Transcriptomic Cell Type Specificity of Local Cortical Circuits
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PROVIDER: PRJNA1086941 | ENA |
REPOSITORIES: ENA
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Project description:The complex functions of the neocortex rely on networks of interconnected excitatory and inhibitory interneurons, each of which are composed of multiple neuron types. Prior studies have established rules of local connectivity between major subclasses of inhibitory and excitatory cortical neurons, but the advent of single-cell transcriptomic technologies has revealed a remarkable diversity in transcriptomic neuronal subtypes. Is there specificity of synaptic connections between cortical neurons classified at the level of transcriptomic subtypes, as might be expected if the different types mediate different functions? Here we present a novel method that links transcriptomic cell type to anatomical connectivity, “Single Transcriptome Assisted Rabies Tracing” (START). START combines monosynaptic rabies tracing and single-nuclei RNA sequencing (snRNA-seq) to identify the transcriptomic cell types providing monosynaptic inputs to defined populations of neurons. We employed START in conjunction with Cre driver mouse lines to transcriptomically characterize 35,717 neurons providing monosynaptic input to 5 different layer-specific excitatory cortical neuron populations in mouse V1. At the subclass level, we observed results consistent with findings from prior studies that resolve neuronal subclasses using antibody staining, Cre-expressing mouse lines, or morphological characterization. With improved neuronal subtype granularity achieved with START, we demonstrate transcriptomic subtype specificity of inhibitory inputs to various subclasses of excitatory neurons. These results establish local connectivity rules at the resolution of transcriptomic inhibitory cell types.
2024-09-19 | GSE261436 | GEO
Project description:Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits
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Project description:How neuronal connections are established and organized in functional networks determines brain function. In the mouse cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made parsing interneuron diversity, yet the molecular mechanisms by which interneuron subtype-specific connectivity motifs emerge remain unclear. Here we investigate transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits. We found that whether the interneurons synapse with pyramidal neurons on their dendrites, soma, or axon initial segment is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.
2019-01-25 | GSE120161 | GEO
Project description:Cortical wiring by synapse type-specific control of local protein synthesis
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Project description:Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. Here we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy.
2021-02-22 | GSE161654 | GEO
Project description:Most cortical synapses are local and excitatory. Local recurrent circuits could implement amplification, allowing pattern completion and other computations1-4. Cortical circuits contain subnetworks that consist of neurons with similar receptive fields and increased connectivity relative to the network average5,6. Cortical neurons that encode different types of information are spatially intermingled and distributed over large brain volumes5-7, and this complexity has hindered attempts to probe the function of these subnetworks by perturbing them individually8. Here we use computational modelling, optical recordings and manipulations to probe the function of recurrent coupling in layer 2/3 of the mouse vibrissal somatosensory cortex during active tactile discrimination. A neural circuit model of layer 2/3 revealed that recurrent excitation enhances sensory signals by amplification, but only for subnetworks with increased connectivity. Model networks with high amplification were sensitive to damage: loss of a few members of the subnetwork degraded stimulus encoding. We tested this prediction by mapping neuronal selectivity7 and photoablating9,10 neurons with specific selectivity. Ablation of a small proportion of layer 2/3 neurons (10-20, less than 5% of the total) representing touch markedly reduced responses in the spared touch representation, but not in other representations. Ablations most strongly affected neurons with stimulus responses that were similar to those of the ablated population, which is also consistent with network models. Recurrence among cortical neurons with similar selectivity therefore drives input-specific amplification during behaviour.
| S-EPMC8092186 | biostudies-literature
Project description:Cortical interneurons display a remarkable diversity in their morphology, physiological properties and connectivity. Elucidating the molecular determinants underlying this heterogeneity is essential for understanding interneuron development and function. We discovered that alternative splicing differentially regulates the integration of somatostatin- and parvalbumin-expressing interneurons into nascent cortical circuits through the cell-type specific tailoring of mRNAs. Specifically, we identified a role for the activity-dependent splicing regulator Rbfox1 in the development of cortical interneuron subtype specific efferent connectivity. Our work demonstrates that Rbfox1 mediates largely non-overlapping alternative splicing programs within two distinct but related classes of interneurons.
2018-10-12 | GSE119998 | GEO
Project description:Neurons use local protein synthesis to support their morphological complexity, which requires independent control across multiple subcellular compartments up to the level of individual synapses. Here we identify a signaling pathway that regulates the local synthesis of proteins required to form excitatory synapses on parvalbumin-expressing (PV+) interneurons in the mouse cerebral cortex. This process involves regulation of the TSC subunit 2 (Tsc2) by the Erb-B2 receptor tyrosine kinase 4 (ErbB4), which enables local control of mRNA translation in a cell type-specific and synapse type-specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins downstream of ErbB4 signaling required to form excitatory inputs on PV+ interneurons. Thus, specific connections use local protein synthesis to control synapse formation in the nervous system.
2022-11-24 | GSE214258 | GEO
Project description:Local calcium accumulations promote phagocyte-mediated synapse removal in cortical neuroinflammation
| PRJNA679032 | ENA