Publications by authors named "Goran Sedmak"

18 Publications

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The Accuracy of Direct Targeting Using Fusion of MR and CT Imaging for Deep Brain Stimulation of the Subthalamic Nucleus in Patients with Parkinson's Disease.

J Neurol Surg A Cent Eur Neurosurg 2021 Feb 22. Epub 2021 Feb 22.

Department of Neurosurgery, Clinical Hospital Dubrava, Zagreb, Croatia.

Introduction:  In 33 consecutive patients with Parkinson's disease (PD) undergoing awake deep brain stimulation (DBS) without microelectrode recording (MER), we assessed and validated the precision and accuracy of direct targeting of the subthalamic nucleus (STN) using preoperative magnetic resonance imaging (MRI) and stereotactic computed tomography (CT) image fusion combined with immediate postoperative stereotactic CT and postoperative MRI, and we report on the side effects and clinical results up to 6 months' follow-up.

Materials And Methods:  Preoperative nonstereotactic MRI and stereotactic CT images were merged and used for planning the trajectory and final lead position. Immediate postoperative stereotactic CT and postoperative nonstereotactic MRI provided the validation of the final electrode position. Changes in the Unified Parkinson's Disease Rating Scale III (UPDRS III) scores and the levodopa equivalent daily doses (LEDD) and appearance of adverse side effects were assessed.

Results:  The mean Euclidian distance (ED) error between the planned position and the final position of the lead in the left STN was 1.69 ± 0.82 mm and that in the right STN was 2.12 ± 1.00. The individual differences between planned and final position in each of the three coordinates were less than 2 mm. The UPDRS III scores improved by 75% and LEDD decreased by 45%. Few patients experienced complications, such as postoperative infection (= 1), or unwanted side effects, such as emotional instability ( = 1).

Conclusion:  Our results confirm that direct targeting of an STN on stereotactic CT merged with MRI could be a valid method for placement the DBS electrode. The magnitude of our targeting error is comparable with the reported errors when using MER and other direct targeting approaches.
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http://dx.doi.org/10.1055/s-0040-1715826DOI Listing
February 2021

White Matter Interstitial Neurons in the Adult Human Brain: 3% of Cortical Neurons in Quest for Recognition.

Cells 2021 01 19;10(1). Epub 2021 Jan 19.

Croatian Institute for Brain Research, University of Zagreb School of Medicine, Šalata 12, 10 000 Zagreb, Croatia.

White matter interstitial neurons (WMIN) are a subset of cortical neurons located in the subcortical white matter. Although they were fist described over 150 years ago, they are still largely unexplored and often considered a small, functionally insignificant neuronal population. WMIN are adult remnants of neurons located in the transient fetal subplate zone (SP). Following development, some of the SP neurons undergo apoptosis, and the remaining neurons are incorporated in the adult white matter as WMIN. In the adult human brain, WMIN are quite a large population of neurons comprising at least 3% of all cortical neurons (between 600 and 1100 million neurons). They include many of the morphological neuronal types that can be found in the overlying cerebral cortex. Furthermore, the phenotypic and molecular diversity of WMIN is similar to that of the overlying cortical neurons, expressing many glutamatergic and GABAergic biomarkers. WMIN are often considered a functionally unimportant subset of neurons. However, upon closer inspection of the scientific literature, it has been shown that WMIN are integrated in the cortical circuitry and that they exhibit diverse electrophysiological properties, send and receive axons from the cortex, and have active synaptic contacts. Based on these data, we are able to enumerate some of the potential WMIN roles, such as the control of the cerebral blood flow, sleep regulation, and the control of information flow through the cerebral cortex. Also, there is a number of studies indicating the involvement of WMIN in the pathophysiology of many brain disorders such as epilepsy, schizophrenia, Alzheimer's disease, etc. All of these data indicate that WMIN are a large population with an important function in the adult brain. Further investigation of WMIN could provide us with novel data crucial for an improved elucidation of the pathophysiology of many brain disorders. In this review, we provide an overview of the current WMIN literature, with an emphasis on studies conducted on the human brain.
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http://dx.doi.org/10.3390/cells10010190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833373PMC
January 2021

The total number of white matter interstitial neurons in the human brain.

