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At least 19 recordsLinked to original sources
PubMed2025

Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex.

The human cortex undergoes extensive epigenetic remodeling during development, although the precise temporal and cell-type-specific dynamics of DNA methylation remain incompletely understood. In this study, we profiled genome-wide DNA methylation across human cortex tissue from donors aged 6 post-conception weeks to 108 years of age. We observed widespread, developmentally regulated changes in DNA methylation, with pronounced shifts occurring during early- and mid-gestation that were distinct from age-associated modifications in the postnatal cortex. Using fluorescence-activated nuclei sorting, we optimized a protocol for the isolation of SATB2-positive neuronal nuclei, enabling the identification of cell-type-specific DNA methylation trajectories in the developing cortex. Developmentally dynamic DNA methylation sites were significantly enriched near genes implicated in autism and schizophrenia, supporting a role for epigenetic dysregulation in neurodevelopmental conditions. Our findings underscore the prenatal period as a critical window of epigenomic plasticity in the brain with important implications for understanding the genetic basis of neurodevelopmental phenotypes.

Humans↗
PubMed2026

3D epigenome of glial cell types in developing human cortex.

The human cortex is complex and heterogeneous, undergoing extensive expansion during development1,2. Our prior study of neurogenesis, including radial glia (RG), intermediate progenitor cells, excitatory neurons and interneurons demonstrated that chromatin looping underlies transcriptional regulation for lineage-specific genes, shedding light on how non-coding genetic variants contribute to neuropsychiatric disorders by means of cell-type-specific gene regulation3. RG have a crucial role in generating cellular diversity through both neurogenesis and gliogenesis and can be further classified into ventricular RG (vRG) and outer RG (oRG)4,5. Given their significance in cortical development, we conducted a comprehensive three-dimensional (3D) epigenomic analysis of four main glial populations, including vRG, oRG, oligodendrocyte precursor cells and microglia, from the mid-gestational human neocortex. By integrating gene expression, chromatin accessibility, DNA methylation and 3D chromatin interactions, we identified cell-type-specific candidate cis-regulatory elements (cCREs) and validated their regulatory function using transgenic mouse embryos. Using machine learning, we prioritized 112 schizophrenia risk variants within glia cCREs and further confirmed the predicted vRG enhancer disruption by the rs4449074 risk allele in vivo. Finally, oRG cCREs are enriched for human accelerated regions compared with other cCREs and a subset of human accelerated regions show activity differences from their chimpanzee orthologues that interact with genes involved in neuronal development. Our findings advance the understanding of human-specific gene regulation during corticogenesis.

Journal Article↗
PubMed2025

Combined somatic mutation and transcriptome analysis reveals region-specific differences in clonal architecture in human cortex.

The human cerebral cortex is specialized into regions, but little is known about how human cellular lineages shape cortical regional variation and neuronal cell-type distribution during development. Here, we map single-cell lineages of human cortical regions and neuronal subtypes using >1,000 somatic single-nucleotide variants (sSNVs) identified from deep bulk whole-genome sequencing and analyzed over 25 regions and >72,000 single cells. In the fronto-parietal cortex, sSNVs are rarely restricted, marking neuron-generating clones that disperse into neighboring regions. In contrast, the primary visual cortex harbors 30%-70% more sSNVs than the neighboring secondary visual cortex. Clones at this border exhibit more restricted dispersion, suggesting late developmental lineage segregation. Single-nucleus sSNV and whole-transcriptome analysis reveal glutamatergic neuron clones with modest regional restrictions that share low-mosaic sSNVs with some GABAergic neurons, suggesting a recent dorsal cortical progenitor. Our analysis reveals human-specific cortical lineage patterns, regional differences in clonal patterns, and late divergence of some glutamatergic/GABAergic lineages.

Humans↗
PubMed1988

Ring-substituted amphetamine interactions with neurotransmitter receptor binding sites in human cortex.

