Layer 5 myelination gates corticothalamic coincidence detection

Abstract

Abstract Myelin is essential for the rapid conduction of action potentials (APs) but its role in long-range processing of disparate inputs remains unclear. Here, using a cell-type-specific approach we recorded optogenetically evoked pyramidal neuron responses via in vivo juxtacellular patch-clamp and Neuropixels probes, tracking spike transmission from layer 5 (L5) to the posteromedial thalamic nucleus (POm) in the mouse. Cuprizone-induced demyelination caused millisecond-scale delays, increased temporal jitter and impaired transmission of high-frequency AP bursts. Computational modeling of the saltatory propagation from L5 to POm revealed that myelin loss from neocortical internodes acts as a low-pass filter, impeding high-frequency spikes within the burst. Finally, pairing optogenetic stimulation with whisker input showed that intact myelination is crucial for coincidence detection in the thalamus. These findings suggest that the continuous myelin pattern of L5 axons not only speeds conduction but also enables precise temporal integration of sensory and cortical signals across long-range pathways.