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As in the spinal cord, so also in the primitive brain ("urbrain") the perikarya (gray matter) collect around the central fluid space (ependymal canal) while the axons of the neurons (white matter) come to lie peripherally. This basic arrangement is also kept in the brain stem.
Nevertheless, besides the formation of the centrally-situated gray matter in the cerebellum and the cerebral hemispheres, there is an additional development of gray matter in the form of cortex on the surface. In this chapter the generation of the cortex through cell migration is to be explained.

Histogenesis of the cerebral cortex

On the side of the telencephalon two vesicles arise out of which the cerebral hemispheres emerge. Rostrally, after the neuroporus has closed, the neural tube is closed anteriorally by the lamina terminalis.

Fig. 39 - Cross-section through the telencephalon in stage 20 (ca. 48 days)

  1. Location at which the diencephalon is overlaid by the
    spreading of the cerebral hemispheres
  2. 3rd ventricle
  3. Hypothalamus
  4. Thalamus
  5. Medial ventricular eminence
  6. Lateral ventricular eminence
  7. Choroid plexus in the interventricular foramen
  8. Cortex  of the right hemisphere
  9. Lateral ventricle
  10. Cortex of the hippocampus (archicortex)

Fig. 39

This cross-section through the telencephalon at the level of the interventricular foramen shows the anlage of the two cerebral hemispheres as well as the choroid plexus in the lateral ventricle and in the roof of the 3rd ventricle. The ventricular eminences are clearly recognizable, just like the diencephalon (hypothalamus and thalamus as well as lateral ventricular eminence).

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The striate bodies (corpora striata) consist of the caudate nucleus and the putamen. The putamen together with the globus pallidus (or pallidum) – which belongs to the diencephalon – form the lentiform nucleus

The prospective cerebral cortex of the pallium develops in the whole roof of the cerebral vesicle while in the thicker floor or subpallium (ventro-lateral region of the cerebral vesicle) the ventricular eminences arise with their medial (stage 14) and lateral (stage 15) portions. The corpus striatum of the telencephalon emerges from the ventricular eminences as well as the core region of the globus pallidus, which belongs to the diencephalon.

Originally the cerebral surface is smooth. After the 18th week, though, it takes on its typical appearance, which is shaped by fissures, sulci (furrows) and gyri (convolutions).

The formation of the cortex is based on the migration of neuroblasts from where they are created in the immediate vicinity of the ventricle space in the direction of the cerebral surface.
The superficial, layered gray matter of the telencephalon, lying below the pia mater, represents the cerebral cortex and the gray matter in the form of cellular collections in the interior form the basal ganglia (core region of the brain stem part). Ascending and descending cortical fibers cross through the ventricular eminences as an internal capsule and divide them into two portions:

  • the caudate nucleus inside
  • the lentiform nucleus outside

The original layering of the primitive neural tube into three zones (ventricular, intermediate and marginal zones), clearly discernable in the spinal cord, gets blurred in the region of the telencephalon. The neurons of the intermediate zone slowly advance into the marginal zone. In a way that is still incompletely understood, through successive proliferation, migration, and differentiation, they cause the typical six-layered neocortex and the three-layered allocortex to arise.

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Detailed depiction of the histogenesis of the cerebral cortex


Radial cell migration

At around the 5th week (stage 14), two layers can be distinguished initially in the wall of the hemisphere vesicles, the ventricular zone and the subpial marginal zone. As was discussed in another place, the proliferation of the stem cells into the ventricular zone leads to the generation of postmitotic neuroblasts and then to the formation of glia cells. The young neuroblasts leave the ventricular zone and, following their emigration, form a further layer, the intermediate zone (mantle layer) (stage 16). Toward the end of the embryonic development (stage 22), at a point in time when the differentiation of the spinal cord is already far advanced, these young neurons wander along special processes of the radial glia out of the intermediate zone. Through this, from the 8th to the 18th weeks, on the inside of the marginal zone they form a further, temporary layer, the cortical plate (voir fig. 41). Indeed the radial glia represents a transitory embryonic cell group out of which, later, a part of the astrocyte population arises.

