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Cited by 156Neuropeptides and Animal PhysiologyNeuroscience and Neuropharmacology ResearchSingle-cell and spatial transcriptomics

Single-cell transcriptomic evidence for dense intracortical neuropeptide networks

Open access
Smith, Stephen J, Sümbül, Uygar, Graybuck, Lucas T, Collman, Forrest, Seshamani, Sharmishtaa, Gala, Rohan, Gliko, Olga, Elabbady, Leila +8 more·2019·eLife
DOI 10.7554/elife.47889PMC PMC6881117

Published version of a preprint

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Abstract

Seeking new insights into the homeostasis, modulation and plasticity of cortical synaptic networks, we have analyzed results from a single-cell RNA-seq study of 22,439 mouse neocortical neurons. Our analysis exposes transcriptomic evidence for dozens of molecularly distinct neuropeptidergic modulatory networks that directly interconnect all cortical neurons. This evidence begins with a discovery that transcripts of one or more neuropeptide precursor (NPP) and one or more neuropeptide-selective G-protein-coupled receptor (NP-GPCR) genes are highly abundant in all, or very nearly all, cortical neurons. Individual neurons express diverse subsets of NP signaling genes from palettes encoding 18 NPPs and 29 NP-GPCRs. These 47 genes comprise 37 cognate NPP/NP-GPCR pairs, implying the likelihood of local neuropeptide signaling. Here, we use neuron-type-specific patterns of NP gene expression to offer specific, testable predictions regarding 37 peptidergic neuromodulatory networks that may play prominent roles in cortical homeostasis and plasticity.

AI snapshot

Written from the paper’s full text.

TL;DR

This paper reanalyzes a published single-cell RNA-seq dataset of 22,439 mouse neocortical neurons and reports that nearly all cortical neurons express neuropeptide precursor and neuropeptide-receptor genes in highly cell-type-specific patterns. It predicts dozens of dense, locally interconnected peptidergic modulatory networks and argues these may be important for cortical homeostasis, modulation, and plasticity.

Key findings

  • Transcripts for at least one of 18 NPP genes were detected in 97% of sampled neurons at >1 CPM and in 80% at >1,000 CPM; transcripts for at least one of 29 cognate NP-GPCR genes were detected in 98% at >1 CPM and 78% at >100 CPM.
  • The 18 NPP and 29 NP-GPCR genes comprise 37 cognate NPP/NP-GPCR pairs, predicting 37 potentially distinct peptidergic networks; expression patterns were highly conserved between VISp and ALM (NPP fraction correlation ρ = 0.972, p<1.72E-11; NP-GPCR ρ = 0.959, p<2.2E-16).
  • The 47 neuropeptide-signaling genes classified neuron types with average resolution index (RI) = 0.925, significantly higher than random 47-gene subsets (0.641 ± 0.047, n = 100) and expression-matched random subsets (0.843 ± 0.027, n = 100).
  • Coupling matrices predicted dense tiling of neuron-type and subclass connectivity, with all four glutamatergic/GABAergic quadrants showing Gi/o, Gs, and Gq/11 signaling and substantial cross-network redundancy.

Methods

  • Secondary analysis of the Tasic et al. 2018 Allen Institute single-cell RNA-seq dataset: 22,439 isolated mouse cortical neurons, including 13,491 from VISp and 8,948 from ALM, with a median of 9,462 genes detected per cell.
  • Genes were selected as 18 NPPs and 29 cognate NP-GPCRs using expression thresholds, pFPKM ranking, and ligand/receptor pairing resources; expression was compared using CPM and FPKM units.
  • Autoencoder neural networks produced low-dimensional representations of gene expression, and Quadratic Discriminant Analysis with 13-fold cross-validation quantified neuron-type classification; peptidergic coupling matrices were computed as outer products of NPP and NP-GPCR expression across neuron types.

Limitations

  • The paper states that predictions from mRNA depend on assumptions about translation, processing, localization, functional protein status, neuropeptide diffusion and lifetime, and signaling consequences, and that these uncertainties remain substantial.
  • The sampled neuron population was enriched for GABAergic neurons (47% GABAergic, 53% glutamatergic) by design, so it is not a natural cortical proportion; the paper notes this enrichment.
  • The text notes that transcript detection is affected by pulsatile transcription and stochastic RNA-seq sampling, so expression percentages should be considered lower limits; it also states that the Gi/o, Gs, and Gq/11 trichotomy is an oversimplification and that NP-GPCR crosstalk is possible.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.7554/elife.47889

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 45 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Transcripts of one or more neuropeptide precursor (NPP) and one or more neuropeptide-selective G-protein-coupled receptor (NP-GPCR) genes are highly abundant in all, or very nearly all, cortical neurons.

    “This evidence begins with a discovery that transcripts of one or more neuropeptide precursor (NPP) and one or more neuropeptide-selective G-protein-coupled receptor (NP-GPCR) genes are highly abundant in all, or very nearly all, cortical neurons.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 22,439 neurons sampled from VISp and ALM are representative of all mouse neocortical neurons.
  • Findingown data

    Individual neurons express diverse subsets of NP signaling genes from palettes encoding 18 NPPs and 29 NP-GPCRs.

    “Individual neurons express diverse subsets of NP signaling genes from palettes encoding 18 NPPs and 29 NP-GPCRs.”
    Quote in the paperSubstantial claim
  • Findingown data

    Expression levels of most of the 18 NPP genes are extremely high in the range of values for all 21,931 protein-coding genes detected in all 22,439 neurons sampled.

