Neocortical neurogenesis in humans is restricted to development

Abstract

Stem cells generate neurons in discrete regions in the postnatal mammalian brain. However, the extent of neurogenesis in the adult human brain has been difficult to establish. We have taken advantage of the integration of (14)C, generated by nuclear bomb tests during the Cold War, in DNA to establish the age of neurons in the major areas of the human cerebral neocortex. Together with the analysis of the neocortex from patients who received BrdU, which integrates in the DNA of dividing cells, our results demonstrate that, whereas nonneuronal cells turn over, neurons in the human cerebral neocortex are not generated in adulthood at detectable levels but are generated perinatally.

Fig. 1.

Determination of the age of neocortical neurons. (A) Neuronal (NeuN-positive) and nonneuronal (NeuN-negative) cell nuclei from the adult human cerebral necortex were separated and isolated by flow cytometry. (B) The levels of ¹⁴C in the atmosphere have been stable over long time periods, with the exception of a large addition of ¹⁴C in 1955–1963 as a result of nuclear weapons tests (blue line, data from ref. 26), making it possible to infer the time of birth of cell populations by relating the level of ¹⁴C in DNA to that in the atmosphere (horizontal arrows) and reading the age off the x axis (vertical arrows). The average age of all cells in the prefrontal cortex is younger than the individual (black arrows), indicating cell turnover. Dating of nonneuronal cells demonstrates they are younger, whereas neurons are approximately as old as the individual. The vertical bar indicates the year of birth of the individual. ¹⁴C levels from modern samples are, by convention, given in relation to a universal standard and corrected for radioactive decay, giving the Δ¹⁴C value (50).

Fig. 2.

Neocortical neurons are as old as the individual. (A) The cerebral lobes are outlined (the large colored fields), and the cortical area analyzed within each lobe is color-coded. Both prefrontal (blue) and premotor (light blue) areas were analyzed in the frontal lobe. The analysis of occipital cortex was reported in ref. . (B) A representative example of values obtained from one individual born after the nuclear weapons tests plotted on to the curve of atmospheric ¹⁴C levels indicates that nonneuronal cells turn over, whereas the cortical neurons were generated close to the time of birth. (C) A representative example of the analysis of an individual born before the nuclear tests, indicating no measurable cortical neurogenesis. The ¹⁴C level in the nonneuronal cells demonstrates there is turnover within this population, but there are several possible interpretations of these data, and the age of this population cannot be concluded from this material alone. The coloring of symbols in B and C corresponds to the regions in A. Vertical bars in B and C indicate the birth date of the individual.

Fig. 3.

BrdU incorporation in the adult human cerebral cortex. (A) Distribution of BrdU-labeled cells in the adult human motor cortex. (B) A subset of BrdU-labeled cells are immunoreactive to the astrocyte marker GFAP. (C and D) None of the BrdU-labeled cells are immunoreactive to the neuronal markers NeuN (C) or neurofilament (D). [Scale bars, 70 μm (B) and 100 μm (C and D).]