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

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.

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Prevalent presence of periodic actin–spectrin-based membrane skeleton in a broad range of neuronal cell types and animal species

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1605707113 ◽

2016 ◽

Vol 113 (21) ◽

pp. 6029-6034 ◽

Cited By ~ 87

Author(s):

Jiang He ◽

Ruobo Zhou ◽

Zhuhao Wu ◽

Monica A. Carrasco ◽

Peri T. Kurshan ◽

...

Keyword(s):

Glial Cell ◽

Animal Species ◽

Homo Sapiens ◽

Neuronal Cell ◽

Cell Types ◽

Membrane Skeleton ◽

Brain Regions ◽

Inhibitory Neurons ◽

Periodic Distribution ◽

Neuronal Types

Actin, spectrin, and associated molecules form a periodic, submembrane cytoskeleton in the axons of neurons. For a better understanding of this membrane-associated periodic skeleton (MPS), it is important to address how prevalent this structure is in different neuronal types, different subcellular compartments, and across different animal species. Here, we investigated the organization of spectrin in a variety of neuronal- and glial-cell types. We observed the presence of MPS in all of the tested neuronal types cultured from mouse central and peripheral nervous systems, including excitatory and inhibitory neurons from several brain regions, as well as sensory and motor neurons. Quantitative analyses show that MPS is preferentially formed in axons in all neuronal types tested here: Spectrin shows a long-range, periodic distribution throughout all axons but appears periodic only in a small fraction of dendrites, typically in the form of isolated patches in subregions of these dendrites. As in dendrites, we also observed patches of periodic spectrin structures in a small fraction of glial-cell processes in four types of glial cells cultured from rodent tissues. Interestingly, despite its strong presence in the axonal shaft, MPS is disrupted in most presynaptic boutons but is present in an appreciable fraction of dendritic spine necks, including some projecting from dendrites where such a periodic structure is not observed in the shaft. Finally, we found that spectrin is capable of adopting a similar periodic organization in neurons of a variety of animal species, including Caenorhabditis elegans, Drosophila, Gallus gallus, Mus musculus, and Homo sapiens.

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

10.1101/2022.01.05.475032 ◽

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.

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GABAergic Neuron Specification in the Spinal Cord, the Cerebellum, and the Cochlear Nucleus

Neural Plasticity ◽

10.1155/2012/921732 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Kei Hori ◽

Mikio Hoshino

Keyword(s):

Spinal Cord ◽

Nervous System ◽

Cochlear Nucleus ◽

Neuronal Cell ◽

Cell Types ◽

Brain Regions ◽

Lineage Tracing ◽

Inhibitory Neurons ◽

Genetic Lineage ◽

Genetic Lineage Tracing

In the nervous system, there are a wide variety of neuronal cell types that have morphologically, physiologically, and histochemically different characteristics. These various types of neurons can be classified into two groups: excitatory and inhibitory neurons. The elaborate balance of the activities of the two types is very important to elicit higher brain function, because its imbalance may cause neurological disorders, such as epilepsy and hyperalgesia. In the central nervous system, inhibitory neurons are mainly represented by GABAergic ones with some exceptions such as glycinergic. Although the machinery to specify GABAergic neurons was first studied in the telencephalon, identification of key molecules, such as pancreatic transcription factor 1a (Ptf1a), as well as recently developed genetic lineage-tracing methods led to the better understanding of GABAergic specification in other brain regions, such as the spinal cord, the cerebellum, and the cochlear nucleus.

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Differential Protein Expression in Striatal D1- and D2-Dopamine Receptor-Expressing Medium Spiny Neurons

Proteomes ◽

10.3390/proteomes8040027 ◽

2020 ◽

Vol 8 (4) ◽

pp. 27

Author(s):

M. Shahid Mansuri ◽

Gang Peng ◽

Rashaun S. Wilson ◽

TuKiet T. Lam ◽

Hongyu Zhao ◽

...

