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1 Animal models of postoperative d elirium research Zhongcong Xi e, M.D., Ph.D. Geriatric Anesthesia Research Unit Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital Harvard Med dical School November 12, 2015 (Boston) Why do we need the animal model to study postoper rative delirium? Mechanistic hypothesis testing: - Interaction of A /Tau and neuroinflammation. Vulnerable window assessment: - Age dependent? Are there less provocative anesthetic: - Isoflurane versuss desflurane. Potential treatment and prevention. - Anti-A, anti-tau and anti-inflammation. Animal studie es of delirium There are few animal models available to study delirium at the present time. It is important to establish animal models of delirium. We then can determine whether the perioperative p factors (e.g., anesthesia, surgery, pain, and sleep deperivation, which could contribute to POCD) can also contribute to th e postoperative delirium. T-maze alternation: working memory Dr. Colm Cu unningham Since the nature of these deficits are acute and transient, with impairments in attention, recall, and short-term/working memory, this model displays key core features of delirium as defined by DSM-IV (American Psychiatricc Association, 1994) and ICD-10 (World Health Organization, 1 992) and will be useful in delineating mechanisms. (Murray et al., Neurobiology of Aging, 2012)

2 T-maze alternation: working memory Dr. Colm Cu unningham Mice will escape from shallow water. It needs training period (10 trails). It assesses working memory in rodents. Animal studie es of delirium We have set out to observe several animal nature behaviors following the treatment of scopolamine and following the abdominal surgery under isoflurane anesthesia. The ultimate t goal is to de evelop a method of CAM in mice or even 3D-CAM in mice. (Murray et al., Neurobiology of Aging, 2012) CAM in mice Acute onset and fluctuating course - Timecourse studies s. Inattention - Attention deficit assessment, buried food. Disorganized thinking - Freezing behavior, Y-maze Altered level of consciousness - Open field test and others. Nature behavio ral observation Attention level (Millecamp et al., 2004). Freezing episodes. Open field tests. Timecourse investigation. Attention level Freezing episodes Definition: No movement except respiration. Detected and analyzed by Any-Maze (Stoelting, Wood Dale, IL). (Millecamps et al., 2004)

3 Definition: The time spent during the open field test. Open fie eld test Detected and analyzed by Dale, IL). in the zone near the wall Any-Maze (Stoelting, Wood A Scopolami ne in mice ring %) explor t (100% spent e object Time s new P = * level of chance 0 Saline Scopolamine B C Numbe er of fre eezing ep pisode es Saline P = ** Scopolamine Time spent near th he wall (10 00%) Saline P = Scopolam mine F = Pretreatmentt 30 minutes *

4 Anesthesia and surgery in mice (Ren et al., 2015) Effects ofanesthesia and dsurgery on mice CAM Scopolamine Anesthesia & Surgery 2-8-month mice 2-8-month mice 18-month mice On going g studies 30 min 12h 24h 48h 72h 12h 24h 48h 72h Near the wall Attention level Freezing episode and indicate significant increase (P < 0.05) and decrease (P <0.05) compared with saline or sham group at the same time point, respectively Metho ods CAM-in mi ice battery Surgery+anesthesia Control group (n=14) Baseline 6h 9h 24h C57BL/6J mice CAM-in mice battery Buried food test Open field test (4 months old) Surgery+anesthesi a group (n=14) Baseline 6h 9h 24h Two trial recognition Y- maze test

5 Open field test Buried food test Two trial recognition Y-maze test Effects of Surgery and An nesthesia on mice CAM and indicate significant increase (P < 0.05) and decrease (P <0.05) compared with control group at the same time point, respectively Limitations of the animal models in studying postope p erative delirium Mouse and human alike, yet different - Genomes: only 85% same - Mouse brain is 70% neurons and 3% glia; human brain is opposite Animal models of perioperative factors Human delirium mouse behavior - Mouse does not show disorganized thinking - We cannot measure level of consciousness in mice - Inattention: Maybe Acute onset and fluctuating course: Yes

6 Animal: Rats. General anesthesia Anesthesia: 1.2% isoflurane, 70% nitrous oxide, and 30% oxygen for two hours. Cognitive function determ mination: 12-arm radial maze. (Culley et al., Anesthesiology, 2004) Anesthesia: Halothane (0.8 1%) or isoflurane (0.9 1%) in 30% oxygen, balanc ced by N2 for two hours. Cognitive function determ ination: Morris Water Maze. (Bianchi et al., Neurobiology of Aging, 2008) Morris Water Maze studies Smart Not-Smart

7 Anesthesia: 1.4% isoflurane for two hours. Cognitive function determination: Fear conditioning i system. (Bianchi et al., Neurobiology of Aging, 2008) (Zhang et al., Annals of Neurology, 2012) Fear Conditioning System (FCS) Surgery plus general anesthesia Smart Good memory = More freezing time Not-Smart Bad memory = less freezing time Animal: Rats. Surgery: Splenectomy. Anesthesia: Fentanyl and droperidol (i.p.). Cognitive function determination: Y-Maze. Surgery: Hepatectomy. Anesthesia: Chloral hydrate (i.p.). Cognitive function determination: Morris Water Maze. (Wan et al., Anesthesiology, 2007) (Wan et al., Critical Care Medicine, 2010)

8 Surgery: Open tibial fracture. Anesthesia: 2.1% isoflurane briefly. Analgesia: Buprenorphinee (Buprenex, 0.1 mg/kg s.c). Cognitive function determ mination: Fear conditioning system. (Wan et al., Critical Care Medicine, 2010) (Terrando et al., PNAS, 2010) Surgery plus lo ocal anesthesia Surgery: Opening and closing abdomen. Anesthesia: local injectionn of bupivacaine. Analgesia: EMLA (local anesthetics). Cognitive function determination: Fear conditioning system and Morris Water Maze. (Xu et al., Scientific Reports, 2014) (Xu et al., PLoS One, 2014) Pa ain Surgery: Incisional or chem mical pain. Cognitive function determ ination: Fear conditioning system. (Zhang et al., Journal of Neuroscience, 2013) (Yang et al.., Anesthesia and Analgesia, 2014) Sleep de eprivation No sleep for 24 hours. Cognitive function determination: Fear conditioning system. (Zhu et al., Neurobiology of Disease, 2012) Summary and Conclusion The employment of several animal models has suggested that perioperative factors, e.g., anesthesia, surgery, pain and sleep deperivation, may contribute to the cognitive impairment in rodents. Whether these perioperative factors can contribute to postoperative delirium remains largely to be investigate ed. Thus, it is important to establish animal models of postoperative delirium.

9 Acknowle edgements Xie lab: Yuanlin Dong Yiying (Laura) Zhang Mian Peng Shiming Yang Guanghong Xu Han Lu Yunye Yao Yang Yu Ce Zhang Xin Xin Dan Chen Yuqing Wu Huihui Miao Kali Stevens Capital Medical University, Beijing- Tianzuo Li Anshi Wu Ming Tian Collaborator rs: Harvard- Rudolph E. Tanzi Gregory Crosby Deborah Culley Edward Marcantonio University of New Mexico- Ke Jian (Jim) Liu Tongji Unive ersity, Shanghai- Yuan Shen Supports: NIH R01 GM NIH R01 AG NIH R21 AG Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital