Researchers identified a specific amygdala circuit underlying anxiety and showed that correcting excess expression of the Grik4 gene in that circuit rapidly reversed anxiety-like and social withdrawal behaviours in mice. Targeting pyramidal neurons in the basolateral nucleus restored normal signaling with the centrolateral amygdala and normalized behaviour in both genetically modified and naturally anxious mice. Findings, published in iScience, point to a precise, testable neural target for future therapies, though human translation will require more research.
Anxiety Traced to a Tiny Amygdala Circuit — Reversed in Mice by Fixing One Gene
Researchers identified a specific amygdala circuit underlying anxiety and showed that correcting excess expression of the Grik4 gene in that circuit rapidly reversed anxiety-like and social withdrawal behaviours in mice. Targeting pyramidal neurons in the basolateral nucleus restored normal signaling with the centrolateral amygdala and normalized behaviour in both genetically modified and naturally anxious mice. Findings, published in iScience, point to a precise, testable neural target for future therapies, though human translation will require more research.
08:07 PM, 11/12/2025Science
Anxiety Traced to a Tiny Amygdala Circuit — Reversed in Mice by Fixing One Gene
Anxiety has long been linked broadly to hyperactivity in the amygdala, the brain region that processes emotional stimuli. A new study narrows that connection to a specific circuit: researchers found that excess expression of the Grik4 gene in pyramidal neurons of the basolateral nucleus of the amygdala disturbs signaling with the centrolateral amygdala and drives anxiety-like behavior in mice — and that restoring normal Grik4 levels rapidly reverses those symptoms.
Anxiety disorders affect hundreds of millions of people worldwide and more than 40 million adults and 4 million children in the U.S. While stress, inflammation, and disrupted neurotransmitter systems (for example, serotonin and norepinephrine) are known contributors, this study provides a more precise neural locus that helps explain how circuit-level changes produce anxiety and social withdrawal.
Led by neuroscientist Juan Lerma at the Institute for Neurosciences in San Juan de Alicante, Spain, the team studied mice engineered to overexpress Grik4. The Grik4 gene encodes a protein that enhances excitatory signaling at synapses. When its expression rises too high, pyramidal neurons in the basolateral amygdala become hyperexcitable and alter communication with neurons in the central amygdala — especially cells in the centrolateral subdivision responsible for triggering downstream responses.
“The amygdala, particularly its hyperactivity, is strongly implicated in anxiety,” Lerma and colleagues wrote in a paper published in iScience. “Mice overexpressing the Grik4 gene display anxiety, depression, social deficits, and disrupted amygdala excitability.”
To test whether this molecular imbalance could be corrected, researchers injected treatments aimed at normalizing Grik4 expression specifically into the basolateral nucleus. They then assessed neural activity with electrophysiological recordings and measured behavior using established assays. Untreated Grik4-overexpressing mice showed classic anxiety-like measures: a preference for enclosed spaces, social avoidance, and reduced interest in unfamiliar mice. After treatment, communication between the basolateral and centrolateral amygdala normalized and the mice’s anxiety-like and social-avoidant behaviors reversed.
Importantly, the intervention improved outcomes not only in genetically modified mice but also in naturally anxious wild-type mice, suggesting the mechanism may be relevant beyond the engineered model. The authors note that the identified population of centrolateral neurons, because of their distinct firing properties, may be a promising, testable target for future therapies for affective disorders.
However, the team cautions against overinterpreting immediate clinical implications. Other brain regions — the hippocampus among them — likely contribute to anxiety, and translating targeted molecular or circuit interventions from mice to humans will require substantial further research. Still, the study points to a clear, specific circuit and molecular target that may guide future therapeutic development.
Until such treatments are available, clinicians continue to recommend evidence-based self-help strategies for acute anxiety, such as paced deep breathing and other grounding techniques.