Submitted by WELTON FERREIRA DE ASSIS null (welton_assis@hotmail.com) on 2017-04-10T17:09:20Z No. of bitstreams: 1 Dissertação completa - 09-04-2017 - Welton.pdf: 1291272 bytes, checksum: bd90cdf026889501b5fafade3fb3c408 (MD5) / Approved for entry into archive by Luiz Galeffi (luizgaleffi@gmail.com) on 2017-04-17T17:38:24Z (GMT) No. of bitstreams: 1 assis_wf_me_rcla.pdf: 1291272 bytes, checksum: bd90cdf026889501b5fafade3fb3c408 (MD5) / Made available in DSpace on 2017-04-17T17:38:24Z (GMT). No. of bitstreams: 1 assis_wf_me_rcla.pdf: 1291272 bytes, checksum: bd90cdf026889501b5fafade3fb3c408 (MD5) Previous issue date: 2016-08-06 / O diabetes mellitus é um quadro patológico que traz diversas complicações como prejuízos metabólicos, endócrinos, cognitivos, sarcopenia, emagrecimento, hiperfagia e polidispia. Estudos prévios têm demonstrado que a manutenção de animais em ambiente enriquecido traz um conjunto de benefícios através dos estímulos que oferece, sendo a atividade física um desses estímulos. Apesar disso, poucos estudos investigaram os efeitos da manutenção de animais diabéticos em ambiente enriquecido. Desta forma, a presente dissertação teve por objetivos investigar os efeitos do diabetes na atividade física realizada no ambiente enriquecido e investigar os efeitos do ambiente enriquecido em parâmetros bioquímicos, morfométricos, cognitivos e nas proteínas AKT, RhoA e RhoE musculares. Para isso, na primeira etapa do desenho experimental, ratos wistar foram distribuídos em dois grupos: controle e diabetes. O diabetes foi induzido por estreptozotocina via intraperitonial (50 mg/kg) e os animais foram inseridos em gaiolas amplas contendo objetos coloridos e rodas de atividade com contador de giros. O rastreamento foi realizado pelo sistema para análises cinemáticas, Digital Video For Biomechanics - Windows 32 bits (DVIDEOW® ) e software Matlab® . Na segunda etapa do desenho experimental, os animais foram distribuídos nos seguintes grupos: controle, diabetes e diabetes gaiola enriquecida. O diabetes foi induzido por estreptozotocina via intraperitonial (50 mg/kg) e os animais foram mantidos em gaiolas padrão ou ambiente enriquecido. A massa corporal, ingestão hídrica e alimentar foram coletadas duas vezes por semana e a glicemia no início e final do experimento. Ao final do período experimental foi registrado o comprimento corporal e coletadas amostras do músculo gastrocnêmio para as análises da fosforilação da AKT e expressão de RhoA e RhoE. Para estas análises, foram utlizados o teste t ou Mann-Whitney para as análises entre dois grupos e análise de variância (ANOVA) two way, com posthoc de Bonferroni (significância de 5%) para as demais análises. O software SPSS® foi utilizado para as análises. O diabetes reduziu o acúmulo de atividade física no ambiente enriquecido. A manutenção no ambiente enriquecido amenizou o aumento da hiperglicemia e melhorou, parcialmente, o desempenho no labirinto aquático de Morris dos animais diabéticos. A redução na massa corporal, índice de Lee e o aumento na ingestão hídrica e alimentar nesses animais diabéticos não foram influenciados pelo ambiente enriquecido. Ainda, neste período de 6 semanas, não houve efeitos do diabetes ou do ambiente enriquecido na fosforilação da AKT e expressão das proteínas RhoA e RhoE. Pode ser concluído que a manutenção no ambiente enriquecido traz benefícios aos animais diabéticos, apesar deste realizar menos atividade física que animais controles. / Diabetes mellitus is a pathological condition that brings several complications such as metabolic, endocrine, cognitive loss, sarcopenia, weight loss, hyperphagia and polydipsia. Previous studies have shown that keeping animals in enriched environment brings a set of benefits through the stimuli it provides, and the physical activity is one of these stimuli. Despite this, few studies have investigated the effects of the maintenance of animals in diabetic enriched environment. The present dissertation aimed to investigate the effects of diabetes on physical activity performed in the enriched environment and to investigate the effects of enriched environment on biochemical parameters, morphometric, cognitive, and AKT, RhoA and RhoE proteins in the muscle. For this, in the first step of the experimental design, wistar rats were distributed into two groups: control and diabetes. Diabetes was induced streptozotocin via intraperitoneal (50 mg/kg) and the animals were placed in large cages, containing colored objects and the wheels of activity and a counter of revolutions. The tracking was carried out by the system for analysis, kinematics, Digital Video For Biomechanics - 32-bit Windows (DVIDEOW®) and Matlab® software. In the second step of the experimental design, the animals were distributed into the following groups: control, diabetic and diabetic - enriched cage. Diabetes was induced streptozotocin via intraperitoneal (50 mg/kg) and the animals were kept in cages of standard or enriched environment. The body mass, the intake of water and food were collected twice per week and the blood glucose at the beginning and end of the experiment. At the end of the experimental period was recorded and the length of the body and collected samples of the gastrocnemius muscle for the analysis of the phosphorylation of AKT and expression of RhoA and RhoE. For these analyses, were used the t test or the Mann-Whitney test for analyses between two groups and analysis of variance (ANOVA) two way, with posthoc Bonferroni (significance of 5%) for all other analyses. The software SPSS® was used for the analyses. Diabetes reduced the accumulation of physical activity in the enriched environment. The maintenance in the enriched environment slowdown the increase of hyperglycemia and improved, in part, the performance of the diabetic animals in the water maze of Morris. The reduction in the body mass, index of Lee and the increase in the intake of water and food of these diabetic animals were not influenced by the enriched environment. Still, in this period of 6 weeks, there were no effects of the diabetes or from the enriched environment in the phosphorylation of AKT and expression of the RhoA and RhoE proteins. It can be concluded that maintenance in enriched environment brings benefits to the animals and diabetic patients, although this perform less physical activity than control animals.

