Two major troponin I (TnI) genes, fetal TnI (ssTnI) and adult TnI (cTnI), are expressed in the mammalian heart under the control of a developmentally regulated program. In this study, the up-stream domain (~1,800 bp) of mouse fetal TnI gene has been cloned and characterized. There is a high homology of this region among mouse, rat and human. Transfection assays indicated that conserved GA-rich sequences, CREB and a CCAAT box within the first 300 bp upstream of the transcription start site were critical for the gene expression. Electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) assays revealed binding proteins to CREB site in nuclear extracts from myocardial cells. Thyroid hormone (T3) caused a significant inhibitory effect on ssTnI expression in myocardial cells. Cardiac troponin I (cTnI) mutations have been linked to the development of restrictive cardiomyopathy (RCM) in human patients. We modeled one mutation in human cTnI Cv terminus, arginine1 92 histidine (R192H) by cardiac specific expression of the mutated protein (cTnI193His in mouse sequence) in transgenic mice. The main functional alteration detected in cTnI193His mice by ultrasound cardiac imaging examinations was impaired cardiac relaxation manifested by a decreased left ventricular end diastolic dimension (LVEDD) and an increased end diastolic dimension in both atria. Echocardiography revealed a series of changes on the transgenic mice including a reversed E-to-A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. At the age of 12 months, cardiac output in cTnI193His mice was significantly declined, and some transgenic mice showed congestive heart failure. The negative impact of cTnI193His on ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. / Dobutamine stimulation increased heart rate in cTnI193His mice but did not improve CO.The cTnI193His mice had a phenotype similar to that in human RCM patients carrying the cTnI mutation. The results demonstrate a critical role of the COOH-terminal domain of cTnI in the diastolic function of cardiac muscle. This mouse model provides us with a tool to further investigate the pathophysiology and the development of RCM. / by Jianfeng Du. / Thesis (Ph.D.)--Florida Atlantic University, 2008. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2008. Mode of access: World Wide Web.

Desde a abertura dos primeiros cursos de farmácia no Brasil, a estrutura curricular sofreu inúmeras alterações com vistas à adequação do curso com as necessidades locais. Após a homologação das Diretrizes Curriculares Nacionais de Farmácia de 2002, passou a ficar mais urgente a necessidade do desenvolvimento de habilidades e atitudes pelos farmacêuticos, não apenas o acúmulo de conhecimento técnico. Este trabalho teve como objetivo estudar as variáveis envolvidas na organização e estruturação do Integrado de Fisiopatologia e Farmacologia III, uma disciplina central na formação dos farmacêuticos da Universidade de São Paulo, incluindo a investigação dos fatores que influenciam no processo de aprendizagem dos alunos, bem como a aplicação de um método ativo de ensino-aprendizagem neste integrado e, por fim, realizar uma avaliação comparativa entre a opinião dos alunos com relação aos dois métodos. Observou-se resposta positiva estatisticamente significativa dos alunos em favor do método ativo contra o método tradicional em todos os aspectos avaliados, incluindo todos os aspectos relacionados ao plano disciplinar, assim como o impacto no desenvolvimento de competências e auto avaliação dos alunos. Estes resultados sustentam a necessidade de aplicação de métodos nos quais os alunos sejam o centro do processo educacional e tenham responsabilidade sobre sua própria aprendizagem, para assim formar profissionais generalistas, críticos e líderes. / Since the opening of the first pharmacy schools in Brazil, the curriculum has undergone numerous changes in order to keep up with local needs. After the approval of the National Curricular Guidelines for Pharmacy on 2002, it became more urgent for pharmacists to develop skills and attitudes, rather than only to accumulate technical knowledge. This work aimed to study the variables involved in organizing and structuring the Integrated Pathophysiology and Pharmacology III, a central discipline in the curriculum of pharmacy school at the University of São Paulo. Additionally it focused on investigate all factors that influences students\' learning process as well as applying an active learning in this integrated. And, finally, to compare students\' opinions regarding the two methods. We observed a statistically significant positive response of students in favor of the active method against the traditional one in all aspects evaluated, including all aspects of the disciplinary proceedings, impact on skills development and self-assessment of students. These results support the idea of implementation of methods in which students are the center of the educational process and are accountable for their own learning. This way we will be able to assist the development of pharmacists with clinical thinking and leadership skills.

