The neocortex is the most recently evolved part of the mammalian brain and enables the intelligent, adaptable behaviour that has allowed mammals to conquer much of planet earth. The human neocortex consists of a thin sheet of neural tissue containing approximately 20*10^9 neurons. These neurons are connected by a dense network of highly plastic synapses whose efficacy and structure constantly change in response to internal and external stimuli. Understanding exactly how we perceive the world, plan our actions and use language, using this computational substrate, is one of the grand challenges of computing research. One of the ways to address this challenge is to build and simulate neural systems, an approach neuromorphic systems such as SpiNNaker are designed to enable. The basic computational unit of a SpiNNaker system is a general-purpose ARM processor, which allows it to be programmed to simulate a wide variety of neuron and synapse models. This flexibility is particularly valuable in the study of synaptic plasticity, which has been described using a plethora of models. In this thesis I present a new SpiNNaker synaptic plasticity implementation and, using this, develop a neocortically-inspired model of temporal sequence learning consisting of 2*10^4 neurons and 5.1*10^7 plastic synapses: the largest plastic neural network ever to be simulated on neuromorphic hardware. I then identify several problems that occur when using existing approaches to simulate such models on SpiNNaker before presenting a new, more flexible approach. This new approach not only solves many of these problems but also suggests directions for architectural improvements in future neuromorphic systems.

The thesis presented here utilizes a variety of methods and study systems to address how ecological promote plasticity in reproductive behaviours. We study mate choice, copulation and parental care as the different reproductive behaviours, as they can be envisioned as representatives of different stages of the reproductive cycle and can be subject to different selection pressures. With the use of computer simulations we study the conditions of sex ratio and cost of courting under which a learned mate preference in males or in both sexes can evolve. We found that for males, maternal imprinting is the most advantageous imprinting strategy, but when both sexes imprint, paternal imprinting in both sexes is the most advantageous strategy. We show that environmental change can lead to the evolution of sexual imprinting by both sexes. A study using mesocosm and mating trial experiments, measuring female survival and male mating success was used to study the role of intra- and interspecific interactions in mating behaviour (competition and harassment) in Calopteryx splendens. We showed that intense intraspecific male-male competition reduces harassment over females and increases female survival. On the other side, interspecific reproductive interference can reduce male mating success and can increase female survival. Finally, theory on the use of social learning was tested using Drosophila melanogaster oviposition site choice. We show that fruit flies use social learning more after they experience heterogeneous environments. However, our results suggest that the use of social learning was driven by fruit flies signalling more when they experience heterogeneous environments, instead of driven by copying others decisions, as theoretical predictions suggest. We also show that the use of social learning is an innate trait, opening the opportunity for the study of the genomic basis of social learning.

The annual killifish, Austrofundulus limnaeus, may enter embryonic diapause at three distinct points of development, termed diapause I, II, and III. Previous studies suggest a role for steroid hormones in the regulation of diapause in annual killifish. This study concerns the hormonal and genomic components involved in the developmental decision to enter or escape diapause II from both a maternal and embryonic perspective. Steroid hormone levels were measured in tissues isolated from adult female fish that were producing either high or low proportions of escape embryos. Levels of steroid hormones were also measured in new fertilized embryos that were known to be on either an escape or diapausing developmental trajectory. In addition, cDNA microarray gene expression analysis was used to identify gene sequences that may be associated with the regulation of entry into diapause in this species. Decreases in maternal estrogen levels associated with aging are correlated with decreasing escape embryo production, but there is no direct association between measured steroid hormone levels and escape embryo production. However, maternal production of escape embryos is correlated with increased ratios of 17 ß-estradiol to testosterone in ovary tissue, and cDNA microarray gene expression analysis indicates differentially regulated sequences associated with escape embryo production in maternal tissues. Both of these independent measures suggest hormonal involvement in the regulation of diapause. Embryonic levels of steroid hormones in newly fertilized embryos are not correlated with entry or escape from diapause II, although incubation in exogenous cortisol and 17 ß-estradiol causes an increase in the proportion of escape embryos. Gene expression analysis again suggests hormonal involvement. Interestingly, genes involved in epigenetic control of gene expression though chromatin condensation are differentially regulated in both maternal tissues producing escape embryos, and in embryos on the different developmental trajectories. These data suggest that hormonal control of gene expression through alterations of chromatin condensation may regulate the decision to enter or escape diapause II.

