Transcriptomic Divergence Between Prefrontal Cortex and Limbic Circuits in Human Aging

1.1. Selective Decline in Synaptic and Glutamatergic Pathways

A hallmark of PFC aging is the targeted downregulation of neuron-enriched genes required for synaptic plasticity. This vulnerability is particularly evident in the glutamatergic signaling of layers II/III, the phylogenetically most recent additions to the human neocortex.

PTGS2 (COX-2) and CREB1: There is evidence of a significant decrease in PTGS2 and CREB1 expression, directly correlated with weakened long-term potentiation (LTP) mechanisms. Unlike stable subcortical structures, these genes in the prefrontal cortex become "victims" of increased transcriptional noise, leading to a loss of synaptic density and dendritic spine stability.

DRD4 and SST: Reduced expression of dopamine D4 receptors (DRD4) in the prefrontal cortex undermines dopaminergic modulation of cognitive control. Concomitantly, reduced SST (somatostatin) expression in inhibitory interneurons leads to impaired filtering of "neuronal noise," allowing irrelevant emotional stimuli to bypass prefrontal barriers.

1.2. Cell-Type-Specific Vulnerability: Erosion of Inhibitory Control

Recent spatial transcriptomics studies using stereosequencing technology (2025) (hypothetical high-throughput benchmark for 2026) indicate that aging of the prefrontal cortex (PFC) is not a uniform decline, but a cell-specific crisis.

Atrophy of SST interneurons: the most critical impact falls on GABAergic interneurons expressing somatostatin. Loss of SST markers leads to impaired inhibition directed to the dendrites of pyramidal neurons. This impairment is the primary cause of "top-down" dysregulation, in which the cortex loses the ability to effectively modulate subcortical inputs.

The most advanced regions of the PFC, such as the dlPFC, which are responsible for logical tasks, are the first to deteriorate due to the loss of transcriptional support. At the same time, more conserved regions such as the vmPFC remain functionally connected to the limbic system and are more resilient. Unlike the dopamine-dominated dorsolateral PFC, the vmPFC is more closely tied to affective regulation.

HTR2C (serotonin receptor 2C): Expression of this gene in the vmPFC and amygdala remains relatively stable. It is responsible for the modulation of mood and fear. The stability of this receptor allows the vmPFC to receive signals from the limbic system even when cognitive control (dlPFC) weakens. The dlPFC contains the highest density of large pyramidal neurons in layers II/III in the brain. These neurons have complex dendritic "trees" for integrating abstract information. Under the influence of neurodegenerative diseases, these connections are more vulnerable, and the dendrites degenerate.

OXTR (oxytocin receptor): Highly expressed in the limbic and vmPFC, it supports social cognition and empathy. During evolution, the vmPFC was a crucial part of the prefrontal cortex for social development and communication, and it developed more rapidly and stably. High cognitive performance requires tremendous energy support, which is the first to degrade with aging. It is less saturated with the fragile neural networks created by the ARHGAP11B gene.

1.3. Inflammatory Shift and Metabolic Fragility

In parallel with neuronal erosion, the aging PFC exhibits compensatory or pathological increases in transcripts associated with glial activity and the innate immune response. Inflammatory-senescence profile: Increased expression of microglial and complement system genes creates a pro-inflammatory environment that is significantly more aggressive in the prefrontal cortex than in the more conservative cerebellum or amygdala. Mitochondrial stress: Reduced transcriptional support for mitochondrial homeostasis makes prefrontal cortex neurons—with their high metabolic demands and complex morphology—uniquely susceptible to oxidative damage. This "metabolic cost" of higher cognitive functions becomes unbearable in the eighth and ninth decades of life.

1.4. Regional Transcriptomic Mismatch: PFC vs Limbic Stability

Aging-related transcriptomic changes are region-dependent: while the PFC shows clear patterns of synaptic and signaling gene downregulation, other brain regions, including subcortical limbic nuclei, exhibit more conserved expression patterns for key immediate-early and reactivity-associated genes. For instance, early response genes such as ARC and FOS, which are rapidly induced by neural activity and emotional stimuli, tend to maintain more stable expression in limbic structures relative to cortex in the absence of degenerative pathology. This divergence creates a transcriptomic mismatch between higher-order control areas and evolutionarily older emotional centers.

