Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus

Zheng, Yi-Nan; Fan, Weidong; Zhang, Xianquan; Dong, Erbao

doi:10.1080/15592294.2016.1146850

Cited by 79 publications

(81 citation statements)

References 63 publications

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“…Levels of N3RC1 methylation in fetal cord blood were further found to predict infant HPA reactivity (cortisol response to stress) at three months of age, suggesting a possible functional consequence of this epigenetic variation. In another study, maternal depressive symptoms during pregnancy predicted not only increased NR3C1 DNA methylation in buccal cells of male infants but also decreased BDNF IV DNA methylation in both male and female infants [100], further implicating epigenetic changes in BDNF in response to maternal adversity, as previously shown by animal studies [51,61,62]. Maternal stress during pregnancy was also shown to affect offspring’s N3RC1 DNA methylation beyond infancy [101].…”

Section: Evidence From Human Studiesmentioning

confidence: 79%

“…Brain-derived neurotrophic factor ( Bdnf ) is another candidate gene for which the epigenetic sensitivity to prenatal stress was examined by multiple studies [51,61,62]. BDNF is crucial for neurodevelopment and synaptic plasticity [63], and its deficiency, including BDNF promoter hypermethylation, has been linked to multiple psychiatric disorders that are associated with early-life adversity, including SCZ [64], depression [65,66], bipolar disorder [67], and autism [68].…”

Section: Experimental Evidence From Animal Studiesmentioning

confidence: 99%

“…Prenatal stress-induced molecular changes were further associated with hyperactivity and impaired social interaction, drawing a possible link between the epigenetic effects of prenatal stress and neurodevelopmental disorders such as SCZ. In addition, Zheng et al [62] showed that maternal stress exposure during pregnancy induces anxiety- and depression-like behavior in the offspring, which is associated with transcriptional and epigenetic changes within the Bdnf gene. This research group specifically looked in the hippocampus and demonstrated that prenatal stress was associated with reduced Bdnf expression as well as increased DNA methylation and decreased histone acetylation (H3K14ac) at specific Bdnf promoters.…”

Section: Experimental Evidence From Animal Studiesmentioning

confidence: 99%

“…Studies by Dong et al [51] and Zheng et al [62] have also shown that gestational stress induces long-term changes in the expression of epigenetic regulators, such as DNA methylation machinery (DNMT1 and TET1) and histone modifiers (histone deacetylases HDAC1 and HDAC2). The enduring effect on epigenetic machinery may provide a possible mechanism through which prenatal stress induces epigenetic changes, suggesting that the changes may be widespread, including hundreds and thousands of genes.…”

Section: Experimental Evidence From Animal Studiesmentioning

confidence: 99%

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The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

Kundaković

Jarić

2017

Genes

145

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Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf). These epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. Although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. An extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders.

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Section: Evidence From Human Studiesmentioning

confidence: 79%

Section: Experimental Evidence From Animal Studiesmentioning

confidence: 99%

Section: Experimental Evidence From Animal Studiesmentioning

confidence: 99%

Section: Experimental Evidence From Animal Studiesmentioning

confidence: 99%

See 2 more Smart Citations

The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

Kundaković

Jarić

2017

Genes

145

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“…BDNF , CDK5 ) involved in learning and memory, as well as multiple genes involved in synaptic plasticity, (e.g. SYP, STY1) as downstream targets (3, 6, 16). Collectively, these studies provide unequivocal support that localized HDAC expression levels drive pivotal epigenetic mechanisms that modulate neuronal function.…”

Section: Introductionmentioning

confidence: 99%

Insights into neuroepigenetics through human histone deacetylase PET imaging

et al. 2016

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Epigenetic dysfunction is implicated in many neurological and psychiatric diseases, including Alzheimer’s disease and schizophrenia. Consequently, histone deacetylases (HDACs) are being aggressively pursued as therapeutic targets. However, a fundamental knowledge gap exists regarding the expression and distribution of HDACs in healthy individuals for comparison to disease states. Here, we report the first-in-human evaluation of neuroepigenetic regulation in vivo. Using positron emission tomography (PET) with [11C]Martinostat, an imaging probe selective for class I HDACs (isoforms 1–3), we found HDAC expression is higher in cortical gray matter than white matter with strikingly conserved regional distribution patterns within and between healthy individuals. Among gray matter regions, HDAC expression is lowest in the hippocampus and amygdala. Through biochemical profiling of postmortem human brain tissue, we confirmed [11C]Martinostat selectively binds HDAC isoforms 1–3, the HDAC subtypes most implicated in regulating neuroplasticity and cognitive function. To relate the PET imaging signal to the epigenetic regulation of gene transcription, we measured mRNA expression changes elicited by Martinostat in human stem cell-derived neural progenitor cells. We demonstrate that genes closely associated with synaptic plasticity, including BDNF (brain derived neurotrophic factor) and SYP (synaptophysin), as well as genes implicated in neurodegeneration, including GRN (progranulin), were markedly increased at the transcript level in concert with increased acetylation at both histone H3 lysine 9 and histone H4 lysine 12. This study provides the first quantification of HDAC expression in the living human brain, and provides the foundation for gaining unprecedented in vivo epigenetic information in the healthy and diseased human brain.

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A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder

Hing

Sathyaputri

Potash

2017

American J of Med Genetics Pt B

104

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Major depressive disorder (MDD) is a mood disorder that affects behavior and impairs cognition. A gene potentially important to this disorder is the brain derived neurotrophic factor (BDNF) as it is involved in processes controlling neuroplasticity. Various mechanisms exist to regulate BDNF's expression level, subcellular localization, and sorting to appropriate secretory pathways. Alterations to these processes by genetic factors and negative stressors can dysregulate its expression, with possible implications for MDD. Here, we review the mechanisms governing the regulation of BDNF expression, and discuss how disease-associated single nucleotide polymorphisms (SNPs) can alter these mechanisms, and influence MDD. As negative stressors increase the likelihood of MDD, we will also discuss the impact of these stressors on BDNF expression, the cellular effect of such a change, and its impact on behavior in animal models of stress. We will also describe epigenetic processes that mediate this change in BDNF expression. Similarities in BDNF expression between animal models of stress and those in MDD will be highlighted. We will also contrast epigenetic patterns at the BDNF locus between animal models of stress, and MDD patients, and address limitations to current clinical studies. Future work should focus on validating current genetic and epigenetic findings in tightly controlled clinical studies. Regions outside of BDNF promoters should also be explored, as should other epigenetic marks, to improve identification of biomarkers for MDD.

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Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus

Cited by 79 publications

References 63 publications

The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

Insights into neuroepigenetics through human histone deacetylase PET imaging

A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder

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