The purpose of this study was to determine if resistance exercise altered peripheral BDNF concentration. Eighteen trained male subjects were split into two groups performing varied repetition ranges. DUP-HR and DUP-LR groups trained 3x/week for 8 weeks, and were equated for total volume (repetitions X sets X intensity). Plasma BDNF and interleukin-6 (IL-6) levels were measured prior to and immediately following the first exercise session of weeks 1, 2, 4 and 6. Pre-exercise levels were also assessed prior to the second and third sessions of week 1 and 6. Lastly, resting levels were measured before and after training intervention. No group differences (p>0.05) were detected for either biomarker. An acute BDNF elevation (p=0.018) was detected only in the final week of training. IL-6 elevations were detected at all acute measurements (p<0.01). BDNF and IL-6 percentage change correlated significantly (p<0.05) in week-1. No chronic alterations were observed (p>0.05). / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2015 / FAU Electronic Theses and Dissertations Collection

Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart. My study's objective was to assess cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function was monitored in cTnI193His mice and wild-type littermates for a period of 12 months. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with micro- echocardiography by a reversed E/A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. The negative impact of cTnI193His on cardiac function was further demonstrated in isolated mouse working heart preparations. Dobutamine stimulation increased heart rate in cTnI193His mice but did not improve CO. The cTnI193His mice had a phenotype similar to that in human RCM patients carrying the cTnI mutation characterized morphologically by enlarged atria and restricted ventricle and functionally by diastolic dysfunction. / by Nariman Gobara. / Thesis (M.S.)--Florida Atlantic University, 2009. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2009. Mode of access: World Wide Web.

Obesity is associated with elevated levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), contributing to systemic insulin resistance. Fibroblast growth factor 21 (FGF21) is a vital metabolic and inflammatory regulator, however circulating FGF21 concentrations are elevated in obese individuals. Acute aerobic exercise increases systemic FGF21 in normal-weight individuals, however the effect of acute aerobic exercise on plasma FGF21 response and the relationships with inflammation (IL-6 and TNF-α), insulin resistance, and energy expenditure in obese individuals is unknown. Following 30 minutes of treadmill running at 75% VO2max, plasma FGF21 response, as indicated by area-under-the-curve “with respect to increase” (AUCi) analyses, was attenuated in 12 obese compared to 12 normalweight subjects. Additionally, FGF21 AUCi positively correlated with glucose AUCi, total relative energy expenditure, and relative VO2max, suggesting that cardiorespiratory fitness levels may predict FGF21 response, contributing to the enhanced regulation of glucose and energy metabolism. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2014. / FAU Electronic Theses and Dissertations Collection

