Molecular landscape of immature neurons in the human hippocampus across the lifespan
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ABSTRACT:
PROVIDER: PRJNA768440 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16194335_1.fastq.gz | Fastqsanger.gz | |||
| SRR16194335_2.fastq.gz | Fastqsanger.gz | |||
| SRR16194336_1.fastq.gz | Fastqsanger.gz | |||
| SRR16194336_2.fastq.gz | Fastqsanger.gz | |||
| SRR16206458_1.fastq.gz | Fastqsanger.gz |
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Project description:Hippocampus is a critical region involved in learning, memory and various brain disorders. The molecular diversity of various glial cells in the human hippocampus and their temporal changes over the postnatal life remain largely unknown. Here we performed single-nucleus RNA-sequencing to create a transcriptome atlas of the human hippocampus across the postnatal lifespan and in Alzheimer’s disease (AD). Detailed analyses of astrocytes, oligodendrocyte lineages, and microglia identified subpopulations with distinct transcriptomic signatures, transcription factor expression patterns, association with specific biological processes, and changes in their abundance with age. Enrichment analysis of brain disorder risk gene expression further implicates specific glial cells and subpopulations in various brain disorders. Furthermore, we identified dysregulated gene expression in specific glial subpopulations in the hippocampus of AD patients. Together, these data provide a rich resource and significantly extend our understanding of human glial cell diversity and their temporal distribution across the postnatal lifespan.
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Project description:Neurogenesis in the adult hippocampus contributes to information processing critical for cognition, adaptation, learning and memory, and is implicated in numerous neurological disorders. New neurons are continuously produced from neural stem cells via a well-controlled developmental process. The immature neuron stage defined by doublecortin (DCX) expression is the most sensitive to regulation by extrinsic factors. However, little is known about the dynamic biology within this critical interval that drives maturation and confers susceptibility to regulating signals. This study aims to test the hypothesis that DCX-expressing immature neurons in adult mouse hippocampus progress through developmental stages via activity of specific transcriptional networks. Using single-cell RNA-seq combined with a novel integrative bioinformatics approach, we discovered that individual immature neuron can be classified into distinct developmental subgroups based on characteristic gene expression profiles and subgroup-specific markers. Comparisons between immature and more mature subgroups revealed novel pathways involved in neuronal maturation. Genes enriched in more immature cells shared significant overlap with genes implicated in neurodegenerative diseases, while genes positively associated with neuronal maturation were enriched for autism-related gene sets. Our study thus discovers molecular signatures of individual adult-born immature neurons and unveils potential novel targets for therapeutic approaches to treat neurodevelopmental and neurological diseases. mRNA sequencing and expression estimation in 64 individual DCX-dsRed+ cells isolated from transgenic DCX-dsRed mice by FACS sorting
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Project description:Neurons born in the adult dentate gyrus develop, mature, and connect over a long interval that can last from six to eight weeks. It has been proposed that, during this period, developing neurons play a relevant role in hippocampal signal processing owing to their distinctive electrical properties. However, it has remained unknown whether immature neurons can be recruited into a network before synaptic and functional maturity have been achieved. To address this question, we used retroviral expression of green fluorescent protein to identify developing granule cells of the adult mouse hippocampus and investigate the balance of afferent excitation, intrinsic excitability, and firing behavior by patch clamp recordings in acute slices. We found that glutamatergic inputs onto young neurons are significantly weaker than those of mature cells, yet stimulation of cortical excitatory axons elicits a similar spiking probability in neurons at either developmental stage. Young neurons are highly efficient in transducing ionic currents into membrane depolarization due to their high input resistance, which decreases substantially in mature neurons as the inward rectifier potassium (Kir) conductance increases. Pharmacological blockade of Kir channels in mature neurons mimics the high excitability characteristic of young neurons. Conversely, Kir overexpression induces mature-like firing properties in young neurons. Therefore, the differences in excitatory drive of young and mature neurons are compensated by changes in membrane excitability that render an equalized firing activity. These observations demonstrate that the adult hippocampus continuously generates a population of highly excitable young neurons capable of information processing.
