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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., Competing Interests: Declaration of interests The authors declare there are no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Instinctive behaviours have evolved across animal phyla and ensure the survival of both the individual and species. They include behaviours that achieve defence, feeding, aggression, sexual reproduction, or parental care. Within the vertebrate subphylum, the brain circuits that support instinctive behaviour output are evolutionarily conserved, being present in the oldest group of living vertebrates, the lamprey. Here, I will provide an evolutionary and comparative perspective on the function of a conserved brainstem region central to the initiation and execution of virtually all instinctive behaviours-the periaqueductal gray. In particular, I will focus on recent advances on the neural mechanisms in the periaqueductal gray that underlie the production of different instinctive behaviours within and across species., Competing Interests: Declaration of competing interest The author declares no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

When faced with predatory threats, escape towards shelter is an adaptive action that offers long-term protection against the attacker. Animals rely on knowledge of safe locations in the environment to instinctively execute rapid shelter-directed escape actions 1,2 . Although previous work has identified neural mechanisms of escape initiation 3,4 , it is not known how the escape circuit incorporates spatial information to execute rapid flights along the most efficient route to shelter. Here we show that the mouse retrosplenial cortex (RSP) and superior colliculus (SC) form a circuit that encodes the shelter-direction vector and is specifically required for accurately orienting to shelter during escape. Shelter direction is encoded in RSP and SC neurons in egocentric coordinates and SC shelter-direction tuning depends on RSP activity. Inactivation of the RSP-SC pathway disrupts the orientation to shelter and causes escapes away from the optimal shelter-directed route, but does not lead to generic deficits in orientation or spatial navigation. We find that the RSP and SC are monosynaptically connected and form a feedforward lateral inhibition microcircuit that strongly drives the inhibitory collicular network because of higher RSP input convergence and synaptic integration efficiency in inhibitory SC neurons. This results in broad shelter-direction tuning in inhibitory SC neurons and sharply tuned excitatory SC neurons. These findings are recapitulated by a biologically constrained spiking network model in which RSP input to the local SC recurrent ring architecture generates a circular shelter-direction map. We propose that this RSP-SC circuit might be specialized for generating collicular representations of memorized spatial goals that are readily accessible to the motor system during escape, or more broadly, during navigation when the goal must be reached as fast as possible., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)