The diversity of GABAergic neurons and neural communication elements

Probably not a substantial claim: may not pass S2 (checkable).

Deciphering the logic of interneuron diversity requires comprehensive analysis of multi-modal cell features and a framework of neuronal identity that reflects biological mechanisms and principles.

“Deciphering the logic of this diversity requires comprehensive analysis of multi-modal cell features and a framework of neuronal identity that reflects biological mechanisms and principles.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

The phenotypic diversity of cortical GABAergic neurons is probably necessary for their functional versatility in shaping spatiotemporal dynamics of neural circuit operations underlying cognition.

“The phenotypic diversity of cortical GABAergic neurons is probably necessary for their functional versatility in shaping the spatiotemporal dynamics of neural circuit operations underlying cognition.”

Probably not a substantial claim: may not pass S4 (based).

Cardinal interneuron types can be defined by their synaptic communication properties, which are encoded in key transcriptional signatures.

“We posit that cardinal interneuron types can be defined by their synaptic communication properties, which are encoded in key transcriptional signatures.”

Probably not a substantial claim: may not pass S2 (checkable).

The communication-element framework may advance understanding of the appropriate granularity of neuron types towards a biologically grounded and operationally useful interneuron taxonomy.

“This conceptual framework integrates multi-modal cell features, captures neuronal input–output properties fundamental to circuit operation and may advance understanding of the appropriate granularity of neuron types, towards a biologically grounded and operationally useful interneuron taxonomy.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

The communication-element framework captures input-output properties fundamental to circuit operation.

“This conceptual framework integrates multi-modal cell features, captures neuronal input–output properties fundamental to circuit operation and may advance understanding of the appropriate granularity of neuron types, towards a biologically grounded and operationally useful interneuron taxonomy.”

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

Sparse and partial reconstructions of individual cells preclude truly quantitative analysis of cell morphology.

“For example, sparse and partial (that is, non-systematic and incomplete) reconstructions of individual cells preclude truly quantitative analysis of cell morphology.”

May combine two claims.

Another study using adult mouse visual cortex brain slices reconstructed 254 spiny and 207 aspiny neurons and identified 19 spiny m-types and 19 aspiny m-types by unsupervised hierarchical clustering.

“In another study using brain slices of adult mouse visual cortex from a large set of transgenic lines, 254 spiny and 207 aspiny neurons were reconstructed36. Using unsupervised hierarchical clustering, 19 spiny m-types and 19 aspiny m-types were identified.”

• cites [36] Gouwens, N. W. et al. Classification of electrophysiological and morphological types in mouse visual cortex. Nat. Neurosci. (in the press).Not checked yet

  Not checked in the free run.

May combine two claims.

Most electrophysiological recordings sample limited and often biased cell populations and only a fraction of the physiological parameters among diverse input-output transformation properties.

“Most electrophysiological recordings sample limited and often biased cell populations and only a fraction of the physiological parameters among the diverse input–output (I/O) transformation properties.”

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

One of the four clusters defined by Vip plus Chat expression might correspond to an interneuron type that directly excites layer 1 interneurons and layer 2/3 pyramidal neurons.

“Certain clusters may correspond to newly discovered types; for example, one of the four clusters defined by Vip plus Chat expression might correspond to a type of interneuron that directly excites layer 1 interneurons and layer 2/3 pyramidal neurons (as described in a preprint report)29.”

• cites [29] Obermayer, J. et al. Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/461723v1 (2018). sourceNot checked yet

  Not checked in the free run.

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

The inherently multi-modal nature of cell phenotypes requires integrative classification across modalities, but it is not clear whether different cell features co-cluster.

“Second, the inherently multi-modal nature of cell phenotypes requires integrative classification across modalities, but it is not clear whether different cell features, as defined and measured by current approaches, indeed co-cluster; this raises the issue of whether congruent multi-modal classification is ultimately achievable.”

May combine two claims.

