New neurons continue to be born in the subgranular zone (SGZ) in the dentate gyrus (DG) of the adult mammalian hippocampus1–5. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease6–10. In humans, some studies suggest that hundreds of new neurons are added to the adult DG every day11, while other studies find many fewer putative new neurons12–14. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the SGZ during human fetal or postnatal development. We also find that proliferating progenitors and young neurons in the DG sharply decline in the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult normal and epileptic patients(18–77 years; n=17 postmortem; n=12 epilepsy), young neurons were not detected in the DG. In the monkey (M. mulatta) hippocampus, a proliferative SGZ was present in early postnatal life, but diminished during juvenile development as neurogenesis declined. We conclude that recruitment of young neurons to the primate hippocampus declines rapidly during the first years of life, and that DG neurogenesis does not continue, or is extremely rare, in the adult human. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.

Cortical inhibitory circuits are formed by GABAergic interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis1-5, is that cortical interneurons are overproduced, and then following their migration into cortex, excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we have characterized the developmental cell death of mouse cortical interneurons in vivo, in vitro, and following transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax- (Bcl-2 associated X-) dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Remarkably, over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by central nervous system (CNS) neurons6-8. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Together, our findings indicate that interneuron cell death is intrinsically determined, either cell-autonomously, or through a population-autonomous competition for survival signals derived from other interneurons.

While the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. Here, we developed a high-content pipeline, the Large-area Spatial Transcriptomic (LaST) map, which can quantify singlecell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, we identified superficial, mid, and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in early postnatal cortex, mostly persisted in adult mouse and human cortex. Single cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.