Neuroscientists make progress towards deciphering the human brain


Former US President Barack Obama at the 2013 launch of the BRAIN initiative with Francis Collins, Director of the National Institutes of Health.Credit: Jason Reed / Reuters / Alamy

In 2013, then-US President Barack Obama launched a US $ 5 billion project to improve our understanding of the human brain. The company would take advantage of new techniques to probe the genetics and physiology of the brain. This week, Nature reports some of the results of the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative.

Although medical science continues to advance, the underlying causes of many brain disorders are not well understood at the cellular level. By the end of the BRAIN initiative in 2026, those involved say it will have created a “gold mine” for clinical researchers working on psychiatric, neurodegenerative and neurodevelopmental disorders.

The data sources described in the current articles come from the BRAIN Initiative Cell Census Network (BICCN). This work should help scientists identify suitable animal models of human brain disorders – such as Parkinson’s disease, motor neuron disease, and Alzheimer’s disease – that share cellular characteristics.

The results of the BICCN project also help explain how neurons and brain circuits are involved in emotions, behavior and learning. These are the first steps towards a more complete understanding of the neural foundations of human cognitive abilities – such as language and reasoning – and will occupy scientists for decades.

The BRAIN Initiative is a collaboration between hundreds of researchers from around the world. Fundamental knowledge of the BICCN project includes a comparison of primary motor cortex cells in three species: mice, marmosets and humans1. The primary motor cortex is the part of the brain responsible for skillful movement, and the findings will help reveal what cellular mechanisms are conserved across species. This will help researchers establish the most suitable model organism for studying neurodegenerative diseases.

The scientists also created an atlas that reveals the locations of about 25 subclasses of cells in the primary motor cortex of the same three species.1,2. The researchers report what neuroscientists call an input-output wiring diagram of this region in mice. This details all of the long-distance neural connections, called axons, that come in and out of this region; this will help neuroscientists in their research on how the brain exercises motor control3.

Researchers also understood how cells in the human neocortex – the thin outer layers of both brain hemispheres – acquire their identity during embryonic development.4. And the project provides scientists with tools to visualize and exploit vast new data sets. In addition, researchers have started to create a genetic “toolbox” that exploits characteristic differences in gene expression in particular cell types to label and manipulate those cells.5. In just a few years, scientists hope to be able to browse an online atlas that tracks the type and location of every cell in the mouse brain. All data will be available free of charge.

However, it’s a big step between creating what researchers call a cell census and understanding the precise information that a particular network of neurons processes. Scientists don’t yet know how the brain processes the flow of sensory information that tells us we’re hungry or cold, or that creates a lifetime of memories.

Some neuroscientists believe they will be able to decipher the basis of these calculations by breaking them down into their individual physiological and behavioral components. Others are pinning their hopes on a universal theory of brain function. One of these theories, called active inference, visualizes the brain using predictive models to regulate physiology and behavior.6. It is based on a processing hierarchy with predictions flowing in one direction and prediction errors reported in the opposite direction.

BICCN researchers provide some of the tools needed to test the theory, including those needed to identify and manipulate cells that might be involved in such a circuit. But one of the experimental challenges will be to combine these tools at the cellular level with models of a particular aspect of perception, cognition or behavior in living animals. Another challenge is to determine to what extent animal models could reveal useful information about the human brain.

The BRAIN initiative has already revealed a high degree of evolutionary conservation between the basic cellular components of the brain in different mammals. This is not surprising, given the extensive genetic overlap and the similarities between species in behaviors such as feeding and reproduction. But it’s also reassuring, given the challenges we already experience with the extent to which animal models provide useful information about the human brain. While the mouse brain is home to around 70 million neurons, the human brain has 86 billion, each bristling with synapses, which allow them to connect to other cells. Many neurons have thousands of synaptic connections.

This difference in scale is one reason why Hongkui Zeng, author of a number of articles in this collection and director of the Allen Institute for Brain Science in Seattle, Washington, says it will take at least 50 years to even create a wiring diagram of a typical human brain. But as the papers published today show, scientists are making significant strides in deciphering the brain and creating tools that will one day unlock the secrets of our unique human cognitive attributes.

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