PerspectiveNeuroscience

What the Bomb Said About the Brain

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Science  07 Jun 2013:
Vol. 340, Issue 6137, pp. 1180-1181
DOI: 10.1126/science.1240681

There are few positive things to be said about above-surface nuclear bomb tests, but one of their most unexpected fallouts will be the proof of neurogenesis in the adult human brain. With help from atomic-age history, Spalding et al. (1) have derived a model predicting that neurogenesis-based plasticity in humans reaches much greater levels than previously assumed.

The hippocampal region of the brain in most, if not all, mammals, including humans, generates new neurons. A landmark study 15 years ago applied a method routinely used in animal research to human subjects and revealed new neurons in the adult human brain in five individuals up to 72 years of age (2). But this classical method involved injecting a label that permanently integrates into the DNA of dividing cells. The compound, bromodeoxyuridine (BrdU), can be recognized with antibodies and used to visualize cells that originate from a cell that took up the label when it was injected, and subsequently divided. For a short time, BrdU was used in clinical studies for tumor-staging purposes. The 1998 study relied on the availability of a cohort of patients that had received BrdU injections and were willing to donate their brains after death. This situation will not occur again, as BrdU is no longer given to patients for safety reasons. Thus, information on adult hippocampal neurons in humans has relied on this one influential study, although there has been some additional indirect evidence since then. For example, the characteristic molecular markers that identify adult hippocampal neurogenesis in the mouse are also present in the adult and old human hippocampus (3).

The brain, time-stamped.

Atmospheric 14C that was released during nuclear bomb tests between 1945 and 1963 has been incorporated into the DNA of dividing cells, providing a time-stamp. This has been used to prove adult hippocampal neurogenesis in humans, thereby confirming a particular type of structural and functional brain plasticity involved in higher cognitive function.

CREDIT: H. MCDONALD/SCIENCE

The long-awaited, more direct proof has finally been provided by Spalding et al. through an ingenious approach (see the figure). Their strategy makes use of the extreme peak of carbon isotope 14 (14C) that was released into the atmosphere during the aboveground nuclear bomb tests between 1945 and 1963. Following the Limited Test Ban Treaty of 1963, most aboveground blasts ceased. Since then, the amount of atmospheric 14C has declined. Dividing cells require carbon, and as this carbon is ultimately taken from the atmosphere, 14C finds its way into the DNA of proliferating cells, where the atoms are stably integrated into chromosomes as they are being duplicated. Conveniently, the amount of incorporated 14C correlates with the atmospheric 14C at the time of cell division. So one "only" has to measure 14C in the DNA to estimate, quite precisely, the age of a cell, based on the age of its DNA (the decline in 14C over time is used to calculate the age). The technical realization of this kind of cellular carbon dating turned out to be a tremendous challenge (4), but over the years, it has been used to study the cellular turnover in several tissues, such as adipose (5).

Spalding et al. not only confirm that adult brain neurogenesis is restricted to the hippocampus, but the size of their data set (genomic DNA was isolated from hippocampal neurons from subjects 19 to 92 years of age) enabled the authors to attempt a quantitative estimate on the dynamics of the process. Based on a sophisticated modeling approach, they conclude that contrary to some expectations, humans have at least as much adult hippocampal neurogenesis as mice. They calculate a considerable turnover of neurons in the dentate gyrus portion of the hippocampus and put forth a model of how the composition of this hippocampal structure changes over the course of life. In the proposed model, "turnover" does not imply that specific neurons are renewed one-by-one. Rather, a subpopulation of neurons renews consistently and continually, whereas another population is nonrenewing. Spalding et al. estimate that one-third of adult hippocampal neurons are turning over. This amounts to 700 new neurons added per day, for an annual turnover rate of 1.75% (or 0.004% of dentate gyrus neurons). This turnover rate was not significantly different between men and women and declined only modestly with age. The author's modeling suggests that nonrenewing neurons in the hippocampus die without being replaced and account for the slow decrease in total neuron number throughout life. By contrast, adult-born neurons in the renewing population do not survive as long and are preferentially lost. The half life of the latter is about 7 years, 10 times shorter than that of the former.

The big question is whether adult-born neurons contribute to brain function. Indeed, other models already have suggested that such continual turnover is highly efficient for meeting some of the particular computational needs that the hippocampus has to face (6). It is the young, immature neurons that seem to play a critical role in the function of the dentate gyrus (7, 8); essentially all long-term potentiation (which underlies learning and memory) measurable under normal conditions can be attributed to the newborn cells. Adult neurogenesis would not only provide plasticity but also add to stability because some new neurons are also integrated for a longer amount of time, presumably resulting in relatively long-lasting adaptations of the local network. Acute benefits from neurogenesis might be translated into lasting ones, depending on actual activity and cognitive demand.

At the behavioral level, adult neurogenesis adds a particular type of cognitive flexibility to the hippocampus (8). Adult neurogenesis does not appear to be required for hippocampal function per se, even though tampering with adult neurogenesis affects the efficiency of hippocampal functions such as "pattern separation" (which allows storing similar representations in a nonoverlapping manner) (9). Perhaps, the advantage of having a dentate gyrus, as mammals do, lies in the ability it provides to cope with change and novelty (10). Adult neurogenesis in this region might add a particular functionality not achievable by other types of plasticity. By staying "forever young," the dentate gyrus could command unique solutions to computational problems only found in the brain region central to learning, memory, and many higher cognitive functions considered essential for humans.

The evolutionary advantage attributable to the mammalian dentate gyrus compared to the analogous structures in other vertebrates might result from adult hippocampal neurogenesis and might even prominently contribute to the individualization of the brain and thus the shaping of personality (11). In such context, Spalding et al. provide a confirmation with the highest possible impact. Neurogenesis researchers can stop worrying and love the bomb.

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