J Anat 2019 09 7;235(3):626-636. Epub 2019 Jun 7.

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.

In the adult human brain, the interstitial neurons (WMIN) of the subcortical white matter are the surviving remnants of the fetal subplate zone. It has been suggested that they perform certain important functions and may be involved in the pathogenesis of several neurological and psychiatric disorders. However, many important features of this class of human cortical neurons remain insufficiently explored. In this study, we analyzed the total number, and regional and topological distribution of WMIN in the adult human subcortical white matter, using a combined immunocytochemical (NeuN) and stereological approaches. We found that the average number of WMIN in 1 mm of the subcortical white matter is 1.230 ± 549, which translates to the average total number of 593 811 183.6 ± 264 849 443.35 of WMIN in the entire subcortical telencephalic white matter. While there were no significant differences in their regional distribution, the lowest number of WMIN has been consistently observed in the limbic cortex, and the highest number in the frontal cortex. With respect to their topological distribution, the WMIN were consistently more numerous within gyral crowns, less numerous along gyral walls and least numerous at the bottom of cortical sulci (where they occupy a narrow and compact zone below the cortical-white matter border). The topological location of WMIN is also significantly correlated with their morphology: pyramidal and multipolar forms are the most numerous within gyral crowns, whereas bipolar forms predominate at the bottom of cortical sulci. Our results indicate that WMIN represent substantial neuronal population in the adult human cerebral cortex (e.g. more numerous than thalamic or basal ganglia neurons) and thus deserve more detailed morphological and functional investigations in the future.
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http://dx.doi.org/10.1111/joa.13018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704240PMC
September 2019

Gene expression profiling of the dorsolateral and medial orbitofrontal cortex in schizophrenia.

Transl Neurosci 2016 27;7(1):139-150. Epub 2016 Nov 27.

Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb Medical School, Zagreb, Croatia.

Schizophrenia is a complex polygenic disorder of unknown etiology. Over 3,000 candidate genes associated with schizophrenia have been reported, most of which being mentioned only once. Alterations in cognitive processing - working memory, metacognition and mentalization - represent a core feature of schizophrenia, which indicates the involvement of the prefrontal cortex in the pathophysiology of this disorder. Hence we compared the gene expression in postmortem tissue from the left and right dorsolateral prefrontal cortex (DLPFC, Brodmann's area 46), and the medial part of the orbitofrontal cortex (MOFC, Brodmann's area 11/12), in six patients with schizophrenia and six control brains. Although in the past decade several studies performed transcriptome profiling in schizophrenia, this is the first study to investigate both hemispheres, providing new knowledge about possible brain asymmetry at the level of gene expression and its relation to schizophrenia. We found that in the left hemisphere, twelve genes from the DLPFC and eight genes from the MOFC were differentially expressed in patients with schizophrenia compared to controls. In the right hemisphere there was only one gene differentially expressed in the MOFC. We reproduce the involvement of previously reported genes TARDBP and HNRNPC in the pathogenesis of schizophrenia, and report seven novel genes: , and . As the differentially expressed genes only partially overlap with previous studies that analyzed other brain regions, our findings indicate the importance of considering prefrontal cortical regions, especially those in the left hemisphere, for obtaining disease-relevant insights.
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http://dx.doi.org/10.1515/tnsci-2016-0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234522PMC
November 2016

Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain.

Cereb Cortex 2016 12 1;26(12):4574-4589. Epub 2015 Oct 1.

Croatian Institute for Brain Research

Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2-immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of α- and β-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca-dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia.
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http://dx.doi.org/10.1093/cercor/bhv218DOI Listing
December 2016

Stathmin is enriched in the developing corticospinal tract.

Mol Cell Neurosci 2015 Nov 12;69:12-21. Epub 2015 Sep 12.

Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire ST5 5BG, UK. Electronic address:

Understanding the intra- and extracellular proteins involved in the development of the corticospinal tract (CST) may offer insights into how the pathway could be regenerated following traumatic spinal cord injury. Currently, however, little is known about the proteome of the developing corticospinal system. The present study, therefore, has used quantitative proteomics and bioinformatics to detail the protein profile of the rat CST during its formation in the spinal cord. This analysis identified increased expression of 65 proteins during the early ingrowth of corticospinal axons into the spinal cord, and 36 proteins at the period of heightened CST growth. A majority of these proteins were involved in cellular assembly and organization, with annotations being most highly associated with cytoskeletal organization, microtubule dynamics, neurite outgrowth, and the formation, polymerization and quantity of microtubules. In addition, 22 proteins were more highly expressed within the developing CST in comparison to other developing white matter tracts of the spinal cord of age-matched animals. Of these differentially expressed proteins, only one, stathmin 1 (a protein known to be involved in microtubule dynamics), was both highly enriched in the developing CST and relatively sparse in other developing descending and ascending spinal tracts. Immunohistochemical analyses of the developing rat spinal cord and fetal human brain stem confirmed the enriched pattern of stathmin expression along the developing CST, and in vitro growth assays of rat corticospinal neurons showed a reduced length of neurite processes in response to pharmacological perturbation of stathmin activity. Combined, these findings suggest that stathmin activity may modulate axonal growth during development of the corticospinal projection, and reinforces the notion that microtubule dynamics could play an important role in the generation and regeneration of the CST.
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http://dx.doi.org/10.1016/j.mcn.2015.09.003DOI Listing
November 2015

Association of new deletion/duplication region at chromosome 1p21 with intellectual disability, severe speech deficit and autism spectrum disorder-like behavior: an all-in approach to solving the enigma.

Transl Neurosci 2015 2;6(1):59-86. Epub 2015 Mar 2.

Department for Functional Genomics, Center for Translational and Clinical Research, University of Zagreb Medical School, University Hospital Center Zagreb, Šalata 2, 10000 Zagreb, Croatia.

We describe an as yet unreported neocentric small supernumerary marker chromosome (sSMC) derived from chromosome 1p21.3p21.2. It was present in 80% of the lymphocytes in a male patient with intellectual disability, severe speech deficit, mild dysmorphic features, and hyperactivity with elements of autism spectrum disorder (ASD). Several important neurodevelopmental genes are affected by the 3.56 Mb copy number gain of 1p21.3p21.2, which may be considered reciprocal in gene content to the recently recognized 1p21.3 microdeletion syndrome. Both 1p21.3 deletions and the presented duplication display overlapping symptoms, fitting the same disorder category. Contribution of coding and non-coding genes to the phenotype is discussed in the light of cellular and intercellular homeostasis disequilibrium. In line with this the presented 1p21.3p21.2 copy number gain correlated to 1p21.3 microdeletion syndrome verifies the hypothesis of a cumulative effect of the number of deregulated genes - homeostasis disequilibrium leading to overlapping phenotypes between microdeletion and microduplication syndromes. Although appears to be the major player in the 1p21.3p21.2 region, deregulation of the dihydropyrimidine dehydrogenase) gene may potentially affect neighboring genes underlying the overlapping symptoms present in both the copy number loss and copy number gain of 1p21. Namely, the all-in approach revealed that is a complex gene whose expression is epigenetically regulated by long non-coding RNAs (lncRNAs) within the locus. Furthermore, the long interspersed nuclear element-1 () transposon inserted in intronic transcript 1 () lncRNA with its parasites, and pair of repeats appears to be the "weakest link" within the gene liable to break. Identification of the precise mechanism through which is epigenetically regulated, and underlying reasons why exactly the break () happens, will consequently pave the way toward preventing severe toxicity to the antineoplastic drug 5-fluorouracil (5-FU) and development of the causative therapy for the dihydropyrimidine dehydrogenase deficiency.
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http://dx.doi.org/10.1515/tnsci-2015-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936614PMC
March 2015

Spatial mapping of structural and connectional imaging data for the developing human brain with diffusion tensor imaging.