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第24756号 / 生博第497号 / 新制||生||66(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 北島 智也, 教授 見学 美根子, 教授 今吉 格 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DGAM

No description available.

This thesis examined whether it is possible to enhance core elements of the information processing system with specific forms of environmental stimulation. The first series of experiments demonstrated that a preweaning environmental enrichment procedure that provided 60 minutes of daily multisensory stimulation accelerated the development of long-term contextual memory and enhanced inhibitory processing in young rats. That is, whilst stimulated and non-stimulated rats exhibited long-term memory of a context at 26 days of age, only stimulated rats showed this ability at 18 days of age. In addition, stimulated rats showed a faster rate of extinction of long-term contextual memory at 21 days of age, which was taken as evidence of enhanced inhibitory learning (i.e., context ??? no US) in these rats. Subsequent experiments with adult rats demonstrated that a combination of preweaning multisensory stimulation and postweaning rearing in an enriched environment improved the (1) specificity of long-term contextual memory, (2) speed of contextual information processing, and (3) availability of attentional resources. More specifically, enriched-reared rats demonstrated superior ability to discriminate between two similar contexts in comparison to standard-reared rats. In addition, enriched-reared rats showed superior memory of a context when there was limited time available to form a memory of that context. This finding was taken to indicate that rats that receive environmental enrichment are able to process contextual information more rapidly. Finally, standard-, but not enriched-, reared rats showed less conditioning to a discrete stimulus when it was presented in combination with a stronger stimulus during training compared to when it was presented by itself. The finding that enriched-reared rats did not show this overshadowing effect suggests that these rats have greater availability of attentional resources to divide between two stimuli that are competing for attention. The experiments with rats were followed by two experiments with children that investigated the effects of a computerised cognitive training procedure on information-processing speed. These experiments demonstrated that 30-minutes per weekday of training in rapid decision-making for three to five weeks improved children???s performance on two tests of processing speed (i.e., a choice reaction time and odd-man-out task). In addition, the speeded training improved children???s ability to sustain their attention and inhibit impulsive responses on a continuous performance test (Test of Variables of Attention). The cognitive training procedure had no effect on children???s performance on a measure of fluid intelligence (Raven???s Standard Progressive Matrices). The results of the experiments reported in this thesis suggest that a number of fundamental cognitive processes can be modified by environmental conditions that place increasing demands on the information-processing system. A neurobiological model, focusing on myelin, axon diameter, and the glutamatergic, glucocorticoid, noradrenergic, and cholinergic systems, was proposed in order to explain the observed effects of environmental stimulation on cognition in children and rats. The rationale for attempting to enhance fundamental cognitive processes was that improving these processes should ultimately improve general intellectual functioning. With respect to this aim, the correlational data from the present experiments with children revealed promising trends towards greater improvements on the tests of fundamental cognitive processes in those children in the training group with slower processing speed at the start of the intervention. This finding suggests that cognitive training may be even more effective at enhancing processing speed and other fundamental cognitive processes in children with intellectual impairments???who reportedly have slower processing speed than normal children. However, the extent to which training-related improvements in fundamental cognitive processes generalise to improvements in general cognitive functioning is unclear. That is, there is insufficient evidence that processing speed and other fundamental cognitive processes are causally related to intelligence. It is therefore essential that future cognitive training research is mindful of related developments within the intelligence and information processing literature.

