O objetivo geral deste estudo foi verificar os efeitos terapêuticos do enriquecimento ambiental e do exercício físico forçado sobre as conseqüências funcionais e cognitivas da Hipoperfusão Encefálica Crônica (HEC) em ratos Wistar. Além disso, padronizamos protocolo alternativo de HEC, a fim de aumentar a taxa de sobrevivência característica deste modelo, juntamente com a análise comportamental e imunohistoquímica do sétimo ao sexto mês após a cirugia, analisando o comportamento de neurônios e astrócitos no hipocampo. Os resultados mostraram que o protocolo modificado, ou seja, com a oclusão das carótidas realizadas com uma semana de intervalo, apresentam resultados comportamentais e morfológicos similares aos do protocolo padrão; todavia, a taxa de sobrevida dos animais no protocolo modificado é significativamente maior quando comparados ao padrão. Além disso, em ambos os protocolos, os animais hipoperfundidos apresentam um déficit cognitivo no Teste Water Maze três meses após a cirurgia, mas os grupos isquêmicos não apresentaram diferenças morfológicas quando comparados ao seus controles em relação a volume total Hipocampal e área Estriatal. Ao analisar o tempo pós- lesão do déficit cognitivo, verificamos que a HEC causa danos comportamentais a longo prazo, chegando a seis meses após o evento isquêmico. Enquanto a cognição é afetada na fase crônica, as células neuronais e astrogliais são acometidas nas fases mais agudas deste modelo, começando a aparecer morte neuronal (através da quantificação de NeuN) e astrogliose reativa (através da quantificação do imunoconteúdo de GFAP) já nos primeiros dias, permanecendo até aproximadamente 3 meses após a lesão. Após o dano estabelecido, testamos estratégias terapêuticas com o objetivo de amenizar principalmente o dano cognitivo apresentado pelos animais a partir dos três meses após cirurgia. Inicialmente foi analisado o efeito pré e pós - isquemia do exercício físico forçado através de uma esteira para ratos na memória espacial e de trabalho, através do Water Maze e bioquimicamente no estado oxidativo cerebral. Posteriormente, os mesmos parâmetros foram testados, só que com a intervenção do enriquecimnto ambiental tanto pré quanto pós-isquemia também. O modelo de hipoperfusão cerebral crônica causa como citado anteriormente, um déficit bastante importante na memória e no apredizado. Somado a isso, em relação ao estresse oxidativo, a quantidade de radicais livres e o estado de lipoperoxidação celular encontra-se bastante aumentados no hipocampo de animais submetidos a isquemia, assim como as enzimas antioxidantes. O protocolo de atividade física regular forçada (3 vezes por semana, durante 20 minutos num período de 3 meses), sobretudo nos grupos pré e pré+pós-isquemia, preveniu os efeitos cognitivos e bioquímicos da HEC. Tal reversão também ocorreu com o uso do enriquecimento ambiental realizado 3 vezes por semana, 1 hora durante 3 meses em todos os grupos estimulados. / The aim of this study was to verify the experimental therapeutic effects of environmental enrichment and forced physical exercise on the consequences of cognitive and functional chronic cerebral hypoperfusion (CCH) in Wistar rats. To do that, a CCH alternative protocol was standardized, in order to increase the survival rate of this model, together with the behavioral and immunohistochemistry analysis done up to the sixth month after the surgery, analyzing hippocampus neurons and astrocytes. Results showed that the modified protocol, with occlusion of both carotid arteries performed with a one-week interval, presents morphological and behavioral results similar to the standard protocol; however, the rate of survival after the modified protocol was significantly greater when compared to the standard one. In addition, both protocols produced ischemic animals with cognitive deficits in the Water Maze Task, three months after the surgery, however with no gross morphological lesion, as assessed by hippocampal volume and estriatal area. The cognitive deficit in CCH rats is long lasting, reaching six months after the ischemic event. While the cognition is affected in the chronic phase of hypoperfusion, the neuronal and astrogliais cells are affected in acute phases of this model; neuronal death (through quantification of NeuN) and reactive astrogliosis (through quantification of imunocontent of GFAP) are already present in the first days and remain until approximately 3 months after the lesion. We tested therapeutic strategies with the aim of alleviating mainly the cognitive damage presented by animals, as from three months after surgery. Initially, the effects of preand post-ischemia forced physical exercise in spatial and working memory, through the Water Maze Tak and oxidative stress parameters were analyzed. Subsequently, we tested the effects of environmental enrichment, both pre- and post-ischemia. The model of chronic cerebral hypoperfusion as previously mentioned, causes an important deficit in spatial learning and memory; the free radicals content and cellullar lipid peroxidation is also substantially increased in the hippocampus of animals submitted to hypoperfusion, as well as the antioxidant enzymes. Forced regular physical activity protocol (20-min, 3 times per week during 12 weeks – moderate), especially in groups pre and pre+post-ischemia, warned cognitive and biochemical preventive effects in CCH rats; the same occurred with the use of enrichment environmental performed 1- hr, 3 times per week during 12 weeks in all groups stimulated.