Methods 2015 Feb 6;73:27-37. Epub 2014 Nov 6.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States. Electronic address:

During human brain development from fetal stage to adulthood, the white matter (WM) tracts undergo dramatic changes. Diffusion tensor imaging (DTI), a widely used magnetic resonance imaging (MRI) modality, offers insight into the dynamic changes of WM fibers as these fibers can be noninvasively traced and three-dimensionally (3D) reconstructed with DTI tractography. The DTI and conventional T1 weighted MRI images also provide sufficient cortical anatomical details for mapping the cortical regions of interests (ROIs). In this paper, we described basic concepts and methods of DTI techniques that can be used to trace major WM tracts noninvasively from fetal brain of 14 postconceptional weeks (pcw) to adult brain. We applied these techniques to acquire DTI data and trace, reconstruct and visualize major WM tracts during development. After categorizing major WM fiber bundles into five unique functional tract groups, namely limbic, brain stem, projection, commissural and association tracts, we revealed formation and maturation of these 3D reconstructed WM tracts of the developing human brain. The structural and connectional imaging data offered by DTI provides the anatomical backbone of transcriptional atlas of the developing human brain.
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http://dx.doi.org/10.1016/j.ymeth.2014.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329045PMC
February 2015

The relevance of human fetal subplate zone for developmental neuropathology of neuronal migration disorders and cortical dysplasia.

CNS Neurosci Ther 2015 Feb 14;21(2):74-82. Epub 2014 Oct 14.

Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.

The human fetal cerebral cortex develops through a series of partially overlapping histogenetic events which occur in transient cellular compartments, such as the subplate zone. The subplate serves as waiting compartment for cortical afferent fibers, the major site of early synaptogenesis and neuronal differentiation and the hub of the transient fetal cortical circuitry. Thus, the subplate has an important but hitherto neglected role in the human fetal cortical connectome. The subplate is also an important compartment for radial and tangential migration of future cortical neurons. We review the diversity of subplate neuronal phenotypes and their involvement in cortical circuitry and discuss the complexity of late neuronal migration through the subplate as well as its potential relevance for pathogenesis of migration disorders and cortical dysplasia. While migratory neurons may become misplaced within the subplate, they can easily survive by being involved in early subplate circuitry; this can enhance their subsequent survival even if they have immature or abnormal physiological activity and misrouted connections and thus survive into adulthood. Thus, better understanding of subplate developmental history and various subsets of its neurons may help to elucidate certain types of neuronal disorders, including those accompanied by epilepsy.
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http://dx.doi.org/10.1111/cns.12333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495198PMC
February 2015

Temporal specification and bilaterality of human neocortical topographic gene expression.

Neuron 2014 Jan 26;81(2):321-32. Epub 2013 Dec 26.

Department of Neurobiology and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:

Transcriptional events involved in the development of human cerebral neocortex are poorly understood. Here, we analyzed the temporal dynamics and laterality of gene expression in human and macaque monkey neocortex. We found that interareal differences exhibit a temporal hourglass pattern, dividing the human neocortical development into three major phases. The first phase, corresponding to prenatal development, is characterized by the highest number of differential expressed genes among areas and gradient-like expression patterns, including those that are different between human and macaque. The second, preadolescent phase, is characterized by lesser interareal expression differences and by an increased synchronization of areal transcriptomes. During the third phase, from adolescence onward, differential expression among areas increases again driven predominantly by a subset of areas, without obvious gradient-like patterns. Analyses of left-right gene expression revealed population-level global symmetry throughout the fetal and postnatal time span. Thus, human neocortical topographic gene expression is temporally specified and globally symmetric.
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http://dx.doi.org/10.1016/j.neuron.2013.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931000PMC
January 2014

The significance of the subplate for evolution and developmental plasticity of the human brain.

Front Hum Neurosci 2013 2;7:423. Epub 2013 Aug 2.

Section of Developmental Neuroscience, Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine Zagreb, Croatia.

