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Anterior cingulate cortex dysfunction underlies anxiety-like behaviors in MT2-deficient mice
Xiaodan Wang1, Lixia Zhuo2, Wei Wu2
1Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Neuropharmacology
|August 24, 2025
Summary
Melatonin MT2 receptor deficiency causes anxiety-like behaviors by disrupting the anterior cingulate cortex (ACC). Restoring MT2 signaling in the ACC alleviates these anxiety phenotypes, suggesting a therapeutic target.
Area of Science:
- Neuroscience
- Psychiatry
- Molecular Biology
Background:
- Anxiety disorders significantly impact quality of life.
- The melatonin type 2 receptor (MT2) is linked to anxiety, but its precise role is unknown.
- Neural mechanisms underlying anxiety require further elucidation.
Purpose of the Study:
- To investigate the role of MT2 in anxiety-like behaviors.
- To determine the neural mechanisms mediated by MT2 in the anterior cingulate cortex (ACC).
- To explore MT2 as a potential therapeutic target for anxiety disorders.
Main Methods:
- Utilized global knockout (MT2-KO) and ACC-specific conditional knockout (MT2-cKO) mouse models.
- Assessed anxiety-like phenotypes using standardized behavioral tests.
- Performed electrophysiological recordings to analyze neuronal function.
- Employed chemogenetics to manipulate MT2-positive neurons in the ACC.
Main Results:
- MT2 deficiency robustly induced anxiety-like phenotypes in mice.
- ACC dysfunction was identified as a key mediator of these anxiety behaviors.
- MT2 deficiency disrupted the excitatory-inhibitory (E/I) balance in ACC pyramidal neurons.
- Chemogenetic activation of ACC MT2 neurons restored E/I balance and reduced anxiety in a chronic stress model.
Conclusions:
- MT2 is a critical regulator of ACC neurocircuitry and emotional regulation.
- Targeting ACC MT2 signaling offers a potential therapeutic strategy for anxiety disorders.
