Shared Dorsal Periaqueductal Gray Activation Patterns during Exposure to Innate and Conditioned Threats

Abstract

The brainstem dorsal periaqueductal gray (dPAG) has been widely recognized as being a vital node orchestrating the responses to innate threats. Intriguingly, recent evidence also shows that the dPAG mediates defensive responses to fear conditioned contexts. However, it is unknown whether the dPAG displays independent or shared patterns of activation during exposure to innate and conditioned threats. It is also unclear how dPAG ensembles encode and predict diverse defensive behaviors. To address this question, we used miniaturized microscopes to obtain recordings of the same dPAG ensembles during exposure to a live predator and a fear conditioned context in male mice. dPAG ensembles encoded not only distance to threat, but also relevant features, such as predator speed and angular offset between mouse and threat. Furthermore, dPAG cells accurately encoded numerous defensive behaviors, including freezing, stretch-attend postures, and escape. Encoding of behaviors and of distance to threat occurred independently in dPAG cells. dPAG cells also displayed a shared representation to encode these behaviors and distance to threat across innate and conditioned threats. Last, we also show that escape could be predicted by dPAG activity several seconds in advance. Thus, dPAG activity dynamically tracks key kinematic and behavioral variables during exposure to threats, and exhibits similar patterns of activation during defensive behaviors elicited by innate or conditioned threats. These data indicate that a common pathway may be recruited by the dPAG during exposure to a wide variety of threat modalities.

Neural correlates of distinct levels of predatory threat in dorsal periaqueductal grey neurons

“…In the present study, using the Poisson GLM analysis estimating only the influence of the behaviours to predict the neuronal activity, we found an increase in cell firing during freezing (22% of the cells), risk assessment (49% of the cells), and exploratory behaviour (27% of the cells). Similar results were obtained in previous studies investigating mice during predatory exposure to a rat and reported dorsal PAG cells activated during various defensive behaviour, such as escape, freezing, and risk assessment (Deng et al, 2016; Masferrer et al, 2020; Reis et al, 2021). However, when the GLM model also controls for the stimulus conditions, the effect that the model found for each specific behaviour is far less pronounced (% of cells with increased firing during freezing [0%]; risk assessment [32%]; exploration [22%]).…”

“…During cat exposure (stimulus condition 3), the animals alternated between freezing and risk assessment, and most of the time stayed away from the cat. Thus, while we succeeded in our intention of exposing the rats to a very strong threat stimulus, unlike the more active interaction between mice and rats seen in the predatory interaction of the previous studies (Deng et al, 2016;Masferrer et al, 2020;Reis et al, 2021), our experimental approach rendered it difficult to differentiate cell populations responding to approaching or fleeing away from the predator. As the cat was removed from the stimulus box, the rat was kept in the experimental apparatus during the post-cat condition.…”

“…These results were expanded with miniaturized microscope studies to obtain recordings of dorsal PAG ensembles in mice exposed to a live predator (i.e., rat). Accordingly, miniaturized microscope analysis revealed cells that were more active near the rat, and during higher periods of mouse or rat speed, in addition to cells with the opposite pattern of responses, that were more active far from the rat and during periods of low mouse or rat speed (Reis et al, 2021). Moreover, these studies revealed cells that were activated during various defensive behaviours, such as escape, freezing, and risk‐assessment stretch‐attend postures (Reis et al, 2021).…”

“…Accordingly, miniaturized microscope analysis revealed cells that were more active near the rat, and during higher periods of mouse or rat speed, in addition to cells with the opposite pattern of responses, that were more active far from the rat and during periods of low mouse or rat speed (Reis et al, 2021). Moreover, these studies revealed cells that were activated during various defensive behaviours, such as escape, freezing, and risk‐assessment stretch‐attend postures (Reis et al, 2021). Notably, the authors found that distance‐to‐rat variables were not strongly correlated with behavioural variables, suggesting that dorsal PAG cells' activity encodes distance to threat and defensive behaviours independently.…”

“…Given that the PAG is thought to integrate primal emotional affect, we sought to investigate whether the PAG activity would somehow reflect the primal state of fear emotion. Notably, in the previous studies investigating dorsal PAG response to predatory threats, despite being effective in producing clear antipredatory reactions, the authors used relatively weak predator threats, like predator odour or rats confronting mice (Deng et al, 2016; Masferrer et al, 2020; Reis et al, 2021). Interestingly, the rat defensive response to a live cat is much stronger than that seen in the antipredatory conditions typically tested in other studies (i.e., mice exposed to a live rat) (Ribeiro‐Barbosa et al, 2005).…”