Dividing up the neocortex.
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Cerebral Cortex↗
Biomedical subjects
P Rakic
Publications and source records attributed to P Rakic.
Immunocytochemical localization of DARPP-32, a dopamine and cyclic-AMP-regulated phosphoprotein, in the primate brain.
The localization of DARPP-32, a dopamine and cAMP-regulated phosphoprotein, has been studied in monkey brain by immunocytochemistry. This study indicates that DARPP-32 is enriched in neurons in regions receiving a dense dopamine input from the substantia nigra and ventral tegmental area. Thus, the majority of somata in the anterior olfactory area, nucleus accumbens, caudate nucleus, and putamen are immunoreactive for DARPP-32. In the caudate nucleus, immunoreactive spines receive asymmetric contacts from unlabeled axon terminals. Immunoreactive somata have diameters of 10-15 microns. In regions known to receive projections from these nuclei, immunoreactivity is confined to small puncta that represent axons and axon terminals. Regions in which immunoreactivity is present in puncta include the ventral pallidum, globus pallidus, and substantia nigra pars reticulata. Dopaminergic neurons themselves are not immunoreactive. Neurons containing moderate to weak immunoreactivity for DARPP-32 are observed in portions of the cerebral cortex, particularly in the temporal cortex (layer VI). DARPP-32-positive neurons are also present in the cerebellum, in the medial habenula, and in portions of the bed nucleus of the stria terminalis and amygdaloid complex. DARPP-32 immunoreactivity is also present in astrocytes in the subcortical white matter and in tanycytes in the arcuate nucleus and median eminence. DARPP-32 may be an effective marker for dopaminoceptive neurons in which the actions of dopamine on the D-1 dopamine receptor are mediated through cAMP and its associated protein kinase.
Animals↗
Genesis of neurons in the retinal ganglion cell layer of the monkey.
We have analyzed the genesis of various neuronal classes and subclasses in the ganglion cell layer of the primate retina. Neurons were classified according to their size and the time of their origin was determined by pulse labeling with 3H-thymidine administered to female monkeys 38 to 70 days pregnant. All offspring were sacrificed postnatally, and their retinas processed for autoradiography. The somata of cells in the retinal ganglion cell layer generated on embryonic day (E) 38 ranged from 9 to 14 microns in diameter. Between E40 and E56, the minimum soma diameter remained around 8-9 microns, while the maximum gradually increased to 22 microns. As a consequence, the means of the distributions of labeled cells also increased with age, from 11.8 microns diameter for cells generated on E38 to 14.6 microns diameter at E56. Over this period the percentage of labeled cells in the 10.5-16.5 microns and greater than 16.5 microns diameter range gradually increased. The proportion of the labeled cells in the less than 10.5 microns diameter range decreased from E38 to E45, but subsequently increased rapidly. At the end of neurogenesis in the retinal ganglion cell layer, around E70, most labeled cells were considerably smaller (7-9 microns) than those generated earlier. Our results indicate that within the ganglion cell layer of the macaque, neurons of small caliber are generated first, followed successively by medium sized cells. Large, putative P alpha cells are generated late. The production between E56 and E70 of cells with the smallest somata suggests that the last-generated neurons in the ganglion cell layer are predominantly displaced amacrine cells. Within the same sector of retina, different classes of neurons in the ganglion cell layer of the rhesus monkey appear to have a sequential schedule of production.
Animals↗
Selective role of N-type calcium channels in neuronal migration.
Analysis of neuronal migration in mouse cerebellar slice preparations by a laser scanning confocal microscope revealed that postmitotic granule cells initiate their migration only after the expression of N-type calcium channels on their plasmalemmal surface. Furthermore, selective blockade of these channels by addition of omega-conotoxin to the incubation medium curtailed cell movement. In contrast, inhibitors of L- and T-type calcium channels, as well as those of sodium and potassium channels, had no effect on the rate of granule cell migration. These results suggest that N-type calcium channels, which have been predominantly associated with neurotransmitter release in adult brain, also play a transient but specific developmental role in directed migration of immature neurons before the establishment of their synaptic circuits.
Animals↗
Neurogenesis of the amygdaloid nuclear complex in the rhesus monkey.
