View source for Biology:Subgranular zone

[[File:Doublecortin expression-2.png|400px|thumb|The subgranular zone (in rat brain). (A) Regions of the dentate gyrus: the hilus, subgranular zone (sgz), granule cell layer (GCL), and molecular layer (ML). Cells were stained for doublecortin (DCX), a protein expressed by neuronal precursor cells and immature neurons. (B) Closeup of subgranular zone, located between the hilus and GCL. From a paper by Charlotte A. Oomen, et al., 2009.]]
The '''subgranular zone''' ('''SGZ''') is a [[Biology:Brain|brain]] region in the [[Biology:Hippocampus|hippocampus]] where [[Biology:Adult|adult]] [[Biology:Neurogenesis|neurogenesis]] occurs.  The other major site of [[Biology:Adult neurogenesis|adult neurogenesis]] is the [[Biology:Subventricular zone|subventricular zone]] (SVZ) in the brain.<ref>{{Cite journal|last=Ohira|first=Koji|title=Cortical adult neurogenesis and its biological implication|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/cen3.12652|journal=Clinical and Experimental Neuroimmunology|year=2023 |volume=14 |pages=44–51 |language=en|doi=10.1111/cen3.12652|s2cid=236282146|issn=1759-1961}}</ref>

== Structure ==
The subgranular zone is a narrow layer of cells located between the [[Biology:Granule cell|granule cell]] layer and hilus of the [[Biology:Dentate gyrus|dentate gyrus]]. This layer is characterized by several types of cells, the most prominent type being [[Biology:Neural stem cell|neural stem cell]]s (NSCs) in various stages of development. However, in addition to NSCs, there are also [[Biology:Astrocyte|astrocyte]]s, [[Biology:Endothelium|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”.<ref name="Doetsch2003a" /><ref name="Riquelme2008" /><ref name="Ma2008" /> 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.<ref name="Tavazoie2008" />

=== Neural stem cells and neurons ===
[[File:subgranular zone structure and components.png|220px|thumb|Structure and features of the neurogenic niche. Adapted from a paper by Ilias Kazanis, et al., 2008.]]
The brain comprises many different types of [[Biology:Neuron|neuron]]s, but the SGZ generates only one type: [[Biology:Granule cell|granule cell]]s—the primary excitatory neurons in the [[Biology:Dentate gyrus|dentate gyrus]] (DG)--which are thought to contribute to cognitive functions such as [[Memory|memory]] and [[Learning|learning]]. The progression from neural stem cell to granule cell in the SGZ can be described by tracing the following lineage of cell types:<ref name="Kemperman2008" /><ref name="Seri2004" />

#''Radial glial cells''. Radial glial cells are a subset of [[Biology:Astrocyte|astrocyte]]s, which are typically thought of as non-neuronal support cells. The radial glial cells in the SGZ have cell bodies that reside in the SGZ and vertical (or radial) processes that extend into the molecular layer of the DG. These processes act as a scaffold upon which newly formed neurons can migrate the short distance from the SGZ to the granule cell layer. Radial glia are astrocytic in their morphology, their expression of glial [[Biology:Biomarker (cell)|markers]] such as [[Biology:Glial fibrillary acidic protein|GFAP]], and their function in regulating the NSC microenvironment. However, unlike most astrocytes, they also act as neurogenic progenitors; in fact, they are widely considered to be the neural stem cells that give rise to subsequent neuronal precursor cells. Studies have shown that radial glia in the SGZ express [[Biology:Nestin (protein)|nestin]] and [[Biology:SOX2|Sox2]], biomarkers associated with neural stem cells, and that isolated radial glia can generate new neurons ''in vitro''.<ref name="Palmer1997" /> Radial glial cells often divide [[Biology:Asymmetric cell division|asymmetrically]], producing one new stem cell and one neuronal precursor cell per division. Thus, they have the capacity for self-renewal, enabling them to maintain the stem cell population while simultaneously producing the subsequent neuronal precursors known as transiently amplifying cells.<ref name="Doetsch2003b" />  
#''Transiently amplifying progenitor cells''. Transiently amplifying (or transit-amplifying) [[Biology:Progenitor cell|progenitor cell]]s are highly proliferative cells that frequently divide and multiply via [[Biology:Mitosis|mitosis]], thus "amplifying" the pool of available precursor cells. They represent the beginning of a transitory stage in NSC development in which NSCs begin to lose their glial characteristics and assume more neuronal traits. For instance, cells in this category may initially express glial markers like GFAP and stem cell markers such as nestin and Sox2, but eventually, they lose these characteristics and begin expressing markers specific to granule cells such as NeuroD and [[Biology:PROX1|Prox1]]. It is thought that the formation of these cells represents a [[Biology:Cell fate determination|fate-choice]] in neural stem cell development. 
#[[Biology:Neuroblast|''Neuroblasts'']]. Neuroblasts represent the last stage of precursor cell development before cells exit the [[Biology:Cell cycle|cell cycle]] and assume their identity as neurons. Proliferation of these cells is more limited, although [[Medicine:Brain ischemia|cerebral ischemia]] can induce proliferation at this stage.
#''Postmitotic neurons.'' At this point, after exiting the cell cycle, cells are considered immature neurons. The large majority of postmitotic neurons undergo [[Biology:Apoptosis|apoptosis]], or cell death. The few that survive begin developing the morphology of hippocampal granule cells, marked by the extension of dendrites into the molecular layer of the DG and the growth of axons into the CA3 region, and subsequently the formation of synaptic connections. Postmitotic neurons also pass through a late maturation phase characterized by increased [[Biology:Synaptic plasticity|synaptic plasticity]] and a decreased threshold for [[Biology:Long-term potentiation|long-term potentiation]]. Eventually, the neurons are integrated into the hippocampal circuitry as fully matured granule cells.

