Neuroscientist Gary Lynch at the University of California, Irvine, proposed that the fundamental act by which a memory was encoded involved a nearly instantaneous physical restructuring of portions of brain cells, called neurons. That restructuring allowed neurons to be built into small networks. Each small network would be a memory, he thought. Lynch’s research focused on a structure in the brain called the hippocampus, long thought to be involved in memory. Most neurons in the hippocampus have roughly triangular bodies. Slender fibre extensions called dendrites sprout from the top and bottom. The branches coming out of the top are called apical dendrites. Those coming from the bottom are called basal dendrites. Also coming out of the bottom is a single larger extension called an axon. All along their lengths, the dendrites are marked by microscopic nubs called spines, thousands of them per dendrite. The axons of one neuron extend to meet the dendritic spines of other neurons. These dendrite-axon junctions are the synapses. Lynch proposed that the dendritic spines at these junctions changed shape during a process known as long-term potentiation (LTP), which resulted in the strengthening of the bond between a dendrite and an axon. The remodeled dendrites, he said, were the base elements of memory. There are about 100 billion neurons in the human brain. Each neuron has dozens of dendrites, and each dendrite has thousands of potential synapses. So the synapses offered immense storage capacity. But how could storage be so long-lasting? “For me it was really, really obvious it had to be structural, but beyond that, what could I tell you?” Lynch said. Laura Colgin, a postdoc in the lab, was intrigued by weak electric pulses that apparently originated in the same area as the mossy fibres. Other researchers had reported similar low-frequency waves occurring elsewhere in the brain during sleep and periods of wakeful rest. They called them sharp waves. No one knew what the sharp waves did until Colgin discovered that in the right circumstances, they seemed to erase LTP. In other words, if LTP was the mechanism for memory, sharp waves could be a mechanism for forgetting In Lynch’s work, it was clear that LTP was greatly diminished in elderly rats, but there were no experimental data to support the notion of middle-aged decline. If LTP were the underpinning of memory, and memory began declining in middle age, then LTP’s decline should mirror that of memory. Lynch had a vague idea that one reason no one had ever found LTP decline in middle-aged animals was that everyone had looked in the wrong places. That they did so was largely a matter of convenience. The apical dendrites are more numerous and easier to study, so most research focused there. Lynch sent graduate student, Chris Rex, who was a student of Lynch’s collaborator, Christine Gall., off into the basal dendrites of middle-aged rats, where Rex found distinct failure of LTP. Since Colgin’s discovery that forgetting could be the result not of a failure but of an active process, Lynch had begun formulating a broader view of LTP. He began to see it as the result of an exquisitely balanced set of inputs. Some of the inputs encouraged LTP. Others inhibited it. Lynch had known since the early 1990s that too much of a molecule called adenosine outside a neuron interfered with LTP. He suggested Rex administer a drug known to block adenosine to brain slices of middle-aged rats where LTP was inhibited. After a couple of weeks of false starts, including another computer crash and some difficulty administering the drug, Rex decided to wait until after LTP was induced to block the adenosine. In February 2005, Rex erased the LTP deficit. It was completely, utterly gone. Full LTP was restored. In brain science, even many successful experiments have vague results that could be read in various ways. Seldom is anything this clear-cut. The result was astonishing. What Rex seemed to have discovered was a major cause —if not the cause—of one of the most persistent, widespread real-world effects of ageing: forgetfulness. And it seemed to be caused mainly by too much of a single molecule, adenosine. After weeks of repeated failures on almost every other front, Lynch was ecstatic. “You mean this crap actually works?” he said. “You don’t expect to see a result this black-and-white. You expect ambiguity. Ageing does not occur uniformly even across a single neuron. It’s an instant default explanation for memory loss. It’s getting to the point where we might have to start believing we were right.” Eniko Kramar had struggled for weeks with the experiment that was intended to validate Lynch’s hypothesis that the dendrites of neurons were physically reorganised during LTP. She spent hours alone in the imaging room, studying her results. She produced stunning images showing the cellular reorganisation Lynch had hypothesised as the end stage of LTP, the step that locked a memory in. She did a series of experiments to block LTP, and the cellular reorganization disappeared. She incorporated Rex’s adenosine findings. The results were clear-cut. Adenosine blocked the reorganization. Take it away, and the process worked perfectly. She blocked the integrins, the molecules that stitched everything else into place. The LTP disappeared. After decades of struggle, all of the pieces were falling into place. Lynch’s long-standing hypothesis was being borne out to the smallest detail.-terry mcdermott (Los Angeles Times)
