Corticogenesis is the process in which the cerebral cortex of the brain is formed during the development of the nervous system. The cortex is the outer layer of the brain and is composed of up to six layers. Neurons formed in the ventricular zone migrate to their final locations in one of the six layers of the cortex. The process occurs from embryonic day 10 to 17 in mice and between gestational weeks seven to 18 in humans.
Visualization
of corticogenesis in the mouse. The 6 cortex layers migrate from the
ventricular zone through the subplate to come to rest in the cortical
plate (layers 2 through 6) or in the marginal zone (layer 1)
Cortical plates and zones
Plates
The
preplate is the first stage in corticogenesis prior to the development
of the cortical plate. The preplate is located between the pia and the ventricular zone. According to current knowledge, the preplate contains the first-born or pioneer neurons. These neurons are mainly thought to be Cajal-Retzius cells.
The preplate also contains the predecessor to the subplate, which is
sometimes referred to as a layer. As the cortical plate appears, the
preplate separates into two components. The Cajal-Retzius cells go into
the marginal zone, above the cortical plate, while the subplate moves to
below the 6 cortical layers. It is during this transition from preplate to cortical plate when many malformations may arise.
The cortical plate is the final plate formed in corticogenesis. It includes the cortex layers two through six.
The subplate is located beneath the cortical plate. It is named
for both its location relative to the cortical plate and for the time
frame in which it is created. While cortical plate matures, the cells
located in the subplate establish connections with neurons that have not
yet moved to their destination layer within the cortical plate. Pioneer
cells are also present in the subplate and work to create fibers and synapses within the plate.
Zones
The
intermediate zone is located between the ventricular zone and the
cortical plate. The white matter in this area is where neurons, that are
created in the ventricular zone, migrate through in order to reach the
cortical plate. This zone is only present during corticogenesis and eventually transforms into adult white matter.
The ventricular and subventricular zones exist below the
intermediate zone and communicate to other zones through cell
signalling, also creating neurons destined to migrate to other areas in
the cortex.
The marginal zone, along with the cortical zone, make up the 6
layers that form the cortex. This zone is the predecessor for layer 1 of
the cortex. Astrocytes form an outer limiting membrane to interact with the pia. In humans it has been found that the cells here also form a subpial layer.
Cajal-Retzius cells are also present in this zone and release reelin
along the radial axis, a key to proper neuronal migration during
corticogenesis.
Formation of layers
The cerebral cortex is divided into layers. Each layer is formed by radial glial cells located in the ventricular zone or subventricular zone, and then migrate to their final destination.
Layer I
Layer I, the molecular layer, is the first cortical layer produced during neurogenesis at mouse E10.5 to E12.5. Of the six layers found within the neocortex, layer I is the most superficial composed of Cajal–Retzius cells and pyramidal cells.
This layer is unique in the aspect that these cells migrate to the
outer edge of the cortex opposed to the migration experienced by the
other 5 layers. Layer one is also characterized by expression of reelin,
transcription factor T-box brain 1, and cortical migratory neuronal marker.
Layers 2 and 3
The
second and third layers, or the External Granular layer and External
Pyramidal layer respectively, are formed around mouse E13.5 to E16.
These layers are the last to form during corticogenesis and include pyramidal neurons, astrocytes, Stellates, and radial glial cells. The pyramidal and stellate neurons express SATB2 and CUX1. SATB2 and CUX1 are DNA binding proteins involved in determining the fate of cortical cells.
Layers 4, 5 and 6
The
fourth, fifth and sixth layers, or the Internal Granular layer,
Internal Pyramidal layer, and Polymorphic or Multiform layer
respectively, are formed during mouse E11.5 to E14.5. Included in these
layers are stellates, radial glia, and pyramidal neurons. Layer six is
adjacent to the ventricular zone. During the production of these layers,
transcription factors TBR1 and OTX1 are expressed along with CTIP2, or corticoneuronal zinc finger protein.
Neuronal migration
Neuronal migration
plays significant role in corticogenesis. Throughout the process of
creating the six cortical layers, all the neurons and cells migrate from
the ventricular zone, through the subplate, and come to rest at their
appropriate layer of the cortex. Neuronal migration is generally
subdivided into radial migration, tangential migration and multipolar migration. The migration of subcortical brain functions to the cortex is known as corticalization.