The binding affinities of 3 ring-substituted amphetamine compounds were determined at 9 neurotransmitter binding sites in human cortex. (+/-)-3,4-Methylenedioxyamphetamine (MDA), (+/-)-3,4-methylenedioxyethamphetamine (MDE), and (+/-)-3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') all display highest affinity (approximately 1 microM) for the recently identified 'DOB binding site' labeled by [77Br]R(-)4-bromo-2,5-dimethoxyphenylisopropylamine [( 77Br]R(-)DOB). MDA displays moderate affinity (4-5 microM) for the 5-hydroxytryptamine1A (5-HT1A), 5-HT1D, and alpha 2-adrenergic sites in human cortex. MDE and MDMA display lower affinity or are inactive at all other sites tested in the present study. These observations are discussed in relation to the novel psychoactive effects of the ring-substituted amphetamines.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Differentiation of muscarinic cholinergic receptor subtypes in human cortex and pons: implications for anti-motion sickness therapy.

Radioligand binding studies were used to analyze muscarinic cholinergic receptor subtypes in human cortex and pons. Muscarinic cholinergic receptors were labeled by 3H-quinuclidinyl benzilate (3H-QNB). Scopolamine was equipotent in both brain regions and did not discriminate subtypes of 3H-QNB binding. By contrast, the M1 selective antagonist pirenzepine was approximately 33-fold more potent in human cortex than pons. Carbachol, a putative M2 selective agonist, was more than 100-fold more potent in human pons than cortex. These results demonstrate that the human pons contains a relatively large proportion of carbachol sensitive muscarinic cholinergic receptors. Drugs targeted to this subpopulation of muscarinic cholinergic receptors may prove to be effective anti-motion sickness agents with less side effects than scopolamine.

Carbachol↗
PubMed1992

Non-specific binding of normal human IgG, including F(ab')2 and Fc fragments, to embryonic rat brain neurons and human cortex synaptosomes.

Binding of normal human IgG to embryonic rat brain neurons was quantitated by flow cytometry. IgG binding was linear between 0.05 and 1.5 mg/ml; slight binding was detectable even at normal cerebrospinal fluid concentrations. Similar binding curves were obtained for purified Fc and F(ab')2 fragments from normal human IgG. Normal human IgG also bound to synaptosomes (resealed nerve terminals) from human cerebral cortex. However, competition assays utilizing 125I-IgG showed no evidence for specific binding. This study indicates that the specificity of putative anti-neuronal antibodies should be confirmed by competition assays as for other receptor-ligand binding.

Animals↗
PubMed1987

Distinct topographical localisation of two somatostatin receptor subpopulations in the human cortex.

The use of two different radioligands, [125I]Leu8, D-Tryp22,Tyr25-somatostatin-28 and the stable somatostatin octapeptide analog [125I]204-090, D-Phe-Cys[125I]Tyr-D-Trp-Lys-Thr-Cys-Thr(ol), allowed to differentiate between two somatostatin receptor subpopulations in the human cortex. In homogenates, octapeptide somatostatin analogs displaced only part of the somatostatin-28 radioligand with high affinity. Autoradiography showed that the receptor subpopulation labelled with [125I]204-090, which we named SS1, was preferentially localized in layers V and VI, whereas the subpopulation having low affinity for somatostatin octapeptides (named SS2), measured with somatostatin-28 radioligand, was concentrated in the superficial cortical layers (I-IV) and particularly enriched in parts of lamina IV.

Aged↗
PubMed1989

Hallucinogenic drug interactions with neurotransmitter receptor binding sites in human cortex.

The binding affinities of four hallucinogenic agents were analyzed at nine neurotransmitter binding sites in human cortex. d-Lysergic acid diethylamide (d-LSD), N,N-dimethyltryptamine (DMT), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB) display highest affinity for the recently identified "DOB binding site" labeled by 77Br-R(-)DOB. The phenalkylamines, DOI and DOB, display subnanomolar affinity for the 77Br-R(-)DOB-labeled site, whereas the indolealkylamines, d-LSD and DMT, display nanomolar affinity for this site. d-LSD was the most potent of the four hallucinogens at six of the other eight sites analyzed in this study. All four hallucinogens also display high affinity for the 5-hydroxytryptamine2 (5-HT2) receptor subtype, with potencies ranging from 4 to 360 nM. Marked differences in relative affinities were observed between the indolealkylamines and the phenalkylamines at the 5-HT1A, 5-HT1D, and DOB binding sites. These rank-order differences in affinities are likely to account for the differing effects of these agents in various biochemical and physiological assays.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMedDate not supplied

A computer-assisted direct-imaging system to obtain numerical densities of neurons in human cortex.

