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The present thesis investigated the effects of a western diet (WD) on cell death and functional outcome following global ischemia in rats. Experiment 1 assessed the effects of a 60-day WD regimen on temperature, activity and glucose levels in normal rats. Experiment 2 evaluated the influence of a 60-day WD regimen on hippocampal CA1 injury and cognition following global ischemia. Results from experiment 1 revealed significant differences in activity levels only; animals fed the WD were less active than control diet animals. Results from experiment 2 suggested that a WD did not aggravate CA1 injury or behavioral deficits. The second portion of my thesis examined the effects of a 120-day WD regimen on stroke severity and cognition following global ischemia. Briefly, the surgical protocol used to induce a global ischemic insult did not produce consistent damage across all animals. Plausible reasons for this surgical variability and future directions are discussed.

Neurons are sensitive to specific aspects of natural stimuli, which are according to different statistical criteria an optimal representation of the natural sensory input. Since these representations are purely sensory, it is still an open question whether they are suited to generate meaningful behavior. Here we introduce an optimization scheme that applies a statistical criterion to an agent s sensory input while taking its motor behavior into account. We first introduce a general cognitive model, and second develop an optimization scheme that increases the predictability of the sensory outcome of the agent s motor actions and apply this to a navigational paradigm.In the cognitive model, place cells divide the environment into discrete states, similar to hippocampal place cells. The agents learned the sensory outcome of its action by the state-to-state transition probabilities and the extent to which these motor actions are caused by sensory-driven reflexive behavior (obstacle avoidance). Navigational decision making integrates both learned components to derive the actions that are most likely to lead to a navigational goal. Next we introduced an optimization process that modified the state distributions to increase the predictability of the sensory outcome of the agent s actions.The cognitive model successfully performs the navigational task, and the differentiation between transitions and reflexive processing increases both behavioral accuracy, as well as behavioral adaptation to changes in the environment. Further, the optimized sensory states are similar to place fields found in behaving animals. The spatial distribution of states depends on the agent s motor capabilities as well as on the environment. We proofed the generality of predictability as a coding principle by comparing it to the existing ones. Our results suggest that the agent s motor apparatus can play a profound role in the formation of place fields and thus in higher sensory representations.

Introdução: o Diabetes Mellitus é uma epidemia mundial de incidência crescente e alta morbi-mortalidade. Apesar de a neuropatia diabética ser a complicação neurológica mais comum, é crescente o conhecimento de que existe um acometimento do sistema nervoso central, notadamente no que concerne às alterações cognitivas. Objetivos: investigar, por meio de duas tarefas cognitivas objetivas, simples, rápidas, de baixo custo e de fácil aplicação, diferenças entre pacientes com Diabetes Mellitus Tipo 1 (DM1) e controles quanto a medidas de atenção e impulsividade, componentes-chave das funções executivas tradicionalmente avaliados por questionários subjetivos, longos, de difícil reprodutibilidade e que exigem psicólogos treinados; correlacionar as diferenças encontradas com características clínicas; explorar as correlações entre as duas tarefas. Métodos: Foram comparados os desempenhos de 20 pacientes com DM1 e 20 controles, de ambos os sexos, com idades entre 12 e 15 anos, utilizando a tarefa Agir-Não Agir e uma tarefa de Labirintos, e verificadas correlações entre eles. Resultados: o grupo DM1 teve mais respostas antecipatórias (RA) na tarefa Agir-Não Agir (p<0,05) e fez mais mudanças de trajetória nos Labirintos (p <0,01). Houve correlação entre hipoglicemias não-graves e RA (p=0,01), e entre hipoglicemias graves e número de toques nas paredes dos labirintos (p <0,05). HbA1c> 9% correlacionou-se com um maior número de becos sem saída nos labirintos (p <0,05). Os parâmetros mostraram-se coerentes dentro de cada tarefa e entre elas. Conclusões: Encontramos indicadores de desatenção e impulsividade coexistindo no DM1, o primeiro estando mais relacionado à hiperglicemia, e o último à hipoglicemia. Investigações adicionais são necessárias para estudar o declínio cognitivo associado ao diabetes por meio de avaliações mais objetivas, e avaliar a confiabilidade e as propriedades psicométricas das tarefas aqui propostas. / Background : Diabetes Mellitus is a worldwide epidemic of increasing incidence and high morbidity and mortality. Although diabetic neuropathy is the most common neurological complication, the knowledge that there is an involvement of the central nervous system is increasing, especially in relation to cognitive changes. Aims: To investigate with two simple, inexpensive, rapid, objective and easy-to-apply tasks, differences between patients with Type 1 Diabetes Mellitus (T1DM) and controls in outcome measures of attention and impulsivity, key-executive function components traditionally assessed by subjective and long questionnaires of difficult reproducibility that require trained psychologists; to correlate the alterations with clinical characteristics; to explore correlations between the tasks. Methods: We compared the scores of 20 T1DM to 20 controls, both sexes, aged 12 to 15 years, using a Go-NoGo and a Maze task, and verified correlations between them. Results: T1DM group had more anticipatory answers (AA) in Go-NoGo task (p<0,05) and made more direction changes in Mazes (p<0,01). There was correlation between non-severe hypoglycaemias and AA (p=0,01), and between severe hypoglycaemias and number of touches in Mazes’ walls (p<0,05). HbA1c>9% correlated to a greater number of alleys in Mazes (p<0,05). The tasks’ parameters were coherent among each task and between them. Conclusions: We found indicators of inattention and impulsivity coexisting in T1DM, the first more related to hyperglycaemia and the later to hypoglycemia. Further research is needed to study diabetes-associated cognitive decline with more objective parameters and evaluate the reliability and psychometric properties of the tasks herein proposed. / Dissertação (Mestrado)

