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Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain

ABSTRACT: We developed an affinity purification approach to isolate tagged nuclei in mice (similar to INTACT; [Deal R.B. and Henikoff S. A simple method for gene expression and chromatin profiling of individual cell types within a tissue. Dev. Cell 18,1030-1040. (2010)]) and used it to characterize genome-wide patterns of transcription, DNA methylation, and chromatin accessibility in 3 major neuron classes of the neocortex (excitatory pyramidal neurons, parvalbumin (PV)-positive GABAergic interneurons, and vasoactive intestinal peptide (VIP)-positive GABAergic interneurons). By combining cell purification and integrative analysis, our findings relate the phenotypic and functional complexity of neocortical neurons to their underlying transcriptional and epigenetic diversity.

ORGANISM(S): Mus musculus

PROVIDER: GSE63137 | GEO | 2015/06/17

SECONDARY ACCESSION(S): PRJNA266828

REPOSITORIES: GEO

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Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain

Project description:We developed an affinity purification approach to isolate tagged nuclei in mice (similar to INTACT; [Deal R.B. and Henikoff S. A simple method for gene expression and chromatin profiling of individual cell types within a tissue. Dev. Cell 18,1030-1040. (2010)]) and used it to characterize genome-wide patterns of transcription, DNA methylation, and chromatin accessibility in 3 major neuron classes of the neocortex (excitatory pyramidal neurons, parvalbumin (PV)-positive GABAergic interneurons, and vasoactive intestinal peptide (VIP)-positive GABAergic interneurons). By combining cell purification and integrative analysis, our findings relate the phenotypic and functional complexity of neocortical neurons to their underlying transcriptional and epigenetic diversity. RNA-seq, MethylC-seq, ATAC-seq, and ChIP-seq for histone modifications using INTACT-purified nuclei from the mouse neocortex

2015-06-17 | E-GEOD-63137 | biostudies-arrayexpress

HDAC3 Inhibition Causes the Impairment in Development of Neocortical VIP Interneurons via dysregulation of Notch Signaling and Autism-like Behaviors

Project description:Autism spectrum disorders (ASDs) are a neurodevelopmental disorder characterized by impairments in social interactions and stereotyped behaviors. While ASD has a strong genetic background, environmental factors including toxins, pesticides, infection and drugs are also known to confer autism susceptibility, likely by inducing epigenetic changes. Exposure to Valproic acid (VPA), a drug for epilepsy and bipolar disorders, during pregnancy is highly associated with the risk of ASD children. In rodents, in utero VPA exposure can precipitate behavioral phenotypes related to ASD in the offspring. Since VPA is an inhibitor of histone deacethytransferase (HDAC) activity, it thought to cause ASD with epigenetic modification. However, the core mechanism by which prenatal VPA exposure causes onset of ASD is still not fully uncovered. Here we revealed that prenatal VPA exposure strongly influences development of vasoactive intestinal peptide (VIP) - positive neurons, a subtype of cortical GABAergic interneurons. The number of VIP+ interneurons was severely reduced in somatosensory area of VPA-exposed ASD animals. We then found that the reduction in VIP+ interneurons is caused by the inhibition of HDAC3 activity upon prenatal VPA exposure. Importantly, prenatal HDAC3 inhibition caused not only the selective reduction in VIP+ interneurons but also the ASD-like behaviors in mice. We then demonstrated that the HDAC3 inhibition aberrantly activates Notch signaling, which influences the cell fate determination of VIP+ interneuron progenitors in caudal ganglionic eminence. Thus, this study uncovers the mechanism by which specific HDAC inhibition during development influences a specific type of GABAergic interneurons in the ASD model. The findings provide a novel insight into the understanding of ASD pathophysiology.

2022-06-20 | GSE133932 | GEO

Cell type-specific oxidative stress genomic signatures in the globus pallidus of dopamine depleted mice

Project description:We developed a new viral affinity purification strategy, Cre-Specific Nuclear Anchored Independent Labeling (cSNAIL), to isolate Cre recombinase-expressing (Cre+) nuclei from the adult mouse brain. cSNAIL is an AAV that delivers a modified version of the nuclear-anchored protein tag developed for INTACT nuclei isolation (Deal & Henikoff, Dev Cell. 2010. 18:1030-1040; Mo et al., Neuron. 2015. 86(6):1369-1384). Applying cSNAIL technology in Pvalb-2A-Cre mice, we performed targeted assessment of the cell type-specific transcriptomic and epigenetic effects of dopamine depletion on parvalbumin-expressing (PV+) neurons and PV- nuclei. We recovered signatures of oxidative stress response involving Hif2a signaling that was specific to external globus pallidus (GPe) PV+ neurons, a consequence of dopamine depletion that may have theraputic implications for Parkinson's disease.

2020-09-07 | GSE157359 | GEO

Single genomic enhancers drive experience-dependent GABAergic plasticity to maintain sensory processing in the adult cortex

Project description:Experience-dependent plasticity of synapses modulates information processing in neural circuits and is essential for cognitive functions. The genome, via non-coding enhancers, was proposed to control information processing and circuit plasticity by regulating experience-induced transcription of genes that modulate specific sets of synapses. To test this idea, we analyze here the cellular and circuit functions of the genomic mechanisms that control the experience-induced transcription of Igf1 (insulin-like growth factor 1) in vasoactive intestinal peptide (VIP) interneurons (INs) in the visual cortex of adult mice. We find that two sensory-induced enhancers selectively and cooperatively drive the activity-induced transcription of Igf1 to thereby promote GABAergic inputs onto VIP INs and to homeostatically control the ratio between excitation and inhibition (E/I ratio)—in turn, this restricts neural activity in VIP INs and principal excitatory neurons and maintains spatial frequency tuning. Thus, enhancer-mediated activity-induced transcription maintains sensory processing in the adult cortex via homeostatic modulation of E/I ratio.