=== Astrocytes ===
Two main types of [[Biology:Astrocyte|astrocyte]]s 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.<ref name="Seri2001b" /> 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 and blood vessels ===
[[Biology:Endothelium|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 [[Biology:Vascular endothelial growth factor|vascular endothelial growth factor]] (VEGF) that help induce both [[Biology:Angiogenesis|angiogenesis]] and neurogenesis. In fact, studies have shown that neurogenesis and angiogenesis share several common [[Biology:Signal transduction|signaling pathways]], implying that neurogenic cells and endothelial cells in the SGZ have a reciprocal effect on one another. Blood vessels carry [[Biology:Hormone|hormone]]s and other molecules that act on the cells in the SGZ to regulate neurogenesis and angiogenesis.<ref name="Riquelme2008" />

== Hippocampal neurogenesis ==
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 [[Biology:Prenatal development|prenatal development]] but throughout adult life in most mammals, including humans.

=== Regulation of neurogenesis ===
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 [[Biology:Neurotransmitter|neurotransmitter]]s. 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 [[Biology:Nerve growth factor|nerve growth factor]] (NGF) are also present in the SGZ and are presumed to affect neurogenesis, though the exact mechanisms are unclear. [[Biology:Wnt signaling pathway|Wnt]] and bone morphogenic protein (BMP) signaling also are neurogenesis regulators, as well as classical neurotransmitters such as glutamate, GABA, [[Biology:Dopamine|dopamine]], and [[Chemistry:Serotonin|serotonin]].<ref name="Johnson2009" />
Neurogenesis in the SGZ is also affected by various environmental factors such as age and [[Medicine:Stress|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 [[Chemistry:Glucocorticoid|glucocorticoid]]s 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.

=== Role in memory and learning ===
There is a reciprocal relationship between neurogenesis in the SGZ and [[Learning|learning]] and [[Memory|memory]], particularly spatial memory.<ref name="Abrous" /> 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.

== Clinical significance ==
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 [[Medicine:Parkinson's disease|Parkinson's disease]] and [[Medicine:Alzheimer's disease|Alzheimer's disease]] generally exhibit a decrease in cell proliferation, which is expected. However, those who experience [[Medicine:Epilepsy|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.<ref name="Das2008" /><ref name="DeCarolis2010" /><ref name="Limke2003" />

== See also ==

* [[Biology:Neurogenesis|Neurogenesis]]
* [[Biology:Subventricular zone|Subventricular zone]]
* Stem cell niche