Cell signaling
Appropriate
formation of the cerebral cortex relies heavily on a densely
intertwined network of multiple signaling pathways and distinct
signaling molecules. While the majority of the process remains to be
understood, some signals and pathways have been carefully unraveled in
an effort to gain full knowledge of the mechanisms that control
corticogenesis.
Reelin-DAB1 pathway
The Reelin-DAB1 pathway is a well-defined pathway involved in corticogenesis.
Cajal-Retzius cells located in the marginal zone secrete reelin to
start the cascade. Reelin is able to interact with specific neurons in
the cortical plate and direct these neurons to their proper locations.
It is thought that the result downstream from this signalling could
influence the cytoskeleton.
Reelin is secreted only by the Cajal-Retzius cells located in the
marginal zone, and its receptors are confined to the cortical plate.
This segregation could be used to understand the actions of Reelin.
DAB1 is a regulator protein downstream of the reelin receptors.
This protein is located inside cells residing in the ventricular zone,
displaying highest concentrations in migrating pyramidal cells. When
either reelin or DAB1 are inactivated in mice, the resulting phenotypes
are the same. In this case, the neurons are unable to migrate properly
through the cortical plate. It does not affect the proliferation of
neurons and in the wild does not seem to have detrimental effects on
memory or learning.
Sonic hedgehog
Knocking out the Sonic hedgehog, or Shh, has been shown to severely affect corticogenesis in the genetically modified mice. The ventral and dorsal sides of the cerebrum are affected as Shh expresses the transcription factors to Nkx2 which is important in patterning the cortex. Shh is also important to corticogenesis as it affects cell proliferation and differentiation, helping neuronal progenitor cells in fate determination.
Bmp-7
Bone morphogenetic protein 7 (Bmp-7), is an important regulator in corticogenesis, though it is not understood whether it promotes or inhibits neurogenesis. Bmp-7 can be detected in the ventricular zone and is secreted into cerebrospinal fluid
(CSF). The CSF is an area to promote neurogenesis and it is believed
that the synergy between Bmp-7 and other regulators promote cell
division along with homeostasis.
Other bone morphogenetic proteins
are also known to impact corticogenesis. Bmp2, 4, 5, and 6 are
expressed during the process and can compensate for one another. For
example, if Bmp-4 was absent from corticogenesis, very little would
change in the cortex phenotype, due to the other Bmps helping accomplish
the tasks of Bmp-4. However, Bmp-7 is the only Bmp that promotes radial
glia survival and therefore considered more important.
Cdk5-p35 pathway
Cdk5
has a pathway parallel to the Reelin-DAB1. This pathway affects the
neuronal positioning, and results in similar malformations when absent
as the Reelin or DAB1 malformations except that migration is affected at
an earlier stage on the cortical plate. Cdk5/p35 pathway is also
responsible for actin and microtubule dynamics involved in neuronal migration.
Cyclin-dependent kinase inhibitor 1C,
or p57, also affects corticogenesis. It has been shown the p57 induces
cells to exit from the cell cycle and begin differentiation, but it is
dependent on Cdks.
p57 is able to induce neuronal progenitor cells to start
differentiating into highly specialized neurons in the cortex. However,
the mechanism by which p57 is able to affect such control is not yet
known.
Other signals
Besides the ones listed above, there are several more signals that affect corticogenesis. Cnr1 is a g protein receptor that is widely expressed throughout the brain, and in interneurons. In knockout mice, the cortex exhibited decreased immunoreactivity. Nrp1, Robo1, and Robo2 have also been shown to be present and important in the development of interneurons. Cdh8
is known to be expressed in the intermediate and subventricular zone,
though not in specific neurons in that area, and it is suggested to
regulate fiber releasing.
Disorders
Lissencephaly
Lissencephaly, or 'smooth brain', is a disorder in which the brain does not properly form the gyri and sulci as a result from neuronal migration and cortical folding. This disorder can also result in epilepsy and cognitive impariment. Type 1 lissencephaly is due to an error in migration. LISI, also known as PAFAH1B, is expressed in both dividing and migrating cells found in the brain. When LIS1 is deleted, lissencephaly occurs.
