scholarly journals Transcriptional and cell type profiles of cortical brain regions showing ultradian cortisol rhythm dependent responses to emotional face stimulation

2022 ◽  
Author(s):  
Philippe C Habets ◽  
Konstantinos Kalafatakis ◽  
Oleh Dzyubachyk ◽  
Steven van der Werff ◽  
Arlin Keo ◽  
...  
Keyword(s):  
Emotional Processing ◽  
Experimental Studies ◽  
Neuronal Cell ◽  
Cell Types ◽  
Brain Regions ◽  
Specific Cell ◽  
Protein Signaling ◽  
Cell Type ◽  
Endogenous Circadian Rhythm ◽  
Significant Enrichment

The characteristic endogenous circadian rhythm of plasma glucocorticoid concentrations is made up from an underlying ultradian pulsatile secretory pattern. Recent evidence has indicated that this ultradian cortisol pulsatility is crucial for normal emotional response in man. In this study, we investigate the anatomical transcriptional and cell type signature of brain regions sensitive to a loss of ultradian rhythmicity in the context of emotional processing. We combine human cell type and transcriptomic atlas data of high spatial resolution with functional magnetic resonance imaging (fMRI) data. We show that the loss of cortisol ultradian rhythm alters emotional processing response in cortical brain areas that are characterized by transcriptional and cellular profiles of GABAergic function. We find that two previously identified key components of rapid non-genomic GC signaling - the ANXA1 gene and retrograde endocannabinoid signaling - show top differential expression and the most significant enrichment. Our results further indicate that specific cell types, including a specific NPY-expressing GABAergic neuronal cell type, and specific G protein signaling cascades underly the cerebral effects of a loss of ultradian cortisol rhythm. Our results provide a biological mechanistic underpinning of our fMRI findings, indicating specific cell types and cascades as a target for manipulation in future experimental studies.

scholarly journals Single nucleus analysis of the chromatin landscape in mouse forebrain development

2017 ◽  
Author(s):  
Sebastian Preissl ◽  
Rongxin Fang ◽  
Yuan Zhao ◽  
Ramya Raviram ◽  
Yanxiao Zhang ◽  
...  
Keyword(s):  
Neuronal Cell ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Regulatory Sequences ◽  
Specific Cell ◽  
Cell Type ◽  
Tissue Samples ◽  
Forebrain Development ◽  
Cell Type Specific ◽  
Accessible Chromatin

ABSTRACTGenome-wide analysis of chromatin accessibility in primary tissues has uncovered millions of candidate regulatory sequences in the human and mouse genomes1–4. However, the heterogeneity of biological samples used in previous studies has prevented a precise understanding of the dynamic chromatin landscape in specific cell types. Here, we show that analysis of the transposase-accessible-chromatin in single nuclei isolated from frozen tissue samples can resolve cellular heterogeneity and delineate transcriptional regulatory sequences in the constituent cell types. Our strategy is based on a combinatorial barcoding assisted single cell assay for transposase-accessible chromatin5 and is optimized for nuclei from flash-frozen primary tissue samples (snATAC-seq). We used this method to examine the mouse forebrain at seven development stages and in adults. From snATAC-seq profiles of more than 15,000 high quality nuclei, we identify 20 distinct cell populations corresponding to major neuronal and non-neuronal cell-types in foetal and adult forebrains. We further define cell-type specific cis regulatory sequences and infer potential master transcriptional regulators of each cell population. Our results demonstrate the feasibility of a general approach for identifying cell-type-specific cis regulatory sequences in heterogeneous tissue samples, and provide a rich resource for understanding forebrain development in mammals.

scholarly journals Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development

2020 ◽  
Author(s):  
Anoushka Joglekar ◽  
Andrey Prjibelski ◽  
Ahmed Mahfouz ◽  
Paul Collier ◽  
Susan Lin ◽  
...  
Keyword(s):  
Single Cell ◽  
Brain Region ◽  
Cell Types ◽  
Brain Regions ◽  
Specific Cell ◽  
Cell Type ◽  
Anatomic Structure ◽  
Link Type ◽  
Long Read ◽  
Isoform Expression

