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. / Ministry of Higher Education, Malaysia and University Sultan Zainal Abidin, Malaysia (UNisZa)

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The ability to recall a spatial layout from multiple orientations – spatial flexibility – is a challenging cognitive process, especially when the global configuration cannot be viewed from a single vantage point, as spatial information must first be integrated before it can be flexibly recalled. The current study examined if experiencing the transition between multiple viewpoints enhances spatial flexibility for both non-integrated (Exp. 1) and integrated environments (Exp. 2), if the type of transition matters, and if action provides an additional advantage over passive visual flow. In Experiment 1, participants viewed an array of dollhouse furniture from four viewpoints that presented the global configuration from multiple orientations. In Experiment 2, the array was viewed piecemeal, from four viewpoints that presented the global configuration in partial chunks. The control condition presented the dollhouse as a series of static views, whereas in the remaining conditions, visual flow was continuous. Participants viewed the natural transition between viewpoints, and either passively experienced the transitions (i.e., by watching the dollhouse rotate or being rolled around it), or actively generated them (i.e., by rotating the dollhouse or walking around it). Across both experiments, continuous visual flow significantly enhanced spatial flexibility when paired with observer movement around the dollhouse, either active or passive. Furthermore, when participants had to integrate spatial information across discrete learning experiences (Exp. 2), active movement provided a significant advantage above passive experience. These findings suggest that array stability is key to flexible spatial memory, with action providing an additional boost to spatial integration. / Psychology

Corvids are important seed and nut dispersers in North America. To date, the caching and recovery behaviors of four North American Corvids have been documented, n10st notably Clark1s Nutcracker (Nucifraga columbiana). Blue Jays (Cyanocitta cristata) are important dispersers of Quercus, Fagus, and Castanea nuts in eastern North America and their caching behavior in the wild has been well documented. Recovery of caches by the same individual Blue Jay that created the caches has not been demonstrated. In order to do this, I conducted a laboratory study in which I examined caching and recovery behaviors. I 'compared the performance of caching birds with noncaching birds and with a random foraging model. Blue Jays do return to their own caches with success rates higher than predicted by random searching and they also probe fewer sites than predicted by random. They also recover caches at success rates higher than non-caching birds searching for the same caches as well as probe fewer sites than the non-caching birds. There is a difference in probing patterns for recovered caches between caching birds and non-caching birds that suggests the use of spatial memory by caching birds and a difference in foraging strategies between the two groups. Cache recovery order does not exhibit either a primacy or recency effect and cache recovery order does not appear to correlate to nearest neighbor distance models. / Master of Science

Les modifications post-traductionnelles des histones jouent un rôle majeur dans la régulation de l’expression de gènes impliqués dans la plasticité et la mémoire. Parmi ces modifications, l’acétylation des histones permet le maintien de la chromatine dans un état « permissif », accessible pour la transcription. Nos travaux visent à identifier le rôle joué par l’acétylation de deux histones, H3 et H4, dans la formation de différentes formes de mémoire mettant en jeu les systèmes hippocampique et striatal chez la souris. Nous avons également recherché si des perturbations d’acétylation des histones sont responsables des déficits mnésiques observés au cours du vieillissement. Nous avons utilisé deux types d’apprentissage en piscine de Morris permettant de dissocier la mémoire spatiale, impliquant principalement l’hippocampe et la mémoire procédurale/indicée, impliquant le striatum. Nos résultats mettent en lumière une régulation différentielle de l’acétylation des histones dans l’hippocampe et le striatum selon la nature de la tâche et l’âge des animaux. L’apprentissage spatial induit une augmentation de l’acétylation des histones sélectivement dans l’hippocampe (CA1 et gyrus denté) alors que la tâche indicée augmente l’acétylation des histones spécifiquement dans le striatum. Nous montrons également que des changements opposés de l’acétylation de H3 (augmentation) et de H4 (diminution) dans l’hippocampe pourraient contribuer aux déficits de mémoire spatiale observés chez les souris âgées. Lors d’un test de compétition en piscine de Morris, durant lequel les souris ont le choix entre les stratégies spatiale et indicée pour résoudre la tâche, l’injection intra-hippocampique de Trichostatine A (TSA), un inhibiteur des histones déacétylases, immédiatement après l’apprentissage, perturbe la fonction striatale et favorise l’utilisation préférentielle de la stratégie spatiale hippocampique. Cependant, cet effet de la TSA est absent chez les souris âgées dont la fonction hippocampique est altérée. Dans une dernière série d’expérience, l’analyse des effets d’une injection intra-hippocampique de TSA, après un apprentissage spatial, a permis de préciser les contributions respectives des histones H3/H4 et du facteur de transcription CREB dans les déficits mnésiques associés au vieillissement. Dans leur ensemble, nos travaux apportent des éléments importants concernant l’importance de l’acétylation des histones dans la modulation des interactions entre systèmes de mémoire hippocampique et striatal. / Post-translational modifications of histone proteins play a crucial role in regulating plasticity and memory-related gene expression. Among these modifications, histone acetylation leads to a relaxed or “opened” chromatin state, permissive for transcription. Our work aims to identify the role played by histone H3 and H4 acetylation in the formation of different forms of memory involving hippocampal and striatal systems in mice. We also examined whether alterations of histone acetylation are responsible for age-associated memory deficits. We used two versions of the Morris water maze learning task to dissociate a spatial form of memory that relies on the hippocampus and a procedural/cued memory supported by the striatum. Our results highlight a differential regulation of histone acetylation within the hippocampus and striatum depending on the nature of the task and age of animals. Spatial and cued learning elicited histone acetylation selectively in the hippocampus (CA1 region and dentate gyrus) and the striatum, respectively. Age-related spatial memory deficits were associated with opposite changes in H3 acetylation (increase) and H4 (decrease) selectively in the hippocampus. During a water maze competition task in which mice can choose between spatial and cue-guided strategies, intra-hippocampal injection of Trichostatin A (TSA), an histone deacetylase inhibitor, immediately post-acquisition, impaired striatal function and promoted the use of a hippocampus-based spatial strategy. However, this effect of TSA was absent in old mice in which hippocampal function is impaired. In a final series of experiments, analysis of the effects of intra-hippocampal TSA injection immediately after a spatial training helped to clarify the respective contributions of histone H3/H4 and the transcription factor CREB in spatial memory deficits associated with aging. Taken together, our work provides important information regarding the importance of histone acetylation in modulating interactions between hippocampal and striatal memory systems.

