O exercício físico (EF) tem relação com melhora na qualidade de vida. Quando nos referimos ao sistema nervoso (SN), o EF diminui efeito lesivo causado por doenças, possibilitando a recuperação em menor tempo, além de contribuir com processos relacionados à melhora cognitiva e redução da ansiedade. Contudo, o EF pode elevar à formação de radicais livres (RL) que, em contato com o SN pode reduzir seu potencial protetor e terapêutico. Os flavonoides são compostos com ação antioxidante e entre eles estão as antocianinas, um dos mais importantes flavonoides com ação antioxidante e anti-inflamatória. O açaí possui grande quantidade de flavonoide podendo, portanto, em associação com EF, potencializar efeitos benéficos ao SN. O presente estudo investigou os efeitos do EF combinado com ingestão de polpa de açaí sobre o comportamento e eventos moleculares em ratos. Para tanto, 32 ratos machos com aproximadamente 120 dias de vida foram divididos em 4 grupos experimentais: i) Sedentário suplementado com açaí (SedA); ii) Sedentário (Sed); iii) Exercício (Exe) e iv) Exercício suplementado com açaí (ExeA). O protocolo de EF na esteira foi de 7 dias, sendo nos dois primeiros sessões de 30 minutos com velocidade de 14m/min. Do terceiro ao sétimo dia, apenas a duração foi aumentada para 1 hora. A suplementação com polpa de açaí foi feita por gavagem com dosagem de 500mg/Kg diluído em água e ocorreu uma hora antes do EF. Os animais sem suplementação (i e ii) receberam água. Após 24 horas da última sessão de treinamento, os animais foram submetidos, individualmente, aos testes de campo aberto (CA) para avaliar ansiedade e reconhecimento de objeto (RO) para avaliar a memória. Após os testes os animais foram eutanasiados sob anestesia e os tecidos do hipocampo e amígdala foram analisados. As proteínas BDNF, GDNF, GAP43 e GFAP foram analisadas por Western blot e a cinética da atividade das enzimas antioxidantes CAT, GPx e SOD foi testada por imunoensaio. Os dados comportamentais e moleculares foram avaliados estatisticamente através do software Prisma. O peso corporal foi diferente entre os grupos sedA e Exe (0,0001). O teste de rearing (ansiedade) apontou diferenças entre os grupos SedA e ExeA quando comparados com Sed (0,0003). A micção diminuiu nos grupos SedA e ExeA (0,0121). Os grupos SedA e ExeA (0,0042) tiveram comportamentos diferentes no teste de RO em comparação com grupo Sed (0,0026). Houve aumento da atividade de GPx no hipocampo dos animais do grupo Exe em comparação com grupo Sed (0,0002) e, na amígdala, houve diferenças entre grupos Exe e ExeA quando comparados com Sed (0,0037). Houve efeito da administração de açaí sobre o BDNF maduro no hipocampo, levando à diferença na razão BDNF maduro e BDNF total entre os grupos SedA e ExeA em relação ao Sed (0,0107) e (0,0035). Não houve diferença entre os grupos nas análises das proteínas GDNF, GAP43 e GFAP. A associação de EF a açaí influenciou positivamente alguns parâmetros relacionados à ansiedade, denotando possível efeito ansiolítico. Houve ainda efeitos sobre atividade da enzima antioxidante GPx no hipocampo e amígdala, indicando que, possivelmente, essa possa ser uma das vias que recebeu influência do EF e açaí / Physical exercise (PE) is related to an improvement in the quality of life. When we refer to nervous system (NS), the PE reduce the harmful effect caused by diseases, allowing recovery in a shorter time, besides contributing with processes related to cognitive improvement and reduction of anxiety related events. However, EF can raise the formation of free radicals (FR) which, in contact with CN can reduce the protector and therapeutic potential. Flavonoids are compounds with antioxidant action such as anthocyanins, one of the most important flavonoids with antioxidant and anti-inflammatory activity. Açaí has a large amount of this flavonoid and associated to PE can potencialize benefits to CN. The present study investigated the effects of PE combined with ingestion of açaí pulp on behavior and molecular events in rats. For this, 32 male rats with approximately 120 days of life were divided into 4 experimental groups: i) Sedentary supplemented with açaí (SedA); ii) Sedentary (Sed); iii) Exercise (Exe) and iv) Exercise supplemented with açaí (ExeA). The PE protocol was 7 days of treadmill running. The first two sessions was 30 minutes of PE with speed of 14m / min. From the third to the seventh day only the duration was increased to 1 hour. Supplementation with açaí pulp was made by gavage at a dosage of 500mg/kg diluted in water, one hour before EF. The animals without supplementation (i and ii) received water. After 24 hours of the last training session, the animals were individually submitted to the open field (OF) tests in order to evaluate anxiety and object recognition (OR) to evaluate memory. After the tests the animals were euthanized under deep anesthesia and the hippocampal and amygdala tissues were analyzed. The proteins BDNF, GDNF, GAP43 and GFAP were analyzed by Western Blot and the kinetics of the activity of the antioxidant enzymes CAT, GPx and SOD by immunoassay. The behavioral and molecular data were statistically evaluated using the Prisma software. There was a difference in body weight between SedA and Exe groups (0.0001). The rearing evaluation was different SedA and ExeA when compared with Sed (0.0003). The miction reduced in SedA and ExeA groups 0.0121). The groups SedA and ExeA (0.0042) had had different behaviors in the OR test when compared to Sed (0.0026). There was increase in GPx activity in hippocampus in the Exe group and in the amygdala the activity was higher in Exe and ExeA groups than in Sed group (0.0002). We observed effect of the açaí in the mature BDNF in the hippocampus, resulting in difference in the ratio mature BDNF/total BDNF in the SedA and ExeA in comparison with Sed (0.0107 and 0.0035). We did not found differences in GDNF, GAP43 and GFAP. The association of PE and açaí influenced positively parameters related to anxiety behavior. There was effect over the antioxidant activity of GPx both in hippocampus and amygdala, indicating que, probably, this can be one of the pathways which can be influenced by the PE and açaí

