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Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity

Patients with irritable bowel syndrome (IBS) experience not only enhanced visceral pain but also emotional comorbidities, such as anxiety and depression. Early life stress (ELS) is a high-risk for the development of IBS. Literatures have reported an important epigenetic modulation in sustaining extr...

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Autores principales: Guan, Le, Shi, Xi, Tang, Ying, Yan, Yan, Chen, Liang, Chen, Yu, Gao, Guangcheng, Lin, Chun, Chen, Aiqin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120649/
https://www.ncbi.nlm.nih.gov/pubmed/35600618
http://dx.doi.org/10.3389/fnins.2022.843396
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author Guan, Le
Shi, Xi
Tang, Ying
Yan, Yan
Chen, Liang
Chen, Yu
Gao, Guangcheng
Lin, Chun
Chen, Aiqin
author_facet Guan, Le
Shi, Xi
Tang, Ying
Yan, Yan
Chen, Liang
Chen, Yu
Gao, Guangcheng
Lin, Chun
Chen, Aiqin
author_sort Guan, Le
collection PubMed
description Patients with irritable bowel syndrome (IBS) experience not only enhanced visceral pain but also emotional comorbidities, such as anxiety and depression. Early life stress (ELS) is a high-risk for the development of IBS. Literatures have reported an important epigenetic modulation in sustaining extrinsic phenotypes. The amygdala is closely related to the regulation of visceral functions and emotional experiences. In this study, we hypothesized that ELS-induced reprogramming inappropriate adaptation of histone acetylation modification in the amygdala may result in visceral hypersensitivity and anxiety-like behaviors in ELS rats. To test this hypothesis, the model of ELS rats was established by neonatal colorectal dilatation (CRD). Visceral hypersensitivity was assessed based on the electromyography response of the abdominal external oblique muscle to CRD. Emotional comorbidities were examined using the elevated plus maze test, open field test, and sucrose preference test. Trichostatin A (TSA) and C646 were microinjected into the central amygdala (CeA) individually to investigate the effects of different levels of histone acetylation modification on visceral hypersensitivity and emotion. We found neonatal CRD resulted in visceral hypersensitivity and anxiety-like behaviors after adulthood. Inhibiting histone deacetylases (HDACs) in the CeA by TSA enhanced visceral sensitivity but did not affect anxiety-like behaviors, whereas inhibiting HAT by C646 attenuated visceral hypersensitivity in ELS rats. Interestingly, CeA treatment with TSA induced visceral sensitivity and anxiety-like behaviors in the control rats. Western blot showed that the expressions of acetylated 9 residue of Histone 3 (H3K9) and protein kinase C zeta type (PKMζ) were higher in the ELS rats compared to those of the controls. The administration of the PKMζ inhibitor ZIP into the CeA attenuated visceral hypersensitivity of ELS rats. Furthermore, the expression of amygdala PKMζ was enhanced by TSA treatment in control rats. Finally, western blot and immunofluorescence results indicated the decrease of HDAC1 and HDAC2 expressions, but not HDAC3 expression, contributed to the enhancement of histone acetylation in ELS rats. Our results support our hypothesis that amygdala-enhanced histone acetylation induced by stress in early life results in visceral hypersensitivity and anxiety-like behaviors in ELS rats, and reversing the abnormal epigenetic mechanisms may be crucial to relieve chronic symptoms in ELS rats.
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spelling pubmed-91206492022-05-21 Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity Guan, Le Shi, Xi Tang, Ying Yan, Yan Chen, Liang Chen, Yu Gao, Guangcheng Lin, Chun Chen, Aiqin Front Neurosci Neuroscience Patients with irritable bowel syndrome (IBS) experience not only enhanced visceral pain but also emotional comorbidities, such as anxiety and depression. Early life stress (ELS) is a high-risk for the development of IBS. Literatures have reported an important epigenetic modulation in sustaining extrinsic phenotypes. The amygdala is closely related to the regulation of visceral functions and emotional experiences. In this study, we hypothesized that ELS-induced reprogramming inappropriate adaptation of histone acetylation modification in the amygdala may result in visceral hypersensitivity and anxiety-like behaviors in ELS rats. To test this hypothesis, the model of ELS rats was established by neonatal colorectal dilatation (CRD). Visceral hypersensitivity was assessed based on the electromyography response of the abdominal external oblique muscle to CRD. Emotional comorbidities were examined using the elevated plus maze test, open field test, and sucrose preference test. Trichostatin A (TSA) and C646 were microinjected into the central amygdala (CeA) individually to investigate the effects of different levels of histone acetylation modification on visceral hypersensitivity and emotion. We found neonatal CRD resulted in visceral hypersensitivity and anxiety-like behaviors after adulthood. Inhibiting histone deacetylases (HDACs) in the CeA by TSA enhanced visceral sensitivity but did not affect anxiety-like behaviors, whereas inhibiting HAT by C646 attenuated visceral hypersensitivity in ELS rats. Interestingly, CeA treatment with TSA induced visceral sensitivity and anxiety-like behaviors in the control rats. Western blot showed that the expressions of acetylated 9 residue of Histone 3 (H3K9) and protein kinase C zeta type (PKMζ) were higher in the ELS rats compared to those of the controls. The administration of the PKMζ inhibitor ZIP into the CeA attenuated visceral hypersensitivity of ELS rats. Furthermore, the expression of amygdala PKMζ was enhanced by TSA treatment in control rats. Finally, western blot and immunofluorescence results indicated the decrease of HDAC1 and HDAC2 expressions, but not HDAC3 expression, contributed to the enhancement of histone acetylation in ELS rats. Our results support our hypothesis that amygdala-enhanced histone acetylation induced by stress in early life results in visceral hypersensitivity and anxiety-like behaviors in ELS rats, and reversing the abnormal epigenetic mechanisms may be crucial to relieve chronic symptoms in ELS rats. Frontiers Media S.A. 2022-05-06 /pmc/articles/PMC9120649/ /pubmed/35600618 http://dx.doi.org/10.3389/fnins.2022.843396 Text en Copyright © 2022 Guan, Shi, Tang, Yan, Chen, Chen, Gao, Lin and Chen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Guan, Le
Shi, Xi
Tang, Ying
Yan, Yan
Chen, Liang
Chen, Yu
Gao, Guangcheng
Lin, Chun
Chen, Aiqin
Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity
title Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity
title_full Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity
title_fullStr Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity
title_full_unstemmed Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity
title_short Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity
title_sort contribution of amygdala histone acetylation in early life stress-induced visceral hypersensitivity and emotional comorbidity
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120649/
https://www.ncbi.nlm.nih.gov/pubmed/35600618
http://dx.doi.org/10.3389/fnins.2022.843396
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