Neste projeto investigamos a memória para as informações visual e espacial armazenadas separadamente e de forma conjugada, utilizando o ruído visual dinâmico (RVD) como interferência seletiva. No experimento 1 foi estudado o efeito do (RVD) sobre o desempenho de uma tarefa de memória visual e de memória espacial em situações nas quais essas informações foram apresentadas separadamente. Os resultados mostraram efeito generalizado do RVD em ambas as tarefas de memória, o que levou-nos a questionar a validade da tarefa espacial. No segundo experimento foi realizada uma padronização dos estímulos e parâmetros experimentais desta tarefa. Como esperado, o ruído afetou somente a condição visual. Para verificar o efeito do RVD em uma tarefa de memória para a conjunção visuoespacial foi delineado um terceiro experimento no qual a memória para as características isoladas foi comparada com a memória para a conjunção, sob efeito do ruído. A hipótese era de que se o RVD afetasse a memória espacial em uma tarefa de conjunção visuoespacial, isto seria uma evidência de que aparência visual e posição espacial são armazenados de forma integrada, em uma representação única. Esta hipótese foi confirmada pelos resultados: o ruído afetou a conjunção de informações, independentemente de qual característica (se visual ou espacial) indicava a resposta de rejeição correta na tarefa de reconhecimento da conjunção. Este estudo mostrou evidências de que a memória para a informação isolada é diferente da memória para as informações integradas. Além disto, foi possível demonstrar que uma interferência específica ao armazenador visual (ruído visual dinâmico) afetou a memória para a conjunção visuoespacial. Este resultado é uma evidência de que é formada uma imagem visual da integração visual-espacial. Esta imagem é mantida na consciência, em um sistema que é vulnerável às interferências da percepção, como as ocasionadas pelo ruído visual dinâmico. / In this work we investigate visual and spatial memory information stored separately and combined, using the dynamic visual noise (DVN) as a selective interference. In the experiment 1 we studied the effect of (DVN) on the performance of a visual and spatial memory tasks in situations where these information was presented separately. The results showed an overall DVN effect in both memory tasks, which led us to question the validity of the spatial task. In the second experiment it was performed a standardization of stimuli and experimental parameters of this \"task\". As expected, noise affected only the visual condition. To investigate the DVN effect on a memory task with a visuo-spatial binding it was designed a third experiment in which memory for isolated features was compared with memory binding, under the effect of noise. The hypothesis was that if the DVN affects spatial memory in a visuo-spatial task combination, it would be evidence that the visual appearance and spatial position are stored in an integrated manner in a single representation. This hypothesis was confirmed by the results: the noise affected the binding of information, regardless of what feature (visual or spatial) indicated the rejection response in the task of correct recognition of binding. This study showed that memory for isolated information is different from memory for the integrated information. Moreover, it was demonstrated that a specific interference to the visual cache (dynamic visual noise) affect the memory for the visuo-spatial binding. This result is an evidence that it is formed a visual image of the visuo-spatial binding. This image is maintained in consciousness, in a system that is vulnerable to interference of perception, such as those caused by dynamic visual noise.

