Neuroscientists have discovered how the brain bidirectionally controls sensitivity to threats to initiate and complete escape behavior in mice. These findings may help unlock new directions for discovering therapies for anxiety and post-traumatic stress disorder (PTSD).
The research, published today in Current Biology, outlines how researchers from UCL’s Sainsbury Wellcome Center studied an area of the brain called the periaqueductal gray (PAG), which is known to be hyperactive in people with anxiety and PTSD. Their findings show that inhibitory neurons in the PAG fire continuously, meaning their level can be turned up and down. The team found that this has a direct impact on escape initiation in mice and that the same neurons were also responsible for how long the escape lasts.
‘Escape behavior is not fixed – it can be modified with experience. Our previous studies have shown that mice are more or less likely to escape depending on their past experiences. And so we wanted to understand how the brain regulates sensitivity to threats, because it could. have implications for people with anxiety and PTSD, where these circuits may be misregulated,” said Professor Tiago Branco, group leader at SWC and corresponding author of the paper.
To investigate how the brain controls flight behavior, the team first conducted a study in vitro recordings of PAG inhibitory neurons (in a dish) to view their properties. They found that in the absence of input, the PAG inhibitory neurons always fire. They confirmed this finding via in vivo recordings using calcium imaging and head-mounted miniature microscopes while mice ran around. The team also conducted some connectivity studies in the brain and showed that the PAG inhibitory neurons are directly connected to the excitatory neurons known to initiate escape.
“We found that the entire escape network is under direct inhibitory control. When we looked at what happens during escape, we found a group of cells where activity decreases just before escape. This means that the inhibition is released so that escape can occur. We also found another group of cells where inhibition gradually increases as the animal escapes and reaches a peak when the animal reaches the shelter. This suggests that inhibitory cells not only control escape initiation, but also appear to be important for telling animals to stop the escape when they are in safety,” explains Professor Branco.
To test this further, the team used a technique called optogenetics to directly manipulate the activity of neurons by exciting or inhibiting them. When they artificially increased the activity of the PAG inhibitory neurons, they found that the chance of escape decreased. When they inhibited the PAG inhibitory neurons, the chance of escape increased. This confirmed that the PAG inhibitory neurons act like a dial that can be turned up and down to determine how sensitive the animal is to threat.
“To check whether these neurons are also important for controlling when escape stops, we first activated the neurons after the animals had started to escape and found that they stop before reaching the shelter. When we inhibited the neurons, we found that mice ran past. This means that the neurons have access to the information that the animal uses to know when it has reached safety,” explains Professor Branco.
The next step for the team is to understand how the experience of threat makes the system more or less excitable through the recruitment of these neurons. “If we were able to reveal the specific molecular pathway that links experience to the recruitment of these neurons, then it is conceivable that drugs could be developed to target this pathway so that sensitivity in people with anxiety and PTSD can be increased or decreased,” concluded Professor Branco.
This research was funded by a Wellcome Senior Research Fellowship (214352/Z/18/Z), by the Sainsbury Wellcome Center Core Grant from the Gatsby Charitable Foundation and Wellcome (GAT3755 and 219627/Z/19/Z) and by a European research organization . Council Grant (Consolidator No. 864912), Postdoctoral Fellowships from the German Research Foundation (Project No. 515465001; Project No. STE 2605/1), the UCL Wellcome 4-year PhD Program in Neuroscience, the SWC PhD Program and the Max Planck Society.
