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<p>Theories that engender fundamental transformations in our world view seldom come perfect from the outset for two reasons. First, the empirical discoveries and theoretical framework necessary for their full explanatory efficacy are often not yet in place. Secondly, as a consequence of the first, some of the auxiliary theories and assumptions they rely upon are often antiquated and erroneous. For these reasons, anomalies are frequent in scientific theories. In this thesis, I discuss some of the major scientific anomalies, including particularly, the paradox of altruism. I suggest that the paradox of altruism arises because one of the most fundamental Mendelian genetic principles is misapplied. I show that today’s explanatory models err in supposing altruism and selfishness to be genetic allelomorphs. The supposition is inconsistent with the field data on altruism, and entails a logical inconsistency in accounting for the evolution of altruism. Largely, the models that purport to resolve the paradox hinge on the conditional expression of the altruistic gene, a move which I argue contradicts the theoretical assumption that engenders the paradox in the first place. I demonstrate from the empirical data that altruism and selfishness are rather plastic phenotypic expressions of a single genotype. And by supplanting the standard neo-Darwinian assumptions with the principle of phenotypic plasticity, I provide a parsimonious account of the evolution and maintenance of altruism which entails no paradox.</p> / Master of Arts (MA)

<p> Animal studies have shown that the tonotopic organization of the auditory cortex is not statically fixed, but can be remodeled by experience. The purpose of this study was to investigate whether or not frequency discrimination training can induce changes in the cortical representation of a selected frequency in humans. Six human subjects were trained for approximately 3 weeks to detect a change in pitch between two tones (40Hz amplitude modulated) using a standard frequency of 2040 Hz. Each subject was tested on his/her discriminative ability before and after training using three different standards (2040Hz, 1840Hz, and 2240Hz). EEG data were recorded both before and after training and changes in transient and steady-state responses were investigated. Behaviourally, every subject improved at the discrimination task using the trained frequency. However, only three subjects demonstrated transfer to both untrained frequencies. In the EEG data, the P2-Nl amplitude increased in five of the six subjects and the Nllatency decreased in all six for the 2040Hz set. These two findings were statistically significant (p<0.05) for the group. There were no statistically significant findings for the side frequencies. The change in the 40 Hz steady-state response was also not significant, increasing in three subjects and decreasing in the other three. These findings indicate that changes are expressed in the secondary auditory cortex. These findings may also be applicable to the treatment of tinnitus. </p> / Thesis / Master of Science (MSc)

<p> The possible contribution of neural plasticity to ON, OFF and steady state responses elicited by brief, repetitive trains of stimulation was investigated in the intact human subject with the use of the electroencephalogram (EEG). Experiment One implemented trains of stimulation at three different repetition rates, 1.5Hz, 4Hz and 13Hz. The goal was to investigate the nature of the ON, OFF and steady state responses evoked at these repetition rates. The experiment was carried out in three modalities: visual (n=13), auditory (n=lO) and somatosensory (n=12). The main result was that the ON and OFF responses were enhanced at 13Hz compared to the lower repetition rates. Experiment Two sought to answer the question of whether enhancement depended on the repetition rate or the increased experience provided by the higher frequencies. The number of stimuli in the 13Hz trains was reduced to equal the 1.5Hz condition from Experiment One. Graded exposure was then provided to the 13Hz stimulation. This procedure was implemented in two groups of subjects: Replication One (n=12) used 13Hz stimulation and Replication Two (n=24) used 14Hz stimulation. A subset (n=IO) of the Replication Two subjects returned for a second session (Day 2) 24 hours after the first. An assessment of effects was made after minutes and hours. There were four main results. The OFF response was observed after nine 13Hz pulses and did not change over the course of the experiment. The ON response increased with exposure to the 13Hz trains. Steady state responses diminished and showed a phase shift over the experimental session. Results for Day 1 and Day 2 were not different. Within session changes, as a result of exposure to the stimulus, were seen. These effects were not long lasting. </p> / Thesis / Master of Science (MSc)

Thesis / Master of Science (MS)

