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The subgranular zone (SGZ) is a
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
region in the
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
where
adult An adult is a human or other animal that has reached full growth. In human context, the term ''adult'' has meanings associated with social and legal concepts. In contrast to a " minor", a legal adult is a person who has attained the age of major ...
neurogenesis 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) ...
occurs. The other major site of adult neurogenesis is the
subventricular zone 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 ...
(SVZ) in the brain.


Structure

The subgranular zone is a narrow layer of cells located between the
granule cell A granule is a large particle or grain. It can refer to: * Granule (cell biology), any of several submicroscopic structures, some with explicable origins, others noted only as cell type-specific features of unknown function ** Azurophilic granul ...
layer and hilus of the
dentate gyrus 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 ...
. This layer is characterized by several types of cells, the most prominent type being
neural stem cell 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 ste ...
s (NSCs) in various stages of development. However, in addition to NSCs, there are also
astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), 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 endo ...
s,
endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
, 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.


Neural stem cells and neurons

The brain comprises many different types of
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s, but the SGZ generates only one type:
granule cell A granule is a large particle or grain. It can refer to: * Granule (cell biology), any of several submicroscopic structures, some with explicable origins, others noted only as cell type-specific features of unknown function ** Azurophilic granul ...
s—the primary excitatory neurons in the
dentate gyrus 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 ...
(DG)--which are thought to contribute to cognitive functions such as
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...
and
learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, attitudes, and preferences. The ability to learn is possessed by humans, animals, and some machine learning, machines ...
. 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 cells''. Radial glial cells are a subset of
astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), 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 endo ...
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 markers such as 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 nestin and Sox2, biomarkers associated with neural stem cells, and that isolated radial glia can generate new neurons ''in vitro''. Radial glial cells often divide 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. #''Transiently amplifying progenitor cells''. Transiently amplifying (or transit-amplifying)
progenitor cell A progenitor cell is a Cell (biology), biological cell that can Cellular differentiation, differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor ...
s are highly proliferative cells that frequently divide and multiply via
mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
, 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 NeuroD, 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
Prox1 Prospero homeobox protein 1 is a protein that in humans is encoded by the ''PROX1'' gene. The Prox1 gene is critical for the development of multiple tissues. Prox1 activity is necessary and sufficient to specify a lymphatic endothelial cell fate i ...
. It is thought that the formation of these cells represents a fate-choice in neural stem cell development. # ''Neuroblasts''. Neuroblasts represent the last stage of precursor cell development before cells exit the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
and assume their identity as neurons. Proliferation of these cells is more limited, although
cerebral ischemia Brain ischemia is a condition in which there is insufficient bloodflow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus leads to the death of brain tissue or cerebral infarction/ischemic stroke. ...
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
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, 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 plasticity In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuit ...
and a decreased threshold for
long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
. Eventually, the neurons are integrated into the hippocampal circuitry as fully matured granule cells.


Astrocytes

Two main types of
astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), 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 endo ...
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. 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 cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
, 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 (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(VEGF) that help induce both
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
and neurogenesis. In fact, studies have shown that neurogenesis and angiogenesis share several common
signaling pathways Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
, implying that neurogenic cells and endothelial cells in the SGZ have a reciprocal effect on one another. Blood vessels carry
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s 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 Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...
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
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
s. For example, Notch is a signaling protein that regulates fate-choice, generally maintaining stem cells in a state of self-renewal.
Neurotrophins Neurotrophins are a family of proteins that induce the survival, development, and function of neurons. They belong to a class of growth factors, secreted proteins that can signal particular cells to survive, differentiate, or grow. Growth factor ...
such as
brain derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...
(BDNF) and
nerve growth factor Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was on ...
(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 Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, GABA,
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
, and
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
. Neurogenesis in the SGZ is also affected by various environmental factors such as age and
stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...
. 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
glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
s from the
adrenal cortex The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...
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 is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, attitudes, and preferences. The ability to learn is possessed by humans, animals, and some machine learning, machines ...
and
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...
, 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 Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
and
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
generally exhibit a decrease in cell proliferation, which is expected. However, those who experience
epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
, 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.


See also

*
Neurogenesis 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) ...
*
Subventricular zone 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 ...
*
Stem cell niche Stem-cell niche refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate. The word 'niche' can be in reference to the ''in vivo'' or ''in vitro'' stem-cell ...


References


External links

*{{commons-inline, Subgranular zone, subgranular zone Hippocampus (brain) Developmental neuroscience ru:Субгранулярная зона