Laboratory of Neuronal Plasticity, Leloir Institute-CONICET, Buenos Aires, Argentina.
Laboratory of Integrative Systems Biology, Leloir Institute-CONICET, Buenos Aires, Argentina
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Presenting Author: Natalí Belén Rasetto
rasettonatali@gmail.com
Adult hippocampal neurogenesis is a conserved, multi-stage process essential for cognitive flexibility and memory. In young animals, adult-born granule cells (aGCs) progress through a well-orchestrated developmental trajectory that lasts for about 10 weeks. Aging significantly reduces the rate and speed of neurogenesis. To uncover the molecular stage-specific effects of aging on the generation of new neurons, we combined permanent lineage tracing of aGCs with single-nucleus RNA sequencing (snRNA-seq) in aged mice. This strategy allowed us to generate a temporally resolved transcriptional atlas of neurogenesis in the aging hippocampus. Our analysis revealed a pronounced accumulation of neurons at a specific postmitotic neuroblast stage. Remarkably, this population was highly responsive to behavioral stimuli: voluntary running reduced neuroblast accumulation to re-engage developing neurons towards later stages along the differentiation trajectory. These findings position postmitotic neuroblasts as critical regulatory nodes in the neurogenic sequence, poised to integrate pro-maturational signals. This work offers a high-resolution framework for dissecting the mechanisms of neurogenic decline and points to potential strategies for rejuvenating hippocampal plasticity in aging.