AbstractAlternative RNA splicing varies across brain regions, but the single-cell resolution of such regional variation is unknown. Here we present the first single-cell investigation of differential isoform expression (DIE) between brain regions, by performing single cell long-read transcriptome sequencing in the mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 (www.isoformAtlas.com). Using isoform tests for brain-region specific DIE, which outperform exon-based tests, we detect hundreds of brain-region specific DIE events traceable to specific cell-types. Many DIE events correspond to functionally distinct protein isoforms, some with just a 6-nucleotide exon variant. In most instances, one cell type is responsible for brain-region specific DIE. Cell types indigenous to only one anatomic structure display distinctive DIE, where for example, the choroid plexus epithelium manifest unique transcription start sites. However, for some genes, multiple cell-types are responsible for DIE in bulk data, indicating that regional identity can, although less frequently, override cell-type specificity. We validated our findings with spatial transcriptomics and long-read sequencing, yielding the first spatially resolved splicing map in the postnatal mouse brain (www.isoformAtlas.com). Our methods are highly generalizable. They provide a robust means of quantifying isoform expression with cell-type and spatial resolution, and reveal how the brain integrates molecular and cellular complexity to serve function.

scholarly journals FMRP has a cell-type-specific role in CA1 pyramidal neurons to regulate autism-related transcripts and circadian memory

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Kirsty Sawicka ◽  
Caryn R Hale ◽  
Christopher Y Park ◽  
John J Fak ◽  
Jodi E Gresack ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Rna Binding ◽  
Fragile X ◽  
Neuronal Cell ◽  
Cell Types ◽  
Brain Regions ◽  
Cell Type ◽  
Ca1 Pyramidal Neurons ◽  
Mrna Targets ◽  
Specific Regulation

Loss of the RNA binding protein FMRP causes Fragile X Syndrome (FXS), the most common cause of inherited intellectual disability, yet it is unknown how FMRP function varies across brain regions and cell types and how this contributes to disease pathophysiology. Here we use conditional tagging of FMRP and CLIP (FMRP cTag CLIP) to examine FMRP mRNA targets in hippocampal CA1 pyramidal neurons, a critical cell type for learning and memory relevant to FXS phenotypes. Integrating these data with analysis of ribosome-bound transcripts in these neurons revealed CA1-enriched binding of autism-relevant mRNAs, and CA1-specific regulation of transcripts encoding circadian proteins. This contrasted with different targets in cerebellar granule neurons, and was consistent with circadian defects in hippocampus-dependent memory in Fmr1 knockout mice. These findings demonstrate differential FMRP-dependent regulation of mRNAs across neuronal cell types that may contribute to phenotypes such as memory defects and sleep disturbance associated with FXS.

scholarly journals Single-nuclei transcriptomics of schizophrenia prefrontal cortex primarily implicates neuronal subtypes

2020 ◽  
Author(s):  
Benjamin C. Reiner ◽  
Richard C. Crist ◽  
Lauren M. Stein ◽  
Andrew E. Weller ◽  
Glenn A. Doyle ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Differentially Expressed Genes ◽  
Neuronal Cell ◽  
Cell Types ◽  
Brain Regions ◽  
Differentially Expressed ◽  
Inhibitory Neurons ◽  
Specific Cell ◽  
Dorsolateral Prefrontal ◽  
Layer V

AbstractTranscriptomic studies of bulk neural tissue homogenates from persons with schizophrenia and controls have identified differentially expressed genes in multiple brain regions. However, the heterogeneous nature prevents identification of relevant cell types. This study analyzed single-nuclei transcriptomics of ∼311,000 nuclei from frozen human postmortem dorsolateral prefrontal cortex samples from individuals with schizophrenia (n = 14) and controls (n = 16). 2,846 differential expression events were identified in 2,195 unique genes in 19 of 24 transcriptomically-distinct cell populations. ∼97% of differentially expressed genes occurred in five neuronal cell types, with ∼63% occurring in a subtype of PVALB+ inhibitory neurons and HTR2C+ layer V excitatory neurons. Differentially expressed genes were enriched for genes localized to schizophrenia GWAS loci. Cluster-specific changes in canonical pathways, upstream regulators and causal networks were identified. These results expand our knowledge of disrupted gene expression in specific cell types and permit new insight into the pathophysiology of schizophrenia.

