Tonically active GABAergic neurons in the dorsal periaqueductal gray control instinctive escape in mice

Abstract

Escape behavior is a set of locomotor actions that move an animal away from threat. While these actions can be stereotyped, it is advantageous for survival that they are flexible.^1,2,3 For example, escape probability depends on predation risk and competing motivations,^{4,5,6,7,8,9,10,11} and flight to safety requires continuous adjustments of trajectory and must terminate at the appropriate place and time.^{12,13,14,15,16} This degree of flexibility suggests that modulatory components, like inhibitory networks, act on the neural circuits controlling instinctive escape.^{17,18,19,20,21,22} In mice, the decision to escape from imminent threats is implemented by a feedforward circuit in the midbrain, where excitatory vesicular glutamate transporter 2-positive (VGluT2⁺) neurons in the dorsal periaqueductal gray (dPAG) compute escape initiation and escape vigor.^23,24,25 Here we tested the hypothesis that local GABAergic neurons within the dPAG control escape behavior by setting the excitability of the dPAG escape network. Using in vitro patch-clamp and in vivo neural activity recordings, we found that vesicular GABA transporter-positive (VGAT⁺) dPAG neurons fire action potentials tonically in the absence of synaptic inputs and are a major source of inhibition to VGluT2⁺ dPAG neurons. Activity in VGAT⁺ dPAG cells transiently decreases at escape onset and increases during escape, peaking at escape termination. Optogenetically increasing or decreasing VGAT⁺ dPAG activity changes the probability of escape when the stimulation is delivered at threat onset and the duration of escape when delivered after escape initiation. We conclude that the activity of tonically firing VGAT⁺ dPAG neurons sets a threshold for escape initiation and controls the execution of the flight action.