Whether and how specific portions of the adult brain produce new neurons and integrate them into functional neural circuits, a process known as neurogenesis, is of great importance to the future of regenerative medicine for the brain. It is probably easier to beneficially adjust the operation of existing tissue maintenance mechanisms than to safely deliver cells to a tissue that has no such capacity for regeneration. In the brain in particular, fine structure is enormously important to function, so comparatively blunt approaches to the delivery of replacement cells may prove challenging to implement safely.
In mammals, neural stem cells (NSCs) in the early embryonic period are called neuroepithelial cells. In the adult brain, most NSCs are quiescent. However, NSCs in the ventricular-subventricular zone (V-SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) slowly divide to generate transit amplifying progenitor cells (TAPs) via a state called activated neural stem cells (aNSC) and thus generate new neurons. Such adult neurogenesis in the mammalian brain was first suggested in the 1960s, and neurogenesis has been found to occur primarily in the V-SVZ and SGZ throughout life. New neurons generated in these two neurogenic areas are incorporated into neural circuits and play important roles.
The attenuation of adult neurogenesis in the V-SVZ has been reported to cause abnormal olfactory and sexual behavior in mice. In addition, new neurons generated in the SGZ are also integrated into DG neural circuits and play an important role in the formation of short-term memory. The attenuation of neurogenesis in the mouse SGZ has been reported to result in the impairment of new memory formation. These new neurons are also important for the formation of spatial memories. Furthermore, new integrated neurons in the DG have the function of organizing past memories and alleviating the stress response. However, adult neurogenesis decreases with age, mainly due to a decrease in NSCs and TAPs. Several studies have reported that this reduction is likely to be caused by decreases in extrinsic signals that support the proliferation of NSCs, including mitotic signals such as EGF and FGF-2, and increases in systemic pro-aging factors.
Since the existence of adult NSCs and adult neurogenesis was confirmed, studies on adult neurogenesis have been intensively conducted with the expectation of applying NSCs and neurogenesis for regenerative medicine. Although the mobilization of endogenous NSCs has been studied as one of regenerative approaches to restore lost brain function in cerebrovascular diseases, traumatic brain injuries, neurodegenerative diseases, etc., there are still many issues to be solved, such as the depletion of NSCs and the directed migration of new neurons. From a fundamental point of view, identifying the regulatory mechanisms of adult neurogenesis and its age-related decline will undoubtedly lead to future regenerative medicine strategies.