The approximately 60 atomic GABAergic transcriptomic types at the base of the hierarchy are probably fluidic and may be modified by future scRNAseq and orthogonal data sets.

“The ~60 ‘atomic’ GABAergic t-types at the base of the hierarchy23 are probably fluidic and may well be modified by future scRNAseq and orthogonal data sets.”

• cites [23] Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

Cell function per se is often not readily definable and emerges only at the circuit level, which is difficult to study and often indirectly linked to behavioural performance.

“In practice, however, cell function per se is often not readily definable and emerges only at the circuit level, which is difficult to study and is often indirectly linked to behavioural performance.”

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

The issue of interneuron diversity remains contentious.

“Consequently, the issue of interneuron diversity remains contentious11.”

• cites [11] DeFelipe, J. et al. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat. Rev. Neurosci. 14, 202–216 (2013). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A subsequent large-scale study of about 23,800 cells suggested 113 cortical cell types, including about 60 GABAergic types conserved between visual and frontal cortex and 56 glutamatergic types mostly distinct between these areas.

“A subsequent large-scale study of ~23,800 cells incorporating multiple transgenic lines targeting neuronal subpopulations suggested 113 cortical cell types; these include ~60 GABAergic types conserved between visual and frontal cortex and 56 glutamatergic types that are mostly distinct between these two areas23 (Fig. 1).”

• cites [23] Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

Innovative statistical and computational analyses now enable clustering and typing along each modality and drive efforts to integrate across modalities.

“Innovative statistical and computational analyses now enable clustering and typing along each modality and drive efforts to integrate across modalities.”

May combine two claims.

Brain-slice preparations present inherent limitations for complete morphological reconstruction, precise spatial registration and truly quantitative analysis.

“Despite this progress, brain-slice preparations present inherent limitations for complete morphological reconstruction (for example, many of the spiny neuron axons are transected and cannot be visualized), precise spatial registration and truly quantitative analysis.”

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

Serendipitously identified molecular markers represent a minute fraction of gene expression profiles.

“Serendipitously identified molecular markers represent a minute fraction of gene expression profiles.”

May combine two claims.

Choices of statistical algorithms and stringency of cluster definitions remain largely arbitrary.

“Currently, the choices of statistical algorithms and the stringency of cluster definitions remain largely arbitrary30.”

• cites [30] Tasic, B. Single cell transcriptomics in neuroscience: cell classification and beyond. Curr. Opin. Neurobiol. 50, 242–249 (2018). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These limitations make it difficult to achieve quantitative analysis, to distinguish random or technical variation from reliable and meaningful features, and to compare results from different investigators.

“These limitations make it difficult to achieve quantitative analysis, to distinguish random or technical variation versus reliable and meaningful features, and to compare results from different investigators.”

May combine two claims.

A recent fMOST study achieved complete reconstruction of over 60 chandelier cells in the mouse neocortex; analyses suggested that multiple chandelier cell subtypes can be distinguished by different patterns of input-output connectivity.

“A recent fMOST (fluorescence micro-optical sectioning tomography) study achieved complete reconstruction of over 60 CHCs in the mouse neocortex. Analyses of their laminar position and the distribution of their dendritic and axonal arborizations suggested that multiple CHC subtypes can be distinguished by different patterns of I/O connectivity39.”

• cites [39] Wang, X. et al. Genetic single neuron anatomy reveals fine granularity of cortical axo-axonic cells. Cell Rep. 26, 3145–3159 (2019). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

This landmark data set is the most comprehensive survey of cortical transcriptional types and establishes a scaffold for transcriptome-based classification and a working draft of cortical cell taxonomy, including GABAergic interneuron taxonomy.

“This landmark data set represents the most comprehensive survey of cortical transcriptional types, establishing a scaffold for transcriptome-based classification and a working draft of cortical cell taxonomy, including GABAergic interneuron taxonomy.”

• cites [23] Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable).

