The advancement of the structural steel manufacturing industry has led to the recent emergence of steel members with Elliptical Hollow Sections (EHS) and Semi Elliptical Hollow Sections (SEHS). Although these sections are gaining popularity among architects, the lack of design guidelines specifically tailored towards these sections inhibits their efficient structural use. Within this context, this thesis provides several steps towards the development of such guidelines. A review of the manufacturing process of hot-rolled steel sections is conducted with emphasis on hollow structural sections. The main factors affecting the formation of residual stresses during cooling of the sections are discussed. Lower bound plastic interaction relations for EHS subjected to combinations of axial force, bi-axial bending moments and torsion are then derived. The formulation is based on the lower bound theorem of plasticity and the maximum distortional energy density yield criterion. Its applicability for conducting the cross-sectional interaction check in structural steel design problems is illustrated through a practical example. A simplified and conservative interaction equation is then proposed based on curve fitting of the results of the lower bound solution. Upper bound interaction relations are next developed for EHS subjected to combinations of axial force, bi-axial bending moments, torsion and bimoments. The formulation is based on kinematically admissible strain fields within the context of the upper bound theorem of plasticity. The interaction relations derived successfully capture the effect of confining radial strains present at welded end sections, as well as sections that are free to deform in the radial direction away from end welded sections. An iterative solution technique is developed to solve the resulting highly non-linear system of interaction relations. The effects of residual stresses and initial imperfections on axial compressive resistance of hot-rolled EHS are then incorporated into the lower bound interaction relations. Towards that goal, the thermo-mechanical properties of steel were extracted from the literature. A thermo-mechanical finite element model was developed for prediction of residual stresses in rolled sections. The validity of the model was assessed by comparison against residual stress measurements available in the literature. The model is then applied to predict the residual stresses in hot-rolled EHS. A series of geometric and material nonlinear finite element analyses is conducted on columns of EHS sections. The analyses include predicted residual stresses and initial out-of-straightness imperfections in order to determine the inelastic buckling capacity of EHS members and generate column curves for EHS sections. The column curves are subsequently compared to those based on Canadian, American and European design codes. Two column curve equations are proposed in a format similar to that of the Canadian Standards for buckling about major and minor axes. The column curves were subsequently combined with the interaction relations developed to provide design rules for EHS members under combined loads. The last contribution of the thesis provides a formulation of lower bound interaction relations for SEHS subject to combinations of axial force, bi-axial bending moments and torsion. An iterative scheme for solving the parametric form of the interaction relations is developed and a grid of admissible stress resultant combinations is generated. A series of trial functions are fitted to the grid of internal force combinations and two simplified and conservative interaction equations are proposed.

<p>Long-term plasticity, the long-lasting, activity-dependent change in synaptic efficacy, is a fundamental property of the nervous system. Presynaptic forms of long-term plasticity are widely expressed throughout the brain, having been described in regions such as the cortex, cerebellum, hippocampus, thalamus, amygdala and striatum. Presynaptic long-term potentiation (LTP) is associated with an increase in presynaptic release probability, but further evidence of the cellular basis for the change in release probability is not known. At the molecular level, presynaptic LTP is known to require protein kinase A, the synaptic vesicle protein, Rab3A, and the active zone protein, RIM1alpha. RIM1alpha, a presynaptic scaffold protein, binds to many molecules with known functions at different stages of the neurotransmitter release process and the synaptic vesicle cycle. Understanding which interactions of RIM1alpha mediate presynaptic LTP would shed light on the molecular and cellular mechanisms for presynaptic long-term plasticity.</p><p>Here I developed a novel platform to achieve robust acute genetic</p><p>manipulation of presynaptic proteins at hippocampal mossy fiber synapses, where presynaptic LTP is expressed. With this platform, I perform structure-function analysis of RIM1alpha in presynaptic LTP. I find that RIM1alpha phosphorylation by PKA at serine 413 is not required for mossy fiber LTP, nor does RIM1alpha-Rab3A interation. These findings suggest that RIM1alpha, Rab3A and PKA signaling, instead of functioning synergistically, may represent separate requirements for presynaptic long-term plasticity. I then tested whether Munc13-1, a priming protein, is an effector for RIM1alpha in presynaptic LTP and provide the first evidence for the involvement of Munc13-1 in presynaptic long-term synaptic plasticity. I further demonstrate that the interaction between RIM1alpha and Munc13-1 is required for this plasticity. These results further our understanding of the molecular mechanisms of presynaptic plasticity and suggest that modulation of vesicle priming may provide the cellular substrate for expression of LTP at mossy fiber synapses.</p> / Dissertation

