Predator-like scent activates an anxiety-related brain circuit in mice

by Ingrid Fadelli, Medical Xpress

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Anxiety disorders are some of the most common psychiatric conditions, estimated to affect around 4.4% of people worldwide, according to the World Health Organization. While neuroscientists have been studying these disorders for decades, their neural underpinnings are not yet fully understood.

Mice and some other animals can also exhibit anxiety-like behaviors, such as avoiding exposed spaces. Studying these animals could help researchers understand which brain regions contribute to anxiety-like responses.

Researchers at the Guangdong Institute of Intelligence Science and Technology, Beijing Normal University at Zhuhai and the Chinese Academy of Sciences recently studied anxiety-like behavior in mice and tried to shed more light on the neural networks contributing to it. Their paper, published in Molecular Psychiatry, identifies a brain pathway that appears to contribute to anxiety-like responses in mice exposed to a predator-like odor.

A pathway linked to anxiety-like behavior in mice

To study the neural underpinnings of anxiety-like behaviors, the researchers carried out a series of experiments with mice. The mice were exposed to two different threat-related stimuli: a predator-like odorant called 2-methyl-2-thiazoline (2-MT) and an electric shock to their feet.

The team examined the activity of neurons in the mice's brains using single-cell calcium imaging. This technique relies on changes in fluorescence to track fluctuations in calcium levels, serving as an indirect measure of activity in individual neurons.

The mice were also observed as they navigated an elevated maze with open and walled arms and an open arena with an exposed center. In this experiment, spending less time in the maze's open arms or in the center of the arena was treated as a sign of anxiety-like behavior.

"We identify a cortical–brainstem–thalamic pathway in which Crh-expressing neurons in the anterior and middle insular cortex (a/mIC) engage the parabrachial nucleus (PBN), which in turn recruits the posterior paraventricular thalamic nucleus (pPVT) to contribute to anxiety-related behavior," wrote Zai-Yong An, Ming-Zhe Liu and their colleagues in their paper.

The researchers observed that the predator-like odor and the footshock activated some of the same neurons in the insular cortex, which sent signals to the parabrachial nucleus in the brainstem. This communication pathway was found to extend from the brainstem to the thalamus.

"Single-cell calcium imaging reveals that the predator odorant 2-MT and footshock recruit partially overlapping populations of PBN-projecting a/mIC neurons; neurons activated by both stimuli exhibit increased activity during open-arm approach in the elevated plus maze," wrote the authors. "Exposure to 2-MT increases corticotropin-releasing factor (CRF) signals in the PBN, where CRF enhances PBN neuronal excitability and CRF receptor 1 (CRFR1) signaling facilitates a/mIC-terminal-evoked firing."

When the animals were exposed to the predator-like odor, the team observed stronger signals from corticotropin-releasing factor (CRF), a chemical messenger involved in the stress response, in the parabrachial nucleus. In separate tests, CRF made neurons in this brainstem region easier to activate.

Informing future research into anxiety disorders

This study identified a neural pathway that appears to contribute to anxiety-like behaviors in mice. When the researchers interrupted this pathway or blocked the effects of CRF on brainstem neurons, the mice showed less anxiety-like behavior in response to the predator-like odor.

"Inhibition of Crh⁺ a/mIC–PBN projections, Crh knockdown in the a/mIC, or blockade of CRFR1 signaling within the PBN attenuates 2-MT-induced anxiety-like behavior," wrote the authors. "Human neuroimaging further reveals stronger functional coupling within a putative homologous aIC–PBN–pPVT network in individuals with anxiety symptoms, and the strength of this coupling correlates with anxiety severity."

An, Liu and their colleagues also analyzed human brain scans. They observed that in people with anxiety symptoms, activity in brain regions that could correspond to the mouse circuit varied more closely together. The more severe the symptoms, the stronger this link appeared to be.

The findings of this study could inspire more research examining the pathway identified by the researchers in both animals and humans. Eventually, these efforts may help to better delineate the neural underpinnings of anxiety, potentially contributing to the development of new treatments for anxiety disorders.

Written for you by our author Ingrid Fadelli, edited by Gaby Clark, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

Publication details

Zai-Yong An et al., A Crh-defined insular cortex–brainstem–thalamic circuit regulates anxiety-related behavioral states, Molecular Psychiatry (2026). DOI: 10.1038/s41380-026-03950-4.

Journal information: Molecular Psychiatry

Key medical concepts

Corticotropin-Releasing Hormone

Clinical categories

PsychiatryPsychology & Mental healthNeurology Who's behind this story?

Ingrid Fadelli

Freelance journalist with BSc Psychology and MA International Journalism. Covers AI, robotics, neuroscience, and astrophysics since 2018. Full profile →

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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