The hippocampus plays an important role in the processing of spatial memory. During exploration, theta oscillations (4-12 Hz) are prominent in the hippocampus, whereas during sleep and rest irregular sharp wave/ripple (SWR) events occur spontaneously in the hippocampus and may support memory consolidation. To date, the ventral sub-region of the rodents hippocampus, has received less attention relative to the more accessible dorsal part. It has been suggested that spatial information decreases along the septo-temporal axis in favour of coding salient features and coordinated oscillatory activity might enable the binding of spatial and nonspatial information. The first goal of my research was to investigate how the spatial representation by dorsal and ventral neurons is organised by theta oscillations in the hippocampal network. The second goal was to investigate the role of the ventral hippocampus in spatial learning. Finally, the third goal examined to what extent the firing relationships established during spatial learning are replayed during subsequent sleep in the ventral CA1. I recorded the network activity of dorsal and ventral CA1 in rats performing a spatial memory task on the cheese board maze (Dupret et al., 2010). By using parallel multi-channel extracellular recordings in the dorsal and ventral portions of the hippocampus in behaving rats, I found that dorsal and ventral CA1 were theta coupled at particular times of the spatial learning. High coherence periods across the two regions were characterized by a strong speed-modulation of ventral theta oscillations, which was absent in other conditions. During sleep, it was found that SWR-related activity was presented in the ventral hippocampus as well, when the coordinated population activity established in spatial learning was reactivated within the two sub-regions. By contrast, reactivation across the two regions was observed outside the SWRs epochs. Overall, the data suggests that the ventral hippocampus might be involved in the processing of salient features of the environment such as rewards. On a temporal scale, this non-spatial information might be integrated to the spatial information provided by the dorsal hippocampus during theta oscillation. During sleep/rest periods, the coordinated communication of learned information might underlie the consolidation of memory traces.

La formation de la mémoire spatiale est un mécanisme complexe qui transforme les informations récemment acquises en traces mnésique robustes à long terme. D’un point de vue moléculaire, ces phénomènes sont dépendants de l’expression de deux formes opposées de plasticité synaptique ; la potentialisation à long terme (LTP) et la dépression à long terme (LTD). L’induction de la LTP/LTD dépend de la fine régulation entre des kinases et des phosphatases sensibles au Ca2+ qui vont activer respectivement la LTP et la LTD dans la densité postsynaptique (PSD). Cette régulation met également en jeu des interactions en avale entre les récepteurs et des protéines d’échafaudages spécialisées au sein de la PSD. Scribble1 (Scrib1) est une de ces protéines d’échafaudage appartenant à la famille des LAP (leucine-rich repeats & PDZ domains) avec 16 répétitions riches en leucine et 4 domaines PDZ (PSD-95/Dlg/ZO-1). Lors de cette étude, nous avons développé de souris « knock-out » conditionnelles avec une délétion complète de la Scrib1 dans les principaux neurones de l’encéphale antérieur, dont les neurones excitateurs de l’hippocampe, grâce au système Cre-lox (Scrib1f/f,CaMKII-cre). Les souris Scrib1f/f,CaMKII-cre présentent une altération de la morphologie des dendrites apicales sans modification de la morphologie ni de la densité des épines dans la région CA1 de l’hippocampe. Sur le plan fonctionnel, les neurones du CA1 des souris Scrib1f/f,CaMKII-cre présentent une augmentation du nombre de synapses silencieuses (non-fonctionnelles). Ceci réduit le nombre de synapses actives et entraine une diminution globale de la transmission basale des synapses CA3-CA1 comparée aux synapses Scrib1f/f. Les souris Scrib1f/f,CaMKII-cre montrent une augmentation de la LTP mais sont incapables d’exprimer une LTD ni la depotentiation à long terme. De plus, des protocoles de LTD induisent une LTP chez ces souris. Au niveau moléculaire, nous avons mis en évidence une interaction directe au sein des synapses entre Scrib1 et la phosphatase PP2A impliquée dans la LTD. De plus, l’absence de Scrib1 entraine une réduction des niveaux de PP2A dans la PSD chez les souris Scrib1f/f,CaMKII-cre. Ceci implique une diminution de l’activation de la voie de signalisation de la LTD via PP2A au profit de celle de la CAMKII et la LTP, ce qui pourrait expliquer l’induction d’une LTP à la place d’une LTD chez les souris Scrib1f/f,CaMKII-cre. Sur le plan cognitif, les souris Scrib1f/f,CaMKII-cre présentent des déficits dans la flexibilité de l’apprentissage spatial comparées aux souris Scrib1f/f. Chez les souris Scrib1f/f,CaMKII-cre, la la mémoire spatiale à court terme n’était pas altérée tandis que la mémoire à long terme était déficiente. Ainsi, ces données révèlent un rôle majeur de Srib1 dans consolidation de la mémoire spatiale. Lors de cette étude, nous avons montré un rôle pour Scrib1 dans les connections et la morphologie des neurones CA1, ainsi que la conversion fonctionnelle des synapses silencieuses en synapses actives. D’une manière importante, Scrib1 