68 articles and revealed that the literature reporting associations between trauma and blunted cortisol reactivity contains evidential value. Study 2 examined the relationship between adversity and cortisol reactivity. Thirty articles were included in the analysis, and p-curve demonstrated that adversity is related to heightened cortisol reactivity. These results support an inverted U-shaped function relating severity of adversity and cortisol reactivity, and underscore the importance of distinguishing between “trauma” and “adversity”.

scholarly journals Early-life adversity programs long-term cytokine and microglia expression within the HPA axis in female Japanese quail

2019 ◽  
Vol 222 (6) ◽  
pp. jeb187039 ◽  
Author(s):  
David J. Walker ◽  
Cédric Zimmer ◽  
Maria Larriva ◽  
Susan D. Healy ◽  
Karen A. Spencer
Keyword(s):  
Hpa Axis ◽  
Japanese Quail ◽  
Early Life ◽  
Early Life Adversity

Assessment of the hypothalamic–pituitary–adrenal axis activity: glucocorticoid receptor and mineralocorticoid receptor function in depression with early life stress – a systematic review

2012 ◽  
Vol 24 (1) ◽  
pp. 4-15 ◽  
Author(s):  
Cristiane Von Werne Baes ◽  
Sandra M. de Carvalho Tofoli ◽  
Camila Maria S. Martins ◽  
Mario F. Juruena
Keyword(s):  
Systematic Review ◽  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Life Stress ◽  
Early Life ◽  
Mineralocorticoid Receptor ◽  
Early Life Stress ◽  
Hypothalamic Pituitary Adrenal ◽  
Depressed Patients ◽  
Suppression Test

Objective:The mechanisms involved in the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, especially in the functioning of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in depressed patients, are not well elucidated. The objective of this study was to conduct a systematic review of articles that assess the HPA axis activity from GR and MR in depressed patients and healthy controls with or without early life stress.Methods:We conducted a systematic review of articles in PubMed, SCOPUS and SciELO published between 2000 and 2011, using the following search terms:child abuse,depression,HPA axis,dexamethasone,prednisolone,fludrocortisoneandspironolactone. Thirty-four papers were selected for this review.Results:Most studies identified in this review used the dexamethasone/corticotropin-releasing hormone test and dexamethasone suppression test. In these studies, hypercortisolaemia was associated with depression. We identified three studies with the Prednisolone suppression test, only one study with the use of fludrocortisone and one with spironolactone. This review found nine studies that evaluated the HPA axis in individuals with early life stress.Conclusions:The majority of the studies assessed in this review show that early life stress leads to permanent changes in the HPA axis and may lead to development of depression in adults. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolaemia and reduced inhibitory feedback. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between GR and MR. Evidences have consistently showed that GR function is impaired in major depression, but few studies have assessed the activity of MR in depression and early life stress.

scholarly journals Hair glucocorticoids are associated with childhood adversity, depressive symptoms and reduced global and lobar grey matter in Generation Scotland

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Claire Green ◽  
Aleks Stolicyn ◽  
Mathew A. Harris ◽  
Xueyi Shen ◽  
Liana Romaniuk ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Life Stress ◽  
Early Life ◽  
Childhood Adversity ◽  
Later Life ◽  
Early Life Adversity ◽  
Brain Volumes ◽  
Stable Measure ◽  
Regional Brain ◽  
Generation Scotland

AbstractHypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (βrange = −0.057 to −0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; βrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (β = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: β = −0.059, P = 0.043; nucleus accumbens: β = −0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.

scholarly journals Early maternal loss affects diurnal cortisol slopes in immature but not mature wild chimpanzees

2020 ◽  
Author(s):  
Cédric Girard-Buttoz ◽  
Patrick J. Tkaczynski ◽  
Liran Samuni ◽  
Pawel Fedurek ◽  
Cristina Gomes ◽  
...  
Keyword(s):  
Reproductive Success ◽  
Hpa Axis ◽  
Early Life ◽  
Urinary Cortisol ◽  
Maternal Loss ◽  
Early Life Adversity ◽  
Diurnal Cortisol ◽  
Animal Populations ◽  
Cortisol Levels

AbstractIn mammals, early life adversity negatively affects survival and reproductive success. A key causal mechanism is proposed by the biological embedding model which posits that adversity experienced early in life has deleterious consequences on individual physiology across the lifespan. In particular, early life adversity is expected to be a severe stressor leading to long-term alteration of the hypothalamic pituitary adrenal (HPA) axis activity. Here we tested this idea by assessing whether, as in humans, maternal loss had short and long-term impacts on orphan chimpanzee urinary cortisol levels and diurnal urinary cortisol slopes, as an indicator of the HPA axis functioning. We used 18 years of data on 50 immature and 28 mature male wild chimpanzees belonging to four communities in Taï National Park, Ivory Coast. Immature orphans who experienced early maternal loss had diurnal cortisol slopes characterised by higher early morning and late afternoon cortisol levels indicative of high activation of the HPA axis. Recently orphaned immatures had higher cortisol levels than other immatures, possibly reflecting social and nutritional stress. However, unlike in humans, we did not find significantly different cortisol profiles in orphan and non-orphan adult male chimpanzees. Our study highlights that long-term alteration of stress physiology related to early life adversity may not be viable in some wild animal populations and/or that chimpanzees, as humans, may have access to mechanisms that buffer this physiological stress, such as adoption. Our results suggest that biological embedding of altered HPA axis function is unlikely to be a mechanism contributing to the demonstrated long-term fitness consequences of maternal loss, such as reduced reproductive success, in wild long-lived mammals.

