Cell Types across Neocortical Areas

 

Nature, volume 563, pages 72–78 (2018)

Shared and distinct transcriptomic cell types across neocortical areas

Bosiljka Tasic, et.al., including Christof Koch

Allen Institute for Brain Science, Seattle, WA, USA

Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA

Massachusetts Institute of Technology, Cambridge, MA, USA

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The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133 transcriptomic cell types by deep, single-cell RNA sequencing.    Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, we match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Our study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

The neocortex coordinates most flexible and learned behaviours. In mammalian evolution, the cortex underwent greater expansion in the number of cells, layers and functional areas compared to the rest of the brain, coinciding with the acquisition of increasingly sophisticated cognitive functions. On the basis of cytoarchitectonic, neurochemical, connectional and functional studies, up to 180 distinct cortical areas have been identified in humans and dozens in rodents. Cortical areas have laminar structure (layers (L) 1–6), and are often categorized as sensory, motor or associational, on the basis of their connections with other brain areas. Different cortical areas show qualitatively different activity patterns. Primary visual (VISp) and other sensory cortical areas process sensory information with millisecond timescale dynamics.    Frontal areas, such as the anterior lateral motor cortex (ALM) in mice, show slower dynamics related to short-term memory, deliberation, decision-making and planning. Categorizing cortical neurons into types, and studying the roles of different types in the function of the circuit, is an essential step towards understanding how different cortical circuits produce distinct computations.

Previous studies have characterized various neuronal properties to define numerous types of glutamatergic (excitatory) and GABAergic (inhibitory) neurons in the rodent cortex. Reconciling the morphological, neurophysiological and molecular properties into a consensus view of cortical types remains a major challenge. We leveraged the scalability of single-cell RNA sequencing (scRNA-seq) to define cell types in two distant cortical areas. We analysed 14,249 cells from the VISp and 9,573 cells from the ALM to define 133 transcriptomic types and establish correspondence between glutamatergic neuron projection patterns and their transcriptomic identities. In the accompanying paper, we show that transcriptomic L5 types with different subcortical projections have distinct roles in movement planning and execution.

Research Study — Distinct Descending Motor Cortex Pathways

We report 23,822 single-cell transcriptomes with cluster-assigned identity. Most neurons fall into two major branches corresponding to glutamatergic and GABAergic classes.

Discussion

We used single-cell transcriptomics to uncover the principles of cell type diversity in two functionally distinct areas of neocortex. We define 133 transcriptomic types,    101 types in the ALM    and 111 in the VISp,    79 of which are shared between these areas.    Most glutamatergic types are area-specific. By contrast, and as previously suggested, non-neuronal and most GABAergic neuronal types are shared across cortical areas. Although we detect area-specific differences in gene expression within GABAergic types, they are usually insufficient to define subtypes with our statistical criteria.

This dichotomy correlates with neuronal connectivity patterns and developmental origins. Most glutamatergic types in VISp or ALM    project to different cortical and subcortical targets, whereas nearly all GABAergic interneurons form local connections. Most glutamatergic neurons are born locally within the ventricular–subventricular zone of the developing cortex, which is pre-patterned with developmental gradients—an embryonic protomap—and further segregated into areas through differential thalamic input in development. By contrast, types that are shared across areas are derived from extracortical sources, and migrate into the developing cortex: most GABAergic interneurons are from the medial ganglionic eminence or caudal ganglionic eminence; Meis2 interneurons are from the pallial–subpallial boundary; and Cajal–Retzius cells of the hippocampus and cortex are from the cortical hem. It remains to be investigated whether some of the shared L6b types may originate from the rostro-medial telencephalic wall, a known source for a subset of subplate neurons that are distinct from those generated within the local ventricular–subventricular zone, or whether further sampling may segregate them into area-specific types. Although our taxonomy mostly agrees with the developmental origins of the cells, there are exceptions. For example, tamoxifen induction of Nkx2.1-creERT2 mice at E18 labels not only chandelier cells, but also a suggested second chandelier type, CHC2. Our taxonomy suggests that CHC2 may be a neurogliaform type (Lamp5–Lxh6) that arises from the medial ganglionic eminence, and that neurogliaform types could arise through different developmental pathways and embryonic sources in an example of developmental convergence.

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