O objetivo geral deste estudo foi verificar os efeitos terapêuticos do enriquecimento ambiental e do exercício físico forçado sobre as conseqüências funcionais e cognitivas da Hipoperfusão Encefálica Crônica (HEC) em ratos Wistar. Além disso, padronizamos protocolo alternativo de HEC, a fim de aumentar a taxa de sobrevivência característica deste modelo, juntamente com a análise comportamental e imunohistoquímica do sétimo ao sexto mês após a cirugia, analisando o comportamento de neurônios e astrócitos no hipocampo. Os resultados mostraram que o protocolo modificado, ou seja, com a oclusão das carótidas realizadas com uma semana de intervalo, apresentam resultados comportamentais e morfológicos similares aos do protocolo padrão; todavia, a taxa de sobrevida dos animais no protocolo modificado é significativamente maior quando comparados ao padrão. Além disso, em ambos os protocolos, os animais hipoperfundidos apresentam um déficit cognitivo no Teste Water Maze três meses após a cirurgia, mas os grupos isquêmicos não apresentaram diferenças morfológicas quando comparados ao seus controles em relação a volume total Hipocampal e área Estriatal. Ao analisar o tempo pós- lesão do déficit cognitivo, verificamos que a HEC causa danos comportamentais a longo prazo, chegando a seis meses após o evento isquêmico. Enquanto a cognição é afetada na fase crônica, as células neuronais e astrogliais são acometidas nas fases mais agudas deste modelo, começando a aparecer morte neuronal (através da quantificação de NeuN) e astrogliose reativa (através da quantificação do imunoconteúdo de GFAP) já nos primeiros dias, permanecendo até aproximadamente 3 meses após a lesão. Após o dano estabelecido, testamos estratégias terapêuticas com o objetivo de amenizar principalmente o dano cognitivo apresentado pelos animais a partir dos três meses após cirurgia. Inicialmente foi analisado o efeito pré e pós - isquemia do exercício físico forçado através de uma esteira para ratos na memória espacial e de trabalho, através do Water Maze e bioquimicamente no estado oxidativo cerebral. Posteriormente, os mesmos parâmetros foram testados, só que com a intervenção do enriquecimnto ambiental tanto pré quanto pós-isquemia também. O modelo de hipoperfusão cerebral crônica causa como citado anteriormente, um déficit bastante importante na memória e no apredizado. Somado a isso, em relação ao estresse oxidativo, a quantidade de radicais livres e o estado de lipoperoxidação celular encontra-se bastante aumentados no hipocampo de animais submetidos a isquemia, assim como as enzimas antioxidantes. O protocolo de atividade física regular forçada (3 vezes por semana, durante 20 minutos num período de 3 meses), sobretudo nos grupos pré e pré+pós-isquemia, preveniu os efeitos cognitivos e bioquímicos da HEC. Tal reversão também ocorreu com o uso do enriquecimento ambiental realizado 3 vezes por semana, 1 hora durante 3 meses em todos os grupos estimulados. / The aim of this study was to verify the experimental therapeutic effects of environmental enrichment and forced physical exercise on the consequences of cognitive and functional chronic cerebral hypoperfusion (CCH) in Wistar rats. To do that, a CCH alternative protocol was standardized, in order to increase the survival rate of this model, together with the behavioral and immunohistochemistry analysis done up to the sixth month after the surgery, analyzing hippocampus neurons and astrocytes. Results showed that the modified protocol, with occlusion of both carotid arteries performed with a one-week interval, presents morphological and behavioral results similar to the standard protocol; however, the rate of survival after the modified protocol was significantly greater when compared to the standard one. In addition, both protocols produced ischemic animals with cognitive deficits in the Water Maze Task, three months after the surgery, however with no gross morphological lesion, as assessed by hippocampal volume and estriatal area. The cognitive deficit in CCH rats is long lasting, reaching six months after the ischemic event. While the cognition is affected in the chronic phase of hypoperfusion, the neuronal and astrogliais cells are affected in acute phases of this model; neuronal death (through quantification of NeuN) and reactive astrogliosis (through quantification of imunocontent of GFAP) are already present in the first days and remain until approximately 3 months after the lesion. We tested therapeutic strategies with the aim of alleviating mainly the cognitive damage presented by animals, as from three months after surgery. Initially, the effects of preand post-ischemia forced physical exercise in spatial and working memory, through the Water Maze Tak and oxidative stress parameters were analyzed. Subsequently, we tested the effects of environmental enrichment, both pre- and post-ischemia. The model of chronic cerebral hypoperfusion as previously mentioned, causes an important deficit in spatial learning and memory; the free radicals content and cellullar lipid peroxidation is also substantially increased in the hippocampus of animals submitted to hypoperfusion, as well as the antioxidant enzymes. Forced regular physical activity protocol (20-min, 3 times per week during 12 weeks – moderate), especially in groups pre and pre+post-ischemia, warned cognitive and biochemical preventive effects in CCH rats; the same occurred with the use of enrichment environmental performed 1- hr, 3 times per week during 12 weeks in all groups stimulated.

