Brain Control of Escape Behavior May Unlock Anxiety Treatments

Summary: Researchers discovered how the brain controls sensitivity to threats, influencing escape behavior in mice. The study found that inhibitory neurons in the periaqueductal gray (PAG) regulate both the initiation and termination of escape.

These findings could lead to new therapies for anxiety and PTSD. Future research aims to explore the molecular pathways linking threat experience to neuron activity.

Key Facts:

1. Neuronal Control: PAG inhibitory neurons regulate escape initiation and termination.
2. Therapeutic Potential: Findings may lead to new treatments for anxiety and PTSD.
3. Future Research: Next steps include studying molecular pathways linking threat experience to neuron activity.

Source: Sainsbury Wellcome Center

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 study, published today in Current Biology, outlines how researchers at the Sainsbury Wellcome Centre at UCL studied a region 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 constantly fire, which means that their level can be dialled 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 escape lasts.

“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.

To study how the brain controls escape behaviour, the team first carried out in vitro recordings from PAG inhibitory neurons (in a dish) to look at their properties. They found that in the absence of input, the PAG inhibitory neurons always fire. They confirmed this finding through in vivo recordings using calcium imaging and head mounted miniature microscopes while mice ran around.

The team also performed some connectivity studies in the brain and showed that the PAG inhibitory neurons are directly connected to the excitatory neurons that are known to initiate escape.

“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.

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 escape probability decreased.

When they inhibited the PAG inhibitory neurons, then escape probability increased. This confirmed that the PAG inhibitory neurons are acting as dial that can be turned up and down to control 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 escaping and found that they stop before they reach the shelter.

“Then when we inhibited the neurons, we found that mice run past the shelter and do 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 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 the sensitivity could be dialled up or down 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 Centre Core Grant from the Gatsby Charitable Foundation and Wellcome (GAT3755 and 219627/Z/19/Z) and by a European Research Council grant (Consolidator no. 864912), German Research Foundation postdoctoral fellowships (project no. 515465001; project no. STE 2605/1), the UCL Wellcome 4-year PhD Programme in Neuroscience, the SWC PhD Programme and the Max Planck Society.

About this neuroscience and PTSD research news

Author: April Cashin-Garbutt
Source: Sainsbury Wellcome Center
Contact: April Cashin-Garbutt – Sainsbury Wellcome Center
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Tonically active GABAergic neurons in the dorsal periaqueductal gray control instinctive escape in mice” by Tiago Branco et al. Current Biology

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Abstract

Tonically active GABAergic neurons in the dorsal periaqueductal gray control instinctive escape in mice

Highlights

• GABAergic neurons in the dorsal PAG fire action potentials tonically
• They provide a major source of synaptic inhibition to excitatory PAG neurons
• Tonic GABAergic activity in the PAG sets a threshold for instinctive escape
• PAG GABAergic neurons control both escape initiation and termination

Summary

Escape behavior is a set of locomotor actions that move an animal away from threat. While these actions can be stereotyped, it is advantageous for survival that they are flexible.

For example, escape probability depends on predation risk and competing motivations and flight to safety requires continuous adjustments of trajectory and must terminate at the appropriate place and time.

This degree of flexibility suggests that modulatory components, like inhibitory networks, act on the neural circuits controlling instinctive escape.

In mice, the decision to escape from imminent threats is implemented by a feedforward circuit in the midbrain, where excitatory vesicular glutamate transporter 2-positive (VGluT2⁺) neurons in the dorsal periaqueductal gray (dPAG) compute 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 in vivo neural activity recordings, we found that vesicular GABA transporter-positive (VGAT⁺) dPAG neurons fire action potentials tonically in the absence of synaptic inputs and are a major source of inhibition to VGluT2⁺ dPAG neurons. Activity in VGAT⁺ dPAG cells transiently decreases at escape onset and increases during escape, peaking at escape termination.

Optogenetically increasing or decreasing VGAT⁺ dPAG activity changes the probability of escape when the stimulation is delivered at threat onset and the duration of escape when delivered after escape initiation. We conclude that the activity of tonically firing VGAT⁺ dPAG neurons sets a threshold for escape initiation and controls the execution of the flight action.