Why Do Some Mice Recover From Stress While Others Don’t?

Some people bounce back from trauma, but others get caught in depressive loops that sap the joy from their lives.

Now, scientists at UC San Francisco are learning how the brain creates these divergent experiences. They hope it will help them find a way to treat those who struggle with long-lasting symptoms of stress.

The researchers found that stress changes activity in a brain circuit in mice, and these changes distinguish the mice that will recover from the ones that won’t.

They stimulated some of the neurons in the less resilient mice to make the neurons fire more often. The mice stopped ruminating and sought out pleasure in the form of sugar-sweetened water.

“Seeing that we can set these brain signals back on course in mice suggests that doing the same in humans could act as an antidepressant,” said Mazen Kheirbek, PhD, an associate professor of psychiatry and senior author of the study, which appears Dec. 4 in Nature.

There’s considerable interest in finding out how we can we translate these discoveries to an approach that will work in people. If we can do that, we’ll have a new, non-invasive way of treating depression.”

The stress of indecision

Kheirbek, a member of the UCSF Weill Institute for Neurosciences, set out to find the signature with a team that included Frances Xia, PhD, an associate specialist in psychiatry at UCSF, and two scientists from Columbia University, Valeria Fascianelli, PhD, and Stefano Fusi, PhD.

The researchers looked at a brain region called the amygdala, which helps to evaluate how risky it may be to seek a reward.

First, they observed brain activity while the mice were resting. Stress had changed the activity in the amygdala of the less resilient mice much more than it had in the resilient ones.

When the researchers gave the mice a choice between plain and sugar-sweetened water, the resilient mice easily chose the sugar water. But the less resilient mice became obsessed and often opted for the plain water.

Xia looked at brain recordings of the mice who chose the sweet water. Their amygdala was communicating with a nearby brain region called the hippocampus that remembers and predicts.

She saw a different pattern in the mice that could not decide whether to drink the plain or sweetened water. In those mice, the conversation between the two brain areas sputtered.

Connecting the dots

The process actually wiped out the whole state of indecision and turned these guys into resilient mice.”

Xia thought she could stop the mice from ruminating and improve their decision making if she could get the neurons that connect these two regions to fire more often.

She used a technique called chemogenetics, which employs artificial molecules that interact inside the body. The team attached one of the molecules, a receptor, to the surface of neurons in the hippocampus to make them fire.

Then, Xia injected the less resilient mice with a second molecule that bound to the receptor and made the neurons fire.

When the team once again gave the rumination-prone mice a choice of waters, they took the sweet treat. The mice’s brain activity also looked resilient.

“The whole thing seemed like such a wild idea that I almost couldn’t believe it worked,” Xia said. “The process actually wiped out the whole state of indecision and turned these guys into resilient mice.”

The team plans to look at human brain data to see if they can find similar signatures.

Kheirbek is working with researchers at the Dolby Family Center for Mood Disorders to explore different ways of changing these brain patterns.

“There’s considerable interest in finding out how we can we translate these discoveries to an approach that will work in people,” he said. “If we can do that, we’ll have a new, non-invasive way of treating depression.”

Reference: Xia F, Fascianelli V, Vishwakarma N, et al. Understanding the neural code of stress to control anhedonia. Nature. 2024. doi: 10.1038/s41586-024-08241-y

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