<p>Stroke is the major cause of serious long-term disability with a sufficient acute treatment for only a very limited number of patients. Limited recovery of neurological functions occurs and can be elevated by a permissive post-stroke milieu. Housing animals in an enriched environment modulates regenerative mechanisms in the nonischemic peri-infarct area which might be an attractive target for pharmacological treatments to promote recovery.</p><p>Upon ischemia, cellular lipids are released due to massive cell damage and free lipids significantly contribute to the progression of acute and delayed cell death. The aim of this study was to evalute the effect of enriched environment on lipid metabolism. In particular we characterize the activation of the transcription factor liver X receptor (LXR) in glial scar formation and regulation of cholesterol balance of relevance for functional recovery following stroke.                                      Brain tissues from animals subjected to permanent occlusion of middle cerebral artery (pMCAo) were analysed for LXRα and β protein expression. We found an upregulation and an increased transcriptional activity of LXRβ in the peri-infarct area of rats housing in an enriched environment following pMCAO. Our data anticipate that enriched environment may have positive effects on lipid recycling in the ischemic hemisphere following experimental stroke.<strong></strong></p>

Stroke is the major cause of serious long-term disability with a sufficient acute treatment for only a very limited number of patients. Limited recovery of neurological functions occurs and can be elevated by a permissive post-stroke milieu. Housing animals in an enriched environment modulates regenerative mechanisms in the nonischemic peri-infarct area which might be an attractive target for pharmacological treatments to promote recovery. Upon ischemia, cellular lipids are released due to massive cell damage and free lipids significantly contribute to the progression of acute and delayed cell death. The aim of this study was to evalute the effect of enriched environment on lipid metabolism. In particular we characterize the activation of the transcription factor liver X receptor (LXR) in glial scar formation and regulation of cholesterol balance of relevance for functional recovery following stroke.                                      Brain tissues from animals subjected to permanent occlusion of middle cerebral artery (pMCAo) were analysed for LXRα and β protein expression. We found an upregulation and an increased transcriptional activity of LXRβ in the peri-infarct area of rats housing in an enriched environment following pMCAO. Our data anticipate that enriched environment may have positive effects on lipid recycling in the ischemic hemisphere following experimental stroke.

No description available.

