Extended Data Fig. 10: Protracted neuronal maturation leads to accumulation of immature neurons in the presence of low frequency of de novo new neuron generation.

a, Process of adult hippocampal neurogenesis^1,2. Proliferating intermediate progenitor cells (IPCs) and neuroblasts (brown) arising from activated neural stem cells (NSCs, grey) generate new post-mitotic immature dentate granule cells (imGCs, red), which develop over time into mature dentate granule cells (mGCs, lime-green). b, An “imGC protracted maturation” model explaining how low-rate, continuous IPC generation can lead to a large number of imGCs as a reservoir, as opposed to a “fast maturation” model. The size of the imGC reservoir in the adult hippocampus depends on a number of factors at the cellular level, such as the rate of stem cell activation and IPC generation, the number of progeny each IPC generates, the percentage of progeny that survives⁷⁹, and the duration of imGCs remaining in the immature state, and these parameters may vary tremendously across species and ages⁸⁰. Here we illustrate side-by-side two schematic models showing how changing one factor, the length of imGC maturation duration, alone while keeping all other parameters the same can lead to significant differences in the outcome on the number of imGCs at a given time. For IPCs in a newly generated cohort at a given time t, they go through stereotypical developmental stages to become imGCs and then mGCs (x-axis). At time t+1, a new IPC cohort is generated (y-axis). With all other parameters the same, if the imGCs mature fast, very few imGCs will be observed at any given time (left model). In contrast, if the average length of imGC maturation duration is substantially longer, imGCs in various maturation stages accumulate over time and are present as a large population in any “snapshot” (right model). Prolonged maturation duration of new neurons in the hippocampus has been demonstrated in non-human primates using nucleotide analog tracing analysis to be at least six months⁴⁹ and over a year⁵⁰. Furthermore, human induced pluripotent stem cell-derived transplanted neurons display significantly slower maturation compared to those of three non-human primates⁸¹. c, d, An indifference curve qualitatively depicting different combinations of two factors, the average rate of new neuron generation (\(\bar{{\rm{r}}}\)_g) and the average duration of imGC maturation (\(\bar{{\rm{t}}}\)_d), to achieve an equal size of imGC reservoirs (c). Hypothetical examples shown in d. A significantly longer \(\bar{{\rm{t}}}\)_d in the adult human hippocampus spares the system from high demand of \(\bar{{\rm{r}}}\)_g to maintain the same size of imGC reservoir, which is a potential model to explain the seemingly counterintuitive discrepancy between the few IPCs and a large number of imGCs in our results.