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Feldheim research shows nature and nurture combine to form the right visual connections

Tuesday, May 6, 2008
Written by Branwyn Wagman

A mouse lacking in the gene for neural axon guidance molecules called ephrins and also the gene that causes the retina to fire action potentials will see the world without definition along the horizontal axis. Source: Charlotte Oelerich and Cris Niell, UCSF

Research on the genetic and molecular processes involved in development of the visual system reveals the line between nature and nurture in visual mapping. The work, reported in the February 28, 2008 issue of the journal Neuron, was conducted collaboratively in two laboratories belonging to the California Institute for Quantitative Biosciences (QB3): the UCSC laboratory of developmental biologist David Feldheim, with graduate student Cory Pfeiffenberger, and the UCSF laboratory of neurophysiologist Michael Stryker.

“We are trying to understand how neural connections form in the proper way during development,” Feldheim said. “Connectivity is key for function.”

He explained that neurons form the right connections by two mechanisms. One mechanism is genetic cues that tell the neurons where to go. The other is activity-dependent cues, where the firing patterns of the neurons themselves help organize the connections.

“You can kind of think of that as nature versus nurture,” Feldheim said.

They simulated the nature and nurture components of visual mapping by using mutant mice. Feldheim said, “We have mice that are mutants in a class of axon guidance molecules called ephrins. We also have mutant mice that are deficient in the way the retina fires action potentials during development.”

A deficiency in the retina’s action potential firing simulates the nature aspect, because action potentials are also fired in response to environmental stimuli.

“We asked what happens to the visual map when either one alone or both is missing.”

To investigate the answer, the Stryker lab supplied a functional imaging technique that showed the mice’s response to visual stimuli.

The image on the left shows the brain map of a wild type mouse viewing a line moving horizontally across a computer monitor. On the right, a mutant mouse lacking genes for both ephrins and action potential firing views the same line. Source: Stryker lab, UCSF

With this technique, a camera looks at the mouse brain, detecting which neurons in the brain are responding as the mouse views a computer screen. The computer screen has a bar going across or up-and-down the mouse’s visual field. When the bar is in a certain place on the screen, a set of neurons fires, and the researchers give this set of neurons a color. As the bar moves across the screen, they determine which neurons fire next and give those neurons a different color.

It was already known that the neurons in the mammalian brain associated with what the animal sees directly parallel the animal’s visual input. “There is a specific order. What your retina sees is relayed to the brain in a topographical map,” Feldheim said. Their relationship with respect to each other in a two-dimensional map stays the same.

“We asked, is it genes or activity that is needed to make the two-dimensional map in the brain?” Feldheim said.

“In a wild-type mouse, the neurons that see the line in one place are next to each other,” he said. “In mice mutant for the ephrins, there was only moderate disturbance in the way these maps formed. The same is true in the activity mutant.”

But what about mice deficient in both? “Pow! It completely disrupts the maps,” he said.

He added, “When only one is missing, the organism compensates with the remaining mechanism.”

“In development, it is not just genes or just activity. Here we can look in a model system and see that it is both, and dissect out the relative contribution of each.” For visual field development, he said, “It seemed like it’s probably close to fifty-fifty.”

Not only does this research show the nature–nurture balance, Feldheim said, “This provides an answer to a long-standing question of what the coordinate system is for vision.”

It could have been either Cartesian—based on x-y coordinates—or polar—based on a system of angles and vectors. “In a polar system, you’d expect to see defects on both axes,” Feldheim explained.

As it turns out, missing these genes only disrupts visual perception of the bars going across the screen, along the horizontal axis.

Feldheim said this research confirms what he had predicted, “It is Cartesian. The way development works, there are two independent axes of mapping information.”

The research covered in the recent Neuron paper described the conscious vision controlled by the brain’s cerebral cortex. “But you have other visual centers that are more important for reflexive behaviors, such as putting what you want to see in the center of your visual field and moving your head to follow something.”

Current research in his laboratory is showing that vision related to reflexive behavior reacts differently from conscious vision. “If we do the same experiments in the reflexive areas, taking away ephrins has a strong effect, much less than taking away the activity part.”

This shows a tip toward the nature component in conscious vision. “The nature–nurture ratio may differ depending on the part of the brain. Reflexes may be more hard-wired.”

The first authors of the Neuron paper are Jianhua Cang and Christopher Niell of UC San Francisco. In addition to Feldheim, Stryker, and Pfeiffenberger, the coauthors include Xiaorong Liu of Northwestern University.