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Chasing Memory / First of four parts

One man's epic quest for understanding

What happens when we encounter a new experience that enables us to recall it later at will? And what goes wrong when we can't? Gary Lynch has spent decades seeking the answers.

August 19, 2007|Terry McDermott | Times Staff Writer

The person lynch was most unhappy with was Eniko Kramar, a postdoc neurophysiologist who was running the crucial experiment Lynch expected to prove his basic theory of memory encoding. Kramar could hardly be regarded as a slacker. She typically worked longer and harder than anyone in the lab, excepting Lynch.

Having come relatively late to neuroscience, she was approaching a point in her career where she needed to make discoveries, then move on to lead her own lab, or remain locked in subordinate roles. She had become, like Lynch, a virtual scientific monk, paring away other activities in her life until all that remained was the lab. Unlike Lynch, she had actually had a wide range of outside interests -- family, friendships, athletics.

Although it seemed to her at times that the more she did, the more Lynch demanded, they were in important respects a good team. He was a synthesizer. She was a pointillist, a technically minded bench scientist who took care to not extrapolate beyond the results on her screen. She sometimes found even those suspect, wondering if some mistake hadn't deceived her into false optimism.

When Kramar returned from her brief Christmas holiday, she plunged back into the experiment, which she had been planning since the previous summer. It involved using a novel staining technique that would let the researchers actually see changes in neurons.

For The Record
Los Angeles Times Sunday, August 26, 2007 Home Edition Main News Part Page News Desk 2 inches; 81 words Type of Material: Correction
"Chasing memory": The glossary accompanying the Aug . 19 memory article in Section A defined genes as "strings of amino acids that make up an organism's genome, a sort of blueprint from which the organism is built. Individual genes are strings of amino acids; each string contains instructions for building a particular protein." The definition should have said: "Genes: strings of DNA that form a blueprint from which the organism is built. Each gene contains instructions for building a particular protein."

A key part of Lynch's conception of LTP, and thus memory, was that the process initiated a micro-scale remodeling of the interior skeleton of cells at synapses.

It is generally agreed that memory is somehow built out of networks of brain cells called neurons. How those networks get built is the central question of memory research.

Researchers have established that when you experience a sensation in the outside world -- perhaps seeing, smelling or touching something -- the sensation is translated by the sensory organs into an electrical signal that is routed to neurons in the brain, where, if the signal is strong enough within individual neurons, it causes chemicals called neurotransmitters to be released onto neighboring cells.

Neurons are not physically connected to one another. There are tiny spaces called synapses between them. The neurotransmitters travel across the synapses. Think of the neurotransmitters as keys. On the surface of the neighboring neurons are molecules that receive the neurotransmitters. These are called receptors. Think of the receptors as locks. When neurotransmitters attach to receptors on the surface of a receiving cell, when the key opens the lock, channels open into the cell.

It is because the neurons are not physically connected that communication between them is never certain. You never know whether a key is going to find a lock. This is thought to be why any cognitive activity, including memory, is approximate. Sometimes the connections are made; other times they are not.

The LTP hypothesis can be summarized by saying: After two neurons have successfully made contact once -- that is, after the neurotransmitters have attached to receptors -- the next time the original cell releases its neurotransmitters, there is a much greater chance the neighboring cell will receive them. There is a greater chance a key will find a lock.

Lynch's longtime goal was to figure out why. The general outline of his hypothesis was this: Once a neurotransmitter attaches to a receptor, opening a channel into the cell, calcium pours through the channel, setting off a chemical cascade inside. The end result of that cascade is an interior reorganization of the cell.

A key molecule involved in the interior remodeling is called actin, which is a structural protein used throughout mammalian biology to build internal cell scaffolds. In the same way the outside of a house reflects the shape of the frame beneath it, when an internal cell scaffold is altered, the exterior of its cell is changed too. In this case, Lynch thought a portion of the cell would become squatter, with more surface area. The greater surface area provides space for more receptors. The greater the number of receptors, the greater the chance of a neurotransmitter finding one and making a connection between the two cells.

The lab had recently developed a method in which the actin scaffold proteins could be labeled with a dye. The labeling would occur only after the actin changed shape; in lab terminology this was referred to as polymerized actin.

The idea of Kramar's experiment was that after inducing LTP with the usual electric stimulus, portions of the cells would restructure, creating polymerized actin. Because the actin was stained, you could actually see it under a microscope. If you could see it, it would mean Lynch had been correct in proposing that the whole physical remodeling, the actin polymerization, was the end result of LTP.

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