Developmental ethanol exposure causes both structural and functional changes in the brain that can result in cognitive and behavioral abnormalities. The hippocampal formation, an area of the brain strongly linked with learning and memory, is particularly vulnerable to the teratogenic effects of ethanol. Research in this thesis focused on uncovering the effects of developmental ethanol exposure on hippocampal function in adulthood, particularly synaptic plasticity (a putative neurobiological mechanism of learning and memory). The first experiment sought to determine the temporal vulnerability of hippocampal synaptic plasticity as a function of exposure to ethanol during a single trimester. Ethanol exposure during the 1st or 3rd trimester equivalent resulted in minor changes in synaptic plasticity in adult offspring. In contrast, ethanol exposure during the 2nd trimester equivalent resulted in a pronounced decrease in long-term potentiation (LTP), indicating that the timing of exposure determines the severity of the deficit. The second experiment was aimed at determining the effects of prenatal ethanol exposure (1st and 2nd trimester equivalent combined) on bidirectional synaptic plasticity. Prenatal ethanol exposure resulted in a profound reduction in LTP but did not affect long-term depression. These findings show that prenatal ethanol exposure creates an imbalance in bidirectional synaptic plasticity. The third experiment sought to determine if prenatal ethanol exposure alters the affect of acute ethanol exposure in adulthood on synaptic plasticity. Acute exposure to ethanol in adulthood attenuated LTP in control offspring. Conversely, the magnitude of LTP was not affected by acute ethanol application in prenatal ethanol offspring. These results suggest that prenatal ethanol exposure alters the physiological response to ethanol in adulthood. Together, the results from the experiments undertaken in this thesis demonstrate long-lasting alterations in synaptic plasticity as the result of developmental ethanol exposure. Furthermore, these results allude to a malfunction of neural circuits within the hippocampal formation, perhaps relating to the learning and memory deficits observed in individuals with fetal alcohol spectrum disorders. / Graduate

Neocortical circuits can adapt to changes in sensory input by modifying the strength or number of synapses. These changes have been well-characterized electrophysiologically in primary somatosensory (barrel) cortex of rodents across different ages and with different patterns of whisker stimulation. Previous work from our lab has identified layer-specific critical periods for synaptic potentiation after selective whisker experience (SWE), where all but one row of facial whiskers has been removed. Although whole-cell patch-clamp recording methods enable a mechanistic understanding of how synaptic plasticity can occur in vivo, they are painstakingly slow, typically focus on a small number of observed events, and are focused on a single pathway or restricted anatomical area. For example, most studies of plasticity in barrel cortex have focused on analyses of experience-dependent synaptic changes in layer 4 and layer 2/3, at a single time point, but it is unclear whether such changes are limited to these layers, or whether they persist over long time periods. Here we employ an established electron-microscopic technique that selectively intensifies synaptic contacts, in combination with unbiased, automated synapse detection, to broadly explore experience-dependent changes in synaptic size and density across many neocortical layers, regions, and time periods in a high-throughput fashion. To validate the method, we focused on imaging synaptic contacts at time points surrounding the critical period for strengthening of excitatory synapses in mouse barrel cortex, and compared these to electrophysiological analyses that show a doubling of synaptic events targeting layer 2/3 pyramidal neurons following SWE. We found that the pattern of occurrence of synapses across the cortical layers is significantly different following SWE. Also, an increase in length was observed specifically in layer 3 synapses. Furthermore, we uncovered potential bidirectional plasticity in L6 synapses depending on the developmental state of circuit and a potential critical period onset for L5A synapse at PND 18. The high resolution imaging and unbiased synapse detection has enabled us to potentially tease apart synaptic changes that occur in a laminar specific fashion. This high-throughput method will facilitate analysis of experience-dependent changes in synaptic density by age, sensory experience, genotype, pharmacological treatments or behavioral training, and will enable classification of synaptic structure to identify key parameters that can be changed by these variables.

