Abstract
ABSTRACT Hippocampal neurogenesis supports learning and memory by generating new granule cells throughout life. However, both the rate and speed of this process decline with age. To elucidate the molecular determinants underlying the effects of aging on neuronal differentiation, we combined lineage tracing of adult-born granule cells (aGCs) with single-nucleus RNA sequencing. This approach produced a temporally resolved transcriptional atlas of aGC development. Aging led to a marked accumulation of postmitotic neuroblasts (NBs), revealing a stage-specific bottleneck in the neurogenic trajectory. Voluntary running reduced NB accumulation by restoring the progression through this developmental impasse, allowing neuronal maturation to be resumed. Notably, this effect involved a significant reduction of apoptosis at the NB stage. Together, these findings identify a reversible apoptotic checkpoint that contributes to age-related neurogenic decline and highlight postmitotic NBs as a key regulatory cell state capable of integrating pro-maturational signals to control the neurogenic output.
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ABSTRACT
Hippocampal neurogenesis supports learning and memory by generating new granule cells throughout life. However, both the rate and speed of this process decline with age. To elucidate the molecular determinants underlying the effects of aging on neuronal differentiation, we combined lineage tracing of adult-born granule cells (aGCs) with single-nucleus RNA sequencing. This approach produced a temporally resolved transcriptional atlas of aGC development. Aging led to a marked accumulation of postmitotic neuroblasts (NBs), revealing a stage-specific bottleneck in the neurogenic trajectory. Voluntary running reduced NB accumulation by restoring the progression through this developmental impasse, allowing neuronal maturation to be resumed. Notably, this effect involved a significant reduction of apoptosis at the NB stage. Together, these findings identify a reversible apoptotic checkpoint that contributes to age-related neurogenic decline and highlight postmitotic NBs as a key regulatory cell state capable of integrating pro-maturational signals to control the neurogenic output.
Competing Interest Statement
The authors have declared no competing interest.
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