permet l’expression de la plasticité synaptique bidirectionnelle à travers une interaction avec PP2A et module la formation de la mémoire spatiale à long terme. / Spatial memory formation is a complex process that transforms newly-acquired information into long-lasting and solid memories. Molecularly, these phenomena rely on the expression of two opposite forms of synaptic plasticity; long-term potentiation (LTP) and long-term depression (LTD). LTP/LTD induction relies on a fine balance between Ca2+-sensitive kinases and phosphatases that activate specific pathways of either LTP or LTD, respectively. This regulation also involves downstream interactions between receptors and highly specialized scaffold proteins, at the PSD. Scribble1 (Scrib1) is a scaffold protein that belongs to the LAP (leucine-rich repeats and PDZ domains) protein family, with 16 leucine rich repeats and 4 PDZ (PSD-95/Dlg/ZO-1) domains. Here, we developed conditional knock-out mice with a complete loss of Scrib1 expression in the major neurons of the postnatal forebrain, including hippocampal excitatory neurons, using the Cre-Lox system (Scrib1f/f,CaMKII-cre). Scrib1f/f,CaMKII-cre presented altered morphology of apical dendrites but intact spine density and spine morphology in the CA1 region. Functionally, we found increased number of silent (non-functional) synapses that decreases the number of active synapses in Scrib1f/f,CaMKII-cre CA1 neurons leading to a global decrease in basal glutamatergic synaptic transmission at CA3-CA1 synapses compared to Scrib1f/f synapses. Scrib1f/f,CaMKII-cre synapses displayed enhanced LTP but were unable to express LTD or long-term depotentiation. More strikingly, LTD-inducing protocols generated LTP in Scrib1f/f,CaMKII-cre synapses. Molecularly, we revealed a direct interaction between Scrib1 and the phosphatase PP2A that signals LTD at the synapse. Moreover, we found that the absence of Scrib1 results in a reduction of synaptic PP2A levels in Scrib1f/f,CaMKII-cre mice. This probably leads to a decrease in PP2A signaling pathway activation which favors the competing pathway downstream CaMKII resulting in LTP induction instead of LTD in Scrib1f/f,CaMKII-cre mice. On the cognitive level, we found that spatial learning was slower and inflexible in Scrib1f/f,CaMKII-cre compared to Scrib1f/f mice. Short-term spatial memory was intact while long-term memory was impaired. These results argue for an important role of Scrib1 in spatial memory consolidation. We here report that Scrib1 is important for appropriate neuronal shaping and wiring of CA1 neurons as well as functional conversion of silent synapses into active ones. Importantly, it allows bidirectional synaptic plasticity through interaction with PP2A and modulates long-term spatial memory formation

Alzheimer's disease (AD) is neurodegenerative disorder that causes memory loss and cognitive dysfunction. It affects one in five people over the age of 80 and is distressing for both sufferers and their families. A transitional stage between normal ageing and dementia including AD is termed a mild cognitive impairment (MCI). Recent studies have shown that people with MCI may convert to AD over time although not all MCI cases progress to AD. Much research is now focussing on early detection of AD and diagnosing an MCI that will progress to AD to allow prompt treatment and disease management before the neurons degenerate to a stage beyond repair. Hence, the ability to obtain a method of identifying MCI is of great importance. Virtual reality plays an important role in healthcare and offers opportunities for detection of MCI. There are various studies that have focused on detection of early AD using virtual environments, although results remain limited. One significant drawback of these studies has been their limited capacity to incorporate levels of difficulty to challenge users' capability. Furthermore, at best, these studies have only been able to discriminate between early AD and healthy elderly with about 80% of overall accuracy. As a result, a novel virtual simulation called Virtual Reality for Early Detection of Alzheimer's Disease (VREAD) was developed. VREAD is a quick, easy and friendly tool that aims to investigate cognitive functioning in a group of healthy elderly participants and those with MCI. It focuses on the task of following a route, since Topographical Disorientation (TD) is common in AD. An investigation was set up with two cohorts: non-elderly and elderly participants. The findings with regard to the non-elderly are important as they represent a first step towards implementation with elderly people. The results with elderly participants indicate that this simulation based assessment could provide a method for the detection of MCI since significant correlations between the virtual simulation and existing neuropsychological tests were found. In addition, the results proved that VREAD is comparable with well-known neuropsychological tests, such as Cambridge Neuropsychological Automated Test Battery, Paired Associate Learning (CANTAB PAL) and Graded Naming Test (GNT). Furthermore, analysis through the use of machine learning techniques with regard to the prediction of MCI also obtained encouraging results. This novel simulation was able to predict with about 90% overall accuracy using weighting function proposed to discriminate between MCI and healthy elderly.

