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The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the
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 t ...
of animals, from the earliest stages of
embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm c ...
to adulthood. The field of neural development draws on both
neuroscience Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions and disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, developm ...
and
developmental biology Developmental biology is the study of the process by which animals and plants grow and develop. Developmental biology also encompasses the biology of regeneration, asexual reproduction, metamorphosis, and the growth and differentiation of stem c ...
to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from
nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant- parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a bro ...
s and
fruit flies Fruit fly may refer to: Organisms * Drosophilidae, a family of small flies, including: ** ''Drosophila'', the genus of small fruit flies and vinegar flies ** ''Drosophila melanogaster'' or common fruit fly ** '' Drosophila suzukii'' or Asian fruit ...
to
mammals 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 ...
. Defects in neural development can lead to malformations such as
holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed and ...
, and a wide variety of
neurological disorder A neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Examples of symptoms include paralysis, muscle weakne ...
s including limb paresis and paralysis, balance and vision disorders, and
seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
s, and in
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, an ...
s other disorders such as
Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...
,
Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual di ...
and intellectual disability.


Overview of vertebrate brain development

The
vertebrate Vertebrates () comprise all animal taxon, taxa within the subphylum Vertebrata () (chordates with vertebral column, backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the ...
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 par ...
(CNS) is derived from the
ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the o ...
—the outermost
germ layer A germ layer is a primary layer of cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans (animals that are sister taxa to the sponges) produce two or three pri ...
of the embryo. A part of the dorsal ectoderm becomes specified to neural ectoderm –
neuroectoderm Neuroectoderm (or neural ectoderm or neural tube epithelium) consists of cells derived from ectoderm. Formation of the neuroectoderm is first step in the development of the nervous system. The neuroectoderm receives bone morphogenetic protein-inhi ...
that forms the
neural plate The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ante ...
along the dorsal side of the embryo. This is a part of the early patterning of the embryo (including the invertebrate embryo) that also establishes an anterior-posterior axis. The neural plate is the source of the majority of neurons and glial cells of the CNS. The
neural groove The neural groove is a shallow median groove of the neural plate between the neural folds of an embryo. The neural plate is a thick sheet of ectoderm surrounded on either side by the neural folds, two longitudinal ridges in front of the primitive ...
forms along the long axis of the neural plate, and the neural plate folds to give rise to 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, ...
. When the tube is closed at both ends it is filled with embryonic cerebrospinal fluid. As the embryo develops, the anterior part of the neural tube expands and forms three
primary brain vesicles Brain vesicles are the bulge-like features of the early development of the neural tube in vertebrates. Vesicle formation begins shortly after anterior neural tube closure at about embryonic day 9.0 in the mouse and the fourth and fifth gestational ...
, which become the
forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary b ...
(
prosencephalon In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary ...
),
midbrain The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', "m ...
(
mesencephalon The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal ( alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
), and
hindbrain The hindbrain or rhombencephalon or lower brain is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Metencephalon ...
(
rhombencephalon The hindbrain or rhombencephalon or lower brain is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Metencephalon ...
). These simple, early vesicles enlarge and further divide into the
telencephalon The cerebrum, telencephalon or endbrain is the largest part of the brain containing the cerebral cortex (of the two cerebral hemispheres), as well as several subcortical structures, including the hippocampus, basal ganglia, and olfactory bulb. In ...
(future
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% consisting of ...
and
basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
),
diencephalon The diencephalon (or interbrain) is a division of the forebrain (embryonic ''prosencephalon''). It is situated between the telencephalon and the midbrain (embryonic ''mesencephalon''). The diencephalon has also been known as the 'tweenbrain in ol ...
(future
thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
and
hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...
),
mesencephalon The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal ( alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
(future colliculi),
metencephalon The metencephalon is the embryonic part of the hindbrain that differentiates into the pons and the cerebellum. It contains a portion of the fourth ventricle and the trigeminal nerve (CN V), abducens nerve (CN VI), facial nerve (CN VII), and a por ...
(future
pons The pons (from Latin , "bridge") is part of the brainstem that in humans and other bipeds lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum. The pons is also called the pons Varolii ("bridge of Var ...
and
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...
), and
myelencephalon The myelencephalon or afterbrain is the most posterior region of the embryonic hindbrain, from which the medulla oblongata develops. Development Neural tube to myelencephalon During fetal development, divisions of the neural tube that give ...
(future
medulla Medulla or Medullary may refer to: Science * Medulla oblongata, a part of the brain stem * Renal medulla, a part of the kidney * Adrenal medulla, a part of the adrenal gland * Medulla of ovary, a stroma in the center of the ovary * Medulla of t ...
). The CSF-filled central chamber is continuous from the telencephalon to the
central canal The central canal (also known as spinal foramen or ependymal canal) is the cerebrospinal fluid-filled space that runs through the spinal cord. The central canal lies below and is connected to the ventricular system of the brain, from which it r ...
of the
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 spin ...
, and constitutes the developing
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 c ...
of the CNS. Embryonic
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the b ...
differs from that formed in later developmental stages, and from adult CSF; it influences the behavior of neural precursors. Because the neural tube gives rise to the brain and spinal cord any mutations at this stage in development can lead to fatal deformities like
anencephaly Anencephaly is the absence of a major portion of the brain, skull, and scalp that occurs during embryonic development. It is a cephalic disorder that results from a neural tube defect that occurs when the rostral (head) end of the neural tube fai ...
or lifelong disabilities like
spina bifida Spina bifida (Latin for 'split spine'; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, m ...
. During this time, the walls of the neural tube contain
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 ...
, which drive brain growth as they divide many times. Gradually some of the cells stop dividing and differentiate into
neurons 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 ...
and
glial cells 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 mye ...
, which are the main cellular components of the CNS. The newly generated neurons migrate to different parts of the developing brain to self-organize into different brain structures. Once the neurons have reached their regional positions, they extend
axons An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
and
dendrites Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the n ...
, which allow them to communicate with other neurons via
synapses In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
. Synaptic communication between neurons leads to the establishment of functional
neural circuit A neural circuit is a population of neurons interconnected by synapses to carry out a specific function when activated. Neural circuits interconnect to one another to form large scale brain networks. Biological neural networks have inspired th ...
s that mediate sensory and motor processing, and underlie behavior.