Innovations in more automated reconstruction and registration will be necessary to generate high-throughput and comprehensive data sets.

“Innovations in more automated reconstruction and registration will be necessary to generate high-throughput and comprehensive data sets40,41.”

• cites [40] Li, R. et al. Precise segmentation of densely interweaving neuron clusters using G-Cut. Nat. Commun. 10, 1549 (2019). sourceNot checked yet

  Not checked in the free run.

• cites [41] Yang, J. et al. FMST: an automatic neuron tracing method based on fast marching and minimum spanning tree. Neuroinformatics 17, 185–196 (2019). sourceNot checked yet

  Not checked in the free run.

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

Cell phenotypes and properties derive to a considerable extent from patterns of gene expression.

“To a considerable extent, the phenotypes and properties of cells derive from their patterns of gene expression.”

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

A major current bottleneck is morphological reconstruction, which is mostly achieved by manual procedures that are particularly labour intensive.

“A major current bottleneck is morphological reconstruction, which is mostly achieved by manual procedures that are particularly labour intensive.”

May combine two claims.

Neurons display substantial multi-dimensional variations, some of which are discrete and others continuous.

“First, neurons display substantial multi-dimensional variations, of which some are discrete whereas others seem continuous13,14.”

• cites [13] Harris, K. D. et al. Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics. PLOS Biol. 16, e2006387 (2018). sourceNot checked yet

  Not checked in the free run.

• cites [14] Zeng, H. & Sanes, J. R. Neuronal cell-type classification: challenges, opportunities and the path forward. Nat. Rev. Neurosci. 18, 530–546 (2017). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

Recent advances in single-cell analysis have crossed several technical thresholds and begun to generate high-resolution, quantitative and comprehensive data sets on single-neuron transcriptomes, morphology and electrophysiology.

“In the past few years, spectacular advances in single-cell analysis have finally crossed several technical thresholds and begun to generate high-resolution, quantitative and comprehensive data sets on single-neuron transcriptomes, morphology and electrophysiology.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

Understanding the biological basis of neuron-type identity and granularity probably requires integration of multi-modal cell features, recognition of biologically meaningful variations in each feature and elucidation of their mechanistic bases.

“Such understanding probably requires the integration of multi-modal cell features, recognition of biologically meaningful variations in each feature and the elucidation of their mechanistic bases.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

The problem of neuronal diversity and classification is unlikely to be solved without understanding the biological principles that underlie neuronal identity and the organization of cell types.

“Despite progress in large-scale single-cell transcriptomics, the problem of neuronal diversity and classification is unlikely to be solved without understanding the biological principles that underlie neuronal identity and the organization of cell types.”

May combine two claims.

Octuplet whole-cell recording in adult mouse cortex mapped connectivity between more than 11,000 pairs of identified neurons and identified 15 types of interneurons, each exhibiting a characteristic pattern of connectivity with other interneuron types and pyramidal neurons.

“An impressive profiling of cortical cell types using octuplet whole-cell recording in adult mouse cortex mapped connectivity between more than 11,000 pairs of identified neurons43 and identified 15 types of interneurons, each exhibiting a characteristic pattern of connectivity with other interneuron types and pyramidal neurons.”

• cites [43] Jiang, X. et al. Principles of connectivity among morphologically defined cell types in adult neocortex. Science 350, aac9462 (2015). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

The intrinsic, synaptic and network properties of a neuron type probably all serve in the transformation of information from various synaptic input patterns to appropriate synaptic output patterns, often characterized by a cell-intrinsic style of neurochemical release.

“In terms of physiological features, the intrinsic, synaptic and network properties of a neuron type probably all serve in the transformation of information from various synaptic input patterns to appropriate synaptic output patterns, often characterized by a cell-intrinsic style of neurochemical release.”

Classified as probably not a substantial claim. May combine two claims.

