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Transmissible spongiform encephalopathies (TSEs) or prion diseases are defined by infectivity and by the pathological damage they produce in the central nervous system (CNS), typically involving spongiform degeneration or vacuolation, deposition of abnormal PrP (PrPSc), glial activation and neuronal loss. Much of our understanding of the TSEs has derived from the study of murine scrapie models. The molecular basis of pathological changes is not clear, in particular the relationship between the deposition of PrPSc and neuronal dysfunction. A typical feature of TSE disease is neuronal loss, although the mechanisms leading to this loss are poorly understood. Apoptosis has been proposed as an important mechanism of TSE associated cell death, but which pathways are involved are still to be determined. The main aims of this thesis are to investigate the progression of the characteristic neuropathological changes observed in the TSE infected brain and to analyse the mechanisms involved in neuronal loss. In this study two contrasting scrapie mouse models were used : the ME7/CV model , and the 87V/VM model in which neuronal loss is targeted to different areas of the hippocampus, the CA1, and CA2 respectively. The role of the caspase-dependent pathway of apoptosis in the neuronal loss was investigated. The results of analysis of pro-apoptotic markers of disease in the two scrapie mouse models differed. The results observed in the ME7/CV scrapie mouse model suggest that apoptosis may not be the main mechanism of neuronal loss, whereas the 87V/VM model showed some indication that apoptosis may be involved. Detailed studies in the progression of neurodegenerative changes in the ME7/CV scrapie mouse model revealed that the initial pathological change observed in the hippocampus was the deposition of PrPSc followed by a glial response, spongiform change and subsequent neuronal degeneration. The role of the cytoskeleton and synaptic dysfunction in the neuronal damage observed in the CA1 of the ME7 infected hippocampus was analysed. Cytoskeletal disruption was observed in the post-synaptic dendritic spine, and the apical dendrites of CA1 neurons at 160days, a time point at which neurons are known to be lost. Changes in the expression of the pre-synaptic protein, synaptophysin and the post-synaptic protein PSD-95 were not observed until the terminal stage of disease when the neuronal loss is profound. In conclusion, this research suggests that the mechanisms of neuronal loss may follow different biochemical pathways, which might not necessarily involve an apoptotic mechanism. Cytoskeletal disruption in the post-synaptic dendritic spine plays a major role in the neuronal dysfunction observed in ME7 infected CA1 neurons, although the post synaptic density does not seem to be involved .Pre-synaptic changes and disruption to the innervation of CA1 neurons is not apparent until the end stages of disease. The trigger for this cytoskeletal disruption and the subsequent neuronal loss may be the early deposition of PrPSc in the extracellular space but the precise mechanisms involved are still to be elucidated. The identification of the key events involved in the mechanisms of neruodegeneration in TSE diseases may lead to the development of therapeutic strategies to inhibit the neurodegenerative process.