Parkinson’s disease (PD) is characterized by the loss of dopamine in the basal ganglia and leads to paucity of movements, rigidity of the limbs, and rest tremor. Synaptic plasticity was characterized in the substantia nigra pars reticulata (SNr), a basal ganglia output structure, in 18 PD patients undergoing implantation of deep brain stimulating electrodes. Field evoked potentials (fEPs) in SNr were measured with one microelectrode using single pulses from a second microelectrode ~ 1 mm away. High frequency stimulation (HFS – 4 trains of 2s at 100Hz) in the SNr failed to induce a lasting change in test fEPs amplitudes in patients OFF medication. Following L-Dopa, HFS induced a potentiation of the fEPs that lasted more than 150s. Our findings suggest that extrastriatal dopamine modulates activity dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of PD.

This thesis consists of four chapters. In this thesis we explored associative plasticity of human motor cortex with the use of noninvasive transcranial magnetic stimulation (TMS). Paired Associative Stimulation (PAS) has grown in popularity because of its potential clinical applications. We used TMS techniques in combination with electromyographic (EMG) measurements to study cortical excitability and kinematic features of arm movement. This work has focused in a cohesive approach to answer certain fundamental questions about a) the rules of cortical plasticity and mechanism of PAS, b) the interaction between the state of neuronal excitability at the targeted cortical network and the effects of PAS, and c) translation of these effects into obvious measurable kinematic changes starting from network level changes and ending up with the behavioral modulation of arm movement. First we explored the role of GABAergic intracortical networks and intracortical facilitation on modulation of cortical excitability by showing for the first time that PAS can be conditioned by these inhibitory and facilitatory intracortical networks. Next, using standard indirect approaches utilizing peripheral EMG measures, we showed a graded excitability response for the PAS technique and showed that interactions of PAS with motor learning depends on the degree as well as the state of cortical excitability. Rules governing the interactions of brain stimulation techniques and motor learning are important because brain stimulation techniques can be used to modify, improve or disrupt motor adaptation and skill learning with great potential for clinical applications such as facilitation of recovery after stroke. TMS provide us with a unique opportunity to study the rules of plasticity at a systems level, which is a combination of synaptic and nonsynaptic (metaplastic) changes. These changes can occur either in the direction to limit the physiological range of neuronal functioning (homeostatic) or against the direction established state of neurons.

Parkinson’s disease (PD) is characterized by the loss of dopamine in the basal ganglia and leads to paucity of movements, rigidity of the limbs, and rest tremor. Synaptic plasticity was characterized in the substantia nigra pars reticulata (SNr), a basal ganglia output structure, in 18 PD patients undergoing implantation of deep brain stimulating electrodes. Field evoked potentials (fEPs) in SNr were measured with one microelectrode using single pulses from a second microelectrode ~ 1 mm away. High frequency stimulation (HFS – 4 trains of 2s at 100Hz) in the SNr failed to induce a lasting change in test fEPs amplitudes in patients OFF medication. Following L-Dopa, HFS induced a potentiation of the fEPs that lasted more than 150s. Our findings suggest that extrastriatal dopamine modulates activity dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of PD.

The molecular mechanisms that coordinate postnatal brain enlargement, synaptic properties and cognition remain an enigma. This study demonstrates that neuronal complexity controlled by p21-activated kinases (PAKs) is a key determinant for postnatal brain enlargement and synaptic properties. Double knockout (DK) mice lacking both PAK1 and PAK3 were severely impaired in postnatal brain growth, resulting in a dramatic reduction in brain volume at maturity. Remarkably, the reduced brain was accompanied by minimal changes in total cell count, due to a significant increase in cell density. However, the DK neurons have smaller soma, markedly simplified dendritic arbors/axons and reduced synapse density. Surprisingly, the DK mice were elevated in basal synaptic responses due to enhanced individual synaptic potency, but severely impaired in bi-directional synaptic plasticity. The PAK1/3 action is likely mediated by cofilin-dependent actin regulation because the activity of cofilin and the properties of actin filaments were specifically altered in the DK mice.

