Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1091595 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28437736_1.fastq.gz | Fastqsanger.gz | |||
| SRR28437736_2.fastq.gz | Fastqsanger.gz | |||
| SRR28437737_1.fastq.gz | Fastqsanger.gz | |||
| SRR28437737_2.fastq.gz | Fastqsanger.gz | |||
| SRR28437738_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (DISC1-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by WFS1 expression, whose activity is modulated by adjacent astrocytes. These neurons in DISC1-N mice exhibited diminished firing ability and impaired communication with the astrocytes. Remarkably, optogenetic activation of these astrocytes reinstated neuronal excitability via D-serine acting on BLAWFS1 neurons’ NMDA receptors, leading to improved risk-assessment behavior in the DISC1-N mice. Our findings point to BLA astrocytes as a promising target for treating risk assessment dysfunctions in mental disorders.
2024-04-19 | GSE262541 | GEO
Project description:Adolescent cannabis use has been associated with long-term cognitive dysfunction attributed to action of the main cannabis ingredient, delta-9-tetrahydrocannabinol (Δ9-THC), on the cannabinoid receptor 1 (CNR1). However, not all marijuana users develop cognitive impairment, suggesting a genetic vulnerability to adverse effects of cannabis. As both neurons and glial cells express CNR1, genetic vulnerability could influence Δ9-THC-induced signaling in a cell type-specific manner. Here we use an animal model of inducible expression of dominant-negative Disrupted-In-Schizophrenia-1 (DN-DISC1) selectively in astrocytes to evaluate the molecular mechanisms whereby an astrocyte genetic vulnerability could synergistically interact with adolescent Δ9-THC exposure to impair recognition memory in adulthood. We report that selective expression of DN-DISC1 in astrocytes and adolescent treatment with Δ9-THC synergistically affected recognition memory in adult mice. Similar deficits in recognition memory were observed following knockdown of endogenous Disc1 in hippocampal astrocytes in mice treated with Δ9-THC during adolescence. At the molecular level, DN-DISC1 and Δ9-THC synergistically activated the NF-kB-COX-2 (encoded by Ptgs2 gene) pathway in astrocytes and decreased immunoreactivity of parvalbumin-positive pre-synaptic inhibitory boutons around pyramidal neurons of the CA3 area of the hippocampus. The cognitive abnormalities were prevented in DN-DISC1 mice exposed to Δ9-THC by simultaneous adolescent treatment with the COX-2 inhibitor, NS389. Our data demonstrate that individual vulnerability to cannabis can be exclusively mediated by astrocytes. Results of this work suggest that genetic predisposition within astrocytes can exaggerate Δ9-THC-produced cognitive impairments via convergent inflammatory signaling, suggesting possible targets for preventing adverse effects of cannabis within susceptible individuals.
2018-12-31 | GSE116813 | GEO
Project description:Schizophrenia and other psychiatric disorders are postulated to be developmental disorders resulting from synapse dysfunction. How susceptibility genes for major mental disorders could lead to synaptic deficits in humans is not well-understood. Here we generated induced pluripotent stem cells (iPSCs) from four members of a family in which a frame-shift mutation of Disrupted-in-schizophrenia-1 (DISC1) co-segregated with psychiatric disorders and further produced different isogenic iPSC lines via genetic editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPSC-derived forebrain neurons. Mechanistically, mutant DISC1 dysregulates the expression of many genes related to synapses and psychiatric disorders and depletes wild-type DISC1 and the NCoR1 transcription co-repressor complex. Furthermore, mechanism-guided pharmacological inhibition of phosphodiesterases rescues synaptic defects in mutant neurons. Our study uncovers a novel gain-of-function mechanism through which the psychiatric disorder-relevant mutation affects synaptic functions via transcriptional dysregulation and provides insight into the molecular and synaptic etiopathology of psychiatric disorders. Two patient derived iPSC lines carrying heterozygous 4bp deletion in DISC1 gene and 1 related control were analyzed in biological triplicate
2014-08-01 | E-GEOD-57821 | biostudies-arrayexpress
Project description:Schizophrenia and other psychiatric disorders are postulated to be developmental disorders resulting from synapse dysfunction. How susceptibility genes for major mental disorders could lead to synaptic deficits in humans is not well-understood. Here we generated induced pluripotent stem cells (iPSCs) from four members of a family in which a frame-shift mutation of Disrupted-in-schizophrenia-1 (DISC1) co-segregated with psychiatric disorders and further produced different isogenic iPSC lines via genetic editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPSC-derived forebrain neurons. Mechanistically, mutant DISC1 dysregulates the expression of many genes related to synapses and psychiatric disorders and depletes wild-type DISC1 and the NCoR1 transcription co-repressor complex. Furthermore, mechanism-guided pharmacological inhibition of phosphodiesterases rescues synaptic defects in mutant neurons. Our study uncovers a novel gain-of-function mechanism through which the psychiatric disorder-relevant mutation affects synaptic functions via transcriptional dysregulation and provides insight into the molecular and synaptic etiopathology of psychiatric disorders.
