scholarly journals Diverse inhibitory projections from the cerebellar interposed nucleus

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Elena N Judd ◽  
Samantha M Lewis ◽  
Abigail L Person
Keyword(s):  
Inferior Olive ◽  
Cell Types ◽  
Cerebellar Nuclei ◽  
Inhibitory Neurons ◽  
Cell Type ◽  
Functional Specificity ◽  
Functional Roles ◽  
Interposed Nucleus ◽  
Parallel Circuit ◽  
Cell Type Specific

The cerebellum consists of parallel circuit modules that contribute to diverse behaviors, spanning motor to cognitive. Recent work employing cell-type-specific tracing has identified circumscribed output channels of the cerebellar nuclei (CbN) that could confer tight functional specificity. These studies have largely focused on excitatory projections of the CbN, however, leaving open the question of whether inhibitory neurons also constitute multiple output modules. We mapped output and input patterns to intersectionally restricted cell types of the interposed and adjacent interstitial nuclei in mice. In contrast to the widespread assumption of primarily excitatory outputs and restricted inferior olive-targeting inhibitory output, we found that inhibitory neurons from this region ramified widely within the brainstem, targeting both motor- and sensory-related nuclei, distinct from excitatory output targets. Despite differences in output targeting, monosynaptic rabies tracing revealed largely shared afferents to both cell classes. We discuss the potential novel functional roles for inhibitory outputs in the context of cerebellar theory.

scholarly journals Widespread inhibitory projections from the interposed cerebellar nucleus

2021 ◽  
Author(s):  
Elena N. Judd ◽  
Samantha M. Lewis ◽  
Daniel G. Heck ◽  
Abigail L. Person
Keyword(s):  
Recent Work ◽  
Inferior Olive ◽  
Parallel Computations ◽  
Cerebellar Nucleus ◽  
Inhibitory Neurons ◽  
Functional Specificity ◽  
Functional Roles ◽  
Interposed Nucleus ◽  
Output Neurons ◽  
Inputs And Outputs

AbstractThe cerebellum consists of parallel parasagittal modules that contribute to diverse behaviors, spanning motor to cognitive. Recent work illustrating a role for the anterior interposed nucleus (IntA) in reach control in mice raised questions of its anatomical organization that could confer functional specificity. We employed intersectional cell- and projection- specific labeling methods to map IntA inputs and outputs. In contrast to long-standing dogma of primarily excitatory outputs and restricted inferior olive targeting inhibitory output, we found that inhibitory IntA neurons ramified widely within the brainstem, targeting both motor- and sensory-related nuclei, suggesting potential functional roles in disinhibitory control or predictive sensory cancellation. Using monosynaptic rabies tracing, we then found that excitatory output neurons receive fewer and more precisely organized inputs than inhibitory neurons, which may set them up for distinct computations. Together these data suggest IntA contains at least two distinct output circuits and promise advances in identifying parallel computations of the cerebellum.

scholarly journals Cell-Type Specific Analysis of Selenium-Related Genes in Brain

Antioxidants ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 120
Author(s):  
Alexandru R. Sasuclark ◽  
Vedbar S. Khadka ◽  
Matthew W. Pitts
Keyword(s):  
Neural Development ◽  
Cortical Neurons ◽  
Cell Types ◽  
Inhibitory Neurons ◽  
Brain Atlas ◽  
Cell Type ◽  
Specific Expression ◽  
Rnaseq Data ◽  
Cell Type Specific Expression ◽  
Cell Type Specific

Selenoproteins are a unique class of proteins that play key roles in redox signaling in the brain. This unique organ is comprised of a wide variety of cell types that includes excitatory neurons, inhibitory neurons, astrocytes, microglia, and oligodendrocytes. Whereas selenoproteins are known to be required for neural development and function, the cell-type specific expression of selenoproteins and selenium-related machinery has yet to be systematically investigated. Due to advances in sequencing technology and investment from the National Institutes of Health (NIH)-sponsored BRAIN initiative, RNA sequencing (RNAseq) data from thousands of cortical neurons can now be freely accessed and searched using the online RNAseq data navigator at the Allen Brain Atlas. Hence, we utilized this newly developed tool to perform a comprehensive analysis of the cell-type specific expression of selenium-related genes in brain. Select proteins of interest were further verified by means of multi-label immunofluorescent labeling of mouse brain sections. Of potential significance to neural selenium homeostasis, we report co-expression of selenoprotein P (SELENOP) and selenium binding protein 1 (SELENBP1) within astrocytes. These findings raise the intriguing possibility that SELENBP1 may negatively regulate astrocytic SELENOP synthesis and thereby limit downstream Se supply to neurons.

scholarly journals Large-scale determination and characterization of cell type-specific regulatory elements in the human genome

