Shared and derived features of cellular diversity in the human cerebral cortex

Abstract

The cerebral cortex is the hallmark of the mammalian nervous system, and its large size and cellular diversity in humans support our most sophisticated cognitive abilities. Although the basic cellular organization of the cortex is conserved across mammals, cells have diversified during evolution. An increasingly integrated taxonomy of cell types, especially with the advent of single-cell transcriptomic data, has revealed an unprecedented variety of human cortical cell subtypes. Here, we broadly review the cellular composition and diversity of the mammalian brain, and how progenitor pools generate cell subtypes during development. We then discuss human cortical cells that are distinct from rodent cells, as well as the challenges and advantages of using model systems to study human cell types in health and disease.

Figure 1.. Basic cellular organization of the neocortex is conserved but varies across mammals.

A schematic overview of the major morphological and functional classes of neurons and glia in the adult rodent and human neocortex. The cerebral cortex is traditionally subdivided into 6 layers, each of which contains a unique set of neurons and connections. The major types of neurons and macroglia are depicted in their laminar distributions by shape and color. Glutamatergic excitatory neurons can be subdivided into three major groups: pyramidal intracerebral projection neurons (IcPNs, green); pyramidal subcerebral projection neurons (ScPNs, blue); and layer 4 spiny stellate cells (gray). Layer 5B of certain areas of the human but not rodent neocortex contain large or giant modified pyramidal neurons such as Betz cells in motor cortices, Meynert cells in primary visual cortex, and von Economo spindle neurons and fork cells in fronto-insular cortices. GABAergic inhibitory neurons are diverse, depicted here as a single class (orange). Macroglia consist of oligodendrocytes, and a single class of protoplasmic astroctyes in rodents parallels interlaminar (layer 1), protoplasmic (layer 2-4), and varicose projection (layers 5, 6) astrocytes in humans. See main text for additional details.

Figure 2.. Development of human cortical cell types.

The cortex develops when radial glia give rise to neurons via intermediate progenitor cells. These cells give rise to newborn neurons that migrate to the cortical plate and generate the cortical excitatory neurons in an inside out fashion, with deep layer excitatory neurons generated first followed by the upper layer excitatory neurons. These excitatory neurons have recently been described to be area-specific and to emerge early in development. The human cortex consists of a ventricular zone, and an expanded outer subventricular zone compared to the rodent. Humans have additional subtypes of radial glia, the outer radial glia and truncated radial glia that emerge at later stages of development. After the peak of neurogenesis, radial glia engage in gliogenesis, producing astrocytes.