The Root of Thought (14 page)

The strengthening of synapses, LTP, and synaptogenesis can be astrocyte-dependent as well. It would make sense for the hippocampus
to create new neurons to lay down short-term memory into long-term memory. Without successful cell division and the laying down of neuronal highways, information cannot travel into the cortex to be stored in astrocytes. If someone needs to travel from Iowa to Boston and there is no way to get there, that person stays in Iowa.

Your nose, ears, and eyes all transmit information to the cortex and hippocampus. These quick pathways are vehicles for astrocytes to understand their environment. The hippocampus is the generator. Similar to the guard at a desk who decides whether you can enter a building, the stimulus must have the proper ID or it remains in the short term and is lost, such as what occurs in HM or Alzheimer’s patients whose hippocampuses are destroyed. In this case, the building is locked and nothing can get in. More studies on astrocytes will reveal why.

One interesting side note to Ebbinghaus’s experiments on memory—he noticed that he remembered more of his nonsense words than normal after he slept. Something learned right before sleep is better retained than something learned and attempted to recall shortly afterward with no sleep. He thought it didn’t mean anything, that he hadn’t used random enough nonsense words and discarded any notion that going to sleep would help his memory. Now exhaustive research has shown that sleep does in fact help memory retention. It is possible that glia are more active and regenerative while we sleep, such as fingernails and hair grow more when we are sleeping. Information storage might likely reside in cortical astrocytes. The information gets into the cortex through long-distance neuronal communication combined with glial calcium waves.

A classic story from the Roman essayist Cicero on memory concerns the ancient Greek poet Simonides. Respected for his memory, Simonides was asked to a banquet to recite a poem for the wealthy host. At the time, poets usually included a long homage to the twin gods, Castor and Pollux, who were thought to make up the constellation Gemini. The host, upset that Simonides didn’t devote the poem to him, paid him only half of what he was owed and told him he could pay the other half to Castor and Pollux. A little while later, Simonides received a message that two men wanted to see him outside; he went out, and while he was gone, the banquet hall collapsed and everyone inside was crushed beyond recognition. The two men were Castor and Pollux, and by removing Simonides to safety, they paid him what he was owed and then some. When the families of the deceased wanted to know who was who, Simonides was able to accurately remember where everyone was sitting by using the method of association with other structures that were in the room.

Simonides was able to use his hippocampus more efficiently to lay down new memories normally in the short-term domain and store information into his cortex. Yet researchers still have not been able to understand how the cortex is able to contain information. This knowledge is on the horizon as research on astrocytes progresses.

We now know astrocytes divide and regenerate in the hippocampus. If needed, they can become neurons. As will be seen, astrocytes, not neurons, are capable of dividing and growing in the cortex, providing an interesting method for the possibility of storing new information—the way Simonides was able to store the seating map at the banquet.

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The growth of our brain when we’re born—as flush and full as an Amazonian jungle until we reach young adulthood—was thought to be followed by a period of constant death. As if the rainfall has stopped, global warming has set in, the wind has increased, the jungle is subjected to the elements, and then tragically declines into a desert wasteland and petrified forest. This original belief after Cajal approved the Neuron Doctrine occurred for obvious reasons. Our brain does get smaller as we age, particularly our cortex, and the complete jungle was considered to have enough room for a lifetime of experience.

However, new glial research has shown the brain is more like a living jungle throughout our lifetime than originally thought—with dead trees replaced by new ones and constant spawn and spreading of seeds to spaces suitable for new vegetation. Ground space is limited but growth is constant. One of the largest mistakes of the twentieth century was the notion that after childhood brain development, our brain just remained in the same state until we died. Our neurons were constructed, made connections, and those connections were permanent, similar to a statue constructed to honor our memory, sitting there chipped away by the wind and rain until it crumbled and was covered by dust.

Through the work of Fernando Nottebohm and Arturo Alvarez-Buylla at the Rockefeller Institute, we now know that this is not the case. In the mid-1980s, Nottebohm turned the unchanging brain on its head with his studies on canaries. In the early 1970s, he mapped the areas of the brain responsible for singing in the canary. Starting with the voice box and working his way back into the brain, Nottebohm accurately determined cells in the brain that contributed to song. He and others knew that the canary could learn new songs throughout its lifetime. When the area was damaged, it impaired the canary’s ability to sing.
Nottebohm, along with his student Alvarez-Buylla, looked meticulously at cell division in the canary brain after it learned.

What they found was striking. Previously, it was thought that only the brains of fish and amphibians had the capability to regenerate throughout adulthood. After Nottebohm taught the canaries new songs and then removed their brains at various time points after they died, he discovered the nuclei in the telencephalon for coding and learning new songs was enlarged. These nuclei were not enlarged in this area of the brain in canaries that didn’t learn any new songs. The density of the area had changed—the brain was almost like a stuffed suitcase, swollen from exchanging a pair of pants for three more T-shirts, but still limited to the space of the suitcase.

Nottebohm expected this result when the canaries were developing, but not from just learning songs as an adult. Birds were officially added to the list of animals that could make new neurons into adulthood, and the first entirely land animal to do so. Nottebohm and Alvarez-Buylla then used Joseph Altman’s model of radioactive thymidine to understand cell division. They figured if the telencephalon had more neurons, it could be due to more cell division in this area.

