A burst in synaptic growth occurs about four to five months after conception in the prefrontal cortex of the human foetus. The brain develops unique abilities that enable people to think abstractly, communicate in language and engage in complex social interactions.
What are the molecular ingredients necessary for this blooming of synapses to occur and cause profound changes in the brain? In two papers published on Sept. 29 in the journal Nature, Yale researchers have identified key changes in the expression of genes as well as their structure of the developing human brain that makes it the only animal species.
Researchers believe these insights could have profound implications on understanding the common brain and developmental disorders.
It’s a bit surreal and disappointing that we still don’t know what makes the human brain different from brains of other closely related species. Understanding this is not only an intellectual curiosity to understand what we are as a species -; it may help us understand neuropsychiatric disorders like autism and schizophrenia.”
Nenad Sestan, the Harvey and Kate Cushing Professor of Neuroscience at Yale and professor of genetics, comparative medicine and of psychiatry and senior author of both papers
For the studies, Sestan’s lab team conducted an extensive analysis of gene expressions in the prefrontal cortexes of humans macaque monkeys and mice midway through fetal development and then identified both similarities and differences between the species.
A crucial element in determining the similarities and differences in the developing brains of the two species, they discovered, is the concentration of retinoic acids, or RA, a byproduct of Vitamin A. Retinoic acid, which is crucial for the development of each organ, is tightly controlled in all animals. Too little or too much retinoic acid could cause abnormalities in the development of.
A Yale School of Medicine research team headed by Mikihito and Kartik Shibata, has discovered that RA levels in the PFC increase in the second trimester. This is the critical moment for the development of neural circuitry. The increase in RA at this stage was also found in mice and macaques.
When researchers blocked RA signals in the prefrontal cortex in mice, the animals were unable to form the specific connections and circuits in the areas of the brain that are essential for working memory and cognition. This pathway is also affected in humans with schizophrenia and autism spectrum disorders.
However, a closer examination of the genes which synthesize and also shut off RA in the prefrontal cortex revealed significant differences between primates and mice. The CYP26B1 gene in mice limits RA activity beyond the prefrontal cortex of animals. Researchers shut down this gene in mice, and regions of their brains were associated with motor abilities and sensory processing grew more like synaptic wiring of the prefrontal cortex. This confirms the vital function of RA in extending the prefrontal cortex -; as well as in promoting brain complexity in humans and other primates.
“RA is the first domino to fall, and it sets in motion the intricate gene networks that lead to development of brain areas associated with human thinking,” said Pattabiraman, an associate clinical fellow at the Yale Child Study Center and co-author on both papers.
Researchers then sought to understand the mechanism behind retinoic acid’s work.
The second trimester is marked by a rapid increase in synaptic development. These connections begin in the PFC and gradually decrease when they reach motor and sensory neurons in the brain’s rear.
To better understand why that is the case, Shibata and Pattabiraman in the second study focused on the gene CBLN2 which is found to be enriched in the PFC and plays a crucial role in the formation of these connections. The gene is also directly controlled by RA. CBLN2 is activated earlier in the frontal region of the developing human brain than it is in other areas. They also discovered that CBLN2 is present in the human brain for longer periods of time than in macaques and mice. This suggests that the PFC plays a central role in the development of human-specific traits.
Researchers also found small genomic deletions near the CBLN2 gene that were found to be conserved in human and chimpanzee evolution however, they were not found in other animals. To see whether these deletions played a role in the development of PFC connections they introduced the deletions into the mouse genome. The deletions were identified in mice with a human-like expansion CBLN2 and a 30% increase in connections in the adult mouse PFC.
These papers together show that understanding the genetic mechanism behind advanced cognitive abilities begins with localized productions of RA. This triggers a variety of downstream genes including CBLN2. This determines the location and time at which these vital brain connections are created.
“The prefrontal cortex is the brain that integrates information from the other parts of the central nervous system, and provides top-down control over the mind, attention emotions and actions” Sestan said. “It is also central to problems in a variety of neuropsychiatric disorders. It may also become sick from subtle changes in the connections that comprise the human brain.
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