New Neurons for Old Brains

Neurogenesis in the Adult Human Brain

In 1913, the pioneering neuroscientist Santiago Ramon y Cajal proclaimed that neurogenesis, or the birth of new neurons, occurs exclusively during prenatal development (1). It was difficult to imagine that such complex structures as the adult human brain could permit new neurons into their established networks. Consequently, Cajal’s idea persisted for almost a century (2).

Since then, the “no new neurons after birth” dogma has been discarded. It is now well accepted that neurogenesis in the brains of adult mammals occurs in at least two loci (3). However, the story of adult neurogenesis is still quite controversial. The functional significance of neurogenesis, even in areas where its presence is well documented, is highly debated. Researchers are currently interested in the implications this knowledge will have in many clinical areas, including depression, traumatic injury, and neurodegenerative diseases.

Functional Significance of Adult Neurogenesis
A popular misconception is that the ability to regenerate neurons in the brain would be purely beneficial — curing neuronal diseases, increasing brain power, and healing physical injuries to the brain. Much of this is science fiction. The adult human brain is so complex that anything but the most tightly regulated cell proliferation would simply get in the way.

Adult neurogenesis can be seen as a limited continuation of the rapid neuronal proliferation that occurs in the developing embryo. In humans, this continuation is limited to the olfactory bulb and the hippocampus, but in many other species, adult neurogenesis is more widespread. The extent to which neurogenesis is conserved in the adult brain seems to decrease with rising position on the evolutionary ladder. For example, functional integration of adult-born neurons was first demonstrated in songbirds (4). Further down the ladder, lower vertebrates such as lizards can regenerate entire regions of the brain (5). Increasing brain complexity seems to correlate with reduced regenerative ability in the adult brain.

Human neural networks are intricate, based on years of complex learning interactions with the environment. Therefore, haphazard addition of new neurons into the established system would likely do more harm than good. In fact, activation of certain growth factors causes neuronal progenitors to exhibit tumor-like properties (6).

However, normal levels of neurogenesis are clearly not detrimental. There are two main regions in which neurons are continually regenerated: the subventricular zone (SVZ), which supplies neurons to the olfactory bulb, and the subgranular zone (SGZ) in the hippocampus. Recent research has focused on elucidating the function of neurogenesis in these areas. “Function” can have many definitions depending on the context. According to Fred Gage and his group at the Salk Institute in La Jolla, Cali., function must be demonstrated in at least three levels — cell, network, and system — and possibly a fourth level of higher cognition (5). At the cellular level, new neurons in both the olfactory bulb and the hippocampus have been shown to fulfill the criteria of being stable and displaying the normal electrical properties of neurons (7). At the network level, neurons must extend axons and dendrites, forming functional synapses. Behavioral response is used to demonstrate functionality at the systems level. For example, adult neurogenesis in the SGZ is necessary for certain hippocampus-dependent learning tasks (8). Neurogenesis in the olfactory bulb is modified by olfactory experience, and the ability to learn new scents is impaired if proliferation is blocked (5).

The Subventricular Zone
Neurogenesis has long been known to occur in the SVZ of adult rodents (9). In this area, directly beneath the lateral ventricles, immature neurons arise from neural progenitor cells. Newly born neurons exit the cell cycle and then travel along a tube-shaped formation known as the rostral migratory stream (RMS) to the olfactory bulb, where they mature and integrate into existing networks (10). Last year, the elusive RMS was finally discovered in the human brain (11), confirming that this form of neurogenesis does in fact occur in adult humans.

Odor molecules are detected by olfactory sensory neurons in the olfactory bulb. The signal is sent to highly organized structures known as glomeruli, and the output ultimately reaches the olfactory cortex (12). However, this output is first modified by two types of interneurons: granular and periglomerular neurons. It is these interneurons that are continually regenerated via the RMS (11,13).

Almost half of all new olfactory neurons die within the first few weeks, but those that survive persist for about a year. This wave of death is regulated by olfactory activity, unlike the basal level of neurogenesis and migration from the SVZ, which runs continuously.

What is the function of this steady stream of young neurons entering the olfactory bulb? In rodents, olfactory stimuli increase the rate of neurogenesis in the olfactory bulb, and this increase in neurogenesis improves memory and odor recognition (14). It is speculated that this role may be conserved in humans.

