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New Neurons: Good News, Bad News

Over the last year we have gladly seen an avalanche of news on adult neurogenesis (the creation of new neurons in adult brains), following recent research reports. Further, we have seen how the news that physical exercise can enhance neurogenesis is becoming common knowledge among many health systems we work with.

Now, the obvious question that doesn’t always get asked is, “What good are new neurons if they don’t survive?”. And that’s where learning, enrichment, mental exercise, are critical.

We are glad to introduce a new Expert Contributor, Dr. Bill Klemm, a professor of Neuroscience at Texas A&M University, who summarizes much research on how new neurons are born-and what they need to live long happy lives.

– Alvaro

New Neurons: Good News, Bad News

— By Dr. Bill Klemm

In the last few years, researchers have discovered that new nerve cells (neurons) are born, presumably from residual stem cells that exist even in adults. That should be good news for all of us as we get older and fear mental decline. The bad news is that these new neurons die, unless our minds are active enough.

Ever since the neuron doctrine was firmly established by the independent histological studies of Golgi and Ramon y Cajal, the prevailing dogma was that the after birth, no new neurons appear. We now know that prevailing dogma was wrong. In 1965, Joseph Altman and Goapl Das documented neurogenesis in adult rat hippocampus. Then, in 1977, Michael Kaplan and James Hinds used radioactive thymidine incorporation to show that neurogenesis occurred in the olfactory bulb and hippocampal dentate gyrus of the rat. In these areas, new neurons seem to appear throughout life.

Another apparent exception is in a group of neurons associated with singing in songbirds. In 1983, Fernando Nottebohm documented neurogenesis in the cortex of adult canaries. Here, birth and death of neurons seems to change with seasons of the weather. In Spring, when birds are courting with songs and mating, the neurons in this nucleus proliferate noticeably, only to regress after the mating season.

In 1977, Elizabeth Gould showed that new neurons appeared in adult tree shrews and that stress decreased the number of neurons in the hippocampal dentate gyrus. Ten in 1998, Rusty Gage used the dividing cell marker, bromodeoxyuridine, to show that new neurons occur in adult humans.

There have been claims of adult neurogenesis in several regions of neocortex, but these fndings are in dispute because of methodological issues. Original demonstrations of adult neurogenesis were based on the reasonable approach of injecting radiolabeled cell-division markers and then checking for incorporation in the nucleus of cells, indicative of newly formed DNA. Advanced technology using carbon-14 dating shows that in the human cortex, new neurons do not seem to appear in the adult, though it is clear that they appear in the hippocampus.

Neurogenesis in adults may be manipulable, but research in this area is just beginning. Recently, one study demonstrated that new neurons could be triggered by direct injection of a chemical that stimulates neurogenesis into the feeding center area of the hypothalamus of rodents. Survival of these new neurons in the adult depends on their ability to make functional contacts with existing neurons. Typically, about half of new neurons failed to integrate into existing networks, and they died.

In another study, exposing mice to enriched environments (running wheels, colored tunnels, and playmates) increased the survival percentage of new neurons up to about 80%. “Use it or lose it” seems to be the motto for new neurons.

Exercise has been found important for human brain. Researchers have studied MRI images of exercising humans and found that the blood volume increased in the hippocampus in those subjects that underwent a three-month aerobic exercise program. Those subjects also performed better than controls on memory tasks. Such results indicated that new blood vessels had grown into the brain area. The inference is that this new blood supply was needed to support new neurons, and although there are other explanations, this is a reasonable speculation.

The Hippocampus and Memory.

The brain area known as the hippocampus is the one area where everyone agrees new neurons are born in the adult. The hippocampus is crucial for the for the conversion of certain short-term, scratch pad, memories into permanent form. Animal experiments have shown that the production of new neurons in the hippocampus is stimulated by enriched environments and by learning experiences. But do these new cells function normally? Do they support learning? And do these new neurons survive? Some animal observations indicate that new neurons in the hippocampus only live about one month.

