Evaluating the regulation and function of adult mouse hippocampal neurogenesis induced from running

Exercise is a potent natural stimulator of adult mammalian hippocampal neurogenesis. Relatively little is known about how exercise stimulates neuron formation in the hippocampus, and even less is known about the possible functions of new neurons. Therefore, factors regulating the survival and the potential functions of new hippocampal granule neurons generated from running were studied in adult mice. Chapter 1 examined the formation and activation of adult mouse granule cells over the course of access to running wheels. Granule cell activity (measured by c-Fos immunoreactivity) and net neurogenesis remained elevated at a relatively constant level over 50 days of running, despite observing a gradual increase in running distance over the first 20 days of wheel access. These results in conjunction with recent literature suggest that granule cell activity may be involved in regulating the stable, but elevated levels of neurogenesis, relative to animals housed without wheels, over the course of running. Chapter 2 investigated whether vasculature formation in the granule cell layer adapts to support the elevated level of granule cell activation and the constant addition of the new neurons over several days of running in adult mice. Results showed that vasculature density increased in the granule cell layer, but not across the entire hippocampus of chronically running mice. These data suggest that increased blood vessel density from running is specific to the granule cell layer within the hippocampus. An additional aim of chapter 2 was to test the hypothesis that new neurons from running are recruited into neural activity (measured by c-Fos immunoreactivity) displayed in the granule cell layer from running. The results showed that new neurons preferentially display c-Fos over mostly pre-existing neurons during running, suggesting that one potential function of new neurons is to process information about running behavior itself. Chapter 3 examined whether any form of physical activity can regulate neurogenesis and new and pre-existing granule cell activity (as measured by c-Fos, Zif268, and Arc immunoreactivity), or whether only more robust activity (such as running) is necessary these changes. Results showed that the expression of c-Fos, Arc, and Zif268 in new & pre-existing neurons, as well as net neurogenesis was strongly correlated distance traveled on running wheels, but not distance traveled in cages without running wheels. These data suggest that robust repetitive movements, such as running, are necessary to stimulate neuronal activity and neurogenesis. Evidence from the previous chapters favor the hypothesis that a subset of neurons formed from running may function in processing information related to running behavior itself. The remaining chapters explore an alternative hypothesis that new neurons are highly plastic units that may function in whatever information the hippocampus is processing at any particular moment. Chapter 4 entertained the hypothesis that new neurons generated from running also contribute to improved performance on water maze, contextual fear conditioning, and rotarod. Groups of running and non-running mice were either irradiated to reduce neurogenesis or not irradiated. Results showed that running enhanced performance over sedentary mice on contextual fear conditioning and rotarod, regardless of irradiation. However, only non-irradiated running mice displayed improved performance on the water maze over irradiated runners, irradiated sedentary, and non-irradiated sedentary mice. These data suggest new neurons generated from running may increase plasticity that can be used to improve hippocampal-dependent spatial learning. Chapter 5 examines whether new neurons generated from running become activated in association with spatial learning tasks. The activation of new neurons (as measured by Zif268 immunoreactivity) was assessed in running and sedentary mice following participation in one of three different tasks that engages the hippocampus; the water maze, novel environment exploration, or wheel running. Results show that the proportion of new neurons displaying Zif268 was related to the degree of Zif268 induction in the granule cell layer from each task. Sedentary and runner mice did not differ in the proportion of new neurons expressing Zif268 within each task, demonstrating that a greater number of new neurons are becoming activated in running animals. Taken together, results favor the hypothesis that new neurons from running are highly plastic units that can become activated by distinct tasks that engage the dentate gyrus