Ingrid Wickelgren
The New York Times, December 3, 1996
In bottles lining a wall of a Long Island laboratory there are swarms of fruit flies with an unusual ability. They have been endowed with a gene that gives them photographic memory.
In bottles nearby are their less fortunate cousins genetically engineered for forgetfulness. And one floor below scamper another product of the genetic engineer’s art: amnesiac mice.
These flies and mice are the product of efforts to identify the genes and molecules that are involved in laying down long-term memory. Researchers have found a protein that serves as a kind or logical switch, signaling to the nerve cell whether a memory is to be stored for a fleeting moment or permanently engraved in the mental archives.
This protein switch has its counterparts in flies, mice and humans. “At a nuts and bolts level, our brains are working by the same principles ·and mechanisms as, those of little fruit flies,” said Dr. Alcino Sliva, a neuroscientist at Cold Spring Harbor Laboratory on Long Island who has led much of the mouse work.
Indeed, the recent work on this switch, called CREB, has given scientists “a new vantage point for understanding how memory works.” said Dr. Eric Kandel, a· neurobiologist at Columbia University’s College of Physicians and Surgeons in New York City who has pioneered research on the molecular basis of memory. Many molecules, be noted, are involved in governing something as complicated as long-term memory. But CREB has afforded the most enticing clue to the mystery of how the brain decides what it will and will not remember for good.
“CREB is the clearest example of a molecule involved in long-term memory” to come out of behavioral studies, said Dr. Larry Squire, a neuroscientist at the Veterans Affairs Medical Center in San Diego.
Dr. Howard Eichenbaum, a neuroscientist at Boston University, said: “I’m very excited. It’s amazing that CREB is so specific to memory.”
“The CREB story is growing stronger as new evidence” provides powerful links between the protein and various memory processes, he said.
The discovery of CREB’s role in fruit files and mice bas far-reaching implications. It could answer such questions as why cramming for a test does not work in the long run, or why certain emotional events become instantly etched in the mind. Medically, the findings could possibly lead to drug treatments for memory loss, dementia and post-traumatic stress disorder.
When the CREB switch in a cell is turned on, researchers believe, it sets off the synthesis or other proteins that cement lasting memories by supporting the growth of new connections between nerve cells. When it is turned off, CREB halts the production of those cementing proteins, thus preventing unnecessary memories from forming.
Studies done in Dr. Kandel’s laboratory on sea-slug cells supplied the first hint of a role for CREB in memory. But the recent fruit fly work provides the most striking behavioral demonstration that CREB works as a memory switch.
In fruit files, as in other species, CREB is a so-called transcription factor, a protein in the cell nucleus that binds to DNA and causes nearby genes to be spun into protein. Researchers have discovered how the nerve cell flips the CREB switch on and off. A protein called the CREB activator turns it on, and CREB repressor turns it off.
The gene sequences used to make the CREB activator and CREB repressor proteins have also been identified, and a few years ago Dr. Jerry Yin, a biologist now at Cold Spring Harbor, endowed fruit files with extra genes so that one group acquired an extra CREB activator and the other gained a CREB repressor. To test their memories, he teamed up with Dr. Timothy Tully, a geneticist at Cold Spring Harbor.
Dr. Tully developed a test that measures how fast the files learn to associate an odor with an electric shock in a way that produced a lasting memory. Normal files need 10 training sessions to form a persistent recollection or the test. Flies with an extra dose of CREB repressor could not form lasting memories at all. “That showed beyond reasonable doubt” that CREB repressor blocks long-term memory, Dr. Tully said.
But most surprising of all, the insects fortified with an extra CREB activator gene needed just a single training session. “This implies these flies have a photographic memory,” Dr. Tully said. He said they are just like students “who could read a chapter of a book once, see it in their mind, and tell you that the answer is in paragraph 3 of page 274.”
The state of the CREB switch, at least in fruit flies, seems to depend on the prevailing balance in the nerve cell between supplies of CREB activator and CREB repressor. A preponderance of CREB activator is needed for memory storage, said Dr. Tully, who published his and Dr. Vin’s results last year in the journal Cell.
Ordinarily, there is an equilibrium between activator and repressor, researchers believe. CREB repressor remains present, they suspect, to prevent the storage of boring and unnecessary detail – the clutter in a room, the babble ln a bar, the “ums” in a spoken sentence. “Memory is not about storing information; it’s about storing useful information,” Dr. Sliva explained.
The CREB repressor can be thought of as a memory filter. It dominates, the theory goes, until something important happens, like an emotionally powerful event, that either removes CREB repressor from nerve cells or increases the levels of CREB activator enough to make brain cells lay down a permanent memory. This is presumably the mechanism by which people vividly remember where they were when President John F. Kennedy was assassinated or, as in Dr. SIiva’s case. seeing a little red bicycle he wanted at the age or 5.
Dr. Silva bas recently moved the fruit fly work forward by studying a similar system in experimental mice. Mice learn what is safe to eat by smelling what is on one another’s breath, behavior that Dr. Sliva exploited to measure his mice’s ability to remember what they learn. He has round that mice with a defect in the CREB activator gene that causes them to make much less of its product than is normal are virtually unable to form long-term memories. His article is to appear in January in the journal Current Biology.
Dr. Silva also discovered that his forgetful mice could be made to remember much better when they had short lessons with rests in between. The treatment looks a lot like what good students do – study ln many short bouts instead of cramming just before a final. In both cases, Dr. Sliva suggested, the small amount of available CREB activator in the relevant brain cells may limit the amount of information an animal, or a person, can take in at one time.
Shorter bouts of learning separated by rest, he proposed, allow time for the available activator to recycle from the previous learning trial and respond again – a molecular argument for steady studying. “We can now give you a biological reason why cramming doesn’t work,”
Dr. Tully said. He and others also hope to find chemical ways of enhancing brain cell function in people with dementias like Alzheimer’s disease and even age-related memory loss. Dr. Tully and Dr. Yin are forming a company called Helicon Therapeutics to parlay their knowledge of CREB into pharmaceutical products.
Of course, such products must depend on knowledge of many molecules other than CREB. “It’s hard to link such a complicated process as learning and memory to just one molecule,” said Dr. Richard Good· man, a neuroscientist at Oregon Health Sciences University in Portland. Others agree and are seeking to identify the molecular machinery surrounding CREB, including the thousands of proteins whose genes CREB controls. They are also trying to link molecular memory processes to larger scale changes in brain cells and brain cell circuits.
Indeed, many secrets of memory seem poised to unravel from work on CREB. “CREB is one or the first truly solid molecular clues about memory,” Dr. Sliva said. And memory. Dr. Kandel added, is “who we are.”