This thesis examined whether it is possible to enhance core elements of the information processing system with specific forms of environmental stimulation. The first series of experiments demonstrated that a preweaning environmental enrichment procedure that provided 60 minutes of daily multisensory stimulation accelerated the development of long-term contextual memory and enhanced inhibitory processing in young rats. That is, whilst stimulated and non-stimulated rats exhibited long-term memory of a context at 26 days of age, only stimulated rats showed this ability at 18 days of age. In addition, stimulated rats showed a faster rate of extinction of long-term contextual memory at 21 days of age, which was taken as evidence of enhanced inhibitory learning (i.e., context ??? no US) in these rats. Subsequent experiments with adult rats demonstrated that a combination of preweaning multisensory stimulation and postweaning rearing in an enriched environment improved the (1) specificity of long-term contextual memory, (2) speed of contextual information processing, and (3) availability of attentional resources. More specifically, enriched-reared rats demonstrated superior ability to discriminate between two similar contexts in comparison to standard-reared rats. In addition, enriched-reared rats showed superior memory of a context when there was limited time available to form a memory of that context. This finding was taken to indicate that rats that receive environmental enrichment are able to process contextual information more rapidly. Finally, standard-, but not enriched-, reared rats showed less conditioning to a discrete stimulus when it was presented in combination with a stronger stimulus during training compared to when it was presented by itself. The finding that enriched-reared rats did not show this overshadowing effect suggests that these rats have greater availability of attentional resources to divide between two stimuli that are competing for attention. The experiments with rats were followed by two experiments with children that investigated the effects of a computerised cognitive training procedure on information-processing speed. These experiments demonstrated that 30-minutes per weekday of training in rapid decision-making for three to five weeks improved children???s performance on two tests of processing speed (i.e., a choice reaction time and odd-man-out task). In addition, the speeded training improved children???s ability to sustain their attention and inhibit impulsive responses on a continuous performance test (Test of Variables of Attention). The cognitive training procedure had no effect on children???s performance on a measure of fluid intelligence (Raven???s Standard Progressive Matrices). The results of the experiments reported in this thesis suggest that a number of fundamental cognitive processes can be modified by environmental conditions that place increasing demands on the information-processing system. A neurobiological model, focusing on myelin, axon diameter, and the glutamatergic, glucocorticoid, noradrenergic, and cholinergic systems, was proposed in order to explain the observed effects of environmental stimulation on cognition in children and rats. The rationale for attempting to enhance fundamental cognitive processes was that improving these processes should ultimately improve general intellectual functioning. With respect to this aim, the correlational data from the present experiments with children revealed promising trends towards greater improvements on the tests of fundamental cognitive processes in those children in the training group with slower processing speed at the start of the intervention. This finding suggests that cognitive training may be even more effective at enhancing processing speed and other fundamental cognitive processes in children with intellectual impairments???who reportedly have slower processing speed than normal children. However, the extent to which training-related improvements in fundamental cognitive processes generalise to improvements in general cognitive functioning is unclear. That is, there is insufficient evidence that processing speed and other fundamental cognitive processes are causally related to intelligence. It is therefore essential that future cognitive training research is mindful of related developments within the intelligence and information processing literature.

Background: Approximately a third of all stroke patients develop spatial neglect, a debilitating symptom associated with poor outcome. Spatial neglect is clinically defined as a deficit in processing and responding to stimuli presented on the contralesional side of the body, or the space surrounding that side of the body. The heterogenetic, multi-sensory nature of the symptoms renders it difficult to diagnose and treat; therefor effective methods for screening and intervention for neglect are needed. Virtual reality (VR) is a method of brain–computer interaction that involves realtime simulation of an environment, scenario or activity that allows for user interaction and targets multiple senses. We hypothesize that VR can facilitate identification of spatial neglect in stroke patients and that training with this interface will improve patient’s functional outcome, through stimulation to neuronal networks including those controlling attention. Objective: The objective was to construct and validate a computerized test battery for spatial neglect and to investigate its usability in stroke patients. Also to design and develop a VR rehabilitation method for spatial neglect and to evaluate its effects on spatial attention and on neuronal activity in the brain. Method: We designed, developed and evaluated a new concept for assessment (VR-DiSTRO®) and training (RehAtt®) of spatial attention, using VR technology. The hardware consisted of a PC, monitor, 3D-glasses and a force feedback device to control the tasks (i.e., a robotic pen). The software enabled targets to be moved, rotated and manipulated in the 3D environment using the robotic pen. RehAtt® made it possible to combine intense visual scanning training, multi-sensory stimulation (i.e., audio, visual, tactile) and sensory-motor activation of the contralesional arm. In a first study on 31 stroke patients we performed a construct validation of VR-DiSTRO® against Rivermead Behavioural Test Battery (BIT) and investigated the usability. In a second study, 15 subjects with chronic spatial neglect (symptoms &gt;6 month) had self-training, 3 x 1 hour for 5 weeks using RehAtt®. Outcome were measured by changes in neglect tests and in Cathrine Bergego Scale (CBS). Training-related changes in neuronal activity of the brain was studied using fMRI during task and in resting state. Results: VR-DiSTRO® correctly identified all patients with neglect. The sensitivity was 100% and the specificity 82% for VR-DiSTRO® compared to BIT. Usability was high and no side-effects were noted. Using repeated measurement analysis, improvements due to the RehAtt® intervention were found for Baking tray task (p &lt; 0.001), Star cancellation test (p = 0.006) and Extinction test (p = 0.05). Improvements were also seen in the Posner task as fewer missed targets (p = 0.024). Improvement in activities of daily living (CBS) was shown immediately after training (p &lt; 0.01) and patients still reported improvement at 6 months follow-up. Trainingrelated changes in neuronal activity were seen as an increased task-evoked brain activity in prefrontal and temporal cortex, mainly outside the attention network but in related cortical areas. During resting state, changes in network connectivity were seen after intervention with RehAtt® in the Dorsal Attention Network (DAN) and interhemispheric connectivity. Conclusion: VR-DiSTRO® identified visuospatial neglect in stroke patients quickly and with a high accuracy. RehAtt® training improved in spatial attention in chronic neglect with transfer to functions in daily living. Increased neuronal brain activity was found in and between attention networks and related brain structures. This could represent a compensatory effect in addition to sign of a restorative effect from the RehAtt training. The results obtained in this study are promising, encourage further development of the methods and merit for further studies.

