Regulatory Role of PKR in Systemic Inflammation-Triggered Neuroinflammation and its Modulation of Glucose Metabolism and Cognitive Functions in Cholinergic Neurons

Systemic inflammation may promote neuroinflammation and neurodegeneration. The double-stranded RNA-dependent protein kinase (PKR) is a key signaling molecule that regulates immune responses. This study aims to examine the role of PKR in regulating systemic inflammation-induced neuroinflammation and cognitive dysfunctions using a laparotomy mouse model. In the first part, wild-type C57BL/6J and C57BL/6-Tg(CD68-EGFP)1Drg/J mice were assigned to undergo either laparotomy with sevoflurane anesthesia or sevoflurane alone to examine effects of systemic inflammation on neuroinflammation and cognition. In the second part, PKR-/- mice were used to study the role of PKR in modulating laparotomy-induced systemic inflammation, neuroinflammation, and cognition. For the third part, PKR was inhibited selectively in cholinergic neurons of ChAT-IRES-Cre-eGFP mice via intracerebroventricular injection of rAAV-DIO-PKR-K296R. This examined the effects of inhibiting PKR in cholinergic neurons on glucose metabolism and cognition in the laparotomy model. Our study revealed that genetic deletion of PKR in mice potently attenuated the laparotomy-induced peripheral and neural inflammation and cognitive deficits. Furthermore, inhibiting PKR in the cholinergic neurons rescued the laparotomy-induced brain glucose hypometabolism and cognitive impairment. Our results demonstrated the critical role of PKR in regulating neuroinflammation and cognitive dysfunctions in a peripheral inflammation model. PKR could be a pharmacological target for treating systemic inflammation-induced neuroinflammation and cognitive dysfunctions. ### Competing Interest Statement The authors have declared no competing interest. * AAV-CON : The AAV-treated group given only sevoflurane AAV-LAP : The AAV-treated group subjected to laparotomy AD : Alzheimer’s disease CA : Cornu ammonis CD68-eGFP mice : C57BL/6-Tg(CD68-EGFP)1Drg/J mice DAPI : 4’, 6-Diamidino-2-phenylindole DG : Dentate gyrus DIO : Double-floxed inverse orientation dsRNA : Double-stranded RNA eGFP : Enhanced green fluorescent protein eIF2α : Eukaryotic initiation factor-2alpha GC-MS/MS : Gas chromatography-tandem mass spectrometry Iba1 : Ionized calcium-binding adaptor molecule 1 JNK : c-Jun N-terminal kinase LPS : Lipopolysaccharide LTP : Long-term potentiation MAPKs : Mitogen-activated protein kinases MCP : Monocyte chemoattractant protein NF-κB : Nuclear factor κB NOR : Novel object recognition test OFT : Open field test PD : Parkinson’s disease PKR : Double-stranded RNA-dependent protein kinase PND : Perioperative neurocognitive disorders POD : Postoperative day SAL-CON : The saline-treated control group given only sevoflurane SAL-LAP : The saline-treated group subjected to laparotomy SYM : Spontaneous alternation Y-maze test TMEM119 : Transmembrane protein 119 TRBP : TAR RNA-binding protein