LIS1 is thought to have several important roles in the creation
of the cortex. Since LIS1 is similar to the nuclear distribution protein
F (nudF), they are thought to work similarly. The nud family is known
to be a factor in nuclear translocation, or moving the nuclei of
daughter cells after cell division has occurred. By relation, it is thought that LIS1 is a factor in neuronal migration. LIS1 is also considered to be a factor in controlling dynein, a motor protein that affects intercellular movement such as protein sorting and the process of cell division.
Another protein that contributes to a lissencephaly disorder is DCX, or Doublecortin. DCX is a microtubule associated protein that is responsible for double cortex malformations. DCX is found in the second layer of the cortex, and in fact is still present in immature neurons of an adult cortex.
It is thought that DCX affects neuronal migration through affecting the
microtubule dynamics. Since DCX malformations results as a similar
phenotype as with LIS1 malformations, it is thought they interact with
one another on a cellular level. However, it is not yet known how this
occurs.
Tsc1 knockout
TSC, or tuberous sclerosis, is an autosomal dominate disorder. TSC1 or TSC2
inactivation can cause TSC and the associated tumors in the brain. When
inactivation of TSC1 is present during corticogenesis, malformations of
cortical tubers, or abnormal benign tissue growth, along with white
matter nodes would form in mice. This replicates the effect TSC is found
to have in humans afflicted with TSC. In the mice there would be a lack
of GFAP in astrocytes however astrogliosis would not occur like in the human TSC.
Human Cortex Malformation (Overfolding)
The sodium channel SCN3A has been implicated in cortical malformations.
Recapitulation
Recapitulation
of corticogenesis in both human and mouse embryos have been
accomplished with a three dimensional culture using embryonic stem cells
(ESC). Recapitulation is the theory in which an organism passes through
embryonic development in stages similar to evolution of that organism.
By carefully using embryo body intermediates and cultured in a serum
free environment cortical progenitors form in a space and time related
pattern similar to in vivo corticogenesis. Using immunocytochemical analysis on mouse neural stem cells derived from ESCs, after 6 days there was evidence of neuronal differentiation.
The recapitulation ability only follows after the knowledge of spatial
and temporal patterns have been identified, along with giving the
knowledge that corticogenesis can occur without input from the brain.
The development of the nervous system, or neural development, or 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 field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.
The vertebratecentral nervous system (CNS) is derived from the ectoderm—the outermost germ layer of the embryo. A part of the dorsal ectoderm becomes specified to neural ectoderm – neuroectoderm that forms the neural plate 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 forms along the long axis of the neural plate, and the neural plate folds to give rise to the neural tube. 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, which become the forebrain (prosencephalon), midbrain (mesencephalon), and hindbrain (rhombencephalon). These simple, early vesicles enlarge and further divide into the telencephalon (future cerebral cortex and basal ganglia), diencephalon (future thalamus and hypothalamus), mesencephalon (future colliculi), metencephalon (future pons and cerebellum), and myelencephalon (future medulla). The CSF-filled central chamber is continuous from the telencephalon to the central canal of the spinal cord, and constitutes the developing ventricular system of the CNS. Embryonic cerebrospinal fluid 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 or lifelong disabilities like spina bifida. During this time, the walls of the neural tube contain neural stem cells, which drive brain growth as they divide many times. Gradually some of the cells stop dividing and differentiate into neurons and glial cells, 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 and dendrites, which allow them to communicate with other neurons via synapses. Synaptic communication between neurons leads to the establishment of functional neural circuits that mediate sensory and motor processing, and underlie behavior.
Some landmarks of neural development include the birth and differentiation of neurons from stem cell precursors, the migration of immature neurons from their birthplaces in the embryo to their final positions, outgrowth of axons and dendrites from neurons, guidance of the motile growth cone through the embryo towards postsynaptic partners, the generation of synapses between these axons and their postsynaptic partners, and finally the lifelong changes 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 and axon guidance
to their initial target areas. These processes are thought of as being
independent of neural activity and sensory experience. Once axons
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.
Myelination,
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).
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 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 of the vertebrate, the dorsal ectoderm becomes specified to give rise to the epidermis and the nervous system; a part of the dorsal ectoderm becomes specified to neural ectoderm to form the neural plate which gives rise to the nervous system.
