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Learning and Memories Restored in Mice

Two strategies boost new memory formation in mice and restore access to old memories that had seemed lost, according to a new study. The results raise the possibility that the memories of people with dementia may not be forever gone, but temporarily inaccessible.

As our brains age, they inevitably degenerate, making us less able to think as quickly or remember as well. This degeneration can eventually lead to dementia, in which intellectual function is so impaired that it interferes with normal activities and relationships. Dementia can also be caused by neurodegenerative diseases such as Alzheimer's disease.

Dr. Li-Huei Tsai of the Picower Institute for Learning and Memory at Massachusetts Institute of Technology leads a team that used genetic engineering to develop a type of mouse in which age-dependent degeneration in the brain could be induced with an additive to the diet. The team, which is partially supported by NIH's National Institute of Neurological Disorders and Stroke (NINDS), previously showed that feeding the additive to mice for 6 weeks can reduce their learning ability during fear conditioning or in a maze test.

In the current study, reported in the April 29, 2007, online issue of Nature, the team used this same type of mouse to explore strategies for restoring learning and access to long-term memory after brain degeneration. The researchers found that a more stimulating environment, with wheels, toys, tunnels and things to climb, significantly improved the mice's ability to learn how to get through a maze. The environment had this effect without affecting brain size, implying that the remaining nerve cells in the brain were stimulated to form new connections with existing nerve cells and became more active.

The researchers next tested long-term memory associated with fear conditioning. After 6 weeks of eating the additive, the mice no longer froze when exposed to a signal they'd been trained to fear. Mice that were then put into a stimulating environment for 4 weeks displayed freezing behavior again, indicating a recovery of their long-term memory. A similar test with the maze supported the idea that long-term memories were being recovered.

The apparent "memory loss" in these mice may in fact be an inability to access memories, the researchers reasoned. They compared the phenomenon to that of people with dementia, who have periods of clarity.

The researchers noted that a process called histone acetylation was recently implicated in learning and enhancing the growth and connections between brain cells. When they looked at histone acetylation in the brain, they found higher levels in the mice that had been put in the more stimulating environment. To see if learning and memory could be recovered with a drug rather than an enriched environment, the mice were given a chemical known to enhance histone acetylation. The drug, called a histone deacetylase (HDAC) inhibitor, appeared to reinstate the learning behavior in mice and restore their access to long-term memories without other detectable effects.

Although this mouse research offers a proof of principle, it's relevance to humans is unclear. Nevertheless, it does raise the possibility that people with dementia may one day be able to recover long-term memories. It also suggests a new strategy for developing therapies for learning and memory impairment. HDAC inhibitors are currently in early phase clinical trials for cancer treatment. This study suggests a potential new therapeutic direction for this emerging class of drugs.

— by Harrison Wein, Ph.D.