O objetivo geral deste estudo foi verificar os efeitos terapêuticos do enriquecimento ambiental e do exercício físico forçado sobre as conseqüências funcionais e cognitivas da Hipoperfusão Encefálica Crônica (HEC) em ratos Wistar. Além disso, padronizamos protocolo alternativo de HEC, a fim de aumentar a taxa de sobrevivência característica deste modelo, juntamente com a análise comportamental e imunohistoquímica do sétimo ao sexto mês após a cirugia, analisando o comportamento de neurônios e astrócitos no hipocampo. Os resultados mostraram que o protocolo modificado, ou seja, com a oclusão das carótidas realizadas com uma semana de intervalo, apresentam resultados comportamentais e morfológicos similares aos do protocolo padrão; todavia, a taxa de sobrevida dos animais no protocolo modificado é significativamente maior quando comparados ao padrão. Além disso, em ambos os protocolos, os animais hipoperfundidos apresentam um déficit cognitivo no Teste Water Maze três meses após a cirurgia, mas os grupos isquêmicos não apresentaram diferenças morfológicas quando comparados ao seus controles em relação a volume total Hipocampal e área Estriatal. Ao analisar o tempo pós- lesão do déficit cognitivo, verificamos que a HEC causa danos comportamentais a longo prazo, chegando a seis meses após o evento isquêmico. Enquanto a cognição é afetada na fase crônica, as células neuronais e astrogliais são acometidas nas fases mais agudas deste modelo, começando a aparecer morte neuronal (através da quantificação de NeuN) e astrogliose reativa (através da quantificação do imunoconteúdo de GFAP) já nos primeiros dias, permanecendo até aproximadamente 3 meses após a lesão. Após o dano estabelecido, testamos estratégias terapêuticas com o objetivo de amenizar principalmente o dano cognitivo apresentado pelos animais a partir dos três meses após cirurgia. Inicialmente foi analisado o efeito pré e pós - isquemia do exercício físico forçado através de uma esteira para ratos na memória espacial e de trabalho, através do Water Maze e bioquimicamente no estado oxidativo cerebral. Posteriormente, os mesmos parâmetros foram testados, só que com a intervenção do enriquecimnto ambiental tanto pré quanto pós-isquemia também. O modelo de hipoperfusão cerebral crônica causa como citado anteriormente, um déficit bastante importante na memória e no apredizado. Somado a isso, em relação ao estresse oxidativo, a quantidade de radicais livres e o estado de lipoperoxidação celular encontra-se bastante aumentados no hipocampo de animais submetidos a isquemia, assim como as enzimas antioxidantes. O protocolo de atividade física regular forçada (3 vezes por semana, durante 20 minutos num período de 3 meses), sobretudo nos grupos pré e pré+pós-isquemia, preveniu os efeitos cognitivos e bioquímicos da HEC. Tal reversão também ocorreu com o uso do enriquecimento ambiental realizado 3 vezes por semana, 1 hora durante 3 meses em todos os grupos estimulados. / The aim of this study was to verify the experimental therapeutic effects of environmental enrichment and forced physical exercise on the consequences of cognitive and functional chronic cerebral hypoperfusion (CCH) in Wistar rats. To do that, a CCH alternative protocol was standardized, in order to increase the survival rate of this model, together with the behavioral and immunohistochemistry analysis done up to the sixth month after the surgery, analyzing hippocampus neurons and astrocytes. Results showed that the modified protocol, with occlusion of both carotid arteries performed with a one-week interval, presents morphological and behavioral results similar to the standard protocol; however, the rate of survival after the modified protocol was significantly greater when compared to the standard one. In addition, both protocols produced ischemic animals with cognitive deficits in the Water Maze Task, three months after the surgery, however with no gross morphological lesion, as assessed by hippocampal volume and estriatal area. The cognitive deficit in CCH rats is long lasting, reaching six months after the ischemic event. While the cognition is affected in the chronic phase of hypoperfusion, the neuronal and astrogliais cells are affected in acute phases of this model; neuronal death (through quantification of NeuN) and reactive astrogliosis (through quantification of imunocontent of GFAP) are already present in the first days and remain until approximately 3 months after the lesion. We tested therapeutic strategies with the aim of alleviating mainly the cognitive damage presented by animals, as from three months after surgery. Initially, the effects of preand post-ischemia forced physical exercise in spatial and working memory, through the Water Maze Tak and oxidative stress parameters were analyzed. Subsequently, we tested the effects of environmental enrichment, both pre- and post-ischemia. The model of chronic cerebral hypoperfusion as previously mentioned, causes an important deficit in spatial learning and memory; the free radicals content and cellullar lipid peroxidation is also substantially increased in the hippocampus of animals submitted to hypoperfusion, as well as the antioxidant enzymes. Forced regular physical activity protocol (20-min, 3 times per week during 12 weeks – moderate), especially in groups pre and pre+post-ischemia, warned cognitive and biochemical preventive effects in CCH rats; the same occurred with the use of enrichment environmental performed 1- hr, 3 times per week during 12 weeks in all groups stimulated.

