Differential expression of a stress-regulated gene Nr4a2 characterizes early- and late-born hippocampal granule cells

Neural progenitors acquire GFAP expression during the perinatal period and continue to generate granule cells (GCs) in the hippocampal dentate gyrus throughout adulthood. Cellular characteristics of GFAP+ progenitor-derived late-born GCs in comparison with early-born GCs remain unknown. Using genetic fate mapping in mice, we show that early- and late-born GCs are concentrated in the outer and inner side of the GC layer, respectively. We then identify that a nuclear orphan receptor Nr4A2 is preferentially expressed by early-born GCs. Nr4a2 expression is dynamically regulated in response to restraint stress and glucocorticoid levels, indicating that Nr4a2 is a stress-regulated gene in GCs. Acute stress suppresses but chronic stress conversely induces Nr4a2 expression in GCs. The survival of newly generated GCs is impaired by chronic restraint stress and long-term stress after middle age decreases the proportion of late-born GCs in aged mice. Thus, early- and late-born GCs exhibit characteristic anatomical distribution, differential gene expression, and distinct response to environmental stress.