By David N. Leff

One difference between men and women, it's said, is that when out driving, a man will strongly resist asking for directions. Yet, deep in the brains of both sexes lie two twin structures, the hippocampi, which possess neurons that actually make indelible maps of places worth remembering.

As a cerebral seat of memory, the hippocampus is one key site of neuronal loss in Alzheimer's disease, of which declining memory is a diagnostic hallmark. Another disease, herpes simplex encephalitis, also targets hippocampal neurons for destruction. One victim of this memory-erasing infection is a 77-year-old one-time laboratory technician, now known to science by his initials, E.P. Besides ravaging both hippocampi, the virus wreaked bilateral damage on all components of his brain's medial temporal lobe's memory system.

Since surviving that often fatal viral onslaught in 1992, E.P. has suffered from profound amnesia. "Such patients are not capable of any new learning," observed neuroscientist Larry Squire, at the University of California/San Diego, and its affiliated Veterans Affairs Medical Center. "This means that they're very disabled in their daily life, and isolated. E.P. lives at home with his family, and needs supervisory care.

"Intellectually," Squire continued, "he's alert, vigilant, conscious, aware, and does well on IQ tests. However, E.P. is not capable of recalling events or facts that he learned during the decades prior to his injury. But he has intact memory for his childhood, including spatial knowledge of his old environment. His amnesia is so severe that he failed to recognize his examiners, even after 40 visits to his house in one year."

This spatial aspect has led Squire to explore E.P.'s childhood remembrances of the California neighborhood in which he grew up. Results of his research appear in today's Nature, dated Aug. 12, 1999, under the title: "Memory for places learned long ago is intact after hippocampal damage." Squire is its senior author.

"The point of our paper," he told BioWorld Today, "was to address and explore the question of whether or not the role of the hippocampus is exclusively spatial cognition, or possibly declarative memory as well. We tested that by asking E.P. questions about his childhood environment.

"What we found," Squire went on, "was that the hippocampus is important for declarative memory in general, both spatial and non-spatial."

Recent Versus Remote Memories

E.P. moved away from his boyhood home in California's Castro Valley town of Hayward half a century ago, at age 28. Squire and his co-workers rounded up five of his former high school fellow students. They and E.P. responded to a battery of four spatially-related questions, such as describing how they would navigate from their homes to different locations in the area, and what alternate route they would take if a main street were blocked off.

"E.P. performed as well or better than age-matched control subjects," the Nature paper reported. "In contrast, E.P. has no knowledge of his current neighborhood in San Diego, to which he moved in 1993, after becoming amnesic."

"These results show," Squire summed up, "that despite damage to the large part of his temporal lobe, E.P. has intact ability to spatially navigate his childhood environment. And that tells us that this part of the brain, the hippocampus and related structures, has no special spatial status. Rather the system is essential for forming new memories and for recalling recent memories, both spatial and non-spatial.

"There is some evidence that damage to the analogous structures in the bird brain will affect homing in pigeons, for example."

From One Controversy To Another

A relevant but unrelated paper in the same Aug. 12 issue of Nature bears the title: "Time-dependent reorganization of brain circuitry underlying long-term memory storage." Its senior author is cognitive neuroscientist Robert Jaffard, a full professor at the Universiti Bordeaux I in Talence, France.

Squire's study aimed to determine whether the hippocampus is dedicated to spatial mapping only, or is it a more multipurpose memory bank. Jaffard's purpose was to confirm a different controversial hypothesis: Does the hippocampus conserve memory traces for a lifetime, like a computer hard disk? Or, as time goes by, does it transfer its data to other brain structures, probably the neocortex, like a backup disk?

"This is a very long-lasting process," Jaffard pointed out, "because in humans - if this hypothesis is correct - that transfer would take about three or four years; in the monkey 10 or 12 weeks and in rats or mice, four or five weeks."

In their experiment, Jaffard and his co-authors tested 120 mice for their ability to remember, after five days and 25 days, the location of tempting, sugary food pellets in a rotating maze. Via catheters in their carotid arteries, each animal received doses of an isotopic imaging agent, (14C)2-deoxyglucose.

"This is the first demonstration, we think," Jaffard observed, "using a noninvasive technique." (Previous memory-testing work, he pointed out, analyzed collateral damage to the hippocampus in brain surgery to correct epilepsy.) "Here we show that in confirmation of the classical hypothesis, at 25 days the hippocampus is no longer involved, and the brain metabolism within this structure, when the animals is trying to retrieve information, is not more important than in the control mouse, which is in his home cage, doing nothing.

"But during the same time," Jaffard went on, "between five days and 25 days, there is a decrease in the role of the hippocampus. At five days there is an increase in its metabolism, correlating very strongly with memory performance. But at 25 days there is no correlation, and a strong decrease in the hippocampal metabolism. Conversely, at 25 days, there is an increase in cortical activities, elsewhere in the brain. So we think that there is a change in brain organization, which agrees with the classical hypothesis.

"The basic idea," Jaffard observed, "is that we have a brain, and in this brain there are some neurons in which some information is stored. When this information is lost from these same neurons - we forget. I think this is quite fascinating," he concluded, "like astrophysics."