The conversion of undifferentiated ectoderm to neuroectoderm requires
signals from the mesoderm. At the onset of gastrulation presumptive
mesodermal cells move through the dorsal blastopore lip and form a layer
of mesoderm in between the endoderm and the ectoderm. Mesodermal cells
migrate along the dorsal midline to give rise to the notochord 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. Beginning in the future neck region, the neural folds of this groove close to create the neural tube. The formation of the neural tube from the ectoderm is called neurulation. The ventral part of the neural tube is called the basal plate; the dorsal part is called the alar plate. The hollow interior is called the neural canal, 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 embryos since they have a simple body plan and there are good markers to distinguish between neural and non-neural tissue. Examples of neural inducers are the molecules noggin and chordin.
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 cultures (which allow direct cell-cell interactions) the same cells differentiate into epidermis. This is due to the action of BMP4 (a TGF-β
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, at the mesencephalic flexure or cephalic flexure. Above the mesencephalon is the prosencephalon (future forebrain) and beneath it is the rhombencephalon (future hindbrain).
The alar plate of the prosencephalon expands to form the telencephalon which gives rise to the cerebral hemispheres, whilst its basal plate becomes the diencephalon. 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, 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 is controlled by the notochord, which acts as the 'organiser'. The dorsal half is controlled by the ectoderm 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, noggin and chordin that inhibit BMPs.
The ventral neural tube is patterned by sonic hedgehog (Shh) from the notochord, which acts as the inducing tissue. Notochord-derived Shh signals to the floor plate,
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, leading to activation of the Gli family of transcription factors (GLI1, GLI2, and GLI3).
In this context Shh acts as a morphogen - it induces cell differentiation dependent on its concentration. At low concentrations it forms ventral interneurons, at higher concentrations it induces motor neuron
development, and at highest concentrations it induces floor plate
differentiation. Failure of Shh-modulated differentiation causes holoprosencephaly.
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, which act in the hindbrain and spinal cord. The hindbrain, for example, is patterned by Hox genes, 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. Without this Hoxb-1 expression, a nerve similar to the trigeminal nerve arises.
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem cells and progenitor cells. Neurons are 'post-mitotic', meaning that they will never divide again for the lifetime of the organism.
Neuronal migration
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. This time lapse displays sequences of radial migration (also known as glial guidance) and somal translocation.
Neuronal precursor cells proliferate in the ventricular zone of the developing neocortex, where the principal neural stem cell is the radial glial cell. 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
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 is then transported to the pial surface by nucleokinesis, a process by which a microtubule "cage" around the nucleus elongates and contracts in association with the centrosome to guide the nucleus to its final destination. Radial glial cells,
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 astrocytes or neurons. Somal translocation can occur at any time during development.
Subsequent waves of neurons split the preplate by migrating along radial glial
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 to the cerebral cortex. One example of ongoing tangential migration in a mature organism, observed in some animals, is the rostral migratory stream connecting subventricular zone and olfactory bulb.
Axophilic migration
Many neurons migrating along the anterior-posterior axis of the body use existing axon 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, lead to actin and microtubulecytoskeletal 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.
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
(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. They also showed that the synaptogenic signal is produced by the nerve, and they identified the factor as Agrin.
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.
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.
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.
Neuroligins
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, differentiation and axon guidance
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 development even when sensory input is absent and is observed in many systems such as the developing visual system,auditory system,motor system, hippocampus,cerebellum and neocortex.
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, waves of spontaneous action potentials arise from the retinal ganglion cells and sweep across the retinal surface in the first few postnatal weeks. These waves are mediated by neurotransmitteracetylcholine in the initial phase and later on by glutamate. 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 (SC) and dorsal lateral geniculate nucleus (LGN). Pharmacological disruption and mouse models lacking the β2 subunit of the nicotinic acetylcholine receptor has shown that the lack of spontaneous activity leads to marked defects in retinotopy and eye-specific segregation.
In the developing auditory system, developing cochlea generate bursts of activity which spreads across the inner hair cells and spiral ganglion neurons which relay auditory information to the brain. ATP release from supporting cells triggers action potentials in inner hair cells.
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 during the early stages and by acetylcholine and glutamate at later stages. In the developing zebrafishspinal cord,
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. In the cortex, early waves of activity have been observed in the cerebellum 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-weigthted MRI techniques may also uncover the macroscopic process of axonal development. The connectome can be constructed from diffusion MRI 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 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 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.