2017 ◽  
Author(s):  
Can Wang ◽  
Shihua Zhang
Keyword(s):  
Histone Modifications ◽  
Large Scale ◽  
Chromatin Modification ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cell Type ◽  
Cell Identity ◽  
Functional Roles ◽  
Cancer Occurrence ◽  
Cell Type Specific

AbstractHistone modifications have been widely elucidated to play vital roles in gene regulation and cell identity. The Roadmap Epigenomics Consortium generated a reference catalogue of several key histone modifications across >100s of human cell types and tissues. Decoding these epigenomes into functional regulatory elements is a challenging task in computational biology. To this end, we adopted a differential chromatin modification analysis framework to comprehensively determine and characterize cell type-specific regulatory elements (CSREs) and their histone modification codes in the human epigenomes of five histone modifications across 127 tissues or cell types. The CSREs show significant relevance with cell type-specific biological functions and diseases and cell identity. Clustering of CSREs with their specificity signals reveals diverse histone codes, demonstrating the diversity of functional roles of CSREs within the same cell or tissue. Last but not least, dynamics of CSREs from close cell types or tissues can give a detailed view of developmental processes such as normal tissue development and cancer occurrence.

scholarly journals Cerebellar nuclei evolved by repeatedly duplicating a conserved cell type set

2020 ◽  
Author(s):  
Justus M Kebschull ◽  
Noam Ringach ◽  
Ethan B Richman ◽  
Drew Friedmann ◽  
Sai Saroja Kolluru ◽  
...  
Keyword(s):  
Brain Region ◽  
Cell Types ◽  
Cerebellar Nuclei ◽  
Inhibitory Neurons ◽  
Cell Type ◽  
Cell Class ◽  
Single Nucleus ◽  
Entire Cell ◽  
Region Evolution

AbstractHow have complex brains evolved from simple circuits? Here we investigated brain region evolution at cell type resolution in the cerebellar nuclei (CN), the output structures of the cerebellum. Using single-nucleus RNA sequencing in mice, chickens, and humans, as well as STARmap spatial transcriptomic analysis and whole-CNS projection tracing in mice, we identified a conserved cell type set containing two classes of region-specific excitatory neurons and three classes of region-invariant inhibitory neurons. This set constitutes an archetypal CN that was repeatedly duplicated to form new regions. Interestingly, the excitatory cell class that preferentially funnels information to lateral frontal cortices in mice becomes predominant in the massively expanded human Lateral CN. Our data provide the first characterization of CN transcriptomic cell types in three species and suggest a model of brain region evolution by duplication and divergence of entire cell type sets.

scholarly journals Connectivity characterization of the mouse basolateral amygdalar complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Houri Hintiryan ◽  
Ian Bowman ◽  
David L. Johnson ◽  
Laura Korobkova ◽  
Muye Zhu ◽  
...  
Keyword(s):  
Granular Cell ◽  
Cell Types ◽  
Projection Neurons ◽  
Cell Type ◽  
Connectivity Map ◽  
Analysis Techniques ◽  
Domain Specific ◽  
Cell Type Specific ◽  
Unique Domain

AbstractThe basolateral amygdalar complex (BLA) is implicated in behaviors ranging from fear acquisition to addiction. Optogenetic methods have enabled the association of circuit-specific functions to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted. Here, we apply machine-learning based computational and informatics analysis techniques to the results of circuit-tracing experiments to create a foundational, comprehensive BLA connectivity map. The analyses identify three distinct domains within the anterior BLA (BLAa) that house target-specific projection neurons with distinguishable morphological features. We identify brain-wide targets of projection neurons in the three BLAa domains, as well as in the posterior BLA, ventral BLA, posterior basomedial, and lateral amygdalar nuclei. Inputs to each nucleus also are identified via retrograde tracing. The data suggests that connectionally unique, domain-specific BLAa neurons are associated with distinct behavior networks.

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.

scholarly journals Histone modifications form a cell-type-specific chromosomal bar code that persists through the cell cycle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
John A. Halsall ◽  
Simon Andrews ◽  
Felix Krueger ◽  
Charlotte E. Rutledge ◽  
Gabriella Ficz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Histone Modifications ◽  
Expression Patterns ◽  
Cell Types ◽  
Cell Type ◽  
Bar Code ◽  
Genes Encoding ◽  
Cell Type Specific ◽  
Rolling Windows