Aspects

Some landmarks of neural development include the birth and differentiation 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. ...
s from
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...
precursors, the
migration Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
of immature neurons from their birthplaces in the embryo to their final positions, outgrowth of
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
s and
dendrite Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the n ...
s from neurons, guidance of the motile
growth cone A growth cone is a large actin-supported extension of a developing or regenerating neurite seeking its synaptic target. It is the growth cone that drives axon growth. Their existence was originally proposed by Spanish histologist Santiago Ram� ...
through the embryo towards postsynaptic partners, the generation of
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
s between these axons and their postsynaptic partners, and finally the lifelong
changes Changes may refer to: Books * ''Changes'', the 12th novel in Jim Butcher's ''The Dresden Files'' Series * ''Changes'', a novel by Danielle Steel * ''Changes'', a trilogy of novels on which the BBC TV series was based, written by Peter Dickinson ...
in synapses, which are thought to underlie learning and memory. Typically, these neurodevelopmental processes can be broadly divided into two classes: activity-independent mechanisms and activity-dependent mechanisms. Activity-independent mechanisms are generally believed to occur as hardwired processes determined by genetic programs played out within individual neurons. These include differentiation,
migration Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
and
axon guidance Axon guidance (also called axon pathfinding) is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they mana ...
to their initial target areas. These processes are thought of as being independent of neural activity and sensory experience. Once
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
s reach their target areas, activity-dependent mechanisms come into play. Although synapse formation is an activity-independent event, modification of synapses and synapse elimination requires neural activity. Developmental neuroscience uses a variety of
animal models A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the working ...
including the mouse ''
Mus musculus Mus or MUS may refer to: Abbreviations * MUS, the NATO country code for Mauritius * MUS, the IATA airport code for Minami Torishima Airport * MUS, abbreviation for the Centre for Modern Urban Studies on Campus The Hague, Leiden University, Net ...
'', 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 Ch ...
'', the zebrafish ''
Danio rerio The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
'', the frog ''
Xenopus laevis The African clawed frog (''Xenopus laevis'', also known as the xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the three short claws ...
'', and the
roundworm The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a broa ...
''
Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
''.
Myelination Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
, formation of the lipid myelin sheath around neuronal axons, is a process that is essential for normal brain function. The myelin sheath provides insulation for the nerve impulse when communicating between neural systems. Without it, the impulse would be disrupted and the signal would not reach its target, thus impairing normal functioning. Because so much of brain development occurs in the prenatal stage and infancy, it is crucial that myelination, along with cortical development occur properly. Magnetic resonance imaging (MRI) is a non-invasive technique used to investigate myelination and cortical maturation (the cortex is the outer layer of the brain composed of
gray matter Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astrocytes and oligodendrocytes), synapses, and capillaries. Grey matter is distingui ...
). Rather than showing the actual myelin, the MRI picks up on the myelin water fraction, a measure of myelin content. Multicomponent relaxometry (MCR) allow visualization and quantification of myelin content. MCR is also useful for tracking white matter maturation, which plays an important role in cognitive development. It has been discovered that in infancy, myelination occurs in a caudal–cranial, posterior-to-anterior pattern. Because there is little evidence of a relationship between myelination and cortical thickness, it was revealed that cortical thickness is independent of white matter. This allows various aspects of the brain to grow simultaneously, leading to a more fully developed brain.


