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

Abstract

To establish a clinically relevant mouse model of perioperative delirium. Methods: Aged C57BL/6J mice were tested at baseline in the Y-maze novel arm preference, buried food, simple discrimination task of the attentional set-shifting test, and open field tests. They were subsequently randomized to insult (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 novel arm preference, buried food, attentional, and open field tests at the end of intensive care environment (0 h) and every 6 h up to 24 h. Mouse hippocampi were collected at 24 h for gene expression analyses. Results: Surgery, anesthesia and Intensive Care environment decreased the entries in the Y-maze novel arm at 0 h (P = 0.001), 6 h (P < 0.001), 18 h (P = 0.002), and 24 h (P = 0.029). Insult exposure increased the latency to find a buried cereal reward at 18 h (P = 0.035) and 24 h (P = 0.027), and increased the trials to criterion in the reverse compound discrimination (P = 0.013) and extradimensional shift (P < 0.001) tasks of the attentional test. The overall incidence of delirium was 72% in A/S/I mice. Messenger RNA levels of synuclein alpha (−3.785 fold change relative to controls), Neurotrophic Receptor Tyrosine Kinase1 (−2.267), and syntaxin1a (−1.498) were decreased in the hippocampus of mice 24 h after insult exposure. Protein levels of syntaxin 1a (P = 0.012), Neurotrophic Receptor Tyrosine Kinase1 (P = 0.039), synuclein alpha (P = 0.017), phosphorylated synuclein alpha (P = 0.008), synaptophysin (P = 0.002), postsynaptic density protein 95 (P = 0.003), and microtubule-associated protein 2 (P = 0.013) were also decreased, relative to controls. Conclusion: Surgery, anesthesia and Intensive Care environment impaired mouse behaviors that depend on attention, memory, and thought organization. The changes

Sepsis Induces Physical and Mental Impairments in a Mouse Model of Post-Intensive Care Syndrome

“…Witteveen et al assessed an ICU-AW model using in vivo strength measurements and myosin/actin assays in an Escherichia coli septic peritonitis mouse model [ 27 ]. Illendula et al reported that surgery, anesthesia, and an intensive care environment impaired mouse behaviors involving attention, memory, and thought organization, which allowed for the establishment of a clinically relevant mouse model of perioperative delirium [ 28 ]. These models revealed human-like PICS symptoms; however, neither mouse model was intubated or ventilated.…”

Potential Serum Biomarkers for Postoperative Neurocognitive Disorders Based on Proteomic Analysis of Cognitive-Related Brain Regions

“…Illendula et al used 18- to 20-month-old mice to examine anesthesia, surgery, and the intensive care unit environment and found that these insults impaired mouse behaviors that depend on attention, memory, and thought organization. The changes also showed acute onset and fluctuated over time (Illendula et al, 2020 ). Our research group also used a battery of behavioral tests to assess the effects of laparotomy under isoflurane anesthesia in aged mice and found that inattention, the core symptom of delirium, occurred at 6 or 9 h and recovered at 24 h after anesthesia/surgery (Liu et al, 2020 ).…”

Integrative Analysis of lncRNA and mRNA and Profiles in Postoperative Delirium Patients

“…Inflammatory mediator regulation of TRP channels, neuroactive ligand-receptor interaction and cholinergic synapse were overrepresented during the acute presence of hippocampal inflammation ( Xiang et al, 2019 ). Illendula et al (2020) found that many key proteins for the regulation of synaptic vesicle trafficking, neurotransmitter release and synaptic plasticity-were significantly down-regulated in old mice under surgery, anesthesia and intensive care environment induce delirium. Lipoprotein-associated phospholipase A2 and superoxide dismutase were independent risk factors of cognitive impairment in cerebral small vessel disease, and may be useful for the rapid evaluation of cognitive impairment in cerebral small vessel disease ( Zhu et al, 2019 ).…”