2014-08-01 | GSE57821 | GEO
Project description:Disrupted-in-schizophrenia-1 (DISC1), as one of the schizophrenia susceptibility genes highly expressed in oligodendrocyte precursor cells (OPCs), impacts oligodendroglial differentiation and myelination. Several DISC1 splicing variants, including DISC1-Δ3 (a DISC1 transcript with deleted exon 3 in a single allele), are abnormally upregulated in human schizophrenia patients, however, how they trigger the onset of the disease has not been explored yet. Here, we generate a mouse line that mimics human DISC1-Δ3 in oligodendrocyte lineage cells, and demonstrate that hypertrophic OPCs rather than myelin, are responsible for the neuronal deficits and schizophrenia-like symptoms. RNAseq was performed to analyze the transcriptome change in DISC1-Δ3 OPC, revealing that DISC1-Δ3 elevates the Wnt pathway activity in OPCs, which promotes Wif1 expression, thereby leading to disrupted synapse formation in neighboring neurons. Interfering or knockout of Wif1 in DISC1-Δ3 OPCs could rescue neuronal synaptic and functional deficits in our mouse model. Our findings shed light on the myelination-independent role of OPCs on the onset of schizophrenia, and may pave the way for new rational lines of inquiry in developing therapeutic strategies for schizophrenia.
2022-12-28 | GSE183341 | GEO
Project description:Purpose: Genetic and clinical association studies have identified disrupted-in-schizophrenia 1 (DISC1) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) translocation in a Scottish family, in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We sought to compare the gene expression profiles of human neural progenitor cells (NPCs) and neurons with interruption of the DISC1 gene in exon 2 (affecting all known coding transcripts) or exon 8 (near the site of the Scottish translocation, affecting longer transcripts). Methods: Wild-type and DISC1-targeted iPSCs (wild-type = "WT", exon 8 single allelic frameshift mutant = "ex8_wm", exon 8 biallelic frameshift mutant = "ex8_mm", exon 2 biallelic frameshift mutant = "ex2mm") were differentiated to NPCs and neurons using an embryoid aggregate method. NPC or neuronal cultures were used for RNA harvest and subsequent paired-end stranded sequencing of >50M reads/sample and 3-6 biological replicates per group. Results: We find that a subset of genes related to neuronal differentiation and development are dysregulated with DISC1 disruption at the NPC timepoint, whereas expression of genes related to neuronal function and signaling are altered at the neuronal timepoint. This study implicates DISC1 as a regulator of neuronal development. mRNA profiles of wild-type and DISC1-targeted human iPSC-derived neural progenitor cells (day 17) and neurons (day 50) by paired-end sequencing, with 3-6 biological replicates, using Illumina HiSeq
2015-09-14 | E-GEOD-71289 | biostudies-arrayexpress
Project description:Disrupted-in-schizophrenia 1 (DISC1) is a key protein involved in behavioral processes and various mental disorders, including schizophrenia and major depression. A transgenic rat modestly overexpressing non-mutant human DISC1, modeling aberrant proteostasis of the DISC1 protein, displays behavioral, biochemical and anatomical deficits consistent with aspects of mental disorders, including changes in the dorsal striatum, an anatomical region critical in the development of behavioral disorders. Here, the dorsal striatum of 10 tgDISC1 and 10 littermate control rats was used for synaptosomal membrane preparations and for performing LC-MS-based quantitative proteomics, using TMT 10plex. Enrichment analysis was generated from proteins with level changes. Canonical pathway analysis assigned proteins with level changes to actin cytoskeleton, Gαq, Rho family GTPase and Rho GDI-, axonal guidance, ephrin receptor and dopamine-DARPP32 feedback in cAMP signalling. Functional network components included proteins of the categories "quantity of neurons, extension of axons and neurites and long term potentiation". Our analysis demonstrates that the effects of a relatively small overexpression of non-mutant DISC1 or its missassembly has profound consequences on protein networks essential for behavioral control
2018-02-27 | PXD008123 | Pride