Neural induction

During early
embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm c ...
of the vertebrate, the dorsal ectoderm becomes specified to give rise to the
epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water relea ...
and the nervous system; a part of the dorsal ectoderm becomes specified to neural ectoderm to form the
neural plate The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ante ...
which gives rise to the nervous system. The conversion of undifferentiated ectoderm to neuroectoderm requires signals from the
mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical Embry ...
. At the onset of gastrulation presumptive mesodermal cells move through the dorsal blastopore lip and form a layer of mesoderm in between the
endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gastru ...
and the ectoderm. Mesodermal cells migrate along the dorsal midline to give rise to the
notochord In anatomy, the notochord is a flexible rod which is similar in structure to the stiffer cartilage. If a species has a notochord at any stage of its life cycle (along with 4 other features), it is, by definition, a chordate. The notochord consi ...
that develops into the vertebral column. Neuroectoderm overlying the notochord develops into the neural plate in response to a diffusible signal produced by the notochord. The remainder of the ectoderm gives rise to the epidermis. The ability of the mesoderm to convert the overlying ectoderm into neural tissue is called neural induction. In the early embryo, the neural plate folds outwards to form the
neural groove The neural groove is a shallow median groove of the neural plate between the neural folds of an embryo. The neural plate is a thick sheet of ectoderm surrounded on either side by the neural folds, two longitudinal ridges in front of the primitive ...
. Beginning in the future neck region, the
neural folds The neural fold is a structure that arises during neurulation in the embryonic development of both birds and mammals among other organisms. This structure is associated with primary neurulation, meaning that it forms by the coming together of tis ...
of this groove close to create 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, ...
. The formation of the neural tube from the ectoderm is called
neurulation Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neurula. The process begins when the notochord induces the formati ...
. The ventral part of the neural tube is called the basal plate; the dorsal part is called the
alar plate Daminozide—also known as aminozide, Alar, Kylar, SADH, B-995, B-nine, and DMASA,—is a plant growth regulator, a chemical sprayed on fruit to regulate growth, make harvest easier, and keep apples from falling off the trees before they ripen ...
. The hollow interior is called the
neural canal 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 ...
, and the open ends of the neural tube, called the neuropores, close off. A transplanted blastopore lip can convert ectoderm into neural tissue and is said to have an inductive effect. Neural inducers are molecules that can induce the expression of neural genes in ectoderm explants without inducing mesodermal genes as well. Neural induction is often studied in ''
Xenopus ''Xenopus'' () (Gk., ξενος, ''xenos''=strange, πους, ''pous''=foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-known ...
'' embryos since they have a simple
body plan A body plan, ( ), or ground plan is a set of morphological features common to many members of a phylum of animals. The vertebrates share one body plan, while invertebrates have many. This term, usually applied to animals, envisages a "blueprin ...
and there are good markers to distinguish between neural and non-neural tissue. Examples of neural inducers are the molecules
noggin Noggin may refer to: General * Noggin or gill (volume), a unit of volume * Noggin (cup), a small cup * Noggin, slang for head * Noggin (protein), a signalling molecule involved in embryonic development * Noggin or dwang, a carpentry term Entert ...
and
chordin Chordin (from Greek χορδή, string, catgut) is a protein with a prominent role in dorsal–ventral patterning during early embryonic development. In humans it is encoded for by the ''CHRD'' gene. History Chordin was originally identified ...
. When embryonic ectodermal cells are cultured at low density in the absence of mesodermal cells they undergo neural differentiation (express neural genes), suggesting that neural differentiation is the default fate of ectodermal cells. In
explant culture In biology, explant culture is a technique to organotypically culture cells from a piece or pieces of tissue or organ removed from a plant or animal. The term ''explant'' can be applied to samples obtained from any part of the organism. The extracti ...
s (which allow direct cell-cell interactions) the same cells differentiate into epidermis. This is due to the action of
BMP4 Bone morphogenetic protein 4 is a protein that in humans is encoded by ''BMP4'' gene. BMP4 is found on chromosome 14q22-q23. BMP4 is a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfami ...
(a
TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other si ...
family protein) that induces ectodermal cultures to differentiate into epidermis. During neural induction, noggin and chordin are produced by the dorsal mesoderm (notochord) and diffuse into the overlying ectoderm to inhibit the activity of BMP4. This inhibition of BMP4 causes the cells to differentiate into neural cells. Inhibition of TGF-β and BMP (bone morphogenetic protein) signaling can efficiently induce neural tissue from pluripotent stem cells.


