FASTHUMANNEURON · A novel theory of human cortical microcircuit function: Dedicated neuronal networks for fast cellular and synaptic computation

How human neuronal circuits are organized to produce human cognition is poorly understood. We recently showed (Nature, 2021) that human neocortex contains neuron types not found in other mammals. My preliminary data show that large, human-specialized transcriptomically-defined cell types (t-types) have surprisingly fast processing of synaptic input to action potential output properties. Other human t-types show much slower input-output properties more akin to average mammalian neurons. These fast human-specialized t-types are selectively vulnerable in prevalent human brain disorders with cognitive decline. Mechanisms of fast input-output processing are unknown. We also do not know whether fast-processing neuron t-types form preferential synaptic networks dedicated to fast cortical processing, increasing cortical computational power to support human cognition. Here, I will test this novel concept addressing four fundamental questions: What mechanisms drive fast cellular input-output properties? What mechanisms underlie non-linear dendritic processing of synaptic input? How is coupling between distal dendritic synapses and soma controlled? Do human neuron t-types with fast input-output properties form preferential synaptic networks? These questions can only now be answered with our recent transcriptomic, morpho-electric Patch-seq analysis of adult human neuron t-types. Combined with dendritic and multi-patch recordings, molecular interventions, photonic approaches, and computational modeling, I will provide an unprecedented quantitative understanding of fast cellular computation mechanisms in human cortex supporting human cognition. First preliminary data suggest that biophysical properties of human-specialized neuron t-types and synapses are distinct. Understanding human cortical organization of fast input-output neurons provides a novel framework to understand how selective loss of neuron t-types in human brain disorders gives rise to cognitive decline.