BDNF is a neurotrophin that enhances neural health and is increased by exercise. PURPOSE: To compare moderate continuous (MCE) and high-intensity interval exercise (HIE) effects on serum BDNF levels, and examine the relationship between BDNF and lactate. METHODS: Seven males completed a VO2peak test and two protocols on separate days, (MCE) 28 min at 60% Workrate max (WRmax) and (HIE) 28 min of intervals at 90%WRmax (10- 1 min intervals separated by 2 min of rest). Serum BDNF and lactate were determined prior, during, and following both protocols. RESULTS: BDNF levels (pg/mL) increased from baseline during HIE and MCE (p<.05). The BDNF response to HIE correlated with lactate for area under the curve (AUC) (r=0.901; P<0.05). CONCLUSION: HIE is an effective alternative to MCE at increasing BDNF. Additionally, lactate may act as a measure of intensity or a mediator of the BDNF response to exercise. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2014. / FAU Electronic Theses and Dissertations Collection

The purpose of this study was to examine the acute and temporal response of CK- MM and FGF-21 to 3-day/wk. different repetition-range, volume-equated resistance training programs over 8-weeks in previously trained males. Sixteen trained, college- aged males were counterbalanced into high (DUP-HR) or low (DUP-LR) repetition groups. Subjects performed the squat and bench press 3x/wk. for 8 weeks. Blood samples were collected at various intervals throughout the study. Trained individuals did not elicit significant acute or chronic changes in CK-MM or FGF-21 following training and the lack of change was present in both groups. Additionally, neither biomarker correlated with changes in 1RM strength. There was a very strong correlation between acute mean (r=0.95) and acute percentage change (r=0.97) increase from pre training to post training in week #1. Additionally, a moderate correlation in percentage change was observed (r=0.59) of both biomarkers from pre training to 48 hours post training in week #2. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2015 / FAU Electronic Theses and Dissertations Collection

Parkinson‟s disease (PD) is the most common neurodegenerative movement disorder. It is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Although the etiology of PD remains incompletely understood, emerging evidence suggests that iron homeostasis dysregulation may be involved. A pathological hallmark of PD is the formation of Lewy bodies, intra-cytoplasmic inclusions that are major composed of α-synuclein (α-syn). α-synuclein is encoded by the SNCA gene. It is generally believed that α-synuclein aggregation is a main pathogenic feature and the cause of PD. Previous in vitro studies have provided direct evidence showing that iron could interact with α-synuclein and facilitate its aggregation. Nevertheless, the exact role of iron in the pathogenesis of PD is still inconclusive, and so far no studies have proved the interaction between iron and α-synuclein in vivo. / Here, based on a Drosophila model, we tested the hypothesis that the interaction between iron and α-synuclein accumulation accelerates the pathogenesis of PD, and that restoring brain iron homeostasis provides neuroprotective effects against PD. In our present studies, two groups of Drosophila, including w¹¹¹⁸ control and mutant α-synuclein A53T Drosophila were cultured under normal- (normal medium) and high-iron diet (medium added with 30mM ferric ammonium citrate (FAC)) for up to 30 days. During chronic iron treatment, startle-induced negative geotaxis assay was conducted every ten days to test the locomotor ability in the flies. After that, whole-mount immunostaining was used to assess dopaminergic neuronal survival. These flies were also