The traditional view of systems memory consolidation is that it is a gradual process that takes place over days or weeks. Within this approach, the hippocampus (HPC) is thought to be involved in the rapid encoding of specific events, whilst neocortex is thought to be involved in slow learning. An idea posited recently is that systems consolidation can occur rapidly if an appropriate “schema” into which the new information can be incorporated has been previously created. Using a hippocampaldependent paradigm, rats were trained to learn a schema involving 6 flavour-place paired-associates (PAs). Once the schema was acquired, relevant new information then became assimilated into extra-hippocampal regions and rapidly became hippocampal-independent. Building upon this foundation and the PAs schema paradigm, this thesis has explored several aspects of the neurobiology of schemas in animals. The first part of the thesis examined the importance of a relevant schema in new information processing. Rats were trained in both a consistent and inconsistent schema. In the consistent schema, rats could learn new PAs in a single trial; however, in the inconsistent schema, rats failed to learn the new PAs as they had not established an appropriate schema that could facilitate rapid learning. The second part of the thesis investigated the role of hippocampal NMDA receptors and dopamine receptors during encoding of new PAs. Bilateral hippocampal infusion of either the NMDA receptor antagonist D-AP5 or the D1/D5 dopamine receptor antagonist SCH23390 before encoding of new PAs resulted in impaired memory tested at 24 hr. This result suggests that the encoding of new PAs is dependent upon NMDA receptors in the HPC and also that dopamine is involved in the modulation of encoding new PAs. The final chapters of the thesis attempted to identify the extrahippocampal regions in which these new PAs are integrated with the schema during encoding. To identify the regions that may be involved, immediate early genes (Zif268 and Arc) were used. In a group of cortical structures, including the prelimbic cortex, there was significantly higher Zif268 and Arc expression when encoding 2 new PAs compared to the reactivation of previously learned (original) PAs or the encoding of 6 new PAs. These findings indicate that the prelimbic cortex may be critical for rapid assimilation of new information into a pre-existing schema. Finally, the last experiment in the thesis investigated this finding using bilateral microinfusions of either the AMPA receptor antagonist CNQX or the NMDA receptor antagonist D-AP5 into the prelimbic cortex. Infusions of CNQX and D-AP5 resulted in poor learning of the new PAs in the schema task. This indicates that parallel encoding of new PAs occurred in the prelimbic cortex and the HPC. The experimental results presented in this thesis suggest that the prelimbic cortex, in particular, plays a crucial role along with the HPC during encoding of new information in rapid memory formation.

Three groups of goldfish were prepared; naive, avoidance-conditioned and pseudo-conditioned animals. Five pseudo-conditioned fish were avoidance trained later and found to have no measurable acquisition of the avoidance conditioning paradigm. Several protein fractions were found to have significantly different rates of synthesis when compared across groups. The possible involvement of these proteins in the memory storage process was discussed.

