How the immense population of neurons that constitute the human cerebral neocortex is generated from progenitors lining the cerebral ventricle and then distributed to appropriate layers of distinctive cytoarchitectonic areas can be explained by the radial unit hypothesis. According to this hypothesis, the ependymal layer of the embryonic cerebral ventricle consists of proliferative units that provide a proto-map of prospective cytoarchitectonic areas. The output of the proliferative units is translated via glial guides to the expanding cortex in the form of ontogenetic columns, whose final number for each area can be modified through interaction with afferent input. Data obtained through various advanced neurobiological techniques, including electron microscopy, immunocytochemistry, [3H]thymidine and receptor autoradiography, retrovirus gene transfer, neural transplants, and surgical or genetic manipulation of cortical development, furnish new details about the kinetics of cell proliferation, their lineage relationships, and phenotypic expression that favor this hypothesis. The radial unit model provides a framework for understanding cerebral evolution, epigenetic regulation of the parcellation of cytoarchitectonic areas, and insight into the pathogenesis of certain cortical disorders in humans.

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Golgi and electronmicroscopic methods were used to define the shapes and intercellular relationships of cells migrating from their sites of origin near the ventricular surface across the intermediate zone to the superficial neocortical layers of the parietooccipital region in the brains of 75-to 97-day monkey fetuses. After mitotic division in either ventricular or subventricular zones, the cells enter the intermediate zone and assume an elongated bipolar form oriented toward the cortical plate. The leading processes, 50 to 70 p long, are irregular cytoplasmic cylinders containing prominent Golgi apparatus, mitochondria, microtubules, ribosomal rosettes, immature endoplasmic reticulum and occasional centrioles. They usually terminate in several attenuated expansions, the longest one oriented toward the cortical plate. The trailing processes are more slender, relatively uniform in caliber and display few organelles.Throughout the 3500 p pathway across the intermediate zone the migrating cells are apposed to elongated, radially oriented, immature glial processes which span the full thickness of the cerebral wall. Most of the perikarya of these glial cells in the younger specimens lie in the ventricular or subventricular zones, but in older fetuses of this series many are found in the intermediate zone. The main characteristics of these fibers are : elongated cylindrical form containing numerous microtubules; electronlucent cytoplasmic matrix; short lamellate expansions protruding at right angles from the segment of the fiber which runs through the intermediate zone; and terminal endfeet joined at the pial surface to form a continuous sheet coated externally with basement membrane. It is suggested that glial radial fibers provide guidelines for cell migration through the complex mixture of closely packed cell processes and cell bodies that compose the developing cerebral wall. Strong surface affinity between radial fiber and migrating cell is suggested in regions where both follow precisely the same curving course from subventricular to intermediate zones and also in areas where large extracellular spaces separate other cells and processes but in which migrating cells and radial fibers remain closely paired nonetheless. Specific affinity between them is implied in the failure of migrating cells to follow any of the myriad differently-oriented processes they encounter. Several generations of postmitotic cells appear to migrate along the same radial fiber, a developmental mechanism that would allow for the vertical cell columns of adult neocortex.The classical hypothesis that neocortex is formed by outward movement of postmitotic cells generated in proliferative zones close to the ventricular surface (Vignal, 1888; Ram& y Cajal, 1891; KoUiker, 1896; His, '04) plate itself, and the presence of bipolar cells oriented in the intermediate zone so as to suggest migration. Thymidine-Ha autoradiography has provided further evidence for this hypothesis. In rodents, cells synthesizing DNA at the time of exposure to ...

