scholarly journals The Long Noncoding RNA FEDORA is a Cell-Type- and Sex-Specific Regulator of Depression

2021 ◽  
Author(s):  
Orna Issler ◽  
Yentl Y van der Zee ◽  
Aarthi Ramakrishnan ◽  
Sunhui Xia ◽  
Alexander K Zinsmaier ◽  
...  
Keyword(s):  
Sex Differences ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Postmortem Brain ◽  
Cell Type ◽  
Diagnostic Significance ◽  
Human Postmortem Brain ◽  
Behavioral Abnormalities ◽  
Postmortem Brain Tissue ◽  
Specific Regulation

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify dramatic baseline sex differences in expression of long noncoding RNAs (lncRNAs) in human postmortem brain tissue that are profoundly lost in depression. One such lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and upregulated in several cortical regions of depressed females but not males. We found that virally-expressing FEDORA selectively either in neurons or in oligodendrocytes of prefrontal cortex promoted depression-like behavioral abnormalities in female mice only, changes associated with cell-type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic significance for depressed women. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

scholarly journals Single-Cell RNA Sequencing in Parkinson’s Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 368
Author(s):  
Shi-Xun Ma ◽  
Su Bin Lim
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Rna Sequencing ◽  
Rna Degradation ◽  
Postmortem Brain ◽  
Cell Type ◽  
New Findings ◽  
Postmortem Brain Tissue ◽  
Technical Challenges

Single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) technologies have enhanced the understanding of the molecular pathogenesis of neurodegenerative disorders, including Parkinson’s disease (PD). Nonetheless, their application in PD has been limited due mainly to the technical challenges resulting from the scarcity of postmortem brain tissue and low quality associated with RNA degradation. Despite such challenges, recent advances in animals and human in vitro models that recapitulate features of PD along with sequencing assays have fueled studies aiming to obtain an unbiased and global view of cellular composition and phenotype of PD at the single-cell resolution. Here, we reviewed recent sc/snRNA-seq efforts that have successfully characterized diverse cell-type populations and identified cell type-specific disease associations in PD. We also examined how these studies have employed computational and analytical tools to analyze and interpret the rich information derived from sc/snRNA-seq. Finally, we highlighted important limitations and emerging technologies for addressing key technical challenges currently limiting the integration of new findings into clinical practice.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

Cells in human postmortem brain tissue slices remain alive for several weeks in culture

2002 ◽  
Vol 16 (1) ◽  
pp. 54-60 ◽  
Author(s):  
Ronald W. H. Verwer ◽  
Wim T. J. M. C. Hermens ◽  
Paul A. Dijkhuizen ◽  
Olivier Ter Brake ◽  
Robert E. Baker ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Postmortem Brain ◽  
Tissue Slices ◽  
Human Postmortem Brain ◽  
Postmortem Brain Tissue

scholarly journals Cell-type-specific methylome-wide association studies implicate neurodegenerative processes and neuroimmune communication in major depressive disorder

2018 ◽  
Author(s):  
Robin F. Chan ◽  
Gustavo Turecki ◽  
Andrey A. Shabalin ◽  
Jerry Guintivano ◽  
Min Zhao ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Association Studies ◽  
Postmortem Brain ◽  
Cell Type ◽  
Major Depressive ◽  
P Values ◽  
Human Postmortem Brain ◽  
Cell Type Specific ◽  
Pathway Analyses

We studied the methylome in three collections of human postmortem brain (N=206) and blood samples (N=1,132) of subjects with major depressive disorder (MDD) and controls. Using an epigenomic deconvolution approach we performed cell-type-specific methylome-wide association studies (MWAS) within sub-populations of neurons/glia and granulocytes/T-cells/B-cells/monocytes for bulk brain and blood data, respectively. Multiple MWAS findings in neurons/glia replicated across brain collections (ORs=509-538, P-values<1×10−5) and were reproducible in an array-based MWAS of sorted neurons/glia from a fourth brain collection (N=58). Pathway analyses implicated p75NTR/VEGF signaling, neurodegeneration, and blood-brain barrier perturbation. Cell-type-specific analysis in blood identified associations in CD14+ monocytes -- a cell type strongly linked to neuroimmune processes and stress. Top results in neurons/glia/bulk and monocytes were enriched for genes supported by GWAS for MDD (ORs=2.02-2.87, P-values=0.003 to <1×10−5), neurodegeneration and other psychiatric disorders. In summary, we identified novel MDD-methylation associations by using epigenomic deconvolution that provided important mechanistic insights for the disease.