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The aim of this PhD thesis was to explore the way in which recognition memory changes over time. Of particular interest was how forgetting and systems level consolidation processes alter the qualitative nature of recognition judgments and the impact this has on event related potentials (ERPs) recorded during recognition. An emerging body of fMRI and animal work has started to suggest that changes to the neural basis of memory can be observed after intervals in the order of days and weeks. Although much research has examined the ERP correlates of recent recognition, there has been little attempt to compare this to remote recognition. This gap in the literature is investigated in the present PhD thesis over five ERP and two behavioural experiments. The first set of experiments investigated recognition success i.e. the subjective awareness that a stimulus has been encountered before. Previous work has associated familiarity-based recognition with an early midfrontal ERP effect whereas recollection-based recognition has been linked to a later onsetting parietal ERP effect. These effects were compared for recently studied stimuli and stimuli studied 1 week earlier. Results revealed an attenuation of the late parietal effect. This quantitative difference suggests that the neural networks underlying the ERPs for recent and remote recollection remain the same after a 1 week delay but may be less active after a period of forgetting. Behavioural work linked this to a drop in strength and episodic detail for remote recollection. Examining the midfrontal effect over time produced a more complex pattern of results. The effect was not reliable in Experiment 1 for remote familiarity judgments. In follow up experiments, however, midfrontal effects were reliable for week old memories but were not modulated by either delay or memory strength manipulations. These findings do not permit strong conclusions regarding the way familiarity memory and midfrontal ERPs vary over time, other than to say that the midfrontal effect is not a short lived correlate of recognition memory. A second set of experiments investigated how the length of the delay between study and test impacts on retrieval orientation and retrieval effort. Retrieval orientation refers to the way in which participants strategically alter how a memory cue is processed based on current task demands. Results showed ERP differences when remote memories were cued compared to when recent memories were cued. However, these differences were eliminated when recent and remote memory was matched for performance. This finding indicated that effort required at retrieval rather than memory age per se influenced differential cue processing. A follow up experiment supported this claim but found that participants may utilise delay information during recognition in a very general sense. In this experiment, ERPs indicated different cue processing when participants knew the age of the memories they were trying to retrieve compared to when they did not. Taken together, the results suggest that memory age does not influence the ERP correlates of recognition in a direct manner. More important are the indirect changes occurring over time, such as reduced memory strength, reduced episodic detail, slower reaction times and increased effort at retrieval. These variables, and possibly a range of others, should be controlled as far as possible in studies aiming to explore neural changes driven by systems consolidation. Prospective studies, where the learning phase can be controlled makes this aim feasible, as some of the experiments in this thesis have shown. Future work might benefit from focusing more on variations at encoding, rather than large differences in the length of the retention interval, as has been the traditional approach to this issue.

Despite a central role for morphological knowledge in supporting linguistic generalisation, the neural representations supporting its learning remain largely unexplored. This thesis addressed this gap by exploring the role of memory consolidation in morphological learning and generalisation. In three experiments, adult participants learned an artificial language in which stems (e.g. gleet, shiln) combined with plural affixes (e.g. –aff, -opp; gleetaff, shilnopp) to refer to the occupation of multiple male and female characters. Mimicking properties of morphological systems in natural languages, the plurals varied in their phonological consistency/ambiguity and type/token frequency. Two sets of plurals, distinguished by gender, were trained on two successive days. Experiment 1 revealed that generalisation to novel phonologically ambiguous forms measured on the second day showed a greater influence of token frequency for plurals trained on the previous day, suggesting overnight changes in their underlying representations. Experiment 2 examined this effect further by using fMRI to compare the neural representations underlying plurals learned on the day of scanning or on the previous day. Representational Similarity Analysis revealed increased similarity structure among high type frequency plurals and reduced similarity structure among high token frequency plurals following overnight consolidation in the left superior temporal gyrus (STG). These results are consistent with a Complementary Learning Systems (CLS) model in which overnight consolidation supports the development of overlapping representations among several items sharing the same feature (here, an affix; type frequency) and strengthens item-specific representations for frequently occurring items (token frequency). Additionally, connectivity analyses showed that the functional coupling between the left STG and the left dorsolateral prefrontal cortex was weaker for high type frequency plurals and stronger for high token frequency plurals following overnight consolidation. These results suggest that the engagement of prefrontal control processes in retrieving the newly-learned plurals is subject to overnight consolidation and sensitive to the similarity structure underlying the plurals to be retrieved. However, the overnight changes in similarity structure and functional networks observed in Experiment 2 were not mirrored by changes in generalisation to novel forms as were observed in Experiment 1. Experiment 3 aimed to address the discrepancy in consolidation-related changes in generalisation behaviour between the first two experiments. Type/token frequencies were manipulated to bias learning, consolidation, and generalisation towards high token frequency plurals. Despite this manipulation, no consolidation-related changes in generalisation were observed. Findings from all three experiments are interpreted in the context of the CLS model and a role for overnight consolidation in morphological learning and generalisation is discussed.

