Rodolfo Llinás’s fearless approach to neurophysiology has redefined our thinking about individual neurons and how they create movement and consciousness.

Some Nerve

“My interest in science came from basic curiosity,” says Rodolfo Llinás of the New York University School of Medicine. “My interest in the nervous system came from my grandfather.” As a precocious preschooler, Llinás lived with his paterfamilias, a psychiatrist who ran his practice from home. There, the young boy encountered individuals with a cavalcade of psychiatric and neurological conditions, including one patient who experienced an epileptic seizure in the waiting room.

“I remember being amazed,” says Llinás, who asked his grandfather why the man would behave that way. “‘He didn’t want to do it. He couldn’t help it. His brain did it,’” his grandfather explained. For Llinás, the idea that the brain had a mind of its own was eye opening. “And the more I talked to the old man about these things,” he says, “the more I came to see that everything we do, everything we understand, everything we are, is focused on the brain.”

Llinás has kept his focus on the brain ever since. In addition to mapping out the detailed biophysics of neural activity in the squid giant synapse, Llinás has painstakingly catalogued the distinctive electrical properties of individual nerve cells in the central nervous system. His decades of labor have revealed that certain neurons can generate oscillating currents, an activity that helps to coordinate movement and could even give rise to consciousness.

“He has a real passion for understanding how the brain works and he’s been fearless in adopting whatever techniques will allow him to make progress,” says Terry Sejnowski. “Rodolfo is not only a leader in the field, his work is foundational and inspirational.”

“Rodolfo is one of the most revered, distinguished neurophysiologists in the field today,” says Howard Hughes Medical Institute investigator Terry Sejnowski of the Salk Institute for Biological Studies in La Jolla. “He has a real passion for understanding how the brain works and he’s been fearless in adopting whatever techniques will allow him to make progress. Rodolfo is not only a leader in the field, his work is foundational and inspirational.”

“We’re now in a golden age of cellular neuroscience,” says former postdoc Brian MacVicar of the University of British Columbia. “And its groundwork was built on Rodolfo’s work.” Read complete Article here below

SMOOTH MOVES

Growing up in Bogota, Colombia, Llinás didn’t much enjoy his early years of formal schooling. “I thought it was mostly wrong,” he says. High school was an improvement, as he was taught by intellectuals who fled Europe during World War II. Following in his family’s footsteps, Llinás then trained as a physician. But he soon found himself attracted to research. “I wanted to know the nature of what we are,” he says. “To understand the physiological basis of thought.”

He attacked the problem by studying the systems that allow us to move, because “thinking” and “doing” tend to go hand in hand. “Thought is a basically premotor act, an internalized movement,” says Llinás. “So I wanted to understand the mechanisms by which we turn thought into motion.”

As a research fellow at the University of Minnesota in the early 1960s, Llinás started to study the motor neurons that activate muscles, and how these cells can be inhibited by nerves emanating from the brainstem. He was presenting his results at a meeting in Holland when he received an unusual proposition. “It happened that Sir John Eccles had been sitting in the front row,” says Llinás. “At the end of the talk, he got up and said, ‘Well, I’m not sure about those results. You must come to Australia.’” In Eccles’s lab at the Institute of Advanced studies in Canberra, Llinás quickly backed up his earlier findings—demonstrating that motor neurons could receive inhibitory signals through their dendrites. So Eccles invited him to stay for his PhD.

By 1965, Llinás was back in the Midwest, delving more deeply into the dense network of neurons that ultimately pull muscles’ strings. He focused his attention on a few particular brain regions. The reticular formation, which is part of the brain stem, acts as an on/off switch for motion. “So if you are asleep, your motor neurons are asleep,” says Llinás. Indeed, it’s the reticular formation that keeps animals from acting out their dreams. The reticular formation feeds information to the cerebellum. Tucked just underneath the back end of the brain, the cerebellum is more of a tactician. “It puts the impetus to move in the context of where the animal is, from a motor point of view,” says Llinás. He also probed the inferior olive, which lies next to the reticular formation and coordinates movement by communicating with Purkinje cells in the cerebellum.

Llinás’s goal was to take his studies of movement to the level of single cells. “What I wanted to do was single-cell intracellular recording,” says Llinás. “At the time that was rare, in the sense that most people didn’t know how to do it.” But that didn’t stop Llinás.

“I have a colleague in England who says sometimes you just have to be bloody minded,” says Roger Traub of IBM’s T.J. Watson Research Center in New York. “And Rodolfo was bloody minded. He would take on these very difficult experiments.” For example, Llinás used a sharpened electrode to monitor electrical activity directly from small branches on alligator Purkinje cells. Contrary to the dogma of the day, he discovered that these dendrites could send messages as well as receive them. “It was just an astonishing technical tour de force,” says Traub of the work published in Science in 1968—studies that Llinás extended to mammalian cells 10 years later.

