Editing Cerebral cortex (section)

== Development ==
{{See also|Development of the cerebral cortex}}
The [[prenatal development]] of the cerebral cortex is a complex and finely tuned process called [[Development of the human cerebral cortex|corticogenesis]], influenced by the interplay between genes and the environment.<ref>{{cite journal | vauthors = Pletikos M, Sousa AM, Sedmak G, Meyer KA, Zhu Y, Cheng F, Li M, Kawasawa YI, Sestan N | title = Temporal specification and bilaterality of human neocortical topographic gene expression | journal = Neuron | volume = 81 | issue = 2 | pages = 321–332 | date = January 2014 | pmid = 24373884 | pmc = 3931000 | doi = 10.1016/j.neuron.2013.11.018 }}</ref>

===Neural tube===
The cerebral cortex develops from the most anterior part, the forebrain region, of the [[neural tube]].<ref name="Wolpert">{{cite book | vauthors = Wolpert L |title=Principles of Development |date=2015 |publisher=Oxford University Press |location=UK |isbn=978-0-19-967814-3 |page=533 |edition=Fifth}}</ref><ref name="pmid10498281">{{cite journal | vauthors = Warren N, Caric D, Pratt T, Clausen JA, Asavaritikrai P, Mason JO, Hill RE, Price DJ | title = The transcription factor, Pax6, is required for cell proliferation and differentiation in the developing cerebral cortex | journal = Cerebral Cortex | volume = 9 | issue = 6 | pages = 627–635 | date = September 1999 | pmid = 10498281 | doi = 10.1093/cercor/9.6.627 | doi-access = free }}</ref> The [[neural plate]] folds and closes to form the [[neural tube]]. From the cavity inside the neural tube develops the [[ventricular system]], and, from the [[neuroepithelial cell]]s of its walls, the [[neuron]]s and [[neuroglia|glia]] of the nervous system. The most anterior (front, or cranial) part of the neural plate, the [[prosencephalon]], which is evident before [[neurulation]] begins, gives rise to the cerebral hemispheres and later cortex.<ref>{{cite book | vauthors = Larsen WJ, Sherman LS, Potter SS, Scott WJ |title=Human Embryology |date=2001 |publisher=Churchill Livingstone |location=New York |isbn=978-0-443-06583-5 |edition=3rd | pages = 421–422 }}</ref>

===Cortical neuron development===
{{Further|Neurogenesis|Neuroepithelial cell}}
Cortical neurons are generated within the [[ventricular zone]], next to the [[ventricular system|ventricle]]s. At first, this zone contains [[neural stem cell]]s, that transition to [[radial glial cell]]s–progenitor cells, which divide to produce glial cells and neurons.<ref>{{cite journal | vauthors = Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR | title = Neurons derived from radial glial cells establish radial units in neocortex | journal = Nature | volume = 409 | issue = 6821 | pages = 714–720 | date = February 2001 | pmid = 11217860 | doi = 10.1038/35055553 | s2cid = 3041502 | bibcode = 2001Natur.409..714N | author3-link = Tamily Weissman }}</ref>

====Radial glia====
[[File:Neurogenesis and Differentiation of Cortical Layers.jpg|thumb|Neurogenesis is shown in red and lamination is shown in blue. Adapted from (Sur et al. 2001)]]
The cerebral cortex is composed of a heterogenous population of cells that give rise to different cell types. The majority of these cells are derived from [[Radial glial cell|radial glia]] migration that form the different cell types of the neocortex and it is a period associated with an increase in [[neurogenesis]]. Similarly, the process of neurogenesis regulates lamination to form the different layers of the cortex. During this process there is an increase in the restriction of cell fate that begins with earlier [[Progenitor cell|progenitors]] giving rise to any cell type in the cortex and later progenitors giving rise only to [[neuron]]s of superficial layers. This differential cell fate creates an inside-out topography in the cortex with younger neurons in superficial layers and older neurons in deeper layers. In addition, laminar neurons are stopped in [[Cell cycle|S]] or [[G2 phase]] in order to give a fine distinction between the different cortical layers. Laminar differentiation is not fully complete until after birth since during development laminar neurons are still sensitive to extrinsic signals and environmental cues.<ref>{{cite journal | vauthors = Sur M, Leamey CA | title = Development and plasticity of cortical areas and networks | journal = Nature Reviews. Neuroscience | volume = 2 | issue = 4 | pages = 251–262 | date = April 2001 | pmid = 11283748 | doi = 10.1038/35067562 | s2cid = 893478 }}</ref>

