Person: Culley, Deborah
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Culley
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Deborah
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Culley, Deborah
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Publication Oxytocin alters cell fate selection of rat neural progenitor cells in vitro(Public Library of Science, 2018) Palanisamy, Arvind; Kannappan, Ramaswamy; Xu, Zhiqiang; Martino, Audrey; Friese, Matthew; Boyd, Justin D.; Crosby, Gregory; Culley, DeborahSynthetic oxytocin (sOT) is widely used during labor, yet little is known about its effects on fetal brain development despite evidence that it reaches the fetal circulation. Here, we tested the hypothesis that sOT would affect early neurodevelopment by investigating its effects on neural progenitor cells (NPC) from embryonic day 14 rat pups. NPCs expressed the oxytocin receptor (OXTR), which was downregulated by 45% upon prolonged treatment with sOT. Next, we examined the effects of sOT on NPC death, apoptosis, proliferation, and differentiation using antibodies to NeuN (neurons), Olig2 (oligodendrocytes), and GFAP (astrocytes). Treated NPCs were analysed with unbiased high-throughput immunocytochemistry. Neither 6 nor 24 h exposure to 100 pM or 100 nM sOT had an effect on viability as assessed by PI or CC-3 immunocytochemistry. Similarly, sOT had negligible effect on NPC proliferation, except that the overall rate of NPC proliferation was higher in the 24 h compared to the 6 h group regardless of sOT exposure. The most significant finding was that sOT exposure caused NPCs to select a predominantly neuronal lineage, along with a concomitant decrease in glial cells. Collectively, our data suggest that perinatal exposure to sOT can have neurodevelopmental consequences for the fetus, and support the need for in vivo anatomical and behavioral studies in offspring exposed to sOT in utero.Publication EARLY gestational exposure to isoflurane causes persistent cell loss in the dentate gyrus of adult male rats(BioMed Central, 2017) Palanisamy, Arvind; Crosby, Gregory; Culley, DeborahBackground: Our previous research showed that 4 h of maternal anesthesia with isoflurane during early gestation in pregnant rats leads to a deficit in spatial memory of adult male offspring. Because spatial memory is predominantly a hippocampally-mediated task, we asked the question if early gestational exposure to isoflurane affects development of the hippocampus in the offspring. Findings: Previously behaviorally characterized adult male rats that were exposed to isoflurane during second trimester were sacrificed at 4 months of age (N = 10 and 13, control and isoflurane groups, respectively) for quantitative histology of hippocampal subregions. Sections were stained with cresyl violet and the total number of cells in the granular layer of the dentate gyrus and the pyramidal cell layer in the CA1 region were determined by a blinded observer using unbiased stereological principles and the optical fractionator method. Data were analyzed using Student’s t test; P < 0.05 was accorded statistical significance. Stereological examination revealed 9% fewer cells in the granular layer of the dentate gyrus of isoflurane-exposed adult rats compared to controls (1,002,122 ± 84,870 vs. 1,091,829 ± 65,791, respectively; Mean ± S.D, *P = 0.01). In contrast, there were no changes in the cell number in the CA1 region, nor were there changes in the volumes of both regions. Conclusions: Our results show that maternal isoflurane anesthesia in rodents causes region-specific cell loss in the hippocampus of adult male offspring. These changes may, in part, account for the behavioral deficits reported in adult rats exposed to isoflurane in utero.Publication Systemic Inflammation Impairs Attention and Cognitive Flexibility but Not Associative Learning in Aged Rats: Possible Implications for Delirium(Frontiers Media S.A., 2014) Culley, Deborah; Snayd, Mary; Baxter, Mark G.; Xie, Zhongcong; Lee, In Ho; Rudolph, James; Inouye, Sharon; Marcantonio, Edward; Crosby, GregoryDelirium is a common and morbid condition in elderly hospitalized patients. Its pathophysiology is poorly understood but inflammation has been implicated based on a clinical association with systemic infection and surgery and preclinical data showing that systemic inflammation adversely affects hippocampus-dependent memory. However, clinical manifestations and imaging studies point to abnormalities not in the hippocampus but in cortical circuits. We therefore tested the hypothesis