Neurogenesis, the production of new neurons, is limited to only a few sites in the adult mammalian brain. In the dentate gyrus of the hippocampus, progenitor cells give rise to progeny which can mature into neurons during their migration to appropriate sites and make appropriate connections within the existing network. Thousands of cells are produced every day, although many of them do not survive long enough to integrate. Factors such as physical activity, enriched living environment, learning tasks and antidepressant medications have been shown to enhance neurogenesis. Other factors such as stress, corticosteroid hormones, and aging inhibit genesis and survival of these cells, and this has been correlated both with impairments in formation of certain types of spatial memories and with onset of depression. Many of the drugs currently used to treat cancer and tumor formation in humans act by inhibiting mitosis (cell division) and survival of newborn cancer cells which have mutated in a way to avoid the mechanisms that normally keep these processes in check. There are multiple classes of drugs which accomplish this inhibition via actions at different points in mitosis. However, these antimitotic drugs produce common side- effects such as hair loss, digestive problems, immunosuppression, and anemia, which all result primarily from inhibition of normal, necessary replication and survival of new cells in the body. It stands to reason that any of these drugs which are capable of entering into the brain would also inhibit the cell proliferation normally observed in the hippocampus, with potential negative implications for cognition and behavior. The experiments proposed in this application will address the impact of antimitotic chemotherapy drugs on the normal processes of cell proliferation and survival in the hippocampus of mice using histological methods of identifying newborn cells in brain tissue, as well as cells in which apoptosis (i.e., """"""""programmed cell death"""""""") has been triggered. A selection of drugs with varying capacities to penetrate the brain and with different mechanisms of action will be tested. Drugs impairing these cellular processes will then be tested for effects on cognition and behavior using spatial memory tasks and measuring depression-related behaviors, both of which have been associated with neurogenesis in the dentate gyrus. This work is relevant to public health given the putative contributions of impaired neurogenesis to cognitive and behavioral disorders. ? ? ?
| Wilson, Courtney L; Weber, E Todd (2013) Chemotherapy drug thioTEPA exacerbates stress-induced anhedonia and corticosteroid responses but not impairment of hippocampal cell proliferation in adult mice. Behav Brain Res 236:180-5 |
| Mondie, Christopher M; Vandergrift, Kelley A; Wilson, Courtney L et al. (2010) The chemotherapy agent, thioTEPA, yields long-term impairment of hippocampal cell proliferation and memory deficits but not depression-related behaviors in mice. Behav Brain Res 209:66-72 |
| Legates, Tara A; Dunn, Danielle; Weber, E Todd (2009) Accelerated re-entrainment to advanced light cycles in BALB/cJ mice. Physiol Behav 98:427-32 |
