Neurogenesis, the production of new neurons, was traditionally assumed to occur only during development in the central nervous system (CNS) of mammals. It has become generally accepted that new neurons are indeed added in discrete regions of the adult brain of mammals. Throughout life, new neurons are generated in the subventricular zone (SVZ) of the lateral ventricle and in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus under normal conditions. Whether adult neurogenesis occurs in areas of mammalian brain other than SVZ and SGZ remains controversial. The process of adult neurogenesis, including the proliferation of adult neural stem cells (NSCs) or multipotent neural progenitor cells (NPCs), commitment to a neuronal phenotype, differentiation (development of neuronal features), survival, maturation, and integration of newborn neurons, is highly regulated by physiological and pathological factors. It has been pointed out that two main lines of research have emerged following the investigation of adult neurogenesis. The first is to understand the fundamental biological properties of neural stem cells, eventually leading to repair and regeneration of neurodegenerative diseases. The second is to understand the functional relevance of neurogenesis, especially in DG, meaning the contribution of new-born neurons to brain functions.
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Neurogenic Brain Regions
A brain region that supports neurogenesis is classified as neurogenic. Neurogenic regions contain NSCs or NPCs and have microenvironment permissive for the production of new neurons. In the adult mammalian brain under normal conditions, there are neurogenic regions that are generally accepted, namely the SVZ of the lateral ventricle and the SGZ of the DG in the hippocampus. In the lateral ventricle, new neurons are born in the SVZ and migrate anteriorly into the olfactory bulb where they differentiate into granule neurons and periglomerular neurons. In the hippocampus, new neurons are generated in SGZ, migrate a short distance to granule cell layer, where they differentiate into granule neurons. In addition to these two regions, other adult brains regions, such as neocortex, striatum, and hypothalamus, have been reported to produce new neurons; however, the results are controversial.
Adult neurogenesis is composed of many steps, including the proliferation of adult NSCs or multipotent NPCs, commitment to a neuronal phenotype, differentiation (development of neuronal features), survival, maturation, and integration of newborn neurons.
Most of the neurons in the adult CNS are terminally differentiated and cannot be regenerated. In contrast, NSCs or NPCs have the proliferative capacity to undergo mitosis and generate new neurons. The term "stem, progenitor, and precursor cells" have been used interchangeably in the literature. The NSC is currently defined as an undifferentiated cell that exhibits the ability to self-renew and to differentiate into multiple lineages, including neurons, astrocytes, and oligodendrocytes. There has been an intense debate regarding the identity of neural stem stems in the adult brain for years.
The SGZ is located at the interface between the granule cell layer and the hilus of DG in the hippocampus, deep within the parenchyma. Two types of NSCs have been identified on the basis of morphology and cell marker ex
The proliferation of NSCs or NPCs is regulated by a complex mechanism, including neural stem niche, growth factors, neurotransmitters, and physiological factors. In addition, pathological conditions can also alter neuronal proliferation as described below.
After proliferation, the next class of cells is the intermediate precursors, called D cells (D2 and D3). D cells are clearly different from radial type 1 cells. They have a round soma with short cytoplasm extension. These cells no longer express nestin or Sox2, but began to express the polysiliated form of the neural cell adhesion molecule (Seri, Garcia-Verdugo et al. 2004), and microtubule-associated protein, doublecortin (DCX). DCX was reported to be associated with both of the initiation of neuronal differentiation and migration. The evidence suggested that D2 cells may mature through the D3 stage to form new granule cells since the D3 cells have the morphological characteristics of immature neurons, such as prominent, frequently branched, radial processes extending through the granule cell layer and thin processes projecting into the hilus.
After the new born cells become postmitotic and differentiated, characterized by the transit ex
Newborn cells not differentiated die through apoptotic cell death. After birth, at least 50 % of newborn cells die within three weeks. The survival of newborn cells is subject to regulation by diverse mechanisms. The survival of 1 to 3-week-old newborn neurons is affected by the animal's experience, such as learning and exposure to enriched environment. A recent study showed that the survival of newborn cells is competitively regulated by their own NMDA-type glutamate receptor during a short period soon after birth, suggesting that the survivals of new neurons are regulated in an input-dependent manner. In addition, cell survival is also regulated by other mechanism, such as growth factors. For example, BDNF promotes the survival of newborn cells in the hippocampus.