scholarly journals Regional heterogeneity in gene expression, regulation and coherence in hippocampus and dorsolateral prefrontal cortex across development and in schizophrenia

2018 ◽  
Author(s):  
L Collado-Torres ◽  
EE Burke ◽  
A Peterson ◽  
JH Shin ◽  
RE Straub ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Brain Region ◽  
Dorsolateral Prefrontal Cortex ◽  
Large Scale ◽  
Brain Regions ◽  
Second Phase ◽  
Regional Heterogeneity ◽  
Surrogate Variable Analysis ◽  
Dorsolateral Prefrontal

AbstractRecent large-scale genomics efforts have better characterized the molecular correlates of schizophrenia in postmortem human neocortex, but not hippocampus which is a brain region prominently implicated in its pathogenesis. Here in the second phase of the BrainSeq Consortium (Phase II), we have generated RiboZero RNA-seq data for 900 samples across both the dorsolateral prefrontal cortex (DLPFC) and the hippocampus (HIPPO) for 551 individuals (286 affected by schizophrenia disorder: SCZD). We identify substantial regional differences in gene expression, in both pre- and post-natal life, and find widespread differences in how genes are regulated across development. By extending quality surrogate variable analysis (qSVA) to multiple brain regions, we identified 48 and 245 differentially expressed genes (DEG) by SCZD diagnosis (FDR<5%) in HIPPO and DLPFC, respectively, with surprisingly minimal overlap in DEG between the two brain regions. We further identified 205,618 brain region-dependent eQTLs (FDR<1%) and found that 124 GWAS risk loci contain eQTLs in at least one of the regions. We also identify potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia, and suggest future schizophrenia therapeutics may need to target molecular pathologies localized to specific brain regions.

scholarly journals Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

2020 ◽  
Author(s):  
Kristen R. Maynard ◽  
Leonardo Collado-Torres ◽  
Lukas M. Weber ◽  
Cedric Uytingco ◽  
Brianna K. Barry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Web Application ◽  
Dorsolateral Prefrontal Cortex ◽  
Large Scale ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Sequencing Data ◽  
Dorsolateral Prefrontal ◽  
Transcriptomics Data

AbstractWe used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex (DLPFC). We identified extensive layer-enriched expression signatures, and refined associations to previous laminar markers. We overlaid our laminar expression signatures onto large-scale single nuclei RNA sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially-defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions where morphological architecture is not as well-defined as cortical laminae. We lastly created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research (http://research.libd.org/spatialLIBD).

scholarly journals Widespread transcriptional disruption of the microRNA biogenesis machinery in brain and peripheral tissues of individuals with schizophrenia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Romain Rey ◽  
Marie-Françoise Suaud-Chagny ◽  
Jean-Michel Dorey ◽  
Jean-Raymond Teyssier ◽  
Thierry d’Amato
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Candidate Genes ◽  
Dorsolateral Prefrontal Cortex ◽  
Brain Regions ◽  
Altered Expression ◽  
Peripheral Tissues ◽  
Microrna Biogenesis ◽  
Control Subjects ◽  
Dorsolateral Prefrontal

Abstract In schizophrenia, altered transcription in brain and peripheral tissues may be due to altered expression of the microRNA biogenesis machinery genes. In this study, we explore the expression of these genes both at the cerebral and peripheral levels. We used shinyGEO application to analyze gene expression from ten Gene Expression Omnibus datasets, in order to perform differential expression analyses for eight genes encoding the microRNA biogenesis machinery. First, we compared expression of the candidate genes between control subjects and individuals with schizophrenia in postmortem cerebral samples from seven different brain regions. Then, we compared the expression of the candidate genes between control subjects and individuals with schizophrenia in three peripheral tissues. In brain and peripheral tissues of individuals with schizophrenia, we report distinct altered expression patterns of the microRNA biogenesis machinery genes. In the dorsolateral prefrontal cortex, associative striatum and cerebellum of individuals with schizophrenia, we observed an overexpression pattern of some candidate genes suggesting a heightened miRNA production in these brain regions. Additionally, mixed transcriptional abnormalities were identified in the hippocampus. Moreover, in the blood and olfactory epithelium of individuals with schizophrenia, we observed distinct aberrant transcription patterns of the candidate genes. Remarkably, in individuals with schizophrenia, we report DICER1 overexpression in the dorsolateral prefrontal cortex, hippocampus and cerebellum as well as a congruent DICER1 upregulation in the blood compartment suggesting that it may represent a peripheral marker. Transcriptional disruption of the miRNA biogenesis machinery may contribute to schizophrenia pathogenesis both in brain and peripheral tissues.