Project description:Overall risk for Major Depressive Disorder (MDD) is determined by complex interactions between genetic and environmental factors that influence epigenetic regulation of neuroplasticity and stress pathways1,2. These mechanisms are specific to the distinct regulatory context within regionally-defined brain cell-types3,4. Here, we employed genome-wide chromatin accessibility profiling of neuronal vs. non-neuronal cells in orbitofrontal cortex (OFC) to capture regulatory signatures of MDD. We mapped genetic risk for MDD to active promoters of non-neuronal cell-types in OFC and identified MDD-specific open chromatin regions, which were differentially accessible exclusively in non-neuronal cells. Characterization of these loci revealed a key role for astrocyte dysfunction, and implicated the chromatin remodeling protein ZBTB7A, which coordinates wide-ranging cellular activation programs, including NF-kB inflammatory transcription5. In mice, astrocyte-specific knockdown of Zbtb7a reversed chromatin remodeling, reactive astrocyte transcription, and behavioral deficits associated with chronic stress. Conversely, ZBTB7A overexpression in OFC astrocytes induced stress-related behavioral deficits, promoted widespread inflammatory gene expression, and drove pathophysiological OFC neuronal hyperactivity in response to a mild subthreshold stressor. Our data highlight a critical role for OFC astrocytes in the bidirectional regulation of stress vulnerability and pinpoint ZBTB7A as a key factor mediating maladaptive astrocyte plasticity and OFC neuronal hyperexcitability in MDD.
2023-08-08 | GSE214921 | GEO
Project description:Overall risk for Major Depressive Disorder (MDD) is determined by complex interactions between genetic and environmental factors that influence epigenetic regulation of neuroplasticity and stress pathways1,2. These mechanisms are specific to the distinct regulatory context within regionally-defined brain cell-types3,4. Here, we employed genome-wide chromatin accessibility profiling of neuronal vs. non-neuronal cells in orbitofrontal cortex (OFC) to capture regulatory signatures of MDD. We mapped genetic risk for MDD to active promoters of non-neuronal cell-types in OFC and identified MDD-specific open chromatin regions, which were differentially accessible exclusively in non-neuronal cells. Characterization of these loci revealed a key role for astrocyte dysfunction, and implicated the chromatin remodeling protein ZBTB7A, which coordinates wide-ranging cellular activation programs, including NF-kB inflammatory transcription5. In mice, astrocyte-specific knockdown of Zbtb7a reversed chromatin remodeling, reactive astrocyte transcription, and behavioral deficits associated with chronic stress. Conversely, ZBTB7A overexpression in OFC astrocytes induced stress-related behavioral deficits, promoted widespread inflammatory gene expression, and drove pathophysiological OFC neuronal hyperactivity in response to a mild subthreshold stressor. Our data highlight a critical role for OFC astrocytes in the bidirectional regulation of stress vulnerability and pinpoint ZBTB7A as a key factor mediating maladaptive astrocyte plasticity and OFC neuronal hyperexcitability in MDD.
2023-08-08 | GSE214920 | GEO
Project description:Overall risk for Major Depressive Disorder (MDD) is determined by complex interactions between genetic and environmental factors that influence epigenetic regulation of neuroplasticity and stress pathways1,2. These mechanisms are specific to the distinct regulatory context within regionally-defined brain cell-types3,4. Here, we employed genome-wide chromatin accessibility profiling of neuronal vs. non-neuronal cells in orbitofrontal cortex (OFC) to capture regulatory signatures of MDD. We mapped genetic risk for MDD to active promoters of non-neuronal cell-types in OFC and identified MDD-specific open chromatin regions, which were differentially accessible exclusively in non-neuronal cells. Characterization of these loci revealed a key role for astrocyte dysfunction, and implicated the chromatin remodeling protein ZBTB7A, which coordinates wide-ranging cellular activation programs, including NF-kB inflammatory transcription5. In mice, astrocyte-specific knockdown of Zbtb7a reversed chromatin remodeling, reactive astrocyte transcription, and behavioral deficits associated with chronic stress. Conversely, ZBTB7A overexpression in OFC astrocytes induced stress-related behavioral deficits, promoted widespread inflammatory gene expression, and drove pathophysiological OFC neuronal hyperactivity in response to a mild subthreshold stressor. Our data highlight a critical role for OFC astrocytes in the bidirectional regulation of stress vulnerability and pinpoint ZBTB7A as a key factor mediating maladaptive astrocyte plasticity and OFC neuronal hyperexcitability in MDD.
2023-08-08 | GSE214919 | GEO