    “The Peak FPKM ranking columns in Table 1 show that expression levels of most of the 18 NPP genes are extremely high in the range of values for all 21,931 protein-coding genes detected in all 22,439 neurons sampled.”
    Quote in the paperSubstantial claim
  • Findingown data

    The 47 NP signaling genes comprise 37 cognate NPP/NP-GPCR pairs.

    “These 47 genes comprise 37 cognate NPP/NP-GPCR pairs”
    Quote in the paperSubstantial claim
  • Findingown data

    Percentages of the sampled neuron population with detectible expression of a given NPP gene range from more than 65% for Cck down to ~1% for Nts.

    “Percentages of the sampled neuron population with detectible expression of a given NPP gene range from more than 65% for Cck down to ~1% for Nts.”
    Quote in the paperSubstantial claim
  • May combine two claims. 42
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 27

  • May combine two claims.

    Findingown data

    Eleven of the 18 NPP genes rank in the top percentile and all 18 rank in the top quintile by pFPKM.

    “Eleven of these NPP genes rank in the top percentile and all 18 rank in the top quintile by pFPKM.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Multiple NP-GPCR genes are co-expressed in almost all cortical neurons, and numbers of genes co-expressed are even higher than those noted for co-expression of NPP genes.

    “These data establish that multiple NP-GPCR genes are co-expressed in almost all cortical neurons and that numbers of genes co-expressed are even higher than those noted above for co-expression of NPP genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    97% of the sampled mouse cortical neurons express at least one NPP gene at >1 CPM and 80% express at least one NPP gene at >1,000 CPM.

    “97% of the sampled mouse cortical neurons express at least one NPP gene at >1 CPM and that 80% express at least one NPP gene at >1,000 CPM”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The RNA-seq data suggest that all, or at least very nearly all, neocortical neurons express at least one NP-GPCR gene.

    “The RNA-seq data suggest that all, or at least very nearly all, neocortical neurons express at least one NP-GPCR gene.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 22,439 neurons sampled from VISp and ALM are representative of all mouse neocortical neurons.

  • May combine two claims.

    Findingown data

    98% of the sampled mouse cortical neurons express at least one NP-GPCR gene at >1 CPM and 78% express at least one NP-GPCR gene at >100 CPM.

    “98% of the sampled mouse cortical neurons express at least one NP-GPCR gene at >1 CPM and that 78% express at least one NP-GPCR gene at >100 CPM”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Modal numbers of co-expressed NP-GPCR genes detected is six in both VISp and ALM with broad plateaus extending out to 12 co-expressed NP-GPCR genes per cell.

    “Modal numbers of co-expressed NP-GPCR genes detected is six in both VISp and ALM with broad plateaus extending out to 12 co-expressed NP-GPCR genes per cell.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Each of the 18 NPP genes exhibits a transition from high to very low (commonly zero) expression across the sampled neuron population, with transitions occurring over very different population percentile ranges, providing clear evidence for highly differential single-cell expression of these genes.

    “Each curve exhibits a transition from high to very low (commonly zero) expression across the sampled neuron population, but these transitions occur over very different population percentile ranges, providing clear evidence for highly differential single-cell expression of these genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The modal number of co-expressed NPP genes detected is two in VISp and five in ALM, with distributions flat between 2 and 5, broad plateaus out to seven co-expressed NPP genes per cell, and a substantial tail out to 10.

    “The modal number of co-expressed NPP genes detected is two in VISp and five in ALM, but both distributions are actually quite flat between 2 and 5, with broad plateaus out to seven co-expressed NPP genes per cell and a substantial tail out to 10.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The RNA-seq data suggest that all, or at least very nearly all, neocortical neurons express at least one NPP gene.

    “The RNA-seq data suggest that all, or at least very nearly all, neocortical neurons express at least one NPP gene.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 22,439 neurons sampled from VISp and ALM are representative of all mouse neocortical neurons.

  • May combine two claims.

    Findingown data

    A few coupling matrices (e.g., pairs 6 and 34) predict very sparse coupling, and other predictions are intermediate in sparsity.

    “A few matrices at the other extreme, such as 6 and 34, predict very sparse coupling. Other predictions are intermediate in sparsity.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Expression levels (CPM) of NPP and NP-GPCR genes can be multiplied to predict directed peptidergic coupling/signaling strength between neuron types.
    • Rests on an assumption: Neuropeptide diffusion distances allow any neuron within a local cortical area to signal to any other neuron within that same area, but almost surely not to more distant areas.

  • May combine two claims.

    Findingown data

    Many cases exist where both an NPP gene and its cognate NP-GPCR receptor are expressed in the same neuron type, with Cck/Cckbr and Adcyap1/Adcyap1r1 pairs being particularly prominent.

    “These two heatmaps further show many cases where both an NPP gene and its cognate NP-GPCR receptor are expressed in the same neuron type, with the Cck/Cckbr and Adcyap1/Adcyap1 r1 pairs being particularly prominent examples.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    NP-GPCR genes show greater relative variability than NPP genes, with mean CV = 0.427.

    “Similar for 29 NP-GPCR genes showing greater relative variability, mean CV = 0.427.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CPM expression levels vary across neuron types by factors exceeding 10,000 for many NPP genes and 1000 for many NP-GPCR genes.

