Mothers aren't always right

When I was a child, my mother told me never to head the ball during a soccer game. She believed the impact would kill brain cells, thus leading to an irreversible drop in my neuron count because the brain is incapable of forming new neurons after birth. Luckily, she was wrong. Like my overprotective mother, many people are under the impression that we are born with all of the neurons we will ever have; in fact, until about a decade ago, most scientists were under the same impression. This was a logical assumption, as mature neurons do not divide and are thus incapable of generating new neurons, and anatomical studies have shown that the size and structure of the brain remain constant from soon after birth. The assumption that new neurons are not added to the adult brain became one of the central tenets of neuroscience.

The story of how this dogma was overturned is a fascinating one, filled with drama and subterfuge, but I will investigate that saga in a later post. What you need to know is that since the mid-90s, it has been accepted that adult neurogenesis (the process by which new, functional neurons are generated) exists in restricted regions of the mammalian brain. These regions harbor "adult neural stem cells," which appear to be cells that, unlike mature neurons, continue to divide, producing cells that mature into new neurons in adults. [Note: These cells are vastly different from the embryonic stem (ES) cells that are the subject of political controversy; they are probably only able to generate neurons in any significant numbers, while ES cells can generate many different cell types. They also appear to be capable of only a limited number of divisions, while ES cells are quite proliferative. Also, just to clarify, the name's a bit misleading because they're not only present in adults, but in children and fetuses too.]

The majority of studies of mammalian neurogenesis have been conducted in mice and rats, in which at least 2 regions of the brain have these stem cells and thus retain a robust capacity for adult neurogenesis (although the rate of neurogenesis drops sharply as we age). These regions are the hippocampus, which is primarily associated with memory formation, and the "subventricular zone" (SVZ), which lines the ventricles (the fluid-filled chambers deep in the brain).

The primary destination of the new cells in the SVZ, it is believed, is the olfactory bulb, which receives sensory neurons from the nose and is thought to be involved in discriminating odors. This migration of cells from the SVZ (deep inside the brain) to the olfactory bulb (at the front of the brain) is not trivial; it is possibly the most complex and lengthy migratory routes exhibited in the nervous system. This route is called the rostral migratory stream (RMS), and contains "chains" of cells destined to become neurons (called neuroblasts), moving unidirectionally towards the olfactory bulb. So, "stem cells" in the SVZ give rise to neuroblasts that migrate along the RMS to the olfactory bulb, where they become neurons.

This image shows the RMS of a rodent, with stem cells and neuroblasts (1,2) migrating along the RMS (3) to the olfactory bulb (4). From Ming and Song, ARN 2005.28:223-250.

As for most biological phenomena, the knowledge about adult neurogenesis in humans is far less complete. In 1998, compelling evidence for adult neurogenesis was finally found for humans, although this phenomenon appeared to be limited to the hippocampus. For a long time, evidence for new neurons added to the adult human olfactory bulb was lacking. Many rationalized this conclusion with the assumption that rodents are more dependent on their sense of smell than we humans, and thus require the birth of new olfactory bulb neurons throughout life.

Unfortunately, the techniques for studying neurogenesis in humans is limited and highly debated. Each group of researchers has their own favored techniques, and is often highly critical of those used by others. In brief, these methods involve determining whether a neuron is "new" by using different ways to figure out when it last divided; in other words, when it was "born." Each technique has its drawbacks and must be complemented with other techniques (for example, proving that the recently-divided cell is, in fact, a neuron). So although a number of groups have found evidence for new neurons in the human olfactory bulb, their results were called into question and have not been widely accepted. Basically, evidence has been found for the birth of cells in the SVZ, but it continues to be a matter of debate as to whether these cells can form new neurons and integrate into a functional neural network. There has been some controversial evidence for the existence of "new" neurons in the olfactory bulb, but no one has yet been able to show a way for the cells to travel from the SVZ to the olfactory bulb. In short, no one had found the equivalent to the rodent RMS.

A study that was released yesterday in Science claims to have identified the human rostral migratory stream (RMS), and corroborated evidence for new neurons in the olfactory bulb (although, in poor form, they failed to cite the paper which first published this evidence). This group injected terminally ill cancer patients (30, randing from age 20-80) with a chemical called BrdU, which marks all dividing cells (unfortunately, it can also mark cells that are damaged and/or dying, so it's not perfect). After the patients died, the researchers analyzed their brains, and were able to locate cells containing BrdU in the olfactory bulb. This demonstrated that after the BrdU injection, a new cell was born and found its way to the olfactory bulb (thus distinguishing it from neurons that had been around for the life of the person). As I mentioned, this had been shown before, but no one knew how such cells managed to migrate to the olfactory bulb.

The real significant finding came when the the group sectioned the brains "sagitally," which exposes the plane that we would see from the side. They stained the tissue for a protein that marks neuroblasts, and found the cells distributed along a path that began at the SVZ and, in an intriguingly circuitous route, ended at the olfactory bulb, as in the picture on the right (adapted from Swaminathan, Sci Am 2007). These cells were at various stages of development (likewise in rodents, the neuroblasts are thought to mature as they travel along the RMS), and had the appearance of migrating cells. They then used magnetic resonance imaging (MRI) in 6 living patients to locate a "tube" which they believe ensheaths the RMS.

So there's an RMS, so what? If this finding is true, this has many therapeutic implications. Because these cells are naturally found in the adult brain, they may prove to be the ideal source for cell replacement in neurodegenerative disease and the injured brain (as opposed to grafting in embryonic stem cells from another human). Ideally, if we identify the signals that are guiding the new cells to the olfactory bulb, we might be able to direct their migration to an area that had been damaged by stroke.

Another intriguing question, and matter of intense debate in the field of adult neurogenesis, is why we need new neurons in our olfactory bulbs. Why here (and the hippocampus), and not other regions of the brain? One of the initial intellectual barriers to accepting that neurogenesis occurs in adults is that neuroscientists could not conceive of why or how one would add a new cell to a functional neuronal circuit. Now, hippocampal neurogenesis has been linked to the action of antidepressants and, in theory, to certain aspects of memory formation, but the reasons for olfactory bulb neurogenesis are far more elusive. Perhaps the addition of new neurons helps discriminate new odors from those we have perceived before? Maybe it's involved in associating certain smells with certain memories? Rodents have increased addition of neurons to their olfactory bulbs when pregnant; it would be interesting if a similar phenomenon occurred in pregnant women, and if this would be associated with innate feelings of compassion for the new babe.


Reference: Curtis MA et al. "Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension." Science 2007 (DOI: 10.1126/science.1136281)