Cerebrospinal Fluid Corticotropin-Releasing Factor and Perceived Early-Life Stress in Depressed Patients and Healthy Control Subjects

Introduction Using proton magnetic resonance spectroscopy imaging, the effects of early life stress on nonhuman primate striatal neuronal integrity were examined as reflected by N-acetyl aspartate (NAA) concentrations. NAA measures were interrogated through examining their relationship to previously documented early life stress markers—cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and behavioral timidity. Rodent models of depression exhibit increases in neurotrophic effects in the nucleus accumbens. We hypothesized that rearing under conditions of early life stress (variable foraging demand, VFD) would produce persistent elevations of NAA concentrations (in absolute or ratio form) in ventral striatum/caudate nucleus (VS/CN) with altered correlation to early life stress markers. Methods Eleven bonnet macaque males reared under VFD conditions and seven age-matched control subjects underwent proton magnetic resonance spectroscopy imaging during young adulthood. Voxels were placed over VS/CN to capture nucleus accumbens. Cisternal cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and response to a human intruder had been previously determined. Results VFD-reared monkeys exhibited significantly increased NAA/creatine concentrations in right VS/CN in comparison to normally reared controls, controlling for multiple comparisons. In comparison to controls, VFD cerebrospinal fluid corticotropin-releasing factor concentrations were directly associated with right VS/CN absolute NAA. Left hippocampal volume was inversely associated with left VS/CN NAA/creatine in VFD reared but not in controls. Disruption of a normative inverse correlation between left VS/CN NAA and body mass was noted in VFD. Only non-VFD subjects exhibited a direct relationship between timidity response to an intruder and right VS/CN NAA. Conclusion Early life stress produced persistent increases in VS/CN NAA, which demonstrated specific patterns of association (or lack thereof) to early life stress markers in comparison to non-VFD subjects. The data are broadly consistent with a stable nonhuman primate phenotype of anxiety and mood disorder vulnerability whereby in vivo indicators of neuronal integrity, although reduced in hippocampus, are increased in striatum. The findings may provide a catalyst for further studies in humans and other species regarding a reciprocal hippocampal/nucleus accumbens relationship in affective disorders.

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

Acta Neuropsychiatrica ◽

10.1111/j.1601-5215.2011.00610.x ◽

2012 ◽

Vol 24 (1) ◽

pp. 4-15 ◽

Cited By ~ 26

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.

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Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2014.00440 ◽

2014 ◽

Vol 8 ◽

Cited By ~ 8

Author(s):

Jeremy D. Coplan ◽

Sasha L. Fulton ◽

Wade Reiner ◽

Andrea Jackowski ◽

Venkatesh Panthangi ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Anxiety Disorders ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Hippocampal Volume ◽

Inverse Association ◽

Related Function ◽

Mood And Anxiety Disorders ◽

Hydroxyindoleacetic Acid

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Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5-hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels

Alcohol ◽

10.1016/j.alcohol.2011.11.003 ◽

2012 ◽

Vol 46 (4) ◽

pp. 371-376 ◽

Cited By ~ 9

Author(s):

Kimberly N. Huggins ◽

Tiffany A. Mathews ◽

Jason L. Locke ◽

Kendall T. Szeliga ◽

David P. Friedman ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Brain Tissue ◽

Life Stress ◽

Early Life ◽

Rhesus Macaques ◽

Early Life Stress ◽

System Activity ◽

Tissue Levels ◽

Serotonin System ◽

Hydroxyindoleacetic Acid

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Cortisol awakening reaction in depressed patients with and without early life stress

Pharmacopsychiatry ◽

10.1055/s-0029-1240094 ◽

2009 ◽

Vol 42 (05) ◽

Cited By ~ 2

Author(s):

NC Bührsch ◽

U Swoboda ◽

A Quante ◽

S Zeugmann ◽

M Bajbouj ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Depressed Patients

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Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain

Development and Psychopathology ◽

10.1017/s0954579414001345 ◽

2015 ◽

Vol 27 (1) ◽

pp. 123-135 ◽

Cited By ~ 39

Author(s):

Rick H. A. van der Doelen ◽

Ilse A. Arnoldussen ◽

Hussein Ghareh ◽

Liselot van Och ◽

Judith R. Homberg ◽

...

