Different Mechanisms Must Be Considered to Explain the Increase in Hippocampal Neural Precursor Cell Proliferation by Physical Activity

Abstract

The number of proliferating neural precursor cells in the adult hippocampus is strongly increased by physical activity. The mechanisms through which this behavioral stimulus induces cell proliferation, however, are not yet understood. In fact, even the mode of proliferation of the stem and progenitor cells is not exactly known. Evidence exists for several mechanisms including cell cycle shortening, reduced cell death and stem cell recruitment, but as yet no model can account for all observations. An appreciation of how the cells proliferate, however, is crucial to our ability to model the neurogenic process and predict its behavior in response to pro-neurogenic stimuli. In a recent study, we addressed modulation of the cell cycle length as one possible mode of regulation of precursor cell proliferation in running mice. Our results indicated that the observed increase in number of proliferating cells could not be explained through a shortening of the cell cycle. We must therefore consider other mechanisms by which physical activity leads to enhanced precursor cell proliferation. Here we review the evidence for and against several different hypotheses and discuss the implications for future research in the field.

Keywords: S phase; adult neurogenesis; cell cycle; dentate gyrus; physical exercise; running.

Figure 1

An overview of the most commonly used model of adult hippocampal neurogenesis. The type-1 stem cells (second from left in red) either directly produce astrocytes (far left in purple) or give rise to progenitor cells which progress through several stages before becoming mature neurons or being eliminated through apoptosis. The color of the circular arrows represents average proliferation rate of the cells at different stages; darker shades equate to a more proliferative population. Some of the key markers used in the study of adult neurogenesis are shown with their expression profiles below. GFAP, glial fibrillary acidic protein; DCX, doublecortin.