Your old brain has young neurons, but what are they for?

Immature neurons exist in the cerebral cortex of adult humans. However, there is still a long way to go before this mystery is solved.

The development of our brain does not end when we are born. Some of its regions and neurons continue to mature well into adolescence. In addition, in many mammalian species, new neurons continue to be produced during adult life from the division of stem or progenitor cells: this process is known as adult neurogenesis.

This neurogenesis is mainly restricted to the olfactory bulbs and the hippocampus. The olfactory bulbs are the brain regions responsible for receiving information from the sense of smell, and the hippocampus is a key region for the formation of new memories.

In contrast to what happens in other species with a more developed sense of smell, the production of neurons that are incorporated into the olfactory bulbs is very unimportant in adult humans. In the case of the hippocampus, there is still a strong controversy: some studies support the existence of neurogenesis in the brain of adult humans and others question whether it goes beyond childhood.

Despite all this, we have strong evidence that young or immature neurons exist during adult life in the cerebral cortex of many mammalian species. That includes human beings like you and me.

The cerebral cortex is the profusely folded outer layer that completely covers the surface of our cerebral hemispheres. It is a fundamental region for a large part of the complex cognitive phenomena that occur in our brain.

The discovery of these immature neurons is an interesting story that began 30 years ago, in which we have been fortunate to participate, and to which we have recently added a small but significant piece.

Young neurons in school uniform

In the early 1990s, molecules were identified in rodents that were transiently expressed in neurons as they developed, but were lost once the neurons matured and integrated into circuitry.

To make a comparison, these molecules would be like school uniforms for boys and girls: they allow us to identify them as young individuals while they are wearing them, but once they grow up and take them off we can no longer distinguish them between adults.

This made it possible to identify young neurons of recent generation that were integrating in the hippocampus or in the olfactory bulbs. By looking at the brains of adult rats and mice, some researchers realized that, in addition to these neurogenic regions, cells with these exclusive molecules of immature neurons could also be observed in the cerebral cortex, particularly in the olfactory cortex.

We analyzed this cell population in great detail and concluded that, indeed, they were neurons that had barely begun to establish synaptic connections and were isolated from neuronal circuits.

The first thing we thought is that they were cells born during adult life, such as those of the hippocampus and the olfactory bulbs. But after unsuccessfully trying to verify –many times– their recent origin in adult life, we decided to study whether, like the rest of the neurons of the olfactory cortex, they were produced during embryonic life. And so it was!

Therefore, it was a population of neurons that was generated during embryonic life and remained in an immature state during adult life. In addition, as we verified that the number of these immature neurons was greatly reduced as the animals aged, we thought that it would be possible that they were progressively integrated as typical neurons of the region of the cerebral cortex where they were found.

So it was. Using transgenic mice we have recently shown that they integrate as functional excitatory neurons in the olfactory cortex.

These immature neurons can be found in the cerebral cortex of various mammalian species. They are present in virtually all taxonomic groups, including bats, cetaceans, felines, canids, and primates. Interestingly, as the complexity of the cerebral cortex increases in the evolutionary tree, these immature neurons have a broader distribution and are not restricted to just the olfactory cortex, as is the case in rodents.

A few studies have described the presence of cells that express these molecules typical of immature neurons in some regions of the human cerebral cortex, but no further characteristics of them are known.

How to study immature neurons in humans

To study these immature neurons in humans in depth, we have used postmortem material and biopsies from patients suffering from severe epilepsy, from whom a small portion of cerebral cortex was removed for therapeutic purposes.

Thanks to this valuable material, we have been able to corroborate the immaturity of these cells and demonstrate that they are distributed in practically all regions of our cerebral cortex. They are also found in both children and the elderly.

In addition, we have been able to find out that, if they matured definitively, they would do so in excitatory neurons. In addition, in some of these cells that have a more developed morphology (such as the one in the image, from a 60-year-old woman) we have found evidence of the presence of incipient connections between these neurons and others in our brain.

Obviously many issues remain to be resolved. The first is whether, as occurs in rodents, these neurons end up integrating into the circuits of our brain.

If they do, what drives them to do so, what brain functions do they participate in, what other neurons do they connect with? How can they develop, at least in rodents, and synapse and extend axons and dendrites in an environment as restrictive as the adult central nervous system? Are they generated, as in rodents, during embryonic life? Could they participate in brain repair phenomena?

Many questions and still few answers. We are beginning to get some clues through animal models, but there is still a long, albeit fascinating, way to go.

This article has been published in The Conversation