Studies of the numerical density of microscopic items in brain tissue is a time-consuming endeavor. However, such information is important for numerous issues such as the relationship between structure and function in the normal brain, individual differences, and studies of brains of neuropsychiatric patients. A computer-assisted imaging system specifically devised to obtain estimates of numerical densities in human cortex is described here. Its main advantage is that the microscopist can analyze the original image directly under the microscope, and most aspects of data acquisition and quantitative analysis are accomplished by the computer. The key features of the system are a Microvid (an electronic camera lucida) and the use of X, Y, and Z stage encoders in conjunction with three-dimensional computer software. The complete system is relatively inexpensive and is simple to set up and use. The reliability and validity of the numerical densities obtained using this system are documented.

Cell Differentiation↗
PubMed1992

Differential modulation by dopamine of responses evoked by excitatory amino acids in human cortex.

The responses of human neocortical neurons to iontophoretic application of excitatory amino acids and their modulation by dopamine (DA) were studied in vitro. Brain slices were obtained from children undergoing surgery for intractable epilepsy. Application of N-methyl-D-aspartate (NMDA) to the slices induced slow depolarizations accompanied by decreased input conductances and sustained action potentials in cortical neurons. Glutamate produced rapid depolarizations and firing with few changes in input conductances. Quisqualate also induced depolarization and firing, but input conductances increased during the rising phase of the membrane depolarization. Iontophoretic application of DA alone produced no change in membrane potential or input conductance. However, when DA was applied in conjunction with the excitatory amino acids, it produced contrasting effects. With either bath application of DA or when iontophoresis of DA preceded application of NMDA, the amplitude of the membrane depolarizations and the number of action potentials were increased, whereas the latency of these responses decreased. In contrast, DA decreased the amplitude of the depolarizations and the number of action potentials evoked by glutamate or quisqualate. The fact that DA affects responses to NMDA and glutamate or quisqualate in opposite directions is of considerable importance to the understanding of cellular mechanisms of neuromodulation and the role of DA in cognitive processing and in epilepsy.

Adolescent↗
PubMed1990

Relationship of invasiveness to proliferating activity and to cytoskeletal protein production in human neuroepithelial tumors maintained in an organ culture system: use of human cortex and dura as supporting matrices.

The proliferation and invasiveness of cultured human neuroepithelial tumors were studied. A human malignant astrocytic glioma cell line (U-251 MG) and a medulloblastoma cell line (D283 Med) were maintained for 3 weeks in an organ culture system using adult human brain cortex, dura mater, or Gelfoam sponge as growth matrices. The cells were labeled with bromodeoxyuridine (BrdU) at different time points, and immunohistochemistry was performed for BrdU, glial fibrillary acidic (GFA) protein (in U-251 MG), and neurofilament (NF) protein (in D283 Med). In the U-251 MG line, the cells grew successfully in each matrix, forming a fibrillated solid area and a peripheral zone of invasion. The labeling index (LI) expressed as the percentage of BrdU-labeled cells and the percentage of GFA protein-positive cells in the two zones of the explants were analyzed. The LIs in all cultures were significantly higher in the peripheral than in the central zones. On the other hand, the percentage of GFA protein-positive cells in each matrix was greater in the central zone than in the periphery. The LI was inversely correlated with the percentage of GFA protein-positive cells over the areas counted in each growth matrix. GFA protein production in cells grown on cortex and on dura mater was significantly higher than that in cells grown on Gelfoam. In the D283 Med line, the cells formed an aggregated zone, with peripheral cells infiltrating the Gelfoam. This line showed poor growth on human cortex. Cells grown on the dura demonstrated an LI similar to that on Gelfoam, and cells often infiltrated the dura.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Neoplasms↗
PubMed1986

Do antipsychotic drugs and serotonin down regulate [3H]-spiroperidol binding sites in human cortex?

[3H]-Spiroperidol binds at several specific sites in postmortem human prefrontal cortex at 21 degrees C. The overall selectivity of these sites is serotonergic. At 37 degrees C, there is a marked loss of specific [3H]-spiroperidol binding that occurs between 10 and 60 min. This loss of binding is not apparently due to 3H-ligand degeneration or metabolism, or to non-specific binding site degradation. The loss of binding can also be produced by serotonin (5-HT), haloperidol and chlorpromazine but not by prazosin. The rate of the loss of binding is dependent on 3H-ligand concentration and protein concentration. The loss of binding is correlated with a loss of serotonin selective [3H]-spiroperidol binding sites having a KD of approximately 0.04 nM. Therefore antipsychotic compounds and 5-HT appear to down-regulate a subset of antipsychotic binding sites in human prefrontal cortex.