AbstractChromatin configuration influences gene expression in eukaryotes at multiple levels, from individual nucleosomes to chromatin domains several Mb long. Post-translational modifications (PTM) of core histones seem to be involved in chromatin structural transitions, but how remains unclear. To explore this, we used ChIP-seq and two cell types, HeLa and lymphoblastoid (LCL), to define how changes in chromatin packaging through the cell cycle influence the distributions of three transcription-associated histone modifications, H3K9ac, H3K4me3 and H3K27me3. We show that chromosome regions (bands) of 10–50 Mb, detectable by immunofluorescence microscopy of metaphase (M) chromosomes, are also present in G1 and G2. They comprise 1–5 Mb sub-bands that differ between HeLa and LCL but remain consistent through the cell cycle. The same sub-bands are defined by H3K9ac and H3K4me3, while H3K27me3 spreads more widely. We found little change between cell cycle phases, whether compared by 5 Kb rolling windows or when analysis was restricted to functional elements such as transcription start sites and topologically associating domains. Only a small number of genes showed cell-cycle related changes: at genes encoding proteins involved in mitosis, H3K9 became highly acetylated in G2M, possibly because of ongoing transcription. In conclusion, modified histone isoforms H3K9ac, H3K4me3 and H3K27me3 exhibit a characteristic genomic distribution at resolutions of 1 Mb and below that differs between HeLa and lymphoblastoid cells but remains remarkably consistent through the cell cycle. We suggest that this cell-type-specific chromosomal bar-code is part of a homeostatic mechanism by which cells retain their characteristic gene expression patterns, and hence their identity, through multiple mitoses.

scholarly journals An analytical method for the identification of cell type-specific disease gene modules

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jinting Guan ◽  
Yiping Lin ◽  
Yang Wang ◽  
Junchao Gao ◽  
Guoli Ji
Keyword(s):  
Disease Gene ◽  
Gene Interaction ◽  
Cell Types ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Disease ◽  
Cell Type Specific ◽  
Gene Modules ◽  
Disease Associated Genes

Abstract Background Genome-wide association studies have identified genetic variants associated with the risk of brain-related diseases, such as neurological and psychiatric disorders, while the causal variants and the specific vulnerable cell types are often needed to be studied. Many disease-associated genes are expressed in multiple cell types of human brains, while the pathologic variants affect primarily specific cell types. We hypothesize a model in which what determines the manifestation of a disease in a cell type is the presence of disease module comprised of disease-associated genes, instead of individual genes. Therefore, it is essential to identify the presence/absence of disease gene modules in cells. Methods To characterize the cell type-specificity of brain-related diseases, we construct human brain cell type-specific gene interaction networks integrating human brain nucleus gene expression data with a referenced tissue-specific gene interaction network. Then from the cell type-specific gene interaction networks, we identify significant cell type-specific disease gene modules by performing statistical tests. Results Between neurons and glia cells, the constructed cell type-specific gene networks and their gene functions are distinct. Then we identify cell type-specific disease gene modules associated with autism spectrum disorder and find that different gene modules are formed and distinct gene functions may be dysregulated in different cells. We also study the similarity and dissimilarity in cell type-specific disease gene modules among autism spectrum disorder, schizophrenia and bipolar disorder. The functions of neurons-specific disease gene modules are associated with synapse for all three diseases, while those in glia cells are different. To facilitate the use of our method, we develop an R package, CtsDGM, for the identification of cell type-specific disease gene modules. Conclusions The results support our hypothesis that a disease manifests itself in a cell type through forming a statistically significant disease gene module. The identification of cell type-specific disease gene modules can promote the development of more targeted biomarkers and treatments for the disease. Our method can be applied for depicting the cell type heterogeneity of a given disease, and also for studying the similarity and dissimilarity between different disorders, providing new insights into the molecular mechanisms underlying the pathogenesis and progression of diseases.

Cytoplasmic, nuclear, membrane-bound and secreted [35S]methionine-labelled polypeptide pattern in differentiating fibroblast stem cells in vitro

1989 ◽  
Vol 92 (2) ◽  
pp. 231-239
Author(s):  
P.I. Francz ◽  
K. Bayreuther ◽  
H.P. Rodemann
Keyword(s):  
Protein Fraction ◽  
Fibroblast Cell ◽  
Cell Types ◽  
Specific Marker ◽  
Human Skin Fibroblast ◽  
Nuclear Fraction ◽  
Cell Type ◽  
Marker Proteins ◽  
Cell Type Specific ◽  
Membrane Bound

Methods for the selective enrichment of various subpopulations of the human skin fibroblast cell line HH-8 have been developed. These methods permit the selection of homogeneous populations of the three mitotic fibroblast cell types MF I, II and III, and the four postmitotic cell types PMF IV, V, VI and VII. These seven cell types exhibit differentiation-dependent and cell-type-specific patterns of [35S]methionine-labelled polypeptides in total soluble cytoplasmic and nuclear proteins, also in membrane-bound proteins, and in secreted proteins. In the differentiation sequence MF II-MF III-PMF IV - PMF V - PMF VI 14 cell-type-specific marker proteins have been found in the cytoplasmic and nuclear fraction, also 24 cell-type-specific marker proteins have been found in the membrane-bound protein fraction, and 11 cell-type-specific marker proteins in the secreted protein fraction. Markers in spontaneously arising and experimentally selected or induced populations of a single fibroblast cell type were found to be identical.

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