Hippocampal lesions impair memory for context in some tasks but not others. Factors that may contribute include: a) whether context is encoded in configurally or elementally; b) whether lesions are performed before or after acquisition of contextual information. c) the size of the lesion. This study compared the effects of pre- vs post-acquisition hippocampal lesions on performance of a novel context-dependent odour discrimination task that required explicit processing of the contextual features. As the task required a configuration to be formed between context, odour and reward, it was hypothesised that the hippocampus would be essential for the acquisition and performance of this task. Pre-surgery training consisted of simultaneous presentations of a context-dependent and a context-independent odour discrimination task. In the context dependent task, odour A but not odour B was rewarded in context 1, whereas odour B but not odour A was rewarded in context 2. In the context independent task, odour C was rewarded in both contexts, whereas odour D was rewarded in neither. Rats took around 60 days to reach criterion level (2 days >80% correct on both tasks). Subsequently, they received either bilateral ibotenic acid lesions of the hippocampus or sham surgery. After a 14 day recovery period, post-surgery testing began. On the first 2 days of post-operative testing, lesioned animals were significantly impaired on the CD task, but not on the CI task. Thereafter they performed as well as controls. Thus, the data demonstrate that although the hippocampus normally contributes to the retention of contextual information, it is not necessary for the performance of this context dependent odour discrimination task. Other areas can take over these functional demands in its absence. However, the involvement of the hippocampus cannot be completely disregarded due to the high degree of correlation between spared hippocampal tissue and the immediate post-surgery performance level of the animals (i.e. larger the volume of tissue spared the higher the initial degree of accuracy on the CD task). These findings were shown to be highly replicable, regardless of whether the odorous stimuli were presented simultaneously or successively. Furthermore, the hippocampal and extra-hippocampal methods of task resolution were not identical. When a cue conflict situation arose between intra-maze and selfmotion cues, it affected the two groups in a differentially. The ambiguity between cues had a highly detrimental affect on the performance of the intact animals; yet the hippocampal lesioned animals appeared oblivious to the inconsistency. They continued to perform the context dependent odour discrimination task as normal. Thus although apparently able to process the major contextual cues, the hippocampal lesioned animals had a deficit in detecting and responding to more subtle distinctions that were not integral to normal success on the task. In the final aspect of this thesis, hippocampal lesioned animals were found to demonstrate no deficits in the acquisition of new variants of the context dependent odour discrimination task (new odours / contexts), thus the hippocampus is not essential for learning contextual discriminations. Overall, the hypothesis that the hippocampus would be necessary for contextual representations, is unsupported by this thesis. Nevertheless, if present during training, the hippocampus will contribute to the retention of contextual stimuli and provides a more all encompassing view of ‘context’ than other areas can achieve alone.

APOE ε4 is the major genetic risk factor for Alzheimer’s disease, a dementia characterized by memory impairment and hippocampal atrophy. While associated with episodic impairment and reduced hippocampal volume in healthy aging, APOE ε4 has been related to increased episodic memory performance in young adults. The effect of APOE ε4 on hippocampal volume in young age is uncertain, with studies showing comparable or smaller volumes in ε4 carriers. This thesis aims to further explore the effects of APOE ε4 on episodic memory and hippocampal volume in young adults. In addition to episodic memory, spatial memory will also be assessed, as both these memory types are hippocampus-dependent. Furthermore, potential modulating effects of sex are assessed, as sex differences has been found in relation to APOE-related pathology, episodic and spatial memory and hippocampal volume. Study I examined the effects of APOE ε4 on episodic and spatial memory and hippocampal volume in young adults. Hippocampal volume was assessed by manual tracing of the hippocampal head, body and tail. Study II considered whole-brain structural covariance patterns of the anterior and posterior hippocampus. Furthermore, the association between these patterns and episodic and spatial memory performance was assessed. Study III investigated the effects of APOE ε4 on episodic and spatial memory and hippocampal volume in three different age groups. This was done in order to further explore the different effects of APOE ε4 on cognition and hippocampal volume seen in young and older age. In summary, APOE ε4 was positively associated with spatial function and episodic memory in young adults. Although there were no effects of APOE ε4 on hippocampal volume, structural covariance patterns of the anterior and posterior hippocampus differed as a function of APOE ε4 and sex. Thus, structural covariance may provide an early measure of APOE ε4-related effects on brain structure. Moreover, sex was found to modulate the effects of APOE ε4 to the disadvantage of women. This was seen in both age-related hippocampal volume effects and in structural covariance patterns in young adults, as well as in spatial memory performance across age groups.