The time course of neurogenesis for neurons which comprise the amygdaloid complex in Rhesus monkeys was determined using tritiated thymidine autoradiography. Fourteen pregnant monkeys received injections of tritiated thymidine between embryonic days 27 (E27) and 56 of their 165 day gestation and offspring were sacrificed during the early postnatal period. The first neurons destined for the amygdaloid complex were generated at E33 making them among the earliest postmitotic neurons in the telencephalon. Neurogenesis peaked within all nuclei of the amygdaloid complex between E38 and E48 and had ceased between E50 and E56. While amygdaloid neurogenesis in postnatally sacrificed monkeys displayed a dorsal-to-ventral gradient of radiolabeled neurons, the considerable rotation of the temporal lobe during the latter stages of primate development indicates that neurogenesis in the embryo, during the first third of gestation, actually occurs across a medial-to-lateral gradient. This medial-to-lateral gradient occurs as a smooth wave across the amygdaloid nuclei and does not respect neuroanatomical subdivisions or patterns of connectivity of the amygdaloid nuclei in the Rhesus monkey.
Amygdala↗
Expression of GABA and GABAA receptors by neurons of the subplate zone in developing primate occipital cortex: evidence for transient local circuits.
Several lines of evidence suggest that the transient subplate zone of the embryonic mammalian telencephalon could influence cortical development through synaptic or trophic interactions with growing cortical afferents and migrating neurons. Since such interactions may involve neurotransmitters and their receptor molecules, we have examined the expression of GABA and subunits of the GABAA/benzodiazepine receptor complex in the occipital lobe of embryonic rhesus monkeys by immunochemistry and in situ hybridization. We found that during the second half of gestation, when the subplate zone reaches peak maturity in this species, many neurons can be immunolabeled with both GABA antisera and monoclonal antibodies against GABAA receptor subunits. The most robust labeling occurs at approximately embryonic day (E)125 (birth is at E165). Electron microscopic observations of receptor subunit-immunolabeled material confirmed that subunits of the GABAA receptor are localized in the subplate neurons and their dendritic processes. In many instances the reaction product is associated with the plasma membranes of labeled processes, some of which form symmetrical synapses with small unlabeled axon terminals. The results of in situ hybridization are in accord with the results of receptor subunit immunochemistry. From E80 to E141, hybridization signal for GABAA receptor subunit mRNA occurs in the subplate zone and increases steadily to peak levels between E125 and E141. The present results reveal that all the elements necessary for the formation of functional GABAergic synaptic circuitry are present in the subplate zone. Further, the ages showing the most pronounced receptor and transmitter expression in this primate coincide with the ingrowth of major cortical afferent systems. Taken together, these findings suggest that GABAergic local neuronal circuits in the subplate may be involved in the development of long tract connections stationed in this zone prior to their transfer to the overlying cortical plate.
Animals↗
A quantitative analysis of synaptogenesis in the molecular layer of the dentate gyrus in the rhesus monkey.
Quantitative electron microscopy was used to study synapse formation in the molecular layer of the dentate gyrus in rhesus monkeys ranging in age from embryonic day 62 to adult. Four to eight radial probes, consisting of a series of overlapping electronmicrographs and extending across the full thickness of the molecular layer were made in each specimen. Synaptic density (normalized to volume of neuropil) increased significantly during the last half of gestation, reaching adult levels at the time of birth. However, new synapses were added during infancy, resulting in an apparent peak in density at between 4 and 5 months of age. This increase was followed by a decline in the synaptic density over the next 5 months, to levels comparable to that of the newborn. In addition to synaptic density, synapse type (symmetric, asymmetric), location (on dendritic shafts or spines), and laminar distribution in the developing molecular layer was determined. The decrease in synaptic density is unlikely to be due to 'dilution' caused by an increase in molecular layer volume since no increase in the volume of the dentate gyrus could be detected during this period. Our calculations suggest that a selective overproduction of asymmetrical, axo-spinous synapses occurs during infancy. Finally, synaptic density was significantly greater in the middle third of the molecular layer suggesting that synaptic exuberance may be related to entorhinal input.
Aging↗
Synchronized overproduction of neurotransmitter receptors in diverse regions of the primate cerebral cortex.