Keyword(s):

Dna Methylation ◽

Serotonin Transporter ◽

Life Stress ◽

Early Life ◽

Gene Promoter ◽

Early Life Stress ◽

Corticotropin Releasing Factor ◽

Mrna Levels ◽

Gene Variation ◽

Gene Environment

AbstractThe interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene × Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid release upon exposure to stress. Both endophenotypes are regulated by the neuropeptide corticotropin-releasing factor (CRF) or hormone, which is expressed by the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central amygdala (CeA). Therefore, we hypothesized that altered regulation of the expression of CRF in these areas represents a major neurobiological mechanism underlying the interaction of early life stress and 5-HTT gene variation. The programming of gene transcription by Gene × Environment interactions has been proposed to involve epigenetic mechanisms such as DNA methylation. In this study, we report that early life stress and 5-HTT genotype interact to affect DNA methylation of the Crf gene promoter in the CeA of adult male rats. Furthermore, we found that DNA methylation of a specific site in the Crf promoter significantly correlated with CRF mRNA levels in the CeA. Moreover, CeA CRF mRNA levels correlated with stress coping behavior in a learned helplessness paradigm. Together, our findings warrant further investigation of the link of Crf promoter methylation and CRF expression in the CeA with behavioral changes that are relevant for psychopathology.

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Corticotropin-Releasing Factor and the Psychobiology of Early-Life Stress

Current Directions in Psychological Science ◽

10.1111/j.1467-8721.2007.00481.x ◽

2007 ◽

Vol 16 (2) ◽

pp. 85-89 ◽

Cited By ~ 26

Author(s):

Charles F. Gillespie ◽

Charles B. Nemeroff

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Corticotropin Releasing Factor

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Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome

Psychological Medicine ◽

10.1017/s0033291707001444 ◽

2007 ◽

Vol 38 (7) ◽

pp. 963-973 ◽

Cited By ~ 25

Author(s):

F. Van Den Eede ◽

G. Moorkens ◽

W. Hulstijn ◽

B. Van Houdenhove ◽

P. Cosyns ◽

...

Keyword(s):

Hpa Axis ◽

Life Stress ◽

Early Life ◽

Low Dose ◽

Early Life Stress ◽

Chronic Fatigue ◽

Corticotropin Releasing Factor ◽

Fatigue Syndrome ◽

History Of ◽

Cortisol Responses

BackgroundStudies of hypothalamic–pituitary–adrenal (HPA) axis function in chronic fatigue syndrome (CFS) point to hypofunction, although there are negative reports. Suggested mechanisms include a reduced hypothalamic or supra-hypothalamic stimulus to the HPA axis and enhanced sensitivity to the negative feedback of glucocorticoids. The aim of the current study was to investigate HPA axis function in CFS with the dexamethasone/corticotropin-releasing factor (Dex/CRF) test, in analogy with research in affective disorders.MethodThirty-four well-characterized female CFS patients and 25 healthy control subjects participated in the low-dose Dex/CRF test. Current major depressive episode was an exclusion criterion. History of early-life stress (ELS) was assessed with the Structured Trauma Interview.ResultsSalivary cortisol responses after 0.5 mg Dex were lower in CFS patients than in controls (before 100 μg CRF, p=0.038; after 100 μg CRF, p=0.015). A secondary analysis revealed an influence of early-life stress and of oestrogen intake. After removal of the 10 participants who were taking an oral oestrogen, patients without a history of ELS showed lower cortisol responses than patients with ELS and controls (before CRF, p=0.005; after CRF, p=0.008).ConclusionsCFS is globally associated with reduced cortisol responses in the combined low-dose Dex/CRF test, but this effect is only clearly present in CFS patients without a history of ELS. This study provides further support for an enhanced glucocorticoid negative feedback and/or a reduced central HPA axis drive in CFS. Furthermore, it demonstrates that ELS is an important variable to consider in CFS research.

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Stress and Depression

Stress and Mental Disorders: Insights from Animal Models ◽

10.1093/med-psych/9780190697266.003.0013 ◽

2020 ◽

pp. 395-432

Author(s):

Richard McCarty

Keyword(s):

Life Stress ◽

Early Life ◽

Social Groups ◽

Early Life Stress ◽

Corticotropin Releasing Factor ◽

Epigenetic Alterations ◽

Animal Models Of Depression ◽

Future Drug ◽

Approaches To Study ◽

Chronic Variable Stress

This chapter on animal models of depression includes a summary of additional approaches to modeling a depression-like phenotype in animals. Several risk genes have been evaluated, including genes involved in dopamine, serotonin, and corticotropin-releasing factor signaling. Using a two-hit model, some investigators have examined the effects of early life stress combined with stress in adulthood to unmask the risk for a depression-like phenotype. Female mice were more sensitive than male mice to a sub-chronic paradigm of chronic variable stress and displayed depression-like behavioral changes. A naturally occurring depression-like phenotype has also been documented in captive social groups of cynomolgous monkeys. Three additional approaches to study mechanisms involved in the onset of depression have included stress and neurogenesis, stress and epigenetic alterations in gene transcription, and stress and immune signaling through proinflammatory cytokines. Taken together, these experiments have identified multiple potential targets for future drug development.

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