Renewed focus on the developing human neocortex

Many specifically human psychiatric and neurological conditions have developmental origins. Rodent models are extremely valuable for the investigation of brain development, but cannot provide insight into aspects that are specifically human. The human brain, and particularly the cerebral cortex, has some unique genetic, molecular, cellular and anatomical features, and these need to be further explored. Cortical expansion in human is not just quantitative; there are some novel types of neurons and cytoarchitectonic areas identified by their gene expression, connectivity and functions that do not exist in rodents. Recent research into human brain development has revealed more elaborated neurogenetic compartments, radial and tangential migration, transient cell layers in the subplate, and a greater diversity of early-generated neurons, including predecessor neurons. Recently there has been a renaissance of the study of human brain development because of these unique differences, made possible by the availability of new techniques. This review gives a flavour of the recent studies stemming from this renewed focus on the developing human brain.     

Equations to describe brain size across the continuum of human lifespan

Equations fitting the normative values for gender-specific brain size changes are available. However, these equations do not fit for all age ranges across the human lifespan and particularly have failed to examine the fit across the continuum of prenatal and postnatal human life. We sought to develop a parametric equation that best describes the changes in gender-specific brain size as a function of age across the continuum of prenatal and postnatal human life. Brain weight and brain volume data retrieved from the literature were combined to perform a meta-analysis. Additions to previously published findings included collecting a dataset that spanned the continuum of human lifespan, logarithmic transformation of the data and utilization of the Birch equation. We used Akaike’s Information Criterion (AIC) for quantitative evaluation of the new equations. A total of 2,011 brain weight data points spanning from 10 weeks of fetal gestation to over 90 years of age were retrieved. Using our approach, we developed equations with improved fits and lower or similar AIC values compared to the published equations. The new equations are modifications of the basic Birch model. These equations are the first to describe the gender-specific brain weight changes through the continuum of both prenatal and postnatal human life while achieving a level of accuracy similar to or better than the previous, more age-restricted models. The new equations are improved compared to previously used equations and may be useful to those who study brain development, particularly researchers interested in prenatal and postnatal brain size.     

Urocortin 1-containing neurons in the human Edinger-Westphal nucleus

The topographical location of neurons containing urocortin 1, a peptide related to corticotropin-releasing factor was investigated in human postmortem brain by immunohistochemistry, and compared with the location of neurons containing choline acetyltransferase, a marker for cholinergic cells. A three-dimensional computer reconstruction of the urocortin 1 and choline acetyltransferase-positive population of neurons within the oculomotor area was made. It was shown that the urocortin 1-positive neurons are located within the area identified as the Edinger-Westphal nucleus according to the human brain stem atlas, and that the neurons identified as Edinger-Westphal nucleus in the atlas are not choline acetyltransferase-positive. This finding agrees with recent animal studies showing that urocortin 1-positive neurons are not identical with the parasympathetic cholinergic neurons projecting to the ciliary ganglion. They indicate that the neurons identified as Edinger-Westphal nucleus in the human brain stem atlas belong to the non-preganglionic Edinger-Westphal nucleus, whereas the location of preganglionic Edinger-Westphal nucleus remains unidentified.     

Astrocytes and the evolution of the human brain

Cells within the astroglial lineage are proposed as the origin of human brain evolution. It is now widely accepted that they direct mammalian fetal neurogenesis, gliogenesis, laminar cytoarchitectonics, synaptic connectivity and neuronal network formation. Furthermore, genetic, anatomical and functional studies have recently identified multiple astrocyte exaptations that strongly suggest a direct relation to the increased size and complexity of the human brain.     

Maps of the brain

We review recent developments in brain mapping and computational anatomy that have greatly expanded our ability to analyze brain structure and function. The enormous diversity of brain maps and imaging methods has spurred the development of population-based digital brain atlases. These atlases store information on how the brain varies across age and gender, across time, in health and disease, and in large human populations. We describe how brain atlases, and the computational tools that align new datasets with them, facilitate comparison of brain data across experiments, laboratories, and from different imaging devices. The major methods are presented for the construction of probabilistic atlases, which store information on anatomic and functional variability in a population. Algorithms are reviewed that create composite brain maps and atlases based on multiple subjects. We show that group patterns of cortical organization, asymmetry, and disease-specific trends can be resolved that may not be apparent in individual brain maps. Finally, we describe the creation of four-dimensional (4D) maps that store information on the dynamics of brain change in development and disease. Digital atlases that correlate these maps show considerable promise in identifying general patterns of structural and functional variation in human populations, and how these features depend on demographic, genetic, cognitive, and clinical parameters.     