that systemic inflammation impairs prefrontal cortex function by assessing attention and executive function in aged animals. Aged (24-month-old) Fischer-344 rats received a single intraperitoneal injection of lipopolysaccharide (LPS; 50 μg/kg) or saline and were tested on the attentional set-shifting task (AST), an index of integrity of the prefrontal cortex, on days 1–3 post-injection. Plasma and frontal cortex concentrations of the cytokine TNFα and the chemokine CCL2 were measured by ELISA in separate groups of identically treated, age-matched rats. LPS selectively impaired reversal learning and attentional shifts without affecting discrimination learning in the AST, indicating a deficit in attention and cognitive flexibility but not learning globally. LPS increased plasma TNFα and CCL2 acutely but this resolved within 24–48 h. TNFα in the frontal cortex did not change whereas CCL2 increased nearly threefold 2 h after LPS but normalized by the time behavioral testing started 24 h later. Together, our data indicate that systemic inflammation selectively impairs attention and executive function in aged rodents and that the cognitive deficit is independent of concurrent changes in frontal cortical TNFα and CCL2. Because inattention is a prominent feature of clinical delirium, our data support a role for inflammation in the pathogenesis of this clinical syndrome and suggest this animal model could be useful for studying that relationship further.Publication Peripheral Surgical Wounding and Age-Dependent Neuroinflammation in Mice(Public Library of Science, 2014) Xu, Zhipeng; Dong, Yuanlin; Wang, Hui; Culley, Deborah; Marcantonio, Edward; Crosby, Gregory; Tanzi, Rudolph; Zhang, Yiying; Xie, ZhongcongPost-operative cognitive dysfunction is associated with morbidity and mortality. However, its neuropathogenesis remains largely to be determined. Neuroinflammation and accumulation of β-amyloid (Aβ) have been reported to contribute to cognitive dysfunction in humans and cognitive impairment in animals. Our recent studies have established a pre-clinical model in mice, and have found that the peripheral surgical wounding without the influence of general anesthesia induces an age-dependent Aβ accumulation and cognitive impairment in mice. We therefore set out to assess the effects of peripheral surgical wounding, in the absence of general anesthesia, on neuroinflammation in mice with different ages. Abdominal surgery under local anesthesia was established in 9 and 18 month-old mice. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), Iba1 positive cells (the marker of microglia activation), CD33, and cognitive function in mice were determined. The peripheral surgical wounding increased the levels of TNF-α, IL-6, and Iba1 positive cells in the hippocampus of both 9 and 18 month-old mice, and age potentiated these effects. The peripheral surgical wounding increased the levels of CD33 in the hippocampus of 18, but not 9, month-old mice. Finally, anti-inflammatory drug ibuprofen ameliorated the peripheral surgical wounding-induced cognitive impairment in 18 month-old mice. These data suggested that the peripheral surgical wounding could induce an age-dependent neuroinflammation and elevation of CD33 levels in the hippocampus of mice, which could lead to cognitive impairment in aged mice. Pending further studies, anti-inflammatory therapies may reduce the risk of postoperative cognitive dysfunction in elderly patients.Publication Different effects of anesthetic isoflurane on caspase-3 activation and cytosol cytochrome c levels between mice neural progenitor cells and neurons(Frontiers Media S.A., 2014) Zhang, Yiying; Pan, Chuxiong; Wu, Xu; Dong, Yuanlin; Culley, Deborah; Crosby, Gregory; Li, Tianzuo; Xie, ZhongcongCommonly used anesthetic isoflurane has been reported to promote Alzheimer’s disease (AD) neuropathogenesis by inducing caspase-3 activation. However, the up-stream mechanisms of isoflurane’s effects remain largely to be determined. Specifically, there is a lack of a good model/system to elucidate the underlying mechanism of the isoflurane-induced caspase-3 activation. We therefore set out to assess and compare the effects of isoflurane on caspase-3 activation in neural progenitor cells (NPCs) and in primary neurons from wild-type (WT) and AD transgenic (Tg) mice. The NPCs and neurons were obtained, cultured and then treated with either 2% isoflurane or under control condition for 6 h. The NPCs or neurons were harvested at the end of the treatment and were subjected to Western blot analysis. Here we showed for