Chen Si-Hai, Lan Bo, Zhang Ying-Ying, Li Guo-Hui, Qian Yu-Long, Hu Ming-Xing, Tian Yin-Lin, Zang Wei-Dong, Cao Jing, Wang Guang-Hai, Wang Yi-Gang
Department of Psychiatry, Xiaogan Rehabilitation Hospital, Xiaogan 432000, Hubei Province, China.
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, Henan Province, China.
World J Psychiatry. 2025 Feb 19;15(2):101807. doi: 10.5498/wjp.v15.i2.101807.
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 ( 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.
To explore the relationship between GABAergic neurons in the ZI and depression-like behaviors in mice.
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.
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.
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.
抑郁症是一种常见的情感障碍，但其病理生理学仍不清楚。γ-氨基丁酸（GABA）能系统功能障碍可能导致其发病。最近，引入了靶向GABA-A受体的抗抑郁药（布雷沙诺龙、祖拉诺龙）。未定带（ZI）是丘脑底的一个抑制性区域，主要由GABA能神经元组成，与情绪调节有关。对人类ZI进行深部脑刺激会影响焦虑和抑郁症状，而激活小鼠的ZI神经元则可能加重或减轻焦虑。目前，尚无直接证据表明ZI中的GABA能神经元与啮齿动物的抑郁样行为有关。
探讨ZI中GABA能神经元与小鼠抑郁样行为之间的关系。
利用慢性束缚应激（CRS）模型诱导小鼠抑郁。采用全细胞膜片钳记录评估ZI中GABA能神经元的兴奋性变化。此外，运用化学遗传学技术调节ZI的GABA能神经元。观察小鼠在抑郁和焦虑行为测试中的表现。
研究结果表明，ZI中的GABA能神经元与小鼠的抑郁样行为密切相关。建立CRS模型28天后，观察到小鼠出现抑郁样和焦虑样行为。ZI中GABA能神经元的兴奋性降低。对这些神经元进行化学遗传学激活可减轻CRS诱导的抑郁样和焦虑样行为。相反，抑制ZI中的GABA能神经元会导致小鼠情绪相关行为结果的改变。
ZI中GABA能神经元的活动与小鼠的抑郁样表型密切相关，表明这些神经元可能是治疗抑郁症的潜在治疗靶点。