collected and subjected to the quantification of brain iron content for the characterization of the brain iron content status. Furthermore, quantitative real-time PCR and western-blot analysis were conducted to investigate the amount of various α-synuclein conformations. / In the first part, we observed that α-synuclein A53T fly exhibited age-related increase of brain iron content compared with age-matched control. These were accompanied by shorter life-span, locomotor dysfunction, and TH-positive neuronal loss in PPM1/2 and PPM3 cluster. Meanwhile, we have demonstrated that neuronal toxicity and motor deficits were associated with increased proteinase K resistant, insoluble α-synuclein rather than the total amount of protein level. The insoluble α-synuclein was regarded as α-synuclein aggregation. / In the second part, we found that in α-synuclein A53T fly, excessive iron uptake aggravated locomotion defects and led to specific TH positive neuronal loss in cluster PPM3 after 30 days of iron treatment. Moreover, the excessive iron-induced neurological toxicity and motor dysfunction were also associated with increased α-synuclein aggregation. Overall, these two sets of results suggest that abnormal up-regulation of brain iron content may be associated with α-synuclein, and contribute to the pathogenesis of PD through α-synuclein aggregation-dependent mechanisms. / In the third part, we further explored the potential neuroprotective effect of restoring brain iron homeostasis in PD. We made use of genetic modification to manipulate iron-transport protein DMT1 expression, in turn to identify the protective effect of decreasing brain iron content in α-synuclein Drosophila model. Our present results proved that inactivation of Malvolio in α-synuclein A53T fly can suppress the increase of brain iron contents, and can also prolong life span, partially ameliorate locomotion deficits, and attenuate TH positive neuronal loss in α-synuclein A53T fly. In addition, these beneficial effects might occur through the inhibition of α-synuclein aggregation in α-synuclein A53T fly. Consequently, this result implicates that reducing brain iron by inactivation of iron up-take protein DMT1 can inhibit α-synuclein aggregation and provide beneficial effect on DA neuronal survival in PD model. / In conclusion, we demonstrated that : (1) abnormal up-regulation of brain iron content may be associated with α-synuclein and contributes to the pathogenesis of PD through α-synuclein aggregation-dependent mechanisms; (2) iron uptake protein DMT1 may serve as a potential therapeutic target for alleviating aberrant iron accumulation and retards the progression of neurodegeneration in PD. / 帕金森氏病（PD）是最常見的神經退行性疾病之一，其病理學特徵是黑質緻密部（SNpc）的多巴胺能神經元退行性變性。和，其中α-突觸核蛋白（α-synuclein）是Lewy小體的主要成分。雖然帕金森氏病的發病機制仍不十分清楚，隨著研究的進展，越來越多的證據表明鐵穩態失調可能是其中一個重要的致病因素。細胞內Lewy小體聚集物的形成是帕金森病的一個病理標誌物，其主要的成分是α-synuclein蛋白。α-synuclein是由SNCA基因編碼的蛋白。其聚集通常被認為是帕金森病的一個主要的病理特徵，同時也是導致帕金森病的一個原因。之前的研究證據表明，在體外實驗中，鐵能夠與α-synuclein相互作用並促進α-synuclein的聚集。然而，鐵和α-synuclein的相互關係在帕金森病的發病機制中的確切作用仍不十分確定。 / 我們的課題是基於果蠅模型來驗證腦鐵增加導致的α-synuclein聚集加速了帕金森病的病理進程，且恢復腦鐵平衡可以保護帕金森病人多巴胺能神經元的假說。在我們目前的研究中使用了兩組不同基因型的果蠅，其中包括w¹¹¹⁸對照組和突變體α-synA53T果蠅。兩組果蠅分別同時餵養正常食物（正常培養基）和高鐵食物（30mM檸檬酸鐵銨（FAC））。經過30天的慢性鐵處理，分別收集不同組的果蠅並測定其腦鐵含量用於對不同組果蠅的腦鐵含量進行定量分析。在進行鐵處理的30天期間，每隔10天進行一次趨地性行為學實驗用於評價不同組果蠅的運動能力。行為學實驗過後，可使用整腦免疫染色法來觀察果蠅多巴胺能神經元的存活情況。此外，還运用实时定量PCR和蛋白免疫印跡分析法來檢測不同組果蠅體內α-synuclein mRNA和蛋白的表達情況。 / 在第一部分的實驗中我们發現，與年齡相當的對照組相比，α-synA53T果蠅表現為明顯增高的腦鐵含量，並伴隨著壽命短，運動功能障礙以及PPM1/2和PPM3多巴胺能神經元簇的TH-陽性神經元丟失。