Regionalization

In a later stage of development the superior part of the neural tube flexes at the level of the future midbrain—the
mesencephalon The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal ( alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
, at the mesencephalic flexure or
cephalic flexure Three flexures form in the part of the embryonic neural tube that develops into the brain. At four weeks gestational age in the human embryo the neural tube has developed at the cranial end into three swellings – the primary brain vesicles. The ...
. Above the
mesencephalon The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal ( alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
is the
prosencephalon In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary ...
(future forebrain) and beneath it is the
rhombencephalon The hindbrain or rhombencephalon or lower brain is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Metencephalon ...
(future hindbrain). The alar plate of the prosencephalon expands to form the
telencephalon The cerebrum, telencephalon or endbrain is the largest part of the brain containing the cerebral cortex (of the two cerebral hemispheres), as well as several subcortical structures, including the hippocampus, basal ganglia, and olfactory bulb. In ...
which gives rise to the
cerebral hemisphere The vertebrate cerebrum (brain) is formed by two cerebral hemispheres that are separated by a groove, the longitudinal fissure. The brain can thus be described as being divided into left and right cerebral hemispheres. Each of these hemispheres ...
s, whilst its basal plate becomes the
diencephalon The diencephalon (or interbrain) is a division of the forebrain (embryonic ''prosencephalon''). It is situated between the telencephalon and the midbrain (embryonic ''mesencephalon''). The diencephalon has also been known as the 'tweenbrain in ol ...
. The optical vesicle (which eventually become the optic nerve, retina and iris) forms at the basal plate of the prosencephalon.


Patterning of the nervous system

In
chordates A chordate () is an animal of the phylum Chordata (). All chordates possess, at some point during their larval or adult stages, five synapomorphies, or primary physical characteristics, that distinguish them from all the other taxa. These five ...
, dorsal ectoderm forms all neural tissue and the nervous system. Patterning occurs due to specific environmental conditions - different concentrations of signaling molecules


Dorsoventral axis

The ventral half of the
neural plate The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ante ...
is controlled by the
notochord In anatomy, the notochord is a flexible rod which is similar in structure to the stiffer cartilage. If a species has a notochord at any stage of its life cycle (along with 4 other features), it is, by definition, a chordate. The notochord consi ...
, which acts as the 'organiser'. The dorsal half is controlled by the
ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the o ...
plate, which flanks either side of the neural plate. Ectoderm follows a default pathway to become neural tissue. Evidence for this comes from single, cultured cells of ectoderm, which go on to form neural tissue. This is postulated to be because of a lack of BMPs, which are blocked by the organiser. The organiser may produce molecules such as
follistatin Follistatin also known as activin-binding protein is a protein that in humans is encoded by the ''FST'' gene. Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals. Its primary function is the bindin ...
,
noggin Noggin may refer to: General * Noggin or gill (volume), a unit of volume * Noggin (cup), a small cup * Noggin, slang for head * Noggin (protein), a signalling molecule involved in embryonic development * Noggin or dwang, a carpentry term Entert ...
and
chordin Chordin (from Greek χορδή, string, catgut) is a protein with a prominent role in dorsal–ventral patterning during early embryonic development. In humans it is encoded for by the ''CHRD'' gene. History Chordin was originally identified ...
that inhibit BMPs. The ventral neural tube is patterned by
sonic hedgehog Sonic hedgehog protein (SHH) is encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog''. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and ...
(Shh) from the notochord, which acts as the inducing tissue. Notochord-derived Shh signals to the
floor plate The floor plate is a structure integral to the developing nervous system of vertebrate organisms. Located on the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior axis f ...
, and induces Shh expression in the floor plate. Floor plate-derived Shh subsequently signals to other cells in the neural tube, and is essential for proper specification of ventral neuron progenitor domains. Loss of Shh from the notochord and/or floor plate prevents proper specification of these progenitor domains. Shh binds Patched1, relieving Patched-mediated inhibition of
Smoothened Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecu ...
, leading to activation of the Gli family of
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
s (
GLI1 Zinc finger protein GLI1 also known as glioma-associated oncogene is a protein that in humans is encoded by the GLI1 gene. It was originally isolated from human glioblastoma cells. Function The Gli proteins are the effectors of Hedgehog (Hh) ...
, GLI2, and
GLI3 Zinc finger protein GLI3 is a protein that in humans is encoded by the ''GLI3'' gene. This gene encodes a protein that belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription ...
). In this context Shh acts as a
morphogen A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various ...
- it induces cell differentiation dependent on its concentration. At low concentrations it forms ventral
interneuron Interneurons (also called internuncial neurons, relay neurons, association neurons, connector neurons, intermediate neurons or local circuit neurons) are neurons that connect two brain regions, i.e. not direct motor neurons or sensory neurons. In ...
s, at higher concentrations it induces
motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectly ...
development, and at highest concentrations it induces floor plate differentiation. Failure of Shh-modulated differentiation causes
holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed and ...
. The dorsal neural tube is patterned by BMPs from the epidermal ectoderm flanking the neural plate. These induce sensory interneurons by activating Sr/Thr kinases and altering SMAD transcription factor levels.


