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Aging and disease
Orginal Article |
A Novel Individual-based Determination of Postoperative Cognitive Dysfunction in Mice
Jing Zhong1,2, Jun Li1, Changhong Miao2, Zhiyi Zuo1,*
1Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA.2Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Abstract  

Postoperative cognitive dysfunction (POCD) is a significant clinical issue. Aging is a risk factor for POCD. It is known that not every patient develops POCD. This situation shall be similar in animals. Determination of POCD is individual-based in humans but group-based in animal studies. This difference prevents effective evaluation of biomarkers and interventions for POCD in preclinical studies. The objective of this study was to determine whether individual animal could be assessed for POCD by a system similar to that for patients. Seven-week old CD1 and 18-month old C57BL/6 male mice were subjected to right carotid arterial exposure under isoflurane anesthesia. Mice were evaluated by Barnes maze and fear conditioning either post-surgery alone or both prior to surgery and post-surgery. Surgery increased the time to identify the target box in Barnes maze when tested one day or 8 days after the training sessions and reduced freezing behavior in fear conditioning test. This phenomenon occurred in 7-week old animals with and without evaluation before the surgery and in 18-month old mice evaluated before and after surgery. Based on the method and criteria used for a human whose cognition was evaluated before and after surgery to assess individual decline of cognition, 7 in 21 mice in the surgical group and 1 in 21 mice in control group of 7-week old mice had cognitive dysfunction. Among 18-month old mice, 13 in 21 mice in the surgical group and 2 in 20 mice in the control group had cognitive dysfunction. The incidence of cognitive dysfunction in mice with surgery was higher than that in control mice no matter whether young adult (P = 0.045) or old mice (P < 0.001) were considered. These results indicate that surgery induces POCD in mice. Individual animal-based assessment can be used to identify animals with POCD.

Keywords Individual animal-based assessment      learning and memory      mice      postoperative cognitive dysfunction.     
Corresponding Authors: Zhiyi Zuo   
Just Accepted Date: 31 October 2019  
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Jing Zhong
Jun Li
Changhong Miao
Zhiyi Zuo
Cite this article:   
Jing Zhong,Jun Li,Changhong Miao, et al. A Novel Individual-based Determination of Postoperative Cognitive Dysfunction in Mice[J]. Aging and disease, 10.14336/AD.2019.1029
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http://www.aginganddisease.org/EN/10.14336/AD.2019.1029     OR     http://www.aginganddisease.org/EN/Y0/V/I/0
Figure 1.  Effects of surgery on learning and memory assessed only after surgery in young adult mice. Seven-week old CD1 mice were subjected to right carotid artery exposure under isoflurane anesthesia. Barnes maze training sessions started 1 week after the surgery. (A) Barnes maze training sessions. Results are mean ± S.D. (n = 13). * P < 0.05 compared with the corresponding data on day 1. (B) Barnes maze memory phase. (C) Fear conditioning results. Results in B and C are in box plot format (n = 13). ● : lowest or highest score (the score will not show up if it falls in the 95th percentile); between lines: 95th percentile of the data; inside boxes: 25th to 75th percentile including the median of the data. ^ P < 0.05 compared with the control group. (D) Body weights. Results are mean ± S.D. (n = 13).
Figure 2.  Preoperative evaluation of learning and memory of young adult mice in a self-comparison study. Seven-week old CD1 mice were used in the test. (A) Barnes maze training sessions. Results are mean ± S.D. (n = 21). * P < 0.05 compared with the corresponding data on day 1. (B) Barnes maze memory phase. (C) Fear conditioning results. Results in B and C are in box plot format (n = 21). ●: lowest or highest score (the score will not show up if it falls in the 95th percentile); between lines: 95th percentile of the data; inside boxes: 25th to 75th percentile including the median of the data.
Figure 3.  Postoperative evaluation of learning and memory of young adult mice in self-comparison study. Seven-week old CD1 mice were subjected to right carotid artery exposure under isoflurane anesthesia. Barnes maze training sessions started 1 week after the surgery that was performed 24 h after preoperative evaluation of their learning and memory (preoperative results are shown in figure 2). (A) Barnes maze training sessions. Results are mean ± S.D. (n = 21). * P < 0.05 compared with the corresponding data on day 1. (B) Barnes maze memory phase. (C) Fear conditioning results. Results in B and C are in box plot format (n = 21). ●: lowest or highest score (the score will not show up if it falls in the 95th percentile); between lines: 95th percentile of the data; inside boxes: 25th to 75th percentile including the median of the data. ^ P < 0.05 compared with the control group.