同時我們發現，α-synA53T果蠅的神經元的毒性和運動障礙與α-synuclein的蛋白總量無關，而可能與在蛋白酶K中穩定的不溶性α-synuclein蛋白的增加相關，這部分α-synuclein的增加被認為與α-synuclein聚集有關。 / 此外在第二部分實驗中我們還發現，α-synA53T果蠅經過30天鐵處理後會加劇其運動功能障礙，並導致更嚴重的PPM3多巴胺能神經元簇的TH-陽性神經元丟失。並且這種由腦鐵含量增加而導致的神經毒性和運動功能障礙也與α-synuclein聚集增加有關。這兩部分的實驗結果表明，腦鐵含量異常增加調節α-synuclein聚集可能與帕金森病的發病機制有關。 / 在第三部分實驗中，我們進一步探討維持腦鐵穩態在PD中潛在的神經元保護作用。我們利用遺傳學手段調節鐵轉運蛋白DMT1的表達來研究腦鐵含量減少對α-synuclein果蠅的保護作用。目前的結果表明，降低α-synA53T果蠅中DMT1同源基因-Malvolio的表達可以抑制隨著年齡增加而顯著增加的腦鐵含量，並且可以延長果蠅的壽命，部分改善α-synA53T果蠅的運動功能障礙，以及完全減輕了TH陽性神經元的丟失。這些保護作用可能是由於抑制了α-synA53T果蠅中α-synuclein的聚集。因此，這些結果顯示，通過降低DMT1的表達來減少腦鐵含量DMT1可以抑制α-synuclein蛋白聚集並對神經元有保護作用。 / 綜上所述，我們的實驗結果證明了：（1）腦鐵含量異常增加調節α-synuclein聚集可能與帕金森病的發病機制有關; （2）鐵攝取蛋白DMT1可作為一個潛在的選擇性鐵螯合劑治療靶標來減緩帕金森病神經退行性進程。 / Zhu, Zhoujing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 155-181). / Abstracts also in Chinese. / Title from PDF title page (viewed on 03, October, 2016). / Zhu, Zhoujing. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

BACKGROUND & AIMS: Psychological stress in early childhood has been implicated in the pathophysiology of functional dyspepsia but the mechanism is unclear. This study investigates the effect of early psychological stress on the regulation of satiety function in adulthood using an animal model of neonatal maternal separation stress (NMSS). / CONCLUSIONS: Psychological stress in early life leads to aberrant ghrelin profile and dysregulation of feeding behavior in response to acute psychological or physiological stress in adulthood. / METHODS: Sprague-Dawley (SD) rats underwent 3-hour daily maternal separation (MS) from postnatal day 2 to 22 and were weaned. The rats with no MS served as non-handling controls. Three experiments were conducted on these rats on day 60: (1) Water avoidance stress (WAS); (2): Feeding after overnight fasting and (3) Feeding after overnight fasting and WAS. Serial blood samples were collected for acylated ghrelin (AG) assay. In experiments (1) and (2), tissues from the stomach and hypothalamus were harvested additionally for evaluation of ghrelin expression. In experiments (2) and (3), calorie intake was also monitored at regular time intervals. / RESULTS: Experiment (1): MS rats had significantly higher mRNA ghrelin in hypothalamus (1.012 +/- 0.098 vs 0.618 +/- 0.071, P = 0.009) and plasma AG level (141.6 +/- 28.92 pg/mL vs 97.69 +/- 38.21 pg/mL, P = 0.014) in baseline non-stressed conditions. After WAS, MS rats had further increase in plasma AG level and gastric ghrelin expression. Experiment (2): After overnight fasting, the initial calorie intake was significantly higher in MS rats (at 3 mins: 1.303 +/- 0.293 kcal vs 0.319 +/- 0.159 kcal, P= .011; at 8 mins: 2.578 +/- 0.207 kcal vs 1.299 +/- 0.416 kcal, p = 0.019) but it dropped abruptly afterward and no difference in overall calorie intake over 28 minutes was found. The postprandial plasma AG level and gastric mRNA ghrelin were significantly lower in MS rats (95.92 +/- 12.71 pg/mL vs 154.01 +/- 14.53 pg/mL, p = 0.010). Experiment (3): After both fasting and WAS, the MS rats had significantly higher calorie intake in the first hour (17.24 +/- 1.10 kcal vs 11.95 +/- 1.20 kcal, P= 0.006) but it dropped substantially afterward with significantly lower cumulative calorie intake at 3 hours (at 3 hr: 19.44 +/- 1.50 kcal vs 26.49 +/- 2.25 kcal, P = 0.023). The calorie intake in MS rats remained significantly lower than that of controls up to 48 hours (168.1 +/- 4.76 kcal vs 220.8 +/- 8.27 kcal, P&lt; 0.001). / Cheung, Kwan Yui Cynthia. / Adviser: Justin C.Y. Wu. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 138-154). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Obstructive sleep apnea (OSA) is a common breathing and sleeping disorder, characterized by repeated episodes of airway obstruction during sleep resulting in intermittent hypoxia (IH). From clinical reports, patients with OSA are associated with behavioral and neuropsychological deficits, including impaired spatial learning memory and cognitive deficiencies. Previous studies proposed that reactive oxygen species (ROS) and apoptosis caused by intermittent hypoxia (IH) contributed to this cognitive deficits. However, the exact mechanism is still poorly understood and not settled. / The endoplasmic reticulum (ER) is a cellular organelle in which all secretory and integral membrane proteins are folded and is also the site where proteins are post-translationally modified in ATP-dependent chaperone-mediated processes. In this study, we hypothesized that ER stress in the hippocampus is initiated in the OSA via elevated levels of ROS. Four groups of adult male mice were used, with two of them exposed to normoxia as control, and the other two exposed to IH treatment, each receiving either vehicle or tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor. Eight-armed radial maze was used to investigate the performance of reference memory during the whole IH/normoxia treatment. After behavior test, long-term potentiation (LTP) was measured to investigate synaptic plasticity in hippocampus. Furthermore, ER stress-associated pro-apoptotic effectors were detected by Western blotting, and ultra-structure of rough ER and the morphology of hippocampal dendritic spines and synapses in the hippocampal CA1 area were observed. / LTP was impaired in the hippocampus after IH treatment, which was rescued by TUDCA. Furthermore, ER stress-associated pro-apoptotic effectors, CHOP and caspase-12, were up-regulated after chronic IH treatment and was abolished by co-infusion of TUDCA. Meanwhile, increased cleaved-caspase-3 after chronic IH treatment was reduced by TUDCA via increased expression of Bcl-2. On the other hand, ultrastructural analysis of rough ER in the hippocampal CA1 revealed IH-induced ER luminal swelling, and was attenuated by TUDCA. In addition, the length of synaptic active zone was significantly reduced after chronic IH treatment and was partially rescued by the application of TUDCA. Golgi staining also showed a decrease in mature dendritic spines in IH group, and reversed by TUDCA. In behavioral analysis, the number of reference memory errors significantly increased after IH treatment and rescued by TUDCA injection. Overall, the data suggest a critical role of ER stress underlying the impairment of long-term synaptic plasticity and neurocognitive deficits in chronic IH. Targeting ER stress could be a potential therapeutic strategy for neural dysfunction in OSA. / On the other hand, neuronal firing, especially robust persistent activity of neuron in hippocampus, is critical role in memory formation. Increased ROS induced by IH has been implicated in long-term potentiation of neural activity. IH could be involved in a variety of K⁺ channels which eventually leads to excitotoxicity by increased Ca2⁺-dependent glutamate release. Although the results were just shown in acute IH treatment, the chronic effect of IH on the firing frequency of hippocampus is still unknown. / Therefore, to investigate the effect of chronic IH treatment on firing activities