Os objetivos principais desta tese foram avaliar parâmetros bioquímicos gliais, inflamatórios e comportamentais em pacientes com lesão medular (LM) submetidos a um protocolo de dança, e em ratos submetidos aos protocolos de exercício voluntário e forçado. Para tanto, foram realizados 4 experimentos. No primeiro, os ratos foram submetidos a 4 semanas de exercício moderado em esteira ergométrica (20 min por dia). No segundo, os animais foram submetidos à 4 semanas de exercício voluntário em rodas de correr (12 horas por dia). No terceiro experimento, os ratos foram expostos à esteira ergométrica durante 2 semanas (20 min/dia) e, após o último treino, receberam uma injeção intraperitoneal de LPS. Neste último, a memória e aprendizagem dos animais foram investigadas. Ao término do período de exercício, ou após a injeção de LPS, as análises bioquímicas do hipocampo foram realizadas. O quarto experimento foi realizado com indivíduos com LM que foram submetidos a 4 semanas de dança. Análises sorológicas e comportamentais foram efetuadas. Os resultados mostraram que o exercício forçado promoveu o aumento da glutamina sintetase (GS) e diminuição de proteína glial fibrilar ácida (GFAP) e óxido nítrico (NO) no hipocampo, além de aumentar os níveis de corticosterona, o que pode estar mediando os efeitos do exercício sobre os astrócitos. O exercício voluntário induziu o aumento da GS e BDNF. A aplicação de LPS promoveu aumento dos níveis de TNF-α no hipocampo dos animais, o que coincidiu com o aumento dos níveis de S100B no fluído cerebrospinal. Os indivíduos com LM submetidos à dança apresentaram melhora significativa nos escores da Medida de Independência Funcional, Índice de Barthel, Escala de Berg e Escala Hospitalar de Ansiedade e Depressão, e aumento dos níveis sorológicos de BDNF. A dança não teve efeito sobre os parâmetros gliais, metabólicos e inflamatórios periféricos. Estes resultados sugerem que diferentes tipos de exercício físico exercem diferentes efeitos sobre os astrócitos hipocampais, o que pode interferir na indicação de um ou outro dependendo do objetivo a ser alcançado. O exercício em esteira pode ser uma atividade indicada para prevenção de doenças que envolvem neuroinflamação, e a dança pode ser uma intervenção terapêutica eficaz para reabilitação de indivíduos com lesão medular uma vez que contribui para melhora física e psicológica desta população. Tomados juntos, os resultados desta Tese ressaltam a importância da prática de exercício físico para o metabolismo neural, e a relevância de estudar os astrócitos para compreensão dos mecanismos envolvidos no efeito do exercício físico no SNC. / The main aim of this Thesis was to evaluate the biochemical glial, inflammatory and behavioral parameters, in patient with spinal cord injury (SCI) submitted to a protocol of dance, and in rats submitted to voluntary and forced exercise. Four experiments were made. In the 1st, the rats were submitted to 4 weeks of moderate exercise on treadmill (20 min per day). In the 2nd, the animals were submitted to 4 weeks of voluntary exercise on wheel running (12 hours per day). In the 3rd experiment, the rats were exposed to treadmill during 2 weeks (20 min per day) and, after the last session, they received intraperitoneal injection of LPS. In this last experiment, the memory and learning were investigated. At the finish of the exercise period, or after the LPS injection, the biochemical analysis of the hippocampus was realized. The 4th experiment was realized with individuals with spinal cord injury that were submitted to 4 weeks of dance practice. Behavioral and serological analyses were performed. Data show that treadmill running increased glutamine synthetase (GS) activity and decreased hippocampal glial fibrillary acidic protein (GFAP) and nitric oxide (NO) , as well as increased corticosterone level, that can mediate the effects of the exercise on astrocytes. The voluntary exercise increased GS and BDNF. The LPS administration increased hippocampal TNF-α level in rats concomitantly with the increase in the S100B levels in cerebrospinal fluid. The individuals with spinal cord injury submitted to dance showed a significant improve in the scores of Functional Independency Measure, Barthel Index, Berg Scale and Ansiety and Depression Hospitalar Scale, and a increase in the serologic levels of BDNF. The dance had no effect on glial, metabolic and inflammatory parameters. These results suggest that different types of exercise exert different effects on hippocampal astrocytes, which may interfere with the appointment of one or the other depending on the objective to be achieved. The treadmill exercise can be a good strategy in the prevention of neuroinflammatory diseases, and dance can be an effective therapeutic intervention for rehabilitation of individuals with SCI as it helps to improve physical and psychological conditions in this population. Taken together, the present data highlight the importance of physical exercise for neural functions, and the relevance of studying astrocytes to understand the mechanisms involved in the effect of exercise on CNS.

