Chronic stress leads to epigenetic dysregulation in the neuropeptide-Y and cannabinoid CB1 receptor genes in the mouse cingulate cortex

Lomazzo, Ermelinda; König, F.; Abassi, Leila; Jelinek, Ruth; Lutz, Beat

doi:10.1016/j.neuropharm.2016.10.008

Cited by 36 publications

(28 citation statements)

References 67 publications

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“…Recent research supports a potentially pivotal role for epigenetic regulatory pathways in chronic stress–associated visceral hyperalgesia because these pathways play an important role in inducible and reversible gene expression, including receptors involved in pain signal transduction such as the antinociceptive endocannabinoid‐1 receptor and pro‐nociceptive receptor TRPV1 25,53,54 . Epigenetics has been defined as “the study of changes in gene function that are mitotically and/or meiotically heritable that do not entail a change in DNA sequence.” 55 In practice, epigenetic modifications comprise histone variants, post‐translational modifications of amino acids on the amino‐terminal tail of histones, and covalent modifications of DNA bases.…”

Section: Discussionmentioning

confidence: 99%

“…creased paracellular permeability further confirmed the linkage of pro-inflammatory cytokines and intestinal barrier dysfunction. It will be important to compare our results obtained with IL-6 with other relevant pro-inflammatory cytokines in future studies.Recent research supports a potentially pivotal role for epigenetic regulatory pathways in chronic stress-associated visceral hyperalgesia because these pathways play an important role in inducible and reversible gene expression, including receptors involved in pain signal transduction such as the antinociceptive endocannabinoid-1 receptor and pro-nociceptive receptor TRPV1 25,53,54. Epigenetics has been defined as "the study of changes in gene function that are mitotically and/or meiotically heritable that do not entail a change in DNA sequence.…”

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confidence: 99%

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Histone H3K9 methylation regulates chronic stress and IL‐6–induced colon epithelial permeability and visceral pain

Wiley

Zong

Zheng

et al. 2020

Neurogastroenterology Motil

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Background: Chronic stress is associated with activation of the HPA axis, elevation in pro-inflammatory cytokines, decrease in intestinal epithelial cell tight junction (TJ) proteins, and enhanced visceral pain. It is unknown whether epigenetic regulatory pathways play a role in chronic stress-induced intestinal barrier dysfunction and visceral hyperalgesia. Methods: Young adult male rats were subjected to water avoidance stress ± H3K9 methylation inhibitors or siRNAs. Visceral pain response was assessed. Differentiated Caco-2/BBE cells and human colonoids were treated with cortisol or IL-6 ± antagonists. Expression of TJ, IL-6, and H3K9 methylation status at gene promoters was measured. Transepithelial electrical resistance and FITC-dextran permeability were evaluated. Key Results: Chronic stress induced IL-6 up-regulation prior to a decrease in TJ proteins in the rat colon. The IL-6 level inversely correlated with occludin expression. Treatment with IL-6 decreased occludin and induced visceral hyperalgesia. Chronic stress and IL-6 increased H3K9 methylation and decreased transcriptional GR binding to the occludin gene promoter, leading to down-regulation of protein expression and increase in paracellular permeability. Intrarectal administration of a H3K9 methylation antagonist prevented chronic stress-induced visceral hyperalgesia in the rat. In a human colonoid model, cortisol decreased occludin expression, which was prevented by the GR antagonist RU486, and IL-6 increased H3K9 methylation and decreased TJ protein levels, which were prevented by inhibitors of H3K9 methylation. Conclusions & Inferences: Our findings support a novel role for methylation of the repressive histone H3K9 to regulate chronic stress, pro-inflammatory cytokine-mediated reduction in colon TJ protein levels, and increase in paracellular permeability and visceral hyperalgesia.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Histone H3K9 methylation regulates chronic stress and IL‐6–induced colon epithelial permeability and visceral pain

Wiley

Zong

Zheng

et al. 2020

Neurogastroenterology Motil

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“…Increased CB1R mRNA expression in S1, decreased in ACC Cannabinoid receptor 1 (CB1R) is a Gi/o coupled heteroreceptor and are presynaptically expressed on both inhibitory and excitatory neurons in S1 and ACC (Lomazzo et al, 2017;Yeh et al, 2017). Activation of CB1Rs suppresses presynaptic release.…”

Section: Decreased Mrna Expression Of Trkb In S1mentioning

confidence: 99%

Perinatal fentanyl exposure leads to long-lasting impairments in somatosensory circuit function and behavior

Alipio

Haga

Fox

et al. 2020

Preprint

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One consequence of the opioid epidemic are the lasting neurodevelopmental sequelae afflicting children and adolescents exposed to opioids in the womb. The gravity of these consequences is further amplified by the COVID-19 pandemic, in which the use of synthetic opioids, including fentanyl, has increased among pregnant women. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from fentanyl use during pregnancy. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. First, newborn mice exhibit signs of withdrawal, and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams’ health or maternal behavior, these effects appear to result from the direct actions of perinatal fentanyl on the pups’ developing brain. At adolescence, exposed mice exhibited reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. Our in vitro electrophysiology data demonstrate that perinatal fentanyl leads to a long-lasting reduction in S1 synaptic excitation, as evidenced by decreases in excitatory release probability, NMDA receptor-mediated postsynaptic currents, and frequency of miniature excitatory postsynaptic currents, as well as increased frequency of miniature inhibitory postsynaptic currents. In contrast, anterior cingulate cortical neurons exhibit an opposite phenotype, with increased synaptic excitation in perinatal fentanyl exposed mice. Consistent with these synaptic changes, analysis of electrocorticograms revealed that exposed adolescent mice exhibited suppressed ketamine-evoked γ oscillations. Morphological analysis of S1 pyramidal neurons from exposed mice indicate reduced dendritic complexity, dendritic length, and soma size. Further, exposed mice exhibited abnormal cortical mRNA expression of key receptors involved in synaptic transmission and neuronal growth and development, changes that were consistent with the electrophysiological and morphological changes. These findings demonstrate the lasting sequela of perinatal fentanyl exposure on sensory processing and function.

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“…Interestingly, the CB1r antagonist rimonabant attenuated the anxiolytic-like effects of the HDAC inhibitors, suggesting an association between epigenetic mechanisms and ECS signaling (126). Furthermore, in mice exposed to a chronic unpredictable stress (CUS) there were reduced levels of histone H3K9 acetylation (H3K9ac) associated with CB1r encoding gene (127).…”

Section: Animal Studiesmentioning

confidence: 99%

Endocannabinoid System Components as Potential Biomarkers in Psychiatry

et al. 2020

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Chronic stress leads to epigenetic dysregulation in the neuropeptide-Y and cannabinoid CB1 receptor genes in the mouse cingulate cortex

Cited by 36 publications

References 67 publications

Histone H3K9 methylation regulates chronic stress and IL‐6–induced colon epithelial permeability and visceral pain

Histone H3K9 methylation regulates chronic stress and IL‐6–induced colon epithelial permeability and visceral pain

Perinatal fentanyl exposure leads to long-lasting impairments in somatosensory circuit function and behavior

Endocannabinoid System Components as Potential Biomarkers in Psychiatry

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