Background: The main aim of the studies in this thesis is to provide insights into the neonatal phencyclidine (PCP) induced deficits in male and female rats as a neurodevelopmental animal model of schizophrenia. Methods: Both male and female rats were treated with neonatal PCP on postnatal days (PNDs) 7,9 and 11 or vehicle, followed by weaning on PND 21-22. The rats were then tested in behavioural paradigms such as novel object recognition, spatial memory and social interaction in their adolescent and adult stages and were also tested with acute treatment of typical and atypical antipsychotic agents. Results: Neonatal PCP treatment (10 & 20 mg/kg in males and 10 mg/kg in females; once a day for 3 days on PND 7,9 and 11) caused novel object recognition and spatial memory impairment in male and female rats both in the adolescent (PND35-56) and in the adult stages (PND>56) (chapter 2) and robust deficits in social interaction behaviours in the adolescent stage. The SI deficits were observed in adulthood in female but not in male rats thereby establishing a sex-specific social behavioural deficit (chapter 3). The object memory and social interaction deficits induced by neonatal PCP treatment were reversed following acute risperidone but not haloperidol. Finally, the temporal profile of this treatment regime was investigated and the male and female animals were tested on PND 190 and PND 365. The animals did not have any challenge dose of PCP during their testing stage. The result showed that there was significant deficit in object and spatial recognition memory in both male and female animals at both time points, thereby establishing enduring deficits. Conclusion: Given the heterogeneity of the schizophrenic disorder and its complex aetiology, it is understandably difficult to find animal models that completely mimic most or all of the symptoms associated with the disorder. However, data from the studies in this thesis support the use of neonatal PCP as a valid animal model of cognitive and negative symptoms, and explores the effect of antipsychotics in understanding the model. Also, in light of the efficacy of neonatal PCP to produce robust object, spatial memory and social interaction deficits in rats, it appears that this model may be a useful tool to investigate the potential of novel therapeutic candidates that may help improve therapy and understand the illness.

The hippocampal formation has been implicated in spatial formation for many decades. The hippocampus proper has received the most attention but other regions of the hippocampal formation contribute largely to spatial cognition. This thesis concentrated on one such region, the postsubiculum. The postsubiculum is considered important because it contains head direction cells and because it thought to be a major input to the hippocampus, via the entorhinal cortex. This thesis aims to test the functional role of the rat postsubiculum under two types of situation: one where the rat must rely on idiothetic cues for navigation, and another where the rat has visual cues present and can rely on these for orientation. The thesis also investigates hippocampal place cells and their stability over time after short exposures to novel environments. Chapter 3 of this thesis aimed to test whether the postsubiculum is necessary for path integration during a homing task. Rats were trained on a homing task on a circular platform maze. Once the task was acquired, rats were given lesions of the postsubiculum or sham lesions and then re-tested on the path integration task. The homing performance of rats with lesions of the postsubiculum was as good as that of the sham rats. A series of manipulations suggests that the rats were homing by path integration, confirmed by probe tests. The rats were then tested on a forced-choice delayed alternation T-maze task that revealed a significant impairment in alternation with delays of 5, 30, and 60 seconds. This suggests that the postsubiculum is not necessary for path integration in a homing task but is necessary for avoiding previously visited locations as is necessary in an alternation task. The experiments in Chapters 4 and 5 of this thesis aimed to investigate the effects of postsubiculum pharmacological inactivation on hippocampal CA1 place cells when rats were introduced to a novel environment with visual cues. A necessary first step was to assess place cells without any manipulation of the postsubiculum (Chapter 4) and then use information gained from this in the design of experiments in Chapter 5. Rats chronically implanted with recording electrodes in the CA1 region of the hippocampus were exposed to novel cue-rich environments whilst place fields were recorded. Following delays of 3, 6, or 24 hours, the same cells were recorded again in the same environment but with the cues rotated by 90°. Pixel-by-pixel correlations of the place fields show that stability of the place fields was significantly lower at 24 hours than at 3 hours. Stability after 6 hours was not significantly different from 3 hours. In the third set of experiments, rats were implanted with drug infusion cannulae in the postsubiculum and recording electrodes in CA1. Following infusions of either the AMPA receptor antagonist CXQX, the NMDA receptor antagonist D-AP5 or a control infusion of ACSF, place field stability was assessed as rats were exposed to a cylindrical environment with a single polarising cue card for 3 x 10 minute sessions and then again 6 hours later. There were no differences in place field correlations between the 3 drug conditions, although there was evidence of larger changes in spatial information content between cells in the CNQX and AP5 drug condition, but not the ACSF condition. The results suggest that, under the present testing conditions, place fields stability did not depend upon AMPA receptor-mediated transmission nor did it depend on NMDA receptor-mediated synaptic plasticity.