Growth rates are highly variable, both within and among genotypes and populations. The resolution of the trade-off between size and age at maturity has been the study of extensive research by life historians. The fitness advantages of large body size and rapid development time are well supported, leading to two predictions. First, realized growth rates should be maximized. Second, growth rate will be subject to strong stabilizing or directional selection, and consequently, low genetic variability. In real populations, despite the advantages of rapid growth, animals often, in fact, grow at rates lower than the maximum rate that is physiologically possible, even in the absence of external constraints on growth rate (e.g. resource restriction or risk of predation while foraging). This implies that growth may have direct fitness consequences that are independent of the size and age of maturity, thereby lowering the optimal rate of growth. In addition to inducing plastic declines in growth rate, such costs may also select for lower intrinsic rates of growth. Despite the strong fitness effects arising from attaining a large body size quickly, variation in growth rate persists at both the phenotypic and genetic levels. The evolutionary and ecological factors contributing to this variation in growth rate are the focus of this thesis. Growth rate variation in insect model species was produced by the manipulation of resource levels during development. By comparing fitness-associated traits and body composition of adults from different treatment groups, I identify direct costs of rapid growth that could explain why animals benefit from growth at submaximal rates. In the second part of the thesis, the relationship between environmental variation and genetic variance in growth rate is investigated by quantitative genetic analysis of body size at different ages and in different growth environments. The results of this analysis suggest that environmental stress can lead to increased genetic variance via decanalization. This has consequences for the evolvability of growth rates in changing environments.

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.

Fragile X syndrome (FXS) is caused by the lack of fragile X mental retardation protein (FMRP). The animal model of FXS, Fmr1 knockout (KO) mice, shows impairment in hippocampus-dependent learning and memory. However, results for long-term potentiation (LTP), remain inconclusive in the hippocampus of Fmr1 KO mice. Here, we demonstrate that FMRP is required for glycine-induced LTP (Gly-LTP) in the CA1 of hippocampus. The Gly-LTP requires activation of postsynaptic NMDA receptors and metabotropic glutamateric receptors, as well as the subsequent activation of extracellular signal-regulated kinase (ERK) 1/2. However, paired-pulse facilitation was not affected by glycine treatment. Our study provide evidences that FMRP participates in Gly-LTP by regulating the phosphorylation of ERK1/2, and that improper regulation of these signaling pathways may contribute to the learning and memory deficits observed in FXS.

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.

Brain development and function depend on intrinsic and extrinsic factors. In particular, the proper functioning of sensory systems can be altered according to the quality of extrinsic sensory information received during life. In this context, questions concerning neuroplasticity take on special relevance when considering that sensory experience has a big impact on the degree of plasticity of the brain. In this thesis, we have sought to understand how visual deprivation affects the development and maintenance of visual centers in the brain and the role of visual deprivation on plasticity throughout life. We have addressed this question by studying the retinocollicular projection, which is the neuronal pathway that connects the retina with a visual input processing center, the superior colliculus (SC). Unexpectedly, we found that in Syrian hamsters (Mesocricetus auratus) the size of receptive fields (RFs) of neurons in the SC is plastic in adult animals if they have been deprived of a minimum of visual experience when juveniles. Specifically, dark-reared (DR) hamsters refine SC RFs as do their normally-reared counterparts, but they lose RF refinement if they remain in the dark after their RFs get refined. We found that a well defined period and duration of visual experience can stabilize RF size in adulthood. Furthermore, we sought to investigate the mechanisms by which RF size is increased in adult DR hamsters. By testing the strength of intracollicular inhibition using electrophysiological and molecular techniques, we have found that visually-deprived animals have weaker inhibitory circuitry in their SC than normal animals. The quantity of GABA receptors and GABA containing neurons is decreased in the SC of adult DR animals. We propose that these results explain at least in part the RF enlargement we find in visually-deprived animals. Knowledge from this study provides general insight into sensory system plasticity in adulthood and new information about visual system development that is relevant for treatments of diseases.

Sex determination occurs early in development for most animals, at which time sex is fixed for life. Many teleost fishes, however, exhibit remarkable sexual plasticity throughout their life history, ranging from multiple morphs within a sex to functional adult sex reversal. To understand the development and evolution of adult sex reversal, I examined behavioral, endocrine, and genetic contributions to the regulation of functional sex in adult animals, using the bluebanded goby (Lythrypnus dalli) as an experimental model. This species was found to be equally capable of sexual transitions from female to male (protogyny) as from male to female (protandry). Throughout adult life, sexual phenotype is determined by social status, an emergent property of agonistic behavioral interactions that follows a relatively simple social convention: if dominant become or remain male, or if subordinate, become or remain female. The translation of social status into a change in sexual phenotype in the protogynous direction requires a rapid drop in circulating estrogens and an increase in the gonadal expression of a testis differentiating gene dmrt1. Steroid hormones do not play a significant role in modulating status, but the androgen 11-ketotestosterone does positively correlate with the expression of paternal behavior. Taken together, these findings suggest an evolutionary mechanism in sexually plastic species that has linked the conserved molecular cascades of sexual differentiation to a novel signal that varies over life history, social status, thereby allowing for lifelong phenotypic plasticity.