    “Note that CPM expression levels vary across neuron types by factors exceeding 10,000 for many NPP genes and 1000 for many NP-GPCR genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The aggregate matrices show that the 37 cognate pairs cumulatively predict coupling that densely tiles the entire neuron-type coupling matrix, with the largest area of relatively weak coupling being from NP, CT and L6b subclasses to GABAergic neurons.

    “(1) The aggregate matrices show that the 37 cognate pairs cumulatively predict coupling that densely tiles the entire neuron-type coupling matrix, with the largest area of relatively weak coupling being that from NP, CT and L6b subclasses to GABAergic neurons.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Expression levels (CPM) of NPP and NP-GPCR genes can be multiplied to predict directed peptidergic coupling/signaling strength between neuron types.
    • The authors state this as an assumption: The trichotomous G-protein primary transduction family approximation is a useful first approximation for predicting signaling impacts.
    • Rests on an assumption: Neuropeptide diffusion distances allow any neuron within a local cortical area to signal to any other neuron within that same area, but almost surely not to more distant areas.

  • May combine two claims.

    Findingown data

    Expression of some genes tends to remain constant within some subclasses but changes abruptly at subclass boundaries, though this is not a very general case.

    “This delineation of subclasses shows that expression of some genes tends to remain constant within some subclasses, but to change abruptly at subclass boundaries. This does not seem, however, to be a very general case.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Each gene spans the entire pseudocolor range across neuron types, representing 5 orders of magnitude for NPP and 3 for NP-GPCR.

    “Note that these scales represent 5 (NPP) and 3 (NP-GPCR) orders of magnitude and that each gene spans the entire pseudocolor range across neuron types.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Gs signaling exhibits distinct zones of concentration, but these are not well captured by the quadrant structure.

    “Gs signaling exhibits distinct zone of concentration, but these are not well captured by the quadrant structure.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Expression levels (CPM) of NPP and NP-GPCR genes can be multiplied to predict directed peptidergic coupling/signaling strength between neuron types.
    • The authors state this as an assumption: The trichotomous G-protein primary transduction family approximation is a useful first approximation for predicting signaling impacts.
    • Rests on an assumption: Neuropeptide diffusion distances allow any neuron within a local cortical area to signal to any other neuron within that same area, but almost surely not to more distant areas.

  • May combine two claims.

    Findingown data

    The 47 NP genes can be used to classify neuron types well, with average RI = 0.925 and 62% of neurons classified correctly at the type level.

    “The 47 NP genes can be used to classify neuron types well, with average RI = 0.925 and a majority of the neurons (62%) classified correctly at the type level”
    • Also stated in: § Transcripts of 18 NPP and 29 NP-GPCR genes are exceptionally potent neuron-type markers · boosted
      “Transcripts of 18 NPP and 29 NP-GPCR genes are exceptionally potent neuron-type markers”
    • Also stated in: § Neurotaxonomic profiling of NPP and NP-GPCR gene expression · plain
      “Neurons can be clustered effectively based on just 47 NP genes (18 NPP and 29 NP-GPCR).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Gi/o signaling is the most heavily concentrated, with little signaling in the top two (E-E and E-I) quadrants but tiling the bottom two (I-E and I-I) quite thoroughly.

    “(5) As is particularly notable in the component matrix plots, Gi/o (red) signaling is the most heavily concentrated, with quite little signaling expressed in the top two (E-E and E-I) quadrants but tiling the bottom two (I-E and I-I) quite thoroughly.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Expression levels (CPM) of NPP and NP-GPCR genes can be multiplied to predict directed peptidergic coupling/signaling strength between neuron types.
    • The authors state this as an assumption: The trichotomous G-protein primary transduction family approximation is a useful first approximation for predicting signaling impacts.
    • Rests on an assumption: Neuropeptide diffusion distances allow any neuron within a local cortical area to signal to any other neuron within that same area, but almost surely not to more distant areas.

  • May combine two claims.

    Findingown data

    Within-subclass variation in CPM for NPP genes is a significant fraction of global variability, with mean within-subclass CV/global CV = 0.239.

    “Inset shows within-subclass CV/global CV demonstrating variation within subclasses is a significant fraction of global variability (dotted line mean = 0.239).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There is some family predominance within each quadrant: Gi/o in the E→E quadrant, Gs in the E→I quadrant, and Gi/o in the I→I and I→E quadrants.

    “(4) There is nonetheless some family predominance within each quadrant: Gi/o (blue) in the E→E quadrant, Gs (green) in the E→I quadrant, and Gi/o (red) in the I→I and I→E quadrants.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Expression levels (CPM) of NPP and NP-GPCR genes can be multiplied to predict directed peptidergic coupling/signaling strength between neuron types.
    • The authors state this as an assumption: The trichotomous G-protein primary transduction family approximation is a useful first approximation for predicting signaling impacts.
    • Rests on an assumption: Neuropeptide diffusion distances allow any neuron within a local cortical area to signal to any other neuron within that same area, but almost surely not to more distant areas.

  • May combine two claims.

    Findingown data

    Expression of each of the 47 NP genes (18 NPP and 29 NP-GPCR) is highly specific to particular neuron types, but the degree of type specificity varies greatly from gene to gene.