scholarly journals The ‘Jekyll and Hyde’ of Gluconeogenesis: Early-Life Adversity, Later Life Stress, and Metabolic Disturbances

2021 ◽  
Author(s):  
Snehaa V. Seal ◽  
Jonathan D. Turner
Keyword(s):  
Type 2 Diabetes ◽  
Energy Metabolism ◽  
Hpa Axis ◽  
Physiological Response ◽  
Early Life ◽  
Energy Homeostasis ◽  
Early Life Adversity ◽  
The Metabolic Syndrome ◽  
Psychological Stressor

The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal gland axis and sympathetic nervous system activation upon exposure to a stressor. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis. Glucocorticoid actions have been linked to many severe metabolic diseases including obesity, insulin resistance and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of many genes associated with glucose and lipid regulatory pathways and thereby intricately control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are many elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, the most prominent are early-life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early-life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a &ldquo;Jekyll and Hyde&rdquo; role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.

scholarly journals Effects of early life adversity on meningeal mast cells and proinflammatory gene expression in male and female Mus musculus

2021 ◽  
Author(s):  
Natalia Duque-Wilckens ◽  
Erika Sarno ◽  
Robby E. Teis ◽  
Frauke Stoelting ◽  
Sonia Khalid ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mast Cell ◽  
Immune System ◽  
Mast Cells ◽  
Early Life ◽  
Inflammatory Markers ◽  
Disease Susceptibility ◽  
Early Life Adversity ◽  
Male And Female ◽  
The Brain

ABSTRACTExposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- duramater, arachnoid, and piamater – possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on duramater mast cell histology and expression of inflammatory markers in male and female C57Bl/6 mice. We found that mast cell number, activation level, and relative expression of pseudopodia differ across duramater regions, and that NMSEW exerts region-specific effects on mast cells in males and females. Using gene expression analyses, we next found that NMSEW increases the expression of inflammatory markers in the duramater of females but not males, and that this is prevented by pharmacological inhibition of mast cells with ketotifen. Together, our results show that ELA drives sex-specific, long-lasting effects on the duramater mast cell population and immune-related gene expression, suggesting that the long-lasting effects of ELA on disease susceptibility could be partly mediated by meningeal function.

scholarly journals Early life trauma, depression and the glucocorticoid receptor gene – an epigenetic perspective

2015 ◽  
Vol 45 (16) ◽  
pp. 3393-3410 ◽  
Author(s):  
C. Smart ◽  
G. Strathdee ◽  
S. Watson ◽  
C. Murgatroyd ◽  
R. H. McAllister-Williams
Keyword(s):  
Dna Methylation ◽  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Early Life ◽  
Epigenetic Modification ◽  
Receptor Gene ◽  
Unipolar Depression ◽  
Tissue Cell ◽  
Glucocorticoid Receptor Gene ◽  
Early Life Trauma

Background.Hopes to identify genetic susceptibility loci accounting for the heritability seen in unipolar depression have not been fully realized. Family history remains the ‘gold standard’ for both risk stratification and prognosis in complex phenotypes such as depression. Meanwhile, the physiological mechanisms underlying life-event triggers for depression remain opaque. Epigenetics, comprising heritable changes in gene expression other than alterations of the nucleotide sequence, may offer a way to deepen our understanding of the aetiology and pathophysiology of unipolar depression and optimize treatments. A heuristic target for exploring the relevance of epigenetic changes in unipolar depression is the hypothalamic–pituitary–adrenal (HPA) axis. The glucocorticoid receptor (GR) gene (NR3C1) has been found to be susceptible to epigenetic modification, specifically DNA methylation, in the context of environmental stress such as early life trauma, which is an established risk for depression later in life.Method.In this paper we discuss the progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 gene. Difficulties with the design of these studies are also explored.Results.Future efforts will need to comprehensively address epigenetic natural histories at the population, tissue, cell and gene levels. The complex interactions between the epigenome, genome and environment, as well as ongoing nosological difficulties, also pose significant challenges.Conclusions.The work that has been done so far is nevertheless encouraging and suggests potential mechanistic and biomarker roles for differential DNA methylation patterns in NR3C1 as well as novel therapeutic targets.

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