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Dissecting the Brain, One Cell at a Time

Setting a single-cell baseline for understanding cognitive disorders and disease

Arek Socha/Pixabay
Source: Arek Socha/Pixabay

Researchers at the Chinese Academy of Sciences in Beijing have broken new ground with their recent work examining the prefrontal cortex at the single cell level during human fetal development.

The human prefrontal cortex (PFC), an area of the brain that contains over a billion cells, is often recognized for its role in decision-making, largely mentioned in the context of adolescent maturity (…or lack thereof). Neuroimaging studies strongly suggest our PFC is still developing into our 20s, which makes sense when we find ourselves asking questions like, “Why are these 15-year-olds challenging each other to eat Tide Pods?”

Our PFC is essential for higher-order cognition, including working memory and socio-emotional functioning, as it continues to develop new connections and modifications within its circuitry as we age. Populations of functional cells first arise and migrate throughout the developing PFC in utero, but the molecular changes underlying this early stage of development have remained widely unknown, in part due to the difficulty in accurately defining what cell types lie within the prefrontal cortex, a task far more complex than it may sound.

The Beijing-based research team, led in part by Dr. Xiaoqun Wang, not only analyzed gene expression of over 2,300 individual cells in the PFC, they investigated the developmental trajectories of those cells from gestational weeks 8 through 26 (all work was done in accordance with the Reproductive Study Ethics Committee of Peking University).

Gerd Altmann/Pixabay
Source: Gerd Altmann/Pixabay

Using single-cell RNA sequencing, a technique that allows scientists to determine what genes are being expressed in each cell (based on the transcripts present), researchers identified six main classes of cells in the developing human PFC and 35 subtypes within those classes. In doing so, they not only illustrated the diversity of cell types in the human PFC, indicating the cellular complexity underlying human cognition, they discovered new genetic markers of neural progenitor cells (NPCs). NPCs are cells that not only have the ability to self-replicate but also differentiate to become more specialized cell types, for example, the essential yet somewhat enigmatic glial cells, within the brain.

Uncovering these markers not only showed the heterogeneity within NPCs—it provided scientists an additional tool for investigating how one cell type gives rise to the next and allows for important neural circuits to form over the course of fetal development.

The PFC has been implicated in major cognitive deficits and neurodevelopmental disorders, including schizophrenia. In the case of schizophrenia, changes are seen in PFC structure and function, in part due to cortex thinning. The research team was able to delineate when excitatory and inhibitory neurons, cells in the PFC that have been linked to disorders including schizophrenia and autism, first appear and mature. Understanding how and when these cell types arise could provide the foundation for the development of therapies for these and related neurological defects.

This Beijing-based team was not the first to explore the human brain on a single cell level, and most certainly will not be the last. Researchers are continuously working to optimize how they collect information on different regions of the brain, at different stages of development, creating a complete reference blueprint for studying the molecular basis of human experience, from memory formation to neurodegenerative disease. As high-throughput methods become more commonplace, new discoveries continue to bring us closer to understanding the incredibly daunting, yet beautiful, landscape that is the human brain.