Restoring lost memories
Missing memories have been restored in mice with Alzheimer’s disease
Remembering in a new light
1SOME mice can easily remember where they hide food, but not those genetically engineered to develop Alzheimer’s disease. Like humans they become forgetful. By the time these mice are seven months old they are unable to remember, for example, which arm of a maze they have explored before. Two months later, their brains are riddled with amyloid beta, the protein “plaques” that also characterise the latter stage of the disease in humans.
2Now researchers have managed to restore memories to mice with Alzheimer’s. This helps provide more evidence about how memories are lost during the early stages of the disease and may point to how, some time in the future, those memories might be brought back.
3Susumu Tonegawa and his colleagues at the Massachusetts Institute of Technology used a technique known as optogenetics, which activates clusters of neurons by shining light on them. As they report in Nature, the researchers prepared seven-month-old Alzheimer’s mice by injecting a harmless virus into the rodents’ dentate gyrus, a part of the hippocampus that helps to store fearful memories. The virus contains a gene for channelrhodopsin-2, a light-sensitive protein which forms pores in the cell membranes of neurons infected with the virus. These pores are closed in the dark, but open in response to blue light, flooding neurons with positively charged ions. The resulting pulse of current makes the neurons fire. During their experiments, the researchers were able to illuminate the infected neurons of the mice using optical fibres implanted in their brains.
4Using a standard lab test of memory, a mouse was placed in a box and given a small electrical shock to its feet. Normal mice remember this and freeze in fear if put back in the box the following day, but mice with Alzheimer’s scamper about unfazed. Yet when the researchers stimulated the dentate gyrus of these mice with blue light, they also froze, suggesting that they were now able to recall the original shock.
5Holding on to a fearful memory in the long term, however, requires the brain to strengthen the nerve connections (synapses) that link memory of the box to experience of the shock. This process, known as long-term potentiation, goes awry in the brains of Alzheimer’s patients. Consistent with this idea, the Alzheimer’s mice did not freeze when placed in the box but only when their neurons were illuminated.
6To help the Alzheimer’s mice consolidate and keep their memory of the electric shock, the team flashed their dentate gyrus with blue light at 100 hertz, a frequency known to induce long-term potentiation. After this the Alzheimer’s mice froze in the box for at least six consecutive days, suggesting they were able to remember the shock themselves.
7Work by other groups has suggested that in its early stages, Alzheimer’s principally damages the brain’s ability to process and store memories. This new work, however, indicates that it is the brain’s ability to retrieve memories that is impaired. The distinction is far from an academic one. If memories are garbled before they are stored, they are lost for ever. But if Dr Tonegawa is right, then memories are correctly preserved in the brains of Alzheimer’s patients. That means it may be possible to rescue them—perhaps by adapting optogenetics for use in human sufferers. That remains a distant possibility for now.
8But there is a more immediate consequence of the work for the estimated 40m people with the disease. Electrical stimulation of large areas of the brain of Alzheimer’s patients is already being tried, using electrodes implanted in the skull. But Dr Tonegawa’s team found that stimulating neurons in the dentate gyrus other than those directly involved with holding the fear memory prevented Alzheimer’s mice from remembering their shocks in the long term. That suggests that unless the technique can be refined, deep-brain stimulation may not be effective.
From the print edition: Science and technology
【海马体】主要负责记忆和学习，日常生活中的短期记忆都储存在海马体中，如果一个记忆片段，比如一个电话号码或者一个人在短时间内被重复提及的话海马体就会将其转存入大脑皮层，成为永久记忆。海马区可分为：齿状回（dentate gyrus）、海马、下托（subiculum）、前下托（presubiculum）、傍下托（parasubiculum）、内嗅皮质（entorhinal cortex）。