When the formation of the cortical plate is complete, all of the newly formed neuroblasts in the ventricular zone wander along the radial glia through neurons that have already settled there and accumulate on the outside. This phenomenon is normally referred to as «inside-out layering»

Toward the end of the 6th week (stage 17), the formation of new neuroblast in the ventricular zone decreases and the cell division now takes place more in a proliferations zone between the ventricular zone and the intermediate zone, the so-called subventricular zone. In this zone, until the time of birth, further neurons continue forming that then emigrate into the periphery and form the future cerebral cortex. The accumulated number of layers in the cortex depends on their phylogenetic origin. The maturing of the cortex continues to the end of childhood.
Due to the presence of perikaya the cerebral cortex is referred to as gray matter, while the white matter emerges from the intermediate zone

Fig. 40 - Radial cell migration into the telencephalon

Membrana limitans interna (ependyma)
Membrana limitans externa (pia mater)
Specialized cell process of the radial glia
Posterior process of the migrating neuron
Cell nucleus of the migrating neuron
Migrating neuron
Anterior process of the migrating neuron
Ventricular zone
Subventricular zone
Intermediate zone
Cortical plate
Marginal zone

Fig. 40

The migration of most neurons out of the ventricular zone into the cortex takes place along the processes of the radial glia. Investigations of various species of mammals indicate that a single radial cell can conduct approx. 130 neurons to their destinations.

The lower schematic image represents a neuroblast as it migrates along the process of a radial glia cell. Note the anterior process (7) that corresponds to the growth cone.

Reminder: synonyms
Ventricular zone
Proliferation zone

Intermediate zone
Mantle layer

Zone = layer

Cell differentiation of the cerebral cortex is a complex process. Besides a considerable overlap region, it can be divided into two phases

Embryonic phase:
At around the 28th day (stage 10), the neural tube forms. The neuroepithelium is originally a layer of cuboid cells and then slowly becomes multi-layered. After the 5th week (stage 14), the first neuroblasts wander out of the ventricular zone and form the mantle zone. At the beginning of the 6th week (stage 16), the neural tube is thus triple-layered and consists of the ventricular, the intermediate and the marginal zones. Toward the end of the embryonic phase (stage 22), the cortical plate arises through the migration of neuroblasts out of the intermediate and ventricular zones. The ventricular zone gradually stops forming neuroblasts but in the subventricular zone new neurons continue to form (stage 23).

Fetal phase:
At around the 10th week the ventricular zone differentiates into ependyma. The intermediate zone now contains almost no neuroblasts and slowly delivers the cortical white matter. During the first months of life, the subventricular layer disappears. The molecular layer emerges from the peripheral region of the marginal zone. The various cell layers of the marginal zone that border the cortical plate deliver the gray matter of the cerebral cortex together with them. Depending on which cell types predominate, from the 7th month the formation of the various cortex areas (motor, sensory, associative) each with their specific cytoarchitecture then begins.

Fig. 41 - Cell differentiation of the cerebral cortex

Fig. 41

Up to stage 16, the development of the walls of the neural tube, the spinal cord, and cerebral vesicles proceeds in a similar fashion. From stage 22, though, important differences appear. Toward the end of the 2nd trimester, it is true that the six layers of the neocortex have been formed but their definitive cytoarchitecture, though, is attained only in the 35th week.

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Histology of the neocortex.


Table: Histological and functional subdivision of the neocortex.


Tangential cell migration

At the moment, the mechanisms that steer the tangential migration of the descendents of the ventricular eminences are being intensively researched. The corresponding neurons should reach their target locations along differing pathways, especially along corticifugal fibers. This means that – after they reach the marginal zone – they continue into the intermediate zone and then into the cortical plate. On their way to the cortical plate, they possibly utilize the radial glia, but in a "descending" direction. This would mean that cell movements along the radial glia take place in both directions.

