Summary:
Neuroscientists have discovered that a small adjacent region to the amygdala—the amygdalostriatal transition zone (ASt)—shows sustained, high activity that maintains fear-related behaviors long after an initial threat is detected. While amygdala neurons fire briefly at the onset of danger, the ASt remains active across the duration of a threat, acting as a functional bridge between emotional evaluation and prolonged defensive action.
Key Facts:
- The Engine of Lingering Fear: Unlike the amygdala’s short burst responses when danger first appears, neurons in the amygdalostriatal transition zone (ASt) sustain strong activity across ongoing threat cues, which explains why defensive behaviors persist.
- A Distinct Brain Structure: The research confirms that the mouse ASt is an anatomically and functionally distinct region positioned between the emotional amygdala and the action-selecting striatum, rather than a blurred border zone.
- Causal Role in Defensive Behavior: Optogenetic and chemogenetic experiments showed that activating ASt neurons triggers freezing and avoidance, while inhibiting a specific subset of dopamine-expressing ASt neurons reduces cue-conditioned fear responses.
Source: Salk Institute for Biological Studies
Beyond the Amygdala: Why Fear Persists
Survival depends on the brain’s ability to spot danger quickly and stay vigilant until the threat passes.
For decades, the amygdala has been central to models of fear and defensive behavior. Yet those models left an important question unanswered: amygdala neurons typically fire in brief bursts when a threat first appears, but defensive reactions—freezing, avoidance, heightened arousal—often continue much longer. What sustains those prolonged behaviors when the amygdala’s initial alarm quiets?
Researchers at the Salk Institute addressed this gap by investigating a largely overlooked area beside the amygdala: the amygdalostriatal transition zone (ASt). Their study, published in Neuron, demonstrates that the ASt produces the durable neural signals needed to keep defensive behaviors engaged.
“The amygdala’s immediate response to danger is well documented, but it didn’t explain the persistent, high-alert states we observe,” said co-corresponding author Kay Tye, Ph.D. “We found that the ASt maintains sustained activity that can explain lingering fear.”
Defining an Uncharted Crossroads
The ASt’s small size and deep location meant it was previously treated as an ambiguous border rather than a distinct structure. The Salk team used anatomical, genetic, and functional approaches to show that the mouse ASt is a bona fide brain region, separate from both neighboring amygdala nuclei and striatal tissue.
“The ASt sits at a crossroads linking emotional learning circuits with action-selection systems, but until now its role was largely unknown,” said co-corresponding author Fergil Mills, Ph.D.
Using single-cell and single-nucleus methods, cellular-resolution calcium imaging, and in vivo electrophysiology in freely moving mice exposed to threat cues, the researchers recorded neural activity across the region. They observed that while amygdala responses faded soon after a threat cue, ASt neurons continued to fire robustly for the length of the threat.
Driving and Dissecting the Fear Circuit
To test whether ASt activity actually drives defensive behavior, the team selectively manipulated ASt neurons:
- Targeted Stimulation: Direct activation of ASt neurons produced freezing and active avoidance behaviors, replicating the high-alert defensive states seen after real threats.
- Targeted Inhibition: Suppressing ASt activity reduced defensive responses. In particular, inhibiting Drd2-expressing (dopamine receptor D2) neurons in the ASt impaired cue-conditioned fear behaviors, demonstrating these neurons are necessary for mounting appropriate fear responses.
These experiments indicate the ASt actively translates emotional signals into sustained behavioral outputs rather than merely reflecting upstream amygdala activity.
“When we began, the ASt was a blank spot on the map. Now it’s clear this region is a missing link in fear circuits,” Mills said.
New Pathways for Anxiety and Panic Disorders
Persistent, inappropriate fear underlies conditions such as generalized anxiety disorder, panic disorder, and post-traumatic stress disorder (PTSD). Patients with these conditions often struggle to turn off defensive responses even when threats have passed.
By identifying the ASt as a regulator of sustained fear, the research highlights a new potential target for therapies. Interventions that reduce excessive ASt activity or selectively modulate its dopamine-responsive neurons could, in principle, curb prolonged fear states while preserving rapid threat detection by the amygdala.
“Targeting this circuit could offer more precise treatments for panic attacks, phobias, and PTSD,” Tye said. “Understanding the neural basis of prolonged fear is essential to developing better interventions.”
Funding: This work was supported by multiple funders, including 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), the 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.
- The original journal paper was reviewed in full by the editorial team.
- Additional explanatory context was added by staff to clarify experimental approaches and implications.
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). Title: “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
Effective survival requires rapid threat detection and the ability to remain defensive until danger passes. Although the amygdala has been central to models of fear, neuronal responses there are often brief and do not fully match the duration of defensive behaviors observed in animals.
This study identifies the amygdalostriatal transition zone (ASt) as a critical component of fear circuits. Single-nucleus RNA sequencing shows the ASt is genetically distinct from neighboring amygdalar and striatal regions. In vivo electrophysiology and calcium imaging reveal that ASt neurons display strong, sustained responses to cues that predict shock. Photostimulation of the ASt is sufficient to drive freezing and avoidance, while optogenetic inhibition demonstrates that Drd2+ ASt neurons are necessary for cue-conditioned fear responses.
Together, these results establish the ASt as a previously underappreciated structure that encodes learned threat associations and directs prolonged defensive behavior.