Odor Enrichment Attenuates the Anesthesia/Surgery-induced Cognitive Impairment

Abstract

Objective: To determine the association between olfactory function and cognition in patients and rodents.

Background: Perioperative neurocognitive disorders include delayed neurocognitive recovery (dNCR). The contribution of olfactory function to dNCR remains undetermined. It is unknown whether odor enrichment could mitigate dNCR.

Methods: We performed a prospective observational cohort study to determine potential association between olfactory impairment and dNCR in patients. We assessed the effects of anesthesia/surgery on olfactory and cognitive function in mice using the block test and Barnes maze. We measured interleukin-6 (IL-6), olfactory mature protein, growth-associated protein 43, mature and premature olfactory neurons, postsynaptic density 95, and synaptophysin in blood, nasal epithelium, and hippocampus of mice. Odor enrichment, IL-6 antibody, and knockout of IL-6 were used in the interaction experiments.

Results: Patients with dNCR had worse odor identification than the patients without dNCR [preoperative: 7 (1.25, 9) vs 10 (8, 11), median (interquartile range), P <0.001; postoperative: 8 (2.25, 10) vs 10 (8, 11), P <0.001]. Olfactory impairment associated with dNCR in patients before and after adjusting age, sex, education, preoperative mini-mental state examination score, and days of the neuropsychological tests. Anesthesia/surgery induced olfactory and cognitive impairment, increased levels of IL-6 in blood and nasal epithelium, decreased amounts of olfactory receptor neurons and their markers in the nasal epithelium, and reduced amounts of synapse markers in the hippocampus of mice. These changes were attenuated by odor enrichment and IL-6 antibody.

Conclusion: The anesthesia/surgery-induced olfactory impairment may contribute to dNCR in patients and postoperative cognitive impairment in mice. Odor enrichment could be a potential intervention.

FIGURE 1

Flow diagram for the study to assess the association of olfactory and cognitive impairment in participants from Xuzhou Medical University. We initially evaluated 3574 participants for eligibility; 752 were screened for the study, and 206 were included in the data analysis for baseline and postoperative tests.

FIGURE 2

Anesthesia/surgery impairs olfactory and cognitive function in mice. Effects of anesthesia/surgery on olfactory function detected by block tests 1 (A), 2 (B), and 3 (C) days after the anesthesia/surgery. (D) Effects of anesthesia/surgery on latency to identify and enter the escape box on Barnes maze training days 7–10 days after anesthesia/surgery. Effects of anesthesia/surgery on latency to identify and enter the escape box (E), numbers of wrong holes searched before identifying the escape box (F), and time in the target zone (G) on Barnes maze testing day (day 11 after anesthesia/surgery). Effects of anesthesia/surgery on total distance in the open-field test 1 (H), 2 (I), and 3 (J) days after anesthesia/surgery. ANOVA, analysis of variance; SEM, standard error of the mean. N=10/group. Data are presented as means±SEM. The Student t test was used to analyze the data in A, B, C, H, I, and J; P values refer to the difference in sniffing time or total distance between the control condition and anesthesia/surgery. Data are presented as means±SEM, and 2-way ANOVA and post-hoc analysis with Bonferroni was used to analyze the data presented in D; P value refers to the interaction of treatment (control vs anesthesia/surgery) and time (days 7–10) on latency to identify and enter the escape box. Data are presented as the median and interquartile range (25%–75%). Mann-Whitney U test was used to analyze the data in panels E, F, and G; P values refer to the difference in behavioral changes between control and anesthesia/surgery groups. *P value <0.05; **P value <0.01.

FIGURE 3

Anesthesia/surgery decreases OMP and GAP43 amounts in the olfactory epithelium and amounts of PSD95 and synaptophysin in the hippocampus of mice. Effects of anesthesia/surgery on OMP amounts detected by western blot (A, B) and expression of OMP-positive cells detected by immunohistochemistry (C, D) in the olfactory epithelium of the nasal cavity of mice 12 hours after anesthesia/surgery. Effects of anesthesia/surgery on GAP43 amounts detected by western blot (E, F) and expression of GAP43-positive cells detected by immunohistochemistry (G, H) in the olfactory epithelium of the nasal cavity of mice 12 hours after the anesthesia/surgery. Effects of anesthesia/surgery on amounts of PSD95 (I, J) and synaptophysin (K, L) in the hippocampus of mice 11 days after the anesthesia/surgery. SEM, standard error of the mean. N = 6–10/group. Data are presented as means±SEM, and Student t test was used to analyze the data in panels B, D, F, H, J, and L; P values refer to the difference in protein amounts or number of cells between control and anesthesia/surgery groups. *P value < 0.05; **P value < 0.01, ***P value < 0.001.

FIGURE 4

Odor enrichment mitigates the anesthesia/surgery-induced reductions in OMP and GAP43 amounts in the olfactory epithelium and decreases in PSD95 and synaptophysin amounts in the hippocampus of mice. Effects of anesthesia/surgery plus odor enrichment on amounts of OMP detected by western blot (A, B) and expression of OMP-positive cells detected by immunohistochemistry (C, D) olfactory epithelium of the nasal cavity of mice at 12 hours after the anesthesia/surgery. Effects of anesthesia/surgery plus odor enrichment on the expression of GAP43-positive cells detected by immunohistochemistry (E, F) in the olfactory epithelium of the nasal cavity of mice 12 hours after the anesthesia/surgery. Effects of anesthesia/surgery plus odor enrichment on amounts of PSD95 (G, H) and synaptophysin (I, J) in the hippocampus of mice at 11 days after the anesthesia/surgery. SEM, standard error of mean. Data are presented as means±SEM, and Student test was used to analyze the data in panels B, D, F, H, and J; P values indicate the difference in protein amounts between control and anesthesia/surgery plus odor enrichment groups.

FIGURE 5

IL-6 antibody treatment attenuates the anesthesia/surgery-induced increases in blood IL-6 amounts, reductions in OMP and GAP43 amounts in the olfactory epithelium, and reductions in PSD95 and synaptophysin amounts in the hippocampus of mice. (A) IL-6 antibody attenuates the anesthesia/surgery-induced increases in blood IL-6 amounts of mice. (B) Effects of anesthesia/surgery on IL-6 amounts in olfactory epithelium determined by ELISA. Effects of anesthesia/surgery plus IL-6 antibody treatment on OMP amounts detected by western blot (C, D) and expression of OMP-positive cells detected by immunohistochemistry (E, F) in the olfactory epithelium of the nasal cavity of mice at 12 hours after the anesthesia/surgery. Effects of anesthesia/surgery plus IL-6 antibody on amounts of GAP43 detected by western blot (G, H) and expression of GAP43-positive cells detected by immunohistochemistry (I, J) in the olfactory epithelium of the nasal cavity of mice at 12 hours after anesthesia/surgery. Effects of anesthesia/surgery plus IL-6 antibody treatment on amounts of PSD95 (K, L) and synaptophysin (M, N) in the hippocampus of mice at 11 days after the anesthesia/surgery. N = 6–10/group. Data are presented as means±SEM. Two-way ANOVA was used to analyze the data in panel A; P value refers to the interaction of group (control vs anesthesia/surgery) and treatment (saline vs IL-6 antibody). Data are presented as means±SEM, and Student t test was used to analyze the data in panels B, D, F, H, J, L, and N; P values refer to the difference in protein amounts between control and anesthesia/surgery plus IL-6 antibody groups. ANOVA indicates analysis of variance; ELISA, enzyme-linked immunosorbent assay; IL-6, interleukin-6; SEM, standard error of mean. *P value <0.05; **P value <0.01.