Subgranular zone
Encyclopedia
The subgranular zone is a brain region in the hippocampus
where adult neurogenesis
occurs. It is one of the two major sites of adult neurogenesis
in the brain, along with the subventricular zone
(SVZ).
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.
, 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:
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.
, 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.
. 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.
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.
, 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, sincer 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.
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
where adult neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
occurs. It is one of the two major sites of adult neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
in the brain, along with the subventricular zone
Subventricular zone
The subventricular zone is a paired brain structure situated throughout the lateral walls of the lateral ventricles. It has been associated with having four distinct layers of variable thickness and cell density, as well as cellular composition....
(SVZ).
Structure
The subgranular zone is a narrow layer of cells located between the granule cellGranule cell
In neuroscience, granule cells refer to tiny neurons that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum , the dentate gyrus of the...
layer and hilus of the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
. This layer is characterized by several types of cells, the most prominent type being neural stem cells
Neural stem cell
Neural stem cells are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone of the mouse brain . In 1992, Brent A...
(NSCs) in various stages of development. However, in addition to NSCs, there are also astrocytes
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
, endothelial cells
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, 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”
Stem cell niche
Stem cell niche is a phrase loosely used in the scientific community to describe the microenvironment in which stem cells are found, which interacts with stem cells to regulate stem cell fate. The word 'niche' can be in reference to the in vivo or in vitro stem cell microenvironment...
. 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.
Neural stem cells and neurons
The brain comprises many different types of neuronsNeuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
, but the SGZ generates only one type: granule cells
Granule cell
In neuroscience, granule cells refer to tiny neurons that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum , the dentate gyrus of the...
--the primary excitatory neurons in the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
(DG)--which are thought to contribute to cognitive functions such as memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
and learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
. The progression from neural stem cell to granule cell in the SGZ can be described by tracing the following lineage of cell types:
- Radial glial cellsRadial gliaRadial glial cells are a pivotal cell type in the developing central nervous system involved in key developmental processes, from patterning and neuronal migration to their recently discovered role as precursors during neurogenesis. They arise early in development from neuroepithelial cells...
. Radial glial cells are a subset of astrocytesAstrocyteAstrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
, 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 markersBiomarker (cell)A biomarker can be understood as a molecule that is present from a particular cellular type. This facilitates the characterization of a cell type, their identification, and eventually their isolation. Cell sorting techniques are based on cellular biomarkers...
such as GFAPGlial fibrillary acidic proteinGlial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
, 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 nestinNestin (protein)Nestin is a type VI intermediate filament protein. These intermediate filament proteins are expressed mostly in nerve cells where they are implicated in the radial growth of the axon...
and Sox2SOX2SRY -box 2, also known as SOX2, is a transcription factor that is essential to maintain self-renewal of undifferentiated embryonic stem cells....
, biomarkers associated with neural stem cells, and that isolated radial glia can generate new neurons in vitro. Radial glial cells often divide asymmetricallyAsymmetric cell divisionAn asymmetric cell division produces two daughter cells with different cellular fates. This is in contrast to normal, symmetric, cell divisions, which give rise to daughter cells of equivalent fates...
, 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. - Transiently amplifying progenitor cells. Transiently amplifying (or transit-amplifying) progenitor cellsProgenitor cellA progenitor cell is a biological cell that, like a stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its "target" cell...
are highly proliferative cells that frequently divide and multiply via mitosisMitosisMitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
, 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 NeuroDNeuroDNeuroD, also called Beta2, is a basic helix loop helix transcription factor expressed in certain parts of brain, beta pancreatic cells and enteroendocrine cells. It is involved in the differentiation of nervous system and development of pancreas...
and Prox1PROX1Prospero homeobox protein 1 is a protein that in humans is encoded by the PROX1 gene....
. It is thought that the formation of these cells represents a fate-choiceCell fate determinationWithin the field of developmental biology one goal is to understand how a particular cell develops into the final cell type , essentially how a cell’s fate is determined. Within an embryo, 4 processes play out at the cellular and tissue level to essentially create the final organism...
in neural stem cell development. - NeuroblastsNeuroblastA neuroblast is a dividing cell that will develop into neurons or glia. The characterisation of neuroblasts and their development in Drosophila melanogaster was widely achieved by Chris Doe, Corey Goodman and Mike Bate. In humans, neuroblasts produced by stem cells in the adult subventricular zone...
. Neuroblasts represent the last stage of precursor cell development before cells exit the cell cycleCell cycleThe cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
and assume their identity as neurons. Proliferation of these cells is more limited, although 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 apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, 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 synaptic plasticitySynaptic plasticityIn neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
and a decreased threshold for long-term potentiationLong-term potentiationIn neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
. Eventually, the neurons are integrated into the hippocampal circuitry as fully matured granule cells.
Astrocytes
Two main types of astrocytesAstrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
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 and blood vessels
Endothelial cellsEndothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, 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
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF) that help induce both angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
and neurogenesis. In fact, studies have shown that neurogenesis and angiogenesis share several common signaling pathways
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
, implying that neurogenic cells and endothelial cells in the SGZ have a reciprocal effect on one another. Blood vessels carry hormones
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
and other molecules that act on the cells in the SGZ to regulate neurogenesis and angiogenesis.
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 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 neurotransmittersNeurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
. For example, Notch
Notch
Notch may refer to:* The nock of an arrow* Notch , a Hip hop, R&B, reggae, dancehall and reggaeton artist* Notch signaling pathway, a cell signaling system present in most multicellular organisms...
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
Nerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
(NGF) are also present in the SGZ and are presumed to affect neurogenesis,, though the exact mechanisms are unclear. Wnt
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
and bone morphogenic protein (BMP) signaling also are neurogenesis regulators, as well as classical neurotransmitters such as glutamate, GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
, dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, and serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
.
Neurogenesis in the SGZ is also affected by various environmental factors such as age and stress
Stress (biology)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
. 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
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
from the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
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 learningLearning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing 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.
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 Parkinson’s disease and Alzheimer’s disease generally exhibit a decrease in cell proliferation, which is expected. However, those who experience epilepsyEpilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, 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, sincer 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.