Honors Project--Smith College, Northampton, Mass., 2009. / Includes bibliographical references (p. 125)

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [90]-105).

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: Neuroscience; migration; yeast two-hybrid; MIG-10. Includes bibliographical references (leaves 58-60).

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: axon outgrowth; signal transduction; C. elegans; cell migration; mig-10. Includes bibliographical references (p. 61).

Thesis (Ph. D.)--Rutgers University, 2007. / "Graduate Program in Biomedical Engineering." Includes bibliographical references.

Thesis (Ph.D.) - University of Queensland, 2003. / Includes bibliography.

Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisor: Wesley J. Thompson. Vita. Includes bibliographical references.

The spatial location of cells in neural tissue can be easily extracted from many imaging modalities, but the information contained in spatial relationships between cells is seldom utilized. This is because of a lack of recognition of the importance of spatial relationships to some aspects of brain function, and the reflection in spatial statistics of other types of information. The mathematical tools necessary to describe spatial relationships are also unknown to many neuroscientists, and biologists in general. We analyze two cases, and show that spatial relationships can be used to understand the role of a particular type of cell, the astrocyte, in Alzheimer's disease, and that the geometry of axons in the brain's white matter sheds light on the process of establishing connectivity between areas of the brain. Astrocytes provide nutrients for neuronal metabolism, and regulate the chemical environment of the brain, activities that require manipulation of spatial distributions (of neurotransmitters, for example). We first show, through the use of a correlation function, that inter-astrocyte forces determine the size of independent regulatory domains in the cortex. By examining the spatial distribution of astrocytes in a mouse model of Alzheimer's Disease, we determine that astrocytes are not actively transported to fight the disease, as was previously thought. The paths axons take through the white matter determine which parts of the brain are connected, and how quickly signals are transmitted. The rules that determine these paths (i.e. shortest distance) are currently unknown. By measurement of axon orientation distributions using three-point correlation functions and the statistics of axon turning and branching, we reveal that axons are restricted to growth in three directions, like a taxicab traversing city blocks, albeit in three-dimensions. We show how geometric restrictions at the small scale are related to large-scale trajectories. Finally we discuss the implications of this finding for experimental and theoretical connectomics.

The brain consists of a complex network of axons, transmitting electrical impulses between interconnected neurons across distances that range from fractions of millimeters to meters. Myelinated axons, or nerve fibers, are axons that are wrapped by a myelin sheath, serving as an electrical insulation that increases the propagation speed of the signal along the nerve fiber while conserving the energy consumed and the space needed to maintain such propagation speed without myelin. Changes in the axon and surrounding myelin sheath during development and aging, or as a consequence of pathology, affect conduction and the proper functioning of the axon bundles. It is therefore important to be able to quantify the properties of these axons and their bundles and to discern which features best characterize the observed differences. We study the effects of aging on the myelinated axons in the fornix of the brain. The fornix is the principal subcortical output tract of the hippocampal formation, which plays a central role in memory. We obtain a collection of 328 high-quality electron micrographs from the fornix of 25 different rhesus monkey brains, ranging from young adults to the elderly, with both males and females. In this work, we develop a novel advanced recognition algorithm for automatically identifying myelinated axons and their surrounding myelin sheath. We extract multiple features of the nerve fibers and fully characterize their spatial structure. Using a feature selection algorithm, we discriminate between young and aged rhesus monkeys with a high level of accuracy and pinpoint the differences in the aging process at the ultrastructural level across the life span. We observe a decline in the density of myelinated axons as well as in the fraction of occupied axon area with age, while the average axon area shows no dependence on the age of the subjects. We show an increase in the myelin thickness of axons for the female subjects, while no dependence is observed for the male subjects. This sex dichotomy is also present in the g-ratio of the myelinated axons, i.e., the ratio of the axon diameter to the fiber diameter. The method detailed here could be adapted to enable recognition in other areas as well as for changes caused by brain pathologies or by developmental disorders. Furthermore, the data collected will ultimately be useable in better modeling conduction properties in myelinated axons and better understanding how the aging process affects them.

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