In the group of reptiles, the ability to form memories is still much discussed and neuroanatomical data have suggested the existence of homologies between the areas of the hippocampus and amygdala of mammals and correlated structures of the telencephalon of reptiles. However, there is little functional evidence of these structures in reptiles to give support to this proposal homology. Faced with this situation, this study aimed to conduct a behavioral and neurobiological evaluation of memory in lizards species Tropidurus hispidus. For this, were used 50 lizards adult males, which after 4 days of accommodation were distributed in two experiments: the Experiment 1, aversive memory (n = 40); and the Experiment 2, spatial memory (n = 10). In Experiment 1, the animals were divided into three groups (Control, n = 8; Neutral Stimulus, n = 16; Aversive Stimulus, n = 16). The Control group did not participate in the behavioral steps, since the Neutral Stimulus group was exposed to an empty metal cage, while the Aversive Stimulus group was exposed to a domestic cat. Then all the animals in the Control group and half of the animals Neutral Stimulus and Stimulus Aversive groups had their brains perfused with paraformaldehyde 4% for subsequent analysis. The remaining animals of Neutral and Aversive Stimulus groups returned to the accommodation terrarium and, after 24 hours, passed by a rechallenge to local display of the stimulus, then also had their brains perfused with paraformaldehyde 4%. After fixation, brains were all collected subjected to a imustotoquímica detection technique the ZIF-268, a protein involved in mediating plasticity which occurs during memory formation. We found that during exposure to cat lizards of Aversive Stimulus group had a higher freezing time (p <0.001) and a smaller number of initiated movements (p <0.001) and visited quadrants (p <0.001) when compared with Neutral Stimulus group. Also found that during the re-exposure to aversive environment, the animals Aversive Stimulus group had a higher freezing time (p <0.001) and a smaller number of initiated movements (p <0.001) and visited quadrants (p <0.001), suggesting so that exposure to cat served adequately as an aversive stimulus. There was also an increase in the number of Zif-268 positive cells in regions of the reptilian hippocampus and amygdala lizards Stimulus Aversive group during exposure to cat (p = 0.005 and p = 0.039, respectively) and on re-exposure to aversive context (p = 0.001 and p = 0.009, respectively). In experiment 2, lizards underwent an adaptation of the Morris water maze, where 3 times a day for 19 days, the animals had performed attempts to find a submerged platform. We found a negative correlation (p = 0.012) the time to reach the platform and over the days, indicating an improvement in the performance of lizards in the task. Thus, the present study provided evidence that males of T. hispidus are capable of forming aversive and spatial memories, and that there is an involvement of the hippocampus and amygdala in aversive memory. / No grupo dos répteis, a capacidade de formar memórias é ainda muito discutida e dados neuroanatômicos têm sugerido a existência de homologias entre as áreas do hipocampo e amígdala de mamíferos e estruturas correlatas no telencéfalo de répteis. Contudo, existem poucas evidências funcionais dessas estruturas reptelianas para que forneçam suporte a essa proposta de homologia. Diante de tal conjuntura, esse trabalho teve como objetivo realizar uma avaliação comportamental e neurobiológica da memória em lagartos da espécie Tropidurus hispidus. Para isso foram utilizados 50 lagartos machos adultos, que após 4 dias de acomodação, foram distribuídos em dois experimentos: o Experimento 1, de memória aversiva (n=40); e o Experimento 2, de memória espacial (n=10). No Experimento 1 os animais foram divididos em três grupos (Controle, n=8; Estímulo Neutro, n=16; Estímulo Aversivo, n=16). O grupo controle não participou das etapas comportamentais, já o grupo Estímulo Neutro foi exposto a uma gaiola metálica vazia, enquanto o grupo Estímulo Aversivo foi exposto a um gato doméstico. Em seguida, todos os animais do grupo Controle e metade dos animais dos grupos Estímulo Neutro e Estímulo Aversivo tiveram seus cérebros perfundidos com paraformaldeido 4% para posterior análise. Os animais restantes dos grupos Estímulo Neutro e Estímulo Aversivo foram colocados de volta no terrário de acomodação e após 24 horas passaram por uma reexposição ao local da exibição dos estímulos, então também tiveram seus cérebros perfundidos com paraformaldeido 4%. Após a fixação, todos os cérebros coletados foram submetidos a uma técnica de detecção imustotoquímica de Zif-268, uma proteína envolvida na mediação da plasticidade que ocorre durante a formação de memórias. Verificamos que, durante a exposição ao gato, os lagartos do grupo Estímulo Aversivo apresentaram um maior tempo de congelamento (p<0,001) e um menor número de deslocamentos iniciados (p<0,001) e de quadrantes visitados (p<0,001), quando comparados com o grupo Estímulo Neutro. Verificamos também que, durante a reexposição ao contexto aversivo, os animais do grupo Estímulo Aversivo apresentaram um maior tempo de congelamento (p<0,001) e um menor número de deslocamentos iniciados (p<0,001) e de quadrantes visitados (p<0,001), sugerindo assim que a exposição ao gato atuou adequadamente como um estímulo aversivo. Observou-se também um aumento do número de células Zif-268 positivas nas regiões do hipocampo reptiliano e na amígdala dos lagartos do grupo Estímulo Aversivo, durante a exposição ao gato (p=0,005 e p=0,039, respectivamente) e na reexposição ao contexto aversivo (p=0,001 e p=0,009, respectivamente). No experimento 2, os lagartos foram submetidos a uma adaptação do labirinto aquático de Morris, onde, 3 vezes por dia, durante 19 dias, os animais realizaram tentativas de encontrar uma plataforma submersa. Constatamos uma correlação negativa (p=0,012) do tempo para chegar à plataforma e o passar dos dias, indicando uma melhoria no desempenho dos lagartos na tarefa. Assim, o presente estudo forneceu indícios que machos de T. hispidus são capazes de formar memórias aversivas e espaciais, e que há um envolvimento do hipocampo e amígdala na memória.