The study used DIVA-Seq to detect about 9,000 genes expressed per single cell and to count mRNA transcripts in single cells.

“This study also used a modified version of CEL-seq (cell expression by linear amplification and sequencing), called DIVA-Seq (double in vitro transcription with absolute molecule counts sequencing)48, to detect ~9,000 genes expressed per single cell and to count mRNA transcripts in single cells.”

• cites [48] Paul, A., Huang, Z. J. & Single-cell, R. N. A. sequencing of fluorescently labeled mouse neurons using manual sorting and double in vitro transcription with absolute counts sequencing (DIVA-Seq). J. Vis. Exp. 140, e58690 (2018).Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

Considerable progress has been made by analysing high-resolution single-cell transcriptomes through leveraging deep, although incomplete, knowledge in GABAergic neuron anatomy and physiology.

“Considerable progress has been made by analysing high-resolution single-cell transcriptomes through leveraging the deep, although incomplete, knowledge in GABAergic neuron anatomy and physiology.”

May combine two claims.

Defining neuronal types on the basis of function seems intuitive and most relevant to nervous system operation, but neuronal functions manifest at multiple levels that carry different meanings, vary according to behavioural context, and thus seem not well suited for defining cell types.

“Defining neuronal types on the basis of their ‘function’ seems intuitive and the most relevant to nervous system operation9,51, but neuronal functions manifest at multiple levels that carry different meanings, vary according to behavioural context, and thus seem not to be well suited for use in defining cell types.”

• cites [9] Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318–326 (2014). sourceNot checked yet

  Not checked in the free run.

• cites [51] Lerner, T. N., Ye, L. & Deisseroth, K. Communication in neural circuits: tools, opportunities, and challenges. Cell 164, 1136–1150 (2016). sourceNot checked yet

  Not checked in the free run.

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

This is consistent with an independent proposal to define projection neuron types on the basis of input-output relationships.

“This is consistent with an independent proposal to define projection neuron types on the basis of I/O relationships51.”

• cites [51] Lerner, T. N., Ye, L. & Deisseroth, K. Communication in neural circuits: tools, opportunities, and challenges. Cell 164, 1136–1150 (2016). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

These PCPs were described according to previous anatomical, physiological and developmental research, providing a solid basis for interpretation of and correspondence to the transcriptomic data set.

“These PCPs were described according to previous anatomical, physiological and developmental research, providing a solid basis for the interpretation of and correspondence to the transcriptomic data set.”

• cites [28] Paul, A. et al. Transcriptional architecture of synaptic communication delineates GABAergic neuron identity. Cell 171, 522–539 (2017). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

These data sets are highly valuable, although intrinsic responses measured at the cell soma in vitro provide a rather limited glimpse of the sophisticated spatiotemporal operations of neurons in their network niche.

“These data sets are highly valuable, although the intrinsic responses measured at the cell soma in vitro provide a rather limited glimpse of the sophisticated spatiotemporal operations of neurons in their network niche.”

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

With broad application of scRNAseq, it is now possible to begin to correlate transcriptomic, morphological and physiological data sets with the aim of building a multi-modal cell-classification scheme.

“With the broad application of scRNAseq, it is now possible to begin to correlate transcriptomic, morphological and physiological data sets with the aim of building a multi-modal cell-classification scheme.”

Probably not a substantial claim: may not pass S2 (checkable).

The current ambiguity and disparity in cell clustering across modalities might reflect the lack of a conceptual framework that captures the essence of neuron type and distils overarching properties that encapsulate or extend beyond traditionally described cell phenotypes.

“The current ambiguity and disparity in cell clustering across modalities might reflect the lack of a conceptual framework that captures the essence of neuron type and distils the overarching properties that encapsulate or extend beyond the traditionally described cell phenotypes.”

May combine two claims.

This analysis suggested a trend of correspondence between the identified 17 e-types, 38 m-types and 46 jointly classified me-types; for example, thick tufted cells in L5, called the spiny7 m-type, corresponded quite well to an e-type called Exc_3.

