Cortical somatostatin interneuron subtypes form cell-type specific circuits

Wu, Jicheng; Sevier, Elaine; Saldi, Giuseppe-Antonio; Yu, Sabrina Qiong; Abbott, Lydia; Choi, Da Hae; Sherer, Mia; Qiu, Yanjie; Shinde, Ashwini; Rizzo, Daniella; Xu, Qing; Barrera, Irving; Kumar, Vipin; Marrero, Giovanni; Pörnneke, Alvar; Huang, Sung-Cheng; Rudy, Bernardo; Stafford, David; Macosko, Evan Z.; Chen, Fei; Fishell, Gordon

doi:10.1101/2022.09.29.510081

Cited by 9 publications

(29 citation statements)

References 65 publications

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“…For example, ET cells received inputs from a greater number and diversity of inhibitory cell types than layer 5 IT or NP cells. This large population of highly selective inhibitory cell types, consistent with recent observations of transcriptomically-defined SST neurons 36 , could allow for more complex regulation of these key cortical outputs compared to other layer 5 cells. Most M-types received input from multiple motif groups, suggesting there could be network conditions when different combinations of excitatory subpopulations controlled together as part of a shared circuit.…”

Section: Discussionsupporting

confidence: 85%

“…A principle concern is the generalizability of data, which comes from a single animal, is located toward the edge of VISp, and has at most a few examples per cell type. Concurrent work in the same dataset has found that morphologically-defined cell types show consistent target preferences 85 , and our data also agrees with recent functional measurements of type-specific connectivity of SST cells 36 . We thus believe that the connectivity results will apply generally, although it will be important to measure the variability across individual cells, distinct animals, and locations in cortex.…”

Section: B Limitationssupporting

confidence: 91%

“…Synaptic properties help define excitatory subclasses. While inhibitory neurons have frequently been described as having dense, unspecific connectivity onto nearby neurons 31,62 , many studies have revealed examples not only of layer-specific connectivity 63 , but also selectivity within spatially intermingled excitatory subpopulations 35,36,64 . It is unclear the degree to which inhibition is specific or not, and, in general, the principles underlying which excitatory neurons are inhibited by which inhibitory neurons is not well understood.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, the structure of how inhibition is distributed across different excitatory cells is still a matter of debate, despite being a key determinant of how cortical activity is controlled. While some studies have observed largely unspecific connectivity onto nearby cells 31,32 , other studies have found examples of selective targeting of certain subpopulations of excitatory cells based on their layer position 33 or long-range axonal projection target [34][35][36] . It is not known whether such selectivity is common or rare relative to unspecific connectivity.…”

Section: Introductionmentioning

confidence: 99%

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Cell-type-specific inhibitory circuitry from a connectomic census of mouse visual cortex

Schneider-Mizell

Bodor

Brittain

et al. 2023

Preprint

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Mammalian cortex features a large diversity of neuronal cell types, each with characteristic anatomical, molecular and functional properties. Synaptic connectivity rules powerfully shape how each cell type participates in the cortical circuit, but comprehensively mapping connectivity at the resolution of distinct cell types remains difficult. Here, we used millimeter-scale volumetric electron microscopy to investigate the connectivity of inhibitory neurons across a dense neuronal population spanning all layers of mouse visual cortex with synaptic resolution. We classified all 1183 excitatory neurons within a 100 micron column into anatomical subclasses using quantitative morphological and synapse features based on full dendritic reconstructions, finding both familiar subclasses corresponding to axonal projections and novel intralaminar distinctions based on synaptic properties. To relate these subclasses to single-cell connectivity, we reconstructed all 164 inhibitory interneurons in the same column, producing a wiring diagram of inhibition with more than 70,000 synapses. We found widespread cell-type-specific inhibition, including interneurons selectively targeting certain excitatory subpopulations among spatially intermingled neurons in layer 2/3, layer 5, and layer 6. Globally, inhibitory connectivity was organized into "motif groups," heterogeneous collections of cells that collectively target both perisomatic and dendritic compartments of the same combinations of excitatory subtypes. We also discovered a novel category of disinhibitory-specialist interneurons that preferentially targets basket cells. Collectively, our analysis revealed new organizing principles for cortical inhibition and will serve as a powerful foundation for linking modern multimodal neuronal atlases with the cortical wiring diagram.

