Learning and Memory -- A Long-Term Journey

“If you really want to understand the brain, you have to take the top off and look inside,” says Roger Nicoll, MD. But don’t flip your wig just yet -- Nicoll's UCSF research team is learning about the human brain by working with lab mice and the occasional frog, not with humans. Nicoll is discovering molecules and mechanisms that underlie learning and memory. Memories such as those associated with places or emotional events -- called episodic memory -- depend on the healthy functioning of the hippocampus. This seahorse-shaped structure underlies the brain’s cerebral cortex. Nicoll has identified molecular and cellular events that allow memories to form there. If you want to change your mind, you have to change your brain. Nicoll’s focus is on changes in nerve circuitry that can arise over time, a phenomenon called “plasticity.” The questions Nicoll continues to explore in the lab are likely to be relevant to the development of new drugs -- to treat degenerative brain diseases such as Alzheimer’s, for instance. Of course, learning and memory factor greatly into our individual identities. And like many of us Nicoll has thought about how the brain generates the mind. But he does not dwell on it. Instead he favors experiments that yield clearer insight into a more basic question -- How do nerve cells in the brain talk to one another? Nicoll’s discoveries have helped to make it clear that learning and memory require strengthening of signaling between nerve cells in the brain. At the level of the nerve cell -- known as a neuron, and the junctions linking neurons -- called synapses -- he has identified events responsible for this enhanced signaling.

Inauspicious Beginnings

Although Nicoll today enjoys many honors and accolades, his entry into the field of brain research followed a mediocre early academic career. His acceptance into University of Rochester Medical School with a C-plus average might be considered miraculous by today’s standards. Fortunately, as a young medical student he experienced an epiphany while reading two books by esteemed Australian-born neuroscientist and Nobel laureate Sir John Eccles, a pioneer in electrophysiology. “It was so exciting to find out that with his approach you could study how individuals nerve cells work by putting electrodes into a single neuron,” Nicoll recalls. “It was a way to eavesdrop on the activity of the intact brain.” Nicoll took a year out of medical school to work in a lab at the National Institutes of Health, learning how to conduct experiments in electrophysiology. Nicoll suffered from dyslexia growing up, but was always good at figuring out how to put things together and completing tasks by hand, he says. He discovered that this aptitude translated well into the laboratory world of experimental neuroscience. Nicoll completed his medical internship, but since then he has not practiced medicine. His first faculty position was at the University of Buffalo, where he had a chance to work with Eccles, who also was a faculty member. Nicoll, a professor in the departments of Cellular and Molecular Pharmacology and Physiology, joined the UCSF faculty in 1975. When Nicoll started his career, little was known about the biochemistry of signal transmission between neurons in the brain. Eccles first perfected his electrophysiological techniques on nerves in other parts of the body. “We knew neurons in the brain used chemicals to signal, but we didn’t have a clue about what those chemicals were,” Nicoll says. “A synapse in the brain was a total black box. It was an incredibly exciting time. I wanted to know how neurons in the brain talk to one another. They have a very rich language, and that’s what I wanted to understand.”

Evidence after a Century of Speculation

That some event or change in the brain must occur for us to learn -- and to retain what we have learned -- has long been appreciated by neuroscientists. One early idea was that memories were preserved as a result of continual reverberations of electrical signals in the brain. According to Nicoll, that might play a role in working memory -- remembering a phone number long enough to dial it, for instance. But long-term memory persists even among those who have recovered from episodes during which no electrical activity can be measured -- in patients who had been on a respirator following a barbiturate overdose, for example. A century ago, Santiago Ramón y Cajal, an early Nobel laureate, suggested that changes in the synapses connecting neurons were the basis for learning and memory. In the decades that followed, researchers learned that an electrical signal is transmitted though one neuron until it reaches a synapse. There the impulse triggers the release of chemical neurotransmitters contained in vesicles – little sacs, essentially -- from this pre-synaptic neuron. In the post-synaptic neuron, receptors receive the signal from the neurotransmitters. For synapses in the brain the neurotransmitter is typically the amino acid glutamate. If the chemical signal is strong enough, it may again be translated into another electrical impulse that travels through the post-synaptic cell to the next synapse down the line. In addition, researchers discovered that the brief repetitive activation of a synapse resulted in long-lasting strengthening of this signaling connection between neurons. This strengthening is called long-term potentiation (LTP). For cellular changes that underlie learning and memory, LTP has all the properties that neuroscientists had envisaged. Nicoll eventually determined that the persistent increase in synaptic strength during LTP is due to the recruitment of glutamate receptors into the synapse from the post-synaptic neuron. Is LTP really responsible for memory? “I think the evidence is really quite good,” Nicoll says. A genetic manipulation in mice that knocks out an enzyme crucial to LTP results in learning and memory defects. This type of experiment has been repeated for several molecules that are needed for LTP, he says.