    “These heatmaps show that expression of every one of these 47 genes is highly specific to particular neuron types, but that type specificity varies greatly from gene to gene.”
    • Also stated in: § Neurotaxonomic profiling of NPP and NP-GPCR gene expression · plain
      “Neurotaxonomic heatmaps reveal highly neuron-type-specific expression of (A) 18 NPP and (B) 29 NP-GPCR genes in 22,439 individual neurons harvested from areas VISp and ALM.”
    • Also stated in: § Summary of findings · boosted
      “we find that patterns of differential expression of the 18 NPP and 29 NP-GPCR genes are very highly specific to neuron types as discerned from genome-wide transcriptomic analysis (Figure 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Each of the NPP and NP-GPCR genes is expressed in multiple neuron types, with Vipr2 in one Pvalb type as a near exception.

    “and that each of the NPP and NP-GPCR genes is expressed in multiple neuron types (with Vipr2 in one Pvalb type as a near exception).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NPP and NP-GPCR expression profiles are strongly conserved between VISp and ALM among common cell types, with NPP correlation ρ = 0.974 and NP-GPCR correlation ρ = 0.877 (both p<2.2e-16).

    “The general conservation of neuron-type-specific expression patterns among common cell types between the two distant neocortical areas (NPP correlation: ρ = 0.974, p<2.2e-16, NP-GPCR: 0.877, p<2.2e-16)”
    • Also stated in: § Conservation of NPP and NP-GPCR gene expression profiles between VISp and ALM · boosted
      “Neurotaxonomic heatmaps show strong conservation of NPP and NP-GPCR expression patterns between two distant neocortical areas.”
    • Also stated in: § Summary of findings · boosted
      “Our analysis shows that very intricate single-cell (Figures 1B,C and 2B,C) and neurotaxonomic (Figure 5) patterns of expression of 18 NPP and 29 cognate NP-GPCR genes are very rigorously conserved between VISp and ALM, two distant and quite different areas of neocortex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    This work has revealed a surprisingly highly structured and abundant expression of cortical NPP and NP-GPCR genes: dozens of neuropeptide signaling genes are expressed at very high levels in very distinctive and highly conserved patterns.

    “This work has revealed a surprisingly highly structured and abundant expression of cortical NPP and NP-GPCR genes: dozens of neuropeptide signaling genes are expressed at very high levels in very distinctive and highly conserved patterns.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The 18 select NPP genes include all but two (Edn3 and Gal) genes for which transcripts ranked in the top quintile by pFPKM of the 94 putative NPP genes.

    “The 18 select NPP genes include all but two (Edn3 and Gal) genes for which transcripts ranked in the top quintile by pFPKM of the 94 putative NPP genes as tabulated in Supplementary file 3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Screening 94 putative mouse NPP genes for median CPM >10 in one or more neuron type in VISp and ALM cortex resulted in 39 NPP genes, with observed range 24-4100 CPM.

    “These 94 NPP genes were further segregated using a preliminary (early 2018) version of the Tasic 2018 neurotaxonomy to select NPP genes exhibiting median CPM expression levels > 10 in one or more neuron type in VISp and ALM cortex. This screening resulted in the list of 39 such NPP genes represented in Supplementary file 4, with most exceeding the 10 CPM threshold by a large margin (observed range”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Primary effects of NP-GPCRs expressed in cortex fall into just three major categories distinguished by G-protein alpha subunit (Gα) family: Gi/o inhibits cAMP production, Gs stimulates cAMP production, and Gq/11 amplifies calcium signaling dynamics.

    “Primary effects of NP-GPCRs expressed in cortex, in turn, fall into just three major categories distinguished by G-protein alpha subunit (Gα) family. The Gi/o family (i/o) inhibits cAMP production, the Gs family (s) stimulates cAMP production, and the Gq/11 family (q/11) amplifies calcium signaling dynamics”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Syrovatkina et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Eventual degradation by interstitial peptidases probably restricts diffusion of most neuropeptides to sub-millimeter, local circuit distance scales.

    “Though present information is limited, eventual degradation by interstitial peptidases nonetheless probably restricts diffusion of most neuropeptides to sub-millimeter, local circuit distance scales.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Peak FPKM values for NP-GPCR transcripts are quite high in the range of transcripts of other durable cellular component genes, suggesting a strong likelihood that they are indeed translated into functionally important protein products.

    “Peak FPKM values for NP-GPCR transcripts are nonetheless quite high in the range of transcripts of other durable cellular component genes, suggesting a strong likelihood that they are indeed translated into functionally important protein products.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    By far the largest family of neuromodulator molecules known comprises the evolutionarily ancient proteinaceous signaling molecules known as neuropeptides.

    “By far the largest family of neuromodulator molecules known, however, comprises the evolutionarily ancient proteinaceous signaling molecules known as neuropeptides”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Baraban and Tallent, 2004 source

      Not checked in the free run.

    • cites Burbach, 2011 source

      Not checked in the free run.

    • cites Gonzalez-Suarez and Nitabach, 2018

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Secreted neuropeptides are thought to persist long enough (e.g., minutes) in brain interstitial spaces for diffusion to very-high-affinity NP-GPCRs hundreds of micrometers distant from release sites.

    “secreted neuropeptides are thought to persist long enough (e.g., minutes) in brain interstitial spaces for diffusion to very-high-affinity NP-GPCRs hundreds of micrometers distant from release sites”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ludwig and Leng, 2006 source

      Not checked in the free run.

    • cites Nässel, 2009 source

      Not checked in the free run.