A remarkable diversity of neurotransmitter receptors develops concurrently in disparate areas of the primate cerebral cortex. The density of dopaminergic, adrenergic, serotonergic, cholinergic, and GABAergic receptors (where GABA is gamma-aminobutyric acid) in rhesus monkey reaches a maximum level between 2 and 4 months of age and then declines gradually to adult levels in all layers of sensory, motor, and association regions. The synchronized development of neurotransmitter receptors in diverse layers and regions of the neocortex occurs pari passu with synaptogenesis, demonstrating unusual coordination of biochemical and structural maturation and supporting the hypothesis that the entire cerebral cortex matures as an integrated network, rather than as a system-by-system cascade.
Aging↗
Cytogenesis in the monkey retina.
Time of cell origin in the retina of the rhesus monkey (Macaca mulatta) was studied by plotting the number of heavily radiolabeled nuclei in autoradiograms prepared from 2- to 6-month-old animals, each of which was exposed to a pulse of 3H-thymidine (3H-TdR) on a single embryonic (E) or postnatal (P) day. Cell birth in the monkey retina begins just after E27, and approximately 96% of cells are generated by E120. The remaining cells are produced during the last (approximately 45) prenatal days and into the first several weeks after birth. Cell genesis begins near the fovea, and proceeds towards the periphery. Cell division largely ceases in the foveal and perifoveal regions by E56. Despite extensive overlap, a class-specific sequence of cell birth was observed. Ganglion and horizontal cells, which are born first, have largely congruent periods of cell genesis with the peak between E38 and E43, and termination around E70. The first labeled cones were apparent by E33, and their highest density was achieved between E43 and E56, tapering to low values at E70, although some cones are generated in the far periphery as late as E110. Amacrine cells are next in the cell birth sequence and begin genesis at E43, reach a peak production between E56 and E85, and cease by E110. Bipolar cell birth begins at the same time as amacrines, but appears to be separate from them temporally since their production reaches a peak between E56 and E102, and persists beyond the day of birth. Müller cells and rod photoreceptors, which begin to be generated at E45, achieve a peak, and decrease in density at the same time as bipolar cells, but continue genesis at low density on the day of birth. Thus, bipolar, Müller, and rod cells have a similar time of origin. The maximal temporal separation of cell birth is between cones and amacrine cells so that cell generation exhibits two relatively distinct phases: the first phase gives rise to ganglion, horizontal, and cone cells, and the second phase to amacrine, bipolar, rod, and Müller cells. In addition, cells of the first phase are generated faster than the second phase cells, and there are differences in the topography of spread of labeled cells between the two phases. Each cell class displays a central-to-peripheral gradient in genesis, although the spatiotemporal characteristics of the gradients differ between the classes.(ABSTRACT TRUNCATED AT 400 WORDS)
Aging↗
Relation of an array of early-differentiating cones to the photoreceptor mosaic in the primate retina.
The retina of diurnal primates, including humans, contains a reiterative mosaic of red-, green- and blue-sensitive cones whose visual pigments are maximally sensitive to long, middle or short wavelengths, respectively. Although the distribution of the cone subtypes in the adult rhesus monkey has been quantified using opsin-specific antisera, the mechanism for the phenotypic specification of the cone subtypes and the establishment of their ratios in the retinal mosaic remain unknown. Here we present immunocytochemical evidence that a subset of cones (about 10%) express their cell-specific opsin two to three weeks before the surrounding cones. Remarkably, these precocious cones are evenly stationed throughout undifferentiated regions of the retinal surface from several weeks after their last mitotic division, and at least one month before the formation of their synapses with bipolar and horizontal cells. Use of confocal laser microscopy reveals that the inner segments of immunolabelled and surrounding unlabelled cones are transiently in apposition with one another, enabling surface mediated interactions to occur during this period. We suggest that the early maturing cones induce neighbouring undifferentiated cones to express an appropriate opsin phenotype, and therefore constitute a 'protomap' for the emergence of the species-specific retinal mosaic.
Animals↗
Experimental manipulation of cerebral cortical areas in primates.
