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Study Offers Glimpse of Molecules That Keep Memories Alive

Problems in how the brain sustains “working memories” may provide clues about how some mental illnesses develop.

Science Update

Working memory is a kind of temporary-storage system in the brain. Unlike long-term memory, it stores disposable information we must keep in mind only transiently, for tasks at hand. But how?

NIMH-funded researchers have now identified, in animals, a series of molecular interactions in the brain that sustains transient memories of locations, also called spatial working memories. Results of the research by Amy F.T. Arnsten, PhD, (Yale University) and colleagues were reported in the April 20 issue of Cell.

The report offers compelling evidence that the team has found a sequence of molecular events directly responsible for a complex cognitive process. The findings can help scientists understand the biological basis of mental illnesses characterized by memory dysfunction, such as schizophrenia and attention-deficit/hyperactivity disorder.

How the scientists made their discoveries

In the laboratory, the team studied spatial working memory in monkeys by training them to look at a specific point, look away, then find it again later. While the monkeys weren't looking at the point, their brains were storing its location. During this period of remembering, the scientists recorded patterns of impulse-firing in networks of brain cells known to regulate working memory. The networks are in the prefrontal cortex, the most evolved part of the brain, which controls "thinking" functions — learning, memory, and judgment, for example.

By then manipulating the impulse-firing with chemical compounds, the researchers were able to identify the molecular interactions that strengthen these networks — and thus strengthen working memory. They found that in response to environmental demands for working memory to go into action, these molecular interactions rapidly enable temporary connections among the cells, thus forming transient networks.

What it means from a practical standpoint

The results demonstrate the power of recently developed molecular and cellular neuroscience techniques to explain complex cognitive processes and behaviors, and have important implications for further research on brain disorders. For mental health researchers, in particular, further investigations in this area may reveal potential new targets for development of treatments for diseases that involve impaired cognition, such as schizophrenia. The findings also hold potential for research on age-related memory problems.

More about the science

In an elegant series of experiments, Arnsten and her team showed the sequence of events in brain cells that enhance working memory.

They identified a specific protein on the cells that, when activated by a chemical messenger, lowers production of another key protein inside the cells. This causes specific ion channels in the cells to close. The result: stronger network connections and enhanced working memory. A likely explanation is that the closing of the channel boosts the cells' ability to fire impulses.

(The molecular players above are, respectively, α2A-adrenoceptor, norepinephrine, cyclic AMP, and the HCN ion channel.)

The scientists confirmed the role of the ion channel more directly by blocking it with a chemical compound in rats trained to find their way through a maze from memory. In the same experiment, the researchers also used a genetic technique to reduce the number of channels present in rats' brain cells. Both techniques had the same effect as closing the channel, and the rats' ability to remember how to get through the maze improved.

A wider view

Cyclic AMP is a key player in this scenario, the molecule that helps determine whether the HCN channels are open or closed, reducing or enhancing working memory. But the story doesn't end there.

Many molecules can activate or inhibit cyclic AMP. It's a crucial go-between molecule that helps activate a number of essential functions in cells. One of the molecules that affects cyclic AMP is an enzyme produced by a gene called DISC1 (short for Disrupted in Schizophrenia). As its name implies, this gene is mutated in some people with some mental illnesses.

Normally, the enzyme produced by the DISC1 gene provides a valuable service: It maintains a balance of cyclic AMP by destroying it when levels in cells are high. Stress, for example, causes cyclic AMP levels to rise, and they need to be restored to normal levels by the enzyme.

But the enzyme doesn't work well in people with a mutation of the DISC1 gene. In this case, cyclic AMP levels could remain high, and HCN channels could remain open - the opposite of the scenario described above. Instead of strengthening brain-cell networks, as happens when low cyclic AMP levels allow HCN channels to close, the persistently high cyclic AMP levels and open HCN channels in people with the DISC1 mutation could temporarily "disconnect" the networks.

This could be among the factors that contribute to some mental illnesses, a question that remains to be answered.

Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AFT. α2A-adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex. Cell 129, 397-410, April 20, 2007.