Acidentes ofídicos constituem um problema de saúde publica. Estudos prévios indicam que constituintes do veneno de Crotalus durissus terrificus injetados sistemicamente promovem, agudamente, aumento dos níveis de ansiedade em ratos; se injetados topicamente na formação hipocampal, região intimamente ligada a processos de memória espacial e ansiedade, induzem alterações citoestruturais. O objetivo deste trabalho foi avaliar, em ratos, efeitos comportamentais decorrentes da injeção sistêmica de veneno bruto de Crotalus durissus terrificus e a eficácia do soro anticrotálico em prevenir esses prejuízos quando administrado variáveis intervalos de tempo depois do envenenamento. Ratos submetidos a uma única injeção sistêmica de veneno bruto 7 dias antes do inicio dos testes foram avaliados nas tarefas de memória de referencia e de memória operacional no labirinto aquático de Morris, e também a uma tarefa envolvendo uma plataforma visível no mesmo aparelho. A seguir, os animais foram submetidos ao paradigma do teste-reteste no labirinto em cruz elevado. Os resultados mostraram que houve prejuízos de memória de referencia e de memória operacional; este último efeito ocorreu quando o intervalo entre as tentativas foi de 10 minutos, mas não quando foi de zero minutos. Potenciais efeitos sensoriais e motores foram excluídos. Alem disso, houve substancial aumento nos níveis de ansiedade. A administração de soro anti-crotálico preveniu os principais prejuízos de memória desde que realizada em ate 10 horas apos a injeção do veneno (foram testados intervalos de 0, 0,5, 2, 10 e 24 horas, em grupos independentes de animais)..O grupo tratado com soro anti-crotálico 24 horas depois do envenenamento apesar de prejudicado em relação aos grupos controle (um injetado com salina e o outro apenas com soro), exibiu desempenho melhor do que o grupo tratado apenas com veneno. Assim, o presente conjunto de resultados representam a primeira demonstração de que (1) uma única dose sistêmica do veneno crotálico produz prejuízos de memória espacial em ratos e aumenta os níveis de ansiedade avaliados 4 semanas apos a injeção, e (2) os prejuízos de memória podem ser prevenidos pela administração de soro anticrotálico desde que essa administração ocorra em ate 10 horas apos o envenenamento. / Snakebites constitute a serious public health problem in Brazil. Prior studies have shown that systemic injections of venom fractions of Crotalus durissus terrificus produce acute increase in anxiety levels in rats; when injected topically within the hippocampal formation, a brain region underlying processes of spatial memory and anxiety, induce damage. The aims of this study included to investigate, in rats, behavioral effects of a single systemic injection of crude venom on performance of spatial memory tasks and on anxiety, and the efficacy and time course of the antivenom administration to prevent memory disruption. Rats subjected to a single systemic injection of venom 7 days before the beginning of behavioral testing were evaluated in modified versions of the reference and working memory tasks in the water maze, and also to a version of the task in which the platform is visible. Then, the subjects were submitted to the test-retest paradigm in the elevated plus maze. Rats injected with the venom exhibited disruption of performance both in reference and working memory versions of the water maze task; in this latter task, however, disruption occurred when the intertrial interval was 10 minutes but not when the it was zero minutes. Anti-crotalic serum injection prevented memory disruptions when its administration occurred up to 10 hours after injection of the venom (time intervals evaluated included 0, 0.5, 2, 10 and 24 hours, in independent groups of rats). Subjects that received anti-crotalic serum 24 hours after venom injection exhibited disruption of memory relative to control groups (one of them treated with saline and the other with anti-crotalic serum only); however, performance of those animals was better when compared to subjects receiving only venom administration. These results show, to our knowledge for the first time, that (1) a single systemic injection of crotalic venom induces disruption of spatial memory and increases anxiety evaluated 4 weeks after injection, and (2) major spatial memory disruptions may be prevented by administration of the anti-crotalic serum up to 10 hours after the venom injection.