阻塞性睡眠呼吸暂停（OSA）是一种常见的睡眠障碍，睡眠过程中反复发作的气道阻塞，导致间歇性低氧血症。OSA 中的間歇性缺氧（IH）一直被视為一個主要致病因素。會影響神經認知功能，包括記憶障礙，遲鈍的反應和其它。以前的研究提示氧化应激产物（ROS）和细胞凋亡是間歇性缺氧引起的认知功能障碍的主要機制之一。然而，确切的机制仍然知之甚少，并没有得到解决。我们基于間隙性缺氧 （IH）的动物模型的实验结果首次发现，即在IH 模型中海馬長時程增強（LTP）的降低，以及腦源性神經營養因子（BDNF）的表达减少。同時我們發現，大脑内注射BDNF 可以有效地恢复LTP 的幅度。因此，我们的研究提供了一种新的可能机制，即在缺乏脑源性神经营养因子可能是阻塞性睡眠呼吸暂停導致的伴有脑功能障碍一个关键因素。 / Ampakine 是一種AMPA 受體調節劑，更重要的是可以增加腦內BDNF 的表達。在这项研究中，我們在不同缺氧時間處理的動物模型中通过腹部注射ampakine 來觀察其效應。我們使用了四组成年雄性小鼠，其中組接受7 天IH处理，另外两组接受14 天缺氧处理。所有四组均分别接受腹腔ampakine 和对照生理盐水注射。 IH 模式仍然是氧含量在90 秒内从21 降到10%，再回复到21%。缺氧时间是每天8 小時周期。从整个IH /正常氧环境的第一天开始，八臂放射迷宮被用来研究参考记忆和工作记忆的表现。然后，我们对脑源性神经营养因子，活性氧和细胞凋亡的分子标记和海马的树突棘形态的表达进行了检查， 海馬突触可塑性的表現，包括E-LTP，L-LTP 也都被檢測。 / Western blot 分析显示，ampakine 注射有效恢复了IH 導致的海马BDNF 水平下降。同时， 我們也發現在ampakine 注射組中ROS 的表达减少，细胞凋亡的减轻，其中包括内质网应激诱导的细胞凋亡。树突棘被認為是海马突触可塑性的结构基础之一。高尔基体染色也表明， ampakine 注射IH 成功回復了7 天IH 導致的較大的，成熟树突棘的減少。 / 此外，八臂放射迷宮的结果表明，无论是参考记忆和工作记忆在7 天IH和14 天IH 均有受損表現。但是，ampkine 的使用同樣挽救了IH 引起的這些记忆障碍。 / 最後，通過研究AMPA 受體調節劑（ampakines）對IH-誘導的神經認知功能障礙及長時程增強障礙影響，我們發現進一步的闡明BDNF 在OSA 所起的重要作用。這些結果也將探索新的藥物治療的OSA 了新的思路。 / 阿爾茨海默病（AD），也叫老年癡呆癥，在65 歲的人的失憶症中，是最常見的原因，也是最常見的神經退行性疾病。 AD 的原因並不清楚，其起病也並不明顯。它的特點是逐漸喪失記憶，語言障礙及其他認知功能障礙，這些症狀可能會變得明顯。在AD 中，兩種蛋白質聚集體的參與和特點的AD 病理澱粉樣斑塊，由澱粉樣蛋白-β 肽，並導致細胞外病變和tau 蛋白纏結，這是由過度磷酸化的絲微管相關蛋白tau，並導致細胞內的病變。 / 鐵是最豐富的微量金屬，在大腦中參與範圍廣泛的細胞過程的運作。然而，鐵臭名昭著的另一方面是其強大的氧化催化性能。事實上，失調的鐵已被發現與細胞老化和各種各樣的神經退行性疾病有牽連。鐵在突觸功能的重要性是對突觸的影響，例如其可以順行軸突運輸突觸功能區域，這也是阿爾茨海默病中的澱粉樣蛋白斑的沉積的起始部位。然而，到現在，鐵的積累是如何影響突觸功能以及更普及的大腦功能很少被研究。 / 為了調查是否高鐵食有任何正常或阿爾茨海默氏病的影響，我們在實驗中引入了APPswe/ps1 轉基因小鼠，這是一個經典的老年癡呆症的疾病的動物模型。研究中，我們使用四組動物模型，即野生型（WT）和APPswe/ps1 小鼠（TG），每組給予至少10 個月正常（ctrl）的食和高鐵（HI）食。 / 海馬LTP 記錄表明，野生小鼠與正常食（WT-HI）的海馬長時程增強下降。 Tg-ctrl 組也相比wt-ctrl 組顯示LTP 水準下降，包括E-LTP 和L-LTP。引人注目的是，高鐵食下的APPswe/ps1 下顯示了被提高和恢復的海馬長時程突觸可塑性。 / 八臂放射迷宮的結果還表明，與高鐵食的野生型以及正常食的APPswe/ps1，無論是在參考記憶體或工作記憶，比野生型與正常食組有較差的記憶水準。同樣，我們驚訝地發現，和APPswe/ps1 正常食的小鼠相比，給予高鐵食的APPswe/ps1 組的迷宮成績要好得多,几乎回复到和野生型对照组一样的水平。 / 這些結果表明，鐵在阿爾茨海默病的功能是非常複雜的，可能會對其神經可塑性顯示雙相調節作用特性。詳細機制有待進一步探討。 / Obstructive sleep apnea (OSA) is a common sleep disorder, characterized by repeated episodes of airway obstruction during sleep resulting in intermittent hypoxemia. Previous studies proposed that reactive oxygen species (ROS) and apoptosis caused by intermittent hypoxia (IH) contributed to cognitive deficits. However, the exact mechanism is still poorly understood and not settled. Our recent studies, for the first time, showed that there is decreased expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and impairment in long-term potentiation (LTP). Intra-brain injection of BDNF can effectively restore the magnitude of LTP. Thus, our study provides a novel mechanism and insight in the etiology of OSA-induced brain dysfunction in that lacking BDNF could be a critical factor. / In this study, ampakine application was used as “BDNF raiser“ during 7-day IH and 14-day IH treatment by intraperitoneal (i.p.) injection. Four groups of adult male mice were used, two of them exposed to 7-day IH and two of them exposed to 14-day IH, each received either vehicle or ampakine i.p. injection. The paradigm of IH consisted of cycles of oxygen levels between 10% and 21% every 90s during the daytime for 8 hrs. Radial arm maze was used to investigate the performance of reference memory and working memory during the whole IH/ normoxia treatment from the first day. After that, expression of BDNF, ROS and molecular markers of apoptosis and morphology of hippocampal dendritic spines were examined, together with the investigation of both hippocamal synaptic plasticity, including early phase LTP (E-LTP) and late phase L-LTP (L-LTP). / Ampakine treatment restored the decreased level of hippocampal BDNF in the IH-treated group, as revealed by Western blot. Meanwhile, decreased ROS expression and alleviated cell death, including ER stress induced-apoptosis are all found in those ampakine injected groups. Golgi staining also showed that ampakine injection IH treatment rescued the decrease of mature dendritc spines, which is the structural basis of hippocampal synaptic plasticity, under 7-day IH treatment. Hippocampal long-term synaptic plasticity, which underlies the proposed mechanism of memory, was also found reversed in those ampakine injected groups, compared with groups under IH treatment. / Furthermore, results of radial arm