    • cites Russo, 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Neuropeptide signaling can be presumed both paracrine and relatively slow (seconds-to-minutes timescale of action).

    “Neuropeptide signaling can thus be presumed both ‘paracrine’, with secretion from individual neurons hitting receptor-positive cells over substantial diffusion distances and converging by diffusion from many local secreting neurons onto single receptor-positive neurons, and to be relatively slow (seconds-to-minutes timescale of action).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Most neuropeptide receptors are encoded by members of the very large superfamily of G-protein-coupled receptor (GPCR) genes.

    “Most neuropeptide receptors are encoded by members of the very large superfamily of G-protein-coupled receptor (GPCR) genes”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hoyer and Bartfai, 2012

      Not checked in the free run.

    • cites Krishnan and Schiöth, 2015

      Not checked in the free run.

    • cites Mains and Eipper, 2006

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In situ hybridization and microarray data, for example the Allen Brain Atlases, have established that mRNA transcripts encoding these five NPPs and that many other NPPs and NP-GPCR genes are expressed differentially in many brain regions.

    “In situ hybridization and microarray data, for example the Allen Brain Atlases (Hawrylycz et al., 2012; Lein et al., 2007), have also established that mRNA transcripts encoding these five NPPs and that many other NPPs and NP-GPCR genes are expressed differentially in many brain regions.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hawrylycz et al., 2012 source

      Not checked in the free run.

    • cites Lein et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    For most NP-GPCR genes, the primary Gα family is now known and offers a good first-order prediction of the encoded GPCR's signal transducing action.

    “For most NP-GPCR genes, the primary Gα family (e.g., i/o, s or q/11) is now known (Alexander et al., 2017) and offers a good first-order prediction of the encoded GPCR’s signal transducing action.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Alexander et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Conservation of NPP expression fractions across VISp and ALM suggests that these patterns have strong connections to conserved features of cortical function and argues against these patterns being secondary to more ephemeral variables such as neuronal activity patterns.

    “Conservation of expression fractions across so many genes in such divergent cortical areas suggests that these patterns have strong connections to conserved features of cortical function and argues against these patterns being secondary to more ephemeral variables such as neuronal activity patterns”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Certain neuropeptides, including VIP, SST, NPY, substance P, and CCK, are detectible at high levels in particular subsets of GABAergic cortical neurons.

    “It is well established that certain neuropeptides, including vasoactive intestinal peptide (VIP), somatostatin (SST), neuropeptide Y (NPY), substance P, and cholecystokinin (CCK), are detectible at high levels in particular subsets of GABAergic cortical neurons (Tremblay et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tremblay et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The near match of the 47 NP gene set to the 47 DE gene set in average RI is striking because the 47 DE genes were chosen with prior knowledge of the Tasic 2018 taxonomy while the 47 NP gene set was not.

    “Note that genes in the 47 DE set were chosen with prior knowledge of the Tasic 2018 taxonomy, while the 47 NP gene set was not. This distinction thus makes the near match of the 47 NP to the 47 DE gene sets in average RI all the more striking.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Most cortical glutamatergic neurons have locally ramifying axon branches and may secrete neuropeptides from their local dendritic arbors.

    “Even so, most cortical glutamatergic neurons also have locally ramifying axon branches and may also secrete neuropeptides from their local dendritic arbors (Vila-Porcile et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vila-Porcile et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Brisk synthesis of precursor proteins suggests brisk processing to active neuropeptide products and secretion of these products.

    “Brisk synthesis of precursor proteins further suggests brisk processing to active neuropeptide products and secretion of these products.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: mRNA transcript abundance is a reliable proxy for protein abundance and functional signaling.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationown data

    The differential expression of NPP genes in GABAergic over glutamatergic types is consistent with the long history of using neuropeptide products as protein markers of GABAergic neuron subsets, which has no parallel in glutamatergic subsets.

    “This differential is consistent with a long history of neuroscientific use of neuropeptide products as protein markers of GABAergic neuron subsets (e.g., VIP, SST, NPY, Substance P), which has no parallel in the marking of glutamatergic neuron subsets.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Expected neuropeptide diffusion distances suggest that any neuron within a local cortical area (e.g., VISp or ALM) might signal by diffusion to any other neuron within that same local area, but almost surely not to more distant areas.

    “As noted in the Introduction, expected neuropeptide diffusion distances suggest that any neuron within a local cortical area (e.g., VISp or ALM) might signal by diffusion to any other neuron within that same local area, but almost surely not to more distant areas (e.g., from VISp to ALM).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    All, or very nearly all, neocortical neurons, both glutamatergic and GABAergic, are both neuropeptidergic and modulated by neuropeptides.

    “Our observations thus support the proposition that all, or very nearly all, neocortical neurons, both glutamatergic and GABAergic, are also both neuropeptidergic and modulated by neuropeptides.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: mRNA transcript abundance is a reliable proxy for protein abundance and functional signaling.

  • May combine two claims.

    Interpretationown data

    The present set of 47 cortical NP genes comprises 37 distinct cognate NPP/NP-GPCR pairs and predicts 37 distinct peptidergic neuromodulation networks.

