Biophysical and computational insights from modeling human cortical pyramidal neurons

Sapir Shapira¹Ido Aizenbud¹Daniela Yoeli^1*Yoni Leibner¹Huib Mansvelder²Christiaan P J De Kock²Michael London^1,3Idan Segev^1,3

• ¹Edmond & Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
• ²Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Faculty of Science, VU Amsterdam, Amsterdam, Netherlands
• ³Department of Neurobiology, The Hebrew University of Jerusalem, Jerusalem, Israel

The human brain's remarkable computational power enables parallel processing of vast information, integrating sensory inputs, memories, and emotions for rapid learning, adaptability, and creativity -far surpassing present-day artificial systems. These capabilities likely arise, in part, from the distinct properties of human neurons, which have only recently been elucidated through collaborative efforts among neurosurgeons, experimental, and theoretical neuroscientists. This effort has yielded unprecedented morphological and biophysical data on human neurons obtained during epilepsy or tumor surgeries. To integrate and interpret this diverse data, two complementary modeling approaches have emerged: detailed biophysical models, unravelling how morphoelectrical properties shape signal processing in human neurons, and machine learning models, which leverage the biophysical models to uncover hidden structure-function relationships. A major focus has been the disproportionately expanded layers 2/3 of the human cortex, where the large L2/3 pyramidal neurons (HL2/3 PNs) can track high-frequency input modulations, exhibit enhanced dendritic signaling, maintain numerous functional dendritic compartments, and display unique dendritic excitability. More recent efforts extend to modeling human hippocampal, cerebellar, and inhibitory cortical neurons. This review synthesizes key theoretical insights from biophysical and machine-learning models of HL2/3 PNs, and explores their implications for understanding "what makes us human".