認知功能的提升是當今神經科學領域中的研究重點之一，但其神經機制尚有待釐清。本研究利用一種用於改善阿茲海默症臨床的非競爭型N-甲基-D-天門冬胺酸受體拮抗劑memantine，檢測其對於大白鼠在不同時距相關操作式制約行為及空間工作記憶行為之影響效果。實驗一為針對時間屬性的操作式制約行為實驗，運用大白鼠的區辯性增強低頻反應作業（DRL 10秒行為）與固定時距作業（FI 30秒行為）之行為作業，並操弄連續訓練與間歇訓練的兩種不同模式，測試memantine對前述四組受試的操作式制約行為在表現、消除與自發恢復等三階段之劑量反應。實驗二利用配對性延遲T迷津作業區分出不等基準線(表現好與表現差)之受試，再加以藥理實驗，測試memantine對於前述兩組受試之劑量反應。實驗一結果顯示，受試在兩種不同訓練模式下經十五次習得訓練後，在兩種操作式壓桿行為的壓桿反應相關指標中都有明顯的差異，這證實不同的行為訓練模式會導致學習後的表現有差異之別。memantine藥理實驗結果顯示，此藥對於上述四組受試的操作式行為之三階段的影響效果，會因為不同訓練模式與不同作業而異。實驗二結果顯示，memantine提高空間工作記憶的正確率在表現不好的組別有很顯著的藥效，這證實memantine對於空間式工作記憶行為的影響，也會因學習基準線的不同水平而異。在行為實驗後所進行的蛋白質表現量檢測中，memantine（5 mg/kg）只對五個測試腦區中的背側紋狀體中ERK1磷酸化程度有明顯上升的影響，而其對ERK2及CREB的磷酸化在所有腦組織中皆沒有顯著的影響。綜合以上結果，memantine影響時間與空間屬性的相關行為之藥理效果，會依行為的不同習得歷程(或行為背景經驗)及基準線表現程度而異，而此項行為藥理效果，可能與紋狀體中ERK1的磷酸化有關。 / The neural basis of cognitive enhancement is one of the intriguing topics in neuroscience research; however, the underlying neural mechanisms remain to be elucidated. This study examined the effects of memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which is used to treat Alzheimer’s disease in clinic, on operant behaviors and spatial working memory. In Experiment 1, using the differential reinforcement for low-rate-response 10 sec (DRL 10s) and the fixed-interval 30 sec (FI 30s) operant tasks, and with the manipulation of two different training regimens (continuous vs. intermittent) in the acquisition phase, the effects of memantine were evaluated in three stages of behavioral tests including the performance (right after the end of 15-day acquisition), the extinction, and the spontaneous recovery (after the extinction). In Experiment 2, memantine were tested in the subjects with different level of baseline performance (good vs. bad) on the distinctive patterns of operant responding in four different groups which received DRL 10s and FI 30s with different training regimens; indicating that behavioral task and training background are critical to the operant performance of temporal operant behaviors. Such behavioral outcomes led the dissociable effects of memantine appeared in between the four groups as tested in all three different stages. The results of Experiment 2 showed a profound improvement of the correct responses rate on spatial working memory in the low-baseline group as compared to the higher-baseline group. With a pretreatment of memantine (5 mg/kg), brain tissues in five selected areas were collected for western blot assays of ERK 1, ERK 2, and CREB. The results only revealed a significant increase of ERK 1 phosphorylation in the dorsal striatum. Together, the effects of memantine to improve cognition-associated processes in the temporal operant behaviors and the baseline of performance, and the present observation of cognition-enhancing effects of memantine may be resulted by the ERK 1 phosphorylation in the dorsal striatum.