Summary:
While neurons in the amygdala fire only transiently when a threat first appears, scientists have discovered that the neighboring amygdalostriatal transition zone (ASt) exhibits sustained, powerful activity that keeps fear-related behaviors active. The findings identify the ASt as a distinct anatomical brain region acting as a critical bridge between emotional appraisal and prolonged defensive action.
Key Facts:
- The Engine of Lingering Fear: Unlike the amygdala’s transient burst firing at the onset of danger, neurons within the amygdalostriatal transition zone (ASt) maintain strong, persistent activity across threat cues, explaining why defensive behaviors endure.
- Confirmed Distinct Brain Structure: The study provides definitive evidence that the mouse ASt is an anatomically and functionally distinct brain structure, positioned directly at the crossroads between the emotional amygdala and the action-selecting striatum.
- Causal Role in Defensive Behavior: Optogenetic and chemogenetic manipulation confirmed that stimulating ASt neurons directly triggers freezing and avoidance behaviors, while a specific subset of dopamine-expressing neurons in the ASt is required to mount fear responses.
Source: Salk Institute for Biological Studies
Beyond the Amygdala: Why Fear Persists
Our survival hinges on the brain’s ability to detect imminent danger and remain on high alert until safety is restored. For decades, neuroscience dogma has placed the amygdala at the center of the brain’s fear circuitry.
Yet a major mechanistic paradox has lingered: neurons within the amygdala fire primarily in brief, initial bursts when a danger cue emerges. If the primary “alarm” quickly quiets down, what sustains protracted fight, flight, or freezing behaviors long after the initial shock?
To solve this puzzle, neuroscientists at the Salk Institute investigated a long-neglected anatomical pocket nestled alongside the amygdala: the amygdalostriatal transition zone (ASt).
In a study published in Neuron, the team revealed that the ASt exhibits the sustained, durable activity missing from canonical amygdala models, identifying the elusive neural bridge that keeps fear responses engaged.
“People always thought the amygdala was the fear center, while ignoring the space between the basolateral and central amygdala entirely,” said co-corresponding author Kay Tye, Ph.D., professor, holder of the Wylie Vale Chair at Salk, and a Howard Hughes Medical Institute investigator. “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?”
Defining an Uncharted Crossroads
The ASt has evaded detailed scientific scrutiny due to its minuscule footprint and deep location, leaving researchers uncertain whether it was merely an ambiguous border zone or a self-contained structure. The Salk team established that the mouse ASt is a distinct, bona fide brain region separate from both the adjacent amygdala and the striatum.
“The ASt is at a crossroads between the brain’s systems for emotional associations and action selection, but its function was largely unknown,” explained co-corresponding author Fergil Mills, Ph.D., former postdoctoral researcher in Tye’s lab and currently an assistant professor at the University of Utah.
Using cellular-resolution calcium imaging and in vivo electrophysiology in freely moving mice exposed to danger cues, the investigators tracked neural dynamics across the region. While amygdala activity dropped off shortly after threat exposure, ASt neurons maintained robust, prolonged firing throughout the duration of the threat.
Driving and Dissecting the Fear Circuit
To establish causality between ASt neural dynamics and defensive states, the researchers selectively manipulated ASt cell populations:
- Targeted Stimulation: Activating ASt neurons directly elicited freezing and active avoidance behaviors in mice, mirroring high-alert defensive states.
- Targeted Inhibition: Silencing the region attenuated defensive responses, revealing that a distinct population of dopamine-expressing neurons within the ASt is necessary to execute fearful behaviors.
These experiments demonstrate that the ASt does not passively register emotional salience; rather, it coordinates the conversion of an emotional signal into prolonged behavioral output.
“When we started, we knew almost nothing about the ASt, and were truly exploring unknown territory in the brain,” Mills said. “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.”
New Pathways for Anxiety and Panic Disorders
Anxiety disorders, post-traumatic stress disorder (PTSD), and panic conditions affect hundreds of millions of people worldwide. These clinical conditions are characterized by an inability to turn off persistent fear responses even after threats dissipate.
By defining the ASt’s role in sustaining defensive behaviors, the researchers have opened a new therapeutic window. Future interventions aimed at dampening the overactivity of ASt circuits or selectively targeting its dopamine-receptor-bearing cells could yield precise treatments for persistent fear states without dampening healthy, initial threat detection.
“The ASt and this circuit could be really relevant in developing therapies for panic attacks or phobias,” Tye emphasized. “Understanding what happens in the brain when it’s in high-alert danger mode is key to addressing those disorders.”
Funding: This study was funded by the National Institutes of Health (P30 CA014195, P30 AG068635, S10-MH124757, R01-MH115920, R37-MH102441, DP1-AT009925, K99 MH121563, K99 DA055111-01, K99 AA029180, K00 MH132569), Henry L. Guenther Foundation, Waitt Foundation, JPB Foundation, New York Stem Cell Foundation, Klingenstein Foundation, McKnight Foundation, Howard Hughes Medical Institute, Clayton Foundation, Kavli Foundation, Dolby Family Fund, Canadian Institutes of Health Research, Duke University, and China Scholarship Council.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Autism Research:
- Media Contact: Salk Communications
- Source: Salk Institute
- Image Credit: Image credited to Neuroscience News
- Original Research is Open Access: Neuron (September 14, 2026). “Amygdalostriatal transition zone neurons encode sustained cue responses to guide defensive behaviors.” Authors: Fergil Mills, Christopher R. Lee, James R. Howe, Hao Li, Maria N. Keisler, Shan Shao, Felix H. Taschbach, Mackenzie E. Lemieux, Faith Aloboudi, Jesse White, May G. Chan, Matilde Borio, Laurel R. Keyes, Hannah S. Chen, Fabiha Bushra, Gates P. Schneider, Dani P. Lemmon, Kyung J. Lee, Alexa L. Gross, Kanha Batra, Reesha R. Patel, Meenakshi M. Asokan, Jeremy Delahanty, Christian Cazares, Christopher R. Heyman, Nicholas B. Poll, Liezl Maree, Romy Wichmann, Talmo D. Pereira, Marcus K. Benna, Cory M. Root, and Kay M. Tye.
- DOI: 10.1016/j.neuron.2026.08.012
Abstract
Amygdalostriatal transition zone neurons encode sustained cue responses to guide defensive behaviors
To ensure survival, the brain must rapidly identify threats and maintain defensive behaviors for as long as danger is present. The amygdala has been studied as a key site for fear responses, but responses to threat cues in amygdala neurons are largely transient and shorter in duration than defensive responses observed.
Here, we present the amygdalostriatal transition zone (ASt) as a missing piece of the circuits mediating fear responses. Using single-nucleus RNA sequencing (snRNA-seq), we demonstrate that the ASt is genetically distinct from adjacent striatal and amygdalar structures.
In vivo electrophysiology and calcium imaging reveal that ASt neurons have robust, sustained responses to shock-predicting cues. Further, photostimulation of the ASt is sufficient to drive freezing and avoidance behaviors, and optogenetic inhibition experiments show that Drd2+ ASt neurons are necessary for cue-conditioned fear responses.
Our findings establish the ASt as a previously unappreciated yet critical structure for encoding learned associations and directing defensive behaviors.
