Iowa researchers identify neural circuits associated with stress responses

Iowa researchers identify neural circuits associated with stress responses

At some point, we have all felt paralyzed by a threat or danger.

Researchers at the University of Iowa have discovered where this response to a threat occurs. In a new study, researchers confirmed that a neural circuit connecting two separate regions in the brain determines how animals, including humans, respond to a stressful situation. Through experiments, the researchers showed how rats responded to a threat either passively or actively, linking each response to a specific signaling pathway in the brain.

In another test, researchers successfully manipulated the neural circuitry so that rats overcame a paralyzing response to danger and instead responded aggressively to the threat.

The neural circuit identified with the stress response connects the caudal medial prefrontal cortex with the dorsolateral periaqueductal gray of the midbrain. Because of the well-known physical and psychological effects of chronic stress, it is important to establish the connection and how it regulates stress.

Many chronic stress disorders such as depression and anxiety disorders are associated with what is known as passive coping behavior. We know that many of these illnesses are caused by life stress. The simplest reason we are interested in this pathway is to view it as a circuit that can promote resilience to stress.”

Jason Radley, Associate Professor, Department of Psychological and Brain Sciences and corresponding author of the study

Previous research has identified the caudal medial prefrontal cortex-midbrain-dorsolateral periaqueductal gray as a key pathway that determines how animals respond to stress. Radley's team confirmed the importance of the pathway by inactivating it and then observing how the rats responded to a threat. The rats could respond in two basic ways: One is passive, meaning they essentially didn't move in response to the threat. The other is active, through a range of behaviors such as burying the threat (a shock probe in the experiments), rearing up on its hind legs or seeking an escape route.

The researchers learned that when they deactivated the rats' neural stress circuitry, the animals responded passively, meaning they did not respond directly to the threat.

“This shows that this pathway is necessary for active coping behavior,” says Radley.

Next, the researchers forced the rats to respond passively by removing the bedding from their cage, which prevented them from burying the threat mechanism. When the team activated the neural pathway, the rats changed their behavior and actively responded to the threat. The active response occurred even though the animals were left without bedding, which should have triggered a passive response. Additionally, blood samples taken before and after the rats' neural circuits were activated showed that their stress hormone levels did not increase when confronted with the threat.

“This means that we saw broad stress-buffering effects through activation of the signaling pathway,” says Radley. “Not only did it revive the rats’ active coping behaviors, it also restored them and greatly reduced the release of stress hormones.”

In a third set of experiments, researchers exposed rats to chronic variable stress, meaning they were exposed to regular stress over two weeks. After two weeks of conditioning, the rats were placed in cages and exposed to threat. They reacted passively, refusing to move, and their stress hormones spiked, as the researchers suspected.

The chronic stress test is important, Radley says, because people are exposed to chronic stress. For unknown reasons, some people continue to carry these stress burdens, which can lead to physical and psychological disorders. However, others show little to no memory of the chronic stress. The researchers call this behavior “stress resilience.”

“It's possible that if we could understand the processes in the brain that can regulate resilience, we could co-opt some of these brain circuits,” says Radley, although he adds that this is not an immediate option.

The researchers plan to examine the neutral connections that lie upstream and downstream of the caudal medial prefrontal cortex-midbrain-dorsolateral periaqueductal gray pathway.

“We don’t understand how these effects change the brain more broadly,” says Radley.

The study, "Activity in a prefrontal-periaqueductal gray circuit overcomes behavioral and endocrine features of passive coping with stress responses," was published online Oct. 28 in the journal Proceedings of the National Academy of Sciences (PNAS).

The first author from Iowa is Shane Johnson. Co-authors, all from Iowa, include Ryan Lingg, Timothy Skog, Dalton Hinz, Sara Romig-Martin and Nandakumar Narayanan. Victor Viau of the University of British Columbia in Vancouver is a contributing author.

The National Institutes of Health Office of Mental Health and the Brain and Behavior Research Foundation funded the research.

Source:

University of Iowa

Reference:

Johnson, S., et al. (2022) Activity in a prefrontal-periaqueductal gray circuit overcomes behavioral and endocrine features of the passive stress coping response. PNAS.

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