Functional adult neurogenesis: adult brains can and do make new cells

Duy Phan

Johns Hopkins University

Publication Date: January 1, 2015

Until recently, it was believed that the adult mammalian brain is incapable of producing new neurons (Ramon y Cajal 1913). Although reports of adult neurogenesis appeared as early as 1898 (Allen 1912; Levi 1898), those studies were largely ignored. During the 1990’s, adult neurogenesis began to attract more acceptances within the neuroscience field with the publication of Eriksson’s landmark study (Eriksson et al., 1998). By utilizing bromodeoxyuridine (BrdU) co-labeling with neuronal specific markers, Eriksson’s work provided one of the first direct evidence for human adult neurogenesis in the hippocampus. Widely used in animal research, BrdU is a compound that integrates into the cell’s DNA during the S Phase and can later be labeled with antibodies. Although BrdU used to be injected into cancer patients for clinical studies of tumor cell proliferation, this technique is no longer performed due to safety concerns. Thus, for nearly a decade, evidence for human adult hippocampal neurogenesis relied on this one study. Furthermore, Eriksson’s study did not quantify the number of new neurons produced, raising the question of whether there is sufficient neurogenesis in order to have functional significance. Spalding’s recent report utilizing a carbon dating approach provided a much-needed confirmation of human adult neurogenesis, suggesting that up to 700 new neurons are added to each hippocampus per day, implying an unexpected level of neurogenesis-driven neural plasticity (Spalding et al., 2013).

Current understanding holds that adult mammalian neurogenesis is restricted to two main distinct neurogenic niches of the brain: the subgranular zone (SGZ) of the dendate gyrus and the subventricular zone (SVZ) of the lateral ventricle. The journey from neural stem cell to neuron in these two areas involve three general cell types: 1) quiescent radial-glia like GFAP-expressing neural stem cells, 2) rapidly dividing neural progenitor cells, 3) neuroblasts that differentiate into neurons. Mouse literature indicates that stem cells from the SVZ gives rise to GABAergic and dopaminergic interneurons in the olfactory bulb, whereas stem cells from the SGZ produce glutamatergic dentate granule cells. Since 60-80% of young adult-born neurons undergo apoptosis (Sun et al., 2004), only a few of these newborn neurons survive over a long-term and integrate into pre-existing neural circuits. While the human hippocampus also generates new neurons, whether the human SVZ also gives rise to olfactory neurons remains a controversy since very little if any human adult olfactory bulb neurogenesis has been found (Bergmann et al., 2012). Instead, the human SVZ has been suggested to give rise to adult-born neurons in the striatum, which is adjacent to the SVZ neurogenic niche (Ernst et al., 2014). This shift of adult neurogenesis from the olfactory bulb to the striatum could potentially be explained by the fact that mice have greater dependence on olfactory functions than humans.

What role does adult neurogenesis have in brain function? In order to keep up with environmental demands, animals and humans require the abilities to adapt to novel changes, and constant production of new neurons may provide for such plasticity necessary for learning and formation of new memories throughout life. For instance, adult neurogenesis has been suggested to be required for behavioral pattern separation, a type of learning that underlies the capacity to differentiate between two very similar yet different cues (Sahay et al., 2011; Tronel et al., 2010). Ablation of adult neurogenesis has also been reported to increase anxiety-related behavior and block some behavioral effects of antidepressants, suggesting that neurogenesis may play a role in mood regulation in addition to learning and memory (Revest et al., 2009; Li et al., 2008; Santarelli et al., 2003). Indeed, decreased neurogenesis has been hypothesized to play at least a partial role in the pathogenesis of major depression disorder. More interestingly, stroke has been shown to stimulate neurogenesis in the adult rat brains (Arvidsson et al., 2002), implying the therapeutic potential of neurogenesis upregulation for treatments of nervous system disorders and injuries.

On the other hand, however, too much neurogenesis can be detrimental to brain function and health. In fact, a recent study published in Science suggested that excessive neurogenesis decreases memory retention, as preexisting neurons that encode old memories may be erased in order to accommodate newly generated neurons (Akers et al., 2014). Additionally, experimental mouse data and human brain tissues have suggested that epileptic seizures potently induce neuronal proliferation and neurogenesis, resulting in abnormal maturation and integration of neurons that may contribute to network reorganization responsible for recurrent spontaneous seizures and cognitive dysfunction. Thus, rather than playing a compensatory regenerative role, neurogenesis could be a major pathology in epilepsy and other neurological disorders.

Regardless of the nearly century-old dogma that posits newborn neurons do not exist in the adult mammalian brain, the past two decades of research have begun to reverse this outdated belief. Indeed, adult neurogenesis is now one of the central tenets of contemporary neuroscience. Rigorous investigations into adult neurogenesis has unveiled novel insights and unexpected importance of newborn neurons not only the regulation of cognition and behavior but also in the etiologies of nervous system diseases. While adult neurogenesis is still in the age of exploration, a better fundamental understanding of the physical and biological events underlying the generation of adult-born neurons will pave the way for the exciting age of exploitation, in which modulation of neurogenesis may potentially emerge as a powerful new therapeutic avenue for treatments of neurological disorders.

References:

1) Ramon Y., Cajal S. Degeneration and Regeneration of the Nervous System. London: Oxford University Press; 1913. 1928. Trans. R. M. Day, from the Spanish.

2) Ramon Y., Cajal S. Degeneration and Regeneration of the Nervous System. London: Oxford University Press; 1913. 1928. Trans. R. M. Day, from the Spanish.

3) Eriksson, P. S., Perfilieva, E., Björk-Eriksson, T., Alborn, A. M., Nordborg, C., Peterson, D. A., & Gage, F. H. (1998). Neurogenesis in the adult human hippocampus. Nature medicine4(11), 1313-1317.

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5) Sun, W., Winseck, A., Vinsant, S., Park, O. H., Kim, H., & Oppenheim, R. W. (2004). Programmed cell death of adult-generated hippocampal neurons is mediated by the proapoptotic gene Bax. The Journal of neuroscience24(49), 11205-11213.

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9) Tronel, S., Belnoue, L., Grosjean, N., Revest, J. M., Piazza, P. V., Koehl, M., & Abrous, D. N. (2012). Adult‐born neurons are necessary for extended contextual discrimination. Hippocampus22(2), 292-298.

10) Revest, J. M., Dupret, D., Koehl, M., Funk-Reiter, C., Grosjean, N., Piazza, P. V., & Abrous, D. N. (2009). Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Molecular psychiatry14(10), 959-967.

11) Li, Y., Luikart, B. W., Birnbaum, S., Chen, J., Kwon, C. H., Kernie, S. G., … & Parada, L. F. (2008). TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron59(3), 399-412.

12) Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., … & Hen, R. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science301(5634), 805-809.

13) Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., & Lindvall, O. (2002). Neuronal replacement from endogenous precursors in the adult brain after stroke. Nature medicine8(9), 963-970.

14) Akers, K. G., Martinez-Canabal, A., Restivo, L., Yiu, A. P., De Cristofaro, A., Hsiang, H. L. L., … & Frankland, P. W. (2014). Hippocampal Neurogenesis Regulates Forgetting During Adulthood and Infancy. science344(6184), 598-602.

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