biostudies-literatureZhang MNatural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)Natural Science Foundation of Shandong ProvinceNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)3858https://www.ebi.ac.uk/biostudies/studies/S-EPMC12022087biostudies-literatureUnknown16(1)The neural substrates of anxiety are poorly understood, which hinders treatment of anxiety disorders. Here we found, αCaMKII⁺ neurons in the ventral medial hypothalamic nucleus (VMH) responded to stressors with increased activity in male mice, both under physiological conditions and after repeated restraint stress. Activation of VMH αCaMKII⁺ neurons were necessary and sufficient to ameliorate stress-induced anxiety. The peripheral metabolic hormone ghrelin and receptor GHS-R1a play a complex role in emotion regulation; however, the mechanism is uncertain. A delayed increase in GHS-R1a expression in VMH αCaMKII⁺ neurons coincided with the development of stress-induced enhancement of anxiety-related behavior. GHS-R1a expression in VMH αCaMKII⁺ neurNature communicationsGHS-R1a signaling drives anxiety-related behavior by shaping excitability of ventromedial hypothalamic neurons.PMC12022087ZR2019ZD34917321103207114132371211Yang JYu MYang LZhang JLu YWang CZhang MSun XZhou YYu HLi NMi XLi XHu GWang SNiu MWang YfalseGHS-R1a signaling drives anxiety-related behavior by shaping excitability of ventromedial hypothalamic neurons.The neural substrates of anxiety are poorly understood, which hinders treatment of anxiety disorders. Here we found, αCaMKII⁺ neurons in the ventral medial hypothalamic nucleus (VMH) responded to stressors with increased activity in male mice, both under physiological conditions and after repeated restraint stress. Activation of VMH αCaMKII⁺ neurons were necessary and sufficient to ameliorate stress-induced anxiety. The peripheral metabolic hormone ghrelin and receptor GHS-R1a play a complex role in emotion regulation; however, the mechanism is uncertain. A delayed increase in GHS-R1a expression in VMH αCaMKII⁺ neurons coincided with the development of stress-induced enhancement of anxiety-related behavior. GHS-R1a expression in VMH αCaMKII⁺ neur2025-01-01T00:00:00Z2025 Apr2025-07-01T03:05:48.554Z2025-07-01T03:05:48.554ZS-EPMC120220874027484510.1038/s41467-025-59116-3