Of Mice and Memory

A compound that helps memory recall in brain-damaged mice could pave the way for new drugs to treat dementia.

Treating brain-damaged mice with compounds that affect gene expression restores their ability to recall long-term memories, according to a study in this week's Nature. Raising the mice in a stimulating environment has the same effect. The results suggest that memories, once consolidated, can remain accessible even after significant loss of brain cells. They also open up the possibility of developing drugs to treat the memory loss associated with conditions such as Alzheimer's disease and dementia.

Environmental enrichment: Mice housed in an interesting environment—in this case, a large cage containing toys of various colors, shapes, and textures and a running wheel that permits voluntary exercise—were better able to recover long-term memories after brain damage. The findings could aid in the development of memory-enhancing drugs for humans. Credit: Li-Huei Tsai

Previous research had produced results similar to the study's finding that environmental enrichment can improve learning. "That's no big deal," says coauthor Li-Huei Tsai of MIT's Picower Institute for Learning and Memory, "but in terms of recovery of long-term memory ... we were all stunned."

Tsai and her colleagues conducted the study on mice genetically engineered to express a protein called p25 under certain conditions. The protein triggers massive brain-cell death and has been implicated in neurodegenerative diseases. Researchers can switch the expression of p25 on and off by controlling the mice's diet, inducing brain damage at will. Without the special diet, the mice behave like normal mice.

To test the mice's memory, Tsai and her colleagues started by conditioning them to be afraid of a certain place. The mice were moved from their cages to a chamber providing an interesting new environment they want to explore, she explains. But in that chamber, the mice received a mild shock on their feet. "It doesn't hurt," Tsai says, "but they hate it."

This fear conditioning gets coded in the hippocampus area of the brain before being transferred three to four weeks later to the cortex, where it becomes a stable, long-term memory. After that, if the mice are returned to the chamber they remember the bad experience and freeze in place instead of exploring.

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After establishing this memory in the genetically engineered mice, Tsai and her colleagues induced brain damage by turning on the p25 gene. As expected, the mice lost their fear of the chamber, failing to freeze as normal mice would after the same conditioning.

But giving the brain-damaged mice a compound called a histone deacetylase (HDAC) inhibitor produced very different results. Histones are proteins that DNA strands wrap themselves around, forming a structure called chromatin. The way in which chromatin assembles itself affects gene regulation and expression. Mice given an HDAC inhibitor, which allow the DNA to unwind from the histones making the DNA accessible to transcription, were able to recover long-term memories much better than untreated mice.