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Project description:Purpose: Virus infections of the CNS cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFN) are crucially important in controlling CNS virus infections. Semliki Forest virus (SFV) infection of the mouse provides a well-characterised and tractable model to study the pathogenesis of virus encephalitis. The maturity of neuronal populations is an established critical factor determining the outcome of CNS virus infection. Using primary cultures of mouse cortical neurons, we investigated the relationships between neuronal maturation, type I IFN responses and the outcome of SFV infection. Methods: mRNA profiles of immature and mature of primary mouse cortical neurons that were mock or iFNβ treated and mock or SFV infected were generated by deep sequencing, in triplicate, using Illumina HiSeq 2500. All 100-base-pair single-end reads were mapped to the reference mouse genome (GRCm38/mm10) using Salmon ultrafast aligner. Mapped reads were quantitated to the gene level estimates and genecount data was imported using the tximport package and differential expression analysis of RNA sequencing data was carried out using the edgeR and limma-voom packages in Bioconductor. Results: Using an optimized data analysis workflow, we mapped the 100 bp single end reads to the mouse genome (build mm10) and identified 14,933 genes in the immature and mature primary neurons with different treatments. Transcriptomic profiling revealed 3,666 genes differentially expressed between resting immature and mature cells. Multidimensional scaling plots revealed key differences between immature and mature neurons with different treatments. Immature neurons pre-treated with type I IFN and mock-infected or infected without prior IFN, clustered close to the basal (resting) control samples,indicating limited changes in gene expression under either condition. This was also the case for mature neurons treated with IFNβ. Whereas, immature neurons pre-treated with IFN and then infected, as well as mature neurons pre-treated or not with IFN and then infected underwent more dynamic changes in gene expression Conclusions: Complete transcriptome analysis demonstrated that resting immature neurons lacked the transcriptional competence to mount antiviral responses. They had no detectable transcription of the genes Ddx58 and Ifih1 which encode the key RNA virus cytoplasmic sensors RIG-I and MDA5 and no, or very low, expression of genes encoding key regulators of downstream and associated signalling pathways. Upon infection, immature neurons failed to mount an antiviral response as evidenced by their failure to produce chemokines, IFNs and other cytokines. Treatment of immature neurons with exogenous IFNb prior to infection resulted in antiviral responses and lower levels of virus replication and infectious virus production. In contrast, resting mature neurons expressed Ddx58 and Ifih1 and upon infection generated a robust antiviral response. This was augmented by pre-treatment with IFNb. Infection of mature neurons derived from IFNAR-/- mice did not make an antiviral response and replicated virus to high levels.
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Project description:Neurogenesis in the adult hippocampus contributes to information processing critical for cognition, adaptation, learning and memory, and is implicated in numerous neurological disorders. New neurons are continuously produced from neural stem cells via a well-controlled developmental process. The immature neuron stage defined by doublecortin (DCX) expression is the most sensitive to regulation by extrinsic factors. However, little is known about the dynamic biology within this critical interval that drives maturation and confers susceptibility to regulating signals. This study aims to test the hypothesis that DCX-expressing immature neurons in adult mouse hippocampus progress through developmental stages via activity of specific transcriptional networks. Using single-cell RNA-seq combined with a novel integrative bioinformatics approach, we discovered that individual immature neuron can be classified into distinct developmental subgroups based on characteristic gene expression profiles and subgroup-specific markers. Comparisons between immature and more mature subgroups revealed novel pathways involved in neuronal maturation. Genes enriched in more immature cells shared significant overlap with genes implicated in neurodegenerative diseases, while genes positively associated with neuronal maturation were enriched for autism-related gene sets. Our study thus discovers molecular signatures of individual adult-born immature neurons and unveils potential novel targets for therapeutic approaches to treat neurodevelopmental and neurological diseases.
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