DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors

Wei, Jing; Cheng, Jia; Waddell, Nicholas J.; Wang, Zi Jun; Pang, Xiaodong; Cao, Qing; Liu, Aiyi; Chitaman, Javed M.; Abreu, Kristen; Jasrotia, Rahul Singh; Duffney, Lara J.; Zhang, Jinfeng; Dietz, David M.; Feng, Jian; Yan, Zhen

doi:10.1093/cercor/bhaa337

Cited by 14 publications

(8 citation statements)

References 90 publications

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“…The genome-wide molecular changes in response to chronic stress have been extensively characterized (1)(2)(3)(4)(5)(6)(7)(8), as chronic stress is a major risk factor for neuropsychiatric disorders (9)(10)(11)(12). Much less is known about the genome-wide response to acute stress, although the border between acute and chronic stress is diffuse.…”

Section: Molecular Correlates Of Allostasismentioning

confidence: 99%

The Acute Stress Response in the Multiomic Era

Floriou-Servou

Ziegler

Waag

et al. 2021

Biological Psychiatry

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Studying the stress response is a major pillar of neuroscience research not only because stress is a daily reality but also because the exquisitely fine-tuned bodily changes triggered by stress are a neuroendocrinological marvel. While the genome-wide changes induced by chronic stress have been extensively studied, we know surprisingly little about the complex molecular cascades triggered by acute stressors, the building blocks of chronic stress. The acute stress (or fight-or-flight) response mobilizes organismal energy resources to meet situational demands. However, successful stress coping also requires the efficient termination of the stress response. Maladaptive coping-particularly in response to severe or repeated stressors-can lead to allostatic (over)load, causing wear and tear on tissues, exhaustion, and disease. We propose that deep molecular profiling of the changes triggered by acute stressors could provide molecular correlates for allostatic load and predict healthy or maladaptive stress responses. We present a theoretical framework to interpret multiomic data in light of energy homeostasis and activity-dependent gene regulation, and we review the signaling cascades and molecular changes rapidly induced by acute stress in different cell types in the brain. In addition, we review and reanalyze recent data from multiomic screens conducted mainly in the rodent hippocampus and amygdala after acute psychophysical stressors. We identify challenges surrounding experimental design and data analysis, and we highlight promising new research directions to better understand the stress response on a multiomic level.

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Section: Molecular Correlates Of Allostasismentioning

confidence: 99%

The Acute Stress Response in the Multiomic Era

Floriou-Servou

Ziegler

Waag

et al. 2021

Biological Psychiatry

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“…Given the profound role of the brain as the central organ for stress sensing and response as well as the regulation of systemic stress, the goal of this study was to define the major molecular changes of stress-associated genes and metabolites in an unbiased manner. Previous rodent studies have been predominantly conducted under repeated or chronic stress conditions [ 27 , 28 , 32 , 36 , 39 , 42 , 43 , 47 ]. However, compared to our understanding of the effects of chronic stress, the impacts of acute stress (AS) on the brain remain largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have explored stress-mediated molecular alterations in the brain [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Some studies have demonstrated transcriptional changes at different time points after stress challenge [ 25 , 34 , 35 , 36 , 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolic and Transcriptomic Signatures of the Acute Psychological Stress Response in the Mouse Brain

2023

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Acute stress response triggers various physiological responses such as energy mobilization to meet metabolic demands. However, the underlying molecular changes in the brain remain largely obscure. Here, we used a brief water avoidance stress (WAS) to elicit an acute stress response in mice. By employing RNA-sequencing and metabolomics profiling, we investigated the acute stress-induced molecular changes in the mouse whole brain. The aberrant expression of 60 genes was detected in the brain tissues of WAS-exposed mice. Functional analyses showed that the aberrantly expressed genes were enriched in various processes such as superoxide metabolism. In our global metabolomic profiling, a total of 43 brain metabolites were significantly altered by acute WAS. Metabolic pathways upregulated from WAS-exposed brain tissues relative to control samples included lipolysis, eicosanoid biosynthesis, and endocannabinoid synthesis. Acute WAS also elevated the levels of branched-chain amino acids, 5-aminovalerates, 4-hydroxy-nonenal-glutathione as well as mannose, suggesting complex metabolic changes in the brain. The observed molecular events in the present study provide a valuable resource that can help us better understand how acute psychological stress impacts neural functions.

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“…In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Chronic stress-induced behavioral abnormalities could be partially attenuated by Dnmt3a expression in PFC ( 65 ). Third, this study only used male rats.…”

Section: Discussionmentioning

confidence: 99%

Maternal Deprivation Increased Vulnerability to Depression in Adult Rats Through DRD2 Promoter Methylation in the Ventral Tegmental Area

Guo

et al. 2022

Front. Psychiatry

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ObjectiveEarly life adversity is a risk factor for depression in adulthood; however, the underlying mechanisms are not well understood. This study aims to investigate the effect of DNA methylation of DRD2 gene on early life stress–induced depression in adult rats.MethodsNewborn Sprague–Dawley rats were randomly assigned to four groups: maternal deprivation group (MD), chronic unpredictable stress (CUS) group, maternal deprivation plus chronic unpredictable stress (MD/CUS) group, and normal control group (NOR). Behaviors were measured by open field test (OFT), sucrose preference test (SPT), and Original Research Article forced swimming test (FST). Fecal CORT level was detected by ELISA. Bisulfite amplicon sequencing PCR was used to assess methylation levels of DRD2 promoter.ResultsCUS and MD/CUS rats had a significantly shorter total distance, longer immobility time, and higher CORT level, while MD and MD/CUS rats had a significantly lower percentage of central distance, more feces, lower rate of sucrose preference, and lower levels of DRD2 protein and mRNA in the VTA than NOR rats. CUS rats showed a significantly higher DRD2 mRNA and protein levels in the VTA than NOR rats. CUS, MD, and MD/CUS rats showed a significantly higher level of DRD2 promoter methylation than NOR rats. CORT level was significantly correlated with the sucrose preference rate in SPT, the immobility time in FST, the total distance, and the number of fecal pellets in OFT. DRD2 protein level was significantly correlated with the sucrose preference rate and the number of fecal pellets. DRD2 mRNA level was significantly correlated with the percentage of central distance and the number of fecal pellets in OFT. The level of DRD2 promoter methylation was significantly correlated with the sucrose preference rate, immobility time, total distance, the percentage of central distance, and the number of fecal pellets.ConclusionsEarly life MD increased vulnerability to stress-induced depressive-like behavior in adult rats. Enhanced DRD2 promoter methylation in the VTA may increase the susceptibility to depression.

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DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors

Cited by 14 publications

References 90 publications

The Acute Stress Response in the Multiomic Era

The Acute Stress Response in the Multiomic Era

Metabolic and Transcriptomic Signatures of the Acute Psychological Stress Response in the Mouse Brain

Maternal Deprivation Increased Vulnerability to Depression in Adult Rats Through DRD2 Promoter Methylation in the Ventral Tegmental Area

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