“This analysis suggested a trend of correspondence between the identified 17 e-types, 38 m-types and 46 jointly classified me-types; for example, thick tufted cells in L5 (called the spiny7 m-type) corresponded quite well to an e-type called Exc_3.”

• cites [36] Gouwens, N. W. et al. Classification of electrophysiological and morphological types in mouse visual cortex. Nat. Neurosci. (in the press).Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable).

Proper distinction of physiological neuron types may require innovation and integration of multiple novel technologies to distil overarching functionally relevant features, for example by measuring input-output properties in the context of circuit operation.

“Proper distinction of physiological neuron types may require the innovation and integration of multiple novel technologies to distil overarching functionally relevant features — for example, by measuring the I/O properties in the context of circuit operation.”

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

The definition of neuron type as a neural communication element rooted in a transcription programme is a higher-level abstraction that integrates multi-modal cell phenotypes, provides a framework for understanding neuronal diversity and may facilitate biologically principled cell-type classification beyond statistical algorithms and arbitrary criteria.

“The definition of neuron type as a neural communication element rooted in a transcription programme is a higher-level abstraction that integrates multi-modal cell phenotypes, provides a framework for understanding neuronal diversity and may facilitate biologically principled cell-type classification beyond statistical algorithms and arbitrary criteria (Fig. 3).”

May combine two claims.

These elements can be task-dependently recruited into larger brain networks for systems-level information processing and computation, representing their distal behavioural and cognitive functions.

“These elements can be task-dependently recruited into larger brain networks for systems-level information processing and computation, representing their distal behavioural and cognitive functions59,60.”

• cites [59] Kvitsiani, D. et al. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature 498, 363–366 (2013). sourceNot checked yet

  Not checked in the free run.

• cites [60] Pi, H. J. et al. Cortical interneurons that specialize in disinhibitory control. Nature 503, 521–524 (2013). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

This transcription profiling method achieves substantially higher resolution than Drop-Seq and 10x Genomics platforms and more accurate mRNA-level measurements than Smart-Seq.

“This transcription profiling method achieves substantially higher resolution than Drop-Seq and 10x Genomics platforms and more accurate mRNA-level measurements than Smart-Seq.”

• cites [48] Paul, A., Huang, Z. J. & Single-cell, R. N. A. sequencing of fluorescently labeled mouse neurons using manual sorting and double in vitro transcription with absolute counts sequencing (DIVA-Seq). J. Vis. Exp. 140, e58690 (2018).Not checked yet

  Not checked in the free run.

May combine two claims.

Most common data sets on intrinsic properties in vitro may not reflect the essence of neuronal physiological operations, so it is not surprising that they have not been particularly informative in neuronal classification.

“As most common data sets on intrinsic properties in vitro may not reflect the essence of neuronal physiological operations, it is perhaps not surprising that they have not been particularly informative in neuronal classification.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

A key feature of the communication element concept is that it seamlessly incorporates the functional attributes of neuron types across levels.

“A key feature of the communication element concept is that it seamlessly incorporates the functional attributes of neuron types across levels.”

May combine two claims.

The same large-scale analysis of adult mouse visual cortex used 28 Cre driver lines to enable broad coverage, selective targeting of rare populations and linking to previous single-cell transcriptomic data sets; intrinsic properties of more than 1,900 neurons were analysed and morphologies of 461 neurons were partially reconstructed.

“The same large-scale analysis of adult mouse visual cortex36 used 28 Cre driver lines to enable broad coverage, selective targeting of rare populations and linking to previous single-cell transcriptomic data sets23 — the intrinsic properties of >1,900 neurons (928 spiny and 1,010 sparsely spiny) were analysed and the morphologies of 461 neurons (254 spiny and 207 aspiny) were partially”

• cites [36] Gouwens, N. W. et al. Classification of electrophysiological and morphological types in mouse visual cortex. Nat. Neurosci. (in the press).Not checked yet

  Not checked in the free run.

