The subgranular zone (SGZ) is a brain region in the hippocampus where adult neurogenesis occurs. The other major site of adult neurogenesis is the subventricular zone (SVZ) in the brain.[1]
The subgranular zone is a narrow layer of cells located between the granule cell layer and hilus of the dentate gyrus. This layer is characterized by several types of cells, the most prominent type being neural stem cells (NSCs) in various stages of development. However, in addition to NSCs, there are also astrocytes, endothelial cells, blood vessels, and other components, which form a microenvironment that supports the NSCs and regulates their proliferation, migration, and differentiation. The discovery of this complex microenvironment and its crucial role in NSC development has led some to label it as a neurogenic “niche”. It is also frequently referred to as a vascular, or angiogenic, niche due to the importance and pervasiveness of the blood vessels in the SGZ.
The brain comprises many different types of neurons, but the SGZ generates only one type: granule cells—the primary excitatory neurons in the dentate gyrus (DG)--which are thought to contribute to cognitive functions such as memory and learning. The progression from neural stem cell to granule cell in the SGZ can be described by tracing the following lineage of cell types:
Two main types of astrocytes are found in the SGZ: radial astrocytes and horizontal astrocytes. Radial astrocytes are synonymous with the radial glia cells described earlier and play dual roles as both glial cells and neural stem cells. It is not clear whether individual radial astrocytes can play both roles or only certain radial astrocytes can give rise to NSCs. Horizontal astrocytes do not have radial processes; rather, they extend their processes horizontally, parallel to the border between the hilus and the SGZ. Moreover, they do not appear to generate neuronal progenitors. Because astrocytes are in close contact with many of the other cells in the SGZ, they are well-suited to serve as sensory and regulatory channels in neurogenesis.
Endothelial cells, which line the blood vessels in the SGZ, are a critical component in the regulation of stem cell self-renewal and neurogenesis. These cells, which reside in close proximity to clusters of proliferating neurogenic cells, provide attachment points for neurogenic cells and release diffusible signals such as vascular endothelial growth factor (VEGF) that help induce both angiogenesis and neurogenesis. In fact, studies have shown that neurogenesis and angiogenesis share several common signaling pathways, implying that neurogenic cells and endothelial cells in the SGZ have a reciprocal effect on one another. Blood vessels carry hormones and other molecules that act on the cells in the SGZ to regulate neurogenesis and angiogenesis.
The main function of the SGZ is to carry out hippocampal neurogenesis, the process by which new neurons are bred and functionally integrated into the granular cell layer of the dentate gyrus. Contrary to long-standing beliefs, neurogenesis in the SGZ occurs not only during prenatal development but throughout adult life in most mammals, including humans.
The self-renewal, fate-choice, proliferation, migration, and differentiation of neural stem cells in the SGZ are regulated by many signaling molecules in the SGZ, including several neurotransmitters. For example, Notch is a signaling protein that regulates fate-choice, generally maintaining stem cells in a state of self-renewal. Neurotrophins such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are also present in the SGZ and are presumed to affect neurogenesis, though the exact mechanisms are unclear. Wnt and bone morphogenic protein (BMP) signaling also are neurogenesis regulators, as well as classical neurotransmitters such as glutamate, GABA, dopamine, and serotonin.Neurogenesis in the SGZ is also affected by various environmental factors such as age and stress. Age-related decreases in the rate of neurogenesis are consistently observed in both the laboratory and the clinic, but the most potent environmental inhibitor of neurogenesis in the SGZ is stress. Stressors such as sleep deprivation and psychosocial stress induce the release of glucocorticoids from the adrenal cortex into circulation, which inhibits neural cell proliferation, survival, and differentiation. There is experimental evidence that stress-induced reductions in neurogenesis can be countered with antidepressants. Other environmental factors such as physical exercise and continual learning can also have a positive effect on neurogenesis, stimulating cell proliferation despite increased levels of glucocorticoids in circulation.
There is a reciprocal relationship between neurogenesis in the SGZ and learning and memory, particularly spatial memory. On the one hand, high rates of neurogenesis may increase memory abilities. For instance, the high rate of neurogenesis and neuronal turnover in young animals may be the reason behind their ability to rapidly acquire new memories and learn new tasks. There is a hypothesis that the constant formation of new neurons is the reason newly acquired memories have a temporal aspect. On the other hand, learning, particularly spatial learning, which depends on the hippocampus, has a positive effect on cell survival and induces cell proliferation through increased synaptic activity and neurotransmitter release. Although more work needs to be done to solidify the relationship between hippocampal neurogenesis and memory, it is clear from cases of hippocampal degeneration that neurogenesis is necessary in order for the brain to cope with changes in the external environment and to produce new memories in a temporally correct manner.
There are many neurological diseases and disorders that exhibit changes in neurogenesis in the SGZ. However, the mechanisms and significances of these changes are still not fully understood. For example, patients with Parkinson's disease and Alzheimer's disease generally exhibit a decrease in cell proliferation, which is expected. However, those who experience epilepsy, a stroke, or inflammation exhibit increases in neurogenesis, possible evidence of attempts by the brain to repair itself. Further definition of the mechanisms and consequences of these changes may lead to new therapies for these neurological disorders. Insights into neurogenesis in the SGZ may also provide clues in understanding the underlying mechanisms of cancer, since cancer cells exhibit many of the same characteristics of undifferentiated, proliferating precursor cells in the SGZ. Separation of precursor cells from the regulatory microenvironment of the SGZ may be a factor in the formation of cancerous tumors.