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Memory is subdivided into short- and long-term memory. The interaction between transcription factors (TF) and expressed genes are essential steps in memory formation. Some TFs that might be involved in memory formation include CREB, NF-kB and Egr-2. We hypothesized that there would be a difference in the expression levels of these TFs following learning in the Morris Water Maze (MWM). In study one, CD1 mice were categorized into two groups. Group 1 assigned as non-trained control group. Group 2 (experimental group) underwent 9 consecutive days of MWM training. In the second study, male C57BL/6 mice were categorized into four groups. Group 1 was a non-trained control group (allowed to swim randomly). Groups 2, 3, and 4 (experimental groups) had variations in their MWM training. Search strategies, escape latency, time spending in the target quadrant and number of attempts passing the missing platform, were measured. To evaluate the expression levels of TFs pre- versus post-learning, mice were sacrificed at the end of MWM. Hippocampi were separated and Western blot and immunohistochemical procedures were done. In study one, the escape latency decreased progressively toward the end of the acquisition phase in the trained group. The search pattern showed that the mice used primarily spatial strategies. Mice spent more time in the target quadrant during the retention phase. The number of passes over the missing platform peaked on the first day of the retention phase. NF-kB and CREB were expressed significantly higher in the control group versus the MWM trained mice (p = 0.0031 and p < 0.0001 respectively). There was no statistically significant difference in expression of Egr-2 between the two groups (p = 0.3092). In study two, Group 4 showed the highest and Group 1 the lowest levels of CREB expression. CREB and NF-kB were decreased following MWM training in study one. In study two CREB levels were highest in the Group 4 which had interval between the acquisition and retention phases. These differences could be due to multiphasic expression patterns and/or other experimental design issues. Further studies are warranted to examine time dependent differential expression of TFs in memory.

Memory is subdivided into short- and long-term memory. The interaction between transcription factors (TF) and expressed genes are essential steps in memory formation. Some TFs that might be involved in memory formation include CREB, NF-kB and Egr-2. We hypothesized that there would be a difference in the expression levels of these TFs following learning in the Morris Water Maze (MWM). In study one, CD1 mice were categorized into two groups. Group 1 assigned as non-trained control group. Group 2 (experimental group) underwent 9 consecutive days of MWM training. In the second study, male C57BL/6 mice were categorized into four groups. Group 1 was a non-trained control group (allowed to swim randomly). Groups 2, 3, and 4 (experimental groups) had variations in their MWM training. Search strategies, escape latency, time spending in the target quadrant and number of attempts passing the missing platform, were measured. To evaluate the expression levels of TFs pre- versus post-learning, mice were sacrificed at the end of MWM. Hippocampi were separated and Western blot and immunohistochemical procedures were done. In study one, the escape latency decreased progressively toward the end of the acquisition phase in the trained group. The search pattern showed that the mice used primarily spatial strategies. Mice spent more time in the target quadrant during the retention phase. The number of passes over the missing platform peaked on the first day of the retention phase. NF-kB and CREB were expressed significantly higher in the control group versus the MWM trained mice (p = 0.0031 and p < 0.0001 respectively). There was no statistically significant difference in expression of Egr-2 between the two groups (p = 0.3092). In study two, Group 4 showed the highest and Group 1 the lowest levels of CREB expression. CREB and NF-kB were decreased following MWM training in study one. In study two CREB levels were highest in the Group 4 which had interval between the acquisition and retention phases. These differences could be due to multiphasic expression patterns and/or other experimental design issues. Further studies are warranted to examine time dependent differential expression of TFs in memory.