maze showed that both the reference memory and working memory are impaired by 7-day IH treatment or 14-day IH treatment. However, the application of ampakine rescued IH-induced memory deficits. / Finally, by studying the effects of the ampakines on IH-induced neurocognitive dysfunction and LTP impairment, the role played by BDNF in OSA was further elucidated. These results were shed new lights on the exploration of novel pharmacological treatments in the OSA. / Alzheimer’s disease is the most common cause of dementia among aged people. The causes of AD are not clear and onset of the disease is also not obvious. Iron is the most abundant trace metal in the brain and dysregulation of iron has been implicated in cell aging and a wide variety of neurodegenerative diseases including Alzheimer disease. However, up to now, very little is known about how iron accumulation is involved in Alzheimer disease. / To investigate whether high iron diet has any effects on normal or Alzheimer’s disease, we introduced APPswe/ps1 transgenic mice, an Alzheimer’s disease animal model, and used four groups in our study, namely wild type (wt) and APPswe/ps1 mice (tg), each with normal (ctrl) diets and high iron (HI) diet for at least 10 months. / Hippocampal LTP recording showed that wild type with high iron diet (wt-HI) decreased than that of wt-ctrl group. Tg-ctrl group also displayed decreased LTP level, including E-LTP and L-LTP, than that of wt-ctrl group. Strikingly, that of APPswe/ps1 under HI diets rescued the impaired hippocampal long-term synaptic plasticity than that of APPswe/ps1 mice under normal diets. / Results from radial arm maze also showed that both APPswe/ps1 with normal diet and wild type with HI diet had worse performance, either in reference memory or working memory, than those of wild type with normal diets. Again, it is surprised to find that performances of tg-HI group were much better than APPswe/ps1 mice under normal diet. / These results showed that the function of iron are very complicated, may have different effects on neural function of normal and AD objects. The detailed mechanisms needs to be further explored. / 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. / 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. / Xie, Hui. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 200-225). / Abstracts also in Chinese. / Declaration --- p.II / ABSTRACT OF THESIS ENTITLED --- p.III / 中文摘要 --- p.VII / Acknowledgements --- p.XI / List of abbreviations --- p.XIII / List of publications --- p.XVI / Chapter CHAPTER 1 --- INTRODUCTION --- p.4 / Chapter 1.1 --- Overview of the study --- p.4 / Chapter 1.2 --- Obstructive sleep apnea --- p.7 / Chapter 1.2.1 --- Epidemiology --- p.8 / Chapter 1.2.2 --- Pathogenesis --- p.10 / Chapter 1.2.3 --- Pathophysiologic Consequences --- p.11 / Chapter 1.2.4 --- Diagnosis --- p.14 / Chapter 1.2.5 --- Treatment --- p.15 / Chapter 1.3 --- Memory and long-term potentiation --- p.17 / Chapter 1.3.1 --- Memory --- p.17 / Chapter 1.3.2 --- Hippocampal Synaptic plasticity --- p.19 / Chapter 1.3.3 --- Dendritic Spines --- p.23 / Chapter 1.4 --- Brain-derived neurotrophic factor --- p.35 / Chapter 1.4.1 --- Introduction of BDNF --- p.35 / Chapter 1.4.2 --- BDNF and synaptic plasticity --- p.36 / Chapter 1.5 --- Intermittent hypoxia impaired memory and neuroplasticity --- p.38 / Chapter 1.5.1 --- Clinical and basic studies on IH-induced neurological dysfunction --- p.38 / Chapter 1.5.2 --- Current mechanisms of IH-induced neurological dysfunction --- p.39 / Chapter 1.5.3 --- ROS generation and intermittent hypoxia --- p.41 / Chapter 1.5.4 --- Critical role of decreased BDNF expression in chronic intermittent hypoxia --- p..46 / Chapter 1.6 --- Ampakine --- p.48 / Chapter 1.6.1 --- Effects of ampakine on receptor activities --- p.49 / Chapter 1.6.2 --- Effects of ampakine on synaptic transmission --- p.50 / Chapter 1.6.3 --- Effects of ampakine on long-term potentiation --- p.52 / Chapter 1.6.4 --- Ampakine, BDNF and neurological disease --- p.53 / Chapter CHAPTER 2 --- METHODS --- p.61 / Chapter 2.1 --- Experimental procedure --- p.61 / Chapter 2.1 --- Animal model of Obstructive Sleep Apnea --- p.62 / Chapter 2.1.1 --- Chronic Intermittent Hypoxia --- p.62 / Chapter 2.1.2 --- Oxygen