== References ==
{{Reflist|refs=
<ref name="Doetsch2003a">{{cite journal | doi=10.1016/j.gde.2003.08.012 | title=A niche for adult neural stem cells | year=2003 | last1=Doetsch | first1=Fiona | journal=Current Opinion in Genetics & Development | volume=13 | issue=5 | pages=543–550 | pmid=14550422 }}</ref>
<ref name="Riquelme2008">{{cite journal | doi=10.1098/rstb.2006.2016 | title=Brain micro-ecologies: Neural stem cell niches in the adult mammalian brain | year=2008 | last1=Riquelme | first1=Patricio A. | last2=Drapeau | first2=Elodie | last3=Doetsch | first3=Fiona | journal=Philosophical Transactions of the Royal Society B: Biological Sciences | volume=363 | issue=1489 | pages=123–137 | pmid=17322003 | pmc=2605490 }}</ref>
<ref name="Ma2008">Ma, D. K., Ming, G., Gage, F. H., & Song, H. (2008). Neurogenic Niches in the Adult Mammalian Brain. In F. H. Gage, G. Kempermann, & H. Song (Eds.), ''Adult Neurogenesis'' (pp. 207-225). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.</ref>
<ref name="Tavazoie2008">{{cite journal | doi=10.1016/j.stem.2008.07.025 | title=A Specialized Vascular Niche for Adult Neural Stem Cells | year=2008 | last1=Tavazoie | first1=Masoud | last2=Van Der Veken | first2=Lieven | last3=Silva-Vargas | first3=Violeta | last4=Louissaint | first4=Marjorie | last5=Colonna | first5=Lucrezia | last6=Zaidi | first6=Bushra | last7=Garcia-Verdugo | first7=Jose Manuel | last8=Doetsch | first8=Fiona | journal=Cell Stem Cell | volume=3 | issue=3 | pages=279–288 | pmid=18786415 | pmc=6864413 }}</ref>
<ref name="Kemperman2008">Kempermann, G., Song, H., & Gage, F. H. (2008). Neurogenesis in the Adult Hippocampus. In F. H. Gage, G. Kempermann, & H. Song (Eds.), ''Adult Neurogenesis'' (pp. 159-174). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.</ref>
<ref name="Seri2004">{{cite journal | doi=10.1002/cne.20288 | title=Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus | year=2004 | last1=Seri | first1=Bettina | last2=García-Verdugo | first2=José Manuel | last3=Collado-Morente | first3=Lucia | last4=McEwen | first4=Bruce S. | last5=Alvarez-Buylla | first5=Arturo | journal=Journal of Comparative Neurology | volume=478 | issue=4 | pages=359–378 | pmid=15384070 | s2cid=38269066 }}</ref>
<ref name="Palmer1997">{{cite journal | doi=10.1006/mcne.1996.0595 | title=The Adult Rat Hippocampus Contains Primordial Neural Stem Cells | year=1997 | last1=Palmer | first1=Theo D. | last2=Takahashi | first2=Jun | last3=Gage | first3=Fred H. | journal=Molecular and Cellular Neuroscience | volume=8 | issue=6 | pages=389–404 | pmid=9143557 | s2cid=6264449 }}</ref>
<ref name="Doetsch2003b">{{cite journal | doi=10.1038/nn1144 | title=The glial identity of neural stem cells | year=2003 | last1=Doetsch | first1=Fiona | journal=Nature Neuroscience | volume=6 | issue=11 | pages=1127–1134 | pmid=14583753 | s2cid=16088822 }}</ref>
<ref name="Seri2001b">{{cite journal | doi=10.1523/JNEUROSCI.21-18-07153.2001 | title=Astrocytes Give Rise to New Neurons in the Adult Mammalian Hippocampus | year=2001 | last1=Seri | first1=Bettina | last2=Garcı́a-Verdugo | first2=Jose Manuel | last3=McEwen | first3=Bruce S. | last4=Alvarez-Buylla | first4=Arturo | journal=The Journal of Neuroscience | volume=21 | issue=18 | pages=7153–7160 | pmid=11549726 | pmc=6762987 }}</ref>
<ref name="Johnson2009">{{cite journal | doi=10.5483/bmbrep.2009.42.5.245 | title=Cell-intrinsic signals that regulate adult neurogenesis in vivo: Insights from inducible approaches | year=2009 | last1=Johnson | first1=Madeleine A. | last2=Ables | first2=Jessica L. | last3=Eisch | first3=Amelia J. | journal=BMB Reports | volume=42 | issue=5 | pages=245–259 | pmid=19470237 | pmc=3601036 }}</ref>
<ref name="Abrous">Abrous, D. N., & Wojtowicz, J. M. (2008). Neurogenesis and Hippocampal Memory System. In F. H. Gage, G. Kempermann, & H. Song (Eds.), ''Adult Neurogenesis'' (pp. 445-461). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.</ref>
<ref name="Das2008">{{cite journal | doi=10.1002/jnr.21585 | title=Inflammation: A new candidate in modulating adult neurogenesis | year=2008 | last1=Das | first1=Sulagna | last2=Basu | first2=Anirban | journal=Journal of Neuroscience Research | volume=86 | issue=6 | pages=1199–1208 | pmid=18058947 | s2cid=23106806 }}</ref>
<ref name="DeCarolis2010">{{doi| 10.1016/j.neuropharm.2009.12.013}}</ref>
<ref name="Limke2003">{{cite journal | doi=10.1089/15258160360732641 | title=Neural Stem Cell Therapy in the Aging Brain: Pitfalls and Possibilities | year=2003 | last1=Limke | first1=Tobi L. | last2=Rao | first2=Mahendra S. | journal=Journal of Hematotherapy & Stem Cell Research | volume=12 | issue=6 | pages=615–623 | pmid=14977471 }}</ref>
}}

==External links==

[[Category:Developmental neuroscience]]

ru:Субгранулярная зона

{{Sourceattribution|Subgranular zone}}