2023-06-27 | GSE210658 | GEO

Single genomic enhancers drive experience-dependent GABAergic plasticity to maintain sensory processing in the adult cortex (RNA-Seq)

2023-06-27 | GSE227382 | GEO

A novel hippocampal long-range VIP-GABAergic projection to subiculum contributes to fear memory formation through region-specific connectivity

Project description:We sequenced seven long-range projection vasoactive intestinal peptide (VIP)-expressing interneurons from the mouse CA1 oriens/alveus area using patch-seq technique to determine their molecular identity.

2018-01-30 | GSE109755 | GEO

Transcriptomic and epigenetic disruptions in excitatory neurons in Dnmt3a conditional knockout mouse

Project description:We created a mouse line in which deletion of exon 19 of Dnmt3a is driven by the Neurod6 promoter (also known as Nex-Cre line). In this conditional knockout (cKO), Dnmt3a is functionally ablated in excitatory neurons in the neocortex and hippocampus starting in mid/late gestation (~E13-15). With an affinity purification approach to isolate tagged nuclei in mice (similar to INTACT; [Deal R.B. and Henikoff S. A simple method for gene expression and chromatin profiling of individual cell types within a tissue. Dev. Cell 18,1030-1040. (2010)]), we characterized the genome-wide patterns of transcription, DNA methylation, and histone modifications in excitatory pyramidal neurons of the frontal cortex from the Dnmt3a cKO and control mice. Our data provide a detailed assessment of the molecular basis of the accompanying changes of neurophysiological and behavioral phenotypes in the cKO mice, and suggest a complex interaction between DNA methylation and Polycomb-mediated repression in the epigenetic regulation in developing brain cells.

2022-05-23 | GSE141587 | GEO

Landscape of ribosome-engaged alternative transcript isoforms across neuronal cell classes

Project description:The goal of this project was to assess how alternative splicing programs are arrayed across neuronal cells types. We systematically mapped ribosome-associated transcript isoforms in genetically-defined neuron types of the mouse forebrain. The endogenous ribosomal protein Rpl22 was conditionally HA-tagged in glutamatergic neurons (using CamK2-cre for most neocortical pyramidal cells and Scnn1a-cre for spiny stellate and star pyramid layer 4 cells), and GABAergic interneurons [with somatostatin-cre (SST), parvalbumin-cre (PV) and vasointestinal peptide-cre (VIP)]. Within the hippocampus, we further targeted Cornu ammonis 1 (CA1) neurons (CamK2-cre), CA3 neurons (Grik4-cre), and SST-positive interneurons (SST-cre). Four replicates were deep sequenced (~100 million reads) using an Illumina platform. We find that neuronal transcript isoform profiles reliably distinguish even closely-related classes of pyramidal cells and inhibitory interneurons in the mouse hippocampus and neocortex, positing transcript diversification by alternative splicing as a central mechanism for the functional specification of neuronal cell types and circuits.

2019-07-01 | GSE133291 | GEO

Transcriptomically-guided pharmacological experiments in neocortical and hippocampal NPY-positive GABAergic interneurons

Project description:Cortical GABAergic interneurons have been shown to fulfil important roles by inhibiting excitatory principal neurons. Recent transcriptomic studies have confirmed seminal discoveries that used anatomical and electrophysiological methods highlighting the existence of multiple different classes of GABAergic interneurons. However, individual studies have rarely addressed regional specific differences in gene expression in a given subclass of neuron. Using single-cell Patch-RNAseq, we characterised neuropeptide Y (NPY)-positive GABAergic interneurons in superficial layers of the primary auditory cortex and in distal layers of area CA3. We found that more than 300 genes are differentially expressed in NPY-positive neurons between these two brain regions. For example, the AMPA receptor auxiliary subunit Shisa9/CKAMP44 and the 5-HT2a receptor are significantly higher expressed in auditory NPY-positive neurons. These findings guided us to perform pharmacological experiments that revealed a role for 5-HT2a receptors in auditory NPY-positive neurons. Specifically, although the application of 5-HT led to a depolarisation of both auditory and CA3 NPY-positive neurons, the 5-HT2a receptor antagonist ketanserin only reversed membrane potential changes in auditory NPY-positive neurons. Our study demonstrates the potential of single-cell transcriptomic studies in guiding directed pharmacological experiments.

2022-04-20 | GSE193293 | GEO

Chronic stress causes striatal disinhibition mediated by SOM-interneurons

Project description:Chronic stress is a major triggering factor for neuropsychiatric disorders including obsessive-compulsive disorder (OCD), a mental health condition characterized by motor stereotypies and striatal overactivation. However, the mechanisms at the cell- and microcircuit-level through which stress triggers motor symptoms is currently unknown. Here, we report that chronic stress (CS) in mice alters dorsomedial striatum (DMS) function, by affecting GABAergic interneuron populations and somatostatin-positive (SOM) interneurons in particular. Specifically, we show that CS impairs communication between SOM interneurons and medium spiny neurons, promoting striatal overactivation / disinhibition and increased motor output. Using probabilistic machine learning for analyzing animal behavior we further demonstrate that in vivo chemogenetic manipulation of SOM interneurons in DMS modulates motor phenotypes in stressed mice. Altogether, we propose a causal link between dysfunction of striatal SOM interneurons and motor symptoms in stress-related neuropsychiatric disorders.

2022-12-13 | PXD031193 | Pride

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