BioEd Online

Adult Neurogenesis

The last decade of the 20th century, proclaimed the "Decade of the Brain," yielded tremendous advances in the field of neuroscience. Scientists discovered several of the genes involved in Alzheimer's disease as well as the gene responsible for Huntington's disease. New treatments were developed for a range of nervous system-related disorders, including Parkinson's disease, multiple sclerosis, and some forms of epilepsy. Insights into the biology of drug addiction, as well as the neuronal mechanisms that underlie learning and memory, provided exciting revelations about some of the brain's primary functions. Perhaps the decade's most surprising finding was the discovery that the human brain is capable of generating new neurons throughout life.

For at least a century before the discovery of neurogenesis (the birth of new neurons) in the adult human brain, a prevailing belief in the field of neuroscience was that the brain of virtually all mammals (not just humans) remained structurally constant throughout life and was incapable of producing new neurons. There were a number of reasons for this belief, including the observation that the mammalian brain and spinal cord have limited capacity for self-repair following injury. In addition, detailed studies of the elaborate architecture of the adult brain indicated that it remained constant in appearance, with an unchanging number of neurons, and that no mitotic (dividing) neurons were present. Indeed, the human brain is enormously complex; it is composed of an estimated 100 billion neurons that make an estimated 100 trillion connections, so it is very difficult to imagine how new neurons could develop and integrate successfully into the mature brain structure. The belief in the constant nature of the brain and spinal cord carried profound implications, namely, that recovery from traumatic injuries such as stroke or spinal cord injury was impossible.

Beginning in the 1960s, studies emerged that contradicted the long-standing dogma of the adult mammalian brain as a static organ. However, the prevailing belief in the stability of the adult brain was upheld for roughly 40 years after these initial reports. During that time, increasingly sensitive techniques were developed to detect cell division. In addition, technological advances enabled scientists to identify the types of new cells produced in the brain. Spurred by these developments, evidence accumulated in support of adult neurogenesis, including the 1998 publication of a seminal paper describing the birth of new neurons in the adult human brain.

Today, the concept of adult neurogenesis is widely accepted by the scientific community. We now know that while most cells in the brain are born during embryonic and early postnatal development, new neurons are generated throughout life and are added to at least two areas of the brain: the hippocampus (which is involved in certain types of learning and memory) and the olfactory bulb (which is involved in the sense of smell). These newly generated neurons arise from populations of cells known collectively as "neural precursors," which can differentiate into the various types of cells that make up the nervous system.

New neurons are born in two regions of the adult brain: the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus.

New hippocampal neurons are generated by neural precursors located in the hippocampus, in a region known as the subgranular zone. In contrast, new olfactory neurons arise from neural precursors located outside of the olfactory system, in a region known as the subventricular zone of the lateral ventricle. These cells migrate to the olfactory bulb through a tract known as the rostral migratory stream.

Over the past decade, adult neurogenesis has become one of the most exciting and rapidly evolving areas of research in the field of neuroscience. A central focus of current investigations is to increase understanding of the functional significance of newly generated neurons—what they do and how they contribute to the brain's activities. While many answers remain unknown, new insights are emerging at a stunning rate.

Indeed, experimental studies suggest that new neurons are not only generated throughout life, they also integrate into the circuitry of the brain and actively participate in its functions. The hippocampus is known to play a critical role in learning and memory and many scientists have hypothesized that newly generated neurons within the hippocampus contribute to these processes. Although currently limited, there is support for this hypothesis. It appears, for instance, that conditions that impair adult neurogenesis, such as stress5, also impair learning. In contrast, conditions that promote the generation of new neurons, such as physical exercise, often are associated with improved memory and learning of tasks that rely on the hippocampus. Studies also have shown that learning promotes the survival of new neurons. In fact, better learners seem to retain more new neurons, especially when trained on difficult tasks. These findings suggest an intriguing link between neurogenesis and learning.

Some evidence suggests that neurogenesis is not only correlated with learning and memory, but actually may be required for some forms of learning. One study has shown that blocking adult neurogenesis in rats leads to specific impairments in the animals' ability to perform some learning and memory tasks that rely on the hippocampus9. This finding suggests that new neurons could be required for the acquisition and retention of new memories. Unfortunately, the methods used in this study, and all other methods currently available to selectively diminish neurogenesis, are likely to have additional affects on brain function, making results less than conclusive. Nevertheless, these studies provide initial support for the hypothesis that newly generated neurons participate in at least some forms of hippocampal learning and memory.

Hippocampal neurogenesis also may play a role in various neurological disorders and diseases, including epilepsy and depression. Studies have shown that many of the therapies and medications used successfully to treat individuals suffering from depression can cause an increase in the production of new hippocampal neurons. Others have demonstrated that the beneficial effects of some antidepressants are blocked when neurogenesis is prevented11. These and other observations suggest that diminished neurogenesis could be an underlying cause of depression. If this hypothesis proves correct, people suffering from depression could potentially be helped through treatments that increase the production of new neurons in the hippocampus.

In contrast, by using animals to study temporal lobe epilepsy, scientists have shown that neurogenesis increases in response to seizure activity. However, in this case, the production of new neurons is not beneficial because those neurons develop, migrate and integrate inappropriately, and actually seem to contribute to recurrent seizures. Although the functional significance of abnormal neurogenesis in these and other medical conditions is not yet understood, it is an area of intense research that may one day yield new treatments for these disorders.

