"More Complex Than the Milky Way?" --Project 'Blue Brain' and New Insights into the Biochemical Makeup of the Human Brain
"Consider the human brain," says physicist Sir Roger Penrose. "If you look at the entire physical cosmos, our brains are a tiny, tiny part of it. But they're the most perfectly organized part. Compared to the complexity of a brain, a galaxy is just an inert lump."
The results of this study are based on extensive analysis of the Allen Human Brain Atlas, specifically, the detailed all-genes, all-structures survey of genes at work throughout the human brain. This dataset profiles 400 to 500 distinct brain areas per hemisphere using microarray technology and comprises more than 100 million gene expression measurements covering three individual human brains to date.
“This study demonstrates the value of a global analysis of gene expression throughout the entire brain and has implications for understanding brain function, development, evolution and disease,” said Ed Lein, Ph.D., Associate Investigator at the Allen Institute for Brain Science and co-lead author on the paper. “These results only scratch the surface of what can be learned from this immense data set. We look forward to seeing what others will discover.”
The results of this study show that, despite the myriad personalities and cognitive talents seen across the human population, our brains are more similar to one another than different. Individual human brains share the same basic molecular blueprint, and deeper analysis of this shared architecture reveals several further findings:
Neighboring regions of the brain’s cortex are more biochemically similar to one another than to more distant brain regions, which has implications for understanding the development of the human brain, both during the lifespan and throughout evolution. The right and left hemispheres show no significant differences in molecular architecture. This suggests that functions such as language, which are generally handled by one side of the brain, likely result from more subtle differences between hemispheres or structural variation in size or circuitry, but not from a deeper molecular basis.
Despite controlling a diversity of functions, ranging from visual perception to planning and problem-solving, the cortex is highly homogeneous relative to other brain regions. This suggests that the same basic functional elements are used throughout the cortex and that understanding how one area works in detail will uncover fundamentals that apply to the other areas, as well.*In addition to such global findings, the study provides new insights into the detailed inner workings of the brain at the molecular level – the level at which diseases unfold and therapeutic drugs take action.
Many previously uncharacterized genes are turned on in specific brain regions and localize with known functional groups of genes, suggesting they play roles in particular brain functions. Synapse-associated genes—those related to cell-to-cell communication machinery in the brain—are deployed in complex combinations throughout the brain, revealing a great diversity of synapse types and remarkable regional variation that likely underlies functional distinctions between brain regions.
“The tremendous variety of synapses we see in the human brain is quite striking,” said Seth Grant, FRSE, Professor of Molecular Neuroscience at the University of Edinburgh and collaborating author on the study. “Mutations in synaptic genes are associated with numerous brain-related disorders, and thus understanding synapse diversity and organization in the brain is a key step toward understanding these diseases and developing specific and effective therapeutics to treat them.”
Fully integrating several different kinds of data across different scales of brain exploration, the Allen Human Brain Atlas is an open, public online resource that details genes at work throughout the human brain. Data incorporated into the Atlas include magnetic resonance imaging (MRI),diffusion tensor imaging (DTI), as well as histology and gene expression data derived from both microarray and in situ hybridization (ISH) approaches.
Users of the Allen Human Brain Atlas comprise a diverse array of biomedical researchers — primarily neuroscientists — throughout the world. They include scientists who study the human brain itself, as well as those working in model systems, providing a rare and important opportunity for them to probe the relevance of the findings to humans. Currently, more than 5,000 unique visitors access the Atlas each month.
The Allen Human Brain Atlas is available via the Allen Brain Atlas data portal at www.brain-map.org.
This past September the EPFL’s Blue Brain Project (BBP) announced it has identified key principles that determine synapse-scale connectivity by virtually reconstructing (in supercomputer) a cortical microcircuit and comparing it to a mammalian sample. These principles now make it possible to predict the locations of synapses in the neocortex, the researchers say.
“This is a major breakthrough, because it would otherwise take decades, if not centuries, to map the location of each synapse in the brain and it also makes it so much easier now to build accurate models,” says Henry Markram, head of the BBP.
One of the greatest challenges in neuroscience is to identify the map of synaptic connections between neurons. Called the “connectome,” it is the holy grail that will explain how information flows in the brain. A longstanding neuroscientific mystery has been: do all the neurons grow independently and just take what they get, as their branches bump into each other, or is a branch specifically guided by chemical signals to find all its target?
To solve the mystery, a research team from the Blue Brain Project set about virtually reconstructing (simulated on a computer) a cortical microcircuit based on unparalleled data about the geometrical and electrical properties of neurons — data from over nearly 20 years of painstaking experimentation on slices of living brain tissue.
Each neuron in the circuit was reconstructed into a 3D model on a powerful Blue Gene supercomputer. About 10,000 virtual neurons were packed into a 3D space in random positions according to the density and ratio of morphological types found in corresponding living tissue. The researchers then compared the model back to an equivalent brain circuit from a real mammalian brain.
To their great surprise, they found that the locations on the model matched that of synapses found in the equivalent real-brain circuit with an accuracy ranging from 75 percent to 95 percent, which means that neurons grow as independently of each other as physically possible and mostly form synapses at the locations where they randomly bump into each other.
A few exceptions were also discovered, pointing out special cases where signals are used by neurons to change the statistical connectivity. By taking these exceptions into account, the Blue Brain team can now make a near perfect prediction of the locations of all the synapses formed inside the circuit.
The goal of the BBP is to integrate knowledge from all the specialized branches of neuroscience, to derive from it the fundamental principles that govern brain structure and function, and ultimately, to reconstruct the brains of different species — including the human brain — in silico.
The current paper provides another proof-of-concept for the approach, by demonstrating for the first time that the distribution of synapses or neuronal connections in the mammalian cortex can, to a large extent, be predicted, EPFL scientists say.
This discovery also explains why the brain can withstand damage and indicates that the positions of synapses in all brains of the same species are more similar than different. “Positioning synapses in this way is very robust,” says computational neuroscientist and first author Sean Hill, “We could vary density, position, orientation, and none of that changed the distribution of positions of the synapses.”
They went on to discover that the synapses’ positions are only robust as long as the morphology (form) of each neuron is slightly different from each other, explaining another mystery in the brain — why neurons are not all identical in shape. “It’s the diversity in the morphology of neurons that makes brain circuits of a particular species basically the same and highly robust,” says Hill.
Overall this work represents a major acceleration in the ability to construct detailed models of the nervous system. The results provide important insights into the basic principles that govern the wiring of the nervous system, throwing light on how robust cortical circuits are constructed from highly diverse populations of neurons — an essential step towards understanding how the brain functions.
They also underscore the value of the BBP’s constructivist approach. “Although systematically integrating data across a wide range of scales is slow and painstaking, it allows us to derive fundamental principles of brain structure and hence function,” explains Hill.
For more information: Sean L. Hilla, Yun Wangb, Imad Riachia, Felix Schürmanna, and Henry Markram. Statistical connectivity provides a sufficient foundation for specific functional connectivity in neocortical neural microcircuits. PNAS September 18, 2012. doi: 10.1073/pnas.1202128109 (open access) neural microcircuits.
Image credit: Allen Institute for Brain Science