Neuroscientists have made a groundbreaking discovery about how the brain controls sensitivity to threats, paving the way for potential new treatments for anxiety and post-traumatic stress disorder (PTSD).
In a new study, researchers at the Sainsbury Wellcome Centre at UCL investigated the periaqueductal gray (PAG) region of the brain, known to be hyperactive in individuals with anxiety and PTSD. Their findings revealed that inhibitory neurons in the PAG exhibit constant firing, offering the potential to modulate their activity. This discovery directly impacts the initiation and duration of escape behavior in mice.
This breakthrough not only sheds light on the intricate mechanisms of the brain but also holds promise for developing novel therapeutic interventions for anxiety and PTSD.
“Escape behaviour is not fixed – it’s adaptable with experience. Our previous studies have shown that mice become more or less likely to escape depending on their past experience. And so, we wanted to understand how the brain regulates sensitivity to threats as this could have implications for people with anxiety and PTSD where these circuits may be misregulated,” commented Professor Tiago Branco, Group Leader at SWC and corresponding author on the paper.
In their quest to understand how the brain governs escape behavior, the team embarked on a fascinating journey. They began by conducting in vitro recordings from PAG inhibitory neurons, uncovering remarkable insights into their properties. Their discoveries were further validated through in vivo recordings using advanced imaging techniques, capturing the neurons’ activity as mice roamed about.
As if that wasn’t captivating enough, the team delved into connectivity studies, unveiling direct links between the PAG inhibitory neurons and the excitatory neurons responsible for triggering escape responses.
“We found that the whole escape network is under direct inhibitory control. When we looked at what happens during escape, we found a group of cells where the activity goes down just before escape. This means that the inhibition is removed so that escape can be initiated. We also found another group of cells where inhibition gradually increases as the animal is escaping and peaks when the animal has reached the shelter. This suggests that not only do inhibitory cells control escape initiation, but they also look to be important for telling the animal to stop when they reach safety,” explained Professor Branco.
In order to further test their findings, the team employed a cutting-edge technique known as optogenetics to directly control the activity of neurons by stimulating or inhibiting them. Through artificially enhancing the activity of the PAG inhibitory neurons, they observed a decrease in escape probability. Conversely, when these neurons were inhibited, the escape probability increased. This compelling evidence solidifies the notion that the PAG inhibitory neurons function as a regulatory mechanism akin to a dial that can be adjusted to modulate the animal’s responsiveness to threats.
“To check whether these neurons are also important for controlling when escape stops, we first activated the neurons after the animals had started escaping and found that they stopped before they reached the shelter. Then, when we inhibited the neurons, we found that mice ran past the shelter and did not stop escaping. This means the neurons have access to the information that the animal uses to know when it has reached safety,” explained Professor Branco.
The next critical step for the team is to unravel how the experience of threat heightens or dampens the excitability of the system through the recruitment of these neurons. Professor Branco’s vision of developing drugs that target the specific molecular pathway linking experience to neuron recruitment is not only groundbreaking but also holds the potential to empower individuals with anxiety and PTSD by adjusting their sensitivity levels.
Journal reference:
- A. Vanessa Stempel, Dominic A. Evans, Oriol Pavón Arocas, Federico Claudi, Stephen C. Lenzi, Elena Kutsarova, Troy W. Margrie, Tiago Branco. Tonically active GABAergic neurons in the dorsal periaqueductal gray control instinctive escape in mice. Current Biology, 2024; DOI: 10.1016/j.cub.2024.05.068