Learning is the means whereby we acquire new working knowledge about the world. Memory is the means whereby we retain that knowledge over time. Our abilities to learn and remember are essential to our sense of self and our ability to function effectively in daily life. Memory is the glue that holds our mental life together. As a result, we are who we are in large part because of what we have learned and what we remember from past experience.
But what is memory? How does the brain capture and sustain it? Why does memory sometimes fail us? Those simple questions, of course, have exceedingly complex answers, and many biological details about the process of memory in humans and other animals remain unknown.
HHMI investigator Eric R. Kandel of Columbia University, however, has provided a good start. His studies of the molecular basis of learning and memory underpin much of what we know about how events are recorded by the brain, processed by individual nerve cells, and etched in gray matter. For his work on learning and memory, Kandel was awarded a share of the 2000 Nobel Prize in Physiology or Medicine.
In the 1960s, Kandel began his studies of learning and memory by focusing on the behavior of the sea slug Aplysia, which he found to be a marvelously tractable system in which to study the cellular basis of these abilities. With only about 20,000 nerve cells — compared with the roughly thousand billion in humans — and a well-delineated neural circuitry, it proved possible to zero in on a biologically interesting reflex pathway. Like humans and other animals, Aplysia is capable of learning to modify this reflex, and this learning involves making memories.
Kandel found that the cellular basis for memory depends on persistent changes in synapses, the connections between nerve cells. The differences in the strength of these connections come about through learning. Kandel found that when, in the simple withdrawal reflex, the gill reacts to touch, the connection between the sensory nerve cell and motor nerve cell of the reflex are activated. When the sea slug was taught to ignore a harmless touch, the connections between the sensory nerve cell and motor cell weakened. When the same light touch was coupled to an unpleasant fearful stimulus the animal became sensitized. It would now react strongly to the light touch because the same set of connections had strengthened.
Kandel later discovered that short-term memory is kindled by the modulation of synapses and that long-term memory is sustained by the activation of genes. The formation of memories, Kandel determined, is a function of biochemical changes that occur at the synapse. To make short-term memories, the proteins involved in a chain of events at the nexus of nerve cells are chemically altered by the addition of phosphate groups. To cement a memory for the long haul, proteins are added at the synapse to make new connections with sensitization and lose connections with habituation.
In the 1990s, he turned from studying simple forms of learning to more complex forms using genetically modified mice and showed that similar principles for short and long term memory were at work here as well.
By laying a foundation for understanding the events that shape our ability to learn and remember, Kandel's work has helped us understand not only the cellular processes that occur during the acts of learning and remembering, but also - through his work on mice - where things can go wrong when dementia and other illnesses that affect memory arise. The cellular processes revealed by Kandel are among the targets of drugs used to alleviate these disorders of memory. Pinpointing the activity of individual nerve cells engaged in the process of learning and memory may help in the development of new, more effective agents to treat diseases that affect the brain.
Photo: Matthew Septimus