The Subgranular Zone
In the hippocampus, neural progenitor cells are found in the subgranular zone (SGZ) of the dentate gyrus (15). They differentiate into immature neurons, which migrate a very short distance to the granule cell layer. There they send out exploratory axons along the mossy fiber pathway into the CA3 region of the hippocampus. They also develop branched dendrites in the opposite direction, reaching the molecular layer in two weeks and further developing for months (2).

The hippocampus is important for learning and memory (16). Blocking adult neurogenesis has been shown to reduce long term potentiation, a mechanism of memory formation, in one region of the hippocampus (8). Certain behavioral learning assays involving the hippocampus are also impaired (16). However, these behavioral results are somewhat controversial due to the timescale of the experiments — evidence of disrupted function would be expected to appear weeks after neurogenesis was stopped, not immediately (5). It seems more likely that the contributions of neurons from the SGZ would be seen in long term adaptations over weeks or months (5).

However, learning does seem to increase neurogenesis in the hippocampus, although the mechanism is not known. Physical activity, hormones such as estrogen, and anti-depression drugs also contribute to neurogenesis (2). On the other hand, neurogenesis is decreased by stressful conditions, as well as depression in animal models. This inhibition of neurogenesis is caused by activation of the hypothalamic-pituitary-adrenal axis. Interestingly, recreational drugs such as methamphetamine and opiates, as well as high alcohol consumption and certain naturally occurring excitatory neurotransmitters also decrease proliferation in the SGZ and decrease the survival rate of new neurons (2).

Although this wide array of factors has been shown to affect neurogenesis, most mechanisms and functions are not clear. Further research into the mechanisms behind these phenomena may help clarify the cellular basis of depression.

The idea of using adult neural progenitor cells to treat injuries such as stroke (ischemic injury) or neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease generates significant interest. In fact, there is a naturally occurring increase in neurogenesis in various regions including the SGZ for such cases, possibly as a compensatory mechanism (2). However, in Parkinson’s disease, the opposite effect is seen, and proliferation is decreased in both the SVZ and the SGZ, perhaps due to the depletion of dopamine. Seizures on the other hand, cause increased neurogenesis, where new neurons migrate aberrantly and develop abnormal axons and dendrites (17). Before neural progenitor cells can be used to treat any of these disorders, the mechanisms by which they affect neurogenesis must be better understood.

Conclusion
The field of adult neurogenesis has come a long way since Cajal’s intuitive “no new neurons after birth” doctrine was first disproved. We now know that neurogenesis occurs in at least two regions in adult human brains. From the SVZ, new neurons travel to the olfactory bulb, where they are important for learning new scents. In the hippocampus, neurons are born in the SGZ and migrate to the granule cell layer in the dentate gyrus. There, they may play a role in memory formation, although evidence is still sparse. There is a link between adult neurogenesis and depression, and several anti-depression drugs may work by increasing neurogenesis in the hippocampus, although the connection to mood and emotion is not clear. There is still significant research to be done before applications for treating brain injury and disorders are feasible.

References
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6. E. L. Jackson, A. Alvarez-Buylla, Cells Tissues Organs 188, 212 (2008).
7. H. van Praag et al., Nature 415, 1030 (2002).
8. X. Zhao et al., Proceedings of the National Academy of Sciences 100, 6777 (2003).
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Interview with Hermes Yeh

To explore the current direction of neurogenesis research, the DUJS spoke to Hermes Yeh, a professor and chairman of the physiology department at Dartmouth Medical School. His research deals primarily with neural plasticity in developing mice. Yeh says that “the type of neurogenesis that goes on [during development] is really recapitulated to a great extent in adult neurogenesis.” The limited neurogenesis in the SVZ and SGZ in adults is simply a continuum from similar process in development, in which neurogenesis occurs much more rapidly, but in the same regions lining the ventricle.

The topic of adult neurogenesis in humans is currently very popular, and controversial, in the scientific community. The use of so-called neural stem cells promises radical new treatments for everything from depression to Alzheimer’s. However, Yeh cautions that “neural stem cells” is a misnomer, because they are much less flexible than true embryonic stem cells, which can give rise to essentially any cell type in the body. Neural progenitor cells, instead, are destined to become either neurons or neuron-associated cells such as glia or oligodendrocytes.
Yeh also cautions about jumping to conclusions based on certain techniques. For example, certain dyes are incorporated into newly synthesized DNA, marking dividing cells and therefore neurogenesis. However, these dyes might also label non-dividing cells in which routine DNA repair is occurring.

Despite these important caveats, the study of adult neurogenesis is vital for understanding how the brain works, and continues to revolutionize the way we think about our minds, from Cajal’s static network, to today’s complex structure with its remarkable capacity for limited self-regeneration.