Adolescent↗
PubMed1987

The spatial distribution of neurons and glia in human cortex based on the poisson distribution.

A method was devised that employs deviations from the Poisson distribution to analyze the spatial arrangement of neurons and glia in human cerebral cortex. A field of randomly distributed points equal in number of a sample field of neuronal or glial cells is generated by computer, and the proportion of cells in the sample field that are closer to the nearest neighboring cells than to the nearest randomly distributed point is determined. We call this proportion the "Poisson ratio." When the cells are randomly distributed, the Poisson ratio is equal to 0.5. If the Poisson ratio is less than 0.5, the cells are farther away from one another than a random distribution would predict (exclusionary pattern); if the Poisson ratio is greater than 0.5, the cells are closer to one another than a random distribution would predict (clustering). A simple nonparametric statistical test is used to determine the significance of differences in the ratios. This method was applied to samples of human cerebral cortex in order to test the hypothesis that patients with schizophrenic psychosis may have an altered pattern of neuronal clustering. The analysis revealed that there is no difference in the nearest-neighbor distribution of either neurons or glia between psychotic patients and controls. It was found, however, that there is a highly significant difference in the spatial distribution of neurons versus glia in human cerebral cortex. Neurons of layers II to VI in the human cortex show greater-than-expected distances among them and are distributed according to an exclusionary pattern, while neurons in layer I show a clustering pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral Cortex↗
PubMed1987

Dopaminergic innervation of the primary visual cortex in the rat, and some correlations with human cortex.

Dopaminergic terminals have been identified in the primary visual cortex with three techniques; immunocytochemistry with an anti-dopamine antiserum, retrograde axonal transport techniques using unconjugated wheat germ agglutinin and HPLC determination of catecholamines and metabolites in microdissected sub-regions of occipital cortex in the rat. The results demonstrate a specific dopaminergic innervation, arising from the ventral tegmental area, which is found mainly in laminae VI and V, but with minor innervation also in lamina I. Dopaminergic innervation to adjacent cortical regions is also described. Neurochemical data from post-mortem human material suggests that a similar innervation exists in man. An analysis of the distribution of dopaminergic fibres in relation to the known connections and possible functions of the deep laminae of visual cortex suggests that dopaminergic axons may participate in the corticofugal control of visual afferent pathways.

Aged↗
PubMed1988

Noninvasive mapping of human motor cortex.

Human motor cortex was stimulated using brief, high-voltage electrical stimulation. Constant-voltage stimuli were delivered through a bipolar surface stimulator with the anode placed at multiple positions on the scalp and the cathode situated 2.5 cm anterior to the anode. Recordings were bilateral from the abductor pollicis brevis, tibialis anterior, and risorius. We averaged the amplitudes of three muscle responses obtained from stimulation of each scalp position and assigned the resultant value to that position. The findings in eight normal volunteers were similar and reproducible. The maximal responses of the right hand were obtained when stimulating over C3, of the left hand when stimulating over C4, of the right and left legs when stimulating over Cz, and of the right side of the mouth when stimulating over T3.

Adult↗
PubMed1988

Expression of ETS proto-oncogenes in astrocytes in human cortex.

In order to investigate a possible function of ETS proto-oncogenes in human brain, we incubated a polyclonal antibody raised against the viral region of E26 homologous to ETS1 and ETS2 with human brain frontal cortex sections. Our results show that this antibody decorates astrocytes but not neurons. By using astrocytomas of different grades as a source of astrocytes, we demonstrate the presence of ETS1 and ETS2 messenger RNAs and proteins. This leads to the idea that ETS genes are expressed in cells with dividing potentialities in human cortex and that they could provide a new marker for glial cells. Recently, a microduplication on chromosome 21 including ETS2 locus was described in karyotypically 'normal' Down's syndrome and suspected in Alzheimer's disease; when testing Alzheimer's disease-affected brain cortex sections, no obvious difference was observed with the technique used.

Antigens, Viral↗