Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function

In the paper

“The offspring of High LG mothers show significantly increased hippocampal GR mRNA and protein expression, enhanced glucocorticoid negative feedback sensitivity and decreased hypothalamic CRF mRNA levels.”

In the paper

“Individual differences in the frequency of pup LG among adult female rats are reliable across multiple litters, and thus a stable feature of the maternal phenotype.”

In the paper

“Chronic, central infusion of adult offspring of Low LG mothers with the broad spectrum HDAC inhibitor, trichostatin A (TSA),109 significantly increased H3K9ac, NGFI-A binding to the GR-17 promoter, and GR expression to levels comparable to those observed in the offspring of High LG mothers.”

What the sources say

• Not checked yetcites [109] Weaver IC., 2006, Proc Natl Acad Sci U S A. source

In the paper

“The results reveal significant differences in methylation at the 5' CpG dinucleotide of the NGFI-A consensus sequence. This site is hypermethylated in the offspring Low LG mothers, and hypomethylated in those of High LG dams.”

In the paper

“Thus we find increased H3K9ac and H3K4me3 at both regions of the exon 17 GR promoter, and the levels of these individual marks are very highly correlated.92”

What the sources say

• Not checked yetcites [92] Zhang TY., 2013, Neuropsychopharmacology. source

In the paper

“Cross-fostering reverses the differences in the methylation of the 5' CpG site and suggests a direct relation between maternal care and DNA methylation of the exon 17 GR promoter.70”

What the sources say

• Not checked yetcites [70] Weaver IC., 2004, Nat Neurosci. source

In the paper

“Decreased expression levels of GR exon 1B, 1C and 1H transcripts were also associated with alterations in methylation of the respective sequences, with particular sites significantly correlated with expression levels.”

In the paper

“We recently addressed this issue in PTSD patients and provide evidence suggesting that variation in the methylation of the exon 1F GR promoter associated with PTSD symptoms and predicted treatment outcome.135-137”

What the sources say

• Not checked yetcites [135] Yehuda R., Biol Psychiatry. In press.
• Not checked yetcites [136] Yehuda R., 2014, Am J Psychiatry. source
• Not checked yetcites [137] Yehuda R., 2013, Front Psychiatry. source

In the paper

“Moreover, the exon 1F sequence shows increased DNA methylation and decreased NGFI-A binding in samples from suicide victims with a history of maltreatment.”

In the paper

“Splice variant analysis revealed decreased expression of noncoding exons 1B, 1C, 1F and 1H in suicides with a history of childhood maltreatment compared with both controls and suicides without a history of maltreatment that correlated with differential DNA methylation patterns between groups in the corresponding exon 1 variant promoters.”

In the paper

“The increase in basal cortisol levels was particularly marked in melancholic and psychotic depression,43 but not in atypical depression.”

What the sources say

• Not checked yetcites [43] Gold PW., 2002, Mol Psychiatry. source

In the paper

“Antidepressant treatment increases GR expression, GR function, and GR-mediated HPA axis feedback inhibition in rodents as well as in humans, thereby reducing resting and stimulated HPA axis activity.40”

What the sources say

• Not checked yetcites [40] Pariante CM., 2008, Trends Neurosci. source

In the paper

“Interestingly Cushing's disease or prolonged corticosteroid therapy can precipitate Major Depressive Disorder (MDD), but also mania.44”

What the sources say

• Not checked yetcites [44] Starkman MN., 1981, Psychosom Med. source

In the paper

“Since elevated levels of cortisol act to inhibit subsequent HPA activity, this finding suggests impaired glucocorticoid negative feedback in depressed patients.”

What the sources say

• Not checked yetcites [44] Starkman MN., 1981, Psychosom Med. source

In the paper

“Broader forms of familial dysfunction including persistent emotional and physical neglect, family conflict, cold, distant parent-child relationships, and conditions of harsh, inconsistent discipline compromise cognitive and emotional development and increase the risk for depression and anxiety disorders to a level comparable to that for abuse.16-23”

What the sources say

• Not checked yetcites [16] Ammerman RT., 1986, Clini Psychol Rev.
• Not checked yetcites [17] Trickett PK., 1995, Dev Rev. source
• Not checked yetcites [18] Repetti RL., 2002, Psychol Bull. source
• Not checked yetcites [19] Lupien SJ., 2009, Nat Rev Neurosci. source
• Not checked yetcites [20] Hill J., 2001, Br J Psychiatry. source
• Not checked yetcites [21] Holmes SJ., 1987, J Child Psychol Psychiatry. source
• Not checked yetcites [22] Canetti L., 1997, Adolescence.
• Not checked yetcites [23] Parker G., 1989, Psychiatr Dev.