Phenotypic plasticity allows some animals to change their behavioural, morphological, performance, and life history traits in response to changes in environmental conditions such as the presence of predators. These changes can enhance survival, but come at a cost. Some of these phenotypic changes are predator and diet specific. I examined the effects of predator diet on the performance, life-history, and morphology of developing Northern Leopard Frog (Lithobates pipiens) tadpoles. Tadpoles were either exposed to cues from fish free water, cues from Brown Bullhead (Ameiurus nebulosus) fed a diet of trout pellets, or cues from A. nebulosus fed a L. pipiens tadpoles diet. Tadpoles exposed to predatory fish cues had smaller bodies, deeper tail fins, slower growth and development rates, and better rotational performance than tadpoles that were not exposed to predatory fish cues. Moreover, tadpoles appeared to differentiate between predatory fish diet and produced diet-specific responses in tail morphology and activity, although the latter effect was only marginally significant. Hatching, metamorphosis rates, and linear performance were not affected by the treatments. These results suggest that A. nebulosus can induce phenotypic changes in L. pipiens tadpoles, with some of these changes being diet specific.

The microstructure of low alloy Transformation Induced Plasticity (TRIP) assisted steels has been systematically varied through the combination of computational and experimental methodologies in order to enhance the mechanical performance and to fulfill the requirement of the next generation Advanced High Strength Steels (AHSS). The roles of microstructural parameters, such as phase constitutions, phase stability, and volume fractions on the strength-ductility combination have been revealed. Two model alloy compositions (i.e. Fe-1.5Mn-1.5Si-0.3C, and Fe-3Mn-1Si-0.3C in wt%, nominal composition) were studied. Multiphase microstructures including ferrite, bainite, retained austenite and martensite were obtained through conventional two step heat treatment (i.e. intercritical annealing-IA, and bainitic isothermal transformation-BIT). The effect of phase constitution on the mechanical properties was first characterized experimentally via systematically varying the volume fractions of these phases through computational thermodynamics. It was found that martensite was the main phase to deteriorate ductility, meanwhile the C/VA ratio (i.e. carbon content over the volume fraction of austenite) could be another indicator for the ductility of the multiphase microstructure. Following the microstructural characterization of the multiphase alloys, two microstructural design criteria (i.e. maximizing ferrite and austenite, suppressing athermal martensite) were proposed in order to optimize the corresponding mechanical performance. The volume fraction of ferrite was maximized during the IA with the help of computational thermodyanmics. On the other hand, it turned out theoretically that the martensite suppression could not be avoided on the low Mn contained alloy (i.e. Fe-1.5Mn-1.5Si-0.3C). Nevertheless, the achieved combination of strength (~1300MPa true strength) and ductility (~23% uniform elongation) on the low Mn alloy following the proposed design criteria fulfilled the requirement of the next generation AHSS. To further optimize the microstructure such that the designed criteria can be fully satisfied, further efforts have been made on two aspects: heat treatment and alloy addition. A multi-step BIT treatment was designed and successfully reduced the martensite content on the Fe-1.5Mn-1.5Si-0.3C alloy. Microstructure analysis showed a significant reduction on the volume fraction of martensite after the multi-step BIT as compared to the single BIT step. It was also found that, a slow cooling rate between the two BIT treatments resulted in a better combination of strength and ductility than rapid cooling or conventional one step BIT. Moreover, the athermal martensite formation can be fully suppressed by increasing the Mn content (Fe-3Mn-1Si-0.3C) and through carefully designed heat treatments. The athermal martensite-free alloy provided consistently better ductility than the martensite containing alloy. Finally, a microstructure based semi-empirical constitutive model has been developed to predict the monotonic tensile behavior of the multiphase TRIP assisted steels. The stress rule of mixture and isowork assumption for individual phases was presumed. Mecking-Kocks model was utilized to simulate the flow behavior of ferrite, bainitic ferrite and untransformed retained austenite. The kinetics of strain induced martensitic transformation was modeled following the Olson-Cohen method. The developed model has results in good agreements with the experimental results for both TRIP steels studied with same model parameters.