Neuroscientists have uncovered how the brain regulates sensitivity to threats to trigger escape behavior in mice. This discovery may pave the way for new treatments for anxiety and post-traumatic stress disorder (PTSD).
Neuroscientists have discovered how the brain bidirectionally controls sensitivity to threats to initiate and complete escape behaviour in mice. These findings could help unlock new directions for discovering therapies for anxiety and post-traumatic stress disorder (PTSD).
The research, detailed in a recent article in Current Biology, focuses on the periaqueductal gray (PAG) region of the brain, known to be hyperactive in individuals with anxiety and PTSD. It was observed that inhibitory neurons in the PAG are continually active, allowing for their activity levels to be adjusted. These neurons influence both the onset and duration of escape behavior in mice.
“Escape behavior is flexible and influenced by experience. Previous studies have shown that mice respond differently based on past encounters. We aimed to investigate how the brain modulates sensitivity to threats, a factor that may be crucial for individuals dealing with anxiety or PTSD where these circuits could be dysregulated,” noted Professor Tiago Branco, lead author of the study from the Sainsbury Wellcome Centre at UCL.
To delve into how the brain manages escape behavior, researchers initially conducted experiments on PAG inhibitory neurons in vitro to examine their characteristics. Through in vivo studies using calcium imaging and miniature microscopes on mice, the team confirmed that PAG inhibitory neurons are connected to excitatory neurons responsible for initiating escape.
“We discovered that the entire escape pathway is subject to inhibitory regulation. Prior to initiating escape, a group of cells shows reduced activity, signaling the removal of inhibition. Conversely, another cell group exhibits increasing inhibition as the animal escapes, peaking once the animal reaches safety. This suggests that inhibitory neurons not only initiate escape but also signal when to cease upon reaching safety,” explained Professor Branco.
Further investigations involved optogenetics, a technique used to manipulate neuron activity. When PAG inhibitory neurons were stimulated, escape likelihood decreased, while inhibition led to increased escape probability. This confirms the role of these neurons in adjusting the sensitivity to threats.
“By activating these neurons mid-escape, we noticed a halt before reaching safety, whereas inhibition resulted in prolonged escape past the shelter. This indicates that these neurons interpret data informing the animal of when it’s safe,” Professor Branco elaborated.
The next phase of research aims to comprehend how threat exposure impacts the excitability of this system via neuron recruitment. Understanding this molecular pathway could spark the development of targeted medications to modulate sensitivity in individuals with anxiety and PTSD.
Funding for this study was provided by Wellcome Trust, Sainsbury Wellcome Centre, Gatsby Charitable Foundation, European Research Council, German Research Foundation, UCL Wellcome PhD Programme, SWC PhD Programme, and Max Planck Society.