the first time that the isoflurane treatment induced caspase-3 activation in neurons, but not in NPCs, from either WT or AD Tg mice. Consistently, the isoflurane treatment increased cytosol levels of cytochrome c, a potential up-stream mechanism of isoflurane-induced caspase-3 activation in the mice neurons, but not NPCs. Finally, the isoflurane treatment induced a greater casapse-3 activation in the neurons, but not the NPCs, from AD Tg mice as compared to the WT mice. These data demonstrated that investigation and comparison of isoflurane’s effects between mice NPCs and neurons would serve as a model/system to determine the underlying mechanism by which isoflurane induces caspase-3 activation. These findings would promote more research to investigate the effects of anesthetics on AD neuropathogenesis and the underlying mechanisms.Publication Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice(Nature Publishing Group, 2014) Xu, Zhipeng; Dong, Yuanlin; Wang, Hui; Culley, Deborah; Marcantonio, Edward; Crosby, Gregory; Tanzi, Rudolph; Zhang, Yiying; Xie, ZhongcongPost-operative cognitive dysfunction (POCD) is associated with increased cost of care, morbidity, and mortality. However, its pathogenesis remains largely to be determined. Specifically, it is unknown why elderly patients are more likely to develop POCD and whether POCD is dependent on general anesthesia. We therefore set out to investigate the effects of peripheral surgery on the cognition and Alzheimer-related neuropathology in mice with different ages. Abdominal surgery under local anesthesia was established in the mice. The surgery induced post-operative elevation in brain β-amyloid (Aβ) levels and cognitive impairment in the 18 month-old wild-type and 9 month-old Alzheimer's disease transgenic mice, but not the 9 month-old wild-type mice. The Aβ accumulation likely resulted from elevation of beta-site amyloid precursor protein cleaving enzyme and phosphorylated eukaryotic translation initiation factor 2α. γ-Secretase inhibitor compound E ameliorated the surgery-induced brain Aβ accumulation and cognitive impairment in the 18 month-old mice. These data suggested that the peripheral surgery was able to induce cognitive impairment independent of general anesthesia, and that the combination of peripheral surgery with aging- or Alzheimer gene mutation-associated Aβ accumulation was needed for the POCD to occur. These findings would likely promote more research to investigate the pathogenesis of POCD.Publication Isoflurane-Induced Apoptosis: A Potential Pathogenic Link Between Delirium and Dementia(Oxford University Press (OUP), 2006) Xie, Zhongcong; Dong, Y.; Maeda, U.; Moir, Robert; Inouye, Sharon; Culley, Deborah; Crosby, Gregory; Tanzi, RudolphBackground. Dementia and delirium have been postulated to share common pathophysiologic mechanisms; however, identification of these unifying mechanisms has remained elusive. The inhalation anesthetic isoflurane has been shown to enhance β-amyloid protein (Aβ) oligomerization and generation, to potentiate the cytotoxicity of Aβ, and to induce apoptosis. To address the molecular mechanisms of dementia and delirium associated with anesthesia and surgery, we assessed whether the Aβ fibrillar aggregation inhibitor Congo red can attenuate isoflurane-induced caspase-3 activation in H4 human neuroglioma cells overexpressing human β-amyloid precursor protein (APP). Methods. H4 human neuroglioma cells stably transfected to express human full-length wild-type APP were exposed to 2% isoflurane for 6 hours. The cells were harvested at the end of the treatment. Caspase-3 activation was measured with quantitative Western blotting. Results. We found that isoflurane induces cellular apoptosis in a dose-dependent manner, and that Congo red inhibits isoflurane-induced apoptosis in H4 human neuroglioma cells overexpressing APP. Interestingly, Congo red also inhibits staurosporine-induced apoptosis. Conclusion. The demonstration that isoflurane contributes to well-described mechanisms of Alzheimer's neuropathogenesis provides a plausible link between the acute effects of anesthesia, a well-described risk factor for delirium, and the more long-term sequelae of dementia. These findings suggest that isoflurane-induced Aβ oligomerization and apoptosis may contribute to the risk of postoperative cognitive dysfunction and provide a potential pathogenic link between delirium and dementia.Publication Review Article: Serum Biomarkers for Delirium(Oxford University Press (OUP), 