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April 7, 2014
An Atlas of the Developing Human Brain
Scientists released the first comprehensive 3-D atlas of gene expression in the developing human brain. The resource will help reveal the early roots of brain-based disorders such as autism and schizophrenia.
Animal studies have provided insights in the basic mechanisms of brain function. But the human brain has many unique qualities. One key area, for example, is the neocortex, the outermost brain region involved in higher functions such as action and thought. The neocortex is smooth in rodents; in humans and non-human primates, it’s elaborately folded. Specific regions of the neocortex are also known to differ greatly between humans and nonhuman primates.
The structure and function of the human brain is guided by gene expression patterns during prenatal development. Many psychiatric disorders show altered gene activity in the cortex, suggesting harmful changes during development of this region. However, our understanding of the transcriptome—when and where genes are turned on—in the developing brain has been limited.
Led by Dr. Ed Lein at the Allen Institute for Brain Science, researchers studied 4 donated, intact human prenatal brains—2 from 15–16 weeks and 2 from 21 weeks post-conception. The work was funded by NIH’s National Institute of Mental Health (NIMH) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) as part of the BrainSpan Atlas of the Developing Human Brain. This project aims to profile gene expression throughout the course of brain development. The first set of results appeared online on April 2, 2014, in Nature.
The scientists gathered data using a variety of genomic and imaging techniques. Regional patterns of gene expression were analyzed in thin cryosections using in situ hybridization. Custom microarrays revealed gene expression levels in laser-microdissected brain regions. Ultra-high resolution MRI and diffusion tensor imaging provided structural information about the brains. The scientists combined the gene activity data with the neuroimaging data and anatomical reference atlases.
The results provide a powerful map to pin brain areas to genes tied to neurodevelopmental disorders and human-specific brain functions. Among the results, the researchers identified transcription patterns reflecting differences in cortical development between humans, nonhuman primates, and rodents.
“Knowing where a gene is expressed in the brain can provide powerful clues about what its role is,” Lein says. “Many neuropsychiatric diseases are likely the result of abnormal brain development during prenatal life. An anatomically precise molecular atlas of the brain during this time period is a first step to understanding how the human brain develops normally and what can go wrong.”
“Although the many genes associated with autism and schizophrenia don’t show a clear relationship to each other in the adult brain, the BrainSpan Atlas reveals how these diverse genes are connected in the developing brain,” says NIMH Director Dr. Thomas R. Insel. “Findings of what goes on early in the prenatal brain can lead to the development of biomarkers for diagnosing brain disorders and for matching patients to treatment options most likely to be successful.”
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Reference: Transcriptional landscape of the prenatal human brain. Miller JA, Ding SL, Sunkin SM, Smith KA, Ng L, Szafer A, Ebbert A, Riley ZL, Royall JJ, Aiona K, Arnold JM, Bennet C, Bertagnolli D, Brouner K, Butler S, Caldejon S, Carey A, Cuhaciyan C, Dalley RA, Dee N, Dolbeare TA, Facer BA, Feng D, Fliss TP, Gee G, Goldy J, Gourley L, Gregor BW, Gu G, Howard RE, Jochim JM, Kuan CL, Lau C, Lee CK, Lee F, Lemon TA, Lesnar P, McMurray B, Mastan N, Mosqueda N, Naluai-Cecchini T, Ngo NK, Nyhus J, Oldre A, Olson E, Parente J, Parker PD, Parry SE, Stevens A, Pletikos M, Reding M, Roll K, Sandman D, Sarreal M, Shapouri S, Shapovalova NV, Shen EH, Sjoquist N, Slaughterbeck CR, Smith M, Sodt AJ, Williams D, Zöllei L, Fischl B, Gerstein MB, Geschwind DH, Glass IA, Hawrylycz MJ, Hevner RF, Huang H, Jones AR, Knowles JA, Levitt P, Phillips JW, Sestan N, Wohnoutka P, Dang C, Bernard A, Hohmann JG, Lein ES. Nature. 2014 Apr 2. doi: 10.1038/nature13185. [Epub ahead of print]. PMID: 24695229.
Funding: NIH’s National Institute of Mental Health (NIMH) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).