The developmental mechanisms underlying the subdivision of the neocortex into structurally and functionally distinct areas is central to our understanding of the development of human cognitive capacity and the pathogenesis of congenital disorders of higher brain functions. The protomap hypothesis suggests how the cytoarchitectonic pattern of the cerebral cortex may be generated by a combination of intrinsic and extrinsic influences during embryonic development. Although little is known about the genetic and molecular mechanisms underlying this individual and species-specific diversity of cellular and synaptic architecture, experimental manipulation of development in the primate embryo provides a glimpse into the cascade of cellular events involved in the control of cell numbers, specification of neuronal phenotypes, their apportions into cytoarchitectonic areas, and establishment of area-specific synaptic circuitry.
Afferent Pathways↗
A novel cytoarchitectonic area induced experimentally within the primate visual cortex.
The cerebral cortex is divisible into a number of cytoarchitectonic areas, but developmental mechanisms that regulate their number and size remain unknown. Here we provide evidence that reducing the population of selected thalamic fibers projecting into the primary visual cortex (area 17) of monkeys during midgestation induces the formation of a novel cytoarchitectonic area situated along the border of and embedded within area 17. This region, termed area X, differs cytoarchitectonically from both area 17 and the adjacent secondary visual cortex (area 18). We propose that an aberrant combination of thalamic and cortical connections acting on a portion of prospective area 17 deprived of its normal thalamic input may result in formation of a hybrid cortex. Our results support the protomap hypothesis of cortical parcellation and suggest how during evolution new cytoarchitectonic regions may arise by cell-cell interactions that depend on a unique combination of intrinsic properties of cortical neurons and afferent fibers.
Animals↗
Early phenotype expression of cortical neurons: evidence that a subclass of migrating neurons have callosal axons.
The use of [3H]thymidine labeling in combination with various axonal transport tracers has revealed that a subset of migrating neurons in the fetal monkey cerebrum issue axons to the opposite cerebral hemisphere while still migrating to their final positions in the cortical plate. Other cortical neurons with the same "birthdate" (i.e., that underwent their last round of DNA synthesis on the same day) are not retrogradely labeled by tracer injections of the opposite hemisphere. These findings suggest that the cardinal distinction between projection and local circuit neurons may be specified in postmitotic neurons before they acquire their final positions in the cortex.
Animals↗
Glial cell lineage in the cerebral cortex: a review and synthesis.
The present review is focused on the cell lineage relationships underlying gliogenesis in the cerebral cortex. Studies conducted both in vivo and in vitro suggest that the process of cortical gliogenesis involves a hierarchy of progressively restricted progenitor cell pools. In the cerebral cortex, as well as other areas of the central nervous system, glial cells differentiate from one another through a series of steps that can be defined at molecular, structural, and functional levels. Although the precise timing, sequence, and diversity of the steps involved in cortical gliogenesis are still not fully defined, the emerging picture suggests that both cell lineage and cell-cell interactions play a synergetic role in the determination and maintenance of the proper blend of glial cells in the cerebrum.
Animals↗
Distribution of dopaminergic receptors in the primate cerebral cortex: quantitative autoradiographic analysis using [3H]raclopride, [3H]spiperone and [3H]SCH23390.