    “The present set of 47 cortical NP genes (18 NPP and 29 NP-GPCR) comprises the 37 distinct cognate NPP/NP-GPCR pairs enumerated in Table 3 and predicts accordingly 37 distinct peptidergic neuromodulation networks.”
    • Also stated in: § Prediction of local peptidergic signaling from expression of cognate NPP/NP-GPCR pairs · hedged
      “The 18 NPP and 29 NP-GPCR genes of Tables 1 and 2 constitute 37 cognate NPP/NP-GPCR pairs and predict at least 37 potentially distinct peptidergic modulatory networks.”
    • Also stated in: § Prediction of peptidergic networks from neurotaxonomic NP gene expression profiles · plain
      “Neurotaxonomic expression profiles of 37 cognate NPP/NP-GPCR pairs predict 37 peptidergic networks.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Expression levels (CPM) of NPP and NP-GPCR genes can be multiplied to predict directed peptidergic coupling/signaling strength between neuron types.
    • Rests on an assumption: Neuropeptide diffusion distances allow any neuron within a local cortical area to signal to any other neuron within that same area, but almost surely not to more distant areas.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Neuropeptides secreted from glutamatergic neurons may act in remote cortical or extracortical projection target areas.

    “On the other hand, most of the glutamatergic neurons do emit long axons, so it is possible that neuropeptides secreted from such neurons may act in remote cortical or extracortical projection target areas.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Neuropeptide diffusion and lifetime in cortical interstitial spaces are adequately approximated by the study's assumptions.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Published physiological results on cortical neuropeptide signaling are surprisingly rare given the breadth of neuroscientific interest in cortex.

    “published physiological results are surprisingly rare given the breadth of neuroscientific interest in cortex.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Crawley, 1985 source

      Not checked in the free run.

    • cites Férézou et al., 2007 source

      Not checked in the free run.

    • cites Gallopin et al., 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    NP-GPCRs could play roles in credit assignment analogous to those postulated for dopamine-selective GPCRs.

    “commonalities of signal transduction downstream from widely varying GPCRs suggest that NP-GPCRs could play roles in credit assignment analogous to those postulated for dopamine-selective GPCRs (Hamilton et al., 2013; Roelfsema and Holtmaat, 2018; but see Edelmann and Lessmann, 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hamilton et al., 2013 source

      Not checked in the free run.

    • cites Roelfsema and Holtmaat, 2018

      Not checked in the free run.

    • cites Edelmann and Lessmann, 2011

      Not checked in the free run.

    • The authors state this as an assumption: Signaling consequences of neuropeptide binding to cortical NP-GPCR receptors are adequately approximated by the study's assumptions.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductreasoning

    The uncertainties in the predictions remain substantial.

    “Though we have already discussed several factors that mitigate such concerns, we stipulate here that these uncertainties remain substantial.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Expression of NPP and NP-GPCR mRNA transcripts predicts functional peptidergic modulatory connections.
    • The authors state this as an assumption: Neuropeptide diffusion and lifetime in cortical interstitial spaces are adequately approximated by the study's assumptions.
    • The authors state this as an assumption: Signaling consequences of neuropeptide binding to cortical NP-GPCR receptors are adequately approximated by the study's assumptions.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GPCRs have long been known as among the most druggable of targets, and their druggability is currently advancing rapidly due to advances in GPCR structural biology and molecular dynamic simulations.

    “Moreover, while GPCRs have long been known as among the most ‘druggable’ of targets (Gurrath, 2001; Lundstrom, 2009), the ‘druggability’ of GPCRs is currently advancing very rapidly due to advances in GPCR structural biology and molecular dynamic simulations (Hilger et al., 2018; Koehl et al., 2018; Weis and Kobilka, 2018).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gurrath, 2001 source

      Not checked in the free run.

    • cites Lundstrom, 2009 source

      Not checked in the free run.

    • cites Hilger et al., 2018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The sampled neuron population is roughly half GABAergic (47%) and half glutamatergic (53%) due to enrichment by design.

    “This enrichment procedure resulted, by design, in a disproportionate representation of GABAergic neurons, canonically ~20% of neurons (Sahara et al., 2012), such that the sampled neuron population is roughly half GABAergic (47%) and half glutamatergic (53%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sahara et al., 2012 source

      Not checked in the free run.

    • Rests on an assumption: The disproportionate GABAergic representation in the sampled neuron population does not invalidate inferences about cortical neuron types.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Greater neuron-type-specificity may translate to NP-targeting drugs being less troubled by side-effects and compensation.

    “Greater neuron-type-specificity may translate to NP-targeting drugs being less troubled by side-effects and compensation (Hoyer and Bartfai, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoyer and Bartfai, 2012

      Not checked in the free run.

    • Rests on an assumption: Expression of NPP and NP-GPCR mRNA transcripts predicts functional peptidergic modulatory connections.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    New knowledge of neuron-type-specificity of NP signaling gene expression will substantially advance development of NP-targeting pharmaceuticals.

    “It seems likely that new knowledge of the neuron-type-specificity of NP signaling gene expression will substantially advance the development of NP-targeting pharmaceuticals.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Expression of NPP and NP-GPCR mRNA transcripts predicts functional peptidergic modulatory connections.

  • Classified as probably not a substantial claim.

    Premisecitation

    The neurotaxonomy of Tasic et al. (2018) defines hierarchical relationships of neuronal cell types.

    “The neurotaxonomy of Tasic et al. (2018) defines hierarchical relationships of neuronal cell types.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tasic et al., 2018

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The study relied on the reasonably exhaustive list of 96 classical and candidate human and mouse NPP genes from Burbach 2010.