scholarly journals Cell-Type-Specific Proteomics: A Neuroscience Perspective

Proteomes ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 51 ◽  
Author(s):  
Rashaun S. Wilson ◽  
Angus C. Nairn
Keyword(s):  
Protein Detection ◽  
Analytical Techniques ◽  
Cell Types ◽  
Brain Regions ◽  
Cell Populations ◽  
Specific Cell ◽  
Cell Type ◽  
Specific Analysis ◽  
Cell Type Specific ◽  
Proteomics Research

Cell-type-specific analysis has become a major focus for many investigators in the field of neuroscience, particularly because of the large number of different cell populations found in brain tissue that play roles in a variety of developmental and behavioral disorders. However, isolation of these specific cell types can be challenging due to their nonuniformity and complex projections to different brain regions. Moreover, many analytical techniques used for protein detection and quantitation remain insensitive to the low amounts of protein extracted from specific cell populations. Despite these challenges, methods to improve proteomic yield and increase resolution continue to develop at a rapid rate. In this review, we highlight the importance of cell-type-specific proteomics in neuroscience and the technical difficulties associated. Furthermore, current progress and technological advancements in cell-type-specific proteomics research are discussed with an emphasis in neuroscience.

scholarly journals Extracellular spike waveform dissociates four functionally distinct cell classes in primate cortex

2019 ◽  
Author(s):  
Caterina Trainito ◽  
Constantin von Nicolai ◽  
Earl K. Miller ◽  
Markus Siegel
Keyword(s):  
Visual Information ◽  
Neuronal Cell ◽  
Cell Types ◽  
Brain Regions ◽  
Frontal Eye Field ◽  
Visual Response ◽  
Cell Type ◽  
Response Dynamics ◽  
Distinct Cell ◽  
Behaving Monkeys

SummaryUnderstanding the function of different neuronal cell types is key to understanding brain function. However, cell type diversity is typically overlooked in electrophysiological studies in awake behaving animals. Here, we show that four functionally distinct cell classes can be robustly identified from extracellular recordings in several cortical regions of awake behaving monkeys. We recorded extracellular spiking activity from dorsolateral prefrontal cortex (dlPFC), the frontal eye field (FEF), and the lateral intraparietal area of macaque monkeys during a visuomotor decision-making task. We employed unsupervised clustering of spike waveforms, which robustly dissociated four distinct cell classes across all three brain regions. The four cell classes were functionally distinct. They showed different baseline firing statistics, visual response dynamics, and coding of visual information. While cell class-specific baseline statistics were consistent across brain regions, response dynamics and information coding were regionally specific. Our results identify four waveform-based cell classes in primate cortex. This opens a new window to dissect and study the cell-type specific function of cortical circuits.

scholarly journals Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains

2019 ◽  
Author(s):  
Ekaterina Khrameeva ◽  
Ilia Kurochkin ◽  
Dingding Han ◽  
Patricia Guijarro ◽  
Sabina Kanton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neuronal Cell ◽  
Cell Types ◽  
Brain Regions ◽  
Human Cognition ◽  
Human Lineage ◽  
Cell Type ◽  
Cell Nuclei ◽  
Tissue Samples ◽  
Cell Type Specific

ABSTRACTIdentification of gene expression traits unique to the human brain sheds light on the mechanisms of human cognition. Here we searched for gene expression traits separating humans from other primates by analyzing 88,047 cell nuclei and 422 tissue samples representing 33 brain regions of humans, chimpanzees, bonobos, and macaques. We show that gene expression evolves rapidly within cell types, with more than two-thirds of cell type-specific differences not detected using conventional RNA sequencing of tissue samples. Neurons tend to evolve faster in all hominids, but non-neuronal cell types, such as astrocytes and oligodendrocyte progenitors, show more differences on the human lineage, including alterations of spatial distribution across neocortical layers.

scholarly journals Cellular and pathological heterogeneity of primary tauopathies

