GHS-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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> neurons coincided with the development of stress-induced enhancement of anxiety-related behavior. GHS-R1a expression in VMH αCaMKII<sup>+</sup> neurons promoted anxiety-related behavior, whereas GHS-R1a knockdown had the opposite effect. GHS-R1a upregulation inhibited the excitability of VMH αCaMKII<sup>+</sup> neurons. We conclude that GHSR1a signaling drives stress-induced anxiety by shaping the activity of VMH αCaMKII<sup>+</sup> neurons. GHS-R1a may be a therapeutic target for treating anxiety disorders such as post-traumatic stress disorder.
Authors
- Gonghui Hu (ORCID: https://orcid.org/0000-0001-6825-9375)
- Meng Zhang (ORCID: https://orcid.org/0009-0004-0684-472X)
- Minglu Niu (ORCID: https://orcid.org/0009-0004-6317-497X)
- Liu Yang (ORCID: https://orcid.org/0000-0002-2496-6761)
- Jingsai Zhang
- Yu Zhou (ORCID: https://orcid.org/0000-0002-8193-7561)
- Haoyi Yu (ORCID: https://orcid.org/0000-0002-9480-8443)
- Xianchao Li
- Chen Wang (ORCID: https://orcid.org/0000-0003-4645-3227)
- Nan Li (ORCID: https://orcid.org/0000-0002-5828-6975)
- Yuyang Wang (ORCID: https://orcid.org/0000-0002-0527-9720)
- Xue Mi (ORCID: https://orcid.org/0000-0001-7265-5477)
- Sihan Wang (ORCID: https://orcid.org/0000-0002-3481-9167)
- Jie Yang (ORCID: https://orcid.org/0000-0002-8524-2580)
- Xiaomin Sun
- Ming Yu
- Yingchang Lu
Institutions
- Qingdao University (CN)
- Shandong University (CN)
- Wenzhou Medical University (CN)
- Ningbo University of Finance & Economics (CN)
- Affiliated Hospital of Qingdao University (CN)
- Qingdao Municipal Hospital (CN)
- Heze University (CN)
- Dongyang People's Hospital (CN)
- Qingdao Center of Resource Chemistry and New Materials (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1038/s41467-025-59116-3
- Citations
- 1
- Primary Topic
- Stress Responses and Cortisol
- Type
- article
- Field-Weighted Citation Impact
- 1.11
Funders
- National Science Foundation
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province