Adjacent
advertisements in an 1885 newspaper for the makers of two competing ore
concentrators (machines that separate out valuable ores from undesired
minerals). The lower ad touts that their price is lower, and that their
machine's quality and efficiency was demonstrated to be higher, both of
which are general means of economic competition.
In economics, competition is a condition where different economic firms seek to obtain a share of a limited good by varying the elements of the marketing mix:
price, product, promotion and place. In classical economic thought,
competition causes commercial firms to develop new products, services
and technologies, which would give consumers greater selection and
better products. The greater selection typically causes lower prices for
the products, compared to what the price would be if there was no
competition (monopoly) or little competition (oligopoly).
Early economic research focused on the difference between price-
and non-price-based competition, while later economic theory has focused
on the many-seller limit of general equilibrium.
Role in market success
Competition is generally accepted as an essential component of markets, and results from scarcity—there
is never enough to satisfy all conceivable human wants—and occurs "when
people strive to meet the criteria that are being used to determine who
gets what." In offering goods for exchange, buyers competitively bid
to purchase specific quantities of specific goods which are available,
or might be available if sellers were to choose to offer such goods.
Similarly, sellers bid against other sellers in offering goods on the
market, competing for the attention and exchange resources of buyers.
The competitive process in a market economy exerts a sort of
pressure that tends to move resources to where they are most needed, and
to where they can be used most efficiently for the economy as a whole.
For the competitive process to work however, it is "important that
prices accurately signal costs and benefits." Where externalities occur, or monopolistic or oligopolistic conditions persist, or for the provision of certain goods such as public goods, the pressure of the competitive process is reduced.
In any given market, the power structure will either be in favor of sellers or in favor of buyers. The former case is known as a seller's market; the latter is known as a buyer's market or consumer sovereignty. In either case, the disadvantaged group is known as price-takers and the advantaged group known as price-setters.
Competition bolsters product differentiation as businesses try to
innovate and entice consumers to gain a higher market share. It helps
in improving the processes and productivity as businesses strive to
perform better than competitors with limited resources. The Australian
economy thrives on competition as it keeps the prices in check.
Historical views
In his 1776 The Wealth of Nations, Adam Smith described it as the exercise of allocating productive resources to their most highly valued uses and encouraging efficiency, an explanation that quickly found support among liberal economists opposing the monopolistic practices of mercantilism, the dominant economic philosophy of the time. Smith and other classical economists before Cournot
were referring to price and non-price rivalry among producers to sell
their goods on best terms by bidding of buyers, not necessarily to a
large number of sellers nor to a market in final equilibrium.
Real
markets are never perfect. Economists who believe that in perfect
competition as a useful approximation to real markets classify markets
as ranging from close-to-perfect to very imperfect. Examples of
close-to-perfect markets typically include share and foreign exchange
markets while the real estate market is typically an example of a very
imperfect market. In such markets, the theory of the second best
proves that, even if one optimality condition in an economic model
cannot be satisfied, the next-best solution can be achieved by changing
other variables away from otherwise-optimal values.
Time variation
Within competitive markets, markets are often defined by their sub-sectors, such as the "short term" / "long term",
"seasonal" / "summer", or "broad" / "remainder" market. For example,
in otherwise competitive market economies, a large majority of the
commercial exchanges may be competitively determined by long-term
contracts and therefore long-term clearing prices. In such a scenario, a
“remainder market” is one where prices are determined by the small part
of the market that deals with the availability of goods not cleared via
long term transactions. For example, in the sugar industry,
about 94-95% of the market clearing price is determined by long-term
supply and purchase contracts. The balance of the market (and world
sugar prices) are determined by the ad hoc demand for the
remainder; quoted prices in the "remainder market" can be significantly
higher or lower than the long-term market clearing price.
Similarly, in the US real estate housing market, appraisal prices can
be determined by both short-term or long-term characteristics, depending
on short-term supply and demand factors. This can result in large
price variations for a property at one location.
Anti-competitive pressures and practices
Competition requires the existing of multiple firms, so it duplicates fixed costs.
In a small number of goods and services, the resulting cost structure
means that producing enough firms to effect competition may itself be
inefficient. These situations are known as natural monopolies and are usually publicly provided or tightly regulated.
The printing equipment company American Type Founders explicitly states in its 1923 manual that its goal is to 'discourage unhealthy competition' in the printing industry.
International competition
also differentially affects sectors of national economies. In order to
protect political supporters, governments may introduce protectionist measures such as tariffs to reduce competition.