Collectively, these findings support a model wherein the prefrontal cortex undergoes progressive transcriptomic erosion affecting synaptic, signaling, and inhibitory control networks, while subcortical and limbic regions retain more robust molecular reactivity. This regional mismatch in gene expression profiles provides a molecular substrate for the observed dissociation between weakening cognitive control and preserved emotional reactivity in aging, manifesting as increased impulsivity and emotional lability in later life.

2.1. Human-Enriched Developmental Programs and Metabolic Debt

A number of genes enriched in humans contribute to the expansion of the upper layers (II/III) of the PFC. Notably, ARHGAP11B promotes the proliferation of basal progenitors by inducing mitochondrial glutaminolysis. While this ensures increased neuron numbers and complex dendritic arbors, it establishes a high metabolic baseline. Although its activity declines postnatally, the PFC is left with a "metabolic debt"—a vast population of energy-hungry neurons that lack sustained developmental support. Other factors, such as NOTCH2NL and SRGAP2C, further increase synaptic density, creating a structural load that is highly sensitive to the mitochondrial and oxidative stress associated with aging.

2.2. Cortical Reserve and the Gradient of Vulnerability

The "cortical reserve" is not uniform across the frontal lobe. The dorso-lateral PFC (dlPFC), which underwent the most significant recent expansion, exhibits the lowest resilience due to its reliance on fragile layer II/III networks. In contrast, the ventromedial PFC (vmPFC) acts as a "cortical anchor," retaining a more phylogenetically conservative transcriptomic profile (characterized by stable HTR2C and OXTR expression). This internal gradient explains why executive logic (dlPFC) often fails before social-emotional wisdom (vmPFC) during cognitive aging.

2.3. Evolution as a Double-Edged Sword

The intersection of human-specific expansion and age-related erosion suggests that our most advanced cognitive areas are "evolutionary outliers." The globularization of the Homo sapiens brain over the last 300,000 years optimized connectivity but prioritized rapid maturation over long-term stability. When combined with the selective downregulation of PTGS2, CREB1, and SST, these structural liabilities lead to the "transcriptomic mismatch" where the robust, stable limbic system (supported by constant FAT4 and ARC expression) eventually dominates a weakening, energy-depleted prefrontal cortex.

4.1. ARHGAP11A and ARHGAP11B: Minimal Genetic Divergence with Disproportionate Effects.

ARHGAP11B arose through a partial duplication of the ancestral ARHGAP11A gene in the hominin lineage approximately 5 million years ago. While ARHGAP11A is conserved in primates and functions as a canonical Rho GTPase-activating protein involved in cytoskeletal regulation, ARHGAP11B acquired a frameshift mutation, resulting in a new C-terminal domain with altered cellular localization and function. This seemingly minor genetic modification led to a qualitative shift in developmental outcomes.

Unlike ARHGAP11A, ARHGAP11B localizes to the mitochondria of neural progenitor cells and induces a metabolic shift toward mitochondrial glutaminolysis. This metabolic rewiring selectively promotes the proliferation of basal radial glial cells (bRG), a progenitor cell population that is rare in non-human primates but abundant in the human fetal neocortex. The expansion of the bRG population significantly increases the activity of excitatory projection neurons, particularly those populating supragranular layers II/III.

A key consequence of this discrepancy is that ARHGAP11B not only modulates neuronal differentiation but also increases neuronal number through an energy-intensive developmental pathway. Thus, a single human-specific gene has created a developmental cascade leading to an exponential increase in the density and connectivity of cortical neurons, particularly in the association areas of the cerebral cortex.