Figure 4.  Effects of surgery on learning and memory assessed in a self-comparison fashion in young adult mice. Seven-week old CD1 mice were subjected to preoperative evaluation and postoperative evaluation of their learning and memory. Those results are shown in figures 3 and 4. The difference between preoperative values and postoperative values was calculated and presented here. (A) Barnes maze memory phase. (B) Fear conditioning results. Results are in box plot format (n = 21). ●: lowest or highest score (the score will not show up if it falls in the 95th percentile); between lines: 95th percentile of the data; inside boxes: 25th to 75th percentile including the median of the data. ^ P < 0.05 compared with the control group.
Figure 5.  Escape distance traveled by young adult mice in Barnes maze test in self-comparison study. Seven-week old CD1 mice were subjected to right carotid artery exposure under isoflurane anesthesia. Barnes maze tests were performed before and after surgery (those results of latency to identify the target box are shown in figures 2 and 3). (A) Barnes maze training sessions before surgery. (B) Barnes maze memory phase before surgery. (C) Barnes maze training sessions after surgery. (D) Barnes maze memory phase after surgery. Results are mean ± S.D. for panels A, C and D (n = 21). * P < 0.05 compared with the corresponding data on day 1. Results in panel B are in box plot format (n = 21). ● : lowest or highest score (the score will not show up if it falls in the 95th percentile); between lines: 95th percentile of the data; inside boxes: 25th to 75th percentile including the median of the data.
Figure 6.  Preoperative evaluation of learning and memory of old mice in self-comparison study. Eighteen-month old C57BL/6 mice were used in the test. (A) Barnes maze training sessions. * P < 0.05 compared with the corresponding data on day 1. (B) Barnes maze memory phase. (C) Fear conditioning results. Results in all three panels are mean ± S.D. (n = 20 for control group and = 21 for mice assigned to surgery group).
Figure 7.  Postoperative evaluation of learning and memory of old mice in self-comparison study. Eighteen-month old C57BL/6 mice were subjected to right carotid artery exposure under isoflurane anesthesia. Barnes maze training sessions started 1 week after the surgery that was performed 24 h after preoperative evaluation of their learning and memory (preoperative results are shown in figure 6). (A) Barnes maze training sessions. Results are mean ± S.D. (n = 20 for control group and = 21 for surgery group). * P < 0.05 compared with the corresponding data on day 1. (B) Barnes maze memory phase. (C) Fear conditioning results. Results in B and C are in box plot format (n = 20 for control group and = 21 for surgery group). ●: lowest or highest score (the score will not show up if it falls in the 95th percentile); between lines: 95th percentile of the data; inside boxes: 25th to 75th percentile including the median of the data. ^ P < 0.05 compared with the control group.
Figure 8.  Effects of surgery on learning and memory assessed in a self-comparison fashion in old mice. Eighteen-month old C57BL/6 mice were subjected to preoperative evaluation and postoperative evaluation of their learning and memory. Those results are shown in figures 7 and 8. The difference between preoperative values and postoperative values was calculated and presented here. (A) Barnes maze memory phase. (B) Fear conditioning results. Results are mean ± S.D. (n = 20 for control group and = 21 for surgery group). ^ P < 0.05 compared with the control group.
Individual mouseYoung adult miceElderly mice
Control groupSurgery groupControl groupSurgery group
10.9263.7250.131-3.768^
21.828-5.265^*-1.232*-0.787
30.074-0.605-0.359-2.004^
40.015-0.8030.243-2.093^
5-0.5961.700-0.884-4.131^*
60.390-0.337-0.293-2.034^
70.8001.0510.221-3.113^*
8-2.067^-7.026^*-0.535-2.933^
90.226-0.6411.506-0.180
10-0.334-1.2400.782-2.388^*
111.775-0.8420.045-0.542
12-1.333-6.122^*0.759-2.061^
13-0.6591.651-2.619^*0.243
141.334-4.273^*0.526-3.510^*
15-0.811-0.0151.305-3.017^*
160.408-0.4060.576-2.479^*
17-0.482-4.268^*-1.283-2.832^*
180.662-2.619^0.810-1.467
19-0.844-0.980-0.590-1.064
20-0.695-0.8760.892-0.212
21-0.617-4.168^*-0.921
Table 1  Composite Z scores.
Figure 9.  Performance of old mice in novel object recognition and open field tests in self-comparison study. Eighteen-month old C57BL/6 mice were used in the test. (A) Novel object recognition. (B) Travel distance in open field. (C) Time spent in specific regions in open field. Results in all three panels are mean ± S.D. (n = 20 for the control group and = 21 for the surgery group).
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