Llinás’s examination of frog Purkinje cells led to “one of the first realistic models of an active neuron based on actual morphology and physiology,” says former postdoc Jim Bower of the University of Texas Health Science Center at San Antonio. That 1970s-era model, says Bower, “was way ahead of its time.”

MAKING WAVES

More important, work Llinás conducted throughout the 70s and 80s—in Chicago, Detroit, and ultimately at NYU—showed that all neurons are not the same. “They are not simply elements that respond to synaptic input,” he says. “Rather, they have their own intrinsic activity: they have a point of view, they have a personality.” That means that the brain can be active on its own—even without any input from the outside.

“That was a key insight,” says Sejnowski. It meant that the brain is not a reflex machine, with stimuli coming in and responses going out. “Each neuron has a life of its own,” he adds. “This endogenous activity allows animals to be autonomous—to make decisions independently from things going on outside them.”

He also discovered that for some neurons, this intrinsic activity can make waves. “Single cells can oscillate,” says Llinás. “Their membrane potential goes up and down in a sinusoidal fashion.” And because groups of cells in a particular brain region are very similar, says Llinás, “they can hold hands and oscillate together.” That rhythm, he says, “is really gorgeous.” But why is it important? Because it allows neurons to synchronize their activities. “To jump up and hit a tennis ball, you have to activate millions of motor neurons simultaneously,” notes Llinás.

The same sort of rhythmic oscillation, Llinás found, also occurs in neurons within the thalamus, a brain region that regulates consciousness and sleep. “So it’s now possible to say something about the cellular basis of sleep,” says Traub. “Without a mechanism, you have no hope of ever understanding sleep’s function. Which is a big theme in Rodolfo’s work. He sees the big picture, from the properties of cells to the properties of whole organisms.”

“Everyone who gets into neuroscience wants to figure out how the brain works,” says Alan Kay, a collaborator at the University of Iowa. “But you quickly realize that to survive you have to narrow your interests to one tiny aspect of the field. Rodolfo has an amazing ability to cover the entire span of neuroscience, from the microscopic to the macroscopic—from single neurons to overall brain function.”

“Here’s a man who spends summers at Woods Hole working on the squid giant synapse, and in winter he’s putting patients into an MEG machine,” says Edward Jones of the University of California, Davis. Over the past few years, Llinás has taken to charting thalamic oscillations in human subjects—the idea being that dysfunctions in these clockwork neurons might lead to disorders in movement and speech, and even to depression. “He can translate his findings on the opening and closing of a single calcium channel into how neurons function in the higher integrative capacity of the brain. That’s remarkable. Very, very few people are able to think about the brain in the way Rodolfo does.”

And Llinás supports colleagues who also think outside the box. “He won’t push just any crazy idea,” says Traub. “But if an idea is novel and different, and it fits in with his intuitions, he’ll take a stand. Rodolfo doesn’t just go with the flow. He goes with what he believes.”

And he goes the distance. Over his 40 or so summers in Woods Hole, Llinás has laid out the mechanics of synaptic transmission—in particular, the role that calcium plays in stimulating neurotransmitter release. “That was just a beautiful, beautiful series of experiments,” says MacVicar of the seminal studies in the 1970s, work that several people insist should have garnered Llinás a Nobel Prize. “I still show that data when I teach synaptic transmission.”

For Llinás, Woods Hole is a “magic place. You remove yourself from administration,” he says, “and do experiments until midnight.” And beyond.

“He doesn’t seem to sleep,” says Traub. “He works like a fanatic and gets people in his lab to work like fanatics.”

“I’ve been with him at Woods Hole, and he’s there at the rig doing recordings until 12 o’clock at night,” agrees Kay. But for Llinás, the late-night sessions recording the activity at the squid giant synapse are about more than just the data. “He can see past the wiggles on the oscilloscope,” says Traub, “to what lies beyond.”

And what he sees brings him great joy. “One night, Rodolfo told me, ‘Every time I make a recording, I get the same thrill I got the very first time,’” says Kay.

Bower agrees. “That’s where he derives his energy for science,” he says. “To this day, the moment Rodolfo positions those electrodes, he sits back, looks at the oscilloscope, and says, ‘That’s beautiful.’ And he’s been doing this for more than 35 years. But for him, the system is a thing of beauty. He has a deep aesthetic connection to what he’s doing, and to the brain. And he sees himself as uncovering beauty.”

Source: The Scientist Original article

Volume 24 | Issue 9 | Page 52 Date: 2010-09-01 – By Karen Hopkin

© Seth Olenick

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