• cites [23] Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Measuring synaptic properties requires multiple simultaneous patch-clamp recordings, which are technically demanding and even more difficult to scale.

“Measuring synaptic properties requires multiple simultaneous patch-clamp recordings, which are technically demanding and even more difficult to scale.”

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

The concept of modular organization of cortical architecture dates back more than four decades.

“The concept of ‘modular organization’ of cortical architecture dates back more than four decades52,53,54.”

• cites [52] DeFelipe, J. et al. A microcolumnar structure of monkey cerebral cortex revealed by immunocytochemical studies of double bouquet cell axons. Neuroscience 37, 655–673 (1990). sourceNot checked yet

  Not checked in the free run.

• cites [53] Douglas, R. J. & Martin, K. A. Neuronal circuits of the neocortex. Annu. Rev. Neurosci. 27, 419–451 (2004). sourceNot checked yet

  Not checked in the free run.

• cites [54] Szentagothai, J. The ‘module-concept’ in cerebral cortex architecture. Brain Res. 95, 475–496 (1975). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

Neuronal communication elements with specific input-output transformation algorithms carry out a specific set of definable circuit operations, such as feedforward inhibition, lateral inhibition, disinhibition, gain control or gamma-oscillations, which are their proximal level functions.

“Neuronal communication elements with specific I/O transformation algorithms carry out a specific set of definable circuit operations (such as feedforward inhibition, lateral inhibition, disinhibition, gain control or γ-oscillations) — their proximal level functions.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

The two fundamental features of a communication element are its connectivity, that is, communication partners, and input-output transformation, that is, communication mode, which encapsulate and extend the more conventional descriptions of cell features.

“The two fundamental features of a communication element are its connectivity (that is, communication partners) and I/O transformation (that is, communication mode), which encapsulate and extend the more conventional descriptions of cell features.”

May combine two claims.

Although the transcription profile of a cell is influenced by extrinsic factors of the cellular milieu including neural activity, core transcription programmes are primarily shaped by cell-intrinsic epigenomic landscapes, which mainly derive from differential developmental programming of the genome.

“Although the transcription profile of a cell is influenced by extrinsic factors of the cellular milieu (including neural activity)65, core transcription programmes are primarily shaped by cell-intrinsic epigenomic landscapes (Box 1), which mainly derive from differential developmental programming of the genome.”

• cites [65] Hrvatin, S. et al. Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex. Nat. Neurosci. 21, 120–129 (2018). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

Variation in a neuron's intrinsic physiological properties may be understood only through how it affects I/O transformation.

“In addition, the importance of the variation of intrinsic physiological properties may be interpretable only in the context of their effect on I/O transformation.”

May combine two claims.

Measuring I/O transformations at scale across neuronal subpopulations in living tissue is still very difficult and might need wholly new methods.

“However, despite much progress, large-scale measurement of I/O transformations in neuronal subpopulations in vivo remains a considerable challenge and may require entirely new technologies.”

• AssumptionRests on an assumption: No single method currently exists for measuring I/O transformation.

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

Once identified, tighter correlations in specific subpopulations may emerge.

“Once identified, tighter correlations in specific subpopulations may emerge.”

Probably not a substantial claim: may not pass S2 (checkable).

Defining finer granularity may require a clearer understanding of the I/O transformation properties of a broader neuron type.

“A better understanding of the I/O transformation properties of a broader neuron type may be necessary to define finer granularity.”

May combine two claims.

Small differences can give a subset of cells a new property within a general I/O transformation, which may justify calling them a distinct subtype, as seen with the 15 retinal bipolar cell types.

“In some cases, seemingly subtle variations may endow novel properties of a generic type of I/O transformation to a subset of cells, thereby warranting their classification as a separate subtype (for example, the 15 types of retinal bipolar cell69).”

