Newborn Neurons Abundant in Adult Human Hippocampus

Scientists know that the adult human brain makes new neurons, but they debate whether those fledgling cells have a functional role. Now, using carbon-14 to estimate the age of neurons, researchers led by Jonas Frisén, Karolinska Institutet, Stockholm, Sweden, calculate that the human brain produces around 700 new neurons per day, enough to replace all the neurons in the dentate gyrus over a lifetime. That equates to the birthrate of new neurons in the middle-aged rodent brain, where neurogenesis proves essential for synaptic plasticity. The findings, published in the June 6 Cell, suggest that human neurogenesis serves a similar function, wrote the researchers.

The authors "have derived a model predicting that neurogenesis-based plasticity in humans reaches much greater levels than previously assumed,” wrote Gerd Kempermann, Center for Regenerative Therapies, Dresden, Germany, in a commentary for Science. “Previous concerns about low levels of neurogenesis in humans and its potentially limited importance in aged individuals can now be tempered," suggested Mazen Kheirbek and René Hen, Columbia University, New York, in an accompanying Cell Preview. “The big question is whether adult-born neurons contribute to brain function,” Kempermann added.

During the Cold War, nuclear bomb tests released carbon-14 (C14) into the atmosphere. Traces of the isotope eventually wound up in every person's DNA. However, after an international treaty banned above-ground nuclear tests in 1963, atmospheric levels of C14 began to rapidly decline.

In 2005, Frisén’s group figured out that they could estimate a cell’s age, within about 1.5 years, by matching the C14 content of its DNA to historical atmospheric levels (see ARF related news story). Using this method, the researchers found no young neurons in adult human cerebral cortex, or olfactory bulb, suggesting adult-born neurons fail to establish themselves in those regions (see Bergmann et al., 2012). In this study, the authors focused on incorporation of new neurons into the hippocampus.

First author Kirsty Spalding and colleagues isolated neuronal nuclei from postmortem hippocampi of 55 people, aged 19-92. Using accelerator mass spectrometry, the researchers measured C14 in the DNA and found that on average, the neurons were younger than the individuals themselves, indicating ongoing neurogenesis. Comparing birth dates to historical C14 levels in the atmosphere, the scientists then tested a variety of models to find one that best explained the isotope data in all 55 people. The models accounted for birth and death rates of neurons, as well as whether renewal took place in all hippocampal cells or only in certain subpopulations. The model with the best fit predicted that about 35 percent of the hippocampal cells turned over. Interestingly, the human dentate gyrus occupies about one-third of the hippocampus, and markers of neurogenesis have been detected there before. The authors concluded that the vast majority of dentate gyrus neurons must be replaced over the human lifespan. Almost 2 percent of those neurons turn over each year.

What does this mean for the role of neurogenesis in the human brain? Comparable rates of neurogenesis occur in humans and in middle-aged mice, Frisén told Alzforum. Since neurogenesis assists in cognition, formation of memories, and mood regulation in animals, it could play similar roles in humans, Frisén said. Some research suggests neurogenesis, or lack thereof, may contribute to human conditions, such as depression (see ARF related news story). Frisén plans to examine tissue from people with psychiatric disorders and Alzheimer’s disease (AD) to see if rates of neurogenesis differ from healthy controls.

Interestingly, while mouse neurogenesis declines steeply with age, Spalding and colleagues found it drops modestly in humans. Data also suggest only 10 percent of murine dentate gyrus neurons are ever replaced. Neither of these observations discount mice as models of human neurogenesis, said Frisén. As long as they produce a comparable number of adult-born cells, they should be similar enough to humans for basic study, he suggested.

"This study is of profound importance, given that it will further invigorate the field for the study of the contribution of adult hippocampal neurogenesis to human behavior and mental health," wrote Kheirbek and Hen. Researchers will want to figure out ways to image new cell birth in vivo to see how it changes with disease and treatment, and investigate how its manipulation could treat age-related cognitive disorders, they suggested. It would also be interesting to know how various lifestyle factors, such as exercise, contribute to the variability in neurogenesis rates shown in this study, wrote Orly Lazarov, University of Illinois at Chicago, to Alzforum in an e-mail. Exercise has been shown to increase neurogenesis in mice and also attenuate Alzheimer's pathology (see ARF related news story and ARF related news story).—Gwyneth Dickey Zakaib

Comments

  1. These observations clearly determine that the extent of hippocampal neurogenesis is comparable in humans and rodents, and provide profound evidence for the critical role of neurogenesis in the human dentate gyrus. Several noteworthy unknowns in this study would be interesting to explore. One aspect is information about the participants in the study: their lifestyle, level of education, level of exercise, etc. Neurogenesis plays a major role in adaptation to novel environments and is context dependent. In addition, neurogenesis is an inducible set of processes, and more new neurons might be recruited in individuals that engage in activities that require neurogenesis. Indeed, the authors indicate a high variability in the data obtained from participants in the study, which might be attributed to lifestyle and environmental parameters.

    Another aspect is related to the role of neurogenesis in cognitive function and dysfunction. The study suggests only a steady moderate decline in neurogenesis with aging, suggesting that in contrast to previous assumptions, neurogenesis may play a significant role during aging in humans. Nevertheless, the extent of decline in neurogenesis that manifests in cognitive deficits is unknown. In addition, it is unknown if neurogenesis is as inducible in the old brain as in the young.

    Lastly, Alzheimer’s disease is not normal aging. Thus, in the context of pathological aging, the question arises whether the rate of age-dependent decline in neurogenesis is faster in individuals with cognitive impairments and if individuals exhibiting a greater decline in neurogenesis are more susceptible to the development of cognitive deficits. More studies are required to answer these questions.

    View all comments by Orly Lazarov

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References

News Citations

  1. Dating the Birth of Human Cells—Carbon 14 Runs Rings around Competition
  2. Taos: Disease, Drug Development, and Adult Neurogenesis
  3. Stem Cells Restore Some Spinal Cord Function
  4. Exercise Helps Mouse Elders Learn, Generate New Neurons

Paper Citations

  1. Bergmann O, Liebl J, Bernard S, Alkass K, Yeung MS, Steier P, Kutschera W, Johnson L, Landén M, Druid H, Spalding KL, Frisén J. The age of olfactory bulb neurons in humans. Neuron. 2012 May 24;74(4):634-9. PubMed.

Further Reading

Papers

  1. Knoth R, Singec I, Ditter M, Pantazis G, Capetian P, Meyer RP, Horvat V, Volk B, Kempermann G. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS One. 2010;5(1):e8809. PubMed.
  2. Bergmann O, Liebl J, Bernard S, Alkass K, Yeung MS, Steier P, Kutschera W, Johnson L, Landén M, Druid H, Spalding KL, Frisén J. The age of olfactory bulb neurons in humans. Neuron. 2012 May 24;74(4):634-9. PubMed.
  3. Li G, Fang L, Fernández G, Pleasure SJ. The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus. Neuron. 2013 May 22;78(4):658-72. PubMed.
  4. Kempermann G. New neurons for 'survival of the fittest'. Nat Rev Neurosci. 2012 Oct;13(10):727-36. PubMed.

Primary Papers

  1. Kempermann G. Neuroscience. What the bomb said about the brain. Science. 2013 Jun 7;340(6137):1180-1. PubMed.
  2. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisén J. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013 Jun 6;153(6):1219-27. PubMed.
  3. Kheirbek MA, Hen R. (Radio)active Neurogenesis in the Human Hippocampus. Cell. 2013 Jun 6;153(6):1183-4. PubMed.

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