Rejuvenating neurons restores learning and memory in mice

Age-related memory decline and neurodegenerative diseases like Alzheimer’s are often thought of as irreversible. But the brain is not static; neurons continually adjust the strength of their connections, a property called “synaptic plasticity”, and this flexibility is the basis of memory and learning.

But aging and Alzheimer’s disrupt many cell processes that support synaptic plasticity. A key question is whether and how the affected cells can be helped to sustain their plasticity.

Memories are thought to rely on sparse groups of neurons called “engrams”, which become active during learning and reactivated during recall, forming part of the brain’s “memory trace”. In aged brains and animal models of Alzheimer’s disease, engrams can malfunction, and memory recall suffers.

A team led by Johannes Gräff at EPFL’s Brain Mind Institute asked whether rejuvenating these engram neurons could recover memory after decline has already begun? In a study published in Neuron, the team reports that “partial reprogramming” of engram neurons restores memory performance in multiple mouse settings. The approach uses a short, controlled pulse of three genes, Oct4, Sox2 and Klf4 referred together as “OSK”.

Previous studies have shown that carefully timed expression of these factors can reset several aging-related features in cells. Here, the team targeted OSK specifically at the engram neurons that are active during learning, rather than broadly across the entire brain.

Tagging and controlling OSK

Working on mice, the researchers used gene therapy vectors (adeno-associated viruses) delivered by precise brain injections. They combined two elements: a system that adds a fluorescent tag to neurons that are activated by learning, and a switch that briefly turns OSK on during a defined time window.

The team used their approach in brain areas known to support different kinds of memory: the dentate gyrus of the hippocampus, which is important for learning and recent recall, and the medial prefrontal cortex, which contributes to remote recall two weeks later.

Back to a younger state

In aged mice, briefly activating OSK in learning-related hippocampal engram neurons restored memory, essentially bringing performance back to levels seen in young controls. When the same approach was applied to prefrontal cortex engrams, it also recovered remote memories formed weeks earlier.

The reprogrammed engram neurons also showed signs of improved health. They maintained their neuronal identity and displayed molecular features associated with a younger state, including changes in nuclear structure linked to aging.

The team then tested mouse models of Alzheimer’s disease. In a spatial-learning task, the mice showed inefficient navigation and impaired memory strategies. Reprogramming dentate gyrus engrams improved learning strategies during training, while targeting prefrontal engrams restored long-term spatial memory.

Further analysis revealed that Alzheimer’s-related changes in gene activity and neuronal firing within engram cells were partly reversed by turning OSK on.

A proof of concept

The study stands as a proof of concept for restoring function in a specific group of memory-related neurons to improve memory performance, even after cognitive decline has begun. By limiting OSK expression to a small number of neurons and a short time window, the approach captures beneficial effects while reducing the risk of disrupting cell functions.

Other contributors

• EPFL Laboratory of Neuroepigenetics
• Synapsy Center for Mental Health Research