A neurogênese hipocampal é modulada por muitos fatores que incluem envelhecimento, estresse, enriquecimento ambiental, atividade física e aprendizado. Atividade física voluntária (espontânea) estimula a proliferação celular no giro denteado e facilita a aquisição e/ou retenção de tarefas dependentes do hipocampo, incluindo o Labirinto Aquático de Morris. Embora seja bem estabelecido que o exercício físico regular melhore o desempenho em tarefas de memória e aprendizado, não está claro qual a duração desses benefícios após o final da atividade física. Neste estudo investigamos a relação temporal entre os efeitos benéficos da atividade física associado ao aprendizado de tarefa dependente da função hipocampal, e sua relação com a neurogênese, levando em consideração também o tempo decorrido desde o término da atividade física. Grupos independentes de ratos tiveram acesso a roda de atividade ao longo de 7 dias (Grupo EXE) ou roda bloqueada (Grupo Ñ-EXE) e receberam injeções de BrdU nos últimos 3 dias de exposição roda. Após um INTERVALO de 1, 3 ou 6 semanas após o final da exposição a roda de atividade após o final da exposição a roda de atividade, os animais foram testados no labirinto aquático de Morris, sendo uma parte deles expostos a tarefa de memória operacional espacial, dependente da função hipocampal (H), e outra parte a uma tarefa de busca por uma plataforma visível, independente da função hipocampal (ÑH). Em ambos os casos, o intervalo entre as tentativas (ITI) foi de 10 minutos durante as sessões 1-6 e (virtualmente) zero minutos durante as sessões 7-10. Concluída a tarefa os cérebros foram processados para imuno-histoquímica. Foram feitas imunoistoquímicas para a detecção de Ki-67 (proliferação celular), BrdU, NeuN (para identificar neurónios maduros), e DCX (para identificar imaturo neurônios). Nossos dados suportam a ideia que atividade física voluntária induz um aumento na proliferação celular e na diferenciação neuronal (neurogênese) no giro denteado. A introdução de um período de intervalo entre o final do exercício e a execução da tarefa comportamental causa uma redução significativa na sobrevivência dos novos neurônios, como observado com 1 semana de intervalo em comparação com os animais testados com 6 semanas de intervalo. Em contraste, entretanto, o presente resultado não confirma que esse aumento da neurogênese é acompanhado por melhora na memória espacial, como avaliado por meio da versão que envolve memória operacional no labirinto aquático de Morris. O aprendizado da tarefa do labirinto aquático de Morris, na versão de memória operacional que é dependente do hipocampo, leva a um aumento da sobrevivência dos novos neurônios que foram produzidos no período de exercício, ao passo que o aprendizado da versão independente da tarefa leva a uma redução do número absoluto de novos neurônios / Hippocampal adult neurogenesis is modulated by many factors including age, stress, environmental enrichment, physical exercise and learning. Spontaneous exercise in a running wheel stimulates cell proliferation in the adult dentate gyrus and facilitates acquisition and/or retention of hippocampal-dependent tasks including the Morris water maze. While it is well established that regular physical exercise improves cognitive performance, it is unclear for how long these benefits last after its interruption. In this study, we investigate the temporal relation between exercise-induced benefits associated with learning of a hippocampal-dependent task, this relationship with neurogenesis, considering the time after exercise has ended. Independent groups of rats were