In criminology, corporate crime refers to crimes committed either by a corporation (i.e., a business entity having a separate legal personality from the natural persons that manage its activities), or by individuals acting on behalf of a corporation or other business entity. For the worst corporate crimes, corporations may face judicial dissolution,
sometimes called the "corporate death penalty", which is a legal
procedure in which a corporation is forced to dissolve or cease to
exist.
Some negative behaviours by corporations may not actually be
criminal; laws vary between jurisdictions. For example, some
jurisdictions allow insider trading.
Corporate crime overlaps with:
white-collar crime, because the majority of individuals who may act as or represent the interests of the corporation are white-collar professionals;
organized crime, because criminals may set up corporations either for the purposes of crime or as vehicles for laundering the proceeds of crime. The world's gross criminal product has been estimated at 20 percent of world trade. (de Brie 2000); and
state-corporate crime because, in many contexts, the opportunity to commit crime emerges from the relationship between the corporation and the state.
No State shall make or enforce any
law which shall abridge the privileges or immunities of citizens of the
United States; nor shall any State deprive any person of life, liberty,
or property, without due process of law; nor deny to any person within
its jurisdiction the equal protection of the laws.
United
States law currently recognizes corporate criminal capacity.
French law currently recognizes corporate criminal capacity.
German law does not recognize corporate criminal capacity: German
corporations are however subject to fining for administrative violations
(Ordnungswidrigkeiten)
International treaties governing corporate malfeasance thus tend to
permit but not require corporate criminal liability.
Enforcement policy
Corporate crime has become politically sensitive in some countries. In the United Kingdom,
for example, following wider publicity of fatal accidents on the rail
network and at sea, the term is commonly used in reference to corporate manslaughter and to involve a more general discussion about the technological hazards posed by business enterprises (see Wells: 2001).
In the United States, the Sarbanes-Oxley Act of 2002 was passed to reform business practices, including enhanced corporate responsibility, financial disclosures, and combat fraud,
following the highly publicized scandals of Enron, Worldcom, Freddie
Mac, Lehman Brothers, and Bernie Madoff. Company chief executive officer
(CEO) and company chief financial officer (CFO) are required to
personally certify financial reports to be accurate and compliant with
applicable laws, with criminal penalties for willful misconduct
including monetary fines up to $5,000,000 and prison sentence up to 20
years.
The Law Reform Commission of New South Wales offers an explanation of such criminal activities:
Corporate
crime poses a significant threat to the welfare of the community. Given
the pervasive presence of corporations in a wide range of activities in
our society, and the impact of their actions on a much wider group of
people than are affected by individual action, the potential for both
economic and physical harm caused by a corporation is great (Law Reform
Commission of New South Wales: 2001).
At one level, corporations develop
new technologies and economies of scale. These may serve the economic
interests of mass consumers by introducing new products and more
efficient methods of mass production. On another level, given the
absence of political control today, corporations serve to destroy the
foundations of the civic community and the lives of people who reside in
them.
Discussion
Criminalization
Behavior can be regulated by the civil law (including administrative law) or the criminal law. In deciding to criminalize particular behavior, the legislature is making the political judgment that this behavior is sufficiently culpable
to deserve the stigma of being labelled as a crime. In law,
corporations can commit the same offences as natural persons. Simpson
(2002) avers that this process should be straightforward because a state
should simply engage in victimology to identify which behavior causes the most loss and damage to its citizens, and then represent the majority view that justice
requires the intervention of the criminal law. But states depend on the
business sector to deliver a functioning economy, so the politics of
regulating the individuals and corporations which supply that stability
become more complex. For the views of Marxist criminology, see Snider (1993) and Snider & Pearce (1995), for Left realism, see Pearce & Tombs (1992) and Schulte-Bockholt (2001), and for Right Realism, see Reed & Yeager (1996). More specifically, the historical tradition of sovereign state control of prisons is ending through the process of privatisation.
Corporate profitability in these areas therefore depends on building
more prison facilities, managing their operations, and selling inmate
labor. In turn, this requires a steady stream of prisoners able to work.
(Kicenski: 2002)
Bribery and corruption
are problems in the developed world, and the corruption of public
officials is thought to be a serious problem in developing countries,
and an obstacle to development.