No modelo dos multicomponentes da memória de trabalho o problema do armazenamento da ordem serial de eventos visuais e espaciais ainda é muito discutido. A literatura sugere que recursos do executivo central (o sistema de controle atencional da memória de trabalho) são utilizados para manter a representação da posição serial dos estímulos visuais e espaciais na memória. Mais precisamente, é proposto que a função executiva de atualização de informações esteja envolvida com este processo. Esta função promoveria a modificação contínua da representação mental conforme a entrada de novas informações no sistema cognitivo. Entretanto, não está esclarecido se ocorre uma dissociação visual e espacial no uso de recursos da função executiva de atualização de informações para o registro da ordem serial. O objetivo do presente estudo foi verificar o envolvimento da função executiva de atualização da informação na memória para a ordem de eventos visuais e espaciais. Os participantes foram estudantes universitários (n = 71) que realizaram as tarefas de memória delineadas segundo o paradigma de tarefas duplas. Neste procedimento as tarefas primárias de memória visual e espacial foram combinadas a tarefas secundárias executivas de tempo de reação de escolha (CRT) e tarefas que exigiam recursos de atualização da informação (tarefa de tempo de reação de escolha para um item anterior CRT-1). Na tarefa CRT o participante deveria julgar dois tons auditivos como sendo de alta ou baixa frequência. Na tarefa CRT-1 esta resposta deveria ser atrasada em um item, ou seja, a resposta ao estímulo n só deveria ser dada quando o estímulo n + 1 fosse apresentado. As tarefas secundárias eram realizadas durante a apresentação dos estímulos e no intervalo de retenção das tarefas primárias. No primeiro experimento a capacidade máxima de armazenamento espacial e visual (span) de cada participante foi estabelecida em sessão pré-teste, e no segundo experimento o participante memorizou sequências de três a sete itens. Os resultados mostraram que, de modo geral, o desempenho dos participantes nas tarefas primárias foi prejudicado mediante a interferência na função de atualização de informações. As semelhanças entre a memória serial visual e a memória serial espacial foram: curvas de posição serial caracterizadas por primazia e recência; predominância de erros de transposição de deslocamento em um item da posição correta; efeito prejudicial do aumento do tamanho da sequência; queda do desempenho quando recursos executivos são reduzidos, principalmente os designados a sustentar a função executiva de atualização da informação. As diferenças entre os dois tipos de representação serial em geral foram: menor capacidade e precisão na representação de itens na memória visual em comparação à espacial; a memória visual é mais susceptível ao aumento da quantidade de itens para retenção e para este tipo de armazenamento não há uma diferenciação clara entre os efeitos dos dois tipos de interferência executiva (CRT e CRT-1), como pôde ser determinado para a tarefa espacial. Conclui-se que recursos executivos de atualização da informação participam dos mecanismos envolvidos com o registro da ordem serial dos eventos visuais e espaciais de maneira integrada aos recursos específicos do armazenador visuoespacial. Sugere-se que a memória visual conta com um mecanismo de registro da ordem serial semelhante à memória espacial, sendo que as diferenças entre os dois padrões de desempenho são atribuídas às especificidades no registro da identidade dos itens, e não na manutenção da ordem serial dos mesmos. Implicações para a compreensão da interação funcional entre recursos de armazenamento e processamento da informação na memória de trabalho são discutidos. / In the multicomponent model of working memory is still unclear how the serial order of visual and spatial events is retained in memory. The literature suggests that the central executive resources (the attentional control system of working memory) are used to maintain the representation of serial position. More precisely, it is proposed that the executive function of updating information is involved with this process. This function makes continuous modification of mental representation to accommodate new information in the cognitive system. However, until now had not yet been determined whether there is a visual-spatial dissociation in use of executive function of updating information for the registration of serial order. The aim of this study was to investigate the involvement of the executive function of updating information in memory for the order of visual and spatial events. Participants were undergraduate students (n = 71) who performed memory tasks designed under the paradigm of dual-tasks. In this procedure the primary tasks of visual and spatial memory were combined with secondary executive tasks of choice reaction time (CRT) and tasks that occupied resources required to update the information (one-back choice reaction time CRT-1). In the CRT task the participant should judge two auditory tones as high or low frequency. In CRT-1 task this response should be delayed in one item, that is, the response to the n stimulus should only be given when the n + 1 stimulus was presented. The secondary tasks were performed during the presentation of the stimuli and the retention interval of the primary tasks. In the first experiment the capacity (span) to retain spatial and visual information was established in pre-test session, and in the second experiment the participants memorized sequences of three to seven items. The results showed that, overall, participants\' performance on primary tasks was impaired by interference on the updating information. The similarities between visual and spatial serial memory were: primacy and recency in serial position curves; most frequent serial position error of transposition in one item; detrimental effect of increasing the size of the sequence, performance impaired by the interference in the executive resources, especially those designed to support the executive function of updating information. The differences between the two types of serial representation, in general, were: smaller capacity and precision in the representation of visual items as compared to the spatial characteristics; the vulnerability of visual memory to the increasing the amount of items is bigger than in spatial memory, and for visual memory there is not a clear differentiation between the effects of two types of executive interference (CRT and CRT-1) as could be determined for the spatial task. We conclude that executive resources of updating information are part of the mechanisms involved in the registration of the serial order of visual and spatial events, and they work in an integrated manner to specific visuospatial resources. The data suggests that visual memory has a mechanism for registration of serial order like spatial memory, and the differences between the two patterns of performance are attributed to the maintenance of identity of the items, and not the maintenance of serial order. Implications for understanding the functional interaction between storage resources and processing of information in working memory are discussed.