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Section: Discussionsupporting

confidence: 85%

Section: B Limitationssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cell-type-specific inhibitory circuitry from a connectomic census of mouse visual cortex

Schneider-Mizell

Bodor

Brittain

et al. 2023

Preprint

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“…We focused on Martinotti cells (MCs) in layers 4 and 5 (L4, L5), which have distinct morphological features 23,31,32 , are known to be somatostatin positive (Sst+) 24,25 , and span six Sst+ MET-types 21 . Additionally, previous functional studies suggest that MCs may connect broadly in a 'blanket of inhibition' [33][34][35] or inhibit a subset of excitatory targets within and across cortical layers 32,[36][37][38][39] . Finally, in a concurrent study 40 individual MCs are found to preferentially target different excitatory cell types, however, it remains unknown whether Sst-MET-types have distinct synaptic connectivity profiles especially as morphologically similar neurons can have distinct connectivity profiles 41 .…”

Section: Introductionmentioning

confidence: 99%

Integrating EM and Patch-seq data: Synaptic connectivity and target specificity of predicted Sst transcriptomic types

Gamlin

Schneider-Mizell

Mallory

et al. 2023

Preprint

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Neural circuit function is shaped both by the cell types that comprise the circuit and the connections between those cell types1. Neural cell types have previously been defined by morphology 2,3, electrophysiology 4,5, transcriptomic expression 6-8 , connectivity 9-13, or even a combination of such modalities 14-16. More recently, the Patch-seq technique has enabled the characterization of morphology (M), electrophysiology (E), and transcriptomic (T) properties from individual cells 17-20. Using this technique, these properties were integrated to define 28, inhibitory multimodal, MET-types in mouse primary visual cortex 21. It is unknown how these MET-types connect within the broader cortical circuitry however. Here we show that we can predict the MET-type identity of inhibitory cells within a large-scale electron microscopy (EM) dataset and these MET-types have distinct ultrastructural features and synapse connectivity patterns. We found that EM Martinotti cells, a well defined morphological cell type 22,23 known to be Somatostatin positive (Sst+) 24,25, were successfully predicted to belong to Sst+ MET-types. Each identified MET-type had distinct axon myelination patterns and synapsed onto specific excitatory targets. Our results demonstrate that morphological features can be used to link cell type identities across imaging modalities, which enables further comparison of connectivity in relation to transcriptomic or electrophysiological properties. Furthermore, our results show that MET-types have distinct connectivity patterns, supporting the use of MET-types and connectivity to meaningfully define cell types.

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Genetically Defined Subtypes of Somatostatin-Containing Cortical Interneurons

Hostetler

Agmon

2023

Preprint

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Of the four main subclasses of inhibitory cortical interneurons, somatostatin-containing (SOM) interneurons are the most diverse. Earlier studies identified layer 1-projecting (Martinotti) cells in layer 5/6 of the X98 and the Chrna2-cre transgenic lines, and two groups of non-Martinotti cells - long-range projecting SOM cells in layers 2 and 6, and layer 4-projecting X94 cells in layers 4 and 5. Later in-vivo and ex-vivo studies described two morphological types of Martinotti cells which appear to have opposing roles in behaving animals. More recently, large-scale transcriptomic studies attempting to classify all cortical neurons by their gene expression profiles and by their morphological and electrophysiological phenotypes divided all SOM interneurons into 13 morpho-electro-transcriptomic (MET) types. It remains unclear, however, how the previously identified SOM subtypes relate to each other, and how they map onto the suggested MET classification scheme. Importantly, only a small number of Cre or Flp driver line are available to target SOM interneurons, and there are currently no genetic tools to target the majority of the proposed MET types for recording, imaging or optogenetic manipulations, severely hindering progress on understanding the roles SOM interneurons play in sensorimotor processing or in learning and memory. To begin to overcome these barriers, we undertook a systematic examination of SOM interneuron subtypes in layer 5 of mouse somatosensory cortex. We generated 4 intersectional triple-transgenic genotypes, by crossing the Sst-IRES-Flp line with 4 different Cre lines and with a dual-color reporter that labels all Cre expressing SOM cells with GFP and all other SOM cells in the same brain with tdTomato. Brains from adult mice of both sexes were retrogradely labeled by epipial dye deposits, processed histologically, and immunostained for 3 marker proteins known to be expressed in different SOM subsets. By correlating fluorescent protein expression, retrograde label and marker proteins in the same neurons, we found that Cre-expressing SOM cells in the Calb2-IRES-Cre and in the Chrna2-Cre lines, and GFP expressing neurons in the X94 line, comprise three non-overlapping SOM populations which together account for about half of all SOM cell in layer 5. Using whole-cell recordings ex-vivo, we show that they also exhibit electrophysiological properties which are distinctly different from each other. This multimodal convergence of axonal projection target, marker protein expression and electrophysiological properties strongly suggests that these three populations can be considered bona-fide SOM subtypes. Indeed, each of the three subtypes appears to map onto a unique MET type. Our findings call for a renewed effort to generate additional driver lines that can be used combinatorially to provide genetic access to the many remaining SOM subtypes and uncover their roles in cortical computations.

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Cortical somatostatin interneuron subtypes form cell-type specific circuits

Cited by 9 publications

References 65 publications

Cell-type-specific inhibitory circuitry from a connectomic census of mouse visual cortex

Cell-type-specific inhibitory circuitry from a connectomic census of mouse visual cortex

Integrating EM and Patch-seq data: Synaptic connectivity and target specificity of predicted Sst transcriptomic types

Genetically Defined Subtypes of Somatostatin-Containing Cortical Interneurons

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