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

Early exposure to anesthetics may interfere with synaptic development and lead to cognitive deficits. We previously demonstrated a decrease in vesicles docked at and within 100 nm from the presynaptic membrane in hippocampal nerve terminals of neonatal rats after anesthesia. Hence, we designed this study to assess the effects of neonatal anesthesia on Synapsin 1 (Syn 1) and Synaptotagmin 1 (Syt 1), two key regulators of vesicle docking and fusion. To test the link between changes in Syn 1 and Syt 1 and behavioral deficits observed after neonatal anesthesia, we also assessed retention memory and fear conditioning in adolescent rats after neonatal anesthesia. Pups received a combination of clinical anesthetics, then Syn 1 and Syt 1 mRNA and protein expression were determined at the peak (postnatal day 8, P8), part-way through (P12) and end of synaptogenesis (P24) in the CA1-subiculum by qPCR and Western Blotting. Anesthesia decreased Syn1 and Syt1 mRNA expression at P8 (p<0.01 and p<0.001) and P12 (p=0.001 and p=0.017), but not P24 (p=0.538 and p=0.671), and impaired Syn1, p-Syn1 and Syt1 protein levels at P8 (p=0.038, p=0.041 and p=0.004, respectively), P12 (p<0.001, p=0.001 and p<0.0001) and P24 (p=0.025, p=0.031 and p=0.001). Anesthetic-challenged rats displayed deficient long-term retention memory (p=0.019) and hippocampus-dependent fear conditioning (p<0.001). These results suggest that anesthetics alter Syn 1 and Syt 1 during synapse assembly and maturation, raising the possibility that anesthetic interference with Syn 1 and Syt 1 could initiate changes in synaptic function that contribute to the cognitive deficits observed after neonatal anesthesia.

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