Differential effects of voluntary running on hippocampal plasticity in the adult rat brain

Abstract: The continuation of neuronal birth from dividing neural stem cells in the dentate gyrus of the hippocampus throughout adulthood is known to play an important role in maintaining normal hippocampal function, such as memory and learning. Negative alterations in the levels of adult neurogenesis have also been linked to several neurodegenerative diseases, including Alzheimer s disease and mood disorders such as depression. This thesis investigated the effects of varying durations of voluntary running on the proliferation and differentiation of newborn cells in the hippocampus and the regulatory mechanisms involved in running induced hippocampal plasticity in adult rats. Animals were allowed free access to running wheels for 9, 24 or 43 days. On the last two days of voluntary running, bromodeoxyuridine was administered to label new cells and then the animals were sacrificed immediately or four weeks later to measure progenitor proliferation or levels of neurogenesis. We also used a hippocampal-dependent task, the Morris water maze, to measure possible alterations in spatial memory. Moderate levels of voluntary running for nine days were found to significantly increase progenitor proliferation and neurogenesis by almost 500% compared to non-running rats. We found that these effects were regulated through endogenous opioids and that phosphorylated CREB was involved in the running induced effects. Four weeks after the cessation of moderate levels of voluntary running, large pool of new neurons was generated with improvements seen in spatial memory. In contrast, high levels of voluntary running for 24 days were found to decrease progenitor proliferation levels compared to non-running rats. In these animals, we found a concomitant increase in corticosterone levels, an increased adrenal gland size and a decreased thymus size, indicating high levels of a response to stress. These negative effects were prevented by restricting daily running distances to more moderate levels over the 24 days. Interestingly, un-restricted long-term running increased progenitor survival with a small increase in neurogenesis and no effects seen on spatial memory compared to non-running rats. Extended running for 43 days was found to normalise progenitor proliferation, despite indications of a chronic response to stress. In these rats, we found increased levels of brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the hippocampus and frontal cortex, which may be an important part of a compensatory mechanism during periods of stress to maintain homeostasis in the brain. These findings demonstrate that moderate levels of voluntary running are most beneficial in promoting increased levels of neurogenesis in the brain and improving hippocampal function. There also exists an innate compensatory mechanism within the brain to attempt to restore homeostasis under periods of stress.