GHS-R1a signaling drives anxiety-related behavior by shaping excitability of ventromedial hypothalamic neurons

Meng Zhang, Liu Yang, Xue Mi, Gonghui Hu, Yingchang Lu, Chen Wang, Jie Yang, Xiaomin Sun, Minglu Niu, Xianchao Li, Sihan Wang, Jingsai Zhang, Hanbing Yu, Yuyang Wang, Ming Yu, Nan Li and Yu Zhou ()
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Meng Zhang: University of Health and Rehabilitation Sciences
Liu Yang: Qingdao University
Xue Mi: Qingdao University
Gonghui Hu: Qingdao University
Yingchang Lu: Qingdao University
Chen Wang: Qingdao University
Jie Yang: Qingdao University
Xiaomin Sun: Qingdao University
Minglu Niu: Qingdao University
Xianchao Li: Qingdao University
Sihan Wang: Qingdao University
Jingsai Zhang: Qingdao University
Hanbing Yu: Qingdao University
Yuyang Wang: Affiliated Hospital of Qingdao University
Ming Yu: University of Health and Rehabilitation Sciences
Nan Li: University of Health and Rehabilitation Sciences
Yu Zhou: University of Health and Rehabilitation Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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+ neurons promoted anxiety-related behavior, whereas GHS-R1a knockdown had the opposite effect. GHS-R1a upregulation inhibited the excitability of VMH αCaMKII+ neurons. We conclude that GHSR1a signaling drives stress-induced anxiety by shaping the activity of VMH αCaMKII+ neurons. GHS-R1a may be a therapeutic target for treating anxiety disorders such as post-traumatic stress disorder.

Date: 2025
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DOI: 10.1038/s41467-025-59116-3

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