Transcriptomic Divergence Between Prefrontal Cortex and Limbic Circuits in Human Aging

Cognitive aging is characterized by declines in executive functions, yet the molecular mechanisms underlying the dissociation between cortical control and emotional reactivity remain unclear. This article proposes a conceptual model based on divergent transcriptomic erosion in the prefrontal cortex (PFC) compared to the relative resilience of the limbic system. We summarize data showing that the PFC exhibits marked reductions in the expression of genes critical for synaptic integrity and layer II/III glutamatergic signaling, such as PTGS2, DRD4, SST, and CREB1. Furthermore, we propose that postnatal attenuation of human-specific developmental factors, including ARHGAP11B, may limit "cortical reserve," increasing the vulnerability of the neocortex to mitochondrial and oxidative stress. In contrast, phylogenetically older limbic structures, such as the amygdala, exhibit a more conserved expression profile, with relative retention of early response genes (ARC, FOS). FAT4 gene expression in subcortical limbic structures (such as the amygdala) remains relatively constant after brain development is complete. It is less sensitive to momentary neurotransmitter fluctuations, resulting in a flatter expression profile. We posit that this "transcriptomic mismatch" leads to a disruption of descending disinhibition, in which stable limbic reactivity is no longer modulated by weakening prefrontal cortex activity. This evolutionary tradeoff provides a molecular basis for age-related increases in impulsivity and emotional lability, suggesting that more recently evolved brain regions are the first to succumb to the molecular pressures of aging, compared to the more conservative and stable limbic system. This confirms and illustrates how the brain has evolved over the course of evolution and how new cortical areas often become unstable or incompletely developed as they develop further.