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Astrocytic ERK/STAT1 Signaling Contributes to Maintenance of Stress-Related Visceral Hypersensitivity in Rats

  • Author Footnotes
    1 Zhiyu Dong and Tingting Zhan contributed equally to the work.
    Zhiyu Dong
    Footnotes
    1 Zhiyu Dong and Tingting Zhan contributed equally to the work.
    Affiliations
    Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Author Footnotes
    1 Zhiyu Dong and Tingting Zhan contributed equally to the work.
    Tingting Zhan
    Footnotes
    1 Zhiyu Dong and Tingting Zhan contributed equally to the work.
    Affiliations
    Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
    Search for articles by this author
  • Huihui Sun
    Affiliations
    Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Junwen Wang
    Affiliations
    Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Guangbing Duan
    Affiliations
    Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Yan Zhang
    Affiliations
    Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Ying Chen
    Affiliations
    Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Ying Huang
    Correspondence
    Address reprint requests to Ying Huang, PhD, Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Ministry of Education), Department of Physiology and Pharmacology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China.
    Affiliations
    Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Ministry of Education), Department of Physiology and Pharmacology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Shuchang Xu
    Correspondence
    Address reprint requests to Shuchang Xu, MD, Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China.
    Affiliations
    Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
    Search for articles by this author
  • Author Footnotes
    1 Zhiyu Dong and Tingting Zhan contributed equally to the work.

      Highlights

      • Astrocytes in rACC contribute to the maintenance of stress-related VH.
      • Upregulated TSP1 and BDNF induced by astrocytic activation may mediate the effect of astrocytes on VH.
      • STAT1 is a downstream mediator of ERK signaling, resulting in VH via activating astrocytes.

      Abstract

      The rostral anterior cingulate cortex (rACC) has been found to be an important brain region in mediating visceral hypersensitivity. However, the underlying mechanisms remain unclear. This study aimed to explore the role of astrocytes in the maintenance of visceral hypersensitivity induced by chronic water avoidance stress (WAS) as well as the potential signaling pathway that activates astrocytes in the rACC. We found that ACC-reactive astrogliosis resulted in the overexpression of c-fos, TSP-1, and BDNF in stress-related visceral hypersensitivity rats. Visceral hypersensitivity was reversed by pharmacological inhibition of astrocytic activation after WAS, as were the overexpression of c-fos, TSP-1 and BDNF. Activation of the astrocytic Gi-pathway increased the visceral sensitivity and expression of c-fos, TSP-1, and BDNF. Visceral hypersensitivity was also ameliorated by the pharmacological inhibition of ERK and STAT1 phosphorylation after WAS. Furthermore, inhibition of the ERK-STAT1 cascade reduced astrocytic activation. These findings suggest that astrocytic ERK/STAT1 signaling in the rACC contributes to the maintenance of stress-related visceral hypersensitivity.

      Perspective

      Visceral hypersensitivity is a key factor in the pathophysiology of irritable bowel syndrome. This study highlights the important role of astrocytic ERK/STAT1 signaling in activating astrocytes in the rostral anterior cingulate cortex, which contributes to visceral hypersensitivity.

      Key Words

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