What to Learn from the Debate over Adult Human Neurogenesis?

Neurogenesis is the name given to the processes by which new neurons are created and integrated into neural circuits. More neurogenesis is generally agreed to be beneficial, in the same way as stem cell activity in other tissues is beneficial, by helping to maintain tissue function in the face of injury and biological wear and tear. As is the case for stem cell function in general, neurogenesis falters with age where it is known to occur throughout life. Beyond this point of maintenance, a process common to all tissues, there is also the matter of cognitive function to consider, however. Greater neurogenesis may aid in learning, memory, and other capabilities, distinctly from the role it plays in normal tissue maintenance.

Neurogenesis obviously occurs throughout the brain in early life, as this organ is constructed and finalized. Until the 1990s it was thought that this process ceased in most areas of the brain in adults. Then it was proven that adult neurogenesis does in fact occur in mice, in areas of the brain important to memory and cognition, which was at the time quite the upheaval. Since then near all of the research on this topic has taken place in mice, as it is very challenging to investigate human brain tissue. Nonetheless, the consensus has been that the lessons learned in mice also apply to humans. As a consequence, the goal of artificially increased neurogenesis in older people drives many medical research programs. Scientists seek the foundations for therapies that can slow cognitive decline or produce greater recovery following brain injury, and hope that this can be achieved by adjusting levels of regulatory proteins controlling neurogenesis.

Another upheaval in the matter of adult neurogenesis is underway. This past year has seen a vigorous debate over whether or not the findings in mice do apply to humans. This started with a careful study that found no evidence of adult neurogenesis in our species. It was shortly followed by another careful study that did show evidence of adult neurogenesis. A great deal of commentary on all sides followed these findings. Today's paper is an example of the type, in this case siding with the uncomfortable position that perhaps neither older mice nor humans exhibit meaningful neurogenesis. If this case, this may complicate and delay the advent of any therapies based on spurring neurogenesis in the aged brain.

Lessons learned from the adult neurogenesis debate

Since the 1960s, consensus about whether human adults generate new neurons with age has swayed back and forth from "yes, at least in some places in the brain" to "no, not at all." The debate reignited in 2018 when two headline-grabbing papers, published weeks apart, made convincing arguments for each side. "It's clear that there is a lot of controversy, which to me seems unwarranted because a yes or no for 'is there adult neurogenesis' is a little too simplistic and distracts us from other important questions. It's worth asking if methodological differences are the only reason that some people aren't finding new neurons or if there is some truth to the observations that neurogenesis may be limited with age in humans. I wanted to take a quantitative look at the research and see where it all leads."

One stand-out issue is that labs that find more neurogenesis in mice than in humans are studying it in young mice, while human research is often conducted in adults from middle to old age. In addition, primates and rodents develop most of their neurons at different times in their early development: human neuron populations peak during the first half of gestation, while mouse neurogenesis continues through birth or after birth. So the observation that there is more neurogenesis in mice might also be because the rodent brain develops later in life. "The literature also indicates that if you look at a middle-aged rodent, it doesn't have much neurogenesis either. If we were to study the same in relative-aged human subjects, I don't think the story is much different. For much of the adult lifespan, we're not bursting at the seams with new neurons. While that may be disconcerting for people, it does reconcile the field: it's not that some studies are right and some are wrong."

Recalibrating the Relevance of Adult Neurogenesis

Reports of limited neurogenesis in adult humans have been difficult to reconcile with animal work demonstrating persistent neurogenesis throughout life, and with human studies arguing for lifelong neurogenesis. Our review suggests that, once developmental timing is accounted for, the human and animal literatures are generally consistent with one another: the human hippocampus develops largely prenatally, leaving less opportunity for postnatal neurogenesis. In contrast, the rodent dentate gyrus forms postnatally and is typically studied in adolescence and young adulthood, when neurogenesis rates remain high. Thus, some confusion has arisen as a result of modeling adult humans with juvenile rodents. While it remains unresolved whether neurogenesis drops to zero in adult humans, our comparative analysis suggests that it falls to low rates for much of adult life in all species.

What then is the relevance of adult neurogenesis for humans? First, low rates of neurogenesis in adulthood, over years and decades, may have substantial additive effects that promote long-term health. Second, higher rates in early life may play a significant role in childhood and adolescent brain function, when many mental health disorders originate. Uncertainties about human-animal differences, and the extent to which cellular properties reflect maturational states versus persistent features, also highlight opportunities for future research. In summary, consideration of the broader neurodevelopmental context will help us take advantage of the benefits that neurogenesis may offer for human mental health.

Comments

There was a joke that generally the pigs don't fly. But when they do it is not high...

Mice are not human and your brains are quite different. However, I would expect a short lived species to have less neurogenesis than a long lived one. After all, there is less need and selective pressure when one generation is about a month no real pressure to replace the exerting good enough neurons.

On the other hand humans need to preserve more memories and there might be a need for stable and long-lived neurons. If the average neuron has to live for a very long time, then by extension, there will be very little neurogenesis at any given moment.

It also depends on neither type. Some have so many dendrites or are so large that they effectively replace a group of cells. There might be a higher turnaround for the smaller and simpler neurons, and much less for the larger or the one with more complex connections.

Posted by: Cuberat at January 29th, 2019 8:51 PM

@Cuberat: It's not a matter of longer or shorter-lived species. In our case, surely neoteny is more relevant.

Posted by: Antonio at January 30th, 2019 2:22 AM

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