scholarly journals Molecular pathology associated with altered synaptic transcriptome in the dorsolateral prefrontal cortex of depressed subjects

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuta Yoshino ◽  
Bhaskar Roy ◽  
Nilesh Kumar ◽  
M. Shahid Mukhtar ◽  
Yogesh Dwivedi
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Gene Network ◽  
Nervous System Development ◽  
Network Analyses ◽  
Dorsolateral Prefrontal ◽  
Total Fraction ◽  
Transcriptomic Changes

AbstractDisrupted synaptic plasticity is the hallmark of major depressive disorder (MDD), with accompanying changes at the molecular and cellular levels. Often, the maladaptive molecular changes at the synapse are the result of global transcriptional reprogramming dictated by activity-dependent synaptic modulation. Thus far, no study has directly studied the transcriptome-wide expression changes locally at the synapse in MDD brain. Here, we have examined altered synaptic transcriptomics and their functional relevance in MDD with a focus on the dorsolateral prefrontal cortex (dlPFC). RNA was isolated from total fraction and purified synaptosomes of dlPFC from well-matched 15 non-psychiatric controls and 15 MDD subjects. Transcriptomic changes in synaptic and total fractions were detected by next-generation RNA-sequencing (NGS) and analyzed independently. The ratio of synaptic/total fraction was estimated to evaluate a shift in gene expression ratio in MDD subjects. Bioinformatics and network analyses were used to determine the biological relevance of transcriptomic changes in both total and synaptic fractions based on gene–gene network, gene ontology (GO), and pathway prediction algorithms. A total of 14,005 genes were detected in total fraction. A total of 104 genes were differentially regulated (73 upregulated and 31 downregulated) in MDD group based on 1.3-fold change threshold and p < 0.05 criteria. In synaptosomes, out of 13,236 detectable genes, 234 were upregulated and 60 were downregulated (>1.3-fold, p < 0.05). Several of these altered genes were validated independently by a quantitative polymerase chain reaction (qPCR). GO revealed an association with immune system processes and cell death. Moreover, a cluster of genes belonged to the nervous system development, and psychological disorders were discovered using gene–gene network analysis. The ratio of synaptic/total fraction showed a shift in expression of 119 genes in MDD subjects, which were primarily associated with neuroinflammation, interleukin signaling, and cell death. Our results suggest not only large-scale gene expression changes in synaptosomes, but also a shift in the expression of genes from total to synaptic fractions of dlPFC of MDD subjects with their potential role in immunomodulation and cell death. Our findings provide new insights into the understanding of transcriptomic regulation at the synapse and their possible role in MDD pathogenesis.

scholarly journals Publisher Correction: Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

2021 ◽  
Author(s):  
Kristen R. Maynard ◽  
Leonardo Collado-Torres ◽  
Lukas M. Weber ◽  
Cedric Uytingco ◽  
Brianna K. Barry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Dorsolateral Prefrontal

scholarly journals Dynamical consequences of regional heterogeneity in the brain’s transcriptional landscape

2020 ◽  
Author(s):  
Gustavo Deco ◽  
Kevin Aquino ◽  
Aurina Arnatkevičiūtė ◽  
Stuart Oldham ◽  
Kristina Sabaroedin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Global Gene Expression ◽  
Brain Regions ◽  
Biophysical Model ◽  
Neuronal Dynamics ◽  
Regional Heterogeneity ◽  
Magnetic Resonance Imaging Mri

AbstractBrain regions vary in their molecular and cellular composition, but how this heterogeneity shapes neuronal dynamics is unclear. Here, we investigate the dynamical consequences of regional heterogeneity using a biophysical model of whole-brain functional magnetic resonance imaging (MRI) dynamics in humans. We show that models in which transcriptional variations in excitatory and inhibitory receptor (E:I) gene expression constrain regional heterogeneity more accurately reproduce the spatiotemporal structure of empirical functional connectivity estimates than do models constrained by global gene expression profiles and MRI-derived estimates of myeloarchitecture. We further show that regional heterogeneity is essential for yielding both ignition-like dynamics, which are thought to support conscious processing, and a wide variance of regional activity timescales, which supports a broad dynamical range. We thus identify a key role for E:I heterogeneity in generating complex neuronal dynamics and demonstrate the viability of using transcriptional data to constrain models of large-scale brain function.

scholarly journals DDX19B is differentially expressed in the brains of patients with psychotic disorders.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Microarray Data ◽  
Schizoaffective Disorder ◽  
Dorsolateral Prefrontal Cortex ◽  
Psychotic Disorders ◽  
Differentially Expressed ◽  
Dorsolateral Prefrontal ◽  
Significant Gene

