Intrinsic elaboration of prefrontal modularity: a dual-control model of axon bundling and synaptic docking

The evolutionary expansion of the primate prefrontal cortex (PFC) presents a profound biological enigma: how does this region achieve a highly ordered, modular architecture in the absence of direct dense sensory templates that govern primary sensory areas? In this review, we synthesize classical neuroanatomical frameworks with recent advances in spatial transcriptomics and connectomics to delineate a model of intrinsic elaboration. We propose that PFC modularity emerges from a developmental program facilitated by expansion of the outer subventricular zone (OSVZ) and the legacy of whole-genome duplication (2R-WGD). Central to this proposal is a "Dual-Control Model" of circuit assembly, inferred by integrating anatomical tracer data with spatial and spatiotemporal transcriptomic datasets. This framework suggests that long-range connectivity is established through pre-target axon bundling (fasciculation), governed by a high-dimensional navigation code (e.g., ephrin/Eph, PCDH11X, PCDH17, ROBO2), while these bundles are anchored onto vertical columnar scaffolds through synaptic docking mechanisms (e.g., CBLN2, cadherins). By contrasting the PFC with the map-driven visual system, point-driven olfactory system, and layer-driven hippocampus, we argue that PFC uniqueness lies not in novel genes but in a combinatorial logic of a shared molecular toolkit, which can be understood as intrinsic elaboration. This framework may facilitate the emergence of a cognitive scaffold under relatively weak external sensory constraints. These molecular systems are considered to operate in concert with activity-dependent developmental refinement rather than independently of neural activity.