Date of Award

August 2013

Degree Type


Degree Name

Doctor of Philosophy



First Advisor

Rodney A. Swain

Committee Members

Fred J. Helmstetter, James R. Moyer, Ava Udvadia, Karyn Frick


Angiogenesis, Exercise, HIF-1alpha, Hypoxia, Morris Water Maze


Exercise induces a myriad of effects on the brain from the growth of new capillaries and neurons, to improvements in cognitive performance. Additionally, recent research has shown that commencement of an exercise regimen also causes apoptosis. Therefore, it is possible that exercise-induced increases in oxygen demand cause the brain to transiently experience a state of hypoxia. To investigate this hypothesis, we measured protein levels of hypoxia inducible factor 1 alpha (HIF-1α), a transcription factor known to be upregulated in conditions of hypoxia or ischemia, in animals exposed to a single bout of treadmill exercise. After exercise animals were sacrificed at various time points, ranging from immediately post-exercise to six hours after exercise; we also investigated the effects of long-term exercise on HIF-1α expression. We found that animals sacrificed immediately or four hours after exercise had significantly greater HIF-1α expression in area CA1 of the hippocampus. Because the angiogenic factor vascular endothelial growth factor (VEGF) is a target gene for HIF-1α, in another experiment, we investigated whether HIF-1α expression itself and/or downstream angiogenesis mediate improved performance in the Morris Water Maze (MWM). Animals were exposed to one of five different conditions for one week: forced (FX) or voluntary exercise (VX), inactive condition (IC), or treatment with the HIF-1α agonist dimethyloxylylglycine (DMOG) or vehicle injections (VEH). We found significantly increased HIF-1α expression in area CA1 of the hippocampus in VX, FX, and VEH animals, and significantly increased CA1 capillary density in VX, DMOG, and IC animals. Furthermore, VX, DMOG, and IC animals acquired the task the fastest, but VX, FX, and DMOG-treated animals performed significantly better than VEH and IC animals during the reacquisition and retention phases of training. Overall, these findings indicate that voluntary exercise or manipulation of HIF-1α expression results in increased capillary density and behavioral flexibility. Therefore, it is possible that HIF-1α serves as a mediator of exercise-induced improvements in cognitive performance, a process that appears to operate by way of increases in capillary density. Because exercise has been shown to be neuroprotective, this research is of potential interest in investigations of ischemia, brain injury, and neurodegeneration.