Why do we stay afraid for so long when the brain’s first alarm fires so fast?
Our survival depends on brains that constantly search for danger and, if found, stay alert until it has passed. The amygdala—an area that sits deep in the brain, near the brain stem—has long been considered the epicenter of our fear and danger response. But the amygdala’s neurons fire only briefly when a threat first appears, so why do fear-response behaviors like fight, flight, or freeze last so long?
Neuroscientists turned to a mouse model to find an answer: an overlooked brain region that sits next to the amygdala, called the amygdalostriatal transition zone (ASt). Unlike the amygdala’s neurons, neurons in the ASt fire with both strength and longevity—explaining why some defensive responses persist. The insights into the brain’s fear circuitry may be used in future therapeutic development for fear and panic disorders. The study was published in Neuron.
“People always thought the amygdala was the fear center, while ignoring the space between the basolateral and central amygdala entirely,” says a co-corresponding author. “In the amygdala, you have firing right at the beginning of the danger—but what about after that? What is causing that lingering fear? What if it’s the amygdalostriatal transition zone?”
The ASt is tiny—it’s hard to reach, hard to study, and hard to distinguish from surrounding brain regions. Because of these challenges, the ASt has been relatively unexplored, leaving scientists unsure whether it is even a distinct brain region. This is the first landmark in the Salk paper: The researchers show that the mouse ASt is a distinct brain region, separate from the neighboring amygdala and striatum regions.
“The ASt is at a crossroads between the brain’s systems for emotional associations and action selection, but its function was largely unknown,” says another co-corresponding author.
After determining the ASt is distinct, the researchers moved on to characterizing its involvement in the danger response. Electrophysiology and calcium imaging revealed that the ASt’s neurons have a robust, sustained response to danger cues.
To further explore the effect ASt neurons have on danger response behaviors, the Salk team also specifically stimulated and inhibited only the ASt’s neurons. Stimulation of the ASt drove freezing and avoidance behaviors; inhibition of the ASt revealed that a specific subset of dopamine-expressing neurons in the region is necessary to mount fear responses.
“This project has been an amazing adventure. When we started, we knew almost nothing about the ASt, and were truly exploring unknown territory in the brain,” says the author. “Now, we have a much deeper understanding of this structure and have found that the ASt is a ‘missing piece’ of the circuits for fear that was hiding in plain sight for decades.”
“The ASt and this circuit could be really relevant in developing therapies for panic attacks or phobias,” adds the author. “Anxiety disorders affect hundreds of millions of people globally. Understanding what happens in the brain when it’s in high-alert danger mode is key to addressing those disorders.”
Further research is needed to explore the new fear circuit now that it includes the ASt. The findings offer promising insights in the ongoing effort to create more effective, targeted therapeutics for conditions like post-traumatic stress disorder (PTSD), panic disorder, and anxiety.
