52 research outputs found
Interactive histogenesis of axonal strata and proliferative zones in the human fetal cerebral wall
Development of the cerebral wall is characterized by partially overlapping histogenetic events. However, little is known with regards to when, where, and how growing axonal pathways interact with progenitor cell lineages in the proliferative zones of the human fetal cerebrum. We analyzed the developmental continuity and spatial distribution of the axonal sagittal strata (SS) and their relationship with proliferative zones in a series of human brains (8-40 post-conceptional weeks; PCW) by comparing histological, histochemical, and immunocytochemical data with magnetic resonance imaging (MRI). Between 8.5 and 11 PCW, thalamocortical fibers from the intermediate zone (IZ) were initially dispersed throughout the subventricular zone (SVZ), while sizeable axonal "invasion" occurred between 12.5 and 15 PCW followed by callosal fibers which "delaminated" the ventricular zone-inner SVZ from the outer SVZ (OSVZ). During midgestation, the SS extensively invaded the OSVZ, separating cell bands, and a new multilaminar axonal-cellular compartment (MACC) was formed. Preterm period reveals increased complexity of the MACC in terms of glial architecture and the thinning of proliferative bands. The addition of associative fibers and the formation of the centrum semiovale separated the SS from the subplate. In vivo MRI of the occipital SS indicates a "triplet" structure of alternating hypointense and hyperintense bands. Our results highlighted the developmental continuity of sagittally oriented "corridors" of projection, commissural and associative fibers, and histogenetic interaction with progenitors, neurons, and glia. Histogenetical changes in the MACC, and consequently, delineation of the SS on MRI, may serve as a relevant indicator of white matter microstructural integrity in the developing brain
Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
A population of >6 million people worldwide at high risk of Alzheimerās disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of Ī²-amyloid-(AĪ²)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar AĪ² deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical Ī² and Ī³-secretase inhibition. We found that T21-organoids secrete increased proportions of AĪ²-preventing (AĪ²1-19) and AĪ²-degradation products (AĪ²1-20 and AĪ²1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases
Laminar and Dorsoventral Molecular Organization of the Medial Entorhinal Cortex Revealed by Large-scale Anatomical Analysis of Gene Expression
Neural circuits in the medial entorhinal cortex (MEC) encode an animal's position and orientation in space. Within the MEC spatial representations, including grid and directional firing fields, have a laminar and dorsoventral organization that corresponds to a similar topography of neuronal connectivity and cellular properties. Yet, in part due to the challenges of integrating anatomical data at the resolution of cortical layers and borders, we know little about the molecular components underlying this organization. To address this we develop a new computational pipeline for high-throughput analysis and comparison of in situ hybridization (ISH) images at laminar resolution. We apply this pipeline to ISH data for over 16,000 genes in the Allen Brain Atlas and validate our analysis with RNA sequencing of MEC tissue from adult mice. We find that differential gene expression delineates the borders of the MEC with neighboring brain structures and reveals its laminar and dorsoventral organization. We propose a new molecular basis for distinguishing the deep layers of the MEC and show that their similarity to corresponding layers of neocortex is greater than that of superficial layers. Our analysis identifies ion channel-, cell adhesion- and synapse-related genes as candidates for functional differentiation of MEC layers and for encoding of spatial information at different scales along the dorsoventral axis of the MEC. We also reveal laminar organization of genes related to disease pathology and suggest that a high metabolic demand predisposes layer II to neurodegenerative pathology. In principle, our computational pipeline can be applied to high-throughput analysis of many forms of neuroanatomical data. Our results support the hypothesis that differences in gene expression contribute to functional specialization of superficial layers of the MEC and dorsoventral organization of the scale of spatial representations
Neuronal migration and cortical migratory disorders
