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Battery of behavioral tests in mice to study postoperative delirium.

ABSTRACT: Postoperative delirium is associated with increased morbidity, mortality and cost. However, its neuropathogenesis remains largely unknown, partially owing to lack of animal model(s). We therefore set out to employ a battery of behavior tests, including natural and learned behavior, in mice to determine the effects of laparotomy under isoflurane anesthesia (Anesthesia/Surgery) on these behaviors. The mice were tested at 24?hours before and at 6, 9 and 24?hours after the Anesthesia/Surgery. Composite Z scores were calculated. Cyclosporine A, an inhibitor of mitochondria permeability transient pore, was used to determine potential mitochondria-associated mechanisms of these behavioral changes. Anesthesia/Surgery selectively impaired behaviors, including latency to eat food in buried food test, freezing time and time spent in the center in open field test, and entries and duration in the novel arm of Y maze test, with acute onset and various timecourse. The composite Z scores quantitatively demonstrated the Anesthesia/Surgery-induced behavior impairment in mice. Cyclosporine A selectively ameliorated the Anesthesia/Surgery-induced reduction in ATP levels, the increases in latency to eat food, and the decreases in entries in the novel arm. These findings suggest that we could use a battery of behavior tests to establish a mouse model to study postoperative delirium.

SUBMITTER: Peng M

PROVIDER: S-EPMC4951688 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Battery of behavioral tests in mice to study postoperative delirium.

Peng Mian M Zhang Ce C Dong Yuanlin Y Zhang Yiying Y Nakazawa Harumasa H Kaneki Masao M Zheng Hui H Shen Yuan Y Marcantonio Edward R ER Xie Zhongcong Z

Scientific reports 20160720

Postoperative delirium is associated with increased morbidity, mortality and cost. However, its neuropathogenesis remains largely unknown, partially owing to lack of animal model(s). We therefore set out to employ a battery of behavior tests, including natural and learned behavior, in mice to determine the effects of laparotomy under isoflurane anesthesia (Anesthesia/Surgery) on these behaviors. The mice were tested at 24 hours before and at 6, 9 and 24 hours after the Anesthesia/Surgery. Compos ...[more]

PMID: 27435513

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Project description:Delirium is a common postoperative neurologic complication among older adults. Despite its prevalence (14%-50%) and likely association with inflammation, the exact mechanisms that underpin postoperative delirium are unclear. This project aimed to characterize systemic and central nervous system (CNS) inflammatory changes following surgery in mice and humans. Matched plasma and cerebrospinal fluid (CSF) samples from the "Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults" (INTUIT; NCT03273335) study were compared to murine endpoints. Delirium-like behavior was evaluated in aged mice using the 5-Choice Serial Reaction Time Test (5-CSRTT). Using a well established orthopedic surgical model in the FosTRAP reporter mouse we detected neuronal changes in the prefrontal cortex, an area implicated in attention, but notably not in the hippocampus. In aged mice, plasma interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40), and neurofilament light chain (NfL) levels increased after orthopedic surgery, but hippocampal YKL-40 expression was decreased. Given the growing evidence for a YKL-40 role in delirium and other neurodegenerative conditions, we assayed human plasma and CSF samples. Plasma YKL-40 levels were similarly increased after surgery, with a trend toward a greater postoperative plasma YKL-40 increase in patients with delirium. However, YKL-40 levels in CSF decreased following surgery, which paralleled the findings in the mouse brain. Finally, we confirmed changes in the blood-brain barrier (BBB) as early as 9 h after surgery in mice, which warrants more detailed and acute evaluations of BBB integrity following surgery in humans. Together, these results provide a nuanced understanding of neuroimmune interactions underlying postoperative delirium in mice and humans, and highlight translational biomarkers to test potential cellular targets and mechanisms.

Project description:Delirium is a common postoperative complication among older patients with many adverse outcomes. Due to lack of validated biomarkers, prediction and monitoring of delirium by biological testing is not currently feasible. Circulating proteins in cerebrospinal fluid (CSF) may reflect biological processes causing delirium. Our goal was to discover and investigate candidate protein biomarkers in preoperative CSF that were associated with development of postoperative delirium in older surgical patients. We employed a nested case–control study design coupled with high multiplex affinity proteomics analysis to measure 1305 proteins in preoperative CSF. Twenty-four matched delirium cases and non-delirium controls were selected from the Healthier Postoperative Recovery (HiPOR) cohort and the associations between preoperative protein levels and postoperative delirium were assessed using t-test statistics with further analysis by systems biology to elucidate delirium pathophysiology. Proteomics analysis identified 32 proteins in preoperative CSF that significantly associate with delirium (t-test p<0.05). Due to the limited sample size these proteins did not remain significant by multiple hypothesis testing using the Benjamini-Hochberg correction and q-value method. Three algorithms were applied to separate delirium cases from non-delirium controls. Hierarchical clustering classified 40/48 case-control samples correctly, principal components analysis separated 43/48. The receiver operating characteristic curve yielded an area under the curve [95% confidence interval] of 0.91 [0.80-0.97]. Systems biology analysis identified several key pathways associated with risk of delirium: inflammation, immune cell migration, apoptosis, angiogenesis, synaptic depression and neuronal cell death. Proteomics analysis of preoperative CSF identifies 32 proteins that might discriminate individuals who subsequently develop postoperative delirium from matched control samples. These proteins are potential candidate biomarkers for delirium and may play a role in its pathophysiology.

Project description:BackgroundNeuroinflammation and neuronal injury have been reported to be associated with the development of postoperative delirium in both preclinical and clinical settings. This study aimed to investigate the potential correlation between biomarkers of neurofilament light chain and glial fibrillary acidic protein and emergence and postoperative delirium in elderly patients undergoing surgery.MethodsPatients who developed emergence delirium (n = 30) and postoperative delirium (n = 32), along with their matched controls, were enrolled after obtaining ethics approval and written informed consent. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit or Confusion Assessment Method scale, and blood samples were collected before and after surgery for plasma neurofilament light chain and glial fibrillary acidic protein measurements using a single-molecule array.ResultsThe study found that in patients with emergence delirium, the increase in plasma neurofilament light chain protein levels during surgery was significantly higher than in non-delirium patients (P = 0.002). Additionally, in patients with postoperative delirium, both the increase in plasma neurofilament light chain protein levels (P < 0.001) and the increase in plasma glial fibrillary acidic protein levels during surgery (P = 0.008) were significantly higher than in non-delirium patients. Multivariate logistic regression analysis showed that the increase in plasma neurofilament light chain protein was associated with emergence delirium (adjusted OR = 1.872, P = 0.005), and the increase in plasma glial fibrillary acidic protein was associated with postoperative delirium (adjusted OR = 1.419, P = 0.016). Moreover, the American Society of Anesthesiologists Physical Status Classification and surgical duration were also found to be associated with delirium in elderly patients.ConclusionOur findings suggest that emergence delirium is linked to elevated levels of neurofilament light chain, a biomarker of axonal injury, during surgery. Furthermore, in addition to axonal injury, postoperative delirium was also associated with an increase in glial fibrillary acidic protein, a marker of astrocyte activation.

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Battery of behavioral tests in mice to study postoperative delirium.

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Battery of behavioral tests in mice to study postoperative delirium.

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