Cette thèse avait pour but d’étudier dans quelle mesure l’enrichissement des conditions d’hébergement jusqu’à- ou à partir d’-un âge auquel les déficits cognitifs sont déjà présents contribue au maintien de la mémoire spatiale observé chez des rats âgés hébergés toute leur vie en environnement enrichi (EE), et d’étudier certains mécanismes neurobiologiques susceptibles de contribuer à cette préservation. Nous avons montré que l’hébergement en EE n’a pas besoin d’être maintenu jusqu’à la fin de la vie pour permettre la préservation des fonctions cognitives chez le Rat âgé. De plus, un enrichissement tardif ne permet pas de récupérer des capacités déjà altérées mais permet la préservation de certaines fonctions d’altérations subséquentes. Ce maintien de la mémoire spatiale ne semble pas être dû à la modification par l’enrichissement du cycle veille-sommeil. Par contre, cet enrichissement induit une modification de l’activité oscillatoire hippocampique, et pourrait, en favorisant une synchronisation neuronale locale, promouvoir un traitement de l’information au sein de réseaux plus spécialisés. Enfin, l’exposition à un EE pendant toute la vie permet la préservation de l’innervation cholinergique de différentes aires cérébrales, un effet pouvant contribuer au maintien des fonctions cognitives chez les animaux âgés hébergés toute leur vie en EE. / This thesis aimed to investigate in which extent environmental enrichment (EE) until or from an age at which cognitive decline is already apparent contributes to the maintenance of spatial memory observed in aged rats housed all their life in EE, and to study some neurobiological mechanisms likely underlying this preservation. We showed that housing in EE does not need to be maintained until the end of life to allow the preservation of cognitive function in aged rats. Moreover, late EE does not permit the recovery from already altered capabilities, but enables the preservation of some functions of subsequent alterations. The maintenance of spatial memory does not seem to be due to EE-related modification of sleep-wake cycle. But, exposure to EE induces a modification of hippocampal oscillatory activity, and could, by supporting local neuronal synchronization, promote information processing in more specialized networks. Finally, EE preserves the cholinergic system from age-related alteration in different cerebral areas, a mechanism that could participate to the maintenance of cognitive function in aged rats housed all their life in EE.

Ce travail de thèse avait pour objectif d’étudier le rôle de l’habénula latérale (HbL) dans les processus mnésiques chez le Rat en utilisant une approche par inactivation réversible grâce à l’administration de muscimol ou de CNQX. Nous avons ainsi montré l’implication de l’HbL dans : i) les processus d’encodage et de rappel d’une mémoire spatiale en piscine de Morris ; ii) la mémoire de travail, comme relais potentiel d’informations en provenance du cortex préfrontal médian, dans un paradigme de non-appariement différé à la position en boites de conditionnement opérant; iii) la réponse émotionnelle, aux niveaux comportemental et physiologique, à une situation stressante. L’ensemble de ces résultats suggèrent que l’HbL est impliquée dans les processus « online » de gestion des informations sensorielles, et qu’elle participe à la prise en compte de l’aspect émotionnel d’une situation. Ces particularités en font un lien important potentiel entre gestion des émotions et cognition. / The main objective of this thesis was to investigate the role of the lateral habenula (LHb) in mnemonic processes in rats using reversible inactivations with muscimol or CNQX. We have shown the involvement of the LHb in : i) encoding and retrieval of spatial reference memory in the Morris water maze ; ii) working memory, as a potential relay of top-down information coming from the medial prefrontal cortex, in a delayed non-matching to position paradigm using operant chambers ; iii) the behavioral and physiological responses to stressful situations. Altogether, those results suggest that the LHb is involved in the « online » process of sensory information. They also suggest that it is involved in coping with particularly stressful situations, and further position the LHb as an interface between emotions and cognition.

Les mécanismes impliqués dans les troubles cognitifs induits à la suite d’une ischémie cérébrale (IC) demeurent mal compris. En plus du cœur ischémique nécrosé et de la zone de pénombre entourant cette lésion, certaines régions éloignées de la zone ischémique peuvent être fonctionnellement affectées, un phénomène connu sous le nom de «diaschisis». Sachant qu’il existe de fortes interactions fonctionnelles entre l’hippocampe (HPC) et le cortex lors des processus mnésiques, nous avons émis la possibilité que les troubles mnésiques survenant après une IC focale qui préserve l’intégrité de l’HPC, auraient pour origine une perturbation de la connectivité cortico-hippocampique conduisant à un hypofonctionnement hippocampique induit par le phénomène de diaschisis. Afin d’éprouver cette hypothèse, nous avons utilisé le modèle d’occlusion permanente de l'artère cérébrale moyenne chez le rat (OPACM) qui reproduit l’ischémie cérébrale focale humaine. Dans ce modèle, le cortex somato-sensoriel (SS) est endommagé unilatéralement alors que l’intégrité de l’HPC est préservé. Les rats OPACM ont montré une diminution de l’expression du gène c-fos dans l’HPC lors de l'exploration d'un nouvel environnement, indiquant une hypoactivation neuronale. Les rats OPACM ont également présenté une perturbation des mémoires olfactive associative et spatiale lors des tests de transmission sociale de préférence alimentaire (TSPA) et du Barnes maze, respectivement. Afin de confirmer que l’hypofonctionnement hippocampique induit par l’IC résultait d’une réduction des afférences corticales («déactivation») provenant du cortex endommagé, nous avons réalisé des inactivations pharmacologiques spécifiques du cortex SS et ou de l’HPC par injection de lidocaïne ou de CNQX. Ces injections ont induit une hypoactivation hippocampique (réduction du nombre de noyaux Fos-positifs) associée à une perturbation mnésique dans le test de TSPA. L'activité hippocampique chez des rats anesthésiés pendant l’IC ou deux semaines après, ainsi que lors de l’inactivation pharmacologique du cortex SS, a également été examinée par une approche électrophysiologique. Les résultats ont montré une altération de la fréquence d’apparition des «sharp-wave ripples» hippocampiques et révélé une instabilité de la fréquence thêta hippocampique lors de la reperfusion ou deux semaines après IC, ainsi que lors de l’inactivation corticale, suggérant une altération de la dynamique d’interaction entre l’HPC et le cortex. Pris dans leur ensemble, ces résultats identifient le phénomène de diaschisis hippocampique comme