Dynamics of Excitability in Axonal Trees

We report that axons of cortical neurons, structurally intricate excitable media, maintain remarkably high fidelity in transmitting somatic spike timing, even during complex spontaneous network activity that includes extremely short (2-3 msec) inter-spike intervals. This robustness underscores their function as reliable conducting devices under physiological conditions. It is nevertheless well established that under artificially imposed, high-rate pulsing stimuli, axonal conduction can fail, with vulnerability depending on distance and branching. In line with this, we demonstrate that conduction failures can also occur at frequencies as low as 10 Hz, provided that stimulation is sustained for several seconds. Under these conditions, propagation delays increase and failures accumulate, particularly in distal branches, whereas effects are negligible at 1-4 Hz. Simulations incorporating cumulative sodium channel inactivation at vulnerable sites reproduce these dynamics. Our findings refine the view of axons as active, heterogeneous structures: they are exceptionally reliable across most physiological regimes, yet exhibit limits under prolonged or extreme stimulation, a regime rarely encountered in vivo but critical for understanding axonal excitability. Significance StatementAxons are widely regarded as reliable conduits of action potentials from the neuron cell body to downstream targets. We confirm this reliability during spontaneous network activity, even when spikes occur in complex patterns with very short interspike intervals. Prior studies have shown that conduction can fail under rapid, high-frequency trains of artificial stimuli. Here we extend this principle by showing that sustained stimulation at 10 Hz--a frequency within physiological ranges--can also induce propagation delays and failures, particularly in distal and higher-order axonal branches. Simulations incorporating cumulative sodium channel inactivation reproduce these effects. Thus, axons should be understood as highly reliable under natural conditions, yet context-dependent, with excitability shaped by the history of sustained activity.