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The cortex columns
Besides their ordering in layers parallel to the surface, in the cerebral cortex a formation of functional units occurs, which belong to a further organization principle, those of vertical columns. Each of these cortex columns responds to a specific sort of stimulus (for example, to the spatial orientation of an object). Each column extends through the entire thickness of the cortex – that is, around 3 mm – and their diameter amounts to ca. 300 µm. Besides small-scale connections to neighboring columns, each of these modules also maintains far reaching connections via myelinized axons, whether this is to other ipsilateral cerebral areas or to homologous cerebral areas of the contralateral hemisphere. This organization principle has been verified particularly in the primary visual and primary auditory cortices.

In mammals, the double ordering of the cortices into horizontal layers and vertical columns is the result of a comprehensive development process early in the embryonic phase.

Not all of the mechanisms that contribute to a layered arrangement of the migrating neurons are known. The migration of the pyramidal cells, which leave the ventricular zone along the radial glia, are terminated by the protein reelin. This signal protein is secreted by the Cajal-Retzius cells of the marginal zone into the extracellular matrix. In reeler mouse mutants, in which reelin is absent, cortex layering is just as profoundly disrupted as in animals following ablation of the Cajal-Retzius cells.

In contrast to the pyramidal cells most of the non-pyramidal cells stem from medial and lateral ventricular eminences. They also reach their target locations in the cortex via tangential cell migration.

Moreover, prenatal, the neurons of the cortical plate are subject to programmed cell death.


Neocortex and allocortex

From a phylogenic point of view, the cerebral cortex can be divided into the neocortex and allocortex.

The phylogenically older allocortex takes up roughly 10% of the cerebral cortex. It develops early, namely in the 2nd and 3rd months and exhibits 3 to 6 layers. The allocortex is further subdivided into:

  • Mesocortex
    transition zone between the neocortex and archicortex. In adults the mesocortex corresponds to the para-hippocampal cortex and the cingulate gyrus (limbic lobe)
  • Archicortex
    (from the Greek archaios = old): triple layered cortex. In adults, it corresponds to the dentate gyrus and the horn of ammon (cornu ammonis; hippocampus)
  • Paleocortex
    (from the Greek palaios = ancient): 4 to 6 layered cortex that, like the archicortex, is connected with the olfactory system. In adults the paleocortex is to be met with in the region of the olfactory bulb and the olfactory tubercle as well as in the piriform lobe, and in the entorhinal and prorhinal cortices

The neocortex (from the Greek neos = new) possesses roughly 90% of the cerebral cortex. It develops from the 3rd to 7th months and is characterized by the typical 6 layered cytoarchitecture. It arises initially in the island area (insula) and in the parietal lobes and then spreads into the frontal lobes and the occipital lobes.

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Histology of the neocortex.

The creation of the mature neocortex structures over the course of fetal development is complex and was discussed in the previous chapter.

  • The subplate develops with the cortex plate into the cerebral cortex and thus delivers the gray matter of the pallium.
  • From the peripheral part of the marginal zone the molecular layer (layer I) emerges.
  • The intermediate zone contains hardly any neuroblast cells and delivers the white matter of the pallium.
  • Ependyma emerges from the ventricular zone at around the 10th week.

Moreover, from the 7th month, depending on which cell type predominates, the cytoarchitectural particularities of the various regions of the neocortex form (motor, sensory, associative).


Cerebral cortex in brief (human, adult)

  • Entire surface area of the adult cortex: 2,200 - 2,400 cm2
  • Thickness of the cortex: 1,55 to 4,5 mm
  • Cortical neurons: 10 to 16 billion
  • The cortex forms 40% of the total mass of the human brain

Brain in brief (human, adult)

  • Neurons of the CNS: 100 billion
  • Weight: 1300 -1500 g
  • Number of synaptic connections: ca. 10,000 per neuron
  • Ratio glia cells / neurons in the CNS: 10-50 / 1