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O enriquecimento ambiental pode ser considerado uma condição que proporciona aumento da estimulação sensorial, cognitiva e motora, que levaria, a curto e longo prazos, a mudanças comportamentais importantes. O objetivo deste trabalho foi avaliar os efeitos da exposição ao enriquecimento ambiental (1) na ansiedade e memória aversiva, ambos no labirinto em cruz elevado, (2) na memória operacional espacial no labirinto aquático de Morris, e (3) na neurogênese hipocampal, em ratos. Os animais foram expostos ao enriquecimento ambiental a partir do desmame (22 dias), onde permaneceram até o último dia de teste (17º mês). Nesse período, foram submetidos ao Labirinto em Cruz Elevado (LCE) no 3º e 15º mês, e ao Labirinto Aquático de Morris (LAM) no 9º e 16º mês. Uma semana antes da exposição ao labirinto aquático, receberam uma injeção intraperitonal de bromodeoxyuridina (BrdU). Vinte e quatro horas e trinta dias após essa injeção grupos independentes de animais foram sacrificados e seus encéfalos processados imunohistoquímicamente para revelar o BrdU. O enriquecimento ambiental produziu um efeito ansiolítico em animais jovens, mas não nos idosos. A memória aversiva de animais jovens e idosos não se alterou. No labirinto aquático, enquanto os animais expostos ao ambiente enriquecido por 9 meses apresentaram uma estratégia mais eficiente de busca em relação aos respectivos controles, os animais expostos ao ambiente enriquecido por 15 meses apresentaram mais flexibilidade para se adaptar as novas situações; no entanto, o enriquecimento ambiental parece não alterar diretamente o desempenho na memória operacional espacial. Em relação a neurogênese hipocampal, o enriquecimento foi capaz de aumentar cerca de 2 vezes o número de novas células; no entanto, a exposição ao labirinto aquático foi capaz de aumentar a taxa de sobrevivência de novos neurônios / Environmental enrichment in laboratory animals is a housing condition that provides enhanced sensorial, motor and social stimulation as compared to maintenance in standard laboratory cages. It has been claimed that this kind of stimulation improves cognition. The aim of this study was to investigate the effects of exposure to environmental enrichment on anxiety and aversive memory in the elevated plus maze, spatial working memory in the Morris\' water maze, and hippocampal neurogenesis. The animals were subjected to environmental enrichment from weaning (22 days) up to the last test (17 months). During this period, they were tested in the 3rd and 15th months of life in the elevated plus maze, and in the 9th and 16th months of life in the Morris\' water maze. A week before exposure to the water maze, the animals received an intraperitoneal injection of BrdU. Twenty-four hours and 30 days after the injection independent groups of animals were sacrificed for performing immunohistochemistry. Exposure to the enriched environment rendered young animals, but not elderly, less anxious. In addition, the aversive memory of both groups remained unchanged along aging. In the Morris\' water maze, animals exposed to the enriched environment showed a more effective searching strategy to find the hidden platform on the first trial than the controls, when tested at 9 months. In addition, the flexibility to deal with novel situations at 15 months was greater for animals exposed to the enriched environment. Even though, exposure to the enriched environment did not alter performance of spatial working memory. Environmental enrichment doubled hippocampal neurogenesis, and the survival of the new neurons was greater when the subjects were exposed to the Morris\' water maze task