• cites [69] Shekhar, K. et al. Comprehensive classification of retinal bipolar neurons by single-cell transcriptomics. Cell 166, 1308–1323 (2016). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The recent finding that there has been relatively poor correlation between currently described m-types and e-types is perhaps not surprising, as morphology indirectly reflects connectivity, whereas electrophysiological properties measured at somata are just a few of many contributing factors that determine input-output transformations.

“As such, the recent finding that there has been relatively poor correlation between currently described m-types and e-types is perhaps not surprising, as morphology indirectly reflects connectivity, whereas electrophysiological properties measured at somata are just a few of many contributing factors that determine I/O transformations.”

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

The communication element definition may coherently integrate molecular, anatomical, physiological, functional and developmental genetic features; it is a testable hypothesis.

“Therefore, the communication element definition may coherently integrate molecular, anatomical, physiological, functional and developmental genetic features (Fig. 3); it is a testable hypothesis (Box 2).”

May combine two claims.

Communication is inherently a cell-extrinsic feature directly affected by communication partners, but it is rooted in cell-intrinsic transcription programmes.

“An intriguing corollary is that although communication is inherently a cell-extrinsic feature that is directly affected by communication partners, it is rooted in cell-intrinsic transcription programmes.”

Probably not a substantial claim: may not pass S2 (checkable).

To understand neuronal diversity and produce a satisfactory classification and taxonomy, it is necessary to uncover the biological basis of neuron-type identity and granularity.

“We suggest that uncovering the biological basis of neuron-type identity and granularity is necessary to decipher neuronal diversity and to achieve a satisfying classification and taxonomy.”

May combine two claims.

Certain morphological features might be more tightly linked to connectivity, for example chandelier cell axon arborizations, and certain intrinsic and synaptic features might be better linked to input-output properties, for instance fast-spiking basket cells showing fast in-fast out signal dynamics.

“Certain morphological features might be more tightly linked to connectivity (for example, CHC axon arborizations39), and certain intrinsic and synaptic features might be better linked to I/O properties (for instance, fast-spiking basket cells show fast in–fast out signal dynamics66).”

• cites [39] Wang, X. et al. Genetic single neuron anatomy reveals fine granularity of cortical axo-axonic cells. Cell Rep. 26, 3145–3159 (2019). sourceNot checked yet

  Not checked in the free run.

• cites [66] Hu, H., Gan, J. & Jonas, P. Interneurons. fast-spiking, parvalbumin(+) GABAergic interneurons: from cellular design to microcircuit function. Science 345, 1255263 (2014). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Comprehensive analysis and discovery require omics data at high resolution and high coverage; large but lower-resolution data sets by themselves may not allow functional gene expression signatures to be defined.

“First, high-resolution and high-coverage omics data sets are needed to provide the necessary substrates for comprehensive analysis and discovery. Large-scale, lower-resolution data sets alone (for example, assessing the expression on the order of 2,000 genes per cell71,72,73) may preclude the delineation of functional gene expression signatures.”

• cites [71] Campbell, J. N. et al. A molecular census of arcuate hypothalamus and median eminence cell types. Nat. Neurosci. 20, 484–496 (2017). sourceNot checked yet

  Not checked in the free run.

• cites [72] Saunders, A. et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015–1030 (2018). sourceNot checked yet

  Not checked in the free run.

• cites [73] Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014 (2018). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable).

The communication element definition of neuron types should facilitate the delineation of higher-level modular organization of neural circuit architecture by clarifying the developmental genetic basis of elemental building blocks.

“Thus, the communication element definition of neuron types should facilitate the delineation of higher-level modular organization of neural circuit architecture24,53 by clarifying the developmental genetic basis of elemental building blocks.”

• cites [24] Markram, H. et al. Reconstruction and simulation of neocortical microcircuitry. Cell 163, 456–492 (2015). sourceNot checked yet

  Not checked in the free run.

