Summary: Researchers have discovered how the brain controls sensitivity to threats, thereby influencing escape behavior in mice. The study revealed that periaqueductal gray (PAG) inhibitory neurons regulate both the onset and termination of escape.
These findings could lead to new therapies for anxiety and PTSD. Future research aims to explore the molecular pathways linking the experience of threat to neuronal activity.
Highlights:
- Neural control: PAG inhibitory neurons regulate the initiation and termination of escape.
- Therapeutic potential: The findings could lead to new treatments for anxiety and PTSD.
- Future research: Next steps include studying the molecular pathways linking the experience of threat to neural activity.
Source: Sainsbury’s Visitor Center
Neuroscientists have discovered how the brain bidirectionally controls threat sensitivity to initiate and complete escape behavior in mice. These findings could help open new directions for discovering therapies for anxiety and post-traumatic stress disorder (PTSD).
The study, published today in Current biology, describes how researchers at UCL’s Sainsbury Wellcome Center studied a region of the brain called periaqueductal gray (PAG), known to be overactive in people suffering from anxiety and PTSD.
Their results show that PAG inhibitory neurons are constantly firing, meaning their level can be increased or decreased. The team found that this has a direct impact on flight initiation in mice and that the same neurons are also responsible for flight duration.
“Escape behavior is not fixed – it adapts with experience. Our previous studies have shown that mice are more or less likely to escape depending on their past experience.
“We therefore wanted to understand how the brain regulates threat sensitivity, as this could have implications for people with anxiety and PTSD, where these circuits could be misregulated,” commented group leader Professor Tiago Branco at SWC and corresponding author of the article.
To study how the brain controls escape behavior, the team first carried out in vitro recordings from PAG inhibitory neurons (in a plate) to examine their properties. They found that in the absence of input, PAG inhibitory neurons still fire. They confirmed this discovery by alive recordings using calcium imaging and miniature head-mounted microscopes while the mice ran.
The team also performed connectivity studies in the brain and showed that inhibitory neurons in the PAG are directly connected to 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 an escape, we found a group of cells whose activity decreases just before the escape. This means that inhibition is removed so that the escape can be initiated.
“We also discovered another group of cells whose inhibition gradually increases as the animal escapes and peaks when the animal reaches the shelter. This suggests that not only do inhibitory cells control the initiation of escape, but they also appear to play an important role in telling the animal to stop when it reaches safety,” explained 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 PAG inhibitory neurons, they found that the probability of escape decreased.
When they inhibited PAG inhibitory neurons, the probability of escape increased. This confirmed that PAG inhibitory neurons act like a dial that can be turned up and down to control the animal’s sensitivity to threat.
“To test whether these neurons are also important for controlling the cessation of escape, we first activated the neurons after the animals started to escape and found that they stopped before reaching the ‘shelter.
“Then when we inhibited the neurons, we found that the mice ran past the shelter and kept escaping. This means that the neurons have access to information that the animal uses to know when it is safe,” Professor Branco explained.
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 could reveal the specific molecular pathway that links experience to the recruitment of these neurons, then it would be conceivable that drugs could be developed to target this pathway so that sensitivity could be increased or decreased in people with anxiety and PTSD,” concluded Professor Branco.
Funding: 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 fund. Council Grant (Consolidator No. 864912), German Research Foundation Postdoctoral Fellowships (Project No. 515465001; Project No. STE 2605/1), 4-year PhD program in Neuroscience from UCL Wellcome, PhD SWC and Max Planck Society.
About this neuroscience and PTSD research news
Author: April Cashin-Garbutt
Source: Sainsbury’s Visitor Center
Contact: April Cashin-Garbutt – Sainsbury’s Welcome Center
Picture: Image is credited to Neuroscience News
Original research: Free access.
“Tonically active GABAergic neurons in the dorsal periaqueductal gray control instinctive flight in mice” by Tiago Branco et al. Current biology
Abstract
Tonically active GABAergic neurons in the dorsal periaqueductal gray control instinctive flight in mice
Strong points
- GABAergic neurons in dorsal PAG fire action potentials tonically
- They constitute a major source of synaptic inhibition for excitatory PAG neurons
- The tonic GABAergic activity of the PAG establishes a threshold for instinctive escape
- PAG GABAergic neurons control both initiation and termination of escape
Summary
Escape behavior is a set of locomotor actions that move an animal away from a threat. Although these actions may be formulaic, it is beneficial for survival if they are flexible.
For example, the probability of escape depends on the risk of predation and competing motivations, and flight to safety requires continuous adjustments to trajectory and must end at the appropriate place and time.
This degree of flexibility suggests that modulatory components, such as inhibitory networks, act on the neural circuits controlling instinctive escape.
In mice, the decision to escape from imminent threats is implemented by a feedback circuit in the midbrain, where the excitatory vesicular glutamate transporter 2-positive (VGluT2+) dorsal periaqueductal gray (dPAG) neurons calculate escape initiation and escape vigor.
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 alive recordings of neuronal activity, we found that the vesicular GABA-positive transporter (VGAT+) dPAG neurons fire action potentials tonically in the absence of synaptic inputs and are a major source of VGluT2 inhibition.+ dPAG neurons. Activity in VGAT+ dPAG cells transiently decrease at the onset of leakage and increase during escape, reaching a maximum at the end of escape.
VGAT optogenetically increasing or decreasing+ dPAG activity alters the probability of escape when stimulation is delivered at threat onset and the duration of escape when delivered after escape onset. We conclude that tonic gating activity of the VGAT+ dPAG neurons set a threshold for escape initiation and control execution of the flight action.