Investigating the Regulatory Role of PKR in Systemic Inflammation Triggered Neuroinflammation and its Role in Cholinergic Neurons in Modulating Cognitive Functions

Abstract Background Double‐stranded RNA‐dependent protein kinase (PKR) is a key signaling molecule that regulates immune responses by regulating macrophage activation, various inflammatory pathways, and the formation of inflammasomes. Meanwhile, PKR in neurons helps mediate stress responses of Aß to trigger apoptosis and affects cognitive functions. This study aims at investigating whether PKR can be a pharmacological target to prevent systemic inflammation‐triggered neuroinflammation and cognitive dysfunctions. Method The experimental model of laparotomy is adopted to address the systemic inflammation initiated by surgery. Male C57BL/6J and PKR‐KO mice were divided into two groups: control group under sevoflurane anesthesia and laparotomy group under sevoflurane anesthesia. Cytokine mRNA expression in tissues was examined by quantitative RT‐PCR. Behavioral tests were performed to examine the effects of laparotomy on cognitive functions. Furthermore, to examine the role of PKR in cholinergic neurons, stereotaxic injection of dominant negative AAV‐DIO‐PKR‐K296R into the right lateral ventricle of the Rosa‐ChAT‐IRES‐Cre mice was performed to inhibit PKR in cholinergic neurons. Result Our preliminary study showed that laparotomy induced systemic and neural inflammation in male C57BL/6J mice. At 4 h and one day after laparotomy, genetic knockout of PKR in mice potently downregulated the elevated IL‐1ß expression generated by laparotomy in both the liver and frontal brain. Additonally, cognitive impairment was observed in wild type mice following laparotomy in terms of the decline in problem‐solving abilities, impaired short‐term and long term memory in the puzzle box test; reduced recognition memory in the novel object recognition test; and impaired spatial working memory in the spontaneous Y‐maze; while for PKR‐KO mice, cognitive flexibility, short‐term and long term memory recognition memory remained intact after laparotomy. Furthermore, at 4 weeks after stereotaxic injection of AAV‐DIO‐PKR‐K296R, a significant reduction of p‐PKR level was observed in cholinergic neurons. It implies that the AAVcan inhibit the phosphorylation of PKR in cholinergic neurons. Conclusion This study reveals that genetic knockout of PKR in mice could attenuate laparotomy induced systemic inflammation, neuroinflammation, and cognitive impairment.Further studies will be performed to examine the effect of knockout of PKR in cholinergic neurons on cognitive functions. Acknowledgement:The study is supported by General Research Fund (17123217) to RCCC.