U ovom radu pružili smo pregled spoznaja o neurobioloÅ”koj osnovi poremeÄaja migracije koja je važna za njihovu klasifikaciju. Kortikalni neuroni raÄaju se u ventrikularnoj i subventrikularnoj zoni te prolaze dugaÄak put do svojeg konaÄnog odrediÅ”ta, rabeÄi dva osnovna mehanizma i puta migracije: (1) radijalnu migraciju, put uzduž radijalne glije i (2) tangencijalnu, najvjerojatnije āneurofilnuā migraciju. Tijek migracije je složen i može biti poremeÄen utjecajem razliÄitih genetskih i vanjskih Äimbenika. PoremeÄaj proliferacije u ventrikularnoj zoni dovodi do znaÄajnih malformacija, kao Å”to je shizencefalija, a poremeÄaj samog poÄetka migracije uslijed genetskih abnormalnosti (mutacija FILAMIN1 gena) dovodi do periventrikularne nodularne heterotopije i strukturnih promjena vidljivih na slikovnim prikazima magnetskom rezonancijom (MRI). TipiÄni poremeÄaj migracije je lizencefalija tipa 1 koja se trenutno ubraja u spektar poremeÄaja agirija-pahigirija-ābandā heterotopija. Ova skupina poremeÄaja uzrokovana je mutacijama gena LIS1 i DCX (XLIS), a povezana je s Miller-Diekerovim, Lennox-Gastaut sindromom i epilepsijom. PoremeÄaji kasnijih faza migracije uzrokuju lizencefaliju tipa 2 (kompleks ācobblestoneā), koja je povezana s Walker-Warburgovim sindromom, makrocefalijom, malformacijom mrežnice, poremeÄajem miÅ”iÄ-oko-mozak i Fukuyama kongenitalnom miÅ”iÄnom distrofijom. Zellwegerov sindrom je karakteriziran patomorfoloÅ”ki polimikrogirijom i biokemijski grjeÅ”kom mithondrijskih putova desaturacije. PoremeÄaji kasne migracije pokazuju strukturne promjene vidljive MRI-om, koje su ograniÄene na moždanu koru. Drugi migracijski poremeÄaj, fokalna kortikalna displazija, Äesto je prisutna kod rezistentnih oblika epilepsije, a kod dijagnostike je od posebne koristi MRI visoke rezolucije (3T). Genetski testovi zajedno s MRI-om otvaraju nove moguÄnosti za ranu dijagnostiku i poboljÅ”ani pristup u lijeÄenju poremeÄaja migracije.In this review we outline the neurobiological basis for classification of cortical migratory disorders. Neurons of the human cortex are born in the ventricular and subventricular zone and migrate for a long distance to reach their final point of destination in the cortex, using two types of migratory routes and mechanisms: (1) radial migration along radial glia and (2) tangential, presumably āneurophilicā migration. The process of migration is complex and may be disturbed by various genetic and extrinsic factors. The disturbances of proliferation in the ventricular zone result in major malformations such as schizencephaly, while the failure of onset of migration results in periventricular nodular heterotopia with characteristic abnormalities in magnetic resonance imaging (MRI) and with genetic aberration in the background (FILAMIN1 gene mutation). The typical migratory disorder is lissencephaly type I caused by defect of ongoing migration. The lissencephaly type I is currently included in agyria-pachigyria band spectrum disorders. This group of disorders is caused by mutations of LIS1 and DCX (XLIS) gene mutations associated with Miller-Dieker syndrome, Lennox-Gastaut syndrome and epilepsy. The defects of late phases of migration cause lissencephaly type II, cobblestone complex, which is associated with Walker-Warburg syndrome, macrocephaly, retinal malformation, muscle-eye-brain disease and Fukuyama congenital muscular dystrophy. Zellweger syndrome is morphologically characterized by polymicrogyria and biochemically by defects of the mitochondrial desaturation pathway. The disorders with later migration failure show abnormal MRI restricted to the cortex. Another migratory disorder, focal cortical dysplasia, is a frequent cause of drug resistant epilepsy. An especially helpful diagnostic tool for migratory disorders is high resolution (3T) MRI. Genetic testing together with detailed MRI of migratory disorders opens new perspectives for early detection and improved treatment of migratory disorders
Microglial characterisation in transient human neurodevelopmental structures
Human neurodevelopment is characterized by the appearance, development, and disappearance or transformation of various transient structures that underlie the establishment of connectivity within and between future cortical and subcortical areas. Examples of transient structures in the forebrain (among many others) include the subpial granular layer and the subplate zone. We have previously characterized the precise spatiotemporal dynamics of microglia in the human telencephalon. Here, we describe the diversity of microglial morphologies in the subpial granular layer and the subplate zone. Where possible, we couple the predominant morphological phenotype with functional characterizations to infer tentative roles for microglia in a changing neurodevelopmental landscape. We interpret these findings within the context of relevant morphogenetic and neurogenetic events in humans. Due to the unique genetic, molecular, and anatomical features of the human brain and because many human neurological and psychiatric diseases have their origins during development, these structures deserve special attention
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