Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Neuroscience." Includes bibliographical references (p. 94-112).

Thesis (Ph. D.)--Carleton University, 1995. / Also available in electronic format on the Internet.

Thesis (Ph. D.)--University of Wisconsin, 1967. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliography.

Thesis (M.S.)--Montana State University--Bozeman, 2007. / Typescript. Chairperson, Graduate Committee: Michael Babcock. Includes bibliographical references (leaves 43-51).

No description available.

Synaptic activity can encode and store information in the brain through changes in synaptic strength as well as by control of gene expression. One corollary challenge becomes identifying these activity-dependent regulatory proteins and the underlying mechanisms associated with neuronal functions. By using biochemical, electrophysiological and behavioral approaches in combination with genetic and pharmacological manipulation, I report that LIM domain only 4 (LMO4) is a key regulator of calcium induced calcium release (CICR) and protein tyrosine phosphatase 1B (PTP1B) in the hippocampus and amygdala, respectively. Neuronal ablation of LMO4 in the glutamatergic neurons (LMO4KO) was associated with reduced promoter activity, mRNA, and protein expression of ryanodine receptor 2 (RyR2), suggesting the involvement of LMO4 in the transcriptional regulation. CICR function in LMO4KO mice was severely compromised, reflected by inefficient CICR-mediated electrophysiological responses including afterhyperpolarization, calcium rise from internal stores and glutamate release probability. These changes were accompanied with impaired hippocampal long term potentiation (LTP) and hippocampal-dependent spatial learning ability. LMO4 was also shown to exert a cytoplasmic regulation as an endogenous inhibitor for PTP1B that accounts for tyrosine dephosphorylation of mGluR5 in the amygdala. LMO4KO mice had elevated PTP1B activity and decreased mGluR endocannabinoid signaling, resulting in a profound anxiety phenotype. The potential clinical value of PTP1B/LMO4 is promising, given that intra-amygdala injection of the PTP1B inhibitor Trodusquemine or a PTP1B shRNA alleviated anxiety by restoring eCB signal in LMO4KO mice. Thus this study identified PTP1B as a potential therapeutic target for anxiety, besides the previous findings of its association with obesity and diabetes. Moreover, this PTP1B-mediated anxiety may be a general mechanism during chronic stress. Collectively, these findings identify that LMO4 plays an essential role for non-genomic and genomic regulation in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.

No description available.

There is an established link between exercise, neurogenesis, and memory. Most of this research has been focused on rodent models, with little known about the effects of exercise on cognition in young adults. In rodents, exercise promotes hippocampal neurogenesis by enhancing cell proliferation in the dentate gyrus, while cognitive training promotes hippocampal neurogenesis by enhancing cell survival. Both physical exercise and cognitive training independently induce hippocampal neurogenesis in rodents, suggesting that these different forms of training may work through complimentary neurological pathways to benefit hippocampal memory in young adults. The present study examined the effects of six weeks of physical exercise and cognitive training on hippocampal-mediated memory processes in young adults to determine whether combined training yields enhanced memory benefits. Sixty-six sedentary young adults (32 females; age range 17-30 years) were randomly assigned to one of four groups: 1) Exercise training group (n=15), 2) Cognitive training group (n=16), 3) Combined exercise and cognitive training group (n=18), or 4) No-contact control group (n=17). Memory performance was assessed before and after the intervention on a putative hippocampal neurogenesis-dependent task, the Pattern Separation task. Growth factors that support neuron survival and function, brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) were measured in blood serum using enzyme-linked immunosorbent assays (ELISA). Based on the literature, the combination of exercise and cognitive training was expected to improve pattern separation performance more than the exercise or cognitive training alone, and display augmented effects for high responders to the exercise training. Additionally, if BDNF and IGF-1 were found to be involved in the mechanisms regulating the observed changes in memory, they too were expected to increase the most from the combined training and be dependent on individual changes in aerobic fitness. Critically, the combination of exercise and cognitive training led to the greatest increase in memory requiring pattern separation [t(16) = 2.91, p < 0.01] , indicating improved hippocampal-mediated memory function. BDNF and IGF-1 were not associated with this change in memory performance but were associated with the individual’s response to the exercise training, such that high responders to exercise had greater BDNF [F(1, 29) = 7.81, p < 0.01] and IGF-1 [F(1, 29) = 5.09, p < 0.05] than low responders to exercise. The results suggest that exercise and cognitive training may work through synergistic mechanisms to enhance hippocampal neurogenesis and support pattern separation processing. However, BDNF and IGF-1 may not be mediating this change in memory function. / Thesis / Master of Science (MSc)