DUJS: I understand that your work primarily is in the developing nervous system, but there must be significant similarities between the process of neurogenesis during and after development.

Yeh: Yes, I really work with development more than the adult, but the reason I thought it would be good for us to get together and talk is that during development, the type of neurogenesis that goes on is really recapitulated to some great extent in adult neurogenesis, except that the timeframe is a little bit different.

D: So what is the current view of adult neurogenesis?

Y: The story about adult neurogenesis especially is quite controversial. Adult neurogenesis is not a new thing. In a way, there are generations of neurobiologist and neuroscientists that have come into a career and grew up intellectually with the notion that the adult central nervous system is already static, not dynamic, in terms of being able to generate these cells. And the great neuroanatomist Ramon y Cajal was one of them. And the reason was, if you look at these neurons, they look so complicated in terms of their organization and their branches, it was very difficult to imagine that they would divide or do anything, so the idea that the adult nervous system is over and done with, in terms of neurogenesis, really stuck around for almost a hundred years.

Then of course there are other studies, new techniques came along. You know neuroscience is very much driven by new technology and new techniques. A lot of the controversy came into the kind of the markers that are being used to find cells like this. You think of adult neurogenesis and people will refer to that as neural stem cell biology, but it’s kind of a misnomer… because it’s not as if that kind of neurogenesis only happens in the adult, it happens in babies too, it’s just a continuation. So there’s a concept of this whole business about neurogenesis, and now that we’re thinking that the adult brain is plastic, we don’t think of it as a static structure. And development is plastic as well, except that during development the brain is more plastic, so one might look at this whole thing as a continuum. Another thing is, this concept of adult neurogenesis involving stem cells is a misnomer, because if you ask the cancer biology people, they’re talking about real stem cells, stem cells you get from the umbilical cord or something like that. I think for adult neurogenesis, we’re dealing with cells we call neural progenitors, so they’re a little bit less flexible and plastic, if you will, than real stem cells.

D: At what point during development does this change occur?

Y: During development, neurons are obviously generated at a very fast pace. So if you look at a mouse embryo one day, and then the next day the brain looks much bigger, that’s because a lot of neurogenesis has gone on. And the majority of the neurogenesis that goes on in the embryo during dev is no different from the adult. It’s that magic area that is called the ventricular and subventricular zone of the brain, and it’s basically the part of the brain that lines the ventricles, the cavities that are filled with fluid. And that’s where there’s a very fine thin line of epithelium fluid where cells divide very quickly, and in the adult it’s still around those regions primarily, except its very limited in terms of where it might occur, but its still around the subventricular zone.

D: I’ve heard that there is a peak in the maximum number of neurons in the developing animal’s brain, and then after that point they are pruned down. What is the function of that pruning?

Y: So with cells growing during development, the general idea is that more neurons are made than necessary, and that these neurons make more contacts initially than necessary, and all of that seems to be a matter of sort of an insurance policy. Another way to look at it is that the brain is not all that smart, it doesn’t know exactly how many neurons to make or what kind of contacts to make, it just makes them, and later on the environment prunes them off, clips off the ones that are not necessary, kills neurons that are supernumerary. That happens quite a lot, there are a lot of examples of that, and we of course study that quite a bit. And in adult neurogenesis, a very similar process happens, not so much that there are more neurons that are made, but the neurons that are made seem to go through this exploratory timeframe where they make a lot of contacts, appropriate and inappropriate.

D: So if after development new neurons continued to arise, would there be problems with the function of the brain?

Y: There are a lot of developmental disorders, where that kind of stuff is reflected. We call them heterotopies or ectopias, and in a lot of pediatric epilepsy cases one can find that. So yes, and probably all of that is not related to how many are born, but where they migrate, because migration is important too. Cells usually are born where they are not supposed to be and then they go to where they are. Even in adult neurogenesis – you’ve probably heard of the rostral migratory stream – that’s where cells that are born travel to the olfactory bulb.

D: So in adults, what is your opinion on neurogenesis in the hippocampus?

Y: Evidence is good for two areas, and one area is the olfactory bulb, and the other one is inside the hippocampus in the dentate gyrus, where cells are born either continuously, or in response to different injuries, ischemia, and seizure. There’s a review paper by Elizabeth Gould that discusses how widespread adult neurogenesis is. There seems to be some evidence for adult neurogenesis in the neocortex, the striatum, and all these areas line the ventricle.