Which Side of the Synapse Are You On?

A few years after Nicoll first championed a post-synaptic mechanism for LTP in the late 1980s, two other lab groups independently and very prominently published experiments declaring that long-term enhancement of electrical signaling instead was due to changes on the pre-synaptic side of the synapse. The debate has persisted in successive permutations to this day, and it engages hundreds of neuroscientists. It’s not merely an academic question, Nicoll says. The outcome may determine in some cases whether drug development for neurodegenerative diseases focuses more often on the release of signaling neurotransmitters on the pre-synaptic side, or on the control of the receptors that transmit those signals on the post-synaptic side. The momentum shifted again in the mid-1990s, after Nicoll and his colleague Robert Malenka, MD, PhD, designed and completed a new experiment. Although their new results confirmed the previous data others used to champion a pre-synaptic mechanism, Nicoll and Malenka were able to show that the actual changes were postsynaptic in origin. It was the interpretation of the first groups’ experiments had been incorrect, Nicoll says. The new results and their reinterpretation were rapidly embraced by the neuroscience community. Nicoll has sometimes been accused of declaring victory for the post-synaptic camp too early, but he’s not much inclined to tone down his presentation of LTP as he conceives it. “I play by the rules,” he says. “If I lose I take my hat off, but I am competitive.”

Neuroscience Prize Winner, Mentor to “Geniuses”

Nicoll’s skill and drive to discover have led to a rare degree of success and recognition among his colleagues in a popular field that draws more than 30,000 researchers to the annual meeting of the Society of Neuroscience. Researchers cited the work of UCSF scientists nearly one million times during the past decade, and by this measure of scientific importance, Nicoll’s work ranks near the top. This year, his fellow neuroscientists have judged him worthy of the National Academy of Sciences’ Neuroscience Award. The prize has been presented to only nine scientists over the past two decades. Nicoll will travel to Washington, DC to accept the award on April 25. In 2006, Nicoll shared the prestigious Neuroscience Prize of the Peter Gruber Foundation with Matsao Ito, a Japanese scientist and advisor to the RIKEN Brain Science Institute. Philanthropist Peter Gruber noted that, “In a global perspective, Drs. Ito and Nicoll have contributed importantly, over many decades, to furthering neuroscience at all levels, from molecular and cellular to the circuit level, as well as to the training of a new generation of outstanding neuroscientists.” Indeed, just as Nicoll was inspired by Eccles, a branching network of leading neuroscientists also can be traced back to Nicoll. Malenka, for one, now a professor at Stanford, is a luminary in the field of synaptic research. Two scientists who trained in Nicoll’s lab at the same time each in recent years has received a prestigious MacArthur Fellowship, often referred to as a “genius award.” They are former postdoctoral fellow Lu Chen, PhD, now an associate professor at UC Berkeley, and former graduate student Rachel Wilson, PhD, now an assistant professor at Harvard Medical School. Nicoll says the ongoing success of his former students and research fellows reflects their innate talent and his own knack for bringing good scientists into the lab -- more than any training he provides. However, he does try to create an environment in which lab members feel that their work is intensely vital. “Science is the most exciting thing that you could ever possibly do in your life, and the act of discovery is just unbelievably special,” he says. “To share that with people -- it just doesn’t get any better than that. All these people are incredibly special to me because we did it together.” Photo by Christine Jegan

Related Links:

2010 National Academy of Sciences Award in the Neurosciences 2006 Gruber Neuroscience Prize Roger Nicoll – Neuroscience Graduate Program at UCSF