un mécanisme crucial impliqué dans l’hypofonctionnement hippocampique et les déficits mnésiques observés après une IC. / The cognitive consequences and the underlying mechanisms leading to cognitive impairments after cerebrovascular occlusive diseases are still unclear. In addition to the infarct zone that suffer the deadly consequence of ischemic stroke, the penumbra surrounding the lesion site and some brain regions more remote to the ischemic areas can be functionally affected by the insult. This phenomenon is referred to as diaschisis. In light of the importance of interactions between hippocampus and cortex during memory processing, we hypothesized that the cognitive impairments observed following focal ischemia could occur in the absence of direct hippocampal insult, possibly via impaired connectivity within cortico-hippocampal networks leading to diaschisis-induced hypofunctioning in specific hippocampal subregions. To examine this possibility, we used the distal middle cerebral artery occlusion (dMCAO) ischemic model in rats which induces restricted cortical infarct in the somatosensory (SS) cortex in the absence of direct hippocampal injury. dMCAO rats exhibited reduced expression of the activity-dependent gene c-fos in the hippocampus when exploring a novel environment, indicating neuronal hypoactivation. Ischemic rats also showed impaired associative olfactory and spatial memory when tested in the social transmission of food preference (STFP) task and the Barnes maze test, respectively. To confirm that the ischemic-induced hippocampal hypofunctioning resulted from reduced afferent inputs (i.e. deactivation) originating in the damaged cortex, we performed region-specific pharmacological inactivation of SS and/or HPC using lidocaine or CNQX. Fos imaging revealed that these treatments induced hippocampal hypoactivation and impaired memory performance as measured in the STFP task. We additionally performed electrophysiological recordings of hippocampal activity in anesthetized rats during acute stroke and two weeks later or after SS cortex inactivation. We found an alteration in the occurrence of sharp-wave ripples associated with instability of theta frequency during reperfusion after stroke and SS cortex inactivation, suggesting an alteration in the dynamics of hippocampal-cortical interactions. Taken collectively, these findings identify hippocampal diaschisis as a crucial mechanism for mediating stroke-induced hippocampal hypofunction and associated memory deficits.

Il est admis depuis quelque temps déjà qu’une interaction, pour être utile et efficace, doit être pensée “en contexte”. Cependant ce contexte reste une notion floue regroupant de nombreux concepts la rendant difficile à exploiter lors de la conception de techniques d’interaction. La présente thèse se concentre sur la partie spatiale du Contexte dans le cadre des environnements de bureau et de la gestion des fenêtres.Nous avons tout d’abord conçu et implémenté un ensemble de techniques d’interaction regroupées sous l’ap- pellation PowerTools. Ces interactions ont comme particularité de conserver la disposition des éléments à l’écran et de garder l’interaction localisée autour du point d’attention de l’utilisateur. Deux de ces techniques, DeskPop et StackLeafing s’intéressent plus particulièrement à la navigation entre les fenêtres (et le bureau) pendant une interaction de glisser-déposer. DeskPop permet de révéler et d’interagir avec l’espace du bureau sans pour autant déplacer ou cacher les fenêtres. StackLeafing elle, propose d’utiliser le non-chevauchement des fenêtres pour les regrouper en couches et ainsi pouvoir parcourir l’ensemble des fenêtres plus rapidement que par la simple inspec- tion individuelle. TimeShift pour sa part propose une méthode de déclenchement des historiques de copier-coller et glisser-déposer permettant de conserver l’interaction autour du point d’attention de l’utilisateur. La conception des PowerTools nous a conduit à effectuer trois études plus théoriques portant sur le contexte spatial et qui ont donné lieu à des expériences utilisateurs en laboratoire.La première de ces études considère l’acquisition de cibles surgissantes ou animées où nous faisons varier le délai d’apparition et d’animation. Il s’avère que l’animation ou l’apparition soudaine d’une cible reste très proche au niveau des performances du pointage classique (cible statique toujours affichée) pour des délais d’apparition ou d’animation très court (en dessous de 200 ms). Cependant, le cas non statique conduit à plus d’erreurs et, dès que le délai dépasse 200 ms, on observe des différences de performance avec le cas statique. Ces résultats montrent que des techniques telles que StackLeafing et DeskPop qui conservent les cibles potentielles statiques et visibles possèdent un avantage par rapport aux techniques classiques.La seconde étude porte sur la profondeur en gestion des fenêtres. Elle a pour but de déterminer si l’application d’un effet graphique sur les fenêtres peut aider les utilisateurs à mieux percevoir la profondeur de couches de fenêtres comme utilisé dans la technique StackLeafing. Cette étude compare trois effets, appelés indices visuels de profondeur : ombres, flou, et luminosité. Ces indices sont appliqués à des scènes composées de fenêtres disposées en couches (ensemble de fenêtres ne se recouvrant pas), les indices de flou et de luminosité étant appliqués de manière plus forte pour les couches plus profondes. Les sujets devaient alors déterminer le nombre total de couches de la scène. L’expérience montre que l’indice le plus efficace est la luminosité.Enfin, la conception de TimeShift à également porté à notre attention la difficulté d’intégrer de nouvelles tech- niques d’interaction dans un environnement existant. Dans le cas de l’implémentation des historiques de copier- ou-déplacer, nous avons utilisé des interactions “temporisées”. Pour généraliser ces interactions temporelles, nous proposons que l’utilisateur communique avec le système par la reproduction de motifs rythmiques. Nous avons défini un vocabulaire propice à l’interaction homme-machine puis nous avons mené des expériences utilisateurs pour évaluer les capacités de reproduction et de mémorisation d’association de rythmes à des commandes. Les ex- périences montrent que le type d’interaction rythmique que nous proposons est effectivement adapté à l’Interaction Homme-Machine.La proposition de départ de cette thèse était de modifier le moins possible la disposition des éléments affichés et de conserver l’interaction autour du point d’attention de l’utilisateur afin de conserver le contexte et la mémoire spatiale de ce dernier. Nous avons tout d’abord conçu et intégré un ensemble de techniques dans un environnement réel. Puis, nous avons élaboré et mené des expériences en laboratoire afin de mieux comprendre les implications des choix de conception. / It