published_or_final_version / Molecular Biology / Master / Master of Philosophy

Synapses play a critical role in neural circuits, and their highly specialized structures and biochemical characteristics have been widely studied in learning and memory. Along with their role in signal transmission, synapses also serve as adhesion structures, yet their mechanical characteristics have not received much attention. Given the important role of mechanics in cell adhesion, mechanical studies of synapses could offer insights into synaptic development, maintenance, and function. Here, I investigated synaptic elasticity in cultured rat hippocampal neurons and suggest that mechanical elasticity may be related to synaptic plasticity. I used torsional harmonic atomic force microscopy (TH-AFM) to measure the nanomechanical properties of functional mature excitatory synapses, whose identity and activity was verified by fluorescence microscopy. I combined TH-AFM with transmission electron microscopy and found that high stiffness of synapses originated from postsynaptic spines, not presynaptic boutons. I observed that spines at functional mature excitatory synapses were on average 10 times stiffer than dendritic shafts and that the distribution of spine stiffness exhibited a lognormal-like pattern. Importantly, I found that spine stiffness was correlated with spine size, and it is well established that spine size is correlated with synaptic strength. Based on the stiffness measurements and theoretical modelling of cell adhesion stability, I suggest that stiffness not only helps maintain spine morphology in the presence of synapse adhesion, but also helps stabilize synaptic adhesion. I propose a mechanical synaptic plasticity model. According to this model, mechanical strength leads to functional strength, which could provide a potential causal link between structural plasticity and functional plasticity of synapses.

The goal of my thesis was to elucidate the impact of protein-energy malnutrition (PEM, a condition commonly found in aging stroke patients) on outcomes from global ischemia. I first examined the hypothesis that PEM will impair working memory in the adult gerbil as measured in the T-maze. Gerbils were fed an adequate (12.5%) or low protein (2%; PEM) diet for 6wk. Stringent assessment of T-maze performance indicated an improvement with PEM although I was unable to reconcile whether this was increased motivation for the food reward or enhanced working memory.<p> The second hypothesis tested was PEM will decrease expression of plasticity-associated hippocampal mRNA and protein expression following global ischemia in the gerbil. The plasticity markers brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (trkB), and growth-associated protein-43 (GAP-43) were examined in the CA1 hippocampal region post-ischemia. PEM induced in gerbils for 4wk did not alter the global ischemia-induced decrease in CA1 neurons. Ischemia resulted in increased CA1 pyramidal expression of BDNF and trkB mRNA at 1, 3, and 7d post-ischemia and increased trkB protein expression at 3 and 7d. PEM further elevated the increased trkB protein detected at 7d in the fibres. Ischemia resulted in increased GAP-43 protein at 3 and 7d post-ischemia with PEM increasing this expression at 3d in the CA3 and hilar regions in addition to CA1. These findings suggest an increased stress-response and/or hyperexcitability state in the hippocampus of malnourished ischemic animals.<p> Since the reliability of the gerbil model of global ischemia has come into question, the third part of my thesis tested the hypothesis that the influence of pre-existing PEM on global ischemia-induced hippocampal injury can be reliably studied with the 2-vessel occlusion rat model. The impact of PEM on CA1 neuronal death and dendritic damage was examined. Rats received protein adequate (18%) or deficient (2%; PEM) diet for 7-8d prior to global ischemia. PEM did not worsen the decrease in CA1 neurons and dendrites observed at 7d post-ischemia. Importantly, I found that PEM altered blood glucose and acid-base balance during surgery and caused brief hypothermia post-surgically, factors which are important for consistent brain injury.<p> Taken together, these findings reveal (i) that nutritional care, although frequently ignored, can have robust effects on recovery mechanisms after brain ischemia; and (ii) the challenges of studying pre-existing PEM in an established rodent model of stroke.