2006-12-01) Marcantonio, Edward; Rudolph, James; Culley, Deborah; Crosby, Gregory; Alsop, David; Inouye, SharonThis narrative review examines serum biomarkers for the diagnosis and monitoring of delirium. Serum biomarkers for delirium fall into three major groups: 1) those that are present or elevated prior to disease onset—risk markers, 2) those that rise with onset and fall with recovery—disease markers, and 3) those that rise in proportion to the consequences of disease—end products. As risk markers, we examine serum chemistries and genetic risk markers. As disease markers, we examine serum anticholinergic activity, amino acids, melatonin, cytokines, cortisol, and gene expression. As end products of delirium, we examine markers of neuronal injury. Finally, we discuss methodological and biostatistical considerations for future biomarker studies. Identifying accurate biomarkers for delirium may shed further light into its pathophysiology and on the interrelationship between delirium and dementia.Publication Maximizing Clinical Research Participation in Vulnerable Older Persons: Identification of Barriers and Motivators(Wiley-Blackwell, 2008) Marcantonio, Edward; Aneja, Jasneet; Jones, Richard Norman; Alsop, David; Fong, Tamara; Crosby, Gregory; Culley, Deborah; Cupples, L. Adrienne; Inouye, SharonOBJECTIVES: To identify barriers and motivators to participation in long-term clinical research by high-risk elderly people and to develop procedures to maximize recruitment and retention. DESIGN: Quantitative and qualitative survey. SETTING: Academic primary care medicine and pre-anesthesia testing clinics. PARTICIPANTS: Fifty patients aged 70 and older, including 25 medical patients at high risk of hospitalization and 25 patients with planned major surgery. MEASUREMENTS: Fifteen- to 20-minute interviews involved open- and closed-ended questions guided by an in-depth script. Two planned study protocols were presented to each participant. Both involved serial neuropsychological assessments, blood testing, and magnetic resonance brain imaging (MRI); one added lumbar puncture (LP). Participants were asked whether they would be willing to participate in these protocols, rated barriers and incentives to participation, and were probed with open-ended questions. RESULTS: Of 50 participants (average age 78, 44% male, 40% nonwhite), 32 (64%) expressed willingness to participate in the LP-containing protocol, with LP cited as the strongest disincentive. Thirty-eight (76%) expressed willingness to participate in the protocol without LP, with phlebotomy and long interviews cited as the strongest disincentives. Altruism was a strong motivator for participation, whereas transportation was a major barrier. Study visits at home, flexible appointment times, assessments shorter than 75 minutes, and providing transportation and free parking were strategies developed to maximize study participation. CONCLUSION: Vulnerable elderly people expressed a high rate of willingness to participate in an 18-month prospective study. Participants identified incentives and barriers that enabled investigators to develop procedures to maximize recruitment and retention.Publication Delirium is associated with early postoperative cognitive dysfunction(Wiley-Blackwell, 2008) Rudolph, James; Marcantonio, Edward; Culley, Deborah; Silverstein, J. H.; Rasmussen, L. S.; Crosby, Gregory; Inouye, SharonThe purpose of this analysis was to determine if postoperative delirium was associated with early postoperative cognitive dysfunction (at 7 days) and long-term postoperative cognitive dysfunction (at 3 months). The International Study of Postoperative Cognitive Dysfunction recruited 1218 subjects ≥ 60 years old undergoing elective, non-cardiac surgery. Postoperatively, subjects were evaluated for delirium using the criteria of the Diagnostic and Statistical Manual. Subjects underwent neuropsychological testing pre-operatively and postoperatively at 7 days (n = 1018) and 3 months (n = 946). Postoperative cognitive dysfunction was defined as a composite Z-score > 2 across tests or at least two individual test Z-scores > 2. Subjects with delirium were significantly less likely to participate in postoperative testing. Delirium was associated with an increased incidence of early postoperative cognitive dysfunction (adjusted risk ratio 1.6, 95% CI 1.1–2.1), but not long-term postoperative cognitive dysfunction (adjusted risk ratio 1.3, 95% CI 0.6–2.4). Delirium was associated with early postoperative cognitive dysfunction, but the relationship of delirium to long-term postoperative cognitive dysfunction remains unclear.