Rostrocaudal (Anteroposterior) axis

Signals that control anteroposterior neural development include FGF and
retinoic acid Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that mediates the functions of vitamin A1 required for growth and development. All-''trans''-retinoic acid is required in ...
, which act in the hindbrain and spinal cord. The hindbrain, for example, is patterned by
Hox genes Hox genes, a subset of homeobox genes, are a group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals. Hox proteins encode and specify the characteristics of 'position', ensuring that the c ...
, which are expressed in overlapping domains along the anteroposterior axis under the control of retinoic acid. The 3′ (3 prime end) genes in the Hox cluster are induced by retinoic acid in the hindbrain, whereas the 5′ (5 prime end) Hox genes are not induced by retinoic acid and are expressed more posteriorly in the spinal cord. Hoxb-1 is expressed in rhombomere 4 and gives rise to the
facial nerve The facial nerve, also known as the seventh cranial nerve, cranial nerve VII, or simply CN VII, is a cranial nerve that emerges from the pons of the brainstem, controls the muscles of facial expression, and functions in the conveyance of taste ...
. Without this Hoxb-1 expression, a nerve similar to the
trigeminal nerve In neuroanatomy, the trigeminal nerve ( lit. ''triplet'' nerve), also known as the fifth cranial nerve, cranial nerve V, or simply CN V, is a cranial nerve responsible for sensation in the face and motor functions such as biting and chewin ...
arises.


Neurogenesis

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), ...
is the process by which neurons are generated from
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 ...
and
progenitor cells In genealogy, the progenitor (rarer: primogenitor; german: Stammvater or ''Ahnherr'') is the – sometimes legendary – founder of a family, line of descent, clan or tribe, noble house, or ethnic group.. Ebenda''Ahnherr:''"Stammvater eines G ...
. Neurons are 'post-mitotic', meaning that they will never divide again for the lifetime of the organism.
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 Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
in differentiating
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 ...
and are critical for cell fate determination in the developing and adult mammalian brain. Epigenetic modifications include DNA cytosine methylation to form 5-methylcytosine and 5-methylcytosine demethylation. DNA cytosine methylation is catalyzed by DNA methyltransferases (DNMTs). Methylcytosine demethylation is catalyzed in several sequential steps 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 g ...
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.


Neuronal migration

Neuronal
migration Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
is the method by which neurons travel from their origin or birthplace to their final position in the brain. There are several ways they can do this, e.g. by radial migration or tangential migration. Sequences of radial migration (also known as glial guidance) and somal translocation have been captured by
time-lapse microscopy Time-lapse microscopy is time-lapse photography applied to microscopy. Microscope image sequences are recorded and then viewed at a greater speed to give an accelerated view of the microscopic process. Before the introduction of the video tape r ...
.


Radial migration

Neuronal precursor cells proliferate in the
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, whic ...
of the developing
neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, s ...
, where the principal neural stem cell is the
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 ol ...
. The first postmitotic cells must leave the stem cell niche and migrate outward to form the preplate, which is destined to become Cajal-Retzius cells and
subplate The subplate, also called the subplate zone, together with the marginal zone and the cortical plate, in the fetus represents the developmental anlage of the mammalian cerebral cortex. It was first described, as a separate transient fetal zone ...
neurons. These cells do so by somal translocation. Neurons migrating with this mode of locomotion are bipolar and attach the leading edge of the process to the pia. The
soma Soma may refer to: Businesses and brands * SOMA (architects), a New York–based firm of architects * Soma (company), a company that designs eco-friendly water filtration systems * SOMA Fabrications, a builder of bicycle frames and other bicyc ...
is then transported to the pial surface by nucleokinesis, a process by which a
microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
"cage" around the nucleus elongates and contracts in association with the
centrosome In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle progr ...
to guide the nucleus to its final destination.
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 ol ...
s, whose fibers serve as a scaffolding for migrating cells and a means of radial communication mediated by calcium dynamic activity, act as the main excitatory neuronal stem cell of the cerebral cortex or translocate to the cortical plate and differentiate either into
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 or
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. ...
s. Somal translocation can occur at any time during development. Subsequent waves of neurons split the preplate by migrating along
radial glia 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 ol ...
l fibres to form the cortical plate. Each wave of migrating cells travel past their predecessors forming layers in an inside-out manner, meaning that the youngest neurons are the closest to the surface. It is estimated that glial guided migration represents 90% of migrating neurons in human and about 75% in rodents.


Tangential migration

Most interneurons migrate tangentially through multiple modes of migration to reach their appropriate location in the cortex. An example of tangential migration is the movement of interneurons from the
ganglionic eminence The ganglionic eminence (GE) is a transitory structure in the development of the nervous system that guides cell and axon migration. It is present in the embryonic and fetal stages of neural development found between the thalamus and caudate nuc ...
to the cerebral cortex. One example of ongoing tangential migration in a mature organism, observed in some animals, is 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 ...
connecting
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 ...
and
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 (OF ...
.


Axophilic migration

Many neurons migrating along the anterior-posterior axis of the body use existing
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
tracts to migrate along; this is called axophilic migration. An example of this mode of migration is in GnRH-expressing neurons, which make a long journey from their birthplace in the nose, through the forebrain, and into the hypothalamus. Many of the mechanisms of this migration have been worked out, starting with the extracellular guidance cues that trigger intracellular signaling. These intracellular signals, such as
calcium signaling Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allo ...
, lead to
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
and
microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
cytoskeletal The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is comp ...
dynamics, which produce cellular forces that interact with the extracellular environment through cell adhesion proteins to cause the movement of these cells.