    “For the purposes of the present work, we have relied therefore on the reasonably exhaustive list of 96 classical and candidate human and mouse NPP genes put forth in a widely cited publication (Burbach, 2010) and related website (http://neuropeptides.nl/, last accessed 10 October 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Burbach, 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The matching of NP-GPCR and NPP genes neglects a few receptor/ligand pairings rated as very low affinity compared to primary pairings.

    “The matching of NP-GPCR and NPP genes in Table 2 neglects a few receptor/ligand pairings rated on the IUPHAR/BPS website as very low in affinity compared to primary pairings.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The present study raises the possibility that NP-targeted drug discovery and reproducibility of physiological experimentation have been hindered by the same uncharted multiplicity, cell-type-specificity and redundancy of NPP and NP-GPCR expression.

    “The present study raises the possibility that both NP-targeted drug discovery and the reproducibility of physiological experimentation have been hindered by the same uncharted multiplicity, cell-type-specificity and redundancy of NPP and NP-GPCR expression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Expression of NPP and NP-GPCR mRNA transcripts predicts functional peptidergic modulatory connections.

  • Classified as probably not a substantial claim.

    Premisecitation

    Today's psychiatric pharmaceuticals almost all target signaling by monoamine neuromodulators dopamine, serotonin, noradrenaline and/or histamine and their selective GPCR receptors.

    “Today’s psychiatric pharmaceuticals almost all target signaling by the monoamine neuromodulators dopamine, serotonin, noradrenaline and/or histamine and their selective GPCR receptors (Data-Franco et al., 2017; Hamon and Blier, 2013; Millan et al., 2015; Urs et al., 2014).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Data-Franco et al., 2017 source

      Not checked in the free run.

    • cites Hamon and Blier, 2013

      Not checked in the free run.

    • cites Millan et al., 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Single-neuron transcriptomic analysis may improve the odds substantially for both reproducible research and psychiatric drug development.

    “By charting these waters, single-neuron transcriptomic analysis may improve the odds substantially for both reproducible research and psychiatric drug development.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Expression of NPP and NP-GPCR mRNA transcripts predicts functional peptidergic modulatory connections.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    A more realistic materialization of the Figure 8 schematic would involve approximately 100 neuron types and dozens of NPP and NP-GPCR genes.

    “The present analysis suggests that a more realistic materialization of the Figure 8 schematic would involve approximately 100 neuron types and dozens of NPP and NP-GPCR genes.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Expression of NPP and NP-GPCR mRNA transcripts predicts functional peptidergic modulatory connections.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The procedure for assigning resolution index was performed using 13-fold cross validation for all gene sets, and results were pooled.

    “This procedure was performed using 13 fold cross validation for all the different gene sets, and the results were pooled.”
    Quote in the paperNot a substantial claim
61 of 61

  • The paper relies on this without support.

    The 22,439 neurons sampled from VISp and ALM are representative of all mouse neocortical neurons.

    “Neurons were sampled from two distant and very different neocortical areas: 13,491 neurons from primary visual cortex (VISp), and 8948 neurons from anterior lateral motor cortex (ALM).”

  • The paper relies on this without support.

    The Tasic 2018 neurotaxonomy accurately represents mouse neocortical neuron types.

    “all further references here to neuron ‘class’, ‘subclass’ or ‘type’ should be understood to refer specifically to the particular mouse neocortex neurotaxonomy described in the Tasic 2018 publication.”

  • The paper relies on this without support.

    Choice of CPM vs. FPKM units has very little impact on the present outcomes.

    “In any case, choice of CPM vs. FPKM units would have very little impact on the present outcomes.”

  • The paper relies on this without support.

    Very high abundance of a given protein-coding transcript implies the potential for a very high rate of synthesis of the encoded protein.

    “To the simplest first approximation, very high abundance of a given protein-coding transcript implies the potential, at least, for a very high rate of synthesis of the encoded protein.”

  • The paper relies on this without support.

    In a steady state, a high rate of synthesis implies a correspondingly high overall rate of protein product elimination.

    “In a steady state, a high rate of synthesis would then necessarily imply a correspondingly high overall rate of protein product elimination.”

  • The paper relies on this without support.

    For an NP precursor protein, processing and secretion of active neuropeptide is the obvious and most likely route of elimination.

    “For an NP precursor protein, processing and secretion of active neuropeptide would seem the obvious and most likely route of elimination.”

  • The paper relies on this without support.

    mRNA transcript abundance is a reliable proxy for protein abundance and functional signaling.

    “Our observations thus support the proposition that all, or very nearly all, neocortical neurons, both glutamatergic and GABAergic, are also both neuropeptidergic and modulated by neuropeptides.”

  • The paper relies on this without support.

    Expression levels (CPM) of NPP and NP-GPCR genes can be multiplied to predict directed peptidergic coupling/signaling strength between neuron types.

    “The prediction matrices A-E are outer products (CPM*CPM units) of vectors representing expression (CPM units) of an NPP gene (columns) and a cognate NP-GPCR gene (rows) across all VISp or ALM neuron types.”

  • The authors state this as an assumption.

    The trichotomous G-protein primary transduction family approximation is a useful first approximation for predicting signaling impacts.