Although the majority of the cells that compose the cortex are derived locally from radial glia there is a subset population of neurons that [[cell migration|migrate]] from other regions. Radial glia give rise to neurons that are pyramidal in shape and use [[Glutamate (neurotransmitter)|glutamate]] as a [[neurotransmitter]], however these migrating cells contribute neurons that are stellate-shaped and use [[Gamma-Aminobutyric acid|GABA]] as their main neurotransmitter. These GABAergic neurons are generated by progenitor cells in the [[medial ganglionic eminence]] (MGE) that migrate tangentially to the cortex via the [[subventricular zone]]. This migration of GABAergic neurons is particularly important since [[GABA receptor]]s are excitatory during development. This excitation is primarily driven by the flux of chloride ions through the GABA receptor, however in adults chloride concentrations shift causing an inward flux of chloride that [[Hyperpolarization (biology)|hyperpolarizes]] [[postsynaptic neuron]]s.<ref name="Sanes_2012">{{Cite book |title=Development of the Nervous System | vauthors = Sanes DH, Reh TA, Harris WA |publisher=Elsevier Inc. |year=2012 |isbn=978-0-12-374539-2}}</ref>
The glial fibers produced in the first divisions of the progenitor cells are radially oriented, spanning the thickness of the cortex from the [[ventricular zone]] to the outer, [[Pia mater|pia]]l surface, and provide scaffolding for the migration of neurons outwards from the [[ventricular zone]].<ref>{{cite journal | vauthors = Rakic P | title = Evolution of the neocortex: a perspective from developmental biology | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 10 | pages = 724–735 | date = October 2009 | pmid = 19763105 | pmc = 2913577 | doi = 10.1038/nrn2719 }}</ref><ref>{{cite journal | vauthors = Rakic P | title = Extrinsic cytological determinants of basket and stellate cell dendritic pattern in the cerebellar molecular layer | journal = The Journal of Comparative Neurology | volume = 146 | issue = 3 | pages = 335–354 | date = November 1972 | pmid = 4628749 | doi = 10.1002/cne.901460304 | s2cid = 31900267 }}</ref>

At birth there are very few [[dendrite]]s present on the cortical neuron's cell body, and the axon is undeveloped. During the first year of life the dendrites become dramatically increased in number, such that they can accommodate up to a hundred thousand [[synapse|synaptic connections]] with other neurons. The axon can develop to extend a long way from the cell body.<ref name="Gilbert2">{{cite book | vauthors = Gilbert S |title=Developmental Biology |date=2006 |publisher=Sinauer Associates Publishers |isbn=978-0-87893-250-4 |pages=394–395 |edition=8th}}</ref>

===Asymmetric division===
The first divisions of the progenitor cells are symmetric, which duplicates the total number of progenitor cells at each [[Mitosis|mitotic cycle]]. Then, some progenitor cells begin to divide asymmetrically, producing one postmitotic cell that migrates along the radial glial fibers, leaving the [[ventricular zone]], and one progenitor cell, which continues to divide until the end of development, when it differentiates into a [[astrocyte|glial cell]] or an [[ependyma|ependymal cell]]. As the [[G1 phase]] of [[mitosis]] is elongated, in what is seen as selective cell-cycle lengthening, the newly born neurons migrate to more superficial layers of the cortex.<ref>{{cite journal | vauthors = Calegari F, Haubensak W, Haffner C, Huttner WB | title = Selective lengthening of the cell cycle in the neurogenic subpopulation of neural progenitor cells during mouse brain development | journal = The Journal of Neuroscience | volume = 25 | issue = 28 | pages = 6533–6538 | date = July 2005 | pmid = 16014714 | pmc = 6725437 | doi = 10.1523/jneurosci.0778-05.2005 }}</ref> The migrating daughter cells become the [[pyramidal cell]]s of the cerebral cortex.<ref>{{cite journal | vauthors = Rakic P | title = Specification of cerebral cortical areas | journal = Science | volume = 241 | issue = 4862 | pages = 170–176 | date = July 1988 | pmid = 3291116 | doi = 10.1126/science.3291116 | bibcode = 1988Sci...241..170R }}</ref> The development process is time ordered and regulated by hundreds of genes and [[Epigenetic Regulation of Neurogenesis|epigenetic regulatory mechanisms]].<ref>{{cite journal | vauthors = Hu XL, Wang Y, Shen Q | title = Epigenetic control on cell fate choice in neural stem cells | journal = Protein & Cell | volume = 3 | issue = 4 | pages = 278–290 | date = April 2012 | pmid = 22549586 | pmc = 4729703 | doi = 10.1007/s13238-012-2916-6 }}</ref>