Multipolar migration

There is also a method of neuronal migration called multipolar migration. This is seen in multipolar cells, which in the human, are abundantly present in the
cortical intermediate zone Corticogenesis is the process during which the cerebral cortex of the brain is formed as part of the development of the nervous system of mammals including its development in humans. The cortex is the outer layer of the brain and is composed of up ...
. They do not resemble the cells migrating by locomotion or somal translocation. Instead these multipolar cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers.


Neurotrophic factors

The survival of neurons is regulated by survival factors, called trophic factors. The neurotrophic hypothesis was formulated by Victor Hamburger and Rita Levi Montalcini based on studies of the developing nervous system. Victor Hamburger discovered that implanting an extra limb in the developing chick led to an increase in the number of spinal motor neurons. Initially he thought that the extra limb was inducing proliferation of motor neurons, but he and his colleagues later showed that there was a great deal of motor neuron death during normal development, and the extra limb prevented this cell death. According to the neurotrophic hypothesis, growing axons compete for limiting amounts of target-derived trophic factors and axons that fail to receive sufficient trophic support die by apoptosis. It is now clear that factors produced by a number of sources contribute to neuronal survival. *
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): Rita Levi Montalcini and Stanley Cohen purified the first trophic factor, Nerve Growth Factor (NGF), for which they received the Nobel Prize. There are three NGF-related trophic factors: BDNF, NT3, and NT4, which regulate survival of various neuronal populations. The Trk proteins act as receptors for NGF and related factors. Trk is a receptor tyrosine kinase. Trk dimerization and phosphorylation leads to activation of various intracellular signaling pathways including the MAP kinase, Akt, and PKC pathways. * CNTF: Ciliary neurotrophic factor is another protein that acts as a survival factor for motor neurons. CNTF acts via a receptor complex that includes CNTFRα, GP130, and LIFRβ. Activation of the receptor leads to phosphorylation and recruitment of the JAK kinase, which in turn phosphorylates LIFRβ. LIFRβ acts as a docking site for the STAT transcription factors. JAK kinase phosphorylates STAT proteins, which dissociate from the receptor and translocate to the nucleus to regulate gene expression. * GDNF: Glial derived neurotrophic factor is a member of the TGFb family of proteins, and is a potent trophic factor for striatal neurons. The functional receptor is a heterodimer, composed of type 1 and type 2 receptors. Activation of the type 1 receptor leads to phosphorylation of Smad proteins, which translocate to the nucleus to activate gene expression.


Synapse formation


Neuromuscular junction

Much of our understanding of synapse formation comes from studies at the neuromuscular junction. The transmitter at this synapse is acetylcholine. The acetylcholine receptor (AchR) is present at the surface of muscle cells before synapse formation. The arrival of the nerve induces clustering of the receptors at the synapse. McMahan and Sanes showed that the synaptogenic signal is concentrated at the
basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The bas ...
. They also showed that the synaptogenic signal is produced by the nerve, and they identified the factor as
Agrin Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. ...
. Agrin induces clustering of AchRs on the muscle surface and synapse formation is disrupted in agrin knockout mice. Agrin transduces the signal via MuSK receptor to
rapsyn 43 kDa receptor-associated protein of the synapse (rapsyn) is a protein that in humans is encoded by the ''RAPSN'' gene. Function This protein belongs to a family of proteins that are receptor associated proteins of the synapse. It contains a ...
. Fischbach and colleagues showed that receptor subunits are selectively transcribed from nuclei next to the synaptic site. This is mediated by neuregulins. In the mature synapse each muscle fiber is innervated by one motor neuron. However, during development, many of the fibers are innervated by multiple axons. Lichtman and colleagues have studied the process of synapses elimination. This is an activity-dependent event. Partial blockage of the receptor leads to retraction of corresponding presynaptic terminals. Later they used a connectomic approach, i.e., tracing out all the connections between motor neurons and muscle fibers, to characterize developmental synapse elimination on the level of a full circuit. Analysis confirmed the massive rewiring, 10-fold decrease in the number of synapses, that takes place as axons prune their motor units but add more synaptic areas at the NMJs with which they remain in contact.


