Duke Researchers Find That Brain Wiring Depends On Orchestrated Stimulation Of Nerve Cells

April 16, 1997

DURHAM, N.C. -- In animal studies, neurobiologists at Duke University Medical Center have found that the ability of mammals to correctly perceive the world depends on internally generated patterns of electrical activity that occur even before they open their eyes for the first time.

The neurobiologists liken these internal patterns to a "symphony" of electrical bursts between developing neurons in the brain that help "tune" visual abilities. If this symphony is consistently interrupted, as it was in the Duke experiment, animals cannot as easily distinguish vertical from horizontal.

The results of the study, in which the researchers stimulated the optic nerves of newborn ferrets and studied the effects on brain development, are published in the April 10 issue of the journal Nature.

The findings offer strong evidence that the process of wiring the brain is neither one of nature nor nurture, but an interaction between the two, according to Duke researchers Michael Weliky and Lawrence Katz, a Howard Hughes Medical Institute investigator at Duke.

"This shows that the brain can organize itself to generate a set of instructions that tells nerve cells how to build the circuitry of vision, but it also demonstrates that this process can be disrupted by outside influences," Weliky said.

That internal circuit-building is important, he said, because it may mean much of brain development is dependent on these patterns of electrical instruction to establish effective neural circuits. And if that's true, "we may have a new way of thinking about how brain abnormalities, like subtle forms of miswiring, can occur before birth," Katz said. "Anything that disrupts these sets of developmental instructions, such as drugs or abuse, or certain pharmacological agents, could lead to neurological deficits."

Brain researchers know that electrical activity is present during development of neural systems, but they have long debated whether that activity actually carries information or is just a part of the innate physical development of the brain. To address the question, Katz and Weliky decided to experimentally define developmental neuronal activity as either "permissive" or "instructive." Permissive activity, they explained, simply allows development to proceed, but does not carry any specific information. In contrast, instructive activity requires specific types of activity in the brain and actually encodes information on how to construct brain circuits. "There is something special about the patterns of activity that allow the development to happen," Weliky said.

"Using the analogy of music, if intrinsic activity in the developing brain was simply permissive, noise alone would allow normal development," Katz said. "But instructive development would depend on the specific pattern of sound, or the type of activity going on in the brain."

The researchers wanted to determine specifically whether newborn animals see with the same "specificity" that adult animals have. "As soon as they are born, cells in the visual system of many mammals are almost as precisely tuned as those in adults. How can that happen when they have not yet seen the world?" Weliky asked.

To understand the role of activity in development of the brain's visual cortex, Katz and Weliky used newborn ferrets as animal models. At birth, ferrets' eyes are closed and their visual systems undeveloped, the equivalent of other mammals weeks before birth. Thus, they offer scientists easy physical access to an undeveloped visual system in order to study formation of visual circuitry.

The researchers attached electrodes around the optic nerves of the ferrets to deliver a slight electrical pulse every 30 seconds for a period of several weeks. "If development is permissive, and all you need is 'noise,' then if you turned up the volume, more activity should work better," Katz said. "But if it is the pattern of activity that is important, then changing that pattern by adding new stimulation should result in a change of instruction."

The researchers then studied electrical signals from the visual cortex of the experimental animals and compared them to a group of control, or unstimulated, ferrets.

Neurons in the visual cortex are organized into "orientation columns." Neurons within these domains "favor" lines of different orientations, such as vertical or horizontal; that is, they exhibit a stronger electrical signal when they "see" an object oriented either horizontally or vertically, according to researchers.

Katz and Weliky found that in both experimental and control groups, the columns were intact and similarly arranged. However, they discovered that individual neurons within these orientation columns responded differently when stimulated. In control animals, neurons responded strongly to lines of a narrow range of orientation. In the experimental, stimulated group, the "loosely tuned" neurons responded to a much broader range of orientation.

Based on this deficiency, the researchers surmise that the experimental animals would not be able to make fine distinctions between angles. The scientists plan a follow-up study to precisely measure the animals' altered sense of orientation.

"The development of vision appears to be a perfect nexus between nature and nurture," Katz said. "The basic apparatus is very resistant to manipulation through activity patterns. But the tuning of individual neurons is an instructive process, which requires either self-generated activity patterns or interactions with the external world."

Duke University

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