4.2. Structural Consequences in the Prefrontal Cortex: Humans vs. Chimpanzees

The anatomical consequences of ARHGAP11B activity are most evident in the prefrontal cortex, particularly the dorsolateral prefrontal cortex (dlPFC). In humans, the dorsolateral prefrontal cortex (dlPFC) exhibits a marked expansion of layers II/III, characterized by a high density of corticocortical pyramidal neurons with large somata, extensive dendritic arborization, and numerous spines. These neurons form long-range association networks that support abstract thinking, working memory, and flexible behavioral control. In contrast, chimpanzees lack the ARHGAP11B gene and exhibit a more compact prefrontal cortex architecture. Although homologous regions exist, the relative thickness and density of neurons in the supragranular layers are reduced, and corticocortical connectivity is less extensive. Quantitative comparative studies show that, when normalized for cortical volume, the human dlPFC contains approximately two to three times more neurons than that of chimpanzees, accompanied by a significantly greater synaptic and metabolic load. Unlike the dlPFC, the vmPFC: is less dependent on layers II/III, which have a high metabolic cost; utilizes monoaminergic and limbic regulation more actively; maintains more stable expression of receptors such as HTR2C and OXTR; This makes the vmPFC less vulnerable to the same long-term consequences that arise in the dlPFC after ARHGAP11B-accelerated development. Importantly, age-related transcriptional changes in the chimpanzee prefrontal cortex appear to be less pronounced compared to humans. Although both species exhibit molecular signatures of aging, the degree of downregulation of synaptic genes and metabolic stress responses in the chimpanzee frontal cortex is less pronounced, suggesting that human-specific cortical expansion has created a unique vulnerability rather than a universally conserved aging trajectory.

4.3. Developmental Gain and Lifelong Cost: Metabolic Overcommitment of the Human Cortex

Although ARHGAP11B expression is largely restricted to prenatal neurogenesis and rapidly declines after birth, its developmental effects persist throughout the lifespan. The neurons generated under ARHGAP11B-driven conditions remain permanently embedded within cortical circuits that demand sustained energetic and transcriptional support. This creates what can be described as a state of developmental overcommitment: early expansion without parallel mechanisms ensuring long-term molecular resilience. As aging progresses, this overcommitment becomes evident at the transcriptomic level. Genes essential for maintaining synaptic plasticity, inhibitory balance, and mitochondrial function—such as PTGS2, CREB1, and SST—exhibit selective downregulation in the human PFC. Simultaneously, transcriptional noise increases, and compensatory inflammatory and stress-response pathways become upregulated. These processes disproportionately affect neurons with complex morphology and high firing demands, precisely those enriched in expanded dlPFC circuits. In this context, ARHGAP11B does not directly cause neurodegeneration; rather, it biases cortical systems toward a configuration that maximizes early-life cognitive capacity at the expense of long-term metabolic stability. Aging represents the phase at which this imbalance is unmasked.

4.4. Differential Aging Trajectories in Chimpanzee and Human Prefrontal Cortex

The absence of ARHGAP11B in chimpanzees provides a natural comparative framework for understanding human-specific cognitive aging. In chimpanzees, prefrontal circuits are less metabolically overextended and more closely aligned with subcortical regulatory systems. As a result, frontal and limbic regions tend to age in a more synchronized manner, reducing the likelihood of a pronounced regulatory imbalance. In humans, by contrast, the evolutionary decoupling of the dlPFC from older limbic structures generates a progressive mismatch. While limbic circuits retain relatively stable expression of immediate-early and reactivity-associated genes, prefrontal transcriptional support erodes. The ventromedial PFC (vmPFC), which maintains stronger anatomical and molecular coupling with limbic regions and exhibits more conserved receptor expression (e.g., HTR2C, OXTR), partially preserves affective regulation. However, it cannot fully compensate for the decline of dlPFC-mediated executive control. This divergence produces a uniquely human aging phenotype in which emotional reactivity remains intact or even dominant, while abstract reasoning and inhibitory control deteriorate.

4.5. ARHGAP11B as a Driver of Human-Specific Cognitive Aging

Taken together, these observations support a model in which ARHGAP11B functions as an evolutionary amplifier rather than a pathological factor. By enabling rapid expansion of associative cortical networks, it facilitated the emergence of advanced human cognition. However, this same mechanism imposed long-term constraints on metabolic sustainability and transcriptomic stability.Human cognitive aging can therefore be understood as a by-product of human cognitive specialization. The progressive loss of prefrontal transcriptional integrity, coupled with the relative stability of limbic systems, leads to a breakdown of top-down regulation. ARHGAP11B does not determine the timing or severity of aging-related decline, but it shapes the architectural context in which aging unfolds, rendering the human brain uniquely powerful and uniquely fragile across the lifespan.