For animals at high altitude, low oxygen (hypoxia) is an unremitting stressor that has the potential to impair metabolism and performance. The hypoxic chemoreflex senses reductions in the partial pressure of O2 in the arterial blood and thus elicits many of the physiological responses to hypoxia, including increases in breathing and activation of the sympathetic nervous system. The hypoxic chemoreflex is vital to surviving acute exposure to severe hypoxia, but the advantage of this reflex during chronic hypoxia is less clear. The goals of my thesis were to examine how control of breathing by the hypoxic chemoreflex has evolved in high-altitude natives to maintain O2 transport in chronic hypoxia, and to elucidate the potential genetic mechanisms that were involved. This was accomplished using deer mice (Peromyscus maniculatus) native to high- and low-altitudes, in addition to a strictly low-altitude species (P. leucopus). I found that high-altitude deer mice breathe with higher total ventilation using preferentially deeper breaths, contributing to higher O2 saturation of arterial blood, but in contrast to lowland mice highlanders do not exhibit ventilatory plasticity in response to chronic hypoxia. These phenotypes appeared to be uniquely evolved in the highland population and arise during the onset of endothermy in early post-natal development. I then used second-generation inter-population hybrids to evaluate the effects of genetic variation (specifically, in the hypoxia-inducible factor 2a gene Epas1 and in haemoglobin genes) on an admixed genomic background. The high-altitude variant of α-globin could completely explain the deep breathing pattern of highland mice, whereas the high-altitude variant of Epas1 and possibly β-globin contributed to their apparent lack of ventilatory plasticity in response to chronic hypoxia. Together, the physiological changes elicited by these mutations contribute to maintaining O2 uptake and metabolism in the cold and hypoxic environment at high altitude. / Thesis / Doctor of Philosophy (PhD) / High-altitude environments are amongst the harshest on earth, with extremely low levels of oxygen, but some animals not only survive but thrive in these conditions. How these animals do so was previously not well understood. My thesis has uncovered how the evolution of respiratory physiology contributes to high-altitude adaptation in the deer mouse, the species with the broadest altitudinal distribution of any North American mammal, and has elucidated the genetic mechanisms involved. My work contributes to understanding nature’s solutions to oxygen deprivation – an all too common problem in many human and animal diseases.

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Previous research has demonstrated that augmented prenatal sensory stimulation can influence the emergence of normal or species-typical patterns of intersensory perception. For example, unusually early visual experience can produce a facilitative effect on subsequent postnatal perceptual responsiveness, while substantially augmented prenatal visual stimulation can interfere with early postnatal responsiveness. In constructing a link between early experience and neuronal plasticity, it has been established that unusual visual experience can produce measurable changes in post-synaptic structures, particularly dendritic morphology, in brain areas responsible for vision. In avian species, the brain area responsible for vision is the visual Wulst, thought to be analogous to the mammalian visual cortex. This study examined the effects of differing amounts of augmented prenatal visual stimulation on the plasticity of neurons in the visual Wulst and on subsequent postnatal visual responsiveness to maternal cues in bobwhite quail chicks. Results revealed that the pattern of neuronal organization and postnatal behavior was influenced by the amount of prenatal visual experience subjects were provided. Specifically, chicks exposed to 240 min of prenatal visual stimulation during the last 24 hr prior to hatching had neurons with significantly fewer spines/10 mm dendrite and displayed accelerated patterns of species-typical visual responsiveness. In contrast, chicks provided 900 min of prenatal visual stimulation had more complex neurons (including more spines, longer dendrites, and more branches) and failed to display normal species-specific visual responsiveness in the days following hatching. These results suggest that neuronal organization in the bobwhite Wulst proceeds in a selective fashion, molded by experience, and appears to influence early perceptual development and organization during the perinatal period / Ph. D.

