Abstract (for Chapter 2) Objective: The aim was to test the hypothesis that the order is a significant phylogenetic grouping in terms of quantifiable gyrification indices. Method: The gyrification index (GI) was measured from serial sections of the brain of twenty five different mammalian species, representing the different orders i.e. primates, carnivores, artiodactyls and rodents. Image J analysis was used to measure the contours of the cerebral cortex and the GI was calculated using three different methods of analysis i.e. complete vs outer; gyral vs sulcal and outer vs inner surface contours. The measurements were then computed against the brain weights of each species within the order. Results: An increasing GI correlates with an increasing brain weight in all the mammalian orders. Each order has its own specific allometric patterns that are significantly different from the other orders examined. The artiodactyls were the mammals with the most gyrencephalic brains, these species being significantly more gyrencephalic than all other mammals when species of similar brain weights are compared. The North American beaver has an atypically lissencephalic brain for its size, differing from the trend for increased gyrencephaly found in the other rodent species examined. Conclusions: Our results show definite trends and patterns specific to each order. So it would seem that the order is a significant phylogenetic grouping in terms of this neural parameter, from which we can predict with a reasonable degree of certainty, the GI of any species of a particular order, if we know the brain weight. Abstract (for Chapter 3) The mammalian order has proven to be a significant phylogenetic grouping in terms of gyrification from which we can predict with a reasonable degree of certainty, the GI of any species of a particular order, if we know the brain weight. We have attempted in the present study to identify potential causes for gyrification at the class level by investigating relationships at the level of the order. It appears that clues to the extent and pattern of gyrification in the different mammalian orders might be related to the bones that constitute the braincase. The external surface areas of the bones of the cranial vault of seventeen different mammalian species were measured using a microscribe digitiser. These values were plotted against brain weight from which we could then calculate residual values, determining if there was more or less external cranial vault area than expected for the size of the brain. These residuals were then plotted against the gyrification indices determined in a previous study for the species examined. Results indicated that for the primates and artiodactyls the skull may potentially be considered as a limiting factor on the expansion of the cerebral cortex; however, the carnivore and rodent orders show conflicting results which suggest that the relative surface area of the skull appears to have no effect on the quantitative extent of gyrencephaly. These inconclusive findings suggest that causes contributing to the quantitative extent of gyrification across mammals may be multifactorial, and more parameters may need to be included in the analysis to arrive at an answer.

Early life stress (ELS) leads to alterations in anatomy and function of the adult hippocampal dentate gyrus (DG), but the mechanisms by which these lasting changes occur have not been fully elucidated. We tested the hypothesis that the immediate decrease in cell proliferation and neurogenesis induced by stress is the key mediator of the negative long-term outcomes of ELS. First, we tested whether inhibition of cell proliferation during early life is sufficient to reproduce the ELS-induced reduction in adult DG neurogenesis. We demonstrate that targeting dividing stem cells for elimination during the first or third postnatal weeks leads to diminished adult neurogenesis and reduction of the stem cell pool. Also, we hypothesized that ELS leads to more persistent effects on DG function than stress later in life because of the stress-induced elimination of specific birth cohorts of DG granule cells (GCs) that have distinct functions. We tested whether different birth cohorts of DG GCs differ in function by assessing behavioral and stress response outcomes of pharmacogenetic elimination or optogenetic activation of adult GCs born during the first or third postnatal week. We demonstrate that dorsal GCs born during the first or third postnatal week may be involved in modulating exploratory and anxiety behavior, but that only third postnatal week born GCs stimulate HPA activity. These results suggest that mature DG GCs may differ in specific functions with birth date determining their functional role. Third, we directly assessed the effect of ELS on DG development to better understand the immediate effects of ELS on the DG and to identify other potential mediators of the long-term effects. We demonstrate that ELS using the limited bedding/nesting paradigm leads to developmental delay of the DG. The work presented in this dissertation contributes to our understanding of the mechanisms by which ELS produces lasting impairments in DG function and also to our knowledge of how DG GC function is specified.

The current project investigated the brain-behavior relationships between fusiform volume and orthographic processing in children with Reading Disability (RD) and Attention-Deficit/Hyperactivity Disorder (ADHD). It was hypothesized that there would be differences in fusiform volume between those with and without RD. Individuals with and without ADHD were not expected to differ in fusiform volume and an interaction in the RD/ADHD group was not expected. Children with RD/ADHD were expected to have similar volumes to children who have RD. It also was hypothesized that size of the left fusiform segments would be correlated with three orthographic processing tasks and tests of reading achievement (i.e., Orthographic Choice, Homophone/Pseudohomophone Choice and the Colorado Perceptual Speed Task; Letter Word Identification, Word Attack, and Reading Fluency). Results indicated that there were no group differences in fusiform volume between children with and without RD as well as with and without ADHD. There were also no relationships between the left fusiform and any of the orthographic or reading achievement measures. However, all three measures of orthographic processing were significantly related to the right posterior fusiform. Additionally, Homophone/Pseudohomophone Choice and Reading Fluency demonstrated a trend with the right anterior fusiform. The findings reported in this study were largely unexpected and suggest that further research examining the relationship between right fusiform volume and orthographic processing is warranted.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2001. / Bibliography: leaves 71-78.