Edwin Sutherland's
definition of white collar crime also is related to notions of
corporate crime. In his landmark definition of white collar crime he
offered these categories of crime:
Misrepresentation in financial statements of corporations
One
paper discusses some of the issues that arise in the relationship
between private sector and corruption. The findings can be summarized as
follows:
They present evidence that corruption induces informality by
acting as a barrier to entry into the formal sector. Firms that are
forced to go underground operate at a smaller scale and are less
productive.
Corruption also affects the growth of firms in the private sector.
This result seems to be independent of the size of the firm. A channel
through which corruption may affect the growth prospects of firms is
through its negative impact on product innovation.
SMEs pay higher bribes as percentage of revenue compared with large
companies and bribery seems to be the main form of corruption affecting
SMEs.
Bribery is not the only form of corruption affecting large firms.
Embezzlement by a company's own employees, corporate fraud, and insider
trading can be very damaging to enterprises too.
There is evidence that the private sector has as much responsibility
in generating corruption as the public sector. Particular situations
such as state capture can be very damaging for the economy.
Corruption is a symptom of poor governance. Governance can only be
improved via coordinated efforts among governments, businesses, civil
society.
Organi-cultural deviance
Cesare Beccaria (1738-1794) pioneered the study of crime
Organi-cultural deviance is a recent philosophical model used
in academia and corporate criminology that views corporate crime as a
body of social, behavioral, and environmental processes leading to
deviant acts. This view of corporate crime differs from that of Edwin
Sutherland (1949), who referred to corporate crime as white-collar crime,
in that Sutherland viewed corporate crime as something done by an
individual as an isolated end unto itself. With the Organi-cultural
deviance view, corporate crime can be engaged in by individuals, groups,
organizations, and groups of organizations, all within an
organizational context. This view also takes into account micro and
macro social, environmental, and personality factors, using a holistic
systems approach to understanding the causation of corporate crime.
The term derives its meaning from the words organization (a structured unit) and culture
(the set of shared attitudes, values, goals, and practices). This
reflects the view that corporate cultures may encourage or accept
deviant behaviors that differ from what is normal or accepted in the
broader society.
Organi-cultural deviance explains the deviant behaviors (defined by
societal norms) engaged in by individuals or groups of individuals.
Because corporate crime has often been seen as an understudy of
common crime and criminology, it is only recently that the study of
corporate crime been included in coursework and degree programs directly
related to criminal justice, business management, and organizational
psychology. This is partly due to a lack of an official definition for
crimes committed in the context of organizations and corporations.
The social philosophical study of common crime gained recognition through Cesare Beccaria during the 18th century, when Beccaria was heralded as the Father of the Classical School of Criminology.
However, corporate crime was not officially recognized as an independent area of study until Edwin Sutherland provided a definition of white collar crime
in 1949. Sutherland in 1949, argued to the American Sociological
Society the need to expand the boundaries of the study of crime to
include the criminal act of respectable individuals in the course of
their occupation.
In 2008, Christie Husted found corporate crime to be a complex
dynamic of system-level processes, personality traits,
macro-environmental, and social influences, requiring a holistic
approach to studying corporate crime. Husted, in her 2008 doctoral
thesis, Systematic Differentiation Between Dark and Light Leaders: Is a Corporate Criminal Profile Possible?, coined the term organi-cultural deviance to explain these social, situational and environmental factors giving rise to corporate crime.
Application
Renée
Gendron and Christie Husted, through their research conducted in
2008-2012, expanded the concept of organi-cultural deviance, in papers
presented the Academy of Criminal Justice Sciences conference Toronto,
Canada, the American Association of Behavioral and Social Sciences
Annual Conference, Las Vegas, NV, the General Meeting of the
Administrative Sciences Association of Canada, in Regina, Saskatchewan,
Canada, and The Humanities conference in Montréal, Canada.
The term organi-cultural deviance incorporated the terms group think,
and yes-men, to explain decision-related cognitive impairments inherent
of corporations engaging in corporate crime. The researchers have found
several interconnected dynamics that increase the likelihood of
white-collar crime. The researchers have found specific group dynamics
involved in white collar crime are similar to the group dynamics present
in gangs, organized crime organizations as well as cults. Moreover, the
researchers have found that there are systems-level forces influencing
the behaviors and cognitions of individuals.