They found hot spots for cell division near the ventricles of the brain—the same area where cell generation occurs when we are in development. The cells in this area would explode into division when the canaries learned new songs, like a musician in a fit of creativity. But, in humans, we have the ability to create our own songs, whereas birds learn through mimicry.

The adult brain was changing, and it was likely the result of cell division. Hebb, Cajal, LTP, and all the synaptogenesis and synaptic strength theories now seemed a byproduct of new cells being created.

In the early 1980s, a new technique had been developed to study cell division. 5-Bromodeoxyuridine, simply referred to as BrdU, could be injected into the bloodstream. From there it can be accurately stained. BrdU worked in a similar manner as Thymidine by incorporating into the DNA of cells dividing at the time of injection. This method combined with fluorescence and confocal microscopy (the ability to look at cells three-dimensionally through a tissue slice to determine if the stains for neuron and glia match up with the stain for cell division) could definitively remove unwanted and confusing background staining and more accurately determine types of cells and actual cell division.

Alvarez-Buylla found that neurons were being formed, but at a much smaller rate than nonneuronal cells. The fact that neurons were being formed solidified the idea of “adult neurogenesis.” Nottebohm and Alvarez-Buylla pointed out that in the bird, the dividing cells could become neurons, but that in the mammal, emerging studies indicated that cells dividing in this area eventually settle on a glial fate. If the new cells were dominantly glia, this idea was not interesting to the field. The field lusted after new neurons.

What they discovered was similar to Altman but with better techniques. In an adult animal, new neurons and glia were formed during learning. By the late 1980s, this idea was accepted, but only believed to occur in certain areas pertaining to learning and probably not in humans. According to the accepted theory, musicians must create their songs with already established neurons. In an effort to get a closer understanding to what occurs in humans, Alvarez-Buylla decided to tackle the issue further in mammals.

By the 1990s, Alvarez Buylla was at the University of California, San Francisco. He expanded the studies they performed on canaries into mice. It had been known through Altman that cell division resulting in neurons occurred in the hippocampus and near the ventricles. Using BrdU, Alvarez-Buylla focused on the area near the ventricles. This area was also interesting because it was the same area in development that new neurons and glia are formed and where neurons contributed to song learning in adult canaries. Alvarez-Buylla was interested in what cells were dividing and where they were going.

Alvarez-Buylla went beyond what Altman noticed. Altman simply noticed that the cellular genesis occurred in the adult rodent and that a few of these cells became neurons. At the Rockefeller Institute in Nottebohm’s lab, they discovered that cells divided near the ventricle in canaries learning new songs. In the mice, he found that the new cells follow a path to the olfactory bulb, the part of the brain that sticks out like two marbles behind the nose. Smell is the dominant sense in mice, and the percentage of the brain that the olfactory bulb makes up in mice is many times bigger than in humans.

Using BrdU, Alvarez-Buylla’s lab could follow new cells as they traveled from the ventricle to the olfactory bulb. The cells moved by climbing fibers like children in PE class climbing a rope. The migratory stream, originally coined by Altman, is the thoroughfare; similar to the Mississippi river running through the middle of the United States, it is the main river flowing with new cells to the most important sensory area of the mouse brain. Like fish spawning up river and then swimming down to take their place downstream, cells were floating around the brain. The active moving brain, with cells dividing and migrating into adulthood, was an intense revelation.

As mice determine their environment largely through their sense of smell, the olfactory bulb is ever changing and new neurons are required to build highways to glia to understand this environment. Our smell is just sensing molecules floating around in the wind. Like sight is for light particles and hearing is for vibrations, smell is for molecules. Similar to the growth of forests and jungles after rain or the destruction in fire, masses of new cells constantly come in to replace destroyed cells or add to those currently in use to comprehend the molecules. Some of the cells that divided in the brains of the mice migrated to the olfactory bulb and changed into neurons. The new neurons laid down for smell are also tied to our memory—smelling scents linking us to the past is the equivalent to recalling how to add 2 + 2, something that goes through the hippocampus.

In the 1990s, the next thing Alvarez-Buylla and colleagues wanted to accomplish was to try to figure out what types of cells divided. Using markers for many different cell types in addition to BrdU, they found that cells dividing at the ventricle displayed characteristics of astrocytes. Soon it was understood that the dividing cells in the hippocampus were also astrocytes.

Now scientists were armed with the knowledge that astrocyte-type cells divide rapidly at the ventricle. They constantly regenerate, creating offspring like rabbits. Some of them sprout into neuronal precursor cells when necessary. When this happens, these cells migrate out to the olfactory bulb or other deep layers of the brain, to become a neuron and to lay down a highway between our reflexive senses and higher-thinking cortex.

New researchers knew hippocampus and the olfactory bulb both produce new glia constantly. Both areas are known to be areas of constant learning. However, all this research was in mice and birds. The next step was to investigate it further in humans.

In the late 1990s, Fred Gage and colleagues injected humans with BrdU and studied their hippocampuses after they died. He found new cells dividing as well, but not focusing on glia, proceeded to look only at neurons and discovered slight instances of neurogenesis in humans. The neuron-dominated ideas of Ramón y Cajal finally would believe that the adult human brain had the ability to create new cells throughout its lifetime. However, the large amount of glia produced compared to neurons was overlooked.