The hippocampus has been the focus of memory research for decades. While the functional role of this structure is not fully understood, it is widely recognized as being vital for rapid yet accurate encoding and retrieval of associative memories. Since the discovery of adult hippocampal neurogenesis (AHN) in the dentate gyrus (DG) by Altman and Das in the 1960s, many theories and models have been formulated to explain the functional role it plays in learning and memory. These models postulate different ways in which new neurons are introduced into the DG and their functional importance for learning and memory. Few, if any, previous models have incorporated the unique properties of young adult-born dentate granule cells (DGCs) and their developmental trajectory. In this thesis, we propose a novel computational model of the DG that incorporates the developmental trajectory of these DGCs, including changes in synaptic plasticity, connectivity, excitability and lateral inhibition, using a modified version of the restricted boltzmann machine (RBM). Our results show superior performance on memory reconstruction tasks for both recent and distally learned items, when the unique characteristics of young DGCs are taken into account. The unique properties of the young neurons contribute to reducing retroactive and proactive interference, at both short and long time scales, despite the reduction in pattern separation due to their hyperexcitability. Our replacement model is subsequently extended to support learning dependent regulation of neurogenesis and apoptosis, using a convergence based approach to network growing and pruning. This hybrid additive and replacement model provides a more realistic and flexible approach to investigating the role of neurogenesis regulation in learning and memory. Finally, we incorporate the dentate gyrus model into a full hippocampal circuit to assess cued recall performance. Once again, our neurogenesis model shows decreased proactive and retroactive interference. / Thesis / Master of Science (MSc)

Exercise enhances aspects of human cognition, but its intensity may matter. Recent research in animal models suggests that vigorous exercising may be optimal as it releases greater amounts of lactate, which in turn, activates brain-derived neurotrophic factor (BDNF) in the hippocampus to support cognitive function. Furthermore, the effects of exercise on cognition may be augmented when exercise is combined with cognitive training. The sport of orienteering simultaneously combines exercise with spatial navigation and therefore may result in greater cognitive benefits than exercising only, especially when performed at a vigorous intensity. Therefore, the aim of the present study was to examine the effects of an acute bout of orienteering at different intensities compared to exercising only on cognition and BDNF. We hypothesized that vigorous-intensity orienteering would increase lactate and BDNF and improve cognition more than moderate-intensity orienteering, or vigorous exercise alone. To test this, we recruited 63 recreationally active, healthy young adults (Mage = 21.10±2.75 years) with no orienteering experience. The orienteering groups navigated a 1.3km orienteering course while exercising at either a vigorous (80-85% of HRR) or moderate (40-50% of HRR) intensity. The control group exercised at a vigorous intensity on the same course without navigation. Peak lactate, heart rate and rating of perceived exertion during the intervention were used to verify exercise intensity. Immediately before and after the intervention, serum BDNF was extracted, and cognitive function was assessed using the Mnemonic Similarity Task for high-interference memory and the Groton Maze Learning Test for spatial learning and memory. The results show that exercising (M = 5.35±2.52 mmol/L) and orienteering (M = 5.94±2.49) at a vigorous intensity elicited greater peak lactate levels than orienteering at a moderate intensity (M = 2.01±1.20). Vigorous exercise (p = .003) and orienteering (p = .043) elicited greater increases in BDNF, and individuals with higher peak lactate had greater increases in BDNF (rs (56) = .28, p = .037). Vigorous exercise also benefited high-interference memory compared to moderate orienteering (p = .019). All groups increased in spatial learning (p’s < .05), but only the vigorous orienteering group improved in delayed spatial memory performance (p = .007). Overall, the results provide evidence for the beneficial effects of combined exercise plus navigation training interventions for spatial cognitions that are closely related to the process engaged during cognitive training. / Thesis / Master of Science (MSc)