• cites [53] Douglas, R. J. & Martin, K. A. Neuronal circuits of the neocortex. Annu. Rev. Neurosci. 27, 419–451 (2004). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

The framework argues that neuron types are real biological entities formed by molecular genetic mechanisms and understandable via basic principles, rather than only statistical groupings created by arbitrary choices.

“The proposed framework here — that each cardinal neuron type can be defined as a neural communication element with characteristic I/O transformation properties that are encoded by key transcriptional signatures — posits that neuron types are not just statistical constructs shaped by arbitrary criteria but are inherently biological entities built with molecular genetic mechanisms that can be under”

May combine two claims.

Single-cell epigenomics techniques have begun to resolve major cortical cell classes and subclasses, including glutamatergic neurons, GABAergic neurons, parvalbumin-expressing neurons, somatostatin-expressing neurons, and glial cells, though they have not yet reached the resolution and scale of scRNAseq.

“Although these single-cell epigenomics techniques have yet to reach the resolution and scale of scRNAseq, they have begun to resolve major cortical cell classes and subclasses (including glutamatergic neurons, GABAergic neurons, parvalbumin-expressing neurons, somatostatin-expressing neurons, glial cells and so on).”

• cites [83] Luo, C. et al. Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex. Science 357, 600–604 (2017). sourceNot checked yet

  Not checked in the free run.

• cites [84] Preissl, S. et al. Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. Nat. Neurosci. 21, 432–439 (2018). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable).

The communication element concept incorporates the functional definition of neuron types by clarifying and integrating different levels of functional explanations.

“Thus, the communication element concept incorporates the functional definition of neuron types by clarifying and integrating different levels of functional explanations.”

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

Key connectivity and input-output features might potentially be highly correlated once they can be measured at a high enough resolution.

“Key connectivity and I/O features might potentially be highly correlated once they can be measured at a high enough resolution.”

Probably not a substantial claim: may not pass S2 (checkable).

How many cell types exist in a brain region cannot be answered clearly until it is known how finely and reliably cell types must be separated to serve the understanding of circuit function.

“The question of how many cell types a given brain region contains is frequently asked but will not have a clear answer until investigators can determine how finely and firmly cell types should be distinguished to be useful for understanding circuit function.”

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

A separate study used ATAC-seq to infer candidate master transcriptional regulators from chromatin accessibility in roughly 15,000 individual nuclei.

“In another complementary study, potential master transcriptional regulators were inferred from chromatin accessibility assay in ~15,000 single nuclei using ATAC-seq84.”

• cites [84] Preissl, S. et al. Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. Nat. Neurosci. 21, 432–439 (2018). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The cardinal identity of a cell is probably already instilled at the postmitotic stage during development, and its subsequent phenotypic differentiation and expression are regulated by extrinsic signals such as cell interactions and neural activity.

“The cardinal identity of a cell is probably already instilled at the postmitotic stage during development9,61,62,63,64, and its subsequent phenotypic differentiation and expression are regulated by extrinsic signals such as cell interactions and neural activity.”

• cites [9] Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318–326 (2014). sourceNot checked yet

  Not checked in the free run.

• cites [61] Mayer, C. et al. Developmental diversification of cortical inhibitory interneurons. Nature 555, 457–462 (2018). sourceNot checked yet

  Not checked in the free run.

• cites [62] Cao, J. et al. Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361, 1380–1385 (2018). sourceNot checked yet

  Not checked in the free run.

• cites [63] Taniguchi, H., Lu, J. & Huang, Z. J. The spatial and temporal origin of chandelier cells in mouse neocortex. Science 339, 70–74 (2013). sourceNot checked yet

  Not checked in the free run.

• cites [64] Mi, D. et al. Early emergence of cortical interneuron diversity in the mouse embryo. Science 360, 81–85 (2018). sourceNot checked yet

  Not checked in the free run.