Keyword(s):

Drugs Of Abuse ◽

Affinity Purification ◽

Neuronal Cell ◽

Principal Component ◽

Cell Types ◽

Differentially Expressed ◽

Cellular Heterogeneity ◽

Specific Cell ◽

Medium Spiny Neurons ◽

Spiny Neurons

Many neurological disorders and diseases including drug addiction are associated with specific neuronal cell types in the brain. The striatum, a region that plays a critically important role in the development of addictive drug-related behavior, provides a good example of the cellular heterogeneity challenges associated with analyses of specific neuronal cell types. Such studies are needed to identify the adaptive changes in neuroproteomic signaling that occur in response to diseases such as addiction. The striatum contains two major cell types, D1 and D2 type dopaminoceptive medium spiny neurons (MSNs), whose cell bodies and processes are intermingled throughout this region. Since little is known about the proteomes of these two neuronal cell populations, we have begun to address this challenge by using fluorescence-activated nuclear sorting (FANS) to isolate nuclei-containing fractions from striatum from D1 and D2 “Translating Ribosome Affinity Purification” (TRAP) mice. This approach enabled us to devise and implement a robust and reproducible workflow for preparing samples from specific MSN cell types for mass spectrometry analyses. These analyses quantified at least 685 proteins in each of four biological replicates of 50 K sorted nuclei from two D1 mice/replicate and from each of four biological replicates of 50 K sorted nuclei from two D2 mice/replicate. Proteome analyses identified 87 proteins that were differentially expressed in D1 versus D2 MSN nuclei and principal component analysis (PCA) of these proteins separated the 8 biological replicates into specific cell types. Central network analysis of the 87 differentially expressed proteins identified Hnrnpd and Hnmpa2b1 in D1 and Cct2 and Cct7 in D2 as potential central interactors. This workflow can now be used to improve our understanding of many neurological diseases including characterizing the short and long-term impact of drugs of abuse on the proteomes of these two dopaminoceptive neuronal populations.

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Prevalent Presence of Periodic Actin-spectrin-based Membrane Skeleton in a Broad Range of Neuronal Cell Types and Animal Species

10.1101/045856 ◽

2016 ◽

Cited By ~ 1

Author(s):

Jiang He ◽

Ruobo Zhou ◽

Zhuhao Wu ◽

Monica Carrasco ◽

Peri Kurshan ◽

...

Keyword(s):

Glial Cell ◽

Animal Species ◽

Homo Sapiens ◽

Neuronal Cell ◽

Cell Types ◽

Membrane Skeleton ◽

Brain Regions ◽

Inhibitory Neurons ◽

Periodic Distribution ◽

Neuronal Types

AbstractActin, spectrin and associated molecules form a periodic, sub-membrane cytoskeleton in the axons of neurons. For a better understanding of this membrane-associated periodic skeleton (MPS), it is important to address how prevalent this structure is in different neuronal types, different subcellular compartments, and across different animal species. Here, we investigated the organization of spectrin in a variety of neuronal and glial-cell types. We observed the presence of MPS in all of the tested neuronal types cultured from mouse central and peripheral nervous systems, including excitatory and inhibitory neurons from several brain regions, as well as sensory and motor neurons. Quantitative analyses show that MPS is preferentially formed in axons in all neuronal types tested here: spectrin shows a long-range, periodic distribution throughout all axons, but only appears periodic in a small fraction of dendrites, typically in the form of isolated patches in sub-regions of these dendrites. As in dendrites, we also observed patches of periodic spectrin structures in a small fraction of glial-cell processes in four types of glial cells cultured from rodent tissues. Interestingly, despite its strong presence in the axonal shaft, MPS is absent in most presynaptic boutons, but is present in a substantial fraction of dendritic spine necks, including some projecting from dendrites where such a periodic structure is not observed in the shaft. Finally, we found that spectrin is capable of adopting a similar periodic organization in neurons of a variety of animal species, including Caenorhabditis elegans, Drosophila, Gallus gallus, Mus musculus and Homo sapiens.

