BERKELEY -- Neuroscientists thought they understood the basic process.

During very early development, while we're still in the womb, the different areas of the brain are wired like a nation-wide phone network.

Only later do our eyes, ears and other senses turn on and begin firing signals through the network - analogous to person-to-person phone calls - that prune and fine-tune the connections so that our senses are mapped in fine detail on the cerebral cortex.

A study reported in the July 24 issue of Science points out an important exception to this scenario. Susan Catalano and Carla Shatz of the University of California, Berkeley, found that even in very early development, electrical firing is essential if the nerve cell axons growing out of the thalamus are to make the right connection in the neocortex of the brain.

The thalamus is a vital way station within the brain. All of the information coming from the sensory organs, such as the eyes, ears and skin surface, passes through the thalamus on its way to the neocortex. The neocortex is the highly folded layer of neurons on the surface of the brain that is responsible for such functions as language processing. In other words, Catalano says, it is the brain structure that makes us uniquely human.

"This finding has potentially important clinical implications," said Catalano, who conducted the research as a postdoctoral fellow in Shatz's lab at UC Berkeley and recently moved to the California Institute of Technology. "Drugs such as nicotine, which can affect electrical activity within the brain, have the potential to disrupt circuit formation in a developing infant's brain at very early stages, when the major circuits of the brain are being formed. The possibility that developing brains are vulnerable to disruption by activity-altering agents at such early times suggests important areas for future research."

The finding is also a warning to neuroscientists who have assumed that electrical activity in the brain during early development is nonexistent or unimportant.

"Almost all experimentalists working on the mammalian cerebral cortex, from mouse to man, have made that assumption, including us," said Shatz, professor of molecular and cell biology and an investigator in the Howard Hughes Medical Institute at UC Berkeley. "But without this electrical activity in the brain during early development, the connections to the cortex get really screwed up - the visual system ends up sending its early connections to the auditory (hearing) or even somatosensory (touch) systems."

Like a commuter trying to get to work during rush hour, a growing axon must thread its way through a throng of other axons that are headed in many different directions in the developing brain, Catalano said. Axons are the wire-like extensions of nerve cells that carry electrical signals from one place to another in the brain, and during development they must navigate across long distances (many centimeters) to reach their correct address within the brain.

If the axon gets lost, brain circuits cannot form normally and, like the commuter showing up at the wrong office, the axon may not be able to do its job. So how do axons find their way?

Traditionally, scientists studying the mechanisms of axon navigation think in terms of molecular guidance cues. Molecules located in specific places in the brain can tell a growing axon to "grow here", "don't grow there" or "make a left turn here." The collective distribution of these molecules in the developing brain forms a pathway that the axon can follow to get to the right place.

But Catalano and Shatz suspected that the situation might be more complicated than that in the wiring of the cerebral cortex. The brain is too complicated, and the genome too small, for there to be a molecular address at every possible target location in the brain. They suspected that there might be another potential source of guidance cues for the growing axons: electri

To test their hunch, they decided to block electrical activity within the developing brain with a neurotoxin made by the Japanese puffer fish. Their suspicions were confirmed: in the absence of activity many axons fail to find their way to the correct address. Instead they become confused and wander into other regions they normally bypass.

"If the growing axon is like a car, then the highway pavement and traffic signals would be like the guidance molecules," Catalano explained. "Demonstrating that neural activity is critical for axon navigation is like adding a Global Positioning System into the mix; its a whole new level of information that the axon can potentially use to guide its way towards the appropriate target. "

The connections from the thalamus to the cortex are not randomly organized: specific groups of nerve cells within the thalamus (called nuclei) connect up to specific areas of the neocortex. This precise organization, or "map," is critical for proper brain function. In order to form this circuit correctly during development, groups of axons coming from specific places within the thalamus must navigate across the vast expanse of neocortex. They must bypass incorrect areas of the neocortex and choose just the right area to connect with. But without electrical activity, the axons become lost.

How does electrical activity produce this effect? While that is not currently known, clues can be found in studies of other regions in the brain. Previous work from Shatz's lab has shown that very early in development, when the axons from the eye are still navigating toward their targets in the brain, waves of electrical activity sweep across the retina. This means that axons which are nearest-neighbors are electrically active at the same time. Simultaneous activity could alter the molecular environment of the pathway through which the axons grow and allow cohorts of axons to keep together during navigation.

Ever since the pioneering work of Nobel Laureates David Hubel and Torsten Wiesel, it has been known that the pattern of electrical activity carried by different sets of axons can influence the physical shape of the connections made by those axons. During the last phases of development, axons from the thalamus form many branches as they spread out through the neocortex to make their final sets of connections. These branches are literally shaped like the branches of a tree, and hence are called the "terminal arbor".

Changes in the axon's pattern of electrical activity can change the shape of the tree that forms. Less activity results in a shrunken, gnarled axon tree. Surrounding axons with normal levels of activity form many more branches that grow into the shrunken tree's territory, just like their counterparts in nature that grow into the sunlit space created when a neighbor falls.

While the role of electrical activity in the final stages of thalamic axon branch formation had been well established, the possibility that a related process might be crucial in early development during axon navigation remained uninvestigated until now.