Allen Institute for Brain Science

Scientists cannot hope to prevent or cure neurological disease

without a solid understanding of what makes healthy brains tick. But the human brain is an intricate, mysterious machine. Every second, billions of neurons flash electrochemical signals across trillions of synapses.

One year ago today, President Obama announced the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative, a $300 million collaborative research project with the ambitious goal of mapping every neuron in the human brain, with the long-term hope of unraveling the neurological causes of diseases like Parkinson's to autism, which today remain hidden within the black box of the human brain. Today, as part of that effort, scientists at the Allen Institute for Brain Science in Seattle have produced some of the most detailed brain maps that we have seen so far.

One study in the journal Nature, by Ed Lein and colleagues, presents the first comprehensive atlas of the developing human brain. A second paper, by Hongkui Zeng and colleagues, presents the first complete brain-connectivity map for mice.

The Landscape of a Developing Human Brain

Scientists have spent years cataloguing genetic activity across the brain, in search of those rare misread genes that result in crippling disease. Ed Lein and his team resolved to tackle developmental disorders at their source by building a genetic map of the human brain in utero.

"We looked at the developing human brain, which we have extremely little knowledge about," he says. "Our aim was to home in so that we could profile different cells and illustrate how some genes vary across anatomical structures."

Nature

FOLR1, a receptor utilized for proper folate transport in cortex, is most highly expressed in brain areas of new neuron generation during prenatal development. Images: Allen Institute for Brain Science

Lein's research is part of the larger BrainSpan project, an open-access atlas of the developing human brain. A crucial part of the larger Brain Initiative, BrainSpan is a database of transcriptional mechanisms in brain development, or those critical moments when genes are read and expressed. "This project epitomizes the Brain Initiative's intent of forming public–private partnerships to advance neuroscience," he says.

The BrainSpan database holds special promise for identifying candidate genes, or those genes most likely to cause diseases. As a proof of concept, Lein and his team used the database to identify a cluster of genes that is both active in early development and mutated in autism patients. Lein believes that the database will help researchers understand more about autism as well as other neurological disorders by highlighting even more candidate genes.

The next step, Lein says, is to take an even closer look at single brain cells and their genetics. "Now we're pushing toward understanding the nature of individual cells instead of large groups of cells, and at this level, the genes become causative."

Mapping the Connections

Neurological disorders are not isolated events. Every action in the brain is interwoven in layers of cells and tissue, involving complex connections and lengthy pathways. One of the Brain Initiative's biggest challenges will be to map every connection in the human brain so researchers can trace the origins of disease.

Hongkui Zeng is at the helm of the effort to produce a comprehensive connectome—a database of every connection in the human brain. As a step toward this goal, Zeng and her team created a complete connectome of the mouse brain.

Nature

A circular wiring diagram of connections among 215 distinct regions throughout the mouse brain.

"This is really the first comprehensive description of the connections in a mammalian brain," Zeng says. "We now have a structural map of the 86 million neurons and their interconnections."

Before Zeng's research, the only complete connectome database detailed the primitive nematode brain, made up of a paltry 302 neurons. This paper represents a leap to complex mammalian brains. "Researchers can use the map as a guide, experimentally," Zeng says. "They can identify which regions of the brain are involved in a particular behavior and then draw a pathway from start to finish."

The human brain is about 2000 times larger and contains 1000 times more neurons than the mouse brain. But a complete human connectome may not be far off, Zeng says: "I'm optimistic that a comparable human brain map will be generated within the next five to 10 years."

Nature

A high-resolution view of the dense and highly branched axonal projection pattern of the cortico-cortical connections originating from the primary somatosensory cortex.

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