Abnormal development of the human cerebral cortex

This review presents an overview of human cortical malformation based on the insights gained from examination of human fetal brains. Examination at early stages of fetal brain development allows the identification of the specific pathways which are disrupted in human cortical malformation. Detailed examination of human fetal brains in parallel with studies of genetics and animal models is leading to new concepts of cortical malformations. Here we review a range of human cortical malformations based on a simple classification according to the developmental process thought to be disrupted: neuroblast proliferation, undermigration, overmigration, cortical maturation and destructive lesions. A single case example of a dated intrauterine injury illustrates the spectrum of malformations which may result at a single period in development. The recommended methods of examination of human fetal brain are described together with some of their pitfalls. Detailed neuropathological observations indicate the need for caution in the classification of malformations; radiological findings and pathology of the mature brain do not reflect the specific disruptive pathways of cortical malformations. While many insults may lead to the same pattern of malformation, a single insult can lead to multiple patterns of malformation. Our detailed studies of the human fetal brain suggest that the interface between the meninges and the radial glial end feet may be an intriguing new focus of interest in understanding cortical development.     

Characterization of normal human brain cultures. Evidence for the outgrowth of leptomeningeal cells

To establish the histogenetic identity of the predominant cell type in monolayer cultures of normal human adult brain, eight brain specimens were placed into culture and characterized according to cell kinetics, karyotype, antigenic expression, and ultrastructural features. The protein profiles of both the cell layer and the medium were analyzed in selected cultures using sodium dodecyl sulfate polyacrylamide gel electrophoresis and diethylaminoethyl cellulose chromatography. All cultures displayed a limited life span in vitro; marked contact inhibition at confluence; a normal karyotype; an intracytoplasmic and extracellular glycoprotein profile consisting of fibronectin, procollagen type III, laminin, and collagen type IV; specialized intercellular junctions; and interstitial collagen chain synthesis. All of these features were identified in our previous study of human leptomeningeal cultures. The results of immunocytochemical staining for glial fibrillary acidic protein were negative in all cultures of normal human brain, except in early passages in two cultures, which lost the glial cell marker during subsequent passages; immunostains for vimentin were positive in all cells in all cultures. These results support the hypothesis that, in this study, cultures derived from normal human brain are not of glial origin. Our findings also suggest that glial cells are less well-suited to monolayer growth under our culture conditions than are other cell types in enzyme-dissociated brain tissue placed in culture, especially leptomeningeal cells. The identification of leptomeningeal cells as the predominant cell type in normal human brain cultures may prove useful in attempts to foster the growth of human glial cells by culturing brain samples under conditions that prohibit the growth of leptomeningeal cells. Under such conditions, astrocytes, oligodendroglia, and ependymal cells could be isolated with greater ease and cultured separately. These purified cultures of different glial cell types would then provide a more relevant in vitro model for studying human neurological diseases.     

Splice variants of the receptor for advanced glycosylation end products (RAGE) in human brain

Previous studies indicate that the receptor for advanced glycosylation end products (RAGE) plays an important role in multiple pathological processes, including Alzheimer's disease. Currently there are three established isoforms of the RAGE receptor, with each isoform generated as the result of alternative splicing. It is presently unclear which of the RAGE isoforms are normally expressed in the human brain, nor has it been determined if additional RAGE isoforms exist in the human brain. In the present study we demonstrate for the first time that each of the three established RAGE isoforms, as well as three previously unidentified RAGE splicing variants, are normally expressed in the human brain. These data suggest that RAGE may have multiple functions in the human brain, mediated by the individual or coordinated efforts of the different RAGE isoforms, with alternative splicing generating individual RAGE isoforms that specifically interact with the various ligands present in the brain.     

The glia doctrine: Addressing the role of glial cells in healthy brain ageing

Glial cells in their plurality pervade the human brain and impact on brain structure and function. A principal component of the emerging glial doctrine is the hypothesis that astrocytes, the most abundant type of glial cells, trigger major molecular processes leading to brain ageing. Astrocyte biology has been examined using molecular, biochemical and structural methods, as well as 3D brain imaging in live animals and humans. Exosomes are extracelluar membrane vesicles that facilitate communication between glia, and have significant potential for biomarker discovery and drug delivery. Polymorphisms in DNA repair genes may indirectly influence the structure and function of membrane proteins expressed in glial cells and predispose specific cell subgroups to degeneration. Physical exercise may reduce or retard age-related brain deterioration by a mechanism involving neuro-glial processes. It is most likely that additional information about the distribution, structure and function of glial cells will yield novel insight into human brain ageing. Systematic studies of glia and their functions are expected to eventually lead to earlier detection of ageing-related brain dysfunction and to interventions that could delay, reduce or prevent brain dysfunction.     