scholarly journals Chromatin-enriched RNAs mark active and repressive cis-regulation: an analysis of nuclear RNA-seq

2019 ◽  
Author(s):  
Xiangying Sun ◽  
Zhezhen Wang ◽  
Carlos Perez-Cervantes ◽  
Alex Ruthenburg ◽  
Ivan Moskowitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Specific Gene ◽  
Rna Seq ◽  
Cell Type ◽  
Neighboring Gene ◽  
Cis Regulation ◽  
Nuclear Rna ◽  
Cell Type Specific

AbstractLong noncoding RNAs (lncRNAs) localize in the cell nucleus and influence gene expression through a variety of molecular mechanisms. RNA sequencing of two biochemical fractions of nuclei reveals a unique class of lncRNAs, termed chromatin-enriched nuclear RNAs (cheRNAs) that are tightly bound to chromatin and putatively function to cis-activate gene expression. Until now, a rigorous analytic pipeline for nuclear RNA-seq has been lacking. In this study, we survey four computational strategies for nuclear RNA-seq data analysis and show that a new pipeline, Tuxedo, outperforms other approaches. Tuxedo not only assembles a more complete transcriptome, but also identifies cheRNA with higher accuracy. We have used Tuxedo to analyze gold-standard K562 cell datasets and further characterize the genomic features of intergenic cheRNA (icheRNA) and their similarity to those of enhancer RNA (eRNA). Moreover, we quantify the transcriptional correlation of icheRNA and adjacent genes, and suggest that icheRNA may be the cis-acting transcriptional regulator that is more positively associated with neighboring gene expression than eRNA predicted by state-of-art method or CAGE signal. We also explore two novel genomic associations, suggesting cheRNA may have diverse functions. A possible new role of H3K9me3 modification coincident with icheRNA may be associated with active enhancer derived from ancient mobile elements, while a potential cis-repressive function of antisense cheRNA (as-cheRNA) is likely to be involved in transiently modulating cell type-specific cis-regulation.Author SummaryChromatin-enriched nuclear RNA (cheRNA) is a class of gene regulatory non-coding RNAs. CheRNA provides a powerful way to profile the nuclear transcriptional landscape, especially to profile the noncoding transcriptome. The computational framework presented here provides a reliable approach to identifying cheRNA, and for studying cell-type specific gene regulation. We found that intergenic cheRNA, including intergenic cheRNA with high levels of H3K9me3 (a mark associated with closed/repressed chromatin), may act as a transcriptional activator. In contrast, antisense cheRNA, which originates from the complementary strand of the protein-coding gene, may interact with diverse chromatin modulators to repress local transcription. With our new pipeline, one future challenge will be refining the functional mechanisms of these noncoding RNA classes through exploring their regulatory roles, which are involved in diverse molecular and cellular processes in human and other organisms.

Tract tracing, neuronal morphology and ultrastructural studies in human postmortem brain

1992 ◽  
Vol 50 (1) ◽  
pp. 470-471
Author(s):  
Rosalinda C. Roberts ◽  
Michael W. Vogel ◽  
Maarten de Rijk ◽  
Frank J. Peretti ◽  
Robert R. Conley ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Neuronal Morphology ◽  
Postmortem Brain ◽  
Human Brain Tissue ◽  
Tract Tracing ◽  
Human Postmortem Brain ◽  
Ultrastructural Studies ◽  
Carbocyanine Dye ◽  
Postmortem Brain Tissue ◽  
Golgi Staining

Classical and modern neuroanatomical techniques are applied to an analysis of the neuroanatomical basis of schizophrenia using postmortem brain tissue from the Maryland Brain Collection. Techniques for Golgi staining of cell bodies and dendritic arbors, axonal tract tracing with the carbocyanine dye, DiI and ultrastructural analyses will be used to study brain tissue with postmortem times of less than 6 hours. Although these techniques are routinely used in animal models, they are rarely used for studying human brain tissue. These techniques will allow us to characterize neuronal architecture in normal and diseased brains.

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