The diversity of GABAergic neurons and neural communication elements

In the paper

“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.”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [9] Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318–326 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [61] Mayer, C. et al. Developmental diversification of cortical inhibitory interneurons. Nature 555, 457–462 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [62] Cao, J. et al. Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361, 1380–1385 (2018). sourceExperimental — accuracy not yet measured
• Disputed

  Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [64] Mi, D. et al. Early emergence of cortical interneuron diversity in the mouse embryo. Science 360, 81–85 (2018). sourceExperimental — accuracy not yet measured

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

What the sources say

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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [23] Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018). source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [11] DeFelipe, J. et al. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat. Rev. Neurosci. 14, 202–216 (2013). source

In the paper

“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).”

What the sources say

• Not checked yetcites [23] Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018). source

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [30] Tasic, B. Single cell transcriptomics in neuroscience: cell classification and beyond. Curr. Opin. Neurobiol. 50, 242–249 (2018). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [39] Wang, X. et al. Genetic single neuron anatomy reveals fine granularity of cortical axo-axonic cells. Cell Rep. 26, 3145–3159 (2019). source

In the paper

“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.”

What the sources say

• Not checked yetcites [23] Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018). source

In the paper

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

What the sources say

• Not checked yetcites [40] Li, R. et al. Precise segmentation of densely interweaving neuron clusters using G-Cut. Nat. Commun. 10, 1549 (2019). source
• Not checked yetcites [41] Yang, J. et al. FMST: an automatic neuron tracing method based on fast marching and minimum spanning tree. Neuroinformatics 17, 185–196 (2019). source

In the paper

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

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [13] Harris, K. D. et al. Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics. PLOS Biol. 16, e2006387 (2018). source
• Not checked yetcites [14] Zeng, H. & Sanes, J. R. Neuronal cell-type classification: challenges, opportunities and the path forward. Nat. Rev. Neurosci. 18, 530–546 (2017). source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [43] Jiang, X. et al. Principles of connectivity among morphologically defined cell types in adult neocortex. Science 350, aac9462 (2015). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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).

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [9] Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318–326 (2014). source
• Not checked yetcites [51] Lerner, T. N., Ye, L. & Deisseroth, K. Communication in neural circuits: tools, opportunities, and challenges. Cell 164, 1136–1150 (2016). source

In the paper

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

What the sources say

• Not checked yetcites [51] Lerner, T. N., Ye, L. & Deisseroth, K. Communication in neural circuits: tools, opportunities, and challenges. Cell 164, 1136–1150 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [28] Paul, A. et al. Transcriptional architecture of synaptic communication delineates GABAergic neuron identity. Cell 171, 522–539 (2017). source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

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

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

What the sources say

• Not checked yetcites [59] Kvitsiani, D. et al. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature 498, 363–366 (2013). source
• Not checked yetcites [60] Pi, H. J. et al. Cortical interneurons that specialize in disinhibitory control. Nature 503, 521–524 (2013). source

In the paper

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

What the sources say

• Not checked yetcites [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).

In the paper

“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.”

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [36] Gouwens, N. W. et al. Classification of electrophysiological and morphological types in mouse visual cortex. Nat. Neurosci. (in the press).
• Not checked yetcites [23] Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018). source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [53] Douglas, R. J. & Martin, K. A. Neuronal circuits of the neocortex. Annu. Rev. Neurosci. 27, 419–451 (2004). source
• Not checked yetcites [54] Szentagothai, J. The ‘module-concept’ in cerebral cortex architecture. Brain Res. 95, 475–496 (1975). source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [65] Hrvatin, S. et al. Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex. Nat. Neurosci. 21, 120–129 (2018). source

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [69] Shekhar, K. et al. Comprehensive classification of retinal bipolar neurons by single-cell transcriptomics. Cell 166, 1308–1323 (2016). source

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [39] Wang, X. et al. Genetic single neuron anatomy reveals fine granularity of cortical axo-axonic cells. Cell Rep. 26, 3145–3159 (2019). source
• Not checked yetcites [66] Hu, H., Gan, J. & Jonas, P. Interneurons. fast-spiking, parvalbumin(+) GABAergic interneurons: from cellular design to microcircuit function. Science 345, 1255263 (2014). source

In the paper

“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.”

What the sources say

• Not checked yetcites [71] Campbell, J. N. et al. A molecular census of arcuate hypothalamus and median eminence cell types. Nat. Neurosci. 20, 484–496 (2017). source
• Not checked yetcites [72] Saunders, A. et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015–1030 (2018). source
• Not checked yetcites [73] Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014 (2018). source

In the paper

“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.”

What the sources say

• Not checked yetcites [24] Markram, H. et al. Reconstruction and simulation of neocortical microcircuitry. Cell 163, 456–492 (2015). source
• Not checked yetcites [53] Douglas, R. J. & Martin, K. A. Neuronal circuits of the neocortex. Annu. Rev. Neurosci. 27, 419–451 (2004). source

In the paper

“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”

In the paper

“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).”

What the sources say

• Not checked yetcites [83] Luo, C. et al. Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex. Science 357, 600–604 (2017). source
• Not checked yetcites [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). source

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [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). source