and local field potentials of hippocampal neurons, implantation of multi-channel micro-wires electrode array into hippocampus of OSA model rat was performed to monitor spontaneous discharge. The results were shown the firing frequency of pyramidal neurons (PNs) was significantly elevated after 8 hours IH in second and third days, on the other hand, interneurons (INs) seem to be more sensitive to intermittent hypoxia since the higher firing frequency was sustained from third day to seventh day after 8 hours IH, however, at the end of 14 days IH treatment, the firing frequencies of PNs and INs are all both dramatically reduced. Meanwhile, the results in this part will enable us to understand the exact change of firing pattern and local field potential during intermittent hypoxia. The percentage of complex burst spikes was decreased after 14 days IH in PNs and the power of theta rhythms was also impaired. It suggests that the disorder of neuronal pattern and the change of local field potential are associated with cognitive impairment in OSA model. After 1 week recovery, the firing frequency of PNs was rescued again, but not for that of INs. We also found that the power of theta rhythms which had an important role in memory formation was weaker after 2 weeks IH treatment, however, the precise mechanism was still unknown. From the effect of intermittent hypoxia on spontaneous discharges and LFP of hippocampal neurons in free moving rat, it may reveal some roles of IH in cognitive impairment via disorder neuronal function in CA1 region. / 阻塞性睡眠呼吸暫停(OSA) 是一種常見的睡眠障礙疾病，這種疾病的主要特徵是在睡眠過程中反復發作的氣道阻塞，從而導致间歇性缺氧(IH)。從臨床報導中發現，OSA患者表現出行為和神經心理缺陷，包括空間學習記憶的受損和認知缺陷。通過之前的研究表明，活性氧(ROS)的增多和細胞凋亡是間歇性缺氧所引起認知功能障礙的主要機制之一，然而，其具體的機制仍不清楚。 / 作為細胞重要的細胞器，內質網是分泌蛋白和膜蛋白折疊組裝的主要場所，同時，由ATP依賴的分子伴侶所介導的蛋白質翻譯後修飾這一過程也主要在內置網中完成。在本課題中，我們假設在OSA模型的海馬組織中，內質網應激的啟動是由於缺氧引起的與活性氧(ROS)的升高。在本課題中，我們使用了四組成年雄性小鼠，其中兩組作為正常對照組，分別接受生理鹽水和牛磺去氧膽酸（一種常用的內質網抑制劑）的腹腔注射，另外兩組接受缺氧處理，同時也分別接受照生理鹽水和牛磺去氧膽酸注射。八臂放射迷宮被用來研究參考記憶的表現。行為學結束之後，長時程增強(LTP)用來測定海馬的突觸可塑性。用免疫印跡的方法檢測內質網應激的相關凋亡蛋白的表達情況，並且觀察海馬CA1區域中，內質網超微結構和海馬樹突棘數目及突觸形態的變化。 / 從實驗結果中，LTP在缺氧後減弱，而TUDCA能夠部分恢復由於缺氧所導致的LTP的降低。除此之外，內質網應激相關的促凋亡蛋白(CHOP和caspase-12)在缺氧組中表達升高，但是在TUDCA組中有所減低，同時，我們還發現，TUDCA也能夠減低缺氧組中cleaved-caspase-3的表達，而這一作用，可能與提高Bcl-2蛋白的表達（一個可標記的抗凋亡蛋白）有關。在間歇性缺氧組的海馬CA1區域中，粗面內質網出現管腔的腫脹，這一超微結構的變化表明在內質網出現官腔中有的許多未折疊蛋白聚集，並通過TUDCA的注射能夠降解未折疊蛋白來緩解這一現象的發生。同時，在IH處理後，突觸超微結構也發生了形態上的變化。突觸活性區的長度在IH處理組中顯著減少，但是在TUDCA組中有一定程度的恢復。高爾基染色顯示，成熟樹突棘（海馬突觸可塑性的結構基礎）的數目在間歇性缺氧組中有所下降，而在TUDCA治療後，成熟樹突棘的數目有所上升。我們發現參考記憶錯誤次數在缺氧後都有明顯的升高，而在注射TUDCA後，參考記憶錯誤次數都有所降低。總之，這些結果證明，內質網應激在間歇性缺氧的所引起的長時程突觸可塑性減弱和神經認知功能的損傷起到關鍵的作用，而抑制內質網應激對OSA中的出現神經功能紊亂起到一定的預防和治療效果。 / 而另一方面，神經元的放電，特別是海馬中神經元穩定持久的放電形式，對記憶的形成起到關鍵的作用。間歇性缺氧所引起的ROS的升高對於長時程增強的神經活動存在一定的關係，因為，通過以往的研究發現，間歇性缺氧可以通過多種鉀離子通道的啟動，最終由於鈣離子依賴的谷氨酸釋放的增多从而導致興奮性毒性的神經遞質的釋放。而這些結果只在急性缺氧模型中發現，慢性的間歇性缺氧對海馬的放電頻率的影響仍是未知之數。 / 因此，為了探討長時程的間歇性缺氧對海馬神經元的放電頻率和局部場電位的影響，多管道微絲電極陣列植入OSA大鼠的海馬中來監控自發放電的影響。結果表明，錐體細胞的放電頻率在第二天和第三天的8小時的間歇性低氧後明顯的升高了。另一方面，我們觀察到中間神經元似乎對間歇性缺氧更敏感，因為，從第三天到第七天缺氧8小時後，神經元的放電頻率都明顯的增高。但是在間歇性缺氧14天后，錐體細胞和中間神經元的放電頻率都所有顯著性的減少。同時，這一部分結果準確表明了海馬神經元的放電模式和局部場電位在間歇性缺氧的模型的是如何變化的。我們發現錐體細胞所具有的複合簇狀放電的比例減少，同時，theta波(與記憶的形成有關)的能量也有所減低。而這種神經元活動和局部的場電位的異常變化可能與OSA模型中出現的總認知功能障礙有關。在恢復一周後，錐體細胞的放電頻率有所增加，基本上可以恢復到缺氧前的狀態，但是中間神經元的頻率卻沒有多大的改變, 但是，其具體機制仍不清楚。從間歇性缺氧對大鼠海馬神經元自發放電和場電位影響的結果，它揭示了間歇性缺氧通過擾亂海馬CA1區域神經元的功能從而導致認知功能損傷。 / Xu, Linhao. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 167-199). / Abstracts also in Chinese. / Title from PDF title page (viewed on 03, October, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.