Published online 26 January 2011 | Nature | doi:10.1038/news.2011.49

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Research in rats indicates new target for memory enhancement.

A protein promoting growth and repair in certain cells seems to enhance and prolong memory in rats. CONEYL JAY/SCIENCE PHOTO LIBRARY

Preliminary work in rats suggests that a hormone that promotes growth and repair in certain cells may be instrumental in the formation and retention of memories.

When researchers injected the protein, insulin-like growth factor II (IGF-II), directly into the hippocampus — the region of the brain associated with episodic memory — during a particular window after learning, it seemed to both enhance memory and enable it to persist for longer. The study is published online in Nature today1.

"It was exciting to see that it was a memory enhancer," says Cristina Alberini, a neuroscientist at the Mount Sinai School of Medicine in New York who heads the lab leading the research. "There are not many factors that can enhance memory. It's much easier to disrupt memories than to enhance them."

Alberini chose to focus on IGF-II because, as a first step in this research, she and her colleagues identified it as one of the 'target' proteins of memory formation. After learning, the brain begins to synthesize proteins, kick-starting a chain of neurophysiological events that ultimately results in the consolidation of memory. Those initial proteins, known as transcription factors, regulate the production of secondary or target proteins that keep the chain going.

There are many gaps in our knowledge about IGF-II, but previous research has suggested that IGF-II receptors are concentrated in the hippocampus, and researchers have speculated that the expression of IGF-II in the brain is highest in this region. But to determine the exact role of IGF-II in memory consolidation, the researchers began by testing what happened when they blocked it.

Blocked shock

In an initial experiment, Alberini and her colleagues used a technique known as inhibitory-avoidance training. They put rats into a box in which one side was darkened. If the rats entered that side, they experienced a mild foot shock. After the training, the researchers found that levels of IGF-II in the hippocampus of the rats had risen. In a second experiment, to confirm that IGF-II was involved in memory consolidation after learning, they injected an IGF-II blocker into the rats' hippocampus. Later, when the rats were put into the box again, it was clear that they had no memory of the shock associated with the darker side.

This suggested that IGF-II is involved in memory consolidation. In subsequent experiments, the researchers did not disrupt the natural synthesis of IGF-II, and instead injected a further small dose of the growth factor into the hippocampus after the rats had gone through training. This time they found that the memory was not only enhanced — the rats who had received the extra dose steered clear of the dark side for longer — but also persisted for longer after the initial learning episode.

Li-Huei Tsai, a neuroscientist at the Massachusetts Institute of Technology in Cambridge and co-author of an accompanying commentary2, points out that these observations are very preliminary, and that the precise way in which IGF-II enhances memory is not clear. Yet she lauds the promising findings that IGF-II is a "novel memory enhancer", and that this enhancement seems to have a "long-lasting effect".

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"The paper is very intriguing," says Ignacio Torres-Alemán, a neurobiologist at the Cajal Institute in Madrid. He says that he welcomes the insight into IGF-II. Research has focused heavily on insulin and insulin-like growth factor I (IGF-I), whereas IGF-II has been treated like the overlooked younger brother of the family, Torres-Alemán says. "From now on, we'll have to take IGF-II into account," he adds.

What is exciting about these findings is that they could lead to interventions for memory-related disorders such as Alzheimer's disease or other types of dementia. Alberini points out that IGF-II can cross the blood–brain barrier, a physiological effect limiting which chemicals can enter the brain; in terms of clinical applications, that could be an advantage.

Among other things, concerns about a link between an influx of IGF-II and a potential increase in the risk of certain cancers would need to be addressed, and Tsai points out that direct injection into the hippocampus "is highly unlikely to happen in humans". But if future research in rats shows that other delivery methods — such as nasal injection — produce similar results, this could be the first step on a path to promising new interventions.