===Layer organization===
[[File:Human Cortical Development.png|right|thumb|Human cortical development between 26 and 39 week gestational age]]
The [[laminar organization|layered structure]] of the mature cerebral cortex is formed during development. The first pyramidal neurons generated migrate out of the [[ventricular zone]] and [[subventricular zone]], together with [[reelin]]-producing [[Cajal–Retzius cell|Cajal–Retzius neurons]], from the '''preplate'''. Next, a cohort of neurons migrating into the middle of the preplate divides this transient layer into the superficial '''marginal zone''', which will become layer I of the mature neocortex, and the [[subplate]],<ref>{{cite journal | vauthors = Kostovic I, Rakic P | title = Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain | journal = The Journal of Comparative Neurology | volume = 297 | issue = 3 | pages = 441–470 | date = July 1990 | pmid = 2398142 | doi = 10.1002/cne.902970309 | s2cid = 21371568 }}</ref> forming a middle layer called the '''cortical plate'''. These cells will form the deep layers of the mature cortex, layers five and six. Later born neurons migrate radially into the cortical plate past the deep layer neurons, and become the upper layers (two to four). Thus, the layers of the cortex are created in an inside-out order.<ref>{{cite journal | vauthors = Rakic P | title = Neurons in rhesus monkey visual cortex: systematic relation between time of origin and eventual disposition | journal = Science | volume = 183 | issue = 4123 | pages = 425–427 | date = February 1974 | pmid = 4203022 | doi = 10.1126/science.183.4123.425 | s2cid = 10881759 | bibcode = 1974Sci...183..425R }}</ref> The only exception to this inside-out sequence of [[neurogenesis]] occurs in the layer I of [[primate]]s, in which, in contrast to [[rodent]]s, neurogenesis continues throughout the entire period of [[corticogenesis]].<ref>{{cite journal | vauthors = Zecevic N, Rakic P | title = Development of layer I neurons in the primate cerebral cortex | journal = The Journal of Neuroscience | volume = 21 | issue = 15 | pages = 5607–5619 | date = August 2001 | pmid = 11466432 | pmc = 6762645 | doi = 10.1523/JNEUROSCI.21-15-05607.2001 }}</ref>

===Cortical patterning===
[[File:Emx2_and_Pax6_Expression.png|thumb|Depicted in blue, Emx2 is highly expressed at the caudomedial pole and dissipates outward. Pax6 expression is represented in purple and is highly expressed at the rostral lateral pole. (Adapted from Sanes, D., Reh, T., & Harris, W. (2012). ''Development of the Nervous System'' (3rd ed.). Burlington: Elsevier Science)]]
The map of functional cortical areas, which include primary motor and visual cortex, originates from a '[[Protomap (neuroscience)|protomap]]',<ref>{{cite journal | vauthors = Rakic P | title = Specification of cerebral cortical areas | journal = Science | volume = 241 | issue = 4862 | pages = 170–176 | date = July 1988 | pmid = 3291116 | doi = 10.1126/science.3291116 | bibcode = 1988Sci...241..170R }}</ref> which is regulated by molecular signals such as [[fibroblast growth factor]] [[FGF8]] early in embryonic development.<ref>{{cite journal | vauthors = Fukuchi-Shimogori T, Grove EA | title = Neocortex patterning by the secreted signaling molecule FGF8 | journal = Science | volume = 294 | issue = 5544 | pages = 1071–1074 | date = November 2001 | pmid = 11567107 | doi = 10.1126/science.1064252 | s2cid = 14807054 | doi-access = free | bibcode = 2001Sci...294.1071F }}</ref><ref>{{cite journal | vauthors = Garel S, Huffman KJ, Rubenstein JL | title = Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants | journal = Development | volume = 130 | issue = 9 | pages = 1903–1914 | date = May 2003 | pmid = 12642494 | doi = 10.1242/dev.00416 | s2cid = 6533589 | doi-access =  }}</ref> These signals regulate the size, shape, and position of cortical areas on the surface of the cortical primordium, in part by regulating gradients of [[transcription factor]] expression, through a process called [[cortical patterning]]. Examples of such transcription factors include the genes [[EMX2]] and [[PAX6]].<ref>{{cite journal | vauthors = Bishop KM, Goudreau G, O'Leary DD | title = Regulation of area identity in the mammalian neocortex by Emx2 and Pax6 | journal = Science | volume = 288 | issue = 5464 | pages = 344–349 | date = April 2000 | pmid = 10764649 | doi = 10.1126/science.288.5464.344 | bibcode = 2000Sci...288..344B }}</ref> Together, both [[transcription factor]]s form an opposing gradient of expression. [[PAX6|Pax6]] is highly expressed at the [[Anatomical terms of location|rostral lateral]] pole, while [[EMX2|Emx2]] is highly expressed in the [[Anatomical terms of location|caudomedial]] pole. The establishment of this gradient is important for proper development. For example, [[mutation]]s in Pax6 can cause expression levels of Emx2 to expand out of its normal expression domain, which would ultimately lead to an expansion of the areas normally derived from the caudal medial cortex, such as the [[visual cortex]]. On the contrary, if mutations in Emx2 occur, it can cause the Pax6-expressing domain to expand and result in the [[Frontal lobe|frontal]] and [[Motor cortex|motor cortical]] regions enlarging. Therefore, researchers believe that similar gradients and [[Cell signaling|signaling centers]] next to the cortex could contribute to the regional expression of these transcription factors.<ref name="Sanes_2012" />
Two very well studied patterning signals for the cortex include [[Fibroblast growth factor|FGF]] and [[retinoic acid]]. If FGFs are [[Protein production|misexpressed]] in different areas of the developing cortex, [[cortical patterning]] is disrupted. Specifically, when [[FGF8|Fgf8]] is increased in the [[Anatomical terms of location|anterior]] pole, Emx2 is [[Downregulation and upregulation|downregulated]] and a [[caudal (anatomical term)|caudal]] shift in the cortical region occurs. This ultimately causes an expansion of the rostral regions. Therefore, Fgf8 and other FGFs play a role in the regulation of expression of Emx2 and Pax6 and represent how the cerebral cortex can become specialized for different functions.<ref name="Sanes_2012" />

