Molecular neurobiologist Dennis O'Leary spoke about his work on mechanisms governing the development of specialized brain regions recently, giving the European Dana Alliance for the Brain (EDAB) / Max Cowan lecture. O'Leary, who has spent most of his career at the Salk Institute of Biological Sciences in La Jolla, California, gave the talk at the 9th FENS Forum of Neuroscience in Milan earlier this month.
O'Leary obtained his Ph.D. from Washington University in St. Louis, and then moved to the Salk Institute, where he worked as a postdoctoral fellow in Cowan's lab between 1983 and 1985. During this time, he made important discoveries about the formation of neuronal connections in the mouse, revealing some key principles of brain development.
For example, the human brain contains trillions of synapses, the connections between nerve cells, whose exquisite precision is essential for proper functioning of the organ. O'Leary's early work showed that these connections do not start off so precisely. Rather, they initially form somewhat haphazardly, with immature neurons forming more connections than they need and then selectively eliminating inaccurate and exuberant ones.
About a century ago, the German neurologist Korbinian Brodmann identified 52 distinct regions of the human cerebral cortex, based on the types of cells and their arrangements within the 6 cortical layers. Each area is specialized for processing different kinds of information, although this is not set in stone-the brain is remarkably adaptive, and some regions can assume different roles to compensate for insults and injuries.
Among these specialized regions are the supplementary and primary motor cortices, which are located in the frontal lobes, and are involved in the planning and execution of movements, respectively; the primary somatosensory cortex, located further back in the parietal lobes, which process touch information; and the visual cortex, found further back still in the occipital lobes, which contains dozens of smaller areas, each of which processes different aspects of information entering the brain from the eyes.
In recent years, O'Leary has shifted his attention to study the mechanisms by which these distinct areas are generated, focusing on the primary visual cortex (Area V1), which contains cells that are sensitive to simple features of the visual field, such as contrast and the orientation of edges.
To develop into a specialized brain region, specific regulatory genes must be expressed in immature neurons. These genes encode proteins called transcription factors, which drive groups of cells to differentiate along a particular developmental pathway by activating certain sets of genes and deactivating others.
Working with various colleagues and collaborators, O'Leary has identified many of the regulatory genes involved in patterning brain areas, implicating one- called Emx2-as being particularly important in generating Area V1. Studies in genetically engineered mice show that Emx2 confers Area V1 identity upon young neurons, and that the size of this area is closely related to the level of Emx2 activity within it.
Deletion of another regulatory gene, called COUP-TF1, results in compression of Area V1 and an enlargement of the primary motor and somatosensory sensory areas. COUP-TF1 encodes a transcription factor that represses those regulatory genes that specify motor areas and so enhances Emx2 function. It thus balances the development of all three areas, and regulates their size and their positions relative to one another.
In addition, "two or three decades ago there was a big debate as to the extent to which extrinsic mechanisms played a role in regulating area patterning," said O'Leary. Some researchers argued that these genetic factors play a predominant role, while others, including Cowan, emphasised the importance of other mechanisms. "Now we know that both [types of] mechanisms work in co-operation to generate [specialized brain] areas during the course of development."
The most important of the external factors is the sensory information entering the brain, which generates patterns of electrical activity that refine the developing circuitry. In the visual system, information from the eye travels via the optic nerve to the thalamus, deep in the brain. From here, it is relayed to Area V1, which begins to process the information before passing it on to so-called higher-order visual areas.
Before any pattern has emerged in the developing brain, differences in gene activity can be seen between Area V1 and other areas of the visual cortex, with specific genes being expressed in either V1 or all the others, and delineating the boundaries between them.
Last year, O'Leary and his colleagues showed that electrical activity in the bundle of nerve fibers connecting the thalamus to the visual cortex is essential to maintain this genetic pattern. Destroying the bundle alters the genetic activity: Those genes normally delineating V1 from the other visual areas are expressed uniformly throughout the entire visual cortex.
"This tells us that the sensory inputs relaying visual information are critical for generating Area V1 and making it distinct from higher order areas during an early postnatal period of development," said O'Leary. Essentially, he explained, the patterning of brain areas, or at least the visual areas, involves two mechanisms operating in sequence. "High levels of transcription factors specify the visual areas, but then inputs to create the distinction between V1 and other visual areas."
|Dennis O'Leary gives the Max Cowan lecture to a packed house at|
FENS 2014. Photo by Lizzie Gill