saturation measurement under normoxia and intermittent hypoxia --- p.64 / Chapter 2.1.3 --- Body weight during hypoxia treatment --- p.64 / Chapter 2.2 --- Western Blot Analysis --- p.65 / Chapter 2.3 --- ROS measurement --- p.67 / Chapter 2.4 --- Golgi staining --- p.67 / Chapter 2.4.1 --- Analysis of spine density --- p.68 / Chapter 2.4.2 --- Measurement of dendritic spines --- p.68 / Chapter 2.5 --- Electrophysiological Experiments --- p.69 / Chapter 2.5.1 --- Brain Slice Preparation --- p.69 / Chapter 2.5.2 --- Multi-electrode Recording Setup (MED64) --- p.70 / Chapter 2.5.3 --- Slice Superfusion --- p.72 / Chapter 2.5.4 --- Field Potential Recordings --- p.73 / Chapter 2.5.5 --- LTP Induction Protocol --- p.74 / Chapter 2.6 --- Radial arm maze --- p.76 / Chapter CHAPTER 3 --- RESULTS --- p.91 / Chapter 3.1 --- Molecular detection under IH treatment and ampakine injection --- p.91 / Chapter 3.1.1 --- BDNF expression under IH treatment and ampakine injection --- p.91 / Chapter 3.1.2 --- ROS measurement under IH treatment and ampakine injection --- p.92 / Chapter 3.1.3 --- Involvement of ER stress during IH treatment --- p.93 / Chapter 3.2 --- Changes of dendritic spines under IH treatment and ampakine injection --- p.100 / Chapter 3.2.1 --- Changes of total dendritic spine density under IH treatment and ampakine injection --- p.100 / Chapter 3.2.2 --- Changes of different dendritic spine density under IH treatment and ampakine injection --- p.101 / Chapter 3.2.3 --- Changes of dendritic spine morphology under IH treatment and ampakine injection --- p.103 / Chapter 3.3 --- IH-induced impairment in hippocampal synaptic plasticity --- p.110 / Chapter 3.3.1 --- E-LTP measurement of 7-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.110 / Chapter 3.3.2 --- L-LTP measurement of 7-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.111 / Chapter 3.3.3 --- E-LTP measurement of 14-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.112 / Chapter 3.3.4 --- L-LTP measurement of 14-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.113 / Chapter 3.4 --- Behavioral studies under IH treatment and ampakine injection --- p.119 / Chapter 3.4.1 --- Reference memory test under IH treatment and ampakine injection --- p.119 / Chapter 3.4.2 --- Working memory measurement under IH treatment and ampakine injection --- p..122 / Chapter CHAPTER 4 --- DISCUSSION --- p.140 / Chapter 4.1 --- Molecular changes under IH treatment and ampakine application --- p.140 / Chapter 4.1.1 --- Intermittent hypoxia down regulate BDNF expression in hippocampus while ampakine injection rescued IH-induced decreased BDNF level --- p.140 / Chapter 4.1.2 --- Ampakine injection against ROS and apoptosis --- p.143 / Chapter 4.1.3 --- Involvement of ER stress-induced apoptosis during IH treatment --- p.145 / Chapter 4.2 --- Changes of spine morphology and density under IH treatment and ampakine injection --- p.146 / Chapter 4.3 --- Ampakine rescued hippocampal synaptic plasticity --- p.152 / Chapter 4.4 --- IH impaired reference memory and working memory --- p.156 / Chapter 4.5 --- Summary --- p.160 / Chapter Chapter 5 --- Effects of High-iron diet in Alzheimer’s Disease --- p..164 / Chapter 5.1 --- Overview of the study --- p.164 / Chapter 5.2 --- Introduction --- p.166 / Chapter 5.2.1 --- Alzheimer's disease --- p.166 / Chapter 5.2.2 --- Function of iron in brain --- p.167 / Chapter 5.2.3 --- Involvement of iron in oxidative damage --- p.168 / Chapter 5.2.4 --- Role of iron in neurodegeneration diseases --- p.168 / Chapter 5.2.5 --- Role of iron in Alzheimer's disease --- p.169 / Chapter 5.2.6 --- Deleterious effects of iron in memory function --- p.171 / Chapter 5.3 --- Methods --- p.172 / Chapter 5.3.1 --- Experimental design --- p.172 / Chapter 5.3.2 --- T-maze --- p.172 / Chapter 5.4 --- Results --- p.174 / Chapter 5.4.1 --- Validation of animal model of Alzheimer's disease --- p.174 / Chapter 5.4.2 --- Examination of normal and high iron diet on body weight --- p.174 / Chapter 5.4.3 --- Effects of Aβ accumulation and high-iron diet on hippocampal synaptic plasticity --- p.175 / Chapter 5.4.4 --- Effects of Aβ accumulation and high-iron diet on spatial memory measured by T-maze --- p.177 / Chapter 5.4.5 --- Effects of Aβ accumulation and high-iron diet on reference memory and working memory measured by radial arm maze --- p.178 / Chapter 5.5 --- Discussion --- p.180 / Chapter Chapter 6 --- General discussion --- p.195 / Reference --- p.200

