What it is
Using a single-nucleus transcriptomic atlas spanning the human lifespan, the authors show that cell types in the dorsolateral prefrontal cortex follow non-linear transcriptional trajectories: dynamic remodelling during development, relative stability in midlife and selective molecular reactivation in late adulthood. They identify distinct neuronal and glial programs, including early-life neuronal resilience pathways and late-life glial programs associated with immune activation, stress responses and circadian reorganization, and these programs are organized across cortical layers and grey and white matter.
Why it matters
The dorsolateral prefrontal cortex has a central role in higher cognition and is particularly sensitive to age-related decline, yet its cellular and molecular programs across the lifespan had remained poorly defined, because most studies covered restricted age ranges or disease-affected brains. A lifespan-resolved reference of cellular states helps separate normal development and ageing from pathology, and the authors present it as a framework for understanding how cellular programs shift from resilience to vulnerability.
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Filed underSingle-cell and spatial transcriptomics, Memory and Neural Mechanisms, Stress Responses and Cortisol