Rapid expansion of the cortical surface area is regulated by the amount of self-renewal of [[radial glial cell]]s and is partly regulated by [[Fibroblast growth factor|FGF]] and [[Notch signaling pathway|Notch genes]].<ref>{{cite journal | vauthors = Rash BG, Lim HD, Breunig JJ, Vaccarino FM | title = FGF signaling expands embryonic cortical surface area by regulating Notch-dependent neurogenesis | journal = The Journal of Neuroscience | volume = 31 | issue = 43 | pages = 15604–15617 | date = October 2011 | pmid = 22031906 | pmc = 3235689 | doi = 10.1523/jneurosci.4439-11.2011 }}</ref> During the period of cortical neurogenesis and layer formation, many higher mammals begin the process of [[gyrification]], which generates the characteristic folds of the cerebral cortex.<ref>{{cite journal | vauthors = Rajagopalan V, Scott J, Habas PA, Kim K, Corbett-Detig J, Rousseau F, Barkovich AJ, Glenn OA, Studholme C | title = Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero | journal = The Journal of Neuroscience | volume = 31 | issue = 8 | pages = 2878–2887 | date = February 2011 | pmid = 21414909 | pmc = 3093305 | doi = 10.1523/jneurosci.5458-10.2011 }}</ref><ref>{{cite journal | vauthors = Lui JH, Hansen DV, Kriegstein AR | title = Development and evolution of the human neocortex | journal = Cell | volume = 146 | issue = 1 | pages = 18–36 | date = July 2011 | pmid = 21729779 | pmc = 3610574 | doi = 10.1016/j.cell.2011.06.030 }}</ref> Gyrification is regulated by a DNA-associated protein [[Trnp1]]<ref>{{cite journal | vauthors = Stahl R, Walcher T, De Juan Romero C, Pilz GA, Cappello S, Irmler M, Sanz-Aquela JM, Beckers J, Blum R, Borrell V, Götz M | title = Trnp1 regulates expansion and folding of the mammalian cerebral cortex by control of radial glial fate | journal = Cell | volume = 153 | issue = 3 | pages = 535–549 | date = April 2013 | pmid = 23622239 | doi = 10.1016/j.cell.2013.03.027 | hdl-access = free | doi-access = free | hdl = 10261/338716 }}</ref> and by FGF and [[Sonic hedgehog|SHH]] signaling.<ref>{{cite journal | vauthors = Wang L, Hou S, Han YG | title = Hedgehog signaling promotes basal progenitor expansion and the growth and folding of the neocortex | journal = Nature Neuroscience | volume = 19 | issue = 7 | pages = 888–896 | date = July 2016 | pmid = 27214567 | pmc = 4925239 | doi = 10.1038/nn.4307 }}</ref><ref>{{cite journal | vauthors = Rash BG, Tomasi S, Lim HD, Suh CY, Vaccarino FM | title = Cortical gyrification induced by fibroblast growth factor 2 in the mouse brain | journal = The Journal of Neuroscience | volume = 33 | issue = 26 | pages = 10802–10814 | date = June 2013 | pmid = 23804101 | pmc = 3693057 | doi = 10.1523/JNEUROSCI.3621-12.2013 }}</ref>