The human life-history is characterized by long development and introduction of new developmental stages, such as childhood and adolescence. The developing brain had important role in these life-history changes because it is expensive tissue which uses up to 80% of resting metabolic rate (RMR) in the newborn and continues to use almost 50% of it during the first 5 postnatal years. Our hominid ancestors managed to lift-up metabolic constraints to increase in brain size by several interrelated ecological, behavioral and social adaptations, such as dietary change, invention of cooking, creation of family-bonded reproductive units, and life-history changes. This opened new vistas for the developing brain, because it became possible to metabolically support transient patterns of brain organization as well as developmental brain plasticity for much longer period and with much greater number of neurons and connectivity combinations in comparison to apes. This included the shaping of cortical connections through the interaction with infant's social environment, which probably enhanced typically human evolution of language, cognition and self-awareness. In this review, we propose that the transient subplate zone and its postnatal remnant (interstitial neurons of the gyral white matter) probably served as the main playground for evolution of these developmental shifts, and describe various features that makes human subplate uniquely positioned to have such a role in comparison with other primates.
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http://dx.doi.org/10.3389/fnhum.2013.00423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731572PMC
August 2013

Perinatal and early postnatal reorganization of the subplate and related cellular compartments in the human cerebral wall as revealed by histological and MRI approaches.

Brain Struct Funct 2014 Jan 19;219(1):231-53. Epub 2012 Dec 19.

Croatian Institute for Brain Research, University of Zagreb School of Medicine, Šalata 12, 10000, Zagreb, Croatia,

We analyzed the developmental history of the subplate and related cellular compartments of the prenatal and early postnatal human cerebrum by combining postmortem histological analysis with in vivo MRI. Histological analysis was performed on 21 postmortem brains (age range: 26 postconceptional weeks to 6.5 years) using Nissl staining, AChE-histochemistry, PAS-Alcian blue histochemistry, Gallyas' silver impregnation, and immunocytochemistry for MAP2, synaptophysin, neurofilament, chondroitin sulfate, fibronectin, and myelin basic protein. The histological findings were correlated with in vivo MRI findings obtained in 30 age-matched fetuses, infants, and children. We analyzed developmental reorganization of major cellular (cell bodies, growing axons) and extracellular (extracellular matrix) components of the subplate and the developing cortex/white matter interface. We found that perinatal and postnatal reorganization of these tissue components is protracted (extending into the second year of life) and characterized by well-delineated, transient and previously undescribed structural and molecular changes at the cortex/white matter interface. The findings of this study are clinically relevant because they may inform and guide a proper interpretation of highly dynamic and hitherto puzzling changes of cortical thickness and cortical/white matter interface as described in current in vivo MRI studies.
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http://dx.doi.org/10.1007/s00429-012-0496-0DOI Listing
January 2014

Coupling diffusion imaging with histological and gene expression analysis to examine the dynamics of cortical areas across the fetal period of human brain development.

Cereb Cortex 2013 Nov 28;23(11):2620-31. Epub 2012 Aug 28.

Advanced Imaging Research Center.

As a prominent component of the human fetal brain, the structure of the cerebral wall is characterized by its laminar organization which includes the radial glial scaffold during fetal development. Diffusion tensor imaging (DTI) is useful to quantitatively delineate the microstructure of the developing brain and to clearly identify transient fetal layers in the cerebral wall. In our study, the spatio-temporal microstructural changes in the developing human fetal cerebral wall were quantitatively characterized with high-resolution DTI data of postmortem fetal brains from 13 to 21 gestational weeks. Eleven regions of interest for each layer in the entire cerebral wall were included. Distinctive time courses of microstructural changes were revealed for 11 regions of the neocortical plate. A histological analysis was also integrated to elucidate the relationship between DTI fractional anisotropy (FA) and histology. High FA values correlated with organized radial architecture in histological image. Expression levels of 17565 genes were quantified for each of 11 regions of human fetal neocortex from 13 to 21 gestational weeks to identify transcripts showing significant correlation with FA change. These correlations suggest that the heterogeneous and regionally specific microstructural changes of the human neocortex are related to different gene expression patterns.
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http://dx.doi.org/10.1093/cercor/bhs241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792738PMC
November 2013

Human fetal tau protein isoform: possibilities for Alzheimer's disease treatment.

