In his research on brain plasticity, Mark bear asks questions and designs experiments that challenge conventional views.

The kitten experiment “was the most exciting demonstration of experience-dependent brain plasticity ever,” says Bear. “I wanted to understand the mechanisms at the synaptic level and ultimately at the molecular level.” He focused on a group of receptors known as metabotropic glutamate receptors, or mGluRs, which are especially active during periods of high plasticity.

But he took an unconventional route to the answer. He employed a formula in computational biology known as the BCM theory—for Bienenstock, Cooper, and Munro—a model of how synapses change and respond selectively to stimulation. This theory suggested that LTD is a consequence of synaptic activity that fails to strongly activate the target neuron. Using stimulating and recording electrodes, Bear and his graduate student Serena Dudek looked for LTD in the hippocampus, an easy site to study synaptic physiology. They eventually were able to reliably trigger LTD in hippocampal slices freshly prepared from mice and rats, with both electrical stimulation of synapses and with chemicals that stimulate glutamate receptors. Further experiments showed that LTD was widespread in slices from different brain regions—including the visual cortex.

Next, he temporarily deprived young kittens of sight in one eye in two different ways, either by anesthetizing the retina or by closing the eyelid, which allowed the retinal cells to continue firing nerve impulses randomly. A few days later, after the anesthesia wore off and the closed eyes were reopened, the scientists displayed visual patterns to each eye and measured brain activity.

“What really separates great sailors from less great sailors is that they see things that other people don’t.”

Mark Bear

In animals whose eye had been closed temporarily, synapses had predictably weakened. But in animals whose retinas had been anesthetized—and therefore sent no signals to the brain—the cortex responded about equally to stimuli from both eyes. This suggested it wasn’t the absence of visual stimulation that caused blindness—“use it or lose it”—but a mismatch of activity between the signals the brain was getting from the open and closed eyes. Synaptic strength declined through the active process of LTD. Bear had illuminated the mechanisms of the famous Hubel and Wiesel experiments decades earlier.

“He was willing to stick his neck out,” says Richard Huganir, an HHMI investigator and neuroscientist at Johns Hopkins University, coauthor on several of Bear’s papers and a longtime friend. Bear had used discoveries about how LTD takes place in the hippocampus—where it wasn’t even clear what effects that plasticity had—and applied it to the visual cortex, where the end results were obvious: blindness. The conceptual leap drew flak from fellow scientists. As Bear drily recalls, “I can still remember someone saying, ‘The visual cortex is not a hippocampal slice with eyes.’”

Yet his findings were later replicated. Indeed, Bear’s lab is still working on the problem, publishing important papers in 2009 and 2010 that explore molecular mechanisms for perceptual learning and the mechanisms of visual cortex plasticity. “We half-joke about ‘the curing blindness experiment,’” he says. “We haven’t quite succeeded yet, but we’re going to, I hope.”

“He’s one of the few neuroscientists who pays any attention to theoretical arguments,” notes Leon Cooper, director of Brown University’s Institute for Brain and Neural Systems and Bear’s mentor at Brown. (Cooper—the “C” in the BCM theory—shared the 1972 Nobel Prize in Physics for studies on the theory of superconductivity.) “Mark developed a rather deep understanding of theories of synaptic modification and realized that they depended on assumptions about cell behavior that hadn’t been checked. He set out to check them—and in the process, discovered some remarkable new phenomena, including LTD.”

Cooper says this approach to discovery sets Bear apart from many scientists. “They say seeing is believing, but Mark had to believe in order to see.”

Daring Experimentalist

Fragile X syndrome is the most common inherited form of intellectual impairment and the most common known genetic cause of autism. Though its symptoms vary among individuals, they are profound and devastating: low IQ, seizures, autistic behavior, anxiety, attention deficit, and sometimes an abnormal physical appearance. It strikes 1 in 4,000 boys and 1 in 8,000 girls. There is no cure—only treatments for problems such as anxiety and impulsive behavior.

Fragile X is caused by a mutation in the FMR1 gene, discovered in 1991, which leads to loss of a protein, the fragile X mental retardation protein, or FMRP. Under a microscope, the defective X chromosome looks broken—fragile—where the FMR1 gene is disrupted and mutated. In 1994, researchers created an Fmr1 knockout mouse.

Photo: Jeff Barnett-Winsby

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