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Endoplasmic Reticulum Stress-Activated Neuronal and Microglial Autophagy Contributes to Postoperative Cognitive Dysfunction in Neonatal rats


Surgery and anesthesia in neonates may lead to cognitive impairment or abnormal behaviors. It has been shown that autophagy plays a critical role in neuropsychiatric disorders, while the role of autophagy in postoperative cognitive impairment in neonates is not known. Here, we determined this role and the involvement of endoplasmic reticulum (ER) stress in regulating brain cell autophagy after surgery. Seven-day old neonatal rats (P7) had right common carotid artery exposure under anesthesia with 3% sevoflurane for 2 h. Learning and memory were tested using Barnes maze (BM) and fear conditioning (FC) on P31–42 and P42–44, respectively. In another experiment, rat brains were harvested for biochemical studies. The ratio of microtubule-associated protein 1 light chain 3 (LC3) BII/I was increased and sequestosome 1 (P62/SQSTM1) levels were decreased in the brain 24 h after surgery and anesthesia in neonatal rats. Immunofluorescent staining of LC3B was co-localized with a neuronal or a microglial marker but was not co-localized with a marker for astrocytes in rats with surgery. These rats had a poorer performance in the BM and FC tests than control rats when they were adolescent. Pretreatment with an autophagy inhibitor, 3-methyladenine, attenuated the poor performance. Surgery and anesthesia increased the expression of 78 kDa glucose-regulated protein (BIP/GRP78), an indicator of ER stress, 6 h after surgery and anesthesia. The ER stress activator tunicamycin and inhibitor tauroursodeoxycholic acid increased the markers for autophagy in control rats and decreased the autophagy markers in rats with surgery, respectively. Our results suggest that surgery in neonatal rats induces ER stress that then activates neuronal and microglial autophagy, which contributes to learning and memory impairment later in life.

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Data Availability

The data are available upon reasonable request.


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This study was supported by grants (R01 HD089999, RF1 AG061047 and R01 NS099118 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 and the National Natural Science Foundation of China (82001153 to H Zhang), Beijing, China.

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ZZ conceived the project; HZ, JY and ZZ designed the studies; HZ, XS, JL and WS performed the experiments and initial data analysis. HZ drafted the manuscript and prepared the figures. ZZ performed the final analysis of the data and wrote the manuscript.

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Correspondence to Zhiyi Zuo.

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Zhang, H., Sun, X., Li, J. et al. Endoplasmic Reticulum Stress-Activated Neuronal and Microglial Autophagy Contributes to Postoperative Cognitive Dysfunction in Neonatal rats. Neurochem Res 48, 1835–1847 (2023).

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