given free access to either unlocked (EXE Group) or locked (No-EXE Group) running wheels for 7 days, having received daily injections of BrdU for the last 3 days. The animals were then transferred to standard home cages. After a time period of either 1, 3 or 6 weeks, the animals were tested in the Morris water maze, one of them being exposed to the spatial working memory task dependent on hippocampal function (H) and partly to a task search for a visible platform, independent of hippocampal function (NH). In both cases, the interval between trials (ITI) was 10 minutes during sessions and 1-6 and (virtually) zero minute during the sessions 7-10. After the task brains were processed for immunohistochemistry. Cell proliferation and net neurogenesis were assessed in hippocampal sections using antibodies against BrdU, NeuN (to identify mature neurons), and DCX (to identify immature neurons). Data of the present study confirm that exposure of rats to 7 days of spontaneous wheel running increases cell proliferation and neurogenesis. In contrast, however, the present results did not confirm that this neurogenesis is accompanied by a significant improvement in spatial learning, as evaluated using the working memory version of the Morris’ water maze task. The introduction of a delay period between the end of exercise and cognitive training on the Morris water maze reduces cell survival; the number of new neurons was higher in the EXE1 week delay group as compared to the EXE6 week delay. We showed that learning the Morris water maze in the working memory task dependent on hippocampal function (H) increases the new neurons survival, in contrast, learning hippocampal-independent version of the task decreases number of new neurons

Introdução: O etilismo é uma doença crônica e progressiva que tem um impacto significante nos valores sociais e econômicos da sociedade. A interrupção abrupta do consumo crônico de etanol pode levar à Síndrome de Abstinência alcoólica (SAA) com repercussões na saúde do indivíduo. Atualmente, muita atenção também tem sido dada ao consumo espaçado de etanol em doses elevadas, caracterizado como binge. Dentre as várias consequências do consumo agudo e/ou crônico do etanol, podem-se destacar os déficits em teste de aprendizagem e de memória. Objetivos: verificar se a abstinência ao etanol após o consumo involuntário ou semivoluntário de etanol (crônico ou agudo) é capaz de interferir na aprendizagem, na memória e na ansiedade de ratos adultos. Materiais e Métodos: Foram utilizados 196 ratos albinos, Wistar e machos, com 21 dias de vida. Inicialmente os animais foram divididos em dois grandes grupos para compor o Estudo 1 ou o estudo 2. No estudo 1 a via de administração foi semivoluntária (etanol a 6%) e no estudo 2 foi involuntária (por gavagem intragástrica- 1g etanol/kg). Em ambos os estudos os animais foram divididos novamente em relação ao tipo de bebida que receberiam (água ou etanol) e tempo de consumo (agudo- 2 horas ou crônico- 21 dias, sendo que no estudo 2 a ingestão etílica aconteceu a cada 3 dias). No 23º dia (após 48 horas da última ingestão etílica) os animais foram testados no Teste de Memória de Reconhecimento (TMR), no Labirinto em Cruz Elevado (LCE) e no Labirinto Aquático de Morris (LAM) por dois dias consecutivos e retestados após 28 dias. Resultados: No estudo 1 os resultados indicaram que a abstinência ao etanol após o consumo agudo ou crônico de etanol não foi capaz de alterar a aprendizagem e a memória espacial no LAM, porém prejuízos na memória espacial de longo prazo foram observados nos animais submetidos ao consumo agudo de