Int J Biochem Cell Biol 2012 Aug 15;44(8):1290-4. Epub 2012 May 15.

Croatian Institute for Brain Research, University of Zagreb School of Medicine, Šalata 12, 10000 Zagreb, Croatia.

While early 1990s reports showed the phosphorylation pattern of fetal tau protein to be similar to that of tau in paired helical filaments (PHF) in Alzheimer's disease (AD), neither the molecular mechanisms of the transient developmental hyperphosphorylation of tau nor reactivation of the fetal plasticity due to re-expression of fetal protein kinases in the aging and AD human brain have been sufficiently investigated. Here, we summarize the current knowledge on fetal tau, adding new data on the specific patterns of tau protein and mRNA expression in the developing human brain as well as on change in tau phosphorylation in the perforant pathway after entorhinal cortex lesion in mice. As fetal tau isoform does not form PHF even in a highly phosphorylated state, understanding its expression and post-translational modifications represents an important avenue for future research towards the development of AD treatment and prevention.
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http://dx.doi.org/10.1016/j.biocel.2012.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572194PMC
August 2012

Spatio-temporal transcriptome of the human brain.

Nature 2011 Oct 26;478(7370):483-9. Epub 2011 Oct 26.

Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment.
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http://dx.doi.org/10.1038/nature10523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566780PMC
October 2011

Populations of subplate and interstitial neurons in fetal and adult human telencephalon.

J Anat 2010 Oct;217(4):381-99

University of Zagreb School of Medicine, Croatian Institute for Brain Research, Salata 12, Zagreb, Croatia.

In the adult human telencephalon, subcortical (gyral) white matter contains a special population of interstitial neurons considered to be surviving descendants of fetal subplate neurons [Kostovic & Rakic (1980) Cytology and the time of origin of interstitial neurons in the white matter in infant and adult human and monkey telencephalon. J Neurocytol9, 219]. We designate this population of cells as superficial (gyral) interstitial neurons and describe their morphology and distribution in the postnatal and adult human cerebrum. Human fetal subplate neurons cannot be regarded as interstitial, because the subplate zone is an essential part of the fetal cortex, the major site of synaptogenesis and the 'waiting' compartment for growing cortical afferents, and contains both projection neurons and interneurons with distinct input-output connectivity. However, although the subplate zone is a transient fetal structure, many subplate neurons survive postnatally as superficial (gyral) interstitial neurons. The fetal white matter is represented by the intermediate zone and well-defined deep periventricular tracts of growing axons, such as the corpus callosum, anterior commissure, internal and external capsule, and the fountainhead of the corona radiata. These tracts gradually occupy the territory of transient fetal subventricular and ventricular zones.The human fetal white matter also contains distinct populations of deep fetal interstitial neurons, which, by virtue of their location, morphology, molecular phenotypes and advanced level of dendritic maturation, remain distinct from subplate neurons and neurons in adjacent structures (e.g. basal ganglia, basal forebrain). We describe the morphological, histochemical (nicotinamide-adenine dinucleotide phosphate-diaphorase) and immunocytochemical (neuron-specific nuclear protein, microtubule-associated protein-2, calbindin, calretinin, neuropeptide Y) features of both deep fetal interstitial neurons and deep (periventricular) interstitial neurons in the postnatal and adult deep cerebral white matter (i.e. corpus callosum, anterior commissure, internal and external capsule and the corona radiata/centrum semiovale). Although these deep interstitial neurons are poorly developed or absent in the brains of rodents, they represent a prominent feature of the significantly enlarged white matter of human and non-human primate brains.
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http://dx.doi.org/10.1111/j.1469-7580.2010.01284.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992415PMC
October 2010

Early history of subplate and interstitial neurons: from Theodor Meynert (1867) to the discovery of the subplate zone (1974).

