Neurogenesis is the process by which

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...

cells, the

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, are produced by

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). It occurs in all species of animals except the porifera (sponges) and

placozoan The Placozoa are a basal form of marine free-living (non-parasitic) multicellular organism. They are the simplest in structure of all animals. Three genera have been found: the classical '' Trichoplax adhaerens'', '' Hoilungia hongkongensis'', ...

s. Types of NSCs include

neuroepithelial cell 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 ...

s (NECs),

radial glial cell 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 ...

s (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs),

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 ...

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 e ...

s, and

subgranular zone 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. Structure The subgranular zone is a narrow layer of cells ...

radial

s, among others. Neurogenesis is most active during embryonic development and is responsible for producing all the various types of neurons of the organism, but it continues throughout adult life in a variety of organisms. Once born, neurons do not divide (see mitosis), and many will live the lifespan of the animal.

Neurogenesis in mammals

Developmental neurogenesis

During embryonic development, the

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

ian

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

(CNS;

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 ve ...

and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...

) is derived from the

neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, a ...

, which contains NSCs that will later generate

s. However, neurogenesis doesn't begin until a sufficient population of NSCs has been achieved. These early stem cells are called neuroepithelial cells (NEC)s, but soon take on a highly elongated radial morphology and are then known as radial glial cells (RGC)s. RGCs are the primary stem cells of the mammalian CNS, and reside in the embryonic

ventricular zone In vertebrates, the ventricular zone (VZ) is a transient embryonic layer of tissue containing neural stem cells, principally radial glial cells, of the central nervous system (CNS). The VZ is so named because it lines the ventricular system, whi ...

, which lies adjacent to the central fluid-filled cavity (

ventricular system The ventricular system is a set of four interconnected cavities known as cerebral ventricles in the brain. Within each ventricle is a region of choroid plexus which produces the circulating cerebrospinal fluid (CSF). The ventricular system is co ...

) of the

. Following RGC proliferation, neurogenesis involves a final cell division of the parent RGC, which produces one of two possible outcomes. First, this may generate a subclass of neuronal progenitors called intermediate neuronal precursors (INP)s, which will divide one or more times to produce neurons. Alternatively, daughter neurons may be produced directly. Neurons do not immediately form neural circuits through the growth of axons and dendrites. Instead, newborn neurons must first migrate long distances to their final destinations, maturing and finally generating neural circuitry. For example, neurons born in the

migrate radially to the

cortical plate The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...

, which is where neurons accumulate to form the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...

. Thus, the generation of neurons occurs in a specific tissue compartment or 'neurogenic niche' occupied by their parent stem cells. The rate of neurogenesis and the type of neuron generated (broadly, excitatory or inhibitory) are principally determined by molecular and genetic factors. These factors notably include the Notch signaling pathway, and many

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

s have been linked to Notch pathway

regulation Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. Fo ...

. The genes and mechanisms involved in regulating neurogenesis are the subject of intensive research in academic,

pharmaceutical A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

, and government settings worldwide. The amount of time required to generate all the neurons of the CNS varies widely across mammals, and brain neurogenesis is not always complete by the time of birth. For example, mice undergo cortical neurogenesis from about embryonic day (post-conceptional day) (E)11 to E17, and are born at about E19.5. Ferrets are born at E42, although their period of cortical neurogenesis does not end until a few days after birth. In contrast, neurogenesis in humans generally begins around gestational week (GW) 10 and ends around GW 25 with birth about GW 38–40.

Epigenetic modification

As embryonic development of the mammalian brain unfolds, neural progenitor and stem cells switch from proliferative divisions to differentiative divisions. This progression leads to the generation of

s and

glia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...

that populate

cortical layers The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of a ...

Epigenetic modifications Embryonic stem cells are capable of self-renewing and differentiating to the desired fate depending on their position in the body. Stem cell homeostasis is maintained through epigenetic mechanisms that are highly dynamic in regulating the chromati ...

play a key role in regulating gene expression in the

cellular differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...

neural stem cells 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 ...

. Epigenetic modifications include DNA cytosine methylation to form 5-methylcytosine and 5-methylcytosine demethylation. These modifications are critical for cell fate determination in the developing and adult mammalian brain. DNA cytosine methylation is catalyzed by DNA methyltransferases (DNMTs). Methylcytosine demethylation is catalyzed in several stages by

TET enzymes The TET enzymes are a family of ten-eleven translocation (TET) methylcytosine dioxygenases. They are instrumental in DNA demethylation. 5-Methylcytosine (see first Figure) is a methylated form of the DNA base cytosine (C) that often regulates ge ...

that carry out oxidative reactions (e.g. 5-methylcytosine to 5-hydroxymethylcytosine) and enzymes of the DNA

base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...

(BER) pathway.