CNS synapses

Agrin appears not to be a central mediator of CNS synapse formation and there is active interest in identifying signals that mediate CNS synaptogenesis. Neurons in culture develop synapses that are similar to those that form in vivo, suggesting that synaptogenic signals can function properly in vitro. CNS synaptogenesis studies have focused mainly on glutamatergic synapses. Imaging experiments show that dendrites are highly dynamic during development and often initiate contact with axons. This is followed by recruitment of postsynaptic proteins to the site of contact. Stephen Smith and colleagues have shown that contact initiated by dendritic filopodia can develop into synapses. Induction of synapse formation by glial factors: Barres and colleagues made the observation that factors in glial conditioned media induce synapse formation in retinal ganglion cell cultures. Synapse formation in the CNS is correlated with astrocyte differentiation suggesting that astrocytes might provide a synaptogenic factor. The identity of the astrocytic factors is not yet known.
Neuroligin Neuroligin (NLGN), a type I membrane protein, is a cell adhesion protein on the postsynaptic membrane that mediates the formation and maintenance of synapses between neurons. Neuroligins act as ligands for β-neurexins, which are cell ad ...
s and SynCAM as synaptogenic signals: Sudhof, Serafini, Scheiffele and colleagues have shown that neuroligins and SynCAM can act as factors that induce presynaptic differentiation. Neuroligins are concentrated at the postsynaptic site and act via neurexins concentrated in the presynaptic axons. SynCAM is a cell adhesion molecule that is present in both pre- and post-synaptic membranes.


Activity dependent mechanisms in the assembly of neural circuits

The processes of
neuronal migration The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fiel ...
, differentiation and
axon guidance Axon guidance (also called axon pathfinding) is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they mana ...
are generally believed to be activity-independent mechanisms and rely on hard-wired genetic programs in the neurons themselves. Research findings however have implicated a role for activity-dependent mechanisms in mediating some aspects of these processes such as the rate of neuronal migration, aspects of neuronal differentiation and axon pathfinding. Activity-dependent mechanisms influence neural circuit development and are crucial for laying out early connectivity maps and the continued refinement of synapses which occurs during development. There are two distinct types of neural activity we observe in developing circuits -early spontaneous activity and sensory-evoked activity. Spontaneous activity occurs early during
neural circuit A neural circuit is a population of neurons interconnected by synapses to carry out a specific function when activated. Neural circuits interconnect to one another to form large scale brain networks. Biological neural networks have inspired th ...
development even when sensory input is absent and is observed in many systems such as the developing
visual system The visual system comprises the sensory organ (the eye) and parts of the central nervous system (the retina containing photoreceptor cells, the optic nerve, the optic tract and the visual cortex) which gives organisms the sense of sight (the ...
,
auditory system The auditory system is the sensory system for the sense of hearing. It includes both the ear, sensory organs (the ears) and the auditory parts of the sensory system. System overview The outer ear funnels sound vibrations to the eardrum, incre ...
,
motor system The motor system is the set of central and peripheral structures in the nervous system that support motor functions, i.e. movement. Peripheral structures may include skeletal muscles and neural connections with muscle tissues. Central structur ...
,
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 ...
,
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...
and
neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, s ...
. Experimental techniques such as direct electrophysiological recording, fluorescence imaging using calcium indicators and optogenetic techniques have shed light on the nature and function of these early bursts of activity. They have distinct spatial and temporal patterns during development and their ablation during development has been known to result in deficits in network refinement in the visual system. In the immature
retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then p ...
, waves of spontaneous action potentials arise from the
retinal ganglion cells A retinal ganglion cell (RGC) is a type of neuron located near the inner surface (the ganglion cell layer) of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina ...
and sweep across the retinal surface in the first few postnatal weeks. These waves are mediated by
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. Neurotr ...
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts ...
in the initial phase and later on by
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 ...
. They are thought to instruct the formation of two sensory maps- the retinotopic map and eye-specific segregation. Retinotopic map refinement occurs in downstream visual targets in the brain-the
superior colliculus In neuroanatomy, the superior colliculus () is a structure lying on the roof of the mammalian midbrain. In non-mammalian vertebrates, the homologous structure is known as the optic tectum, or optic lobe. The adjective form '' tectal'' is common ...
(SC) and dorsal
lateral geniculate nucleus In neuroanatomy, the lateral geniculate nucleus (LGN; also called the lateral geniculate body or lateral geniculate complex) is a structure in the thalamus and a key component of the mammalian visual pathway. It is a small, ovoid, ventral projec ...
(LGN). Pharmacological disruption and mouse models lacking the β2 subunit of the
nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ne ...
has shown that the lack of spontaneous activity leads to marked defects in
retinotopy Retinotopy (from Greek τόπος, place) is the mapping of visual input from the retina to neurons, particularly those neurons within the visual stream. For clarity, 'retinotopy' can be replaced with 'retinal mapping', and 'retinotopic' with 'r ...
and eye-specific segregation. Recent studies confirm that
microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
, 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 in an activity-dependent manner. In the developing
auditory system The auditory system is the sensory system for the sense of hearing. It includes both the ear, sensory organs (the ears) and the auditory parts of the sensory system. System overview The outer ear funnels sound vibrations to the eardrum, incre ...
, developing
