Switching off noisy neurons in mice restores memories lost to Alzheimer's
Researchers in Germany have discovered a new mechanism by which Alzheimer’s disease impairs memory recall – and, importantly, found a way to reverse it in mice. Neurons encoded with existing memories are being drowned out by noise from neurons encoding new experiences, and silencing these allowed the mice to regain lost memories.
The hippocampus is the region of the brain responsible for encoding experiences into memories, by building networks of neurons that store the information. When we recall a previous situation, those same neurons are activated. But when Alzheimer’s strikes, the hippocampus is usually one of the first brain regions to go. This manifests as the familiar memory loss and confusion that patients suffer from.
It was previously thought that the disease impairs the neurons containing memories so that they can’t be activated during recall, and eventually the memory they hold is lost. But the new study, from researchers at the German Center for Neurodegenerative Diseases (DZNE), found a different mechanism at work.
In tests on mice with models of Alzheimer’s disease, the team discovered that the neurons containing memories were still active and the trouble recalling the memories stored there was actually happening further upstream.
The researchers investigations involved studying two groups of mice – a healthy control group and another group with an Alzheimer’s-like condition. The team used two-photon in vivo microscopy to watch the activity of neurons in the brains of these mice as they explored a new environment.
A few days later, both groups of mice were returned to that environment for a second time and the researchers observed clear differences in behavior. The healthy mice recognized the room, but the diseased mice didn’t, instead exploring the environment like they were encountering it for the first time.
The team also noticed differences in the activity of the neurons of the mice. Intriguingly, those with Alzheimer’s-like pathology were “remembering” the previous experience – the neurons containing those memories were being activated. But the signal was being blocked by other neurons that were busy encoding the experience as “novel.”
“The reason is novel experience-encoding neurons disturbing the signals of memory-containing neurons and superimposing them with their signal,” says Martin Fuhrmann, lead researcher on the study. “It is like a noisy TV signal: the picture becomes diffuse and distorted; you might even see pixels or stripes. Something similar happened inside the mice’s brain: Interfering signals suppressed their memories. This disturbance is obviously a result of the pathological changes in the brain.”
Probing deeper, the researchers then tried controlling these neurons in both healthy and diseased mice. Using a technique called chemogenetics, the team was able to engineer new experience-encoding neurons so they responded to a certain molecule. In doing so, they were able to switch on the noisy neurons in healthy mice, and switch them off in Alzheimer’s-like mice.
And sure enough, the link became clear. When the novel environment experiment was run again, the two groups of mice effectively swapped behaviors.
“Mice with Alzheimer-like pathology now recognized the environment again, their memory was restored,” says Stefanie Poll, first author of the study. “The memory of healthy mice, however, was impaired by the artificial noise.”
It’s an intriguing study, but of course it’s important to remember that so far it’s only been conducted in mice. There’s no guarantee that the same mechanism is at work in humans with Alzheimer’s, nor whether it’s safe to target this as a potential treatment. After all, we need new memories to form every day, and blocking that ability will likely raise its own issues.
If it does translate to humans – which future studies will need to determine – then the technique could potentially be expanded beyond Alzheimer’s.
“Imagining future therapies, we might be able to rescue memories of individuals suffering from Alzheimer’s disease or other diseases impacting memory recall,” says Fuhrmann. “We might achieve this by lowering the activity of these noise-inducing neurons with future methods. Furthermore, it could be possibly helpful for individuals suffering from post-traumatic stress disorders. Here, noise-inducing neurons could be artificially activated to interfere with the traumatic memory aiming to overwrite it.”
The research was published in the journal Nature Neuroscience.