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bioRxiv · 10.64898/2026.07.01.734238

A cellular midbrain mechanism for executing fast and reliable escape

Lefler, Y.·Tan, Y. L.·Ferreira, G.·Fudge, A.·Heffernan, M.·Wang, Y.·Branco, T.
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Abstract

Escape from threat is one of the most ancient and conserved sensorimotor transformations and must satisfy two competing demands. It must be fast and reliable, because failing to escape genuine threats risks death, yet also selective, because escaping indiscriminately costs energy and missed resources 1,2. Speed and reliability favour a system with a low threshold that responds to the slightest indication of danger, whereas selectivity demands a high threshold that filters out innocuous stimuli -- yet both must be achieved simultaneously. While previous work has identified mechanisms for implementing selectivity 3-6, it is not known how the mammalian brain achieves speed and reliability once genuine threats have been identified. Here we use whole-cell recordings from dorsal periaqueductal gray (dPAG) neurons in behaving mice to show that the escape circuit resolves this tension via high intrinsic excitability at the single cell level. We find that while the membrane potential of dPAG neurons does not reach action potential threshold during exploratory behaviour, they require only a small amount of current to fire. Threat stimuli cause a sparse increase in synaptic input rate that, because of the high excitability, produces a sustained depolarizing voltage step that drives spiking and escape behaviour. Individual dPAG neurons respond similarly on escape and non-escape trials --what determines escape is the fraction of the dPAG population that is recruited, a finding we confirm with single-unit recordings in freely moving mice. The membrane voltage step response is also invariant to threat type, in contrast to superior colliculus neurons where membrane potential dynamics reflect stimulus identity. These findings reveal a single neuron mechanism for fast and reliable escape, in which the high intrinsic excitability of dPAG neurons transforms sparse, threat-evoked synaptic input into a rapid and stereotyped voltage signal, converting diverse threat representations into a uniform escape command.

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Lefler, Y., Tan, Y. L., Ferreira, G., Fudge, A., Heffernan, M., Wang, Y., Branco, T.. 2026-07-04. A cellular midbrain mechanism for executing fast and reliable escape. https://doi.org/10.64898/2026.07.01.734238

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