Thesis (Ph. D. in Cell and Developmental Biology)--Vanderbilt University, Dec. 2005. / Title from title screen. Includes bibliographical references.

Thesis (doctoral)--Lund University, 1995. / Added t.p. with thesis statement inserted.

Thesis (Ph.D.)--University of Missouri-Columbia, 2004. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Chicago, Committee on Neurobioloy, March 2001. / Includes bibliographical references. Also available on the Internet.

No description available.

No description available.

During embryonic development neurons of the cerebral cortex are generated from various progenitor cells that have progressively restricted fate. Understanding the multiple regulatory pathways that regulate the cell cycle kinetics and the identity of neurons is crucial to comprehend the etiology of severe developmental defects such as microcephaly and polymicrogyria and also the evolutionary expansion of the mammalian cerebral cortex. Intermediate progenitors (IPCs) express the transcription factor Tbr2 (a T-box gene) and deletion of this gene causes a decrease in brain size and cortical thickness. However, little is known about the molecular mechanisms regulating behavior of IPCs. In this thesis, I studied the molecular mechanisms regulating cell division and cell fate choices in IPCs using an overexpression system. I show that Tbr2 controls the expression of key genes such as Cdk4, Aspm and Wnt5a by directly binding to upstream regulatory sequences. These downstream targets could explain the role played by Tbr2 in cell cycle, spindle assembly and Wnt signaling in intermediate progenitors. The interaction with Aspm also suggests a possible mechanism of self-renewal of IPCs leading to an expanded generation of cortical neurons and ultimately an increased cortical size. While the role of IPCs in cortical neurogenesis is undisputed, it is widely believed that they contribute only towards supragranular layers. Using a knock-in transgenic mouse line (Tbr2^Cre), I show that IPCs provide glutamatergic neurons (but not GABAergic neurons or GFAP+ astrocytes) towards all cortical layers in a significant proportion (20-40%). I also show that clonally generated neurons disperse within tangential dimension across the cortex significantly closer (142.1 ± 76.8 µm) than unrelated ones (294.9 ± 105.4 µm) though within the confines of a cortical column (300-600 µm). Finally, I describe the similarity in the germinal zones of a large-brained gyrencephalic rodent, agouti and a lissencephalic primate, marmoset. Both these species show similar germinal zone cytoarchitecture and distribution of various progenitors. Further, the number of IPCs is grossly expanded thus demonstrating the conserved role of IPCs in cortical expansion regardless of the folding status of the cortex in these two species.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

The neonatal subventricular zone (SVZ) is a site of continued postnatal neurogenesis, and is the source of cortical glial cells. Apoptosis is an endogenous process of cell destruction, and is a key event in the proper development of the SVZ. Despite its importance, there is still a lack of knowledge regarding the temporal and spatial occurrence of neonatal SVZ apoptosis, cell types affected and the underlying intrinsic and extrinsic mechanisms that guide the process. This thesis addresses these issues, and in addition, finds a nontraditional mode of neurotrophic action for cell survival in the neonatal SVZ. We assessed SVZ apoptosis by subregion, employing the cell death markers, pH2ax and cleaved caspase 3. The medial SVZ contained the highest density of dying cells at p0, while at p7 there was no significant difference in the apoptotic cell density distribution in the SVZ subregions. Combining cell type specific markers with the death markers used, revealed immature postmitotic neurons were the primary cell type cleared in the p0 medial SVZ. The majority of dying cells in the p7 dorsolateral SVZ (SVZdl) were unable to be identified. Using stereotactic injection of a GFP expressing lentivirus, we determined the p0 medial SVZ cell population to be migratory cells bound for the olfactory bulb. An investigation into the intrinsic and extrinsic mechanisms mediating cell death in the neonatal SVZ, showed BH3-only protein Bim expression in the p0 and p7 SVZ, as well as significantly decreased p0 medial SVZ apoptosis in Bim knockout mice. Bim knockout mice did not show a significant change in apoptosis in the p7 SVZdl. TrkB knockout mice have shown a survival role for the receptor in the lateral ganglionic eminence of the neonatal SVZ. To test this in the p0 medial SVZ using a more specific method, a TrkB blocking antibody was injected into the p0 medial SVZ. This resulted in a significantly higher number of apoptotic cells in the p1 medial SVZ versus controls. These studies demonstrate the dynamic nature of the SVZ with its changing density and identity of apoptotic cells within the subregions. It has also shown the influence of Bim and TrkB signaling in neonatal SVZ apoptosis and survival. Finally, it has identified a premigratory cell population in the p0 medial SVZ, whose survival is mediated by neurotrophin signaling at their site of origin.

The hippocampus is a brain structure involved in memory as well as anxiety and depression-related behavior. One unique property of the hippocampus is that adult neurogenesis occurs in this region. Rodent studies in which adult hippocampal neurogenesis is ablated have shown a role for this process in the cognitive domain, specifically in pattern separation tasks, as well as in mediating the behavioral effects of antidepressants. These studies have furnished the intriguing hypothesis that increasing adult hippocampal neurogenesis may improve these functions and therefore serve as a target for novel treatments for cognitive impairments as well as depression and anxiety disorders. Here, we use both genetic and pharmacological models to increase adult neurogenesis in mice. Under baseline conditions, we find that increasing adult hippocampal neurogenesis is sufficient to improve performance in a fear-based pattern separation task, but has no effect on exploratory, anxiety or depression-related behavior. In mice exposed to voluntary exercise, increasing adult hippocampal neurogenesis increases exploration, without affecting anxiety or depression-related behavior. Finally, in mice treated with chronic corticosterone, a model of anxiety and depression, increasing adult hippocampal neurogenesis is sufficient to prevent the behavioral effect of CORT on anxiety and depression-related behavior. Here, we therefore describe dissociations between the effects of increasing adult hippocampal neurogenesis under baseline, voluntary exercise and chronic stress conditions. Together, our results suggest that increasing adult hippocampal neurogenesis has therapeutic potential for both cognitive, and anxiety and depression-related disorders.