The research program described in this dissertation updates the knowledge base concerning human navigation and presents new methods for investigating selection and use of cognitive navigational strategies. Four experiments were designed to answer questions about the effects of environmental and experiential factors on cognitive mapping and selection of navigation strategies. Humans are thought to navigate using two different reference frames often referred to as “world based” and “person based”. These reference frames correspond to two probable cognitive/memory systems respectively labelled “allocentric” for the formation and use of cognitive maps of the environment, and “egocentric” for navigation by stimulus response or guidance. Different navigational strategies are associated with the two systems. Allocentric strategies rely on the presence of a stable environmental structure containing a number of more distal, relational stimuli whereas egocentric strategies rely only on the presence of simple, local cues (cue-based egocentric) or on body movements (response-based egocentric). The experiments tested navigation behaviour and strategy selection using virtual environment analogues of an animal model, the Morris water maze. Adaptations included, 1) the Place maze biasing participants toward the use of an allocentric strategy, 2) the Cue maze (and Floor Cue maze) biasing participants toward the use of an egocentric strategy, and 3) the Dual-strategy maze that has no bias because participants can choose to utilize either an allocentric or egocentric strategy. Experiment 1 was a behavioural study testing 101 university students in the Place maze and Floor Cue maze, with and without the opportunity to explore the environment before testing. The experiment showed for the first time that exploration is necessary for allocentric but not for egocentric navigation, suggesting that prior exploration is important for cognitive mapping. Experiment 2 outlined a novel and reliable eye tracking method for differentiating strategy use in the Place and Cue mazes. Eye movements were measured during the first orientation second of behavioural trials to differentiate allocentric from egocentric strategy use. Experiment 3 employed the established eye tracking method to test the effects of experience on strategy selection. Participants were trained in either the Place maze or the Cue maze and then tested in the Dual-strategy maze. A strategy probe trial was introduced at the end of testing to indicate whether participants had selected an allocentric or an egocentric strategy. Training experience had a strong behavioural effect on later strategy selection at the end of testing. Furthermore the effect of experience occurred independently of the gender of participants. However, the experience effect was only briefly shown using eye tracking measures. Experiment 4 was a successful feasibility study showing that eye tracking measures can be utilized to measure navigational strategy use in survivors of traumatic brain injury. Together these experiments may indicate that strategies are not innate or within the person but rather are interactions of the person with the environment. / Graduate

The present thesis investigated the effects of a western diet (WD) on cell death and functional outcome following global ischemia in rats. Experiment 1 assessed the effects of a 60-day WD regimen on temperature, activity and glucose levels in normal rats. Experiment 2 evaluated the influence of a 60-day WD regimen on hippocampal CA1 injury and cognition following global ischemia. Results from experiment 1 revealed significant differences in activity levels only; animals fed the WD were less active than control diet animals. Results from experiment 2 suggested that a WD did not aggravate CA1 injury or behavioral deficits. The second portion of my thesis examined the effects of a 120-day WD regimen on stroke severity and cognition following global ischemia. Briefly, the surgical protocol used to induce a global ischemic insult did not produce consistent damage across all animals. Plausible reasons for this surgical variability and future directions are discussed.

abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects 5.4 million Americans. AD leads to memory loss, changes in behavior, and death. The key hallmarks of the disease are amyloid plaques and tau tangles, consisting of amyloid-β oligomers and hyperphosphorylated tau, respectively. Rho-associated, coiled-coil-containing protein kinase (ROCK) is an enzyme that plays important roles in neuronal cells including mediating actin organization and dendritic spine morphogenesis. The ROCK inhibitor Fasudil has been shown to increase learning and working memory in aged rats, but another ROCK inhibitor, Y27632, was shown to impair learning and memory. I am interested in exploring how these, and other ROCK inhibitors, may be acting mechanistically to result in very different outcomes in treated animals. Preliminary research on thirteen different ROCK inhibitors provides evidence that while Fasudil and a novel ROCK inhibitor, T343, decrease tau phosphorylation in vitro, Y27632 increases tau phosphorylation at a low dose and decreases at a high dose. Meanwhile, novel ROCK inhibitor T299 increases tau phosphorylation at a high dosage. Further, an in vivo study using triple transgenic AD mice provides evidence that Fasudil improves reference memory and fear memory in both transgenic and wild-type mice, while Y27632 impairs reference memory in transgenic mice. Fasudil also decreases tau phosphorylation and Aβ in vivo, while Y27632 significantly increases the p-tau to total tau ratio. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2017