There are two types of stroke: ischemic and hemorrhagic. Intracerebral hemorrhage (ICH) accounts for about 15% of all strokes and is often severe. Currently no treatments are available to reduce injury, but rehabilitation may improve recovery. Most studies focus on ischemia, putting little emphasis on understanding recovery after hemorrhage. In chapter 2, we evaluated exercise prior to and/or following ICH. Similar protocols improve recovery after ischemic stroke, and we hypothesized that the treatment would also reduce deficits after hemorrhagic injury. However, exercise was not beneficial for ICH and increased intensity of treatment worsened functional outcome. In chapter 3 we assessed amphetamine and/or rehabilitation after ICH, an intervention also shown to improve recovery after ischemia. The rehabilitation consisted of environmental enrichment (EE) with modest amounts of training on beam and skilled reaching. Rehabilitation but not amphetamine partially improved recovery. Skilled reaching was not improved by rehabilitation so we decided to combine EE with more reach training. In chapter 4, we found that two weeks of rehabilitation (EE and skilled reaching), started one week after ICH significantly reduced lesion volume, and improved recovery on walking and skilled reaching tests. We were particularly interested in the mechanisms contributing to the reduction in lesion volume after ICH, and attempted to identify these. In chapter 5, we used the same rehabilitation intervention as in chapter 4 to determine if treatment alters dendritic complexity, spine density, or cell proliferation. Unfortunately, the reduction in lesion volume from chapter 4 was not replicated. But we were able to identify several plastic changes. Dendritic complexity was increased in neurons of the forelimb motor cortex ipsilateral to injury. Dendritic complexity of neurons in the peri-hematoma region and corresponding area in the uninjured hemisphere were also increased. In contrast, rehabilitation did not alter spine density or cell proliferation. In summary, we found that treatments that work for ischemic stroke do not necessarily work for hemorrhagic injury. Some methods of rehabilitation are able to reduce functional deficits and in some cases lesion volume after ICH. These rehabilitation effects are likely due to enhanced plasticity and not cell genesis.

Excitatory synaptic transmission and plasticity mediated by glutamate receptors are important for many brain functions, including learning and memory. Various molecular and cellular models have been established to study multiple forms of synaptic plasticity that coexist in the hippocampal CA1 region. Metabotropic glutamate receptor-dependent long-term depression (mGluR-dependent LTD) is a form of long lasting synaptic plasticity thought to play critical roles in diverse physiological and pathological processes. The GluR2 subunit of AMPA receptors has been a focus of neuroscience research over the last decade due to its important roles in endocytic trafficking and Ca2+ permeation in many forms of activity-dependent synaptic plasticity and homeostatic plasticity. However, the underlying mechanisms of mGluR-dependent LTD and the possible involvement of GluR2 in this form of plasticity remain unknown. In this project, I utilized GluR2 knockout (KO) mice and tested the requirement of GluR2 in multiple forms of hippocampal synaptic plasticity at different developmental stages. The results showed that although GluR2 is dispensable for long lasting synaptic plasticity in juvenile mice, it is essential for the expression of mGluR-dependent LTD in adult animals. Next, I examined the involvement of a number of GluR2-specific functions in mGluR-dependent LTD and found that GluR2 N-terminal interaction with the cell adhesion molecule N-cadherin is a key process required for GluR2 to regulate the expression of mGluR-dependent LTD. Furthermore, using a combination of approaches including electrophysiology, biochemical assays, and virus-mediated expression of several mutant GluR2 constructs, I identified a signaling cascade involving N-cadherin/β-catenin complex, Rac1 Rho GTPase, LIM-kinase 1 and cofilin, through which GluR2 exerts its effect on actin regulation and mGluR-dependent LTD. Importantly, the impaired LTD in GluR2 KO mice can be fully rescued by manipulating GluR2-N-cadherin N-terminus interaction or cofilin-mediated actin reorganization. Lastly, I showed that this signaling cascade also plays a critical role in the regulation of dendritic spine plasticity during mGluR-dependent LTD. Together, these results reveal a novel signaling process by which GluR2 regulates long lasting synaptic plasticity and provide insights into how functional and structural plasticity are coordinated in the mammalian central nervous system.