Kwan Hon Pong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 115-156). / Abstracts in English and Chinese. / Abstract --- p.i / 摘要 --- p.iii / Abbreviations --- p.v / Acknowledgment --- p.vii / Chapter 1. --- Introduction / Chapter 1.1 --- Diabetes mellitus - general introduction --- p.1 / Chapter 1.1.1 --- Animal models of diabetes --- p.5 / Chapter 1.1.2 --- Streptozotocin-induced diabetes (SID) --- p.6 / Chapter 1.1.2.1 --- Mechanism of the diabetogenic effect of STZ --- p.7 / Chapter 1.1.2.2 --- Administration of STZ --- p.9 / Chapter 1.2 --- Impairment of cognitive function in diabetes mellitus --- p.9 / Chapter 1.3 --- Common mechanisms suggested in diabetic neuropathy --- p.15 / Chapter 1.3.1 --- Polyol pathway activation --- p.15 / Chapter 1.3.2 --- Redox potential alterations --- p.16 / Chapter 1.3.3 --- Nonenzymatic glycation --- p.17 / Chapter 1.3.4 --- PKC alteration --- p.18 / Chapter 1.4 --- Do the common mechanisms of neuropathy induced the cognitive impairment in diabetes --- p.18 / Chapter 1.5 --- Structure and function of the hippocampus --- p.20 / Chapter 1.6 --- The definition and mechanism of learning and memory --- p.21 / Chapter 1.7 --- The mechanisms underlying the early and late phases of LTP in hippocampus --- p.23 / Chapter 1.7.1 --- Perforant and schaffer collaterals pathways --- p.23 / Chapter 1.7.2 --- Mossy fibre pathway --- p.24 / Chapter 1.7.3 --- Late phase of LTP in hippocampus --- p.25 / Chapter 1.8 --- GABAergic interaction in hippocampal plasticity --- p.25 / Chapter 1.9 --- The objective of the project --- p.27 / Chapter 1.10 --- Hypothesis --- p.27 / Chapter 1.10.1 --- The initial role of glutamate receptors --- p.28 / Chapter 1.10.2 --- Involvement of putative retrograde messengers --- p.30 / Chapter 1.10.3 --- The role of GABA receptors --- p.37 / Chapter 1.10.4 --- The role of the CREB --- p.40 / Chapter 2. --- Materials and methods / Chapter 2.1 --- Animals --- p.43 / Chapter 2.1.1 --- Induction of diabetes mellitus --- p.43 / Chapter 2.1.2 --- Insulin therapy --- p.45 / Chapter 2.1.3 --- Sample collection --- p.46 / Chapter 2.2 --- Isolation of total RNA --- p.47 / Chapter 2.3 --- Quantitation of total RNA --- p.51 / Chapter 2.4 --- Reverse transcription --- p.53 / Chapter 2.5 --- PCR --- p.54 / Chapter 2.5.1 --- Preparation of PCR --- p.54 / Chapter 2.5.2 --- Purification of PCR product --- p.60 / Chapter 2.5.3 --- Confirmation of PCR products by DNA sequencing --- p.61 / Chapter 2.5.4 --- PCR analysis --- p.62 / Chapter 2.5.4.1 --- Quantitation of cDNA --- p.62 / Chapter 2.5.4.2 --- Radioactive PCR --- p.65 / Chapter 2.5.4.3 --- cDNA gel electrophoresis --- p.66 / Chapter 3. --- Results / Chapter 3.1 --- Ionotropic glutamate receptor subtypes --- p.72 / Chapter 3.1.1 --- Non-NMDA receptors --- p.72 / Chapter 3.1.1.1 --- AMPA receptors --- p.72 / Chapter 3.1.1.2 --- Kainate receptors --- p.72 / Chapter 3.1.2 --- NMDA receptors --- p.76 / Chapter 3.2 --- Metabotropic glutamate receptor subtypes --- p.79 / Chapter 3.2.1 --- Group I subtype --- p.79 / Chapter 3.2.2 --- Group II subtypes --- p.79 / Chapter 3.3 --- Synthases of retrograde messengers --- p.79 / Chapter 3.4 --- Calcium-related receptors --- p.82 / Chapter 3.5 --- "GABA receptor subtypes (Aαl-4,BRla)" --- p.85 / Chapter 3.6 --- Glutamic acid decarboxylase (GAD) --- p.88 / Chapter 3.7 --- Enzyme genes related to CREB dephosphorylation --- p.88 / Chapter 3.8 --- Effect of insulin therapy on ionotropic glutamate receptor subtypes --- p.91 / Chapter 3.9 --- Effect of insulin therapy on metabotropic glutamate receptor subtypes --- p.91 / Chapter 3.10 --- Effect of insulin therapy on synthases of retrograde messenger --- p.91 / Chapter 3.11 --- Effect of insulin therapy on GAB A receptor subtype --- p.91 / Chapter 4. --- Discussion / Chapter 4.1 --- SID on Glutamate receptor subtypes --- p.96 / Chapter 4.2 --- SID on Calcium-related receptors --- p.105 / Chapter 4.3 --- SID on Synthases of retrograde messengers --- p.106 / Chapter 4.4 --- SID on GABA receptor subtypes --- p.109 / Chapter 4.5 --- SID on enzyme genes related to dephosphorylation of CREB --- p.111 / Chapter 4.6 --- Effect on insulin therapy on gene expression in hippocampus --- p.113 / Chapter 5. --- References --- p.115