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Behavioral sensitization induced by methamphetamine causes differential alterations in gene expression and histone acetylation of the prefrontal cortex in rats

BMC Neuroscience ◽

10.1186/s12868-021-00616-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Hui Li ◽

Jing-An Chen ◽

Qian-Zhi Ding ◽

Guan-Yi Lu ◽

Ning Wu ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Histone Acetylation ◽

Differentially Expressed Genes ◽

Behavioral Sensitization ◽

Functional Enrichment ◽

Differentially Expressed ◽

Adult Rats ◽

Mrna Microarray ◽

H3 Acetylation

Abstract Background Methamphetamine (METH) is one of the most widely abused illicit substances worldwide; unfortunately, its addiction mechanism remains unclear. Based on accumulating evidence, changes in gene expression and chromatin modifications might be related to the persistent effects of METH on the brain. In the present study, we took advantage of METH-induced behavioral sensitization as an animal model that reflects some aspects of drug addiction and examined the changes in gene expression and histone acetylation in the prefrontal cortex (PFC) of adult rats. Methods We conducted mRNA microarray and chromatin immunoprecipitation (ChIP) coupled to DNA microarray (ChIP-chip) analyses to screen and identify changes in transcript levels and histone acetylation patterns. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed to analyze the differentially expressed genes. We then further identified alterations in ANP32A (acidic leucine-rich nuclear phosphoprotein-32A) and POU3F2 (POU domain, class 3, transcription factor 2) using qPCR and ChIP-PCR assays. Results In the rat model of METH-induced behavioral sensitization, METH challenge caused 275 differentially expressed genes and a number of hyperacetylated genes (821 genes with H3 acetylation and 10 genes with H4 acetylation). Based on mRNA microarray and GO and KEGG enrichment analyses, 24 genes may be involved in METH-induced behavioral sensitization, and 7 genes were confirmed using qPCR. We further examined the alterations in the levels of the ANP32A and POU3F2 transcripts and histone acetylation at different periods of METH-induced behavioral sensitization. H4 hyperacetylation contributed to the increased levels of ANP32A mRNA and H3/H4 hyperacetylation contributed to the increased levels of POU3F2 mRNA induced by METH challenge-induced behavioral sensitization, but not by acute METH exposure. Conclusions The present results revealed alterations in transcription and histone acetylation in the rat PFC by METH exposure and provided evidence that modifications of histone acetylation contributed to the alterations in gene expression caused by METH-induced behavioral sensitization.

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Long-Living Budding Yeast Cell Subpopulation Induced by Ethanol/Acetate and Respiration

The Journals of Gerontology Series A ◽

10.1093/gerona/glz202 ◽

2019 ◽

Vol 75 (8) ◽

pp. 1448-1456 ◽

Cited By ~ 1

Author(s):

Young-Yon Kwon ◽

Seung-Soo Kim ◽

Han-Jun Lee ◽

Seo-Hyeong Sheen ◽

Kyoung Heon Kim ◽

...

Keyword(s):

Differentially Expressed Genes ◽

Budding Yeast ◽

Gradient Centrifugation ◽

Carbon Sources ◽

Cell Types ◽

Glucose Sensing ◽

Differentially Expressed ◽

Cell Subpopulation ◽

Genes Encoding ◽

Cell Transcriptome

Abstract Budding yeast generate heterogeneous cells that can be separated into two distinctive cell types: short-living low-density and long-living high-density (HD) cells by density gradient centrifugation. We found that ethanol and acetate induce formation of HD cells, and mitochondrial respiration is required. From their transcriptomes and metabolomes, we found upregulated differentially expressed genes in HD cells involved in the RGT2/RGT1 glucose sensing pathway and its downstream genes encoding hexose transporters. For HD cells, we determined an abundance of various carbon sources including glucose, lactate, pyruvate, trehalose, mannitol, mannose, and galactose. Other upregulated differentially expressed genes in HD cells were involved in the TORC1–SCH9 signaling pathway and its downstream genes involved in cytoplasmic translation. We also measured an abundance of free amino acids in HD cells including valine, proline, isoleucine, and glutamine. These characteristics of the HD cell transcriptome and metabolome may be important conditions for maintaining a long-living phenotype.