Excitatory synaptic transmission and plasticity mediated by glutamate receptors are important for many brain functions, including learning and memory. Various molecular and cellular models have been established to study multiple forms of synaptic plasticity that coexist in the hippocampal CA1 region. Metabotropic glutamate receptor-dependent long-term depression (mGluR-dependent LTD) is a form of long lasting synaptic plasticity thought to play critical roles in diverse physiological and pathological processes. The GluR2 subunit of AMPA receptors has been a focus of neuroscience research over the last decade due to its important roles in endocytic trafficking and Ca2+ permeation in many forms of activity-dependent synaptic plasticity and homeostatic plasticity. However, the underlying mechanisms of mGluR-dependent LTD and the possible involvement of GluR2 in this form of plasticity remain unknown. In this project, I utilized GluR2 knockout (KO) mice and tested the requirement of GluR2 in multiple forms of hippocampal synaptic plasticity at different developmental stages. The results showed that although GluR2 is dispensable for long lasting synaptic plasticity in juvenile mice, it is essential for the expression of mGluR-dependent LTD in adult animals. Next, I examined the involvement of a number of GluR2-specific functions in mGluR-dependent LTD and found that GluR2 N-terminal interaction with the cell adhesion molecule N-cadherin is a key process required for GluR2 to regulate the expression of mGluR-dependent LTD. Furthermore, using a combination of approaches including electrophysiology, biochemical assays, and virus-mediated expression of several mutant GluR2 constructs, I identified a signaling cascade involving N-cadherin/β-catenin complex, Rac1 Rho GTPase, LIM-kinase 1 and cofilin, through which GluR2 exerts its effect on actin regulation and mGluR-dependent LTD. Importantly, the impaired LTD in GluR2 KO mice can be fully rescued by manipulating GluR2-N-cadherin N-terminus interaction or cofilin-mediated actin reorganization. Lastly, I showed that this signaling cascade also plays a critical role in the regulation of dendritic spine plasticity during mGluR-dependent LTD. Together, these results reveal a novel signaling process by which GluR2 regulates long lasting synaptic plasticity and provide insights into how functional and structural plasticity are coordinated in the mammalian central nervous system.

Thesis (B.S.)--University of Missouri, School of Mines and Metallurgy, 1940. / The entire thesis text is included in file. Typescript. Illustrated by author. Title from title screen of thesis/dissertation PDF file (viewed March 17, 2010) Includes bibliographical references (p. 25) and index (p. 27).

Thesis (Ph. D.)--University of Hong Kong, 1984.

Thesis (Ph. D.)--Lehigh University, 2003. / In two parts. Includes vita. Includes bibliographical references (leaves 394-397).

Long-term potentiation (LTP) is a widely studied cellular mechanism of learning and memory. LTP occurs at excitatory synapses on dendritic spines. Two hours after LTP induction in mature rat hippocampal slices, a reduction in spine number that is perfectly balanced by enlargement of the remaining synapses was previously observed. The sequence of events by which mature synapses enlarge is not well understood, but potential pre- and postsynaptic ultrastructural correlates of synapse growth have been identified. Vesicle-free transition zones (VFTZs) are postsynaptic thickenings contiguous with the PSD that have no apposing presynaptic vesicles perpendicular to the presynaptic membrane. VFTZs could be regions where synapses have expanded postsynaptically, but to which presynaptic vesicles have not yet been recruited. Presynaptic 80-nm dense core vesicles (DCVs) transport active zone proteins to the synapse during synaptogenesis, and may perform the same function during synaptic plasticity. 3-D reconstructions from ssTEM were used to investigate changes in VFTZs, DCVs, and presynaptic vesicles following LTP induction. By 30 minutes, VFTZ area and docked vesicle counts decreased, suggesting mobilization of additional vesicles to the synapse and enhanced release or delayed recycling. By two hours, VFTZs enlarged, suggesting VFTZ assembly contributes to synapse enlargement. DCV counts at 2 hours decreased relative to that at 30 minutes in both control and LTP conditions, suggesting DCVs were inserted at existing synapses to enlarge potentiated synapses in the LTP condition and to support ongoing spinogenesis in the control condition. The overall vesicle count in presynaptic boutons decreased at 2 hours following LTP induction, but docked vesicle count did not. Docked vesicle count was elevated at 2 hours relative to 30 minutes, suggesting that the depletion of docked vesicles observed at 30 minutes was followed by a replenishment and enhancement by 2 hours supplied by the non-docked vesicle pool. That the largest spines had more and larger VFTZs and recruited more DCVs and docked vesicles, and that the ratio of the sum of VFTZ area to the sum of PSD area is constant, provide further evidence that dendritic segments serve as functional units that manage resources in a coordinated and homeostatic way. / text