The Dendrites Decide: Divergent Computation Strategies Define Prefrontal Layer 5 Pyramidal Subtypes

The brain contains a remarkable diversity of neuronal cell types, whose functional roles are shaped by differences in molecular identity, morphology, connectivity, and intrinsic electrophysiological properties. Understanding how these features shape the integration of synaptic inputs within circuits remains a key challenge in neuroscience. The prefrontal cortex (PFC) is a crucial brain area for cognitive function, supporting processes such as decision-making, working memory, and behavioral flexibility. Within the PFC, layer 5 pyramidal neurons are fundamental for this cognitive role, as they extend their dendrites across all cortical layers and act as coincidence detectors for inputs arriving from both cortical and subcortical areas. In these neurons, detection and integration of synaptic inputs rely on back-propagating action potentials (bAPs), which are initiated at the axon initial segment and propagate into the dendritic tree, depolarizing dendrites and modulating the gain and temporal integration of synaptic inputs (Stuart and Sakmann, 1994). By depolarizing dendritic membranes, bAPs activate voltage-gated calcium channels that further influence synaptic integration. Calcium dynamics therefore represent a crucial mechanism underlying dendritic computation (Larkum et al., 1999). Layer 5 pyramidal neurons in the PFC are distinguished by morphology, intrinsic electrophysiological properties, projection targets, and dopamine-receptor expression patterns, subdividing them into D1R-, D2R-, and D3R-expressing pyramidal cells (Moberg and Takahashi, 2022). Morphologically, D1R-pyramidal cells exhibit thin apical dendrites, sparsely branched apical tufts, and limited extension into layer 1, whereas D2R-pyramidal cells display thicker shafts, highly arborized tufts, and extensive layer 1 projections. In addition, D1R- and D2R-expressing neurons can be broadly classified into two electrophysiological classes (Type 1 and Type 2), while D3R-expressing neurons (Type 3) comprise the remaining population and exhibit a distinct intrinsic electrophysiological signature (Gee et al., 2012; Clarkson et al., 2017). Variations in dendritic architecture, including thickness, branching, and layer 1 expansion, are likely to influence how … Correspondence should be addressed to Ana Dorrego-Rivas at ana.dorrego-rivas{at}kcl.ac.uk.