cochlea The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus. A core component of the cochlea is the Organ of Corti, the sensory org ...
generate bursts of activity which spreads across the
inner hair cells Hair cells are the sensory receptors of both the auditory system and the vestibular system in the ears of all vertebrates, and in the lateral line organ of fishes. Through mechanotransduction, hair cells detect movement in their environment. ...
and
spiral ganglion The spiral (cochlear) ganglion is a group of neuron cell bodies in the modiolus, the conical central axis of the cochlea. These bipolar neurons innervate the hair cells of the organ of Corti. They project their axons to the ventral and dorsal co ...
neurons which relay auditory information to the brain. ATP release from supporting cells triggers action potentials in
inner hair cells Hair cells are the sensory receptors of both the auditory system and the vestibular system in the ears of all vertebrates, and in the lateral line organ of fishes. Through mechanotransduction, hair cells detect movement in their environment. ...
. In the auditory system, spontaneous activity is thought to be involved in tonotopic map formation by segregating cochlear neuron axons tuned to high and low frequencies. In the motor system, periodic bursts of spontaneous activity are driven by excitatory GABA and
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 ...
during the early stages and by
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts ...
and
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 ...
at later stages. In the developing
zebrafish The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
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 spin ...
, early spontaneous activity is required for the formation of increasingly synchronous alternating bursts between ipsilateral and contralateral regions of the spinal cord and for the integration of new cells into the circuit. Motor neurons innervating the same twitch muscle fibers are thought to maintain synchronous activity which allows both neurons to remain in contact with the muscle fiber in adulthood. In the cortex, early waves of activity have been observed in the
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...
and cortical slices. Once sensory stimulus becomes available, final fine-tuning of sensory-coding maps and circuit refinement begins to rely more and more on sensory-evoked activity as demonstrated by classic experiments about the effects of sensory deprivation during critical periods. Contemporary diffusion-weighted
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
techniques may also uncover the macroscopic process of axonal development. The
connectome A connectome () is a comprehensive map of neural connections in the brain, and may be thought of as its "wiring diagram". An organism's nervous system is made up of neurons which communicate through synapses. A connectome is constructed by t ...
can be constructed from
diffusion MRI Diffusion-weighted magnetic resonance imaging (DWI or DW-MRI) is the use of specific MRI sequences as well as software that generates images from the resulting data that uses the diffusion of water molecules to generate contrast in MR images. It ...
data: the vertices of the graph correspond to anatomically labelled gray matter areas, and two such vertices, say ''u'' and ''v'', are connected by an edge if the
tractography In neuroscience, tractography is a 3D modeling technique used to visually represent nerve tracts using data collected by diffusion MRI. It uses special techniques of magnetic resonance imaging (MRI) and computer-based diffusion MRI. The results a ...
phase of the data processing finds an axonal fiber that connects the two areas, corresponding to ''u'' and ''v''. Numerous braingraphs, computed from the
Human Connectome Project The Human Connectome Project (HCP) is a five-year project sponsored by sixteen components of the National Institutes of Health, split between two consortia of research institutions. The project was launched in July 2009 as the first of three Grand ...
can be downloaded from the http://braingraph.org site. The Consensus Connectome Dynamics (CCD) is a remarkable phenomenon that was discovered by continuously decreasing the minimum confidence-parameter at the graphical interface of the Budapest Reference Connectome Server. The Budapest Reference Connectome Server (http://connectome.pitgroup.org) depicts the cerebral connections of n=418 subjects with a frequency-parameter k: For any k=1,2,...,n one can view the graph of the edges that are present in at least k connectomes. If parameter k is decreased one-by-one from k=n through k=1 then more and more edges appear in the graph, since the inclusion condition is relaxed. The surprising observation is that the appearance of the edges is far from random: it resembles a growing, complex structure, like a tree or a shrub (visualized on the animation on the left). It is hypothesized in that the growing structure copies the axonal development of the human brain: the earliest developing connections (axonal fibers) are common at most of the subjects, and the subsequently developing connections have larger and larger variance, because their variances are accumulated in the process of axonal development.


Synapse elimination

Several motorneurons compete for each neuromuscular junction, but only one survives until adulthood. Competition ''in vitro'' has been shown to involve a limited neurotrophic substance that is released, or that neural activity infers advantage to strong post-synaptic connections by giving resistance to a toxin also released upon nerve stimulation. ''In vivo'', it is suggested that muscle fibres select the strongest neuron through a retrograde signal or that activity-dependent synapse elimination mechanisms determine the identity of the "winning" axon at a motor endplate.


Mapping

Brain mapping Brain mapping is a set of neuroscience techniques predicated on the mapping of (biological) quantities or properties onto spatial representations of the (human or non-human) brain resulting in maps. According to the definition established in ...
can show how an animal's brain changes throughout its lifetime. As of 2021, scientists mapped and compared the whole brains of eight '' C. elegans'' worms across their development on the neuronal level and the complete wiring of a single mammalian muscle from birth to adulthood.


Adult neurogenesis

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), ...
also occurs in specific parts of the adult brain.


See also


References


External links

*
Neural Development
' (peer-reviewed open access journal). *
Translating Neurodevelopmental Time Across Mammalian Species
'
Brain DevelopmentHow poverty might change the brainThe Teenage Brain
{{Authority control Animal developmental biology Embryology of nervous system