Researchers here demonstrate that a gene therapy able to force an increase in the size of neural stem cell populations improves neurogenesis and cognitive function in old mice. Stem cell populations are balanced in activation and replication versus quiescence as a way to sustain their function over time, though in many old tissues this becomes biased towards quiescence, and there is consequently too little creation of new daughter somatic cells to support tissue function. Still, too much sustained replication could also be harmful in the longer term, causing losses and damage to the stem cell population. Nonetheless, one could reasonably argue that short term upregulation of stem cell replication will act to enhance brain tissue function in a fairly lasting way, via delivery and integration of new neurons into brain tissue.
Researchers wanted to investigate if increasing the number of stem cells in the brain would help in recovering cognitive functions, such as learning and memory, that are lost during ageing. The research group stimulated the small pool of neural stem cells that reside in the brain in order to increase their number and, as a result, to also increase the number of neurons generated by those stem cells. To achieve this goal, researchers used a gene therapy to produce overexpression of the cell cycle regulators Cdk4/cyclinD1. Surprisingly, additional neurons could survive and form new contacts with neighbouring cells in the brain of old mice.
Next, the scientists examined a key cognitive ability that is lost, similarly in mice and in humans, during ageing: navigation. It is well known that individuals learn to navigate in a new environment in a different way depending on whether they are young or old. When young, the brain can build and remember a cognitive map of the environment but this ability fades away in older brains. As an alternative solution to the problem, older brains without a cognitive map of the environment need to learn the fixed series of turns and twists that are needed to reach a certain destination. While the two strategies may superficially appear similar, only a cognitive map can allow individuals to navigate efficiently when starting from a new location or when in need of reaching a new destination.
Would boosting the number of neurons be sufficient to counteract the decreasing performance of the brain in navigation and slow down this ageing process? The answer is "yes": old mice with more stem cells and neurons recovered their lost ability to build a map of the environment and remembered it for longer times making them more similar to young mice. Even better, when neural stem cells were stimulated in the brain of young mice, cognitive impairments were delayed and memory was better preserved over the entire course of the animal natural life. In young individuals, a brain area called the hippocampus is crucial for remembering places and events, and is also responsible for creating maps of new environments. However, old individuals use other structures that are more related to the development of habits. It was very interesting to see that adding more neurons in the hippocampus of old mice allowed them to use strategies typical of young animals.