Amygdala kindling is commonly used to study the neural mechanisms of temporal lobe epilepsy and its behavioral consequences. The repetitive seizure activity that occurs during kindling is thought to induce an extensive array of structural and functional modifications within the brain, particularly in the hippocampus and dentate gyrus regions. Some of these changes include the growth or sprouting of new axonal connections as well as the birth and integration of new neurons into hippocampal circuits. Previous work has shown that these changes in structural and functional plasticity are not necessarily beneficial events. For instance, the growth and reorganization of synaptic terminals in the hippocampus and other brain regions might serve as a substrate that enhances hyperexcitability and seizure generation. In addition, although seizures induce the birth of new neurons, many of these newly generated cells migrate and function improperly within the hippocampal networks. Considering the prominent role of the hippocampus in a variety of behaviours, including learning, memory, and mood regulation, it would appear that alterations involving the structural and functional properties of both mature and newly born neurons in this region could impact these hippocampal-dependent functions. However, to date, the role of kindling-induced changes in hippocampal structural plasticity and neurogenesis on behaviour is incomplete, and the molecular mechanisms that govern these pathological events are poorly understood.<p/> The aim of this dissertation is to gain a better understanding of the changes in synaptic plasticity and neurogenesis within the hippocampus that occur after amygdala kindling. In chapter 2, we will examine if kindling alters the expression of synapsin I, a molecular marker of synaptic growth and activity, in both the hippocampus and other brain regions. In addition, we will also set out to determine if changes in synapsin I are related to the development of behavioural impairments associated with kindling. In chapter 3, the effect of kindling on hippocampal neurogenesis will be examined. In addition, we will also evaluate the effect of kindling on the expression of Reelin and Disrupted-in-Schizophrenia 1 (DISC1), two proteins instrumental for mediating proper neuronal migrational and maturation during development. In chapter 4, the effect of altered DISC1 expression in the dentate gyrus after kindling will be examined more extensively. We will examine whether altered DISC1 expression in the dentate contributes to some of the pathological features associated with seizure-induced hippocampal neurogenesis, such as ectopic cell migration and dentate granule cell layer dispersion. Finally, in chapter 5, the impact of aberrant seizure-induced neurogenesis on behaviour will be examined by determining if seizure-generated neurons functionally integrate and participate in hippocampal circuits related to memory processing. The results of this dissertation enhances our understanding of the functional consequences that altered hippocampal synaptic plasticity and neurogenesis may have on the development of epilepsy and emergence of cognitive impairments associated with chronic seizures.<p/>

Fragile X syndrome (FXS) is caused by the lack of fragile X mental retardation protein (FMRP). The animal model of FXS, Fmr1 knockout (KO) mice, shows impairment in hippocampus-dependent learning and memory. However, results for long-term potentiation (LTP), remain inconclusive in the hippocampus of Fmr1 KO mice. Here, we demonstrate that FMRP is required for glycine-induced LTP (Gly-LTP) in the CA1 of hippocampus. The Gly-LTP requires activation of postsynaptic NMDA receptors and metabotropic glutamateric receptors, as well as the subsequent activation of extracellular signal-regulated kinase (ERK) 1/2. However, paired-pulse facilitation was not affected by glycine treatment. Our study provide evidences that FMRP participates in Gly-LTP by regulating the phosphorylation of ERK1/2, and that improper regulation of these signaling pathways may contribute to the learning and memory deficits observed in FXS.

Growth rates are highly variable, both within and among genotypes and populations. The resolution of the trade-off between size and age at maturity has been the study of extensive research by life historians. The fitness advantages of large body size and rapid development time are well supported, leading to two predictions. First, realized growth rates should be maximized. Second, growth rate will be subject to strong stabilizing or directional selection, and consequently, low genetic variability. In real populations, despite the advantages of rapid growth, animals often, in fact, grow at rates lower than the maximum rate that is physiologically possible, even in the absence of external constraints on growth rate (e.g. resource restriction or risk of predation while foraging). This implies that growth may have direct fitness consequences that are independent of the size and age of maturity, thereby lowering the optimal rate of growth. In addition to inducing plastic declines in growth rate, such costs may also select for lower intrinsic rates of growth. Despite the strong fitness effects arising from attaining a large body size quickly, variation in growth rate persists at both the phenotypic and genetic levels. The evolutionary and ecological factors contributing to this variation in growth rate are the focus of this thesis. Growth rate variation in insect model species was produced by the manipulation of resource levels during development. By comparing fitness-associated traits and body composition of adults from different treatment groups, I identify direct costs of rapid growth that could explain why animals benefit from growth at submaximal rates. In the second part of the thesis, the relationship between environmental variation and genetic variance in growth rate is investigated by quantitative genetic analysis of body size at different ages and in different growth environments. The results of this analysis suggest that environmental stress can lead to increased genetic variance via decanalization. This has consequences for the evolvability of growth rates in changing environments.

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.