One year past Darwin’s bicentennial, Yale has often been in the news for research on evolution. Down at the Yale School of Medicine, however, researchers are at the forefront of another type of evolutionary research: the evolution of the human brain. Some of the most advanced work in the field is done at the Yale Center for Human Brain Development and Evolution, part of the Kavli Institute for Neuroscience.
Paško Rakić, Dorys McConnell Duberg Professor of Neurobiology and Neurology, is one of the world’s leading scientists in his field. Awarded the Kavli Prize in Neuroscience for his work on neuronal migration and the formation of synaptic connections during embryonic development, Rakić continues to contribute significantly to our understanding of the evolution of the cerebral cortex, the part of the brain that makes us human. The
Kavli Prizes, established by philanthropist-entrepreneur Fred Kavli, are awarded biennially in astrophysics, nanotechnology, and neuroscience. The recipients of the prize in each field are selected by a committee of leading international scientists organized by the Norwegian Academy of Science and Letters.
A two-millimeter layer on the outermost surface of the brain, the cerebral cortex is responsible for much of our cognitive ability. The basic structure of the cerebral cortex is similar in all mammals, but the human cortex has a much larger surface area, allowing for more elaborate neurons, new types of connections, and more complex patterns of organization.
Rakić aims to understand the unique complexity of the human cerebral cortex by studying its development. “What interests me in particular is something that most people do not realize,” he states, “None of the cortical neurons are generated in the cortex.”
Instead, cortical neurons are produced in proliferative areas in the center of the developing brain, called the ventricular zone. The growth and migration of these cells is explained by Rakić’s radial unit hypothesis.
According to this model, neural stem cells, or progenitors, first divide symmetrically in the ventricular zone, resulting in an exponential increase in the number of progenitors. In the next stage, the progenitor cells divide asymmetrically—each division yielding both a neuron that migrates away to the cerebral cortex as well as a progenitor cell that remains in the ventricular zone.
The next step involves the migration of the neural cells to the cerebral cortex. This process is extremely important, since proper functioning of the brain hinges upon the migration of neurons to their correct positions.
Rakić discovered that migrating neurons navigate the path from the ventricular zone to the cerebral cortex by following transient scaffolding formed by non-neuronal cells called radial glia. Neurons produced by progenitor cells climb up this scaffolding and bypass previous layers of neurons in the cerebral cortex, creating a new layer over their predecessors.
Eventually, the neurons form six distinct layers in the cerebral cortex. Neurons produced by a single progenitor cell form a so-called cortical column. As Rakić summarized, “In cell lineages, neurons in the same layer are cousins, those in the same column are siblings.” In the past three decades Rakić has worked on deciphering the molecular mechanism behind neuronal and glial cell interactions during migration.
This research provides insight into neuropsychiatric disorders involving the abnormal positioning of cortical neurons, including mental retardation and childhood epilepsy. The radial unit hypothesis also suggests how the human cerebral cortex may have evolved. Rakić has shown that knocking out genes necessary for apoptosis in mice yields a cerebral cortex that has a larger surface area with more cortical columns, which then forms the convolutions observed in the human cortex.
Though the human brain most likely did not evolve by mutation of these particular genes, Rakić’s experiments with genetically altered mice demonstrate how a single mutation could be responsible for significant enlargement of the cerebral cortex of our ancestors.
“Humans have always been interested in what we are and how we came to be here,” claims Rakić, “And this research shows us how we have become what we are, how the complexity of our brain may have emerged at the genetic, molecular and cellular level.”
Rakić, P. Evolution of the neocortex: a perspective from developmental biology. Nature Rew. Neuroscience, 2009. 10: 724-735.
Torii, M, Hashimoto-Torii, K, Levitt, P, Rakic, P. Integration of neuronal clones in the radial cortical columns by EphA/ephrin-A signaling. Nature, 2009. 461: 524-528.
Bystron, I.; Blakemore, C.; Rakić, P. Development of the human cerebral cortex: Boulder Committee revisited. Nature Rew. Neuroscience, 2008. 9: 110-122.