학술논문
Corticosteroid Treatment During Sepsis Alters Hippocampal Function in Male and Female Survivors.
Document Type
Academic Journal
Author
Hill A; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan.; Khalil H; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan.; Laborc K; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan.; Kounelis-Wuillaume S; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan.; Gavade S; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan.; Johnston C; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan.; Singer BH; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan.; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Spencer-Segal JL; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan.; Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Source
Publisher: Elsevier Inc. on behalf of Society of Biological Psychiatry Country of Publication: United States NLM ID: 9918227369306676 Publication Model: eCollection Cited Medium: Internet ISSN: 2667-1743 (Electronic) Linking ISSN: 26671743 NLM ISO Abbreviation: Biol Psychiatry Glob Open Sci Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
Background: Millions of sepsis survivors annually face neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered for sepsis, and their use improves neuropsychiatric outcomes, but the mechanisms are unknown. In light of prior work that has shown persistent inflammation in sepsis survivors, we hypothesized that short-term corticosteroid treatment during illness would reverse the long-term impact of sepsis on inflammatory gene expression in the hippocampus and rescue associated changes to affective behaviors.
Methods: Male and female mice underwent cecal ligation and puncture or a sham surgery to induce acute infection and were treated for 5 days with corticosterone or vehicle. Starting 2 weeks after the surgery, we performed functional phenotyping in the survivor mice followed by hippocampal RNA sequencing to identify underlying mechanisms.
Results: Long-term cecal ligation and puncture survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal axis activity, and persistent systemic and neuroinflammation. Corticosterone treatment during illness did not reverse anxiety-like behavior or inflammation in survivors. Instead, corticosterone treatment impaired object memory and increased active coping behavior in females. History of corticosterone treatment influenced the expression of >10% of detectable transcripts in the dorsal and ventral hippocampus, including a coordinated downregulation of activity-dependent genes.
Conclusions: Corticosterone treatment during sepsis impaired memory formation in survivors and caused a lasting decrease in hippocampal neural activity, which could underlie its effect on memory. Future studies should focus on how this lasting effect of corticosteroid treatment on hippocampal activity and memory translates into improved neuropsychiatric outcomes in human sepsis survivors.
(© 2023 The Authors.)
Methods: Male and female mice underwent cecal ligation and puncture or a sham surgery to induce acute infection and were treated for 5 days with corticosterone or vehicle. Starting 2 weeks after the surgery, we performed functional phenotyping in the survivor mice followed by hippocampal RNA sequencing to identify underlying mechanisms.
Results: Long-term cecal ligation and puncture survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal axis activity, and persistent systemic and neuroinflammation. Corticosterone treatment during illness did not reverse anxiety-like behavior or inflammation in survivors. Instead, corticosterone treatment impaired object memory and increased active coping behavior in females. History of corticosterone treatment influenced the expression of >10% of detectable transcripts in the dorsal and ventral hippocampus, including a coordinated downregulation of activity-dependent genes.
Conclusions: Corticosterone treatment during sepsis impaired memory formation in survivors and caused a lasting decrease in hippocampal neural activity, which could underlie its effect on memory. Future studies should focus on how this lasting effect of corticosteroid treatment on hippocampal activity and memory translates into improved neuropsychiatric outcomes in human sepsis survivors.
(© 2023 The Authors.)