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Dah-eun Chloe Chung ◽  
Shanu Roemer ◽  
Leonard Petrucelli ◽  
Dennis W. Dickson
Keyword(s):  
Experimental Studies ◽  
Cell Types ◽  
Selective Vulnerability ◽  
Brain Regions ◽  
Cell Type ◽  
Tau Pathology ◽  
Protein Tau ◽  
Cryo Electron Microscopy ◽  
Cell Type Specific ◽  
Tau Aggregation

AbstractMicrotubule-associated protein tau is abnormally aggregated in neuronal and glial cells in a range of neurodegenerative diseases that are collectively referred to as tauopathies. Multiple studies have suggested that pathological tau species may act as a seed that promotes aggregation of endogenous tau in naïve cells and contributes to propagation of tau pathology. While they share pathological tau aggregation as a common feature, tauopathies are distinct from one another with respect to predominant tau isoforms that accumulate and the selective vulnerability of brain regions and cell types that have tau inclusions. For instance, primary tauopathies present with glial tau pathology, while it is mostly neuronal in Alzheimer’s disease (AD). Also, morphologies of tau inclusions can greatly vary even within the same cell type, suggesting distinct mechanisms or distinct tau conformers in each tauopathy. Neuropathological heterogeneity across tauopathies challenges our understanding of pathophysiology behind tau seeding and aggregation, as well as our efforts to develop effective therapeutic strategies for AD and other tauopathies. In this review, we describe diverse neuropathological features of tau inclusions in neurodegenerative tauopathies and discuss what has been learned from experimental studies with mouse models, advanced transcriptomics, and cryo-electron microscopy (cryo-EM) on the biology underlying cell type-specific tau pathology.

scholarly journals An Atlas of Gene Regulatory Elements in Adult Mouse Cerebrum

2020 ◽  
Author(s):  
Yang Eric Li ◽  
Sebastian Preissl ◽  
Xiaomeng Hou ◽  
Ziyang Zhang ◽  
Kai Zhang ◽  
...  
Keyword(s):  
Target Genes ◽  
Adult Mouse ◽  
Neuronal Cell ◽  
Cell Types ◽  
Regulatory Elements ◽  
Brain Regions ◽  
Brain Cell ◽  
Mammalian Brain ◽  
Cell Type ◽  
Gene Regulatory

ABSTRACTThe mammalian cerebrum performs high level sensory, motor control and cognitive functions through highly specialized cortical networks and subcortical nuclei. Recent surveys of mouse and human brains with single cell transcriptomics1–3 and high-throughput imaging technologies4,5 have uncovered hundreds of neuronal cell types and a variety of non-neuronal cell types distributed in different brain regions, but the cell-type-specific transcriptional regulatory programs responsible for the unique identity and function of each brain cell type have yet to be elucidated. Here, we probe the accessible chromatin in >800,000 individual nuclei from 45 regions spanning the adult mouse isocortex, olfactory bulb, hippocampus and cerebral nuclei, and use the resulting data to define 491,818 candidate cis regulatory DNA elements in 160 distinct sub-types. We link a significant fraction of them to putative target genes expressed in diverse cerebral cell types and uncover transcriptional regulators involved in a broad spectrum of molecular and cellular pathways in different neuronal and glial cell populations. Our results provide a foundation for comprehensive analysis of gene regulatory programs of the mammalian brain and assist in the interpretation of non-coding risk variants associated with various neurological disease and traits in humans. To facilitate the dissemination of information, we have set up a web portal (http://catlas.org/mousebrain).

scholarly journals Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability

2018 ◽  
Author(s):  
Regina H Reynolds ◽  
Juan Botía ◽  
Mike A Nalls ◽  
John Hardy ◽  
Sarah A Gagliano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Types ◽  
Brain Regions ◽  
Brain Cell ◽  
Specific Gene ◽  
Specific Cell ◽  
Cell Type ◽  
Related Cell ◽  
Cell Type Specific

AbstractParkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set specifically expressed in astrocytic and microglial subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes to which cell types may have varying vulnerability.

Sign in / Sign up

Export Citation Format

Share Document