etanol. Não foram observadas alterações na Memória de Reconhecimento na Sessão treino e na Memória de Reconhecimento de Curto Prazo, porém a exposição aguda ao etanol foi capaz de gerar prejuízos na memória de Reconhecimento de Longo Prazo. Não houve diferenças nos níveis de ansiedade dos animais do estudo. Em relação ao estudo 2, foi possível observar que a abstinência do etanol após o consumo agudo foi capaz de gerar um prejuízo na memória espacial de curto prazo e que o consumo crônico e agudo de etanol não foram capaz de prejudicar a Memória de Reconhecimento dos animais estudados. Ainda que, os animais expostos ao consumo agudo e crônico de etanol, em abstinência ao etanol de 48 horas apresentaram níveis de ansiedade elevados. Conclusão: O etanol influencia de forma diferente a memória espacial, a memória de reconhecimento e os níveis de ansiedade a depender da via de administração (e, portanto da quantidade de etanol ingerida) e do tempo de consumo. / Introduction: Alcoholism is a chronic and progressive disease that has a significant impact on social and economic values of society. Abrupt withdrawal of chronic ethanol consumption can lead to alcohol withdrawal syndrome (AWS) which impacts on the health of the individual. Currently, much attention has also been attributed to the spaced ethanol consumption in high doses, characterized as \"binge\". Among the many consequences of acute and/or chronic consumption ethanol, can highlight the deficits in learning and memory test. Objectives: verify if abstinence to ethanol after the involuntary consumption of ethanol or semi-voluntary (chronic or acute) can interfere in the learning, memory and anxiety in adult rats Materials and Methods: were used 196 albino rats Wistar and males, with 21 days of life. Initially, the animals were divided into two groups to compose the study 1 or 2. In study 1 the administration route was semi voluntary (6% ethanol) and in Study 2 was involuntary (by gavage intragástrica- ethanol 1g / kg). In both studies, the animals were divided again in relation to the type of beverage that receive (water or ethanol) and time consumption (acute- 2 hours or chronic for 21 days, whereas in Study 2 the alcohol consumption occurred every 3 days). On the 23rd days (48 hours after the last alcohol consumption) the animals were tested in Recognition Memory Test (RMT), the Elevated Plus Maze (EPM) and Morris Water Maze (MAM) for two consecutive days (and retested after 28 days). Results: In study 1 the results indicated that abstinence to ethanol after acute or chronic ethanol consumption was not able to alter the learning and spatial memory in LAM, but damage on long-term spatial memory were observed in animals submitted to consumption acute ethanol. No changes were observed in recognition memory in Session training and Short-term recognition memory, but the acute ethanol exposure was able to generate damages on long-term recognition memory. There were no differences in anxiety levels of study animals. Regarding the study 2, we observed that abstinence after acute ethanol consumption was able to generate damage in spatial memory short term and that chronic and acute consumption of ethanol were not able to alter the Recognition Memory of animals studied. Although, animals exposed to acute and chronic ethanol consumption in abstinence to 48 hours ethanol showed elevated levels of anxiety. Conclusion: Ethanol affects differently the spatial memory, recognition memory and anxiety levels depending on the route of administration (and therefore the amount of intake of ethanol) and of the time consumption.