In the paper

“Moreover, childhood maltreatment also associates with an increased severity of illness, reduced treatment responsivity, and increased comorbidity.14,15”

What the sources say

• Not checked yetcites [14] Widom CS., 2007, Arch Gen Psychiatry. source
• Not checked yetcites [15] Nanni V., 2012, Am J Psychiatry. source

In the paper

“A recent meta-analysis confirmed the association of elevated basal levels of both ACTH and cortisol with depression and showed that the greatest difference in cortisol occurred during the afternoon, a time when cortisol levels are normally falling.42”

What the sources say

• Not checked yetcites [42] Stetler C., 2011, Psychosom Med. source

In the paper

“Thus, warm, nurturing families tend to promote resistance to stress and to diminish vulnerability to stress-induced illness.18,25”

What the sources say

• Not checked yetcites [18] Repetti RL., 2002, Psychol Bull. source
• Not checked yetcites [25] Smith J., 1995, J Am Acad Child Adolesc Psychiatry. source

In the paper

“Likewise, variations in parental care associate with individual differences in neuroendocrine and autonomic responses to stress in humans as well as emotional reactivity.18,33-36”

What the sources say

• Not checked yetcites [18] Repetti RL., 2002, Psychol Bull. source
• Not checked yetcites [33] Flinn MV., 1995, Curr Anthropology. source
• Not checked yetcites [34] Luecken LJ., 2000, Psychol Health. source
• Not checked yetcites [35] Pruessner JC., 2004, J Neurosci. source
• Not checked yetcites [36] Taylor SE., 2006, Biol Psychiatry. source

In the paper

“Administration of the GR antagonist, RU486, results in elevated levels of both ACTH and cortisol in humans, which implicates GR activation as a mediator of negative feedback inhibition.45”

What the sources say

• Not checked yetcites [45] Laue L., 1990, J Clin Endocrinol & Metab. source

In the paper

“Elevated CSF levels of CRF in adults associate with a history of childhood maltreatment,58,59 a poor quality of parental care,60 and childhood stressful experience.61”

What the sources say

• Not checked yetcites [58] Heim C., 2000, JAMA. source
• Not checked yetcites [59] Lee R., 2005, Am J Psychiatry. source
• Not checked yetcites [60] Lee RJ., 2006, Neuropsychopharmacology. source
• Not checked yetcites [61] Carpenter LL., 2004, Neuropsychopharmacology. source

In the paper

“High CRF may arise due to GR downregulation and impaired negative feedback inhibition, as evidenced by the finding that childhood abuse58,62 and parental loss63 are associated with higher Cortisol response to the dcxamethasone (DEX)/corticotropin-releasing hormone (CRH) challenge test in adults with and without depression.”

What the sources say

• Not checked yetcites [58] Heim C., 2000, JAMA. source
• Not checked yetcites [62] Rinne T., 2002, Biol Psychiatry. source
• Not checked yetcites [63] Tyrka AR., 2008, Biol Psychiatry. source

In the paper

“Subsequent statistical analyses revealed that childhood abuse was the strongest predictor of ACTH responsiveness, followed by the number of abuse events, adulthood traumas, and depression.”

What the sources say

• Not checked yetcites [58] Heim C., 2000, JAMA. source

In the paper

“Hippocampal infusion of a GR antagonist into the adult offspring of High and Low LG mothers completely eliminates the maternal effect on HPA responses to stress, suggesting a direct relation between hippocampal GR expression and the magnitude of the HPA response to stress.”

In the paper

“An interaction term of childhood and adulthood trauma proved to be the most potent predictor of ACTH responses, suggesting that a history of childhood abuse per se is related to increased stress reactivity, which is further enhanced when additional trauma occurs in adulthood.58”

What the sources say

• Not checked yetcites [58] Heim C., 2000, JAMA. source

In the paper

“Moreover, childhood adversity moderates the relation between stressful life events in adulthood and depression, with increased risk for depression or anxiety in response to moderately stressful circumstances among individuals with a history of childhood adversity.11,14,37”

What the sources say

• Not checked yetcites [11] McLaughlin KA., 2010, Arch Gen Psychiatry. source
• Not checked yetcites [14] Widom CS., 2007, Arch Gen Psychiatry. source
• Not checked yetcites [37] Wichers M., 2009, Br J Psychiatry. source

In the paper

“For example, in a novelty-induced suppression of feeding test in which food-deprived animals are provided food in a novel context, the adult offspring from High LG mothers show a shorter latency to begin eating and eat for a longer period of time.67”

What the sources say

• Not checked yetcites [67] Caldji C., 1998, Proc Nat Acad Sci U S A. source

In the paper

“In cultured hippocampal neurons the effect of 5-HT on GR expression is: (i) blocked by 5-HT7 receptor antagonists or inhibitors of protein kinase A; (ii) mimicked by 5-HT7 receptor agonists or treatments with stable cAMP analogs; and (iii) eliminated by antisense or small interfering RNA (siRNA) knockdown of NGFI-A mRNA.82,83”

What the sources say

• Not checked yetcites [82] Hellstrom IC., 2012, Philos Trans R Soc Lond B Biol Sci. source
• Not checked yetcites [83] Weaver IC., 2007, J Neuroscience. source

In the paper

“However, in these studies the decreased hypothalamic CRF expression occurs earlier in development than does the difference in hippocampal GR expression, suggesting that the difference in CRF expression develops independent of GR regulation.”

