Memory’s Molecules: Learning the Brain’s Vocabulary

The brain operates at many different levels, each of which requires its own kind of scientific investigation. At one level, researchers study how different brain regions communicate with one another. At another, they study how just a few individual brain cells, or neurons, send one another electrical and chemical signals. In an even more detailed examination, researchers might look at the individual molecules at work in single neuron.

Understanding mental processes requires understanding how the brain functions at all levels, from network to neuron to molecule. But what is happening in the brain at the molecular scale has proven especially difficult to study — particularly in the case of memory. It’s clear that memory relies on the constantly changing connections between neurons, which alter how frequently they send signals to one another. But no one can yet explain exactly how neurons use molecules to strengthen and weaken their associations, nor which molecules they use. For 21st-century scientists, discovering the molecular mechanisms that underlie memory would be as big a breakthrough as discovering the molecular structure of DNA was in 1953.

As Society for Neuroscience president Tom Carew put it, “we need to understand the basic vocabulary of the brain in the same way a poet understands the basic element of his art — the word.” For scientists studying memory, the “word” is the neuron and all its molecular mechanisms. And some researchers are determined to translate the brain’s molecular vocabulary.

In the fall of 2009, researchers at Cold Spring Harbor Laboratory in New York identified a particular protein as the conductor of the spacing effect, a fundamental learning process in which study sessions spaced out over time form more effective memories than closely packed sessions. Their findings, published in the October 2009 issue of the journal Cell, could one day help treat individuals with certain memory disabilities.

Yi Zhong and colleagues used the common fruit fly as the subject of their study. Flies do in fact have memory and have been used to study many memory and learning paradigms, according to Zhong. Usually, researchers teach flies to avoid certain areas of their environment using a combination of strong odors and mild electric shocks in repeated learning sessions. Once the flies commit the negative associations to memory, researchers can test the changing strength of these memories over time.

Zhong’s team discovered that a protein called “corkscrew” mediates how long flies must rest between learning sessions to form long-term memories.

During resting intervals, corkscrew triggered a dramatic rise and fall in the activity of certain molecules critical for communication between cells. In order for long-term memories to form, these waves of molecular activity needed enough time during resting intervals to finish their course. If a new learning session interrupted a preceding wave of molecular signaling, the flies would not remember anything for very long. It’s still unclear exactly which molecules are interacting during this wave of chemical activity, but it is clear the process is crucial to memory formation.

What’s more, a mutant form of corkscrew caused the waves of molecular activity to degrade more slowly, meaning flies with this mutant protein needed much longer resting intervals to form long-term memories. Enhancing the expression of normal corkscrew, in contrast, allowed flies to form long-term memories after cramming, with hardly any resting intervals at all — an unprecedented finding. Zhong believes that in these cases an excess of normal corkscrew caused the waves of biochemical activity to rise and fall incredibly quickly, reducing the required length of the resting intervals between learning sessions.

According to Zhong, corkscrew’s true function in the brain is to measure the relative significance of an experience by recording how often it’s happened. From an evolutionary perspective, an organism should only spend its resources forming long-term memories if absolutely necessary. “Our interpretation is that corkscrew is a kind of molecular counting mechanism,” Zhong explained. “Forming long-term memory is costly — it can shorten the lifespan of the fly and make them produce less progeny. Only repeated shocking experiences will produce long-term memory.”

Corkscrew is extremely similar to a human protein called SHP2. Research has implicated a mutant form of SHP2 in Noonan syndrome, a relatively common disorder (occurring in one in every 1,000 to 2,500 births), characterized in part by memory deficits. New therapies could target the gene responsible for the mutant protein. Alternatively, educators could structure special learning environments for afflicted individuals by permitting them longer resting periods between study sessions.

Zhong’s researchers aren’t the only ones searching for memory’s molecules. Lisa Marshall at the University of Lubeck in Germany thinks that Interluekin-6 (IL-6), an important immune system molecule, could be mediating sleep’s influence on memory. Although scientists have long known that memory cannot function normally without sleep, few studies have discovered relevant molecular mechanisms.

Marshall invited 17 healthy young men to the lab and handed out a little assigned reading. After giving some subjects a nasal spray infused with IL-6 and others a placebo, she sent everyone to bed. Subjects who received the IL-6 spray remembered more of what they read the following morning than those who received the placebo.

Unfortunately, an over the counter memory-enhancing nasal spray won’t appear in pharmacies any time soon. Producing IL-6 is quite expensive, Marshall explained, because researchers must genetically engineer batches of bacteria to express human DNA.

The German team, whose work was published in the October 2009 issue of the Federation of American Societies for Experimental Biology Journal, still isn’t sure why or how IL-6 influences the link between sleep and memory. This uncertainty reflects how difficult it is to explain complex brain functions in terms of the cell and molecule. Such thorough explanations require many different kinds of research.

One approach, used by both Zhong and Marshall, is to examine the role of a particular molecule. “I believe that to understand the brain you need to focus on specific systems,” Zhong said. The brain’s molecular activity is remarkably consistent across species, explained Zhong, because the fundamental molecular mechanisms that brains and nervous systems rely on evolved very early in evolutionary history. “If we understand it in the fly, we can understand it in other organisms,” he added.

An equally crucial approach considers how entire networks of neurons interact to enable cognitive abilities, what Marshall called a “top-down” approach. In contrast, both she and Zhong investigate the brain from the bottom up, searching for memory’s molecules.

“Top-down research can sometimes give the bottom-up research a sense of where to investigate,” Marshall said. “You hope to meet somewhere in between.”

Carew, for one, is inspired by new interdisciplinary efforts. “There is a deep interest in cognition and in approaching it at a very sophisticated molecular and biological level,” he said. “People are learning each other’s vocabularies.”