The enlargement and species-specific elaboration of the cerebral neocortex during evolution holds the secret of humans' mental abilities; however, the genetic origin and cellular mechanisms generating the distinct evolutionary advancements are not well understood. This article describes how novelties that make us human may have been introduced during evolution, based on findings in the embryonic cerebral cortex in different mammalian species. The data on the differences in gene expression, new molecular pathways and novel cellular interactions that have led to these evolutionary advances may also provide insight into the pathogenesis and therapies for humanspecific neuropsychiatric disorders.The neocortex, as the name implies, is the newest addition to our brain and is considered to be the crowning achievement of evolution and the biological substrate of human mental prowess. Although its origin can be traced to reptiles 1,2 , that have emerged during the Carboniferous Period, it first appears as a uniform, six-layered sheet consisting of radially deployed neurons in the early small mammals that emerged from their reptilian ancestors during the transition of the Triassic/Jurassic periods. Increases in size and complexity of the cerebral cortex has culminated in the modern human that had separated from the mouse line between 90 and 100 million years ago and from the Old World monkeys, such as macaque, 25 million years before the present time (FIG. 1D and REFS. 3,4 ). If any organ of our body should be substantially different from any other species, it is the cerebral neocortex, the center of extraordinary human cognitive abilities. It is, therefore, surprising how little modern research has been done to elucidate how this human difference emerged. It appears that we are sometimes so seduced by similarities between species that we neglect the differences.There are several possible explanations for this tendency. First, most contemporary researchers of the cerebral cortex, including myself, work on the mouse as the best and most economical experimental model system 5 . However, although the basic principles of cortical development may be similar in all mammals, the modifications of developmental events during the millennia of primate evolution produced not only quantitative, but also qualitative changes in its cellular composition and pattern of synaptic circuitry. Second, we all have accepted the concept, advocated aptly by Charles Darwin, that the biological world is unified, and that "there is no fundamental difference between man and the higher mammals in their mental faculties" 6 . As a result, we hope that all basic human traits can be deduced from this commonality. Thirdly, there is a widespread perception that research on the development of the human brain is basically descriptive. However, the unprecedented possibilities for applying the most advanced methods of molecular and cell biology to the developing human brain is rapidly changing this perception.There are numerous examples of quantitative a...

Caspases are essential components of the mammalian cell death machinery. Here we test the hypothesis that Caspase 9 (Casp9) is a critical upstream activator of caspases through gene targeting in mice. The majority of Casp9 knockout mice die perinatally with a markedly enlarged and malformed cerebrum caused by reduced apoptosis during brain development. Casp9 deletion prevents activation of Casp3 in embryonic brains in vivo, and Casp9-deficient thymocytes show resistance to a subset of apoptotic stimuli, including absence of Casp3-like cleavage and delayed DNA fragmentation. Moreover, the cytochrome c-mediated cleavage of Casp3 is absent in the cytosolic extracts of Casp9-deficient cells but is restored after addition of in vitro-translated Casp9. Together, these results indicate that Casp9 is a critical upstream activator of the caspase cascade in vivo.

The cytological organization and the timetable of emergence and dissolution of the transient subplate zone subjacent to the developing visual and somatosensory cortex were studied in a series of human and monkey fetal brains. Cerebral walls processed with Nissl, Golgi, electron-microscopic, and histochemical methods show that this zone consists of migratory and postmigratory neurons, growth cones, loosely arranged axons, dendrites, synapses, and glial cells. In both species the subplate zone becomes visible at the beginning of the mid-third of gestation as a cell-poor/fiber-rich layer situated between the intermediate zone and the developing cortical plate. The subplate zone appears earlier in the somatosensory than in the visual area and reaches maximal width at the beginning of the last third of gestation in both regions. At the peak of its size the ratio between the width of the subplate zone and cortical plate in the somatosensory cortex is 2:1 in monkey and 4:1 in man while in the occipital lobe these structures have about equal width in both species. The dissolution of the subplate zone begins during the last third of gestation with degeneration of some subplate neurons and the relocation of fiber terminals into the cortex. The subplate zone disappears faster in the visual than in the somatosensory area. The present results together with our previous findings support the hypothesis that the subplate zone may serve as a "waiting" compartment for transient cellular interactions and a substrate for competition, segregation, and growth of afferents originated sequentially from the brain stem, basal forebrain, thalamus, and from the ipsi- and contralateral cerebral hemisphere. After a variable and partially overlapping time period, these fibers enter the cortical plate while the subplate zone disappears leaving only a vestige of cells scattered throughout the subcortical white matter. A comparison between species indicates that the size and duration of the subplate zone increases during mammalian evolution and culminates in human fetuses concomitantly with an enlargement of cortico-cortical fiber systems. The regional difference in the size, pattern, and resolution of the subplate zone correlates also with the pattern of cerebral convolutions. Our findings indicate that, contrary to prevailing notions, the subplate may not be a vestige of the phylogenetically old network but a transient embryonic structure that expanded during evolution to subserve the increasing number of its connections.

The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses [Changeux JP, Danchin A (1976) Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by twoto threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders.association cortex | critical period | schizophrenia | synaptogenesis

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