Scientists Discover Brain Region That Keeps Fear Responses Going

A newly detailed brain region provides the continuous alarm signal needed to keep animals on high alert during a threat.

The research, published in Neuron, indicates that the amygdalostriatal transition zone bridges the gap between learning about a danger and sustaining a defensive response.

The amygdalostriatal transition zone, or ASt, is a small cluster of brain cells located between the amygdala, a center for emotion processing, and the striatum, an area involved in controlling movements. When a threat appears, the brain must rapidly detect it and maintain a defensive state until the danger passes.

A 1995 study of rats demonstrated that fear-learning neurons in the amygdala respond to threat sounds in a very brief, rapid burst lasting only milliseconds. Later, a 2002 laboratory study showed that warning signals travel rapidly from the amygdala directly into the neighboring ASt.

The disconnect between brief brain signals and long-lasting fear responses became a major question, as a 2009 study of rodents highlighted the puzzle that amygdala signals fade almost immediately even though defensive behaviors persist for tens of seconds.

The new study explores this fast pathway to determine whether the ASt provides the continuous alarm signal needed to maintain defensive behaviors over longer periods. The research was led by first author Fergil Mills, an assistant professor at the University of Utah who conducted the study as a postdoctoral fellow in the laboratory of senior author Kay M. Tye at the Salk Institute for Biological Studies.

“It felt as though an important part of the neural circuitry had yet to be found,” Mills told PsyPost. “In this study, we characterized the ‘amygdalostriatal transition zone’ (ASt), a largely unexplored brain region, and discovered that it maintained responses to threat cues for the full duration that they were present.”

“This was a previously unknown role for the structure, and our work identifies the ASt as a ‘missing piece’ of the neural circuits for learning and behavior,” he added.

The scientists began by examining the genetic makeup of the ASt and surrounding brain structures. They extracted and analyzed the genetic material of 97,434 individual cell nuclei from the brains of mice. The analysis indicated that the ASt has a distinct genetic identity.

Specifically, the ASt contains an unusually high concentration of a specific type of brain cell called a Drd2-positive neuron, which carries a specific receptor for the chemical messenger dopamine. About 71 percent of the neurons in the ASt were of this type, compared to just 26 percent for a related cell type known as Drd1a-positive neurons.

Next, the team measured the electrical activity of ASt neurons in 15 live mice. The mice were trained in an environment where a 20-second auditory tone predicted a mild foot shock, while a different 20-second tone predicted a sweet liquid reward. The researchers found that ASt neurons responded strongly to the shock-predicting tone.

Unlike the brief bursts seen in the amygdala, the ASt neurons fired continuously for the entire 20-second duration of the threat cue. Trials where the mice showed the highest levels of defensive behavior, such as freezing in place, were accompanied by ASt firing rates that were over three times higher than in trials with low defensive behavior.

To see if this brain activity actually produced the defensive behavior, the researchers used optogenetics, a technique that allows scientists to control specific neurons using light. They tested 18 mice that were genetically engineered so their ASt neurons could be activated by blue light lasers. When the researchers shined light into the ASt, the mice immediately began to freeze.

In a separate test where one side of an enclosure triggered the laser, the mice actively avoided that side. The team then isolated the effects of the two different cell types by testing 35 additional mice. They found that activating only the Drd2-positive neurons produced the same freezing and avoidance behaviors, while activating the Drd1a-positive neurons had no effect on these behaviors.

A motor coordination test using a rotating rod showed that the freezing was a defensive response, not a general inability to move. The researchers also tracked the activity of these specific cell types during the tone task using miniature microscopes attached to the heads of 15 mice. By observing calcium levels, which rise when neurons are active, they saw that the Drd2-positive neurons maintained high, sustained levels of activity throughout the threat-predicting tones.