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Neural arbitration between social and individual learning systems

eLife ◽

10.7554/elife.54051 ◽

2020 ◽

Vol 9 ◽

Author(s):

Andreea Oliviana Diaconescu ◽

Madeline Stecy ◽

Lars Kasper ◽

Christopher J Burke ◽

Zoltan Nagy ◽

...

Keyword(s):

Prefrontal Cortex ◽

Functional Neuroimaging ◽

Learning Task ◽

Brain Regions ◽

Individual Learning ◽

Learning Systems ◽

Learning System ◽

Relative Precision ◽

Decision Confidence ◽

Dorsolateral Prefrontal

Decision making requires integrating knowledge gathered from personal experiences with advice from others. The neural underpinnings of the process of arbitrating between information sources has not been fully elucidated. In this study, we formalized arbitration as the relative precision of predictions, afforded by each learning system, using hierarchical Bayesian modeling. In a probabilistic learning task, participants predicted the outcome of a lottery using recommendations from a more informed advisor and/or self-sampled outcomes. Decision confidence, as measured by the number of points participants wagered on their predictions, varied with our definition of arbitration as a ratio of precisions. Functional neuroimaging demonstrated that arbitration signals were independent of decision confidence and involved modality-specific brain regions. Arbitrating in favor of self-gathered information activated the dorsolateral prefrontal cortex and the midbrain, whereas arbitrating in favor of social information engaged the ventromedial prefrontal cortex and the amygdala. These findings indicate that relative precision captures arbitration between social and individual learning systems at both behavioral and neural levels.

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Altered neural activity in brain cough suppression networks in cigarette smokers

European Respiratory Journal ◽

10.1183/13993003.00362-2019 ◽

2019 ◽

Vol 54 (3) ◽

pp. 1900362 ◽

Cited By ~ 2

Author(s):

Ayaka Ando ◽

Stuart B. Mazzone ◽

Michael J. Farrell

Keyword(s):

Prefrontal Cortex ◽

Neural Circuits ◽

Brain Regions ◽

Smoking Behaviour ◽

Brain Network ◽

Functional Brain Imaging ◽

Cigarette Smokers ◽

Dorsolateral Prefrontal ◽

Cortical Regions ◽

Airway Irritation

Cough is important for airway defence, and studies in healthy animals and humans have revealed multiple brain networks intimately involved in the perception of airway irritation, cough induction and cough suppression. Changes in cough sensitivity and/or the ability to suppress cough accompany pulmonary pathologies, suggesting a level of plasticity is possible in these central neural circuits. However, little is known about how persistent inputs from the lung might modify the brain processes regulating cough.In the present study, we used human functional brain imaging to investigate the central neural responses that accompany an altered cough sensitivity in cigarette smokers.In nonsmokers, inhalation of the airway irritant capsaicin induced a transient urge-to-cough associated with the activation of a distributed brain network that included sensory, prefrontal and motor cortical regions. Cigarette smokers demonstrated significantly higher thresholds for capsaicin-induced urge-to-cough, consistent with a reduced sensitivity to airway irritation. Intriguingly, this was accompanied by increased activation in brain regions known to be involved in both cough sensory processing (primary sensorimotor cortex) and cough suppression (dorsolateral prefrontal cortex and the midbrain nucleus cuneiformis). Activations in the prefrontal cortex were highest among participants with the least severe smoking behaviour, whereas those in the midbrain correlated with more severe smoking behaviour.These outcomes suggest that smoking-induced sensitisation of central cough neural circuits is offset by concurrently enhanced central suppression. Furthermore, central suppression mechanisms may evolve with the severity of smoke exposure, changing from initial prefrontal inhibition to more primitive midbrain processes as exposure increases.

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

Translational Neuroscience ◽

10.1515/tnsci-2016-0021 ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 4

Author(s):

Mihovil Mladinov ◽

Goran Sedmak ◽

Heidi R. Fuller ◽

Mirjana Babić Leko ◽

Davor Mayer ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Cognitive Processing ◽

Orbitofrontal Cortex ◽

Right Hemisphere ◽

Transcriptome Profiling ◽

Differentially Expressed ◽

Unknown Etiology ◽

Dorsolateral Prefrontal ◽

The Right

AbstractSchizophrenia 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:

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