Two articles on Nature analyze how the unique human brain is formed in the second trimester of pregnancy

About 4 to 5 months after pregnancy, the synapses in the prefrontal cortex (PFC) of the human fetus begin to proliferate
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Through this intricate connection, the developing brain acquires unique properties, allowing humans to think abstractly, use language, and carry out complex social interactions

However, what kind of molecular components can make synapses grow and cause such profound changes in the brain? Researchers at Yale University have recently identified key changes in gene expression and structure in the human brain that make humans unique
.

Two related papers have been published in "Nature" magazine, which helps to understand brain development and brain diseases

Nenad Sestan, the senior author of the two papers and a professor of neuroscience at Yale University, said: “We still don’t know what makes the human brain different from the brains of other related species.
This is surprising and a bit disappointing
.

Understand this.

In these two studies, the research team led by Sestan conducted extensive analysis of gene expression in the prefrontal cortex during embryonic development in humans, macaques, and mice, and then determined the similarities and differences between the various species
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They found that the key factor that determines the similarities and differences of the developing brains of these species is the concentration of retinoic acid (tretinoin, a by-product of vitamin A)
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Retinoic acid is essential for the development of every organ and is strictly regulated in all animals

In the first paper, the research team led by Mikihito Shibata and Kartik Pattabiraman of Yale University School of Medicine found that retinoic acid in the prefrontal cortex increases during the second trimester, the most critical period for the formation of neural circuits and connections
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At this stage, the retinoic acid of mice and macaques also increased

When the researchers blocked the retinoic acid signal in the mouse prefrontal cortex, they failed to form specific circuits and connections in certain areas of the brain, which are essential for human memory and cognition
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For humans, the same pathway is also destroyed during the development of patients with schizophrenia and autism spectrum disorders, which suggests that these diseases may have similar roots during development

Later, they conducted in-depth research on the genes that synthesize and shut down retinoic acid, revealing important differences between mice and primates
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For example, in mice, the CYP26B1 gene limits the activity of retinoic acid to the prefrontal cortex

Next, the researchers tried to figure out how retinoic acid exerts this magic
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The development of the human brain is marked by a sudden increase in synaptic growth in the second trimester
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These connections start in the prefrontal cortex, but as they approach the sensory and motor neurons in the back of the brain, the connections gradually diminish

In order to better understand the reasons behind, Shibata and Pattabiraman focused on the CBLN2 gene in their second study, which is enriched in the prefrontal cortex and plays a key role in the formation of these connections
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At the same time, it is also directly regulated by retinoic acid
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They found that compared with other parts of the brain, CBLN2 turns on earlier in the front of the human brain
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In addition, they found that compared with macaques or mice, the gene is expressed in the human brain for a longer period of time and in a wider area, indicating that the prefrontal cortex plays a central role in the emergence of unique human properties
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The researchers also found a small number of gene deletions near the CBLN2 gene.
This deletion is conserved in the evolution of humans and chimpanzees, but not in other animals
.
To see if these deletions play a role in synaptic growth, they introduced the deletions into the mouse genome
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Mice with these deletions showed CBLN2 expansion similar to humans, and the prefrontal cortex connections of adult mice increased by 30%
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In summary, these two papers show that the genetic mechanism behind advanced cognitive abilities begins with the local production of retinoic acid and then activates various downstream genes, including CBLN2
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This determines when and where these key brain connections are formed
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Sestan said: "The prefrontal cortex integrates information from other parts of the central nervous system, controlling attention, thinking, emotions, and actions from top to bottom
.
It is also the core of the dysfunction of many neuropsychiatric diseases
.
The connection that creates human thinking occurs if it happens.
Subtle changes can also make people sick
.
"

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Shibata, M.
, Pattabiraman, K.
, Lorente-Galdos, B.
et al.
Regulation of prefrontal patterning and connectivity by retinoic acid.
Nature (2021).
https://doi.
org/10.
1038/s41586-021-03953- x

Shibata, M.
, Pattabiraman, K.
, Muchnik, SK et al.
Hominini-specific regulation of CBLN2 increases prefrontal spinogenesis.
Nature (2021).
https://doi.
org/10.
1038/s41586-021-03952-y