An answer has come from some recent animal experiments that examined the role of new neurons in adults in learning of a water maze and the effect of the maze learning on survival of these new cells. The water maze involved training rats to find a submerged safe platform in a tub of water made opaque so that the platform could not be seen. Training was performed under one of two conditions: 1) location of the platform was cued by an overhead black and white striped rod, or 2) location was indicated by the spatial relationship of the platform to objects outside the tub, such as objects on the room walls, that could be seen by the rat.

The existing population of dentate cells was killed by low-level irradiation. Rats so treated could not form long-term memories for the safe location in the spatially cued task. However, if they were trained after new neurons were born, then they learned the task. This effect was specific to spatial cues, because new cells were not needed to learn the task when the platform was indicated by the vertical rod pointer. By irradiating certain groups of rats at different times before and after training, the researchers found that new neurons 4-28 days old at the time of training were important for the spatial learning. Thus, these new neurons were functional. They knew what to do and how to do it.

So, it would seem that new neurons not only can be born in adult hippocampus, but that they perform the learning job that was done by their predecessors, at least as regarding learning that involves spatial relationships. A learning-rich environment helps these new neurons live longer.

New Neurons. Use Them or Lose Them.

In rodents, the number of new neurons in the hippocampus is on the order of thousands per day. These new neurons may not survive and become useful in memory formation if they are not needed. Need seems to be established by ongoing requirements to form more memories. Learning not only stimulates new neurons to proliferate the membrane “sprouts” that make connections with other neurons but also increases the survival of neurons born up to a week before the learning. In other words, use them or lose them..

A recent study of aged rodent learning of spatial relationships in a water maze has revealed that in “smart” rats that were good at learning a water maze, maze learning increased the survival of new cells born before the learning. An earlier study had shown that in young rats, increased survival of new neurons occurred in all rats, irrespective of their previous memory abilities.

Time Is Critical

A critical window of time determines whether or not the new neurons survive. In an experimental test of this time window, mice were housed for one week in an environmentally rich environment (toys, activity wheels, etc.), or for controls in regular cages, beginning one week after injection with a new-neuron DNA-synthesis marker. Results showed that lasting increase was restricted to new neurons that appeared between one and three weeks before living in an enriched environment. This corresponds to the time when new neurons are extending their neurons in search of targets and their dendrites are developing synaptic contacts to the neurotransmitters normally used in the hippocampus. The new neurons that developed during this time window survived up to the four months of monitoring, even when removed the enriched environment. It would seem that the learning experiences encountered in a rich environment provide the stimulus needed to help new neurons get established into memory-forming circuits, but there is a limited critical time when this effect occurs.

Bill Klemm— W. R. (Bill) Klemm, D.V.M., Ph.D. Scientist, professor, author, speaker As a professor of Neuroscience at Texas A&M University, Bill has taught about the brain and behavior at all levels, from freshmen, to seniors, to graduate students to post-docs. His recent books include Thank You Brain For All You Remember and Core Ideas in Neuroscience.

References

– Drapeau, E. et al. 2007. Learning-induced survival of new neurons depends on the cognitive status of aged rats. J. Neuroscience. 27 (22): 6037-6044.

– Finger, S. et al. 1988. Brain Injury and Recovery. Plenum Press, N.Y.,N.Y.

– Goodman, C. S., and Spitzer, N. C. 1979. Embryonic developmento f identified neurons: diferentiation from neuroblast to neuron. Nature. 280: 208-213.

– Gorio, Alfredo, Ed. 1993. Neuroregeneration. Raven Press, N.Y., N.Y.

– Kokoeva,, M. V., Yin, H., and Flier, J. S. 2005. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science. 310: 679-683.

– Macklis, J. D., and Kempermann, G. 2006. Adult neurogenesis and neural precursors, progenitors, and stem cells in the adult CNS, p. 303-325. In Textbook of Neural Repair and Rehabilitation, edited by M. Selzer et al. Cambridge Univ. Press, Cambridge, U.K.

– Pereira, A. C. et al. 2007. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A. 104(13): 5638–5643.

– Snyder, J. S. et al. 2005. A role for adult neurogenesis in spatial long-term memory. Neuroscience. 130: 843-852.

– Tashiro, A., Makino, H., and Gage, F. H. 2007. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: A critical period during an immature stage. J. Neurosci. 27: 3252-3259.

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