Ferritin: the role of aluminum in ferritin function.

We previously showed that human brain ferritin (HBF) binds aluminum (Al) in vivo and in vitro and HBF isolated from Alzheimer's brain had more Al bound compared to aged matched controls (7). To further understand the role ferritin may play in Al neurotoxicity, we have studied in vitro the effect of Al on the function of human ferritin isolated from Alzheimer's (AD) and normal brain tissue, and compared the results with other mammalian ferritins. Al causes a concentration-dependent decrease in the initial rate of iron loading into apo-horse spleen and human brain ferritin and the rates were similar for ferritin isolated from both AD and normal brains. The rates of iron release of mammalian ferritins from different tissues were determined: horse spleen much greater than human liver greater than rat brain greater than human brain = rat liver ferritin. The rates of iron release of AD and normal human brain ferritin were similar and were unaffected by preloading with Al. Several mammalian ferritins were compared for their total iron uptake: horse spleen = human liver greater than human brain (normal) = human brain (AD) ferritin. In 20 mM HEPES (pH 6.0) buffer holoferritin is more resistant to precipitation by Al than apoferritin suggesting that holoferritin is a better chelator for nonferrous metal ions.     

Insulin- and glucagonlike peptides in the brain

The cellular localization and regional distribution of insulin- and glucagonlike substance, C-peptide-like immunoreactivity, thiol:protein disulphide oxidoreductase, TPO (E.C.1.8.4.2.), and insulin/glucagon-specific proteinase, ISP (E.C.3.4.22.-), are studied in the CNS of man, adult and juvenile rats, mice, tortoises, and frogs by use of immunohistochemistry. Furthermore, the content of immunoreactive insulin, glucagon, and C-peptide was estimated in human cadaver brains by radioimmunoassay. It could be shown that insulinlike immunoreactive material is widely distributed in the human brain and the CNS of juvenile rats as well as in mice, whereas in the CNS of adult rats and nonmammalian animals (frogs, tortoises) the polypeptide is restricted to a few nerve cell populations. C-peptide immunoreactivity was demonstrated in human CNS in the same nerve cells as insulin. By use of two different glucagon-antisera it was revealed that gut-type glucagon occurs in many nerve cells of human and mouse brains, as well as in the CNS of juvenile rats. On the other hand, pancreas-type glucagon was less widely distributed in the human brain and nearly not detectable in the CNS of mice and rats. With the exception of neurosecretory nerve cells, there was a high degree of coincidence between the localization of insulin and TPO. The immunoreaction against the ISP antiserum was weak, but correlated well with the distribution of insulin-immunoreactivity. The occurrence of TPO and ISP in the brain demonstrates the ability of nervous tissue to degrade insulin and glucagon. By radioimmunoassay it was established that human brain contains insulin, glucagon and C-peptide at concentrations that exceed blood levels. We conclude from our data that, at least in part, cerebral insulin and glucagon are products of the brain itself.     

Anatomical organization of the eye fields in the human and non-human primate frontal cortex

There are several eye fields in the primate frontal cortex. The number and location of these oculomotor control zones remain controversial, especially in the human brain. In the monkey, the frontal eye field (FEF) is located in the rostral bank of the arcuate sulcus at approximately the level of the posterior end of the sulcus principalis, the supplementary eye field (SEF) is located on the dorsomedial frontal cortex, and the cingulate eye field (CEF) in the dorsal bank of the cingulate sulcus. In the human frontal cortex, the location of the FEF varies depending on the method used, electrical stimulation or functional neuroimaging, to establish it. Some investigators have argued that the SEF is located on the medial wall of the frontal lobe but its presumed location remains controversial. The location of the CEF in the human brain is not known. The present article reviews electrophysiological and functional neuroimaging evidence regarding the location of these frontal oculomotor areas in the macaque monkey and human brains and, in light of new findings in the human brain, attempts to reconcile the differences observed in the location of these eye fields using the different techniques. Together, these data suggest the existence of at least four eye fields in the frontal cortex, i.e. the FEF, the SEF, the CEF, and a premotor eye field, and suggest that their anatomical relationships are preserved from monkey to human brain.     

