Understanding prefrontal cortex functions by decoding its molecular, cellular and circuit organization

The prefrontal cortex (PFC) is functionally one of the most complex regions of mammalian brain. Unlike other cortical areas that process single sensory modalities (like vision, touch, smell, etc.), the PFC integrates information across brain regions to regulate diverse functions ranging from cognition, emotion, executive action to even pain sensitivity. However, it is unclear how such diverse functions are organized at the cellular and circuit levels within the anatomical modules of the PFC. Here we employed spatially resolved single-cell transcriptome profiling to decode PFC’s organizational heterogeneity. The results revealed that PFC has very distinct cell type composition relative to all neighboring cortical areas. Interestingly, PFC also adopts specialized transcriptional features, different from all neighbors, with differentially expressed genes regulating neuronal excitability. The projections to major subcortical targets of PFC emerge from combinations of neuron subclusters determined in a target-intrinsic fashion. These cellular and molecular features further segregated within subregions of PFC, alluding to the subregion-specific specialization of several PFC functions. Finally, using these unique cellular, molecular and projection properties, we identified distinct cell types and circuits in PFC that engage in pathogenesis of chronic pain. Collectively, we not only present a comprehensive organizational map of the PFC, critical for supporting its diverse functions, but also reveal the cluster and circuit identity of a pathway underlying chronic pain, a rapidly escalating healthcare challenge limited by molecular understanding of maladaptive PFC circuits. Major points PFC adopts unique cellular composition, distinct from other cortical areas Selective transcriptomic features emerge in PFC to support its divergent functional portfolio Subcortical projections of PFC assume target-intrinsic specification for innervating clusters A molecularly defined L5 projection neuron cluster (to PAG) potentially mediates chronic pain pathogenesis