Teaching Old Mice New Tricks Opens Door to Lost Memories

BOSTON, April 30 -- Mice with induced brain atrophy that were exposed to new toys and playmates in an "enriched environment" were able to build new pathways to faded memories.

The research by Li-Huei Tsai, Ph.D., of Massachusetts Institute of Technology, and colleagues, implied it may be possible to recover long-term memory in humans with dementia.

Compared with control mice, animals that were placed in enriched environment cages for four weeks demonstrated marked recovery of long-term memory, they reported online in Nature.

Moreover, memories were recovered despite the fact that enriched and non-enriched mice "have a similar extent of neuronal loss and brain atrophy," Dr. Tsai said.

The enriched environment did not trigger new neuronal growth but appeared to correlate with "sprouting of dendrites, an increased number of synapses, and reinstated learning behavior and access to long-term memories," they wrote.

"This is exciting because our results show that learning ability can be improved and 'lost' long-term memories can be recovered even after a significant number of neurons have already been lost in the brain," Dr, Tsai said.

The findings also hint that Alzheimer's disease doesn't wipe out memories, but rather, blocks access to them, she added.

Additionally, the team found that giving mice histone deacetylase (HDAC) inhibitors produced the same beneficial effect as a cage full of new toys.

"To our knowledge, HDACs have not been used to treat Alzheimer's disease or dementia," Dr. Tsai said. "Future research should address whether HDAC inhibitors will be effective for treating neurodegenerative diseases."

The MIT team used CK-p25 Tg mice, which are genetically engineered so that expression of p25-a protein implicated in a number of neurodegenerative diseases--can be switched on or off with a doxycycline diet.

They trained the mice to avoid electric shocks and find their way around mazes to reach food and then induced the brain degeneration via the p25 protein switch. After six weeks, the mice couldn't remember what they had learned.

These mice were randomized to enriched environment or control. After four weeks, the mice in the enriched environment remembered the maze and shock test much better than controls. Mice in the enriched environment also demonstrated the ability to "learn" new things.

Dr. Tsai said the results suggest that the effect of an enriched environment "is likely to be mediated, at least in part, by elevated acetylation of histones H3 and H4, which initiates 'rewiring' of the neural network."

The authors noted that a recent report in the Journal of Clinical Investigation described apparent axonal regrowth in a brain-injured man who was in a minimally conscious state for 20 years.

"Thus, re-establishment of a neural network may allow recovery of long-term memories not only in rodents, but also in humans," they wrote. "If so, this suggests that using small molecules that target HDACs in patients with dementia could facilitate access to long-term memories."