Alzheimer’s disease (AD) is a complex neurodegenerative disorder, involving metabolic dysfunction, pathogenic aggregation of amyloid beta, and deteriorating cognitive function. Patients exhibit deficiency in omega-3,-6,-9 unsaturated fatty acids (UFAs) in plasma and brain membrane phospholipids, suggesting aberrant fatty acid metabolism influences pathology. Cognitive benefits of omega UFAs in AD remain unknown. Here, I examined effects of a four-month dietary supplementation with UFAs for capacity to alter learning and memory behaviour in an AD mouse model. Cognitive impairment in a fifth generation backcross (N5) C57BL/6Crl X C3H/HeJ TgCRND8 (Tg) mice was compared to control (NonTg) littermates, with respect to both males and females, at six months of age using the Morris Water Maze (MWM). Impairment differed between sexes; female Tg mice were severely impaired, whereas male Tg mice displayed delayed learning. A reduced visual acuity in Tg and NonTg mice, shown by adapted SLAG reflex test, did not impair spatial navigation in cued MWM. A four-month omega-6/-9 UFA oral treatment (75 mg/kg/day) improved learning and memory of Tg mice as compared to vehicle and untreated controls. Omega-3 UFAs, or vehicle alone, did not alter learning and memory of Tg and NonTg mice. Thus, dietary supplementation, particularly when enriched in omega-6/9 UFAs, can affect neural function, and delay conversion from a presymptomatic to symptomatic state in the TgCRND8 mouse model.

Two groups of male and female rats were given the same dose of alcohol using an artificial rearing procedure on postnatal days 4-10. One group received the alcohol in a condensed manner each day which caused cyclic blood alcohol concentrations (BACs) with high peaks. A second group received the alcohol in a uniform manner over each day which resulted in moderate, stable BACs. Two control groups consisted of male and female rats artificially reared but not exposed to alcohol and rats reared normally by dams. All rats were raised to 90 days of age and then tested for spatial navigation ability in the Morris water maze, which involved locating a hidden underwater platform using distal extramaze cues. Neither the alcohol treatments nor the artificial rearing had any effects on performance of adult male rats relative to suckle controls in this task. In contrast, the condensed alcohol exposure but not the uniform alcohol exposure resulted in detrimental performance in the Morris water maze by adult female rats. When the ability to locate and escape onto a visible platform was examined, there were no differences between the female groups given condensed alcohol exposure or artificially reared on milk solution alone. Thus, exposure to high BACs during the brain growth spurt has a lasting and selective detrimental effect on spatial navigation learning in adult female but not adult male rats.

The present study investigated the effects of forced overexpression of Phox2a/2b, two transcription factors, in the locus coeruleus (LC) of aged rats on noradrenergic and dopaminergic phenotypes in brains. Results showed that a significant increase in Phox2a/2b mRNA levels in the LC region was paralleled by marked enhancement in expression of DBH and TH per se. Furthermore, similar increases in TH protein levels were observed in the substantial nigra and striatum, as well as in the hippocampus and frontal cortex. Overexpression of Phox2 genes also significantly increased BrdU-positive cells in the hippocampal dentate gyrus and NE levels in the striatum. Moreover, this manipulation significantly improved the cognition behavior. The in vitro experiments revealed that norepinephrine treatments may increase the transcription of TH gene through the epigenetic action on the TH promoter. The results indicate that Phox2 genes may play an important role in improving the function of the noradrenergic and dopaminergic neurons in aged animals, and regulation of Phox2 gene expression may have therapeutic utility in aging or disorders involving degeneration of noradrenergic neurons.

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