Thesis (Ph.D.)--Memorial University of Newfoundland, 2003. / Bibliography: leaves 205-228.

Thesis (Ph.D.)--Memorial University of Newfoundland, 2003. / Bibliography: leaves 150-201.

Fluoxetine is a Selective Serotonin Reuptake Inhibitor (SSRI) often prescribed for the treatment of anxiety and depression. Many of its effects are thought to be mediated by the dentate gyrus, but the mechanism by which some patients respond to treatment and some do not remains poorly understood. In this study we have characterized a previously-unknown component of the behavioral response to fluoxetine in the dentate gyrus, using a combination of genomic, behavioral, and imaging techniques. We have found that different components of the opioid system are involved in the treatment efficacy of fluoxetine in the dentate gyrus. Specifically, we have identified a population of anatomically and transcriptionally distinct mature granule cells that are defined by their high levels of proenkephalin expression after fluoxetine treatment. Furthermore, we have shown that the delta opioid receptor is partly mediating some of the behavioral effects of fluoxetine in a neurogenesis-independent manner. These results open an interesting new avenue for research into the involvement of the opioid system in the behavioral response to SSRIs.

Methylphenidate is a psychostimulant used to treat attention deficit hyperactivity disorder. Neurogenesis occurs throughout adulthood within the dentate gyrus of the hippocampus and can be altered by psychoactive medications; however, the impact of methylphenidate on neurogenesis is not fully understood. We investigated the effects of chronic low (1 mg/kg) and high (10 mg/kg) intraperitoneal doses of methylphenidate on neurogenesis in mouse hippocampus following 28 days and 56 days of treatment. Interestingly, methylphenidate, at both doses, increased neurogenesis. However, if methylphenidate treatment was not continued, the newly generated cells did not survive after 28 days. If treatment was continued, the newly generated neurons survived only in the mice receiving low-dose methylphenidate. To investigate the mechanism for this effect, we examined levels of proteins linked to cell proliferation in the hippocampus, including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), tropomyosin receptor kinase B (TrkB), and beta-catenin. BDNF or GDNF levels were not significantly different between groups. However, hippocampal VEGF, TrkB, and beta-catenin were significantly increased in mice receiving low-dose methylphenidate for 28 days compared to controls. Interestingly, high-dose methylphenidate significantly decreased beta-catenin after 28 days and decreased VEGF, beta-catenin, and TrkB after 56 days compared to controls. Thus, low-dose methylphenidate appears to increase cell proliferation and cell survival in the hippocampus, and these effects may be mediated by increase in VEGF, TrkB, and beta-catenin. While high dose methylphenidate may initially increase neuronal proliferation, newly generated neurons are unable to survive long-term, possibly due to decrease in VEGF, TrkB and beta-catenin.

Alzheimer’s disease (AD) is widely accepted as being linked with abnormal atrophy of the hippocampus. In the nonhuman-focused literature, the hippocampus has been identified as one of the prominent regions of interest with mechanisms of adult neurogenesis from aerobic exercise. Several human studies over the past decade have shown the effect of exercise that improves cardiorespiratory fitness on the size and function of the hippocampus in participants. However, the size of hippocampal subfields, especially the dentate gyrus (DG), has not been examined in humans even though various animal studies have identified the DG subfield as the primary region of adult neurogenesis induced by aerobic exercise. The point of this investigation, therefore, was to investigate the effect of an exercise intervention on the size of the DG subfield and the related subfield of cornu ammonis (CA) 3. The hypothesis was that an endurance training intervention, designed to improve cardiorespiratory fitness, would increase the volume of the DG and CA3 subfields of the hippocampus more than a resistance training intervention, designed to increase strength, flexibility, and balance, and that improvement in cardiorespiratory fitness would positively correlate with the change in volumes of these subfields. For this investigation, 32 participants (young adults from age 20 to 33 with sedentary lifestyles) were selected from a data set collected for an ongoing study by the Brain Plasticity and Neuroimaging (BPN) Laboratory at Boston University School of Medicine (Boston, MA, USA). The fitness data and T1-weighted and T2-weighted structural magnetic resonance imaging (MRI) data were used in the analysis. FreeSurfer v6.0 software was used to extract volumetric data of the hippocampal subfields using a hippocampal subfield segmentation algorithm. Analysis of variance (ANOVA) with repeated measures and linear regression were used to analyze the statistical significance of the results. The change in volumes for the whole hippocampus, DG, and CA3 did not show any statistically significant differences after endurance training compared with after resistance training. The effect of exercise on the volume of the CA3 subfield appeared to be asymmetrical from left to right, with heavier impact on the left CA3 than on the right CA3. There was no statistically significant correlation between the change in cardiorespiratory fitness and the change in volume of any of the regions analyzed. However, the left whole hippocampus showed a slight trend (p = 0.078; R = 0.317) of weak positive correlation between its volume change and the cardiorespiratory fitness change of the participants. This result was consistent with the previous human literature. Although statistically not significant, most data showed that the endurance training group saw more preservation or increase in volume. This result is encouraging and should be explored further to validate the efficacy of cardiorespiratory exercise as a possible prevention mechanism against AD for young adults later in life.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2002. / Bibliography: leaves 78-89.