The subject of organi-cultural deviance was first taught in business management, leadership classes, and in a class titled Corporate Misconduct
in America, at Casper College during 2008-2009. Organi-cultural
deviance was introduced to students as a social philosophical term used
to help describe, explain, and understand the complex social,
behavioral, and environmental forces, that lead organizations to engage
in corporate crime.
Social Dynamics
The term organi-cultural deviance was later expanded and published in a 2011 paper titled Socialization of Individuals into Deviant Corporate Culture.
Organi-cultural deviance was used to describe how processes of
individual and group socialization, within deviant corporate cultures,
serve to invert Abraham Maslow's (1954) Hierarchy of Needs into a theoretical “Hierarchical Funnel of Individual Needs”.
Organi-cultural deviance was further explored by Gendron and Husted,
using a micro-environmental approach, identifying social dynamics
within deviant organizations believed to lure and capture individuals.
However, through the social processes inherent of organi-cultural
deviance, social pressures and influences force the individual to vacate
aspirations to reach self-actualization and become complacent on
satisfying lower needs, such as belongingness. In organi-cultural
deviance, social dynamics and micro-environmental forces are believed,
by Gendron and Husted, to result in the individual's dependence upon the
organization for their basic needs.
Organizations engaging in organi-cultural deviance use
manipulation and a façade of honesty, with promises of meeting the
individual's needs of self-actualization. The social forces such as the
use of physical and psychological violence to maintain compliance with
organizational goals within deviant organizations secure the
individual's dependence upon the organization for satisfaction of their
basic needs. As the process of organi-cultural deviance escalates, the
complacency to meet mid-level needs becomes a dependency on the
organization to satisfy the lower needs of the pyramid, the individual's
basic needs. In the paper Using Gang and Cult Typologies to Understand Corporate Crimes, Gendron and Husted
found organizations engaging in organi-cultural deviance used coercive
power, monetary, physical and/or psychological threats, to maintain
their gravitational hold on the individual.
In the 2011 paper, Using Gang and Cult Typologies to Understand Corporate Crimes,
organi-cultural deviance was used to compare the cultures of: mafias,
cults, gangs and deviant corporations, each of which was assumed to be a
type of deviant organization. In these types of organizations,
organi-cultural deviance was found to be present. In engaging in
organi-cultural deviance, these organizations leverage four resources:
information, violence, reputation and publicity. These types of
organizations engaging in organi-cultural deviance were found to contain
toxic leadership. Deviant organizations, engaging in organi-cultural
deviance, were found to leverage their reputation through publicity to
attract members. The combination of adverse psychological forces,
combined with the real need for its employees to survive (earn a living,
avoid bullying) act as a type of organizational gravitational pull. The
concept of organi-cultural deviance includes both micro (personal,
psychological or otherwise internal forces exercising influence over an
individual's behavior) and macro influences (group dynamics,
organizational culture, inter-organizational forces as well as system
pressures and constraints, such as a legal system or overall economic
environment).
Environmental Influences
In a 2012 paper titled Organi-cultural Deviance: Economic Cycles Predicting Corporate Misconduct?, Gendron and Husted found economic cycles result in strain, seen as a precipitating factor in organi-cultural deviance.
Organi-cultural deviance is based on the premise social pressure and
economic forces exert strain on organizations to engage in corporate
crime. Strain creates motivating tension in organi-cultural deviance.
Robert Merton championed strain theorists in the field of criminology,
believing there to be “a universal set of goals toward which all
Americans, regardless of background and position, strive, chief among
these is monetary success”. Economic cycles result in observable patterns which are indicative of organi-cultural deviance.
Organi-cultural deviance is likely to occur at different points
in an economic cycle and system. The specific location of an economy in
the economic cycle tends to generate specific kinds of leaders.
Entrepreneurial leaders tend to be most visible at the bottom of an
economic cycle, during a depression or recession. Entrepreneurial
leaders are able to motivate their employees to innovate and develop new
products. As the economy strengthens, there is a marked increased of
bureaucratic leaders who standardise and operationalise the successes of
entrepreneurial leaders. As the economy reaches the apex of the
economic cycle, pseudo-transformational leaders are likely to emerge,
promising the same, if not higher, rates of return in a booming or
peaking economy. Often, these pseudo-transformational leaders engage in
deviant practices to maintain the illusion of rising rates of return.
