Brain Health Research Centre
http://hdl.handle.net/10523/611
2024-03-29T00:49:55ZAdaptive motivational signals in the anterior cingulate cortex and ventral tegmental area
http://hdl.handle.net/10523/7934
Adaptive motivational signals in the anterior cingulate cortex and ventral tegmental area
2018
Elston, Thomas Ward
This thesis focused on the role of the anterior cingulate cortex’s (ACC) interactions with the dopaminergic neurons in the ventral tegmental area (VTA) during adaptive behaviour. The overall question guiding this work was: how does information gained during goal pursuit modify and motivate subsequent behaviour? This larger question was operationalized as two projects: (i) to determine whether cortical influence over the dopaminergic midbrain is a mechanism by which ACC signals are implemented as VTA motivation signals; and (ii) to determine the interplay between the ACC and VTA during the initiation and maintenance of behavioural change. In the first project, we monitored and modelled ACC and VTA local field potentials of rats running laps of varying physical difficulty for fixed rewards. The effortful condition required rats to climb over a 30-cm barrier, whereas no barrier was present under the non-effortful condition. The key finding was that ACCVTA 4-12 Hz signalling increased in trials when the lap was easier than expected. Importantly, this increase was significantly correlated with, but not confounded by, changes in motivation, as measured by running speed. The findings of this first project indicated that the ACC-VTA circuit is a plausible mechanism by which behaviour is modified. This led us to ask whether changes in the ACC-VTA circuit are related to the initiation and persistence of behavioural change.
To assess the interplay between the ACC and VTA during the initiation and persistence of behavioural change, we monitored ACC single units and LFPs as well as LFPs in VTA of rats performing a cost-benefit foraging task with changing contingencies. Through a combination of behavioural, electrophysiological, and modelling analyses, we found that the initiation of exploratory behaviour and the persistence of behavioural change were associated with ACC VTA signalling. Additionally, we characterized the content of ACC neuronal task models, and showed that ensembles of ACC neurons encode simple actions and values. This was important because, despite the longstanding assumption that the ACC encodes neuronal models of the task at hand, the content of those internal representations remained unclear. Furthermore, we demonstrated that value-coding elements of ACC neuronal task models are particularly influenced by the VTA. This is important because it suggests that mesocortical dopaminergic signalling is a means by which ACC models of the task at hand could be both initiated and modified.
The thesis concludes by presenting a novel incentive-salience, task-model onset theory of ACC function.
2018-03-20T03:03:08ZRegulation of Zn2+ and aggregation affects Aβ1-42- induced changes in cell culture viability.
http://hdl.handle.net/10523/7491
Regulation of Zn2+ and aggregation affects Aβ1-42- induced changes in cell culture viability.
2017
Potemkin, Nikita
In the story of the pathogenesis of Alzheimer’s Disease, Amyloid-Beta (Aβ) is believed to play a key role. However, evidence suggests that metal ions, in particular Zn2+, may have strong modulatory, or even causative effects on the development of the disease. This study aimed to shed more light on the relationship between Aβ and Zn2+, especially with regards to their effects on cell viability.
First, a protocol for the production of recombinant Aβ1-42 was followed to produce and purify the peptide. The next step was to establish a consistent cellular insult paradigm using Aβ1-42 in SH-SY5Y neuroblastoma cells, paying particular attention to aggregating the peptide – an important factor in Aβ toxicity. Subsequently this study aimed to investigate the effect of addition of exogenous Zn2+ on cell viability and its interaction with Aβ1-42.
The production and purification protocol was successful in yielding quantities of pure Aβ. However, this protocol may require further optimisation. It was noted that while many research groups continue to use the MTT assay to measure cell viability, the large variability of the assay and the reported biochemical interaction with the Aβ peptide make it inappropriate. As such, this study used the resazurin assay. This research was unable to establish a consistent cellular insult paradigm in either SH-SY5Y neuroblastoma cells or cultured rat hippocampal or cortical cells (p>0.05; n=3). This was despite an ageing protocol able to produce oligomers and protofibrils of Aβ, species previously shown to have toxic effects on cell cultures. In fact, protofibril-containing samples of the peptide at 20 and 40 µM increased cell viability of neuroblastoma cultures above the control (by 0.22±0.039 and 0.36±0.041 respectively; p<0.01; n=2). No effect of Aβ1-42 was observed in the primary cells (p>0.1;n=4). Finally, addition of exogenous Zn2+ in some cases complimented Aβ-induced increases in cell viability, although this effect was inconsistent.
This research highlighted some of the difficulties in examining Aβ in cell culture. In particular, it seemed important to not only identify the aggregation state of Aβ peptides, but also isolate and test specific species. This research suggests, however, that Zn2+ does modulate the effects of Aβ on cell viability and this relationship requires further investigation.
2017-08-01T23:59:07ZStructural mechanisms of bidirectional synaptic plasticity in the dentate gyrus of freely behaving rats
http://hdl.handle.net/10523/609
Structural mechanisms of bidirectional synaptic plasticity in the dentate gyrus of freely behaving rats
2010
Bowden, Jared
This research thesis is part of a collaborative study between the laboratories of Kristen M. Harris and Wickliffe C. Abraham; its purpose: to elucidate the structural mechanisms responsible for the expression of memory within the brain. Bidirectional plasticity is a term which delineates the two principal states of cellular memory, and is characterized by persistent increases (long-term potentiation, LTP) and decreases (long-term depression. LTD) in synaptic transmission.
In chapter one, we used chronically implanted electrodes to investigate parameters that may regulate bidirectional synaptic plasticity within the dentate gyrus of freely moving rats. The induction and persistence of bidirectional synaptic plasticity were compared across two different rat strains, two different phases of the circadian cycle, and three patterns of high-frequency stimulation. Results indicated that LTP was larger and more persistent in Long-Evans than Sprague-Dawley rats. Additional testing in Long-Evans rats revealed that short-term potentiation but not LTP was greater when experiments took place during dark rather than light cycles of the circadian rhythm. Input-output testing demonstrated that these effects were associated with significant differences in dentate granule cell excitability. Bidirectional synaptic plasticity was also strongly dependent on the pattern of afferent stimulation: conventional theta-burst stimulation induced negligible amounts of plasticity, while trains utilizing a 400 Hz pulse frequency yielded consistently robust effects. The results from chapter one were used to optimize the procedures used in subsequent experiments.
In chapter two we used serial section transmission electron microscopy (ssTEM) to examine features of anatomical ultrastructure within the dentate gyrus. Results from chapter two served to illustrate that dendrite caliber, microtubule number and spine density were systematically distributed throughout the granule cell dendritic tree. Knowledge of these systematic distributions was used to inform the sampling scheme of subsequent experiments.
In chapter three, bidirectional synaptic plasticity was induced within the dentate gyrus of freely behaving rats; animals were sacrificed 30 min after induction and prepared for ssTEM. Results indicated that LTP was associated with systematic increases in spine head volume and post-synaptic density (PSD) area within the middle molecular layer of the granule cell dendritic tree, and systematic decreases in the inner molecular layer. Interestingly, these structural changes appeared to balance between adjacent layers. This finding indicated that excitatory synaptic structures could be homeostatically coordinated within the dentate granule cell dendritic tree.
The experimenter concludes by discussing the implications of these findings, and suggests directions for future investigation.
2011-03-08T21:45:16Z