We used public and published microarray data (1, 2) to identify the most significant gene expression changes in the brains of patients with psychotic disorders. We DDX19B as differentially expressed in the dorsolateral prefrontal cortex of patients with schizophrenia and schizoaffective disorder. In neurons of the dorsolateral prefrontal cortex from patients with psychotic disorders, DDX19B expression was significantly decreased.

scholarly journals Improving Emotion Regulation Through Real-Time Neurofeedback Training on the Right Dorsolateral Prefrontal Cortex: Evidence From Behavioral and Brain Network Analyses

2021 ◽  
Vol 15 ◽  
Author(s):  
Linlin Yu ◽  
Quanshan Long ◽  
Yancheng Tang ◽  
Shouhang Yin ◽  
Zijun Chen ◽  
...  
Keyword(s):  
Emotion Regulation ◽  
Prefrontal Cortex ◽  
Real Time ◽  
Dorsolateral Prefrontal Cortex ◽  
Near Infrared ◽  
Self Regulation ◽  
Brain Regions ◽  
Functional Near Infrared Spectroscopy ◽  
Network Analyses ◽  
Dorsolateral Prefrontal

We investigated if emotion regulation can be improved through self-regulation training on non-emotional brain regions, as well as how to change the brain networks implicated in this process. During the training period, the participants were instructed to up-regulate their right dorsolateral prefrontal cortex (rDLPFC) activity according to real-time functional near-infrared spectroscopy (fNIRS) neurofeedback signals, and there was no emotional element. The results showed that the training significantly increased emotion regulation, resting-state functional connectivity (rsFC) within the emotion regulation network (ERN) and frontoparietal network (FPN), and rsFC between the ERN and amygdala; however, training did not influence the rsFC between the FPN and the amygdala. However, self-regulation training on rDLPFC significantly improved emotion regulation and generally increased the rsFCs within the networks; the rsFC between the ERN and amygdala was also selectively increased. The present study also described a safe approach that may improve emotion regulation through self-regulation training on non-emotional brain regions.

scholarly journals Single-Pulse TMS to the Temporo-Occipital and Dorsolateral Prefrontal Cortex Evokes Lateralized Long Latency EEG Responses at the Stimulation Site

2021 ◽  
Vol 15 ◽  
Author(s):  
Tomasz A. Jarczok ◽  
Friederike Roebruck ◽  
Lena Pokorny ◽  
Lea Biermann ◽  
Veit Roessner ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Evoked Potentials ◽  
Brain Region ◽  
Dorsolateral Prefrontal Cortex ◽  
Single Pulse ◽  
Stimulation Site ◽  
Long Latency ◽  
Dorsolateral Prefrontal ◽  
Sensory Processes ◽  
Cortical Functions

IntroductionTranscranial magnetic stimulation (TMS)–evoked potentials (TEPs) allow for probing cortical functions in health and pathology. However, there is uncertainty whether long-latency TMS-evoked potentials reflect functioning of the targeted cortical area. It has been suggested that components such as the TMS-evoked N100 are stereotypical and related to nonspecific sensory processes rather than transcranial effects of the changing magnetic field. In contrast, TEPs that vary according to the targeted brain region and are systematically lateralized toward the stimulated hemisphere can be considered to reflect activity in the stimulated brain region resulting from transcranial electromagnetic induction.MethodsTMS with concurrent 64-channel electroencephalography (EEG) was sequentially performed in homologous areas of both hemispheres. One sample of healthy adults received TMS to the dorsolateral prefrontal cortex; another sample received TMS to the temporo-occipital cortex. We analyzed late negative TEP deflections corresponding to the N100 component in motor cortex stimulation.ResultsTEP topography varied according to the stimulation target site. Long-latency negative TEP deflections were systematically lateralized (higher in ipsilateral compared to contralateral electrodes) in electrodes over the stimulated brain region. A calculation that removes evoked components that are not systematically lateralized relative to the stimulated hemisphere revealed negative maxima located around the respective target sites.ConclusionTEPs contain long-latency negative components that are lateralized toward the stimulated hemisphere and have their topographic maxima at the respective stimulation sites. They can be differentiated from co-occurring components that are invariable across different stimulation sites (probably reflecting coactivation of peripheral sensory afferences) according to their spatiotemporal patterns. Lateralized long-latency TEP components located at the stimulation site likely reflect activity evoked in the targeted cortex region by direct transcranial effects and are therefore suitable for assessing cortical functions.

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