Introdução: A cefaleia do tipo tensional crônica (CTTC) é caracterizada por dor de cabeça quase diária e sensibilização central. A acupuntura tem sido estudada no tratamento de diversos tipos de cefaleia, porém os resultados são controversos e apenas sugerem maior eficácia em relação ao placebo. A eletroacupuntura (EA) modula algumas das funções do sistema nervoso central (SNC), podendo modificar a neuroplasticidade. A plasticidade do SNC pode ser rastreada através dos níveis séricos do fator neurotrófico derivado do cérebro (BDNF), um mediador de neuroplasticidade. Objetivo: Este estudo testou a hipótese de que a analgesia pela EA na CTTC estaria relacionada à neuroplasticidade, avaliada através dos níveis séricos de BDNF. Métodos: Foram recrutadas mulheres, com idades entre 18-60 anos, portadoras de CTTC, para um ensaio clinico randomizado, cegado, controlado por placebo-sham. Foram aplicadas 10 sessões de EA, durante 30 minutos (2- 10 Hz, com intensidade conforme a tolerância) na cervical e áreas autonômicas, duas vezes por semana, que foram comparadas com placebosham. Os períodos de tratamento foram separados por duas semanas de intervalo. Avaliou-se dor (através de escala análoga visual (VAS) de 10 cm) e níveis séricos de BDNF como desfechos primários. Resultados: Trinta e quatro pacientes foram randomizadas e vinte e nove completaram o protocolo. Os escores da VAS foram menores durante o tratamento com EA, do que no tratamento com placebo-sham. (2.38±1.77, 3.02±2.49 respectivamente, P=0.005). Os escores de dor variaram conforme a sequência de intervenção, demonstrando efeito de carreamento (P<0.05). Utilizando regressão múltipla, os níveis séricos de BDNF foram ajustados para a escala de depressão de Hamilton e VAS (r-squared= 0.07, standard β coefficients= -0.2, -0.14, respectivamente). Ao final do período da primeira intervenção os valores de BDNF ajustados, foram maiores no grupo EA, (29.31±3.24, 27.53±2.94 ng/mL) a magnitude de efeito mensurada pela diferença na media padronizada expressou um efeito moderado (Cohen´s d= 0.55). Conclusão: A analgesia produzida pela EA pode estar relacionada à neuroplasticidade, avaliada através do BDNF ajustado para dor e depressão. A modulação pela EA na dor e BDNF depende da condição do SNC, uma vez que está relacionada à depressão e depende do momento da aplicação da intervenção. / Background: Chronic tension-type headache (CTTH) is characterized by almost daily headaches and central sensitization. Electroacupunture (EA) is effective for this condition and modules some central nervous system (CNS) functions. CNS plasticity could be tracked in serum using the brain derived neurotrophic factor (BDNF), a neuroplasticity mediator. Objective: We tested the hypothesis that EA analgesia in CTTH would be related to neuroplasticity indexed by the BDNF. Patients and methods: We enrolled females aging 18-60 with CTTH in a randomized, blinded, placebo-controlled crossover trial, comparing ten EA sessions applied during 30 minutes (2-10 Hz, intensity by tolerance) in cervical and autonomic areas twice per week, vs. placebo-sham (PS). Treatment periods were separated by two washout weeks. Pain on the 10 cm visual analog scale (VAS) and serum BDNF were assessed as primary outcomes. Results: Thirty-four subjects underwent randomization, twenty-nine completed the protocol. VAS during EA period was lower than during PS (2.38±1.77, 3.02±2.49 respectively, P=0.005). VAS differed according to intervention sequence demonstrating carry-over effect (P<0.05). Using multiple regression serum BDNF was adjusted for the Hamilton depression rating scale (HDRS) and VAS (r-squared=0.07, standard β coefficients=-0.2, -0.14, respectively; omnibus-test P<0.001). At the end of the first intervention period the adjusted BDNF was higher in the EA cohort (29.31±3.24, 27.53±2.94 ng/mL, Cohen´s d= 0.55). Conclusion: EA analgesia may relate to neuroplasticity indexed by the adjusted BDNF. EA modulation on pain and BDNF depends on the situation of the CNS, as is related to depression and depends on the timing of the intervention.

