This series of experiments used the multiple learning and memory systems hypothesis of the mammalian nervous system to investigate the possibility that the amygdala, dorsal striatum, and hippocampal systems might, in certain situations, interact to produce behavior in the normal animal. Using variations of the conditioned-cue preference (CCP) task, evidence is presented showing that context-specific information acquired by the hippocampus interferes with acquisition of amygdala-based stimulus-reward learning. It was also demonstrated that there are amygdala-, dorsal striatum-, and hippocampus-based forms of place learning and that cue ambiguity and movement are important factors determining which of these learning and memory systems gain behavioral control in place learning situations. These findings provide evidence for interactions among learning and memory systems and implicate the amygdala and dorsal striatum in some types of non-hippocampal based place learning using distal cues.

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A word-generation experiment explored the relative contributions of the left temporal neocortex and the left hippocampal region to verbal recall. Patients with large hippocampal excisions (LTH) were impaired in immediate recall of synonyms, whereas those with small hippocampal excisions (LTh) were not. Both groups were impaired in immediate recall of rhymes, and in delayed recall of both synonyms and rhymes. A nonverbal associative-learning task, where the stimulus-items came from a visual continuum, also resulted in a deficit for the LTH (but not the LTh) group. Patients with right temporal lobectomy performed both tasks normally. On an absolute-judgement task involving the accurate numbering of a set of six individually-presented rectangles, only the groups of patients with large hippocampal excisions were impaired, regardless of side of lesion. These findings support the view that the temporal neocortex is important for gaining access to information in semantic memory, whereas the hippocampal region is essential for the temporary storage of new information beyond the span of immediate memory.

Alzheimer�s disease (AD) is a neurodegenerative disorder, charaeterised by progressive loss of memory. It is important to understand what factors initiate the onset of AD so that effective therapeutic treatments can be developed to target the precise mechanisms that initiate this disease. Currently, synaptic dysfunction is widely believed to be the first significant alteration preceding the onset of AD, and is thought to be initiated by an intracellular accumulation of amyloid-β (Aβ), or a free radical-induced increase of oxidative stress. As Aβ levels rise during the onset of AD, a concomitant reduction of secreted amyloid precursor protein-α (sAPPα) is observed, as the two proteins exist in equilibrium. Intriguingly, the neuroprotective and neurotrophic properties of sAPPα indicate that it is intimately involved in the physiological pathways of the major hypotheses for the cause of AD, and may also be involved in the mechanisms that underlie learning and memory. Therefore, it is possible that during the onset of AD, the decrease of sAPPα may contribute to synaptic dysfunction by disrupting the mechanisms of synaptic plasticity. Long-term potentiation (LTP) is the leading experimental model for investigating the neural substrate of memory formation, and describes the molecular mechanisms that underlie an increase in the strength of synaptic transmission. The role sAPPα may play in the induction and maintenance of LTP has not previously been addressed in vivo. Therefore, the aim of this thesis was to investigate whether sAPPα affects the induction of LTP in the hippocampus of the anaesthetised rat. The present findings are the first to suggest that sAPPα may modulate the induction of LTP in vivo. Decreasing the function of endogenous sAPPα (with sAPPα-binding antibodies and a pharmacological inhibition of α-secretase) significantly reduced the magnitude of LTP induced in the dentate gyrus. Therefore, the reduction of sAPPα during AD is likely to have a detrimental impact on the mechanisms of synaptic plasticity, and by extension, learning and memory. The present investigation has also found that the application of recombinant, purified sAPPα to the rat hippocampus has an �inverted U-shaped� dose-response effect on the magnitude of LTP. Low concentrations of sAPPα significantly enhanced LTP, supporting previous findings that exogenous sAPPα can facilitate in vitro LTP and enhance memory performance in animals. On the other hand, comparatively high concentrations of sAPPα significantly decreased the magnitude of LTP. This observation is also consistent with previous findings, in which high concentrations of sAPPα have been shown to be less synaptogenic and memory enhancing than lower doses. These results are the first to suggest that sAPPα modulates in vivo synaptic plasticity, and have important implications for the development of strategies to treat AD.

Long-term potentiation (LTP) is an activity-dependent increase in the efficacy of synaptic transmission. In concert with long-term depression (LTD), this synaptic plasticity likely underlies some types of learning and memory. It has been suggested that for LTP/LTD to act as effective memory storage mechanisms, homeostatic regulation is required. This need for plasticity regulation is incorporated into the Bienenstock, Cooper and Munro (BCM) theory by a threshold determining LTD/LTP induction, which is altered by the previous history of activity (Bienenstock et al., 1982). The present work aimed to test key predictions of the BCM model. This was done using field and intracellular recordings in area CA1 of hippocampal slices from young, adult male Sprague-Dawley rats. The first prediction tested was that following a strong, high-frequency priming stimulation all synapses on primed cells will show inhibition of subsequent LTP and facilitation of LTD induction (heterosynaptic metaplasticity). This was confirmed using two independent Schaffer collateral pathways to the same CA1 pyramidal cells. Following priming stimulation to one pathway, LTP induction was heterosynaptically inhibited and LTD facilitated. To more fully investigate whether all synapses show metaplastic changes, the priming stimulation was given in a different dendritic compartment, in stratum oriens, prior to LTP induction in stratum radiatum. This experiment supported the conclusion that all synapses show inhibited LTP following priming. A second prediction of the BCM model is that metaplasticity induction is determined by the history of cell firing. To investigate this, cells were hyperpolarized during priming to completely prevent somatic action potentials. Under these conditions inhibitory priming of LTP was still observed, and thus somatic action potentials are not critical for the induction of the effect. The next aim was to determine the mechanism underlying heterosynaptic metaplasticity. One way in which plasticity induction can be altered is through changes in gamma-aminobutyric acid (GABA)-mediated inhibition of pyramidal cells. For this reason, it was tested whether blocking all GABAergic inhibition, for the duration of the experiment, would prevent priming of LTP. However, priming inhibited subsequent LTP and it was concluded that GABAergic changes do not underlie either the induction, or expression, of the metaplastic state. Proposed revisions to the BCM model predict that postsynaptic elevations in intracellular Ca�⁺ determine the induction of metaplasticity. There are many potential sources for postsynaptic Ca�⁺ elevations, including entry through N-methyl-D-asparate receptors (NMDARs) or voltage-dependent calcium channels (VDCCs), or release from intracellular stores. Results of the present work demonstrate that the inhibition of LTP is dependent on the release of Ca�⁺ from intracellular stores during priming; however this release is not triggered by Ca�⁺ entry through NMDARs or VDCCs, or via activation of metabotropic glutamate receptors. Overall, the present results show that, in accordance with the BCM model, a high level of prior activity induces a cell-wide metaplastic state, such that LTD is facilitated and LTP is inhibited. In contrast to predictions of the BCM model, this is not mediated by cell-firing during priming. Instead the release of Ca�⁺ from intracellular stores is critical for induction of the metaplastic state.

Bibliography: 197-226 p. / xiv, 226 p. : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the alterations in electrophysiological function during hypoxia in the rat hippocampal slice, in particular those alterations induced by extracellular accumulation of adenosine. / Thesis (Ph.D.)--University of Adelaide, Faculty of Science, 1996

Dissertation (PhD)--University of Stellenbosch, 2006. / Bibliography. Also available via the Internet.

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 91-106).

Thesis (M. Sc.)--Carleton University, 2002. / Includes bibliographical references (p. 159-161). Also available in electronic format on the Internet.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (p. 175-193).