Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Feb 19, 2025; 15(2): 101807
Published online Feb 19, 2025. doi: 10.5498/wjp.v15.i2.101807
Activation of zona incerta gamma-aminobutyric acid-ergic neurons alleviates depression-like and anxiety-like behaviors induced by chronic restraint stress
Si-Hai Chen, Bo Lan, Ying-Ying Zhang, Guo-Hui Li, Yu-Long Qian, Ming-Xing Hu, Yin-Lin Tian, Wei-Dong Zang, Jing Cao, Guang-Hai Wang, Yi-Gang Wang
Si-Hai Chen, Bo Lan, Guo-Hui Li, Yu-Long Qian, Ming-Xing Hu, Yin-Lin Tian, Guang-Hai Wang, Yi-Gang Wang, Department of Psychiatry, Xiaogan Rehabilitation Hospital, Xiaogan 432000, Hubei Province, China
Si-Hai Chen, Ying-Ying Zhang, Wei-Dong Zang, Jing Cao, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, Henan Province, China
Jing Cao, School of Nursing and Health, Zhengzhou University, Zhengzhou 450000, Henan Province, China
Co-first authors: Si-Hai Chen and Bo Lan.
Co-corresponding authors: Guang-Hai Wang and Yi-Gang Wang.
Author contributions: Wang YG, Wang GH, Cao J, and Chen SH conceptualized the study; Chen SH, Lan B, and Zhang YY designed the methodology; Chen SH and Lan B performed the formal analysis of the data; Li GH, Qian YL, Hu MX, and Tian YL performed the validation of the data; Hu MX performed the investigation; Tian YL provided necessary resources; Wang YG performed the data curation; Chen SH prepared the original draft of the manuscript; Wang YG, Wang GH, and Chen SH reviewed and edited the subsequent versions of the manuscript; Chen SH generated the data visualizations; Zang WD and Cao J provided overall supervision; Wang YG, Wang GH, and Cao J provided overall project administration; All authors read and approved the published version of the manuscript. Chen SH and Lan B were designated as co-first authors due to the importance of their collaboration in the overall generation of the manuscript and performance of the study. Wang GH and Wang YG were designated as co-corresponding authors to reflect their equal duties in the overall management of the study.
Supported by the Natural Science Foundation of Xiaogan, China, No. XGKJ2023010036.
Institutional animal care and use committee statement: The use of the animals was approved by the Animal Care and Use Committee of Zhengzhou University. All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Raw data are available upon reasonable request at wygang1004@163.com.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yi-Gang Wang, Associate Chief Physician, Department of Psychiatry, Xiaogan Rehabilitation Hospital, No. 99 Huanchuan Road, Xiaonan District, Xiaogan 432000, Hubei Province, China. wygang1004@163.com
Received: September 27, 2024
Revised: November 25, 2024
Accepted: December 18, 2024
Published online: February 19, 2025
Processing time: 109 Days and 4.7 Hours
Abstract
BACKGROUND

Depression is a prevalent affective disorder, but its pathophysiology remains unclear. Dysfunction in the gamma-aminobutyric acid (GABA)-ergic system may contribute to its onset. Recently, antidepressants (e.g., brexanolone, zuranolone) targeting the GABA-A receptor were introduced. The zona incerta (ZI), an inhibitory subthalamic region mainly composed of GABAergic neurons, has been implicated in emotional regulation. Deep brain stimulation of the ZI in humans affects anxiety and depression symptoms, while activation of ZI neurons in mice can either worsen or alleviate anxiety. Currently, there is no direct evidence linking GABAergic neurons in the ZI to depression-like behaviors in rodents.

AIM

To explore the relationship between GABAergic neurons in the ZI and depression-like behaviors in mice.

METHODS

A chronic restraint stress (CRS) model was utilized to induce depression in mice. Whole-cell patch-clamp recordings assessed the excitability changes of GABAergic neurons in the ZI. Additionally, chemogenetic techniques were employed to modulate ZI GABAergic neurons. The performance of the mice in behavioral tests for depression and anxiety was observed.

RESULTS

The findings indicated that GABAergic neurons in the ZI were closely associated with depression-like behaviors in mice. Twenty-eight days after the CRS model was established, depression-like and anxiety-like behaviors were observed in the mice. The excitability of GABAergic neurons in the ZI was reduced. Chemogenetic activation of these neurons alleviated CRS-induced depression-like and anxiety-like behaviors. Conversely, inhibition of GABAergic neurons in the ZI led to changes in emotion-related behavioral outcomes in mice.

CONCLUSION

Activity of GABAergic neurons in the ZI was closely associated with depression-like phenotypes in mice, suggesting that these neurons could be a potential therapeutic target for treating depression.

Keywords: Zona incerta; Gamma-aminobutyric acid-ergic; Depression; Anxiety; Animal behavior studies; Whole-cell patch-clamp

Core Tip: Gamma-aminobutyric acid (GABA)-ergic dysfunction may play a role in the onset of depression. Case reports have indicated that deep brain stimulation of the zona incerta (ZI), which is abundant in GABAergic neurons, can modify depressive and anxiety symptoms. However, direct evidence linking ZI GABAergic neurons to depression-related behaviors in rodents is limited. This study demonstrated chronic resistant stress induced depression-like and anxiety-like behaviors in mice and reduced neuronal excitability. Chemogenetic activation alleviated these symptoms, whereas inhibition altered the behavior of normal mice. These findings suggested that ZI GABAergic neurons may serve as potential therapeutic targets for depression.