Early life alcohol exposure primes hypothalamic microglia to later-life hypersensitivity to immune stress: possible epigenetic mechanism

Chastain, Lucy G.; Franklin, Tina; Gangisetty, Omkaram; Cabrera, Miguel A.; Mukherjee, S.; Shrivastava, Pallavi; Jabbar, Shaima; Sarkar, Dipak K.

doi:10.1038/s41386-019-0326-7

Cited by 47 publications

(51 citation statements)

References 52 publications

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“…However, the other half of the animals had values greater than 4%. Similarly, we found that two of the five animals dissected for the hypothalamus have global DNA methylation levels within the previously reported range of 0.5% to 1.25% and the remaining samples have greater than 3.3% global DNA methylation [20]. While these levels of global DNA methylation seem high for brain tissues, our data are similar to that previously reported for cattle [21].…”

Section: Discussionsupporting

confidence: 91%

Global DNA Methylation in the Limbic System of Cattle

et al. 2019

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To elucidate the extent to which DNA methylation varies across multiple tissues in the brain and between animals, we have quantified global DNA methylation in tissues comprising the limbic system for six Red Angus x Simmental steers. Global DNA methylation was measured in nine regions of the bovine brain: amygdala, the bed nucleus of the stria terminalis, cingulate gyrus, dorsal raphe, hippocampus, hypothalamus, nucleus accumbens, periaqueductal gray and prefrontal cortex. DNA methylation varies among animals for each tissue type and varies among tissue types for each animal. The highest amounts of DNA methylation were found in the amygdala, cingulate gyrus and dorsal raphe, while the bed nucleus of the stria terminalis, nucleus accumbens and periaqueductal gray had the lowest amounts of DNA methylation. A heatmap sorted by k-means clustering was generated to graphically display percent DNA methylation in relation to tissue type and animal number. This is the first study to report measures of DNA methylation in the limbic system of the bovine brain and can be used to inform the cattle genomics community of expected variation in cattle brain methylation.

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Section: Discussionsupporting

confidence: 91%

Global DNA Methylation in the Limbic System of Cattle

et al. 2019

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“…In adulthood, similar molecular alterations were detected only in alcohol-fed rats that received an LPS immune challenge later in life. These LPS-induced effects were rescued in animals administered minocycline during alcohol feeding, suggesting a priming effect of early ethanol on microglia [78].…”

Section: Postnatal Environmental Agents and Infectionmentioning

confidence: 92%

“…A large body of literature focusing on alcohol exposure in early postnatal life describes an increase in microglial activation markers and phenotype changes in the cortical and subcortical regions of the brain immediately after treatment [77][78][79][80][81][82][83][84][85][86]. Regarding cell density, contrasting findings have been collected, with some studies showing an increase [78,86] and others a decrease [79,85,87] in the number of microglial cells in both cortical and subcortical compartments. It has also been shown that alcohol induces an increase in amoeboid microglia along with a decrease in resting microglia in the HIP and cerebellum [82].…”

Section: Postnatal Environmental Agents and Infectionmentioning

confidence: 99%

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Catale

Gironda

Iacono

et al. 2020

JCM

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The putative effects of early-life stress (ELS) on later behavior and neurobiology have been widely investigated. Recently, microglia have been implicated in mediating some of the effects of ELS on behavior. In this review, findings from preclinical and clinical literature with a specific focus on microglial alterations induced by the exposure to ELS (i.e., exposure to behavioral stressors or environmental agents and infection) are summarized. These studies were utilized to interpret changes in developmental trajectories based on the time at which the stress occurred, as well as the paradigm used. ELS and microglial alterations were found to be associated with a wide array of deficits including cognitive performance, memory, reward processing, and processing of social stimuli. Four general conclusions emerged: (1) ELS interferes with microglial developmental programs, including their proliferation and death and their phagocytic activity; (2) this can affect neuronal and non-neuronal developmental processes, which are dynamic during development and for which microglial activity is instrumental; (3) the effects are extremely dependent on the time point at which the investigation is carried out; and (4) both pre- and postnatal ELS can prime microglial reactivity, indicating a long-lasting alteration, which has been implicated in behavioral abnormalities later in life.

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“…Additionally, the Kdm6a histone demethylase found differentially expressed in stress and ethanol + stress groups is important for microglia function in the clearance of dying neurons. In fact, developmental alcohol exposure leads to lasting disruption of microglia in rodents [79]. Further work in this area should focus on cell type differences that underlie the observations described here.…”

Section: Discussionmentioning

confidence: 72%

Hippocampal transcriptome analysis following maternal separation implicates altered RNA processing in a mouse model of fetal alcohol spectrum disorder

Alberry

Castellani

Singh

2020

J Neurodevelop Disord

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Background: Fetal alcohol spectrum disorders (FASD) are common, seen in 1-5% of the population in the USA and Canada. Children diagnosed with FASD are not likely to remain with their biological parents, facing early maternal separation and foster placements throughout childhood. Methods: We model FASD in mice via prenatal alcohol exposure and further induce early life stress through maternal separation. We use RNA-seq followed by clustering of expression profiles through weighted gene coexpression network analysis (WGCNA) to analyze transcriptomic changes that result from the treatments. We use reverse transcription qPCR to validate these changes in the mouse hippocampus. Results: We report an association between adult hippocampal gene expression and prenatal ethanol exposure followed by postnatal separation stress that is related to behavioral changes. Expression profile clustering using WGCNA identifies a set of transcripts, module 19, associated with anxiety-like behavior (r = 0.79, p = 0.002) as well as treatment group (r = 0.68, p = 0.015). Genes in this module are overrepresented by genes involved in transcriptional regulation and other pathways related to neurodevelopment. Interestingly, one member of this module, Polr2a, polymerase (RNA) II (DNA directed) polypeptide A, is downregulated by the combination of prenatal ethanol and postnatal stress in an RNA-Seq experiment and qPCR validation (q = 2e−12, p = 0.004, respectively). Conclusions: Together, transcriptional control in the hippocampus is implicated as a potential underlying mechanism leading to anxiety-like behavior via environmental insults. Further research is required to elucidate the mechanism involved and use this insight towards early diagnosis and amelioration strategies involving children born with FASD.

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Early life alcohol exposure primes hypothalamic microglia to later-life hypersensitivity to immune stress: possible epigenetic mechanism

Cited by 47 publications

References 52 publications

Global DNA Methylation in the Limbic System of Cattle

Global DNA Methylation in the Limbic System of Cattle

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Hippocampal transcriptome analysis following maternal separation implicates altered RNA processing in a mouse model of fetal alcohol spectrum disorder

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