Mechanisms of brain glucocorticoid resistance in stress-induced psychopathologies

Меркулов, В. М.; Merkulova, T. I.; Bondar, Natalia P.

doi:10.1134/s0006297917030142

Cited by 44 publications

(28 citation statements)

References 138 publications

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“…Certainly, this one is an argument in favor the other (non-genetic) side of the debate in question [e.g., Fromm (1941, 1973), Berkowitz (1962, 1993), Skinner (Rogers and Skinner, 1956; Skinner, 1981)]. According to recent reports on epigenetics (e.g., Merkulov et al, 2017), various stressors may cause epigenetic reprogramming of the individual genome and, in this way, modulate the actual levels of both individual aggressiveness and social status. Moreover, this reprogrammed pattern of the human genome is inherited from parents to offspring across at least two generations.…”

Section: Resultsmentioning

confidence: 99%

Natural Selection Equally Supports the Human Tendencies in Subordination and Domination: A Genome-Wide Study With in silico Confirmation and in vivo Validation in Mice

et al. 2019

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We proposed the following heuristic decision-making rule: “IF {an excess of a protein relating to the nervous system is an experimentally known physiological marker of low pain sensitivity, fast postinjury recovery, or aggressive, risk/novelty-seeking, anesthetic-like, or similar agonistic-intolerant behavior} AND IF {a single nucleotide polymorphism (SNP) causes overexpression of the gene encoding this protein} THEN {this SNP can be a SNP marker of the tendency in dominance} WHILE {underexpression corresponds to subordination} AND vice versa .” Using this decision-making rule, we analyzed 231 human genes of neuropeptidergic, non-neuropeptidergic, and neurotrophinergic systems that encode neurotrophic and growth factors, interleukins, neurotransmitters, receptors, transporters, and enzymes. These proteins are known as key factors of human social behavior. We analyzed all the 5,052 SNPs within the 70 bp promoter region upstream of the position where the protein-coding transcript starts, which were retrieved from databases Ensembl and dbSNP using our previously created public Web service SNP_TATA_Comparator ( http://beehive.bionet.nsc.ru/cgi-bin/mgs/tatascan/start.pl ). This definition of the promoter region includes all TATA-binding protein (TBP)-binding sites. A total of 556 and 552 candidate SNP markers contributing to the dominance and the subordination, respectively, were uncovered. On this basis, we determined that 231 human genes under study are subject to natural selection against underexpression (significance p < 0.0005), which equally supports the human tendencies in domination and subordination such as the norm of a reaction (plasticity) of the human social hierarchy. These findings explain vertical transmission of domination and subordination traits previously observed in rodent models. Thus, the results of this study equally support both sides of the century-old unsettled scientific debate on whether both aggressiveness and the social hierarchy among humans are inherited (as suggested by Freud and Lorenz) or are due to non-genetic social education, when the children are influenced by older individuals across generations (as proposed by Berkowitz and Fromm).

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Section: Resultsmentioning

confidence: 99%

Natural Selection Equally Supports the Human Tendencies in Subordination and Domination: A Genome-Wide Study With in silico Confirmation and in vivo Validation in Mice

et al. 2019

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“…There are provisional grounds to consider that the long-term behavioral consequences of early life stress are likely maintained by epigenetic mechanisms. Thus, a number of studies show stable changes in CpG methylation in promoter regions of genes encoding glucocorticoid receptor [ 45 , 47 – 49 ], BDNF [ 45 , 50 , 51 ] and others [ 52 ] caused by early postnatal stress. Moreover, maternal separation alters the expression levels in conjunction with the levels of histone H3 acetylation and/or some repressive modifications (H3K9me2, H3K9me3) in promoter regions of GR , Crh , Bdnf , etc.…”

Section: Discussionmentioning

confidence: 99%

Consequences of early life stress on genomic landscape of H3K4me3 in prefrontal cortex of adult mice

et al. 2018

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BackgroundMaternal separation models in rodents are widely used to establish molecular mechanisms underlying prolonged effects of early life adversity on neurobiological and behavioral outcomes in adulthood. However, global epigenetic signatures following early life stress in these models remain unclear.ResultsIn this study, we carried out a ChIP-seq analysis of H3K4 trimethylation profile in the prefrontal cortex of adult male mice with a history of early life stress. Two types of stress were used: prolonged separation of pups from their mothers (for 3 h once a day, maternal separation, MS) and brief separation (for 15 min once a day, handling, HD). Adult offspring in the MS group demonstrated reduced locomotor activity in the open field test accompanied by reduced exploratory activity, while the HD group showed decreased anxiety-like behavior only. In a group of maternal separation, we have found a small number (45) of slightly up-regulated peaks, corresponding to promoters of 70 genes, while no changes were observed in a group of handling. Among the genes whose promoters have differential enrichment of H3K4me3, the most relevant ones participate in gene expression regulation, modulation of chromatin structure and mRNA processing. For two genes, Ddias and Pip4k2a, increased H3K4me3 levels were associated with the increased mRNA expression in MS group.ConclusionThe distribution of H3K4me3 in prefrontal cortex showed relatively low variability across all individuals, and only some subtle changes were revealed in mice with a history of early life stress. It is possible that the observed long-lasting behavioral alterations induced by maternal separation are mediated by other epigenetic mechanisms, or other brain structures are responsible for these effects.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4479-2) contains supplementary material, which is available to authorized users.

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“…Although GR activation increases the expression of FKBP5 , the increased binding of FKBP5 to the GR suppresses GR activity in a negative-feedback way. Thus, alterations in FKBP5 hinders this negative feedback loop and induces “glucocorticoid resistance” (111).…”

Section: The Associations Between Genetic and Epigenetic And Childhoomentioning

confidence: 99%

Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma

et al. 2019

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Adverse childhood experiences (ACEs) may be referred to by other terms (e.g., early life adversity or stress and childhood trauma) and have a lifelong impact on mental and physical health. For example, childhood trauma has been associated with posttraumatic stress disorder (PTSD), anxiety, depression, bipolar disorder, diabetes, and cardiovascular disease. The heritability of ACE-related phenotypes such as PTSD, depression, and resilience is low to moderate, and, moreover, is very variable for a given phenotype, which implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes. Currently, there is increasing interest in the investigation of epigenetic contributions to ACE-induced differential health outcomes. Although there are a number of studies in this field, there are still research gaps. In this review, the basic concepts of epigenetic modifications (such as methylation) and the function of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response are outlined. Examples of specific genes undergoing methylation in association with ACE-induced differential health outcomes are provided. Limitations in this field, e.g., uncertain clinical diagnosis, conceptual inconsistencies, and technical drawbacks, are reviewed, with suggestions for advances using new technologies and novel research directions. We thereby provide a platform on which the field of ACE-induced phenotypes in mental health may build.

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Mechanisms of brain glucocorticoid resistance in stress-induced psychopathologies

Cited by 44 publications

References 138 publications

Natural Selection Equally Supports the Human Tendencies in Subordination and Domination: A Genome-Wide Study With in silico Confirmation and in vivo Validation in Mice

Natural Selection Equally Supports the Human Tendencies in Subordination and Domination: A Genome-Wide Study With in silico Confirmation and in vivo Validation in Mice

Consequences of early life stress on genomic landscape of H3K4me3 in prefrontal cortex of adult mice

Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma

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