Primate Brain Atlas Reveals Details of Gene Expression Across Early Lifespan

In an ambitious effort that combines advanced genomics with classical imaging and staining techniques, researchers have composed a time-lapsed portrait of global brain development in the rhesus macaque from early gestation to adulthood.

Other studies in recent years have revealed some details about how genes are expressed in different parts of the brain over time, but this project—published July 13 in Nature—has resulted in the most comprehensive spatial and temporal map of mammalian development to date, noted lead investigator Ed Lein, Ph.D., of the Allen Institute for Brain Science in Seattle.

As part of their analysis, Lein and his team of nearly 100 scientists from multiple institutes compared the trajectory of gene expression in their samples to existing data for rats and humans. They found that 9 percent of genes had differing activity over time in humans compared with macaques, while 22 percent of genes differed between humans and rats. So while this new map was built from a nonhuman model, Lein believes it still should provide meaningful insights into the human brain.

Some insight has already been gained as it relates to the developmental trajectories of schizophrenia and autism spectrum disorder (ASD), psychiatric disorders with strong genetic links.

These disorders share many clinical characteristics—including social and emotional withdrawal, communication deficits, and poor eye contact. What Lein and his colleagues found was that risk genes associated with ASD and schizophrenia were highly active in the same brain region—the neocortex, which is involved in many higher brain functions like language.

The activity was also clustered in the same types of cells, namely postmitotic cells (progenitor cells that have finished their cycles of proliferating and are in the process of maturing and forming connections with other neurons). In comparison, genes associated with microencephaly were active in premitotic brain cells, which would lead to less proliferation and smaller brains.

The only major difference between schizophrenia and ASD was timing, according to the findings. Autism-related gene activity was highest during the prenatal period (though many genes were also somewhat active after birth), while schizophrenia risk genes didn’t turn on until around three months after birth, which would be consistent with the later onset of this disorder.

This concurrence in space but variance in timing also suggests that while clinical symptoms of these illnesses may appear similar, there likely are differences in the underlying causes. Autism risk genes, for example, impact early processes like the ability of a neuron to form appropriate connections, while schizophrenia risk genes may alter the ability of neurons to change or refine existing connections.

This intriguing observation may be only the first of many, as all of the information gathered by this team has been placed in the National Institutes of Health (NIH) Blueprint Non-Human Primate Brain Atlas, which contains a wealth of imaging, anatomical, and informatics data.

“This tremendous resource is freely available to the research community and will guide important research into the causes of many neurodevelopmental disorders for years to come,” said Michelle Freund, Ph.D., a program officer at the National Institute of Mental Health (NIMH) Office of Technology Development and Coordination, in a statement.

This project was funded by a contract from NIMH as part of the NIH Blueprint for Neuroscience Research. ■

An abstract of “A Comprehensive Transcrip-tional Map of Primate Brain Development” can be accessed here. The NIH Blueprint Non-Human Primate Atlas is available here.