Mimicking opioid analgesia in cortical pain circuits

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 29, 2024

The anterior cingulate cortex plays a pivotal role in the cognitive and affective aspects of pain perception. Both endogenous exogenous opioid signaling within mitigate cortical nociception, reducing unpleasantness. However, specific functional molecular identities cells mediating analgesia remain elusive. Given complexity as sensory emotional experience, richness ethological pain-related behaviors, we developed standardized, deep-learning platform for deconstructing behavior dynamics associated with component mice-LUPE (Light aUtomated Pain Evaluator). LUPE removes human bias quantification accelerated analysis from weeks to hours, which leveraged discover that morphine altered attentional motivational behaviors akin humans. Through activity-dependent genetics single-nuclei RNA sequencing, identified ensembles nociceptive neuron-types expressing mu-opioid receptors. Tuning receptor expression these bidirectionally modulated analgesia. Moreover, employed synthetic promoter-driven approach cell-type optical chemical genetic viral therapies mimic morphine's pain-relieving effects cingulate, without reinforcement. This offers novel strategy precision management by targeting key circuit on-demand, non-addictive, effective

Language: Английский

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Opportunities and challenges of single-cell and spatially resolved genomics methods for neuroscience discovery

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(12), P. 2292 - 2309

Published: Dec. 1, 2024

Language: Английский

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Whole-cortex in situ sequencing reveals peripheral input-dependent cell type-defined area identity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Nov. 6, 2022

Abstract The cortex is composed of neuronal types with diverse gene expression that are organized into specialized cortical areas. These areas, each characteristic cytoarchitecture (Brodmann 1909; Vogt and 1919; Von Bonin 1947), connectivity (Zingg et al. 2014; Harris 2019), activity (Schwarz 2008; Ferrarini 2009; He Meunier 2010; Bertolero 2015), wired modular networks 2019; Huang 2020). However, it remains unclear whether areas their organization can be similarly defined by transcriptomic signatures how such established in development. Here we used BARseq, a high-throughput situ sequencing technique, to interrogate the 104 cell type marker genes 10.3 million cells, including 4,194,658 neurons over nine mouse forebrain hemispheres at cellular resolution. De novo clustering single revealed were consistent previous single-cell RNAseq studies(Yao 2021a; Yao 2021b). Gene distribution fine-grained vary along contours composition highly predictive area identity. Moreover, similar compositions types, which as modules, overlap connected, suggesting same reflected both connectivity. To explore profiles depend on development, compared distributions after neonatal binocular enucleation. Strikingly, enucleation caused compositional visual shift towards neighboring within module, peripheral inputs sharpen distinct identities modules. Enabled high-throughput, low-cost, reproducibility our study provides proof-of-principle for using large-scale reveal brain-wide molecular architecture understand its

Language: Английский

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Continuous cell type diversification throughout the embryonic and postnatal mouse visual cortex development

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 6, 2024

The mammalian cortex is composed of a highly diverse set cell types and develops through series temporally regulated events that build out the type circuit foundation for cortical function. mechanisms underlying development different remain elusive. Single-cell transcriptomics provides capacity to systematically study across entire temporal range development. Here, we present comprehensive high-resolution transcriptomic epigenomic atlas developing mouse visual cortex. was built from single-cell RNA-sequencing dataset 568,674 high-quality transcriptomes single-nucleus Multiome 194,545 nuclei providing both chromatin accessibility profiles, densely sampled throughout embryonic postnatal developmental stages E11.5 P56. We computationally reconstructed trajectory map all excitatory, inhibitory, non-neuronal in cortex, identifying branching points marking emergence new at specific ages defining molecular signatures cellular diversification. In addition neurogenesis, gliogenesis early postmitotic maturation stage which gives rise classes nearly subclasses, find increasingly refined emerge differentiation process, including late many during eye-opening (P11-P14) onset critical period (P21), suggesting continuous diversification Throughout development, cooperative dynamic changes gene expression types, peaks potentially regulating genes transcription factors peaks. Furthermore, single can be by multiple associated with and/or stages. Collectively, our most detailed directly individual reveals logic refinement identities

Language: Английский

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Implementation and validation of single-cell genomics experiments in neuroscience

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(12), P. 2310 - 2325

Published: Dec. 1, 2024

Language: Английский

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