Stress-induced GHS-R1a expression in medial prefrontal cortical neurons promotes vulnerability to anxiety in mice.

The neural basis of anxiety is unclear, which hinders the treatment of anxiety disorders. Here, we found that αCaMKII(+) neurons in the medial prefrontal cortex (mPFC(αCaMKII+)) responded to stressors with increased activity both under physiological conditions and after repeated restraint stress (RRS) in mice. Chemogenetic activation of mPFC(αCaMKII+) neurons ameliorated stress-induced anxiety. A delayed increase in the expression of growth hormone secretagogue receptor 1a (GHS-R1a), the receptor of the peripheral metabolic hormone ghrelin, in mPFC(αCaMKII+) neurons coincided with reduced excitatory synaptic transmission and the development of RRS-induced enhancement of anxiety-related behavior. Virus-mediated GHS-R1a upregulation in mPFC(αCaMKII+) neurons exaggerated the excitation/inhibition (E/I) imbalance and promoted anxiety-related behavior, whereas GHS-R1a knockdown had the opposite effect. We conclude that GHS-R1a signaling contributes to the development of stress-induced anxiety by shaping synaptic activity of mPFC(αCaMKII+) neurons. GHS-R1a may be a new therapeutic target for treating anxiety disorders.