Spatial memory and navigation relies on estimation of location. This can be achieved through several strategies, including the use of landmarks and by path integration. The latter involves inferring location from direction and distance moved relative to a known start point. The neural mechanisms of path integration are not well understood and implementation of experiments that dissociate path integration from alternative strategies is challenging. The roles of specific cell types are also unknown. Although grid cells in layer 2 of the medial entorhinal cortex (MEC) are theorised to be involved given their periodic and repeating firing fields that form a grid-like map that tiles the environment. Two excitatory cell populations have been identified in layer 2 of the MEC. Clusters of pyramidal cells that project to the CA1 are surrounded by dentate gyrus (DG) projecting stellate cells. Both populations have been shown to exhibit grid-like activity. The extent to which these cell types contribute to path integration or other strategies for solving spatial tasks is unknown. To investigate these issues, I developed a spatial memory task for mice, which uses virtual reality to generate sensitive measures of an animal’s ability to path integrate. In this task mice are trained to locate a reward zone marked with a visual cue within a virtual linear track. Use of path integration strategies can be tested in trials in which the reward zone is unmarked. In this task mice can locate the reward zone using either a local beaconing cue or path integration strategies. To assess whether self-motion derived motor information or visual feedback is used for path integration, I manipulated the translation between physical and virtual movement, putting optic and motor feedback in conflict. These manipulations suggest that mice use motor information to locate the reward zone on path integration trials. To test roles of stellate cells in the task I injected adeno-associated virus expressing the light chain of tetanus toxin, conditionally on the presence of Cre, into the MEC of mice expressing Cre specifically in stellate cells. This abolishes synaptic output from stellate cells therefore preventing them from influencing downstream neurons. I find mice with dorsal expression of the tetanus toxin virus in layer 2 stellate cells are unable to locate the reward zone using a local beaconing cue or path integration strategies. In contrast, mice with expression of green fluorescent protein (GFP) were able to locate the reward zone using both strategies. Locating the reward zone using path integration strategies first requires animal’s to learn the reward zone location, as denoted in trials with a beacon cue. To distinguish the role of stellate cells in learning versus execution of the tasks, I temporally modified the activity of stellate cells after mice had learnt to locate the reward zone using both strategies. Temporal control was achieved by use of cre-dependent adeno-associated viruses expressing mutant human muscarinic 4 receptor (hM4). When activated by clozapine - N - oxide (CNO), this receptor opens G-protein inwardly rectifying potassium (GIRK) channels and attenuates neuronal firing. Using this method, the activity of stellate cells can be temporally controlled during task execution and potentially distinguish their involvement in learning and execution of spatial memory tasks. No effect on behavioural performance was seen under these conditions. This may indicate stellate cells are required for learning but not execution of spatial memory tasks that require the use of local beaconing cues or path integration.

abstract: The present series of studies examined whether a novel implementation of an intermittent restraint (IR) chronic stress paradigm could be used to investigate hippocampal-dependent spatial ability in both sexes. In experiments 1 and 2, Sprague- Dawley male rats were used to identify the optimal IR parameters to assess spatial ability. For IR, rats were restrained for 2 or 6hrs/day (IR2, IR6, respectively) for five days and then given two days off, a process that was repeated for three weeks and compared to rats restrained for 6hrs/d for each day (DR6) and non-stressed controls (CON). Spatial memory was tested on the radial arm water maze (RAWM), object placement (OP), novel object recognition (NOR) and Y-maze. The results for the first two experiments revealed that IR6, but not IR2, was effective in impairing spatial memory in male rats and that task order impacted performance. In experiment 3, an extended IR paradigm for six weeks was implemented before spatial memory testing commenced in male and female rats (IR- M, IR-F). Unexpectedly, an extended IR paradigm failed to impair spatial memory in either males or females, suggesting that when extended, the IR paradigm may have become predictable. In experiment 4, an unpredictable IR (UIR) paradigm was implemented, in which restraint duration (30 or 60-min) combined with orbital shaking, time of day, and the days off from UIR were varied. UIR impaired spatial memory in males, but not females. Together with other reports, these findings support the interpretation that chronic stress negatively impairs hippocampal-dependent function in males, but not females, and that females appear to be resilient to spatial memory deficits in the face of chronic stress. / Dissertation/Thesis / Masters Thesis Psychology 2019

Interactive fisheye views use distortion to show both local detail and global context in the same display space. Although fisheyes allow the presentation and inspection of large data sets, the distortion effects can cause problems for users. One such problem is lack of memorability the ability to find and go back to objects and features in the data. This thesis examines the possibility of improving the memorability of fisheye views by adding historical information to the visualization. The historical information is added visually through visit wear, an extension of the concepts of edit wear and read wear. This will answer the question Where have I been? through visual instead of cognitive processing by overlaying new visual information on the data to indicate a users recent interaction history. This thesis describes general principles of visibility in a space that is distorted by a fisheye lens and defines some parameters of the design space of visit wear. Finally, a test system that applied the principles was evaluated, and showed that adding visit wear to a fisheye system improved the memorability of the information space.