The discovery of adult neurogenesis has also uncovered the exciting potential for novel approaches to repair the injured brain and spinal cord. Some animals, such as lizards and goldfish, can regenerate entire segments of their injured nervous systems. While the human brain clearly does not have this capacity, it does appear to have greater regenerative ability than was previously believed. In fact, many studies have shown that neurogenesis is stimulated in the mammalian brain in response to injury and disease4. For example, experiments in rodents have demonstrated that new cells are generated in response to brain injury caused by a stroke. Those new cells can migrate to the site of the injury in the cerebral cortex (where neurogenesis does not normally occur) and differentiate into mature neurons that form connections with neighboring cells. There are also reports of enhanced neurogenesis in the human brain in response to stroke as well as Huntington's disease and Alzheimer's disease. Although this injury-induced neurogenesis does not lead to recovery, many scientists believe it represents the brain's attempt to repair itself. This presents the hope that we can learn how to enhance and guide the brain's existing repair process to promote recovery from injury or neurodegenerative disease. Naturally, this will not be an easy undertaking. It will require an understanding of how to stimulate the generation of new cells, direct their migration to areas that require repair, and control their differentiation into the appropriate kind of neuron. It also may be necessary to manipulate the natural environment of the adult brain to make it more conducive to regeneration. In addition, problems may arise if new neurons do not integrate properly into the existing network of nerve cells. Still, these discoveries raise the hope that we will one day learn how to guide the brain's natural response to injury for therapeutic use.

The discovery of life-long neurogenesis in humans has redefined our understanding of the brain and spinal cord. Although still in its infancy, the study of neurogenesis already has provided insights into the mechanisms of learning and memory, epilepsy, depression, and other disorders and diseases of the nervous system. It also has inspired hope that new strategies will be developed to treat injuries and diseases of the brain and spinal cord. While much progress was made over the past decade, many questions remain unanswered, ensuring that the investigation of neurogenesis in the adult mammalian brain will remain an exciting and intense area of research well into the future.

References

1. Eriksson, P.S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., & Gage, F.H. (1998). Neurogenesis in the adult human hippocampus. Nature Medicine, 4, 1313-1317.
2. Bedard, A. & Parent, A. (2004). Evidence of newly generated neurons in the human olfactory bulb. Developmental Brain Research, 151, 159-168.
3. Curtis, M.A., Kam, M., Nannmark, U., Anderson, M.F., Axell, M.Z., Wikkelso, C., et al. (2007). Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science, 315, 1243-1249.
4. Emsley, J.G., Mitchell, B.D., Kempermann, G., & Macklis, J.D. (2005). Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Progress in Neurobiology, 75, 321-341.
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6. van Praag, H., Christie, B.R., Sejnowski, T.J., & Gage, F.H. (1999). Running enhances neurogenesis, learning, and long-term potentiation in mice. Proceedings of the National Academy of Sciences, 96, 13427-13431.
7. Gould, E., Beylin, A., Tanapat, P., Reeves, A., & Shors, T.J. (1999). Learning enhances adult neurogenesis in the hippocampal formation. Nature Neuroscience, 2, 260-265.
8. Leuner, B., Mendolia-Loffredo, S., Kozorovitskiy, Y., Samburg, D., Gould, E., & Shors, T.J. (2004). Learning enhances the survival of new neurons beyond the time when the hippocampus is required for memory. The Journal of Neuroscience, 24, 7477-7481.
9. Shors, T.J., Miesegaes, G., Beylin, A., Zhao, M., Rydel, T., & Gould, E. (2001). Neurogenesis in the adult is involved in the formation of trace memories. Nature, 410, 372-376.
10. Malberg, J.E. (2004). Implications of adult hippocampal neurogenesis in antidepressant action. Journal of Psychiatry and Neuroscience, 29, 196-205.
11. Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., et al. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301, 805-809.
12. Parent, J.M., Elliott, R.C., Pleasure, S.J., Barbaro, N.M., & Lowenstein, D.H. (2006). Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Annals of Neurology, 59, 81-91.
13. Parent, J.M., Vexler, Z.S., Gong, C., Derugin, N., & Ferriero, D.M. (2002). Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Annals of Neurology, 52, 802-813.
14. Yamashita, T., Ninomiya, M., Hernandez Acosta, P., Garcia-Verdugo, J.M., Sunabori, T., Sakaguchi, M., et al. (2006). Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. The Journal of Neuroscience, 26, 6627-6636.
15. Jin, K., Wang, X., Xie, L., Mao, X.O., Zhu, W., Wang, Y., et al. (2006). Evidence for stroke-induced neurogenesis in the human brain. Proceedings of the National Academy of Sciences, 103,13198-131202.
16. Curtis, M.A., Penney, E.B., Pearson, A.G., van Roon-Mom, W.M., Butterworth, N.J., Dragunow, M., et al. (2003). Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain. Proceedings of the National Academy of Sciences, 100, 9023-9027.
17. Jin, K., Peel, A.L., Mao, X.O., Xie, L., Cottrell, B.A., Henshall, D.C., & Greenberg, D.A. (2004). Increased hippocampal neurogenesis in Alzheimer's disease. Proceedings of the National Academy of Sciences, 101, 343-347.

Image Reference

Crews, F.T. & Nixon, K. (2004). Alcohol, neural stem cells, and adult neurogenesis. National Institute on Alcohol Abuse and Alcoholism. Retrieved 03-19-07 from http://pubs.niaaa.nih.gov/publications/arh27-2/197-204.htm.