The goal of my thesis was to elucidate the impact of protein-energy malnutrition (PEM, a condition commonly found in aging stroke patients) on outcomes from global ischemia. I first examined the hypothesis that PEM will impair working memory in the adult gerbil as measured in the T-maze. Gerbils were fed an adequate (12.5%) or low protein (2%; PEM) diet for 6wk. Stringent assessment of T-maze performance indicated an improvement with PEM although I was unable to reconcile whether this was increased motivation for the food reward or enhanced working memory.<p> The second hypothesis tested was PEM will decrease expression of plasticity-associated hippocampal mRNA and protein expression following global ischemia in the gerbil. The plasticity markers brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (trkB), and growth-associated protein-43 (GAP-43) were examined in the CA1 hippocampal region post-ischemia. PEM induced in gerbils for 4wk did not alter the global ischemia-induced decrease in CA1 neurons. Ischemia resulted in increased CA1 pyramidal expression of BDNF and trkB mRNA at 1, 3, and 7d post-ischemia and increased trkB protein expression at 3 and 7d. PEM further elevated the increased trkB protein detected at 7d in the fibres. Ischemia resulted in increased GAP-43 protein at 3 and 7d post-ischemia with PEM increasing this expression at 3d in the CA3 and hilar regions in addition to CA1. These findings suggest an increased stress-response and/or hyperexcitability state in the hippocampus of malnourished ischemic animals.<p> Since the reliability of the gerbil model of global ischemia has come into question, the third part of my thesis tested the hypothesis that the influence of pre-existing PEM on global ischemia-induced hippocampal injury can be reliably studied with the 2-vessel occlusion rat model. The impact of PEM on CA1 neuronal death and dendritic damage was examined. Rats received protein adequate (18%) or deficient (2%; PEM) diet for 7-8d prior to global ischemia. PEM did not worsen the decrease in CA1 neurons and dendrites observed at 7d post-ischemia. Importantly, I found that PEM altered blood glucose and acid-base balance during surgery and caused brief hypothermia post-surgically, factors which are important for consistent brain injury.<p> Taken together, these findings reveal (i) that nutritional care, although frequently ignored, can have robust effects on recovery mechanisms after brain ischemia; and (ii) the challenges of studying pre-existing PEM in an established rodent model of stroke.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 179-205). Available also in a digital version from Dissertation Abstracts.

Thesis (M.S.)--Florida State University, 2003. / Advisor: Dr. Frank Johnson, Florida State University, College of Arts and Sciences, Dept. of Psychology. Title and description from dissertation home page (viewed Sept. 24, 2003). Includes bibliographical references.

Neuroplasticity research yields mixed results for the differential contribution of perilesional and contralesional brain areas to language recovery in aphasia. This paper will outline variables that mediate the presence and degree of right hemisphere activity and may account for some of the inconsistent research findings. Factors include the site and size of left hemisphere lesions, the phase of recovery, and the language task type and complexity. The performance accuracy of tasks also will be explored to further qualify the nature of homologous activity. Results found right hemisphere activation to be modulated by the damage and preservation of specific brain areas as well as by the presence of large left hemisphere lesions. Right hemisphere activity also was more consistently evident in the acute phase of recovery and returned to the left hemisphere in the chronic stage. Additionally, homologous areas tended to be more active during comprehension-based language tasks and during tasks of greater difficulty. In qualifying the nature of contralesional mechanisms, the activity appears to be more linguistic-oriented in less-recovered individuals with aphasia and more related to cognitive effort in well-recovered individuals. The nature of homologous activation depends on the brain’s ability to reactivate left hemisphere language networks. / text

Not available / text

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Case Study research was conducted to investigate how participation in the Learning Disabilities Association of Saskatchewan (LDAS) Arrowsmith program affected the cognitive, academic, emotional, and interpersonal functioning of five students who attended this program for two to three years. Learning disabilities involve consistent cognitive processing and academic difficulties that are present in individuals who have average or higher functioning in other cognitive processing areas. The average adult with a learning disability has less education, lower employment success, and higher rates of emotional and interpersonal difficulties. The Arrowsmith program is a cognitive training program based on neuroplasticity that claims to reduce or remove cognitive functioning deficits in persons with learning disabilities. Semi-structured interviews were conducted with five students and one or both of their parents. Standardized test results and information from the school cumulative folders of the students were also reviewed. Four of the five students experienced large and significant increases in cognitive, academic, emotional, and/or interpersonal functioning following their participation in the LDAS Arrowsmith program. One of the five students had much smaller gains in cognitive and academic functioning and experienced difficulties with emotional and interpersonal functioning following participation in the program. Several themes related to participation in the LDAS Arrowsmith program are identified for the student, parent, school record perspectives and themes common to these perspectives are also identified. Possible reasons why the students had different outcomes following their participation in the LDAS Arrowsmith program are discussed. Recommendations for parents, school psychologists, teachers, schools/school divisions, the Arrowsmith program, and future research are given.