La plasticité cérébrale est une capacité remarquable des cellules du cerveau à adapter leur structure et fonction en réponse à l’expérience et l’environnement. Cette plasticité cérébrale est favorisée par des conditions de vie favorables qui peuvent être modélisées chez le rongeur par le modèle de l’Environnement Enrichi (EE). L’EE consiste à mettre un grand nombre de souris dans de grandes cages comprenant de nombreux objets (nids, tunnels, roues…) qui sont changés régulièrement. L’EE induit une activité physique volontaire accrue, des conditions optimales pour la stimulation des interactions sociales, du comportement exploratoire et des fonctions cognitives. L’EE exerce des effets bénéfiques sur les processus physiologiques au niveau de nombreux systèmes (hormonal, cardiovasculaire, immunitaire…). L’EE réduit les comportements anxio-dépressifs, améliore l'apprentissage et la mémorisation. Ces effets sont sous-tendus par des changements au niveau du cerveau et en particulier de l’hippocampe, où l’on observe en EE plus de neurogenèse et synaptogenèse. De manière intéressante, chez les souris immunodéficientes, les performances mnésiques et la neurogenèse sont très altérées, suggérant une interaction bidirectionnelle entre le système immunitaire et le cerveau. Parmi les cellules du système immunitaire, les lymphocytes T (LT) semblent jouer un rôle particulièrement important dans les mécanismes de plasticité neuronale. Notre objectif a été de caractériser le rôle des LT dans les effets de l’EE sur la plasticité cérébrale et de chercher si ces effets impliquent une modification des LT par l’EE. / Cerebral plasticity is a remarkable ability of brain cells to adapt their structure and function in response to experience and the environment. This cerebral plasticity is enhanced by favorable living conditions that can be modeled in the rodent by the Enriched Environment (EE) model. The EE consists in large number of mice in large cages including numerous objects (nests, tunnels, wheels ...) which are changed frequently. EE induces increased voluntary physical activity, optimal conditions for stimulation of social interactions, exploratory behavior and cognitive functions. EE has beneficial effects on physiological processes in many systems (hormonal, cardiovascular, immune system...). EE reduces anxio-depressive behavior, improves learning and memory. These effects are underpinned by changes in the brain and particularly in the hippocampus, where EE induce more neurogenesis and synaptogenesis. Interestingly, in immunodeficient mice, memory performance and neurogenesis are highly impaired, suggesting a bidirectional interaction between the immune system and the brain. Among the cells of the immune system, T cells appear to play a major role in neuronal plasticity mechanisms. Our objective was to characterize the role of T cells in EE’s effects on cerebral plasticity and to investigate whether these effects imply a modification of T cells by EE.