What the sources say

• Not checked yetcites [114] Avishai-Eliner S., 2001, J Neuroendocrinol. source

In the paper

“However, subsequent studies reveal effects of early experience on multiple components of the HPA axis, and in each case there is evidence for stable epigenetic programming.”

In the paper

“Thus, chromatin-immunoprecitipation (ChIP) assays reveal increased binding of NGFI-A to the exon 17 promoter in pups of High compared with Low LG mothers, but only in the period following a nursing bout with pup LG: hippocampal tissue samples obtained 20 min following a nursing bout, with no subsequent interaction between the mother and pup, do not reveal the difference in NGFI-A association.”

In the paper

“Pup LG increases hippocampal NGFI-A expression and binding to the exon 17 promoter.70,82,83”

What the sources say

• Not checked yetcites [70] Weaver IC., 2004, Nat Neurosci. source
• Not checked yetcites [82] Hellstrom IC., 2012, Philos Trans R Soc Lond B Biol Sci. source
• Not checked yetcites [83] Weaver IC., 2007, J Neuroscience. source

In the paper

“These findings suggest that variations in maternal care influence the methylation state of the exon 17 GR promoter in hippocampus, regulating NGFI-A binding, GR transcription and HPA stress responses.”

In the paper

“These results suggest a direct relation between maternal care, histone acetylation, DNA methylation of the GR-17 promoter, GR expression and HPA responses to stress.”

In the paper

“Baram and colleagues114 showed that this maternally regulated decrease in CRF expression is accompanied by an increase in hippocampal GR expression.”

What the sources say

• Not checked yetcites [114] Avishai-Eliner S., 2001, J Neuroendocrinol. source

In the paper

“The effect of NGFI-A is eliminated by a site-directed mutation within the NGFI-A response element of the exon 17 promoter83 revealing that it is the physical interaction of NGFI-A with its response element that triggers the increase in transcriptional activity.”

What the sources say

• Not checked yetcites [83] Weaver IC., 2007, J Neuroscience. source

In the paper

“Perhaps most convincingly, artificial tactile stimulation of pups increases hippocampal NGFI-A expression and NGFI-A binding to the exon 17 promoter.”

In the paper

“Maternal separation of neonatal mice produces an enduring hypomethylation of the Pomc gene, which encodes for the ACTH pro-hormone, proopiomelanocortin,119 increased Pomc mRNA expression and increased basal and CRF-induced levels of ACTH.”

What the sources say

• Not checked yetcites [119] Wu Y., 2014, Endocrinology. source

In the paper

“These findings suggest that variations in parent-offspring interactions epigenetically “program” hippocampal GR expression and thus the nature of the HPA response to stress.”

In the paper

“These findings bear considerable similarity to the maternal effect in the rat and are suggestive of early-environment regulation of the neural epigenome in humans.”

In the paper

“At the molecular level this interaction was associated with stable DNA demethylation, which in turn predicted increased FKBP5 expression.”

What the sources say

• Not checked yetcites [133] Klengel T., 2013, Nat Neurosci. source

In the paper

“The program is strengthened by a validated forensic interview that establishes developmental history and mental health status.”

In the paper

“This study demonstrated that polymorphisms in FKBP5 influence the position of the nucleosome, which when combined with childhood trauma (postulated to increase circulating Cortisol) resulted in an increased risk of post-traumatic stress disorder (PTSD).”

What the sources say

• Not checked yetcites [133] Klengel T., 2013, Nat Neurosci. source

In the paper

“These findings are thus consistent with a working hypothesis that links the early social environment to epigenetic modifications of the GR gene and GR expression, and HPA function.”

In the paper

“Since FKBP5 sequesters activated GR and prevents nuclear binding, the decreased FKBP5 methylation and increased FKBP5 expression associated with symptoms of glucocorticoid resistance.”

What the sources say

• Not checked yetcites [133] Klengel T., 2013, Nat Neurosci. source

In the paper

“The exon 1F sequence is of particular interest as it is the homolog of the rat exon 17, is highly expressed in brain and contains an NGFI-A response element.65,121”

What the sources say

• Not checked yetcites [65] McGowan PO., 2009, Nat Neurosci. source
• Not checked yetcites [121] Turner JD., 2005, J Mol Endocrinol. source