Hippocampal GABAergic interneuron deficits are implicated in the pathophysiology of schizophrenia. Postmortem histological analyses show alteration in number and/or function of parvalbumin-expressing (PV+) GABAergic interneurons in the cerebral cortex of these patients. A parallel line of research using functional imaging of cerebral blood flow or volume has shown that hyperactivity of the hippocampus may contribute to psychotic symptoms as well as cognitive deficits in schizophrenia. It is not known if changes in GABA transmission, particularly in the number and function of PV+ interneurons, are causally related to hippocampal hyperactivity and expression of behavioral and cognitive abnormalities in schizophrenia. To help answer this question, we used genetic mouse models with deficits in cortical GABAergic interneuron development to test the hypothesis that a selective deficit in PV+ interneurons in the hippocampus can lead to schizophrenia relevant phenotypes such as hippocampal hyperactivity, dysregulation of the mesolimbic dopamine system, enhanced psychomotor responsiveness to amphetamine, and disruption of hippocampal dependent cognition. Here I describe my studies primarily on a mouse model with a deletion of the cell-cycle gene cyclin D2 (cD2 null). This mutation disrupts interneuron development in the medial ganglionic eminence (MGE), leading to a partial and selective deficit in PV+ interneurons in the neocortex and the hippocampus. I show that the cD2 null mouse shows regionally heterogeneous, persistent structural and functional deficit in PV+ interneurons, with a relatively larger and more functional deficit in the hippocampus. The GABAergic deficit in the hippocampus is associated with signs of disinhibition, such as increased cerebral blood volume as found by functional magnetic resonance imaging (fMRI).Upon establishing the evidence for hippocampal disinhibition in the cyclin D2 null mouse, I examined the relationship between this disinhibition and two areas of neural function know to be altered in psychosis and schizophrenia: Mesostriatal DA system function and hippocampus-mediated cognition. I found that the cD2 null mice showed increased dopamine population activity in the ventral tegmental area and enhanced psychomotor response to amphetamine. The latter was eliminated by a partial lesion of the ventral hippocampus, indicating hippocampal disinhibition as the driver of DA neuron dysregulation. In addition, cD2 null mice showed deficits in cognitive functions that recruit and depend on the hippocampus, such as the contextual and cued fear conditioning. Lastly, to test for a causal relationship between the PV+ interneuron deficit in the hippocampus, and the abnormalities in hippocampal metabolism, imaging phenotype, the mesolimbic dopamine dysfunction and contextual learning and memory, I examined the effects of replacing GABAergic interneurons to the hippocampus. I used transplantation of GABAergic interneuron precursors derived from the medial ganglionic eminence (MGE) into the adult hippocampus of cyclin D2 null mutants. MGE-derived progenitor cells developed into structurally and functionally mature PV+ and other GABAergic cells, and normalized hippocampal hypermetabolism. In addition, the MGE transplants normalized VTA dopamine cell activity, normalized amphetamine sensitivity and improved hippocampus-dependent learning and memory. Taken together, these studies establish the plausibility of a causal relationship between hippocampal PV+ interneuron pathology and psychosis-relevant pathophysiological and cognitive phenotypes. Moreover, they provide a rationale for limbic cortical GABAergic-interneuron-targeted treatment strategies in psychotic disorders.