Psychedelics are currently being researched due to their long-lasting antidepressant, anxiolytic and neuroplasticity inducing actions. The mechanism by which they induce these effects remains poorly understood. Here, we decided to investigate a relatively unexplored possibility. A potential interaction of psilocybin administration and sleep and their combined effects on memory consolidation. Memory formation in animals and humans is greatly influenced by sleep manipulation which led us to assess the possibility with spatial memory tasks. We hypothesized that acute psilocybin administration after learning may have a beneficial influence on memory consolidation in rats. To determine whether an interaction with sleep exists we also subjected the rats to combinations of psilocybin and control vehicle with normal sleep and sleep deprivation. Our data did not suggest such an interaction exists. Secondly, we tried to find out if psilocybin and sleep manipulation leads to changes in neuroplasticity-related events. A process that could very likely be the basis of such a proposed beneficial effect. For this purpose, we analysed the expression of the immediate-early gene Arc and the immature neuron marker doublecortin in the rat hippocampus. Doublecortin's expression was not influenced by any of the factors....

<strong>Background:</strong> Our ability to consolidate what we learn changes with age. However, little is known about the neurophysiological underpinnings of consolidation of motor learning in ageing. This is largely because studies have repeatedly demonstrated a deficit in sleep-dependent consolidation of motor learning in older adults. This thesis aims to reassess commonly held assumptions about consolidation in ageing, as well as to examine the neurophysiological and neurochemical mechanisms that support the learning and consolidation processes. <strong>Methods:</strong> Most of the studies in this thesis are based on the design of a novel whole-hand task for use in older adults, which reduces dependency on fine motor skill. This thesis adopts a number of converging measures to examine learning and memory including electroencephalograhy (EEG), magnetic resonance spectroscopy (MRS), actigraphy recordings, as well as behavioural and self-reported measures of sleep. <strong>Results:</strong> Findings show significant improvements in learning with the adapted motor task in older adults. Importantly, this task reveals significant sleep- dependent enhancements in older adults, which are comparable to those seen in younger controls. Functional changes in sleep architecture with ageing show overall decline in slow wave sleep. Sleep-dependent improvements were specifically associated with activity in stage 3 slow wave sleep and increased hemispheric differences regardless of age. Changes in GABA concentrations with learning on a visuomotor tracking task showed marked variability across participants, and no clear associations were found between GABA and consolidation. <strong>Conclusion:</strong> The evidence presented in this thesis highlight the complex dynamics underlying sleep consolidation, and challenges a commonly held assumption about consolidation in older adults. Specifically, the studies presented here show that observed declines in motor consolidation with ageing may be contaminated by age-related deficits fine motor skill. By removing such kinematic constraints, it was possible to detect marked improvements in motor performance also in older adults despite age-related changes in sleep architecture.

Recent research demonstrates that new verbal memories are retained better if learning is followed by a brief period of wakeful rest. This effect is hypothesised to be the result of wakeful rest providing a state that is conducive for early-stage cellular consolidation (i.e. strengthening of specific memory traces) by protecting this process from interfering sensory input and associated encoding. The aims of this PhD project were to (i) examine whether the benefit of wakeful rest extends to the retention of complex spatial memories, and (ii) explore the effects of different cognitive states on memory consolidation. In order to address the first aim, three virtual reality spatial memory experiments were conducted. In young and older adults, wakeful rest not only enhanced the retention of complex spatial memories, but it also promoted the systems-level integration of spatial memories into accurate cognitive maps, a function, hitherto, assumed to be specific to sleep (Chapters 2-4). Pilot work also tentatively suggested that wakeful rest enhances the retention of complex spatial memories (i.e. a recently travelled route) in patients with amnestic Mild Cognitive Impairment (Chapter 4). In order to address the second aim, five experiments were run in young adults. The first experiment directly compared the effects of wakeful rest and sleep, two states that are positively associated with consolidation. Wakeful rest enhanced the retention of a list of known words, whereas a similar-length period of sleep enhanced the acquisition of novel linguistic constraints (Chapter 5). The final four experiments revealed that, similar to continuous external sensory input, internally generated autobiographical thinking activities (recalling the past and imagining the future) interfere with consolidation (Chapter 6). Together, the findings reported in this thesis reveal that wakeful rest promotes the strengthening (cellular consolidation) and wider integration (systems consolidation) of basic and complex declarative memories, and that this effect is contingent on a reduction in external sensory input as well as rich autobiographical thought.

