Anterior cingulate cortex dysfunction underlies anxiety-like behaviors in MT2-deficient mice

Anxiety disorders are prevalent mental health conditions with significant impacts on quality of life. While the melatonin type 2 receptor (MT2) has been implicated in anxiety, its specific role and neural mechanisms remain unclear. This study investigates the deficiency of MT2 induces robust anxiety-like phenotypes in mice, mediated through anterior cingulate cortex (ACC) dysfunction. Global knockout (MT2-KO) and conditional ACC-targeted deletion (MT2-cKO) models consistently demonstrated increased anxiety responses in standardized behavioral batteries, establishing ACC MT2 as a key neuromodulator in emotional regulation. Electrophysiological recordings revealed that MT2 deficiency disrupted excitatory-inhibitory (E/I) balance of ACC pyramidal neurons. Chemogenetic activation of MT2-positive neurons in the ACC restored E/I balance and ameliorated anxiety-like behaviors in chronic immobility stress (CIS) model mice. These findings establish MT2 as a pivotal regulator of ACC neurocircuitry and implicate targeted modulation of ACC MT2 signaling as a potential therapeutic strategy for anxiety disorders.