Adult neurogenesis

Neurogenesis can be a complex process in some mammals. In rodents for example, neurons in the central nervous system arise from three types of neural stem and progenitor cells: neuroepithelial cells, radial glial cells and basal progenitors, which go through three main divisions: symmetric proliferative division; asymmetric neurogenic division; and symmetric neurogenic division. Out of all the three cell types, neuroepithelial cells that pass through neurogenic divisions have a much more extended cell cycle than those that go through proliferative divisions, such as the radial glial cells and basal progenitors. In the human, adult neurogenesis has been shown to occur at low levels compared with development, and in only three regions of the brain: the adult

(SVZ) of the

lateral ventricles The lateral ventricles are the two largest ventricles of the brain and contain cerebrospinal fluid (CSF). Each cerebral hemisphere contains a lateral ventricle, known as the left or right ventricle, respectively. Each lateral ventricle resemble ...

, the

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verte ...

and 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 t ...

of 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 ...

; although more recent (2020) research confirms adult neurogenesis throughout the brain.

Subventricular zone

In many mammals, including rodents, the

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ( ...

is a brain region containing cells that detect smell, featuring integration of adult-born neurons, which migrate from the SVZ of the

striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...

to the olfactory bulb through the

rostral migratory stream 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 ...

(RMS). The migrating neuroblasts in the olfactory bulb become interneurons that help the brain communicate with these sensory cells. The majority of those interneurons are inhibitory

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, but a small number are

periglomerular cell Periglomerular cells mediate lateral inhibition in the olfactory system together with granule cells. They have inhibitory synapses on mitral cells and tufted cell Tufted cells are found within the olfactory glomeruli. They receive input from the ...

s. In the adult SVZ, the primary neural stem cells are SVZ astrocytes rather than RGCs. Most of these adult neural stem cells lie dormant in the adult, but in response to certain signals, these dormant cells, or B cells, go through a series of stages, first producing proliferating cells, or C cells. The C cells then produce neuroblasts, or A cells, that will become neurons.

Hippocampus

Significant neurogenesis also occurs during adulthood in the

of many mammals, from

rodent Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are na ...

s to some

primate Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians ( monkeys and apes, the latter including ...

s, although its existence in adult humans is debated. The hippocampus plays a crucial role in the formation of new declarative memories, and it has been theorized that the reason human infants cannot form declarative memories is because they are still undergoing extensive neurogenesis in the hippocampus and their memory-generating circuits are immature. Many environmental factors, such as exercise, stress, and antidepressants have been reported to change the rate of neurogenesis within the hippocampus of rodents. Some evidence indicates postnatal neurogenesis in the human hippocampus decreases sharply in newborns for the first year or two after birth, dropping to "undetectable levels in adults."

Neurogenesis in other organisms

Neurogenesis has been best characterized in model organisms such as the fruit fly ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...

''. Neurogenesis in these organisms occur in the medulla cortex region of their optic lobes. These organisms can represent a model for the genetic analysis of adult neurogenesis and brain regeneration. There has been research that discuss how the study of “damage-responsive progenitor cells” in Drosophila can help to identify regenerative neurogenesis and how to find new ways to increase brain rebuilding. Recently, a study was made to show how “low-level adult neurogenesis” has been identified in Drosophila, specifically in the medulla cortex region, in which neural precursors could increase the production of new neurons, making neurogenesis occur. In Drosophila, Notch signaling was first described, controlling a cell-to-cell signaling process called

lateral inhibition In neurobiology, lateral inhibition is the capacity of an excited neuron to reduce the activity of its neighbors. Lateral inhibition disables the spreading of action potentials from excited neurons to neighboring neurons in the lateral direction ...

, in which neurons are selectively generated from epithelial cells. In some vertebrates, regenerative neurogenesis has also been shown to occur.

Substance-induced neurogenesis

* DMT: In September 2020, an in vitro and in vivo study showed that DMT present in the ayahuasca infusion promotes neurogenesis. A study showed that a low dose (0.1 mg/kg) of psilocybin given to mouse increased neurogenesis in the hippocampus 2 weeks after administration, while a high dose (1 mg/kg) significantly decreased neurogenesis.

Other findings

There is evidence that new neurons are produced in the dentate gyrus of the adult mammalian hippocampus, the brain region important for learning, motivation, memory, and emotion. A study reported that newly made cells in the adult mouse hippocampus can display passive membrane properties, action potentials and synaptic inputs similar to the ones found in mature dentate granule cells. These findings suggested that these newly made cells can mature into more practical and useful neurons in the adult mammalian brain. Recent studies confirm that microglia, the resident immune cell of the brain, establish direct contacts with the cell bodies of developing neurons, and through these connections, regulate neurogenesis, migration, integration and the formation of neuronal networks.

References

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External links

A Brief History and Timeline , Neurogenesis

* ttp://www.nature.com/nm/journal/v4/n11/abs/nm1198_1313.html Article: Nature Medicine 4, 1313 - 1317 (1998) doi:10.1038/3305 Neurogenesis in the adult human hippocampus Neuroscience Animal developmental biology Stem cells