A widespread distribution of dopamine D1 receptors in the neocortex is well recognized. However, the presence of dopamine D2 receptors in this structure has only recently been established [Martres et al. (1985) Eur. J. Pharmac. 118, 211-219; Lidow et al. (1989) Proc. natn. Acad. Sci. U.S.A. 86, 6412-6416]. In the present paper, a highly specific antagonist, [3H]raclopride, was used for autoradiographic determination of the distribution of D2 receptors in 12 cytoarchitectonic areas of the frontal, parietal, and occipital lobes of the rhesus monkey. A low density of D2-specific [3H]raclopride binding (1.5-4.0 fmol/mg tissue) was detected in all layers of all cortical areas studied. Throughout the entire cortex, the highest density of binding was consistently found in layer V. This is a unique distribution not observed so far for any other neurotransmitter receptor subtype in monkey cerebral cortex, including D1 receptor. In addition, a comparison was made of the distribution of [3H]raclopride and [3H]spiperone, which has been commonly used in previous attempts to label cortical D2 receptors. We found marked differences in the distribution of these two radioligands. In the prefrontal cortex, the pattern of [3H]spiperone binding in the presence of ketanserin resembled the combined distribution of 5-HT1C serotoninergic and alpha 2-adrenergic sites as well as D2 receptors. Thus, [3H]raclopride provides a better estimation of the D2 receptor distribution than does [3H]spiperone. The distribution of D2-specific binding of [3H]raclopride was also compared with the D1-specific binding of [3H]SCH23390 in the presence of mianserin to block labeling to 5-HT2 and 5-HT1C sites. The density of D1-specific [3H]SCH23390 binding was 10-20 times higher than that of D2-specific [3H]raclopride binding throughout the cortex. The densities of both [3H]raclopride and [3H]SCH23390 binding sites display a rostral-caudal gradient with the highest concentrations in prefrontal and the lowest concentrations in the occipital cortex. However, the binding sites of these two ligands had different laminar distributions in all areas examined. In contrast to preferential [3H]raclopride binding in layer V, a bilaminar pattern of [3H]SCH23390 labeling was observed in most cytoarchitectonic areas, with the highest concentrations in supragranular layers I, II and IIIa and infragranular layers V and VI. Whereas [3H]raclopride binding was similar in all cytoarchitectonic areas, [3H]SCH23390 exhibited some region-specific variations in the primary visual and motor cortex. The different regional and laminar distributions of D1 and D2 dopaminergic receptors indicates that they may subserve different aspects of dopamine function in the cerebral cortex.
Animals↗
Glial cells in development. In vivo and in vitro approaches.
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Animals↗
Growth cone distribution patterns in the optic nerve of fetal monkeys: implications for mechanisms of axon guidance.
The distribution of growth cones was studied in the optic nerve of monkeys during the first half of prenatal development using quantitative electron microscopic methods. Our aim was to test the hypothesis that ganglion cell growth cones extend predominantly along the surfaces of the nerve, just beneath the pia mater. A complete census of growth cones in cross sections of the nerve during the early phase of axon ingrowth, from embryonic day 39 (E39) to E41, demonstrates that growth cones are scattered within the majority of fascicles, even those located far from the surface of the nerve. By E45, growth cones are concentrated around the nasal, dorsal, and ventral edge of the optic nerve. They are less concentrated in the core and around the temporal edge. However, even as late as E49, virtually all fascicles in the nerve, whether deep or superficial, contain growth cones. Growth cones are dispersed within single fascicles and are often located far from glia. Thus, the newest fibers penetrate deep parts of the pathway and push through centers of densely packed bundles of older axons. This finding is consistent with the vagrant paths of growing axons reported in previous work on embryonic monkey optic nerve (Williams and Rakic, 1985). Our data challenge the hypotheses that growth cones extend selectively along the basal lamina, the pia mater, or glial end feet. Gradients found at later stages of development in the nerve are not due to a particular affinity of growth cones for non-neuronal substrata. The pattern we observed is much more likely to result from central-to-peripheral gradients in ganglion cell generation and possible associations between growth cones originating from the same regions of the retina.
Animals↗
Autoradiographic comparison of D1-specific binding of [3H]SCH39166 and [3H]SCH23390 in the primate cerebral cortex.
Quantitative autoradiography was used to compare the binding of the novel dopamine D1 receptor antagonist, [3H]SCH39166, with that of the widely used radioligand, [3H]SCH23390 (in the presence of ritanserin), in the primate cerebral cortex. Specific binding of both radioligands, determined using SCH23390 or cis-flupentixol as displacing agents, had very similar densities and distributions throughout the cortex. However, the specific binding of [3H]SCH39166 obtained with SCH39166 as a blank was significantly higher than that obtained using SCH23390 or cis-flupentixol as displacing agents in some layers of motor, somatosensory and occipital cortices. In addition, the non-specific binding of [3H]SCH39166 obtained in the presence of an excess of SCH23390 of cis-flupentixol displayed a complex laminar pattern very different from that of the specific binding. These observations suggest that [3H]SCH39166 may have a high affinity to more than the D1 receptor subtype bound by SCH23390 or cis-flupentixol. Also, these additional sites are likely to be different from 5-HT2 or 5-HT1C receptors since the latter sites were not displaced by 1 microM SCH23390.
Animals↗