The cockroach, with its large brain and physiological resilience, holds many advantages for the development of behavioral paradigms. The work presented here provides a foundation for, and describes the results of, the implementation of studies of neural correlates of learning and memory on restrained animals.Using the antennal projection response (APR) as an indicator of learning and retention, several learning paradigms have been developed. A visual-olfactory associative and a gustatory-olfactory aversive conditioning paradigm demonstrated a plastic behavior that could be driven in an intact and immobilized cockroach. Conditioning the APR to a visual cue paired with an olfactory cue characterized the role of unilateral and bilateral olfactory input in learning and memory. While unilateral olfactory input is sufficient to learn a visual-olfactory association, bilateral olfactory input is necessary for long-term retention of the association. This comparison identified a critical time period in which memory is consolidated. This time period was subsequently used to analyze gene expression during memory consolidation.The split-brain cockroach preparation was developed to investigate what parts of the brain are necessary and sufficient for learning and retention of a visual-olfactory association; this preparation was also used to examine learning-induced changes in test tissue versus control tissue provided by the same animal. Evidence suggests that half of a brain is sufficient for a visual-olfactory association to be established and sufficient for retention of that association between 12 and 24 hours. However, the entire brain is necessary for long-term memory to be established. Using the split-brain cockroach simultaneously as the control and the test subject, learning-induced alterations in the microglomerular synaptic complexes of the calyces were identified in the trained half, but not in the naïve half.Using the APR, spatial learning and memory was examined. Multiple representations of space were revealed in the brain of the cockroach. Cockroaches represent space in terms of an olfactory gradient map, as well as the visuospatial relationship between objects. When both representations of space can be utilized by the cockroach to localize a cue, the positional visual cue is the one that determines the behavioral response.

The hippocampus supports the initial formation and recall of episodic memories, as well as the consolidation of short-term into long-term memories. The ability of hippocampal neurons to rapidly change their connection strengths during learning and maintain these changes over long time-scales may provide a mechanism supporting memory. However, little evidence currently exists concerning the long-term stability of information contained in hippocampal neuronal activity, likely due to limitations in recording extracellular activity in vivo from the same neurons across days. In this thesis I employ calcium imaging in freely moving mice to longitudinally track the activity of large ensembles of hippocampal neurons. Using this technology, I explore the proposal that long-term stability of hippocampal information provides a substrate for episodic memory in three different ways. First, I tested the hypothesis that hippocampal activity should remain stable across days in the absence of learning. I found that place cells – hippocampal neurons containing information about a mouse’s position – maintain a coherent map relative to each other across long time-scales but exhibit instability in how they anchor to the external world. Furthermore, I found that coherent maps were frequently used to represent a different environment and incorporated learning via changes in a subset of neurons. Next, I examined how learning a spatial alternation task impacts neuron stability. I found that splitter neurons whose activity patterns reflected an animal’s future or past trajectory emerged relatively slowly when compared to place cells. However, splitter neurons remained more consistently active and relayed more consistent spatial information across days than did place cells, suggesting that the utility of information provided by a neuron influences its long term stability. Last, I investigated how protein synthesis, known to be necessary for long-term maintenance of changes in hippocampal neuron connection strengths and for proper memory consolidation, influences their activity patterns across days. I found that along with blocking memory consolidation, inhibiting protein synthesis induced a profound, long-lasting decrease in neuronal activity up to two days later. These results combined demonstrate the importance of rapid, lasting changes in the hippocampal neuronal code to supporting long-term memory.