Polymeric foam cores are widely used as core materials in sandwich panels subject to blast loads, where high strain rates of the order of 4000 /s are observed. Unlike metallic foams polymeric foams exhibit transversely isotropic response when tested in a laboratory setting. More specifically, they exhibit different hardening along the foam thickness than that in a direction transverse to the thickness. Furthermore, polymeric foams harden differently in tension and compression. In this thesis we adopt ideas from the constitutive model developed by Hoo Fatt et al. cite{hoofatt2}, which captures strain hardening, transverse isotropy and distinguishes the response in tension and in compression, to include isotropic strain rate hardening in our constitutive model. A one dimensional prototype of the model is used to aid in the physical explanation of various variables, and the model is generalized to three dimensions. The material model is implemented as a VUMAT (user defined) subroutine in the commercial finite element software ABAQUS Explicit. We show that the model works robustly in uniaxial deformations as well as in sandwich problems using the test data available in the literature. We provide values of the 39 material parameters for H45, H60, H80, H100, H130 and H200 foams. The constitutive relation is utilized in an optimization problem in which the surrogate optimizer is utilized to minimize the backface deflection of a blast loaded clamped sandwich plate of a fixed mass. The core in the optimized sandwich structure has a stratified configuration (not functionally graded) and has 24% less maximum back face deflection as compared to that in which the six core layers vary from highest density to lowest density or vice a versa. For a sandwich panel subject to a blast load, when the strain rate hardening effect are neglected, we observed a 12% reduction in the predicted peak deflection from that when strain rate effects are considered. It is counter intuitive and needs further investigation. / Master of Science / Sandwich panels are widely used in high performance structures requiring high stiffness, low weight and the ability to withstand blasts. Sandwich panels consist of several layers, and it is possible to vary the material and thickness of each layer to arrive at a sandwich panel design which performs optimally. In this thesis, we numerically find an optimum sandwich panel design so that it deflects the least when exposed to a given blast. The problem is studied using ABAQUS Explicit and the Surrogate Optimization solver built into MATLAB. The outer layers of the sandwich panel are made of a highly stiff material and their thicknesses are fixed. The remaining six inner layers are allowed to be any of six different H45, H60, H80, H100, H130, H200 Divinycell polymeric foams and are allowed to vary in thickness. In order to draw a fair comparison between the designs, we constrain the total mass of the sandwich panel to be 1 kg. In our quest to find the best sandwich panel design, we develop and implement, in ABAQUS Explicit, a custom mathematical model which captures the complex behavior of the polymeric foams. Experimental data in the literature and other techniques were utilized to check that this mathematical model accurately predicts the physical response of polymeric foams in different scenarios. The reader is given all of the theory and physical constants needed to use this mathematical model for the six foams. The optimal sandwich panel deflects 24% less than a baseline design, and it is found that the material properties of the six foams do not vary gradually as they did in the baseline designs.

The cholinergic system drives muscle contraction and plays a central role in the formation, maintenance, and repair of mammalian neuromuscular junctions (NMJs) and skeletal muscles. Because of these essential actions, much effort has been devoted to identifying primary and auxiliary modulatory components of the cholinergic system at NMJs and throughout skeletal muscles. Here, I asked if Lynx1, a GPI-anchored protein shown to modulate nAChRs in the brain, is present and affects the activity of nAChRs at NMJs. Molecular and cellular analysis revealed that Lynx1 levels increase in skeletal muscles, specifically at NMJs, during development. Its expression pattern also closely mirrors changes in cholinergic transmission in vivo and in vitro. As expected, I found by co-immunoprecipitation that Lynx1 interacts with muscle nAChRs and using electrophysiology, I show that Lynx1 desensitizes nAChRs to ACh at NMJs. These findings demonstrate that Lynx1 regulates the cholinergic system at NMJs, suggesting roles for this gene in developing and adult NMJs. To determine the role of Lynx1 at NMJs, I examined Lynx1 knockout mice at different ages. While deletion of Lynx1 has no discernable effect on developing NMJs, its absence increases the incidence of NMJs with age-related morphological features, such as fragmentation and denervation, in young adult and middle-aged mice. Loss of Lynx1 also increases the number of slow-type muscle fibers in young and middle-aged mice, another hallmark of aging. Along with these morphological changes, deletion of Lynx1 affects expression of genes associated with NMJ stability, myogenesis, and muscle atrophy in young adult and middle-aged mice. Not surprisingly, the loss of Lynx1 reduces the density and stability of nAChRs at NMJs. Because of these findings, I surmised that loss of Lynx1 would adversely affect NMJs under other physiological stressors. However, I found the opposite as the loss of Lynx1 augments the capacity of NMJs to repair damages during exercise, following injury to motor axons, and during the initial symptomatic stage of amyotrophic lateral sclerosis (ALS). Since Lynx1 modulates the activity of nAChRs, these contrasting findings likely represent the positive and negative effects of heightened cholinergic transmission on aging compared to injury and disease-afflicted NMJs. / Doctor of Philosophy / During normal aging and in neuromuscular diseases, such as amyotrophic lateral sclerosis (ALS), voluntary movement becomes compromised. This is largely due to deterioration of the synapse between motor neurons and skeletal muscles, called the neuromuscular junction (NMJ), which is responsible for voluntary movement. Signaling at the NMJ is driven by cholinergic transmission, which when dysregulated can directly result in degeneration of the NMJ, similar to that seen in both aging and ALS. Thus, it is critical to maintain proper cholinergic transmission for preservation of the NMJ. For the first time, I have characterized the role of an endogenous protein, Lynx1, in modulating cholinergic transmission at the NMJ. Lynx1 functions to dampen cholinergic activity to prevent muscles from becoming overwhelmed and fatigued. The work outlined in this dissertation proposes Lynx1 as a novel therapeutic candidate for preventing neuromuscular degeneration in conditions associated with dysregulated cholinergic transmission, such as ALS.