The ability of the brain to change and form new neuropathways after brain injury is remarkable. The current study investigates the brains ability to form new pathways for language processing following traumatic brain injury (TBI), specifically a left temporal lobectomy. Two subjects participated in this study; one participant with TBI and one age-matched control. Sentence stimuli consisted of four types: semantically correct, semantically incorrect, syntactically correct, and syntactically incorrect. Participants underwent a fMRI scan while the auditory stimuli were presented in four blocks. Participants were asked to record if the sentence was correct or incorrect by pressing the corresponding button. It was found that reaction times for both the participant with TBI and the control were longer for the incorrect conditions. The participant with TBI generally had longer reaction times compared to the control participant and had more errors. During the fMRI scans, patient movement occurred. The block design was not set up to account for movement. Due to this factor, imaging results are questionable. While there were differences between the participant with TBI and the control participant, these differences are expected to be much larger in someone with this degree of brain injury. It is recommended for further studies to be conducted in this area with a revised block design to account for patient movement.

La diferenciació dels precursors neuronals en cèl·lules especialitzades implica una restricció de la seva capacitat proliferativa i la sortida definitiva del cicle cel·lular. Entre les proteïnes HLH activadores de la diferenciació hi ha les proteïnes E (E47, E12, HEB, E2-2), les quals s’expressen a la majoria de teixits. Al nostre laboratori es va descriure que la proteïna E47 forma heterodímers amb la proteïna HLH específica de teixit NeuroD, i activa l’expressió del receptor del BDNF (TrkB) i l’inhibidor de cicle p21CIP en resposta a la senyal diferenciadora d’àcid retinoic (RA). La correcta expressió del receptor TrkB juga un paper clau en el desenvolupament del sistema nerviós en vertebrats i la seva alteració s’ha relacionat amb diferents malalties humanes importants. En aquest treball s’ha demostrat que la quinasa MLK2 interacciona amb la bHLH E47 en cèl·lules de neuroblastoma SHSY-5Y. Es proposa que la MLK2 controla l’activitat del factor bHLH E47 a través de la seva fosforilació, la qual redueix l’activació del promotor de trkB. A més, la inhibició de la MLK2 augmenta l’expressió de l’mRNA de trkB in vivo explicant perquè aquesta inhibició no només prevé l’activació dels processos de mort cel·lular sinó que també ajuda a les vies de supervivència. D’altra banda, estudis molt recents revelen la importància dels processos de localització d’mRNAs als axons i a les dendrites i la seva traducció localitzada. Conèixer com es regula la localització dels mRNAs i la seva traducció localitzada a nivell molecular ajuda a entendre aspectes fonamentals de la plasticitat i la diferenciació neuronal. Durant el transport dels mRNAs, la seva traducció està reprimida i aquesta s’activa a llocs concrets com a resposta a senyals sinàptics, i en conseqüència, s’activa la plasticitat neuronal. Prèviament, al nostre laboratori, es va demostrar que la proteïna KIS pot estimular la traducció localitzada d’mRNAs, afavorir el creixement neurític i la supervivència neuronal. En aquest treball demostrem que la KIS interacciona amb proteïnes i mRNAs implicats en activitat sinàptica, els quals són transportats a través de partícules mRNP. La nostra hipòtesi és que quan el grànul transportat per KIF3A arriba al seu destí, diversos estímuls sinàptics possiblement indueixin l’activació de la quinasa Src, la qual fosforila la KIS, activant la traducció dels mRNAs transportats. / La diferenciación de precursores neuronales en células especializadas implica la restricción de su capacidad proliferativa y la salida definitiva del ciclo celular. Entre las proteínas HLH activadoras de la diferenciación están las proteínas E (E47, E12, HEB, E2-2) las cuales se expresan en la mayoría de los tejidos. En nuestro laboratorio se describió que la proteína E47 forma heterodímeros con la proteína HLH especifica de tejido, NeuroD, y activa la expresión del receptor de BDNF (TrkB) y el inhibidor de ciclo p21CIP en respuesta a la señal diferenciadora del ácido retinoico (RA). La correcta expresión del receptor TrkB juega un papel clave en el desarrollo del sistema nervioso en vertebrados y su alteración se ha relacionado con diferentes enfermedades humanas importantes. En este trabajo se ha demostrado que la quinasa MLK2 interacciona con la bHLH E47 en células de neuroblastoma SHSY-5Y. Se propone que MLK2 controla la actividad del factor bHLH E47 a través de su fosforilación, la cual reduce la activación del promotor de trkB. Además la inhibición de MLK2 aumenta la expresión del mRNA de trkB in vivo explicando por qué esta inhibición no sólo previene la activación de los procesos de muerte celular sino que también ayuda a las vías de supervivencia. Por otro lado, estudios muy recientes revelan la importancia de los procesos de localización de mRNAs en axones y dendritas y de su traducción localizada. Conocer cómo se regula la localización de los mRNAs y su traducción localizada a nivel molecular ayuda a entender aspectos fundamentales de la plasticidad y la diferenciación neuronal. Durante el transporte de los mRNAs su traducción está reprimida y ésta se activa en lugares concretos en respuesta a señales sinápticas resultando en la activación de la plasticidad neuronal. Previamente, en nuestro laboratorio, se demostró que la proteína KIS puede estimular la traducción localizada de mRNAs, favorecer el crecimiento neurítico y la supervivencia neuronal. En este trabajo demostramos que KIS interacciona con proteínas y mRNAs