Neuroglobin and Cytoglobin expression in the human brain

Neuroglobin and Cytoglobin are new members of the heme–globin family. Both globins are primarily expressed in neurons of the brain and retina. Neuroglobin and Cytoglobin have been suggested as novel therapeutic targets in various neurodegenerative diseases based on their oxygen binding and cell protecting properties. However, findings in Neuroglobin-deficient mice question the endogenous neuroprotective properties. The expression pattern of Neuroglobin and Cytoglobin in the rodent brain is also in contradiction to a major role of neuronal protection. In a recent study, Neuroglobin was ubiquitously expressed and up-regulated following stroke in the human brain. The present study aimed at confirming our previous observations in rodents using two post-mortem human brains. The anatomical localization of Neuroglobin and Cytoglobin in the human brain is much like what has been described for the rodent brain. Neuroglobin is highly expressed in the hypothalamus, amygdale and in the pontine tegmental nuclei, but not in the hippocampus. Cytoglobin is highly expressed in the habenula, hypothalamus, thalamus, hippocampus and the pontine tegmental nuclei. We only detected a low expression of Neuroglobin and Cytoglobin in the cerebral cortex, while no expression in the cerebellar cortex was detectable. We provide a neuroanatomical indication for a different role of Neuroglobin and Cytoglobin in the human brain.     

New approaches to the study of human brain networks underlying spatial attention and related processes

Cognitive processes, such as spatial attention, are thought to rely on extended networks in the human brain. Both clinical data from lesioned patients and fMRI data acquired when healthy subjects perform particular cognitive tasks typically implicate a wide expanse of potentially contributing areas, rather than just a single brain area. Conversely, evidence from more targeted interventions, such as transcranial magnetic stimulation (TMS) or invasive microstimulation of the brain, or selective study of patients with highly focal brain damage, can sometimes indicate that a single brain area may make a key contribution to a particular cognitive process. But this in turn raises questions about how such a brain area may interface with other interconnected areas within a more extended network to support cognitive processes. Here, we provide a brief overview of new approaches that seek to characterise the causal role of particular brain areas within networks of several interacting areas, by measuring the effects of manipulations for a targeted area on function in remote interconnected areas. In human participants, these approaches include concurrent TMS-fMRI and TMS-EEG, as well as combination of the focal lesion method in selected patients with fMRI and/or EEG measures of the functional impact from the lesion on interconnected intact brain areas. Such approaches shed new light on how frontal cortex and parietal cortex modulate sensory areas in the service of attention and cognition, for the normal and damaged human brain.     

Human neuronal calcium sensor-1 shows the highest expression level in cerebral cortex

Neuronal calcium sensors (NCS) are important constituents in the intracellular signaling pathways. A novel human gene, NCS-1, was identified in the present study. Among the 16 human tissues examined, NCS-1 is expressed most abundantly in the brain. Among the brain regions, the expression level of NCS-1 in cerebral cortex is the highest, which is about six times higher than the average level of the whole brain and a hundred times higher than the spinal cord. In the 12 different anatomical regions of human brain, the expression level of NCS-1 is very high in the temporal lobe, occipital pole, frontal lobe, thalamus, amygdala and hippocampus; moderate in cerebellum, putamen, caudate nucleus; low in the medulla, substantia nigra and the lowest in corpus callosum. Our results suggest that NCS-1 in human brain might be involved in a variety of brain functions such as sensory processing, motor control, emotional control, learning and memory.     

A study of the organ-specific antigenic properties of the human brain with the aid of sera containing isoimmune antibodies against the brain

Summary Sera of the 16 patients suffering from neuropsychic afflictions containing isoantibodies against the brain were used for studying the antigenic properties of the brain. Investigations were carried out by the method of prolonged complement fixation in cold conditions with water-salt extract of the human and rat brain. Some sera (6) reacted with the same intensity with antigens from various portions of the human brain: frontal lobe, optic thalamus, cerebellum, white matter of the hemispheres, as well as with the antigens from the rate brain. Sera of 8 other persons reacted mainly with the rat brain. Sera of two persons exhibited a selective activity with respect to some portions of the human brain with the absence of any reaction with other antigens. It is suggested that in affection of the brain by a morbid process there appear antibodies to various antigenic components at definite stages of the disease. Brain tissues contain organ-specific antigens, common to all of its portions as well as antigens mainly represented in the individual nerve tissue formations. Antigenic similarities and differences between the human brain and that of the heterologous species were established.(Presented by Active Member AMN SSSR N. N. Zhukov-Verezhnikov) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 54, No. 7, pp. 62–67, July, 1962