Surgery, Anesthesia and Intensive Care Environment Induce Delirium-Like Behaviors and Impairment of Synaptic Function-Related Gene Expression in Aged Mice

Objective: To establish a clinically relevant mouse model of Intensive Care Unit postoperative delirium for further studies of its underlying mechanisms. Methods: Eighteen- to 20- month old C57BL/6J mice were tested at baseline in the Y-maze, buried food, simple discrimination task of the attentional set-shifting test, and open field tests. They were subsequently randomized to insult exposure (anesthesia, surgery and Intensive Care Unit environment) or control group. Insult-exposed mice received laparotomy under sevoflurane anesthesia, propofol sedation and exposure to intermittent lights, sounds and cage shaking. Controls did not receive anesthesia, surgery, or intensive care environment. All mice were tested in the Y-maze, buried food, attentional, and open field tests at the end of intensive care environment (0h) and every 6 hours up to 24 hours. Mouse hippocampi were collected at 24 hours for gene expression analyses. Results: Surgery, anesthesia and Intensive Care Unit environment decreased the number of entries in the Y-maze novel arm at 0h (P=0.001), 6h (P<0.001), 18h (P=0.002) and 24h (P=0.029). Insult exposure increased the latency to find a buried cereal reward at 18h (P= 0.035) and 24h (P=0.027) in the buried food test, and increased the trials to achieve criterion in the reverse compound discrimination (P=0.013) and extradimensional shift (P<0.001) tasks of the attentional test. There were decreases in mRNA levels of synuclein alpha (-3.785 fold change relative to controls), Neurotrophic Receptor Tyrosine Kinase1 (-2.267), and syntaxin1a (-1.498) in the hippocampus of mice 24 h after treatment. Protein levels of syntaxin1a (P=0.012), Neurotrophic Receptor Tyrosine Kinase1 (P=0.039), synuclein alpha (P=0.017), and phosphorylated synuclein alpha (P=0.008) were also decreased after exposure, relative to controls. Conclusions: Surgery, anesthesia and Intensive Care Unit environment impaired mouse behaviors that depend on attention, memory, and thought organization. The changes were acute in onset and fluctuating in time. Mice with delirium-like behaviors had decreased expression of key genes for synaptic functions. Our findings indicate that the behavioral changes induced by anesthesia, surgery, and Intensive Care Unit environment in aged mice are consistent with the features of human delirium, and support the use of our animal model for mechanistic studies of postoperative delirium.