implicados en actividad sináptica, los cuales son transportados a través de partículas mRNPs. Nuestra hipótesis es que cuando el gránulo transportado por KIF3A llega a su destino, varios estímulos sinápticos posiblemente induzcan la activación de la quinasa Src la cual fosforila KIS, activando la traducción de los mRNAs transportados. / The differentiation of neuronal precursors in specialized cells induces an increase of a restriction of their proliferative capacity and a complete exit of the cell cycle. Among the HLH protein activators of differentiation the E protein family (E47, E12, HEB, E2-2) is expressed in most of the tissues. In our laboratory it has been described that in response to the differentiating signal of retinoic acid (RA), E47 heterodimerizes with the HLH protein tissue specific NeuroD which activates the expression of the receptor BDNF (TrkB) and the cell cycle p21CIP inhibitor. TrkB expression plays a key role in the nervous system development in vertebrates, and its alteration has been related with different types of important human diseases. In the present work we identified the kinase MLK2 as an E47-interaction protein in SHSY-5Y human neuroblastoma cells. We propose MLK2 as a controller of the BDNF receptor TrkB through the phosphorylation of bHLH transcription factor E47 which reduces the activation of trkB promoter. Furthermore, MLK2 inhibition increases trkB mRNA expression in vivo. These results could explain the reason why the inhibition of MLKs avoid the activation of cell death program and also increase the cell survival pathway being a key component of their neuroprotector potential. In the other hand, recent studies some recent work reveal the importance of mRNA localization in axons and dendrites and its local translation. Unraveling how mRNA localization and its translation are regulated at molecular level will help to understand basic processes of neuronal differentiation and plasticity. Translation is inhibited during mRNA transport, and is activated in specific synapses in response to synapse signals resulting from activation of neuronal plasticity. Previous work from our laboratory demonstrated that protein kinase KIS can stimulate the local translation of mRNAs, increase the neuritic outgrowth and the neural survival. In the present work we demonstrate that KIS can interact with transported granular proteins and mRNAs importants for the synaptic activity. Our hypothesis is that when the granule reaches his fate through KIF3A, some synaptic stimuli induce the activation of the kinase Src, which phosphorylates KIS, therefore activating the transported transcript.

Neuroeconomics is an interdisciplinary research program with the goal of building a biological model of decision making in economic environments. Neuroeconomists ask, how does the embodied brain enable the mind (or groups of minds) to make economic decisions? By combining techniques from cognitive neuroscience and experimental economics we can now watch neural activity in real time, observe how this activity depends on the economic environment, and test hypotheses about how the emergent mind makes economic decisions. Neuroeconomics allows us to better understand both the wide range of heterogeneity in human behavior, and the role of institutions as ordered extensions of our minds. The brain is the most amazing complex organ in known universe.The brain is a organ with most amazingly magic infinite potential. Neuroplasticity: Transforming the Mind by Changing the Brain.Neuroplasticity refers to structural and functional changes in the brain that are brought about by training and experience. The brain is the organ that is designed to change in response to experience.The decision theories can be categorized into three paradigms:the normative,descriptive and prescriptive theories.The decision processing have four steps:accumulation of sensory evidence,integration of sensory signals with reward expectation and prior knowledge,comparision of current reward expectation with that in prior experience,and the selection of behavioral response.

The extent to which cortical maps may reorganize in adult humans is a significant and topical debate in visual neuroscience. Though there are conflicting findings, evidence from humans and animals indicates that the topography of the visual cortex may change after retinal deafferentation. Remarkably, this reorganization seems to be possible in adults, whose brains are less amenable to plastic change. If adult visual reorganization is legitimate, an understanding of its causes and consequences could be profound considering the millions suffering from age-related visual disorders. This dissertation explores whether visual training may yield a reorganization of sensory maps in the adult visual cortex. It describes research in which patients, diagnosed with age-related macular degeneration (AMD), underwent visual rehabilitation therapy. Functional brain scans and behavioral tests were conducted pre and post training. These interventions generated valuable knowledge regarding whether "reorganized" activity is a true rewiring of feed forward cortical processes or an artifact of attentional feedback. The rehabilitation training produced demonstrable differences in activation patterns along the primary visual cortex (V1), but sparse improvement in the behavioral tests. In contrast, there was significant improvement in fixation tests which assessed oculomotor control. These results suggest that the nature of reorganized activity has more to do with attentional mechanisms than feed forward reorganization. Future investigations could benefit from examining the brain sites that govern visual attention in the frontal and parietal cortices. These areas may have more to do with visual adaptation in AMD patients than V1.

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