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 (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”. [2] [3] [4] 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. [5]
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: [6] [7]
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. [10] 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. [3]
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. [11] 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. [12] 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. [13] [14] [15]
The dentate gyrus (DG) is part of the hippocampal formation in the temporal lobe of the brain, which also includes the hippocampus and the subiculum. The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute to the formation of new episodic memories, the spontaneous exploration of novel environments and other functions.
Adult neurogenesis is the process in which neurons are generated from neural stem cells in the adult. This process differs from prenatal neurogenesis.
In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as Drosophila, neuroblasts are neural progenitor cells which divide asymmetrically to produce a neuroblast, and a daughter cell of varying potency depending on the type of neuroblast. Vertebrate neuroblasts differentiate from radial glial cells and are committed to becoming neurons. Neural stem cells, which only divide symmetrically to produce more neural stem cells, transition gradually into radial glial cells. Radial glial cells, also called radial glial progenitor cells, divide asymmetrically to produce a neuroblast and another radial glial cell that will re-enter the cell cycle.
Astrocytes, also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, regulation of cerebral blood flow, and a role in the repair and scarring process of the brain and spinal cord following infection and traumatic injuries. The proportion of astrocytes in the brain is not well defined; depending on the counting technique used, studies have found that the astrocyte proportion varies by region and ranges from 20% to around 40% of all glia. Another study reports that astrocytes are the most numerous cell type in the brain. Astrocytes are the major source of cholesterol in the central nervous system. Apolipoprotein E transports cholesterol from astrocytes to neurons and other glial cells, regulating cell signaling in the brain. Astrocytes in humans are more than twenty times larger than in rodent brains, and make contact with more than ten times the number of synapses.
Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes. They are typically identified by coexpression of PDGFRA and NG2.
The rostral migratory stream (RMS) is a specialized migratory route found in the brain of some animals along which neuronal precursors that originated in the subventricular zone (SVZ) of the brain migrate to reach the main olfactory bulb (OB). The importance of the RMS lies in its ability to refine and even change an animal's sensitivity to smells, which explains its importance and larger size in the rodent brain as compared to the human brain, as our olfactory sense is not as developed. This pathway has been studied in the rodent, rabbit, and both the squirrel monkey and rhesus monkey. When the neurons reach the OB they differentiate into GABAergic interneurons as they are integrated into either the granule cell layer or periglomerular layer.
Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube in early embryonic development. The neuroepithelial cells span the thickness of the tube's wall, connecting with the pial surface and with the ventricular or lumenal surface. They are joined at the lumen of the tube by junctional complexes, where they form a pseudostratified layer of epithelium called neuroepithelium.
Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor stem cells persist in highly restricted regions in the adult vertebrate brain and continue to produce neurons throughout life. Differences in the size of the central nervous system are among the most important distinctions between the species and thus mutations in the genes that regulate the size of the neural stem cell compartment are among the most important drivers of vertebrate evolution.
Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.
Neuropoiesis is the process by which neural stem cells differentiate to form mature neurons, astrocytes, and oligodendrocytes in the adult mammal. This process is also referred to as adult neurogenesis.
The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone containing neural progenitor cells, which divide to produce neurons in the process of neurogenesis. The primary neural stem cells of the brain and spinal cord, termed radial glial cells, instead reside in the ventricular zone (VZ).
A neurosphere is a culture system composed of free-floating clusters of neural stem cells. Neurospheres provide a method to investigate neural precursor cells in vitro. Putative neural stem cells are suspended in a medium lacking adherent substrates but containing necessary growth factors, such as epidermal growth factor and fibroblast growth factor. This allows the neural stem cells to form into the characteristic 3-D clusters. However, neurospheres are not identical to stem cells; rather, they only contain a small percent of neural stem cells.
Radiation-induced cognitive decline describes the possible correlation between radiation therapy and cognitive impairment. Radiation therapy is used mainly in the treatment of cancer. Radiation therapy can be used to cure care or shrink tumors that are interfering with quality of life. Sometimes radiation therapy is used alone; other times it is used in conjunction with chemotherapy and surgery. For people with brain tumors, radiation can be an effective treatment because chemotherapy is often less effective due to the blood–brain barrier. Unfortunately for some patients, as time passes, people who received radiation therapy may begin experiencing deficits in their learning, memory, and spatial information processing abilities. The learning, memory, and spatial information processing abilities are dependent on proper hippocampus functionality. Therefore, any hippocampus dysfunction will result in deficits in learning, memory, and spatial information processing ability.
Gliogenesis is the generation of non-neuronal glia populations derived from multipotent neural stem cells.
Eomesodermin also known as T-box brain protein 2 (Tbr2) is a protein that in humans is encoded by the EOMES gene.
Endogenous regeneration in the brain is the ability of cells to engage in the repair and regeneration process. While the brain has a limited capacity for regeneration, endogenous neural stem cells, as well as numerous pro-regenerative molecules, can participate in replacing and repairing damaged or diseased neurons and glial cells. Another benefit that can be achieved by using endogenous regeneration could be avoiding an immune response from the host.
Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.
A neuronal lineage marker is an endogenous tag that is expressed in different cells along neurogenesis and differentiated cells such as neurons. It allows detection and identification of cells by using different techniques. A neuronal lineage marker can be either DNA, mRNA or RNA expressed in a cell of interest. It can also be a protein tag, as a partial protein, a protein or an epitope that discriminates between different cell types or different states of a common cell. An ideal marker is specific to a given cell type in normal conditions and/or during injury. Cell markers are very valuable tools for examining the function of cells in normal conditions as well as during disease. The discovery of various proteins specific to certain cells led to the production of cell-type-specific antibodies that have been used to identify cells.
Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.
Adult neurogenesis is the process in which new neurons are born and subsequently integrate into functional brain circuits after birth and into adulthood. Avian species including songbirds are among vertebrate species that demonstrate particularly robust adult neurogenesis throughout their telencephalon, in contrast with the more limited neurogenic potential that are observed in adult mammals after birth. Adult neurogenesis in songbirds is observed in brain circuits that underlie complex specialized behavior, including the song control system and the hippocampus. The degree of postnatal and adult neurogenesis in songbirds varies between species, shows sexual dimorphism, fluctuates seasonally, and depends on hormone levels, cell death rates, and social environment. The increased extent of adult neurogenesis in birds compared to other vertebrates, especially in circuits that underlie complex specialized behavior, makes birds an excellent animal model to study this process and its functionality. Methods used in research to track adult neurogenesis in birds include the use of thymidine analogues and identifying endogenous markers of neurogenesis. Historically, the discovery of adult neurogenesis in songbirds substantially contributed to establishing the presence of adult neurogenesis and to progressing a line of research tightly associated with many potential clinical applications.
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