J Anat 2010 Oct;217(4):344-67

University of Zagreb School of Medicine, Croatian Institute for Brain Research, Salata 12, Zagreb, Croatia.

In this historical review, we trace the early history of research on the fetal subplate zone, subplate neurons and interstitial neurons in the white matter of the adult nervous system. We arrive at several general conclusions. First, a century of research clearly testifies that interstitial neurons, subplate neurons and the subplate zone were first observed and variously described in the human brain - or, in more general terms, in large brains of gyrencephalic mammals, characterized by an abundant white matter and slow and protracted prenatal and postnatal development. Secondly, the subplate zone cannot be meaningfully defined using a single criterion - be it a specific population of cells, fibres or a specific molecular or genetic marker. The subplate zone is a highly dynamic architectonic compartment and its size and cellular composition do not remain constant during development. Thirdly, it is important to make a clear distinction between the subplate zone and the subplate (and interstitial) neurons. The transient existence of the subplate zone (as a specific architectonic compartment of the fetal telencephalic wall) should not be equated with the putative transient existence of subplate neurons. It is clear that in rodents, and to an even greater extent in humans and monkeys, a significant number of subplate cells survive and remain functional throughout life.
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http://dx.doi.org/10.1111/j.1469-7580.2010.01283.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992413PMC
October 2010

Developmental history of the subplate zone, subplate neurons and interstitial white matter neurons: relevance for schizophrenia.

Int J Dev Neurosci 2011 May 29;29(3):193-205. Epub 2010 Sep 29.

Section of Developmental Neuroscience, Croatian Institute for Brain Research, Department of Neuroscience, University of Zagreb School of Medicine, Šalata 12, 10000 Zagreb, Croatia.

The subplate zone is a transient cytoarchitectonic compartment of the fetal telencephalic wall and contains a population of subplate neurons which are the main neurons of the fetal neocortex and play a key role in normal development of cerebral cortical structure and connectivity. While the subplate zone disappears during the perinatal and early postnatal period, numerous subplate neurons survive and remain embedded in the superficial (gyral) white matter of adolescent and adult brain as so-called interstitial neurons. In both fetal and adult brain, subplate/interstitial neurons belong to two major classes of cortical cells: (a) projection (glutamatergic) neurons and (b) local circuit (GABAergic) interneurons. As interstitial neurons remain strategically positioned at the cortical/white matter interface through which various cortical afferent systems enter the deep cortical layers, they probably serve as auxiliary interneurons involved in differential "gating" of cortical input systems. It is widely accepted that prenatal lesions which alter the number of surviving subplate neurons (i.e., the number of interstitial neurons) and/or the nature of their involvement in cortical circuitry represent an important causal factor in pathogenesis of at least some types of schizophrenia--e.g., in the subgroup of patients with cognitive impairment and deficits of frontal lobe functions. The abnormal functioning of cortical circuitry in schizophrenia becomes manifest during the adolescence, when there is an increased demand for proper functioning of the prefrontal cortex. In this review, we describe developmental history of subplate zone, subplate neurons and surviving interstitial neurons, as well as presumed consequences of the increased number of GABAergic interstitial neurons in the prefrontal cortex. We propose that the increased number of GABAergic interstitial neurons leads to the increased inhibition of prefrontal cortical neurons. This inhibitory action of GABAergic interstitial neurons is facilitated by their strategic position at the cortical/white matter interface where limbic and modulatory afferent pathways enter the prefrontal cortex. Thus, enlarged population of inhibitory interstitial neurons (even if they represent a minor fraction of total neuron number, as in the cerebral cortex itself) may alter the differential "gating" of limbic and modulatory inputs (as well as other cortical and subcortical inputs) and cause a functional disconnectivity between the prefrontal and limbic cortex in the adolescent brain. In conclusion, fetal subplate neurons and surviving postnatal interstitial neurons are important modulators of cortical functions in both normal and schizophrenic cerebral cortex.
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http://dx.doi.org/10.1016/j.ijdevneu.2010.09.005DOI Listing
May 2011