    “Such trichotomy is certainly an oversimplification, as it is known that downstream GPCR signal transduction is richly multifaceted (Weis and Kobilka, 2018) and that some GPCRs may signal via members of multiple Gα families, but we postulate here that this simplified scheme may nonetheless offer a first approximation useful for the design of exploratory experimentation and theory.”

  • The paper relies on this without support.

    Neuropeptide diffusion distances allow any neuron within a local cortical area to signal to any other neuron within that same area, but almost surely not to more distant areas.

    “As noted in the Introduction, expected neuropeptide diffusion distances suggest that any neuron within a local cortical area (e.g., VISp or ALM) might signal by diffusion to any other neuron within that same local area, but almost surely not to more distant areas (e.g., from VISp to ALM).”

  • The paper relies on this without support.

    Expression of NPP and NP-GPCR mRNA transcripts predicts functional peptidergic modulatory connections.

    “The present predictions regrading cortical neuropeptidergic coupling are based on detection of cellular mRNA transcripts, but prediction from such data depends upon (1) extrapolation from cellular mRNA census to inference about rates of synthesis, processing, localization and functional status of cellular NPP and NP-GPCR proteins”

  • The authors state this as an assumption.

    Neuropeptide diffusion and lifetime in cortical interstitial spaces are adequately approximated by the study's assumptions.

    “(2) assumptions about neuropeptide diffusion and lifetime in cortical interstitial spaces”

  • The authors state this as an assumption.

    Signaling consequences of neuropeptide binding to cortical NP-GPCR receptors are adequately approximated by the study's assumptions.

    “(3) assumptions about signaling consequences of neuropeptide binding to cortical NP-GPCR receptors.”

  • The paper relies on this without support.

    NP-GPCR selectivity for particular peptide moieties is not perfect, so concentration-dependent crosstalk between nominally separate peptidergic networks is possible.

    “It is also good to keep in mind, however, that the selectivity of NP-GPCRs for particular peptide moieties is not perfect. Various kinds of concentration-dependent ‘crosstalk’ between nominally separate peptidergic networks are therefore possible.”

  • The paper relies on this without support.

    The disproportionate GABAergic representation in the sampled neuron population does not invalidate inferences about cortical neuron types.

    “This enrichment procedure resulted, by design, in a disproportionate representation of GABAergic neurons, canonically ~20% of neurons (Sahara et al., 2012), such that the sampled neuron population is roughly half GABAergic (47%) and half glutamatergic (53%).”
15 of 15

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Single-cell sequencing studies in the brain have shown that neuron types with the genetic constituents required for releasing more than one neurotransmitter are ubiquitous.

    “These studies have also shown the ubiquity of neuron types that have the genetic constituents required for the release of more than one neurotransmitter.6,7,9,40,131”

    From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [7]

  • Most analyses in these single-cell sequencing studies are performed on populations of neurons.

    “An important caveat to these findings is that most analyses performed in these studies are performed on populations of neurons.”

    From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [7]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Gi/o signaling is assigned the wrong color in the E→E conclusion

    Minor

    The paper defines red as the Gi/o channel and blue as the Gq/11 channel, but its interpretation of the E→E quadrant calls Gi/o blue. This changes which signaling family the stated quadrant pattern describes.

  • Table 2 lists a cognate pair omitted from the 37-pair account

    Minor

    Table 2 lists Vip as cognate to Adcyap1r1, whereas Table 1 lists only Vipr1 and Vipr2 as Vip's cognate receptors. The stated total of 37 pairs enumerated in Table 3 also omits Vip→Adcyap1r1, so the tables disagree about a pair underlying the network count.

  • Figure 7 aggregation steps are given in opposite orders

    Minor

    The results say individual coupling matrices are log-scaled and normalized before summation into color channels. The methods instead say matrices are summed before log scaling and normalization; these operations generally produce different maps.

  • Figure 8 panel assignments conflict with its caption

    Minor

    The discussion assigns integration of modulatory and synaptic networks to panel D and describes E and F as synaptic-network panels. The figure caption instead assigns synaptic matrices to D, synaptic graphs to E, and the integrated multigraph to F.

4 of 4

The citation lists haven’t been fetched yet

References 163 · Cited by 156

Authors
Smith, S. J., Sümbül, U., Graybuck, L. T., Collman, F., Seshamani, S., Gala, R., Gliko, O., Elabbady, L., Miller, J. A., Bakken, T. E., Rossier, J., Yao, Z., Lein, E., Zeng, H., Tasic, B., & Hawrylycz, M.
Affiliations
Allen Institute for Brain Science (US)
Corresponding author
  • Smith, Stephen J
  • Hawrylycz, Michael
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2019-11-11
Volume
8
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.47889
PMC
PMC6881117
OpenAlex
W2984612860
Semantic Scholar
326280a9ef61f241ea260c576665f4107977a334
Cited by
156
References
163
Citations by year
2026: 16 · 2025: 22 · 2024: 25 · 2023: 39 · 2022: 20 · 2021: 25 · 2020: 8 · 2019: 1
FWCI
6.45
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (R01NS092474, R01MH104227, 1U24NS109113)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
neuropeptides, neocortical neurons, synaptic plasticity, mouse neocortex
MeSH terms
Animals, Homeostasis, Neuronal Plasticity, Neurons, Neuropeptides, Protein Precursors, Visual Cortex, Signal Transduction, Neocortex, Gene Expression Profiling, Receptors, G-Protein-Coupled, Mice, Gene Regulatory Networks, Single-Cell Analysis

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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