is already well known that for an interaction to be useful, it must be thought “in context”. Unfortunately, this Context remains quite a blurry notion encompassing a lot of different concepts, making it hard to use when designing new interaction techniques. This thesis focus on the spatial part of this context in the field of window management and desktop usage.First, we designed and implemented a set of interaction techniques we called PowerTools. These interactions have the particularity of keeping the position and size of on-screen objects and to keep interaction around the user’s focus of attention. Two of these techniques, DeskPop and StackLeafing more precisely focus on the navigation between windows (and desktop) while using a drag-and-drop interaction. DeskPop allow to uncover and interact with the desktop’s content without requiring to hide or move opened windows. StackLeafing’s purpose is to use the non overlapping of windows to group them in layers, thus allowing to search through them by group instead of individually. On the other hand, TimeShift offer a triggering technique for copy-and-paste histories whose particularity is to keep the interaction around the user’s point of interest.The desing of these PowerTools brought us to conduct three more theorical studies on the spatial context which in turn led to controlled user experiments.The first of these studies looked at the the acquisition of popping and animated targets where we made the delay of apprarition or animation vary. It turns out that the cases where the target is animated or pops are really close to the traditionnal static case in term of pointing performance for small delays (under 200 ms). However, the non static cases lead to more pointing errors and once the delay goes above the 200 ms limit, we observe a drop in performance compared to the static case. These results show that techniques akind to StackLeafing and DeskPop that keep the potential target visible and static have an advantage over classic techniques.The second study looked at the depth dimension in window management. Its purpose was to see if applying some graphical effect on windows could help users better perceive the depth windows layers like the ones used in the StackLeafing technique. This study compared three depth visual cues: shadows, blur and luminance. These cues were used in scenes composed of windows group into layers (set of windows that does not everlap). The blur and luminance cues were applied more strongly on “distant” windows than on closer ones. Participants had then to guess the number of layers in the scene. This sudy shows that the luminance cue is a clear winner.Finally, the desing of TimeShift also brought our attention on the difficulty to integrate a new interaction tech- nique into an existing system. In the case of copy-and-paste histories conception, we used “timed” interactions. In order to generalise this temporal interactions we propose to use rhythmic patterns as a mean to communicate with interactive systems. We defined a vocabulary suited for human-computer interaction. We then evaluated through user studies the capacity for non experts to reproduce and memorise the association of such patterns and commands. These studies indeed show that the type of rhythmic patterns we defined are usable in the context of human-computer-interaction.the starting point of this thesis was to keep the on-screen elements static and to keep the interaction around the user’s locus of attention in order to preserve the user’s memory and spatial context. First, we integrated a set of techniques insite a real environment. Then, in order to better understand conception choices, we designed and ran controlled experiments.

African mole-rats (Bathyergidae) exhibit a wide range of social structures ranging from solitary to eusocial. This allows for studies looking at links between sociality and measurable characteristics such as spatial learning and kin-recognition. Furthermore, the existence of species with differing level of sociality allows for comparison between the highly social species and the solitary species. The existence of differences in spatial learning ability and memory between the sexes has long been debated. Eusocial Damaraland mole-rats (Cryptomys damarensis) and solitary Cape mole-rats (Georychus capensis) were tested to see if there were sex or species differences in the ability to locate food in an artificial maze task with the express purpose of investigating spatial learning and memory. Measurements of the time taken to complete the task, the distance travelled, wrong turns taken, and the average velocity at which animals travelled were used to compare performance between animals. Both sexes in each of the species exhibited learning and a decay in memory over time. The Damaraland mole-rat exhibited superior learning and memory retention when compared to the Cape mole-rat. Male Cape mole-rats had superior learning and longer term memory retention when compared to females of the same species. There was no significant difference in learning curves between male and female Damaraland mole-rats, but this species did exhibit a tendency for females to show better medium term memory retention while males performed better on long term memory trials. Species differences are likely to be linked to social organization and possibly the resultant burrow-structure in the natural environment, while sex-differences may be due to differing life histories. Kin-recognition is important in maintaining the social structure and hierarchy in the eusocial species of African mole-rat, Cryptomys damarensis. Opposite sex sibling pairs from reproductively quiescent colonies were tested to see if exposure to colony urine odour would reinforce recognition of opposite sex siblings and the concomitant incest avoidance. Control sibling pairs from the same colonies were exposed to water. Mating, social, and non-social behaviours were measured in all sibling pairs. In addition, urinary levels of cortisol, progesterone and testosterone were measured to examine the interaction between four factors: colony olfactory cues (urinary odour), hormone levels, mating behaviour and relatedness. Exposure to urinary odour reinforced recognition and was correlated to a decrease in mating behaviour. Hormonal assays suggest that female hormone levels are modified based on exposure to colony urine odour, while males are not affected. Olfactory cues such as colony urinary odour is linked to the alteration and correlation of hormone levels and mating behaviour. The Damaraland mole-rat and other species in the family Bathyergidae provide a useful system for investigating aspects of learning and memory, as well as the potential correlation between cognitive processes and sociality. / Dissertation (MSc (Zoology))--University of Pretoria, 2007. / Zoology and Entomology / unrestricted