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Inhibition of ERK/CREB signaling contributes to postoperative learning and memory dysfunction in neonatal rats

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Abstract

Exposure to surgery with anesthesia early in life may lead to abnormal behavior, learning, and memory in humans. Pre-clinical studies have suggested a critical role of glial cell-derived neurotrophic factor (GDNF) in these effects. We hypothesize that the inhibition of extracellular signal-regulated kinase (ERK)-cAMP response element-binding protein (CREB) pathway contributes to GDNF decrease and the dysfunction of learning and memory. To address this hypothesis, 7-day-old Sprague–Dawley male and female rats were subjected to right carotid artery exposure (surgery) under sevoflurane anesthesia. Their learning and memory were tested by the Barnes maze, and novel object recognition tests started 23 days after the surgery. Blood and brain were harvested at various times after surgery for biochemical analyses. Rats with surgery and anesthesia performed poorly in the Barnes maze and novel object recognition tests compared with control rats. Rats with surgery had a decreased GDNF concentration in the brain and urine. The concentrations of urine GDNF were negatively correlated with the performance of rats in a delayed memory phase of the Barnes maze test. Surgery increased proinflammatory cytokines in the blood and brain. Intracerebroventricular injection of GDNF attenuated the increased inflammatory response in surgery rats. Surgery inhibited ERK and CREB. Inhibiting ERK reduced GDNF and induced poor performance in the Barnes maze and novel object recognition tests of rats without surgery. Surgery also increased brain-derived natriuretic peptide (BNP) in the brain. Intracerebroventricular injection of BNP inhibited ERK and CREB, reduced GDNF, and impaired learning and memory. Surgery, ERK inhibition, and BNP reduced the expression of synaptic proteins. Our results suggest that surgery increases BNP that inhibits ERK-CREB signaling to reduce GDNF, which leads to an unbalanced inflammatory response and a reduced synaptic protein expression for the development of postoperative cognitive dysfunction.

Key messages

  • Surgery increases BNP and decreases ERK/CREB signaling to reduce GDNF.

  • The increase in BNP and decrease in ERK/CREB signaling contribute to postoperative cognitive dysfunction.

  • GDNF reduction contributes to neuroinflammatory response after surgery.

  • Urine GDNF concentrations are negatively corrected with poor spatial memory performance.

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Abbreviations

ANOVA:

Analysis of variance

BNP:

Brain-derived natriuretic peptide

C3:

Complement 3

CRE:

CREB binding site

CREB:

CAMP response element-binding protein

DMSO:

Dimethyl sulphoxide

ERK:

Extracellular signal-regulated kinase

GDNF:

Glial cell-derived neurotrophic factor

IL:

Interleukin

PND7:

Postnatal day 7

ROC:

Receiver operating characteristic

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Funding

This study was supported by grants (R01 HD089999, R01 NS099118, and RF1 AG061047 to Z Zuo) from the National Institutes of Health, Bethesda, MD, USA, the Robert M. Epstein Professorship endowment (to Z Zuo), University of Virginia, Charlottesville, VA, USA.

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Authors and Affiliations

  1. Department of Anesthesiology, University of Virginia, Charlottesville, VA, 22901, USA

    Hui Wang, Gang Ma, Jia Min, Jun Li, Weiran Shan & Zhiyi Zuo

  2. Department of Anesthesiology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China

    Hui Wang & Gang Ma

  3. Department of Anesthesiology, the First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China

    Jia Min

  4. Department of Anesthesiology, University of Virginia Health, 1 Hospital Drive, PO Box 800710, Charlottesville, VA, 22908-0710, USA

    Zhiyi Zuo

Authors
  1. Hui Wang
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  2. Gang Ma
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  3. Jia Min
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  4. Jun Li
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  5. Weiran Shan
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  6. Zhiyi Zuo
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Contributions

ZZ conceived the concept of the project; HW and ZZ designed the studies; HW, GM, JM, JL, and WS performed the experiments; HW performed initial data analysis and drafted the Materials and methods; ZZ performed the final analysis of the data and wrote the manuscript.

Corresponding author

Correspondence to Zhiyi Zuo.

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Ethical approval and consent to participate.

This study did not have human subjects. The animal protocol (protocol number 3114) was approved by the Institutional Animal Care and Use Committee of the University of Virginia (Charlottesville, VA, USA).

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Not a human study. All authors have agreed for its publication. No funding agencies have authorities to decide whether the study can be published.

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The authors declare no competing interests.

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Wang, H., Ma, G., Min, J. et al. Inhibition of ERK/CREB signaling contributes to postoperative learning and memory dysfunction in neonatal rats. J Mol Med 101, 265–278 (2023). https://doi.org/10.1007/s00109-023-02285-9

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  • DOI: https://doi.org/10.1007/s00109-023-02285-9

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