艾司氯胺酮通过激活小鼠mPFC区谷氨酸能神经元发挥抗抑郁样作用

doi:10.12122/j.issn.1673-4254.2026.03.02

南方医科大学学报 ›› 2026, Vol. 46 ›› Issue (3): 489-496.doi: 10.12122/j.issn.1673-4254.2026.03.02

• 基础研究 • 上一篇

艾司氯胺酮通过激活小鼠mPFC区谷氨酸能神经元发挥抗抑郁样作用

张倬宁¹(), 郝新宇¹(), 曹福羊², 郭永馨¹, 郭舒婷¹, 蔡辰¹, 米卫东¹(), 仝黎¹()

^1.解放军总医院第一医学中心麻醉科，北京 100853
^2.解放军总医院第六医学中心麻醉科，北京 100048

收稿日期:2025-09-09 出版日期:2026-03-20 发布日期:2026-03-26
通讯作者: 米卫东,仝黎 E-mail:zhangzhuoning@aliyun.com;haoxinyu19980206@163.com;wwdd1962@163.com;tongli301@aliyun.com
作者简介:张倬宁，在读硕士研究生，E-mail: zhangzhuoning@aliyun.com
郝新宇，在读博士研究生，E-mail: haoxinyu19980206@163.com
第一联系人：本文共同第一作者。
基金资助:
国家自然科学基金(82171180);中华医学会麻醉学分会青年麻醉医师科研基金(Z-2017-24-2421)

Esketamine alleviates depression-like behaviors in mice with chronic restraint stress by activating glutamatergic neurons in the medial prefrontal cortex

Zhuoning ZHANG¹(), Xinyu HAO¹(), Fuyang CAO², Yongxin GUO¹, Shuting GUO¹, Chen CAI¹, Weidong MI¹(), Li TONG¹()

^1.Department of Anesthesia, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
^2.Department of Anesthesia, Sixth Medical Center of Chinese PLA General Hospital, Beijing 100048, China

Received:2025-09-09 Online:2026-03-20 Published:2026-03-26
Contact: Weidong MI, Li TONG E-mail:zhangzhuoning@aliyun.com;haoxinyu19980206@163.com;wwdd1962@163.com;tongli301@aliyun.com
Supported by:
National Natural Science Foundation of China(82171180)

摘要/Abstract

摘要：

目的探索内侧前额叶皮层（mPFC）谷氨酸能神经元在艾司氯胺酮缓解慢性束缚应激（CRS）模型小鼠抑郁样行为中的调控作用。方法选用150只雄性C57BL/6J小鼠，随机分为15组（10只/组）。研究艾司氯胺酮对CRS模型小鼠抑郁样行为的影响时，分为Control+生理盐水（Saline）组、Control+艾司氯胺酮（Sket）组、CRS+Saline组和CRS+Sket组；研究艾司氯胺酮抗抑郁样行为中mPFC区谷氨酸能神经元活性变化时，分为Control+Saline组、CRS+Saline组和CRS+Sket组；研究调控mPFC区谷氨酸能神经元对CRS模型小鼠抑郁样行为的影响时，分为mCherry+Saline组，mCherry+氯氮平-N-氧化物（CNO）组，hM3Dq+CNO组和hM4Di+CNO组；研究艾司氯胺酮是否通过调控mPFC区谷氨酸能神经元发挥抗抑郁作用时，分为mCherry+Saline组、mCherry+Sket组、hM3Dq+Sket组和hM4Di+Sket组。构建CRS模型模拟小鼠的抑郁状态，通过悬尾实验、强迫游泳实验以及糖水偏好实验测试小鼠的抑郁样行为，化学遗传学调控mPFC区谷氨酸能神经元活性，免疫荧光染色观察mPFC区谷氨酸能神经元活性变化。结果与CRS+Saline组相比，CRS+Sket组小鼠的悬尾及强迫游泳实验中的不动时间明显降低，且糖水偏好率显著升高（P<0.001），且CRS+Sket组的小鼠脑切片中谷氨酸能神经元 c-Fos 表达量明显高于CRS+Saline组（P<0.01）。与mCherry组相比，hM3Dq组的小鼠悬尾及强迫游泳实验中不动时间明显减少，且糖水偏好率显著增加（P<0.01），而hM4Di组小鼠的差异无统计学意义（P>0.05）。在均注射艾司氯胺酮的小鼠中，与mCherry组相比，hM4Di组的小鼠悬尾及强迫游泳实验中不动时间明显增加，且糖水偏好率显著减少（P<0.001），而hM3Dq组小鼠的差异无统计学意义（P>0.05）。结论艾司氯胺酮通过激活mPFC区谷氨酸能神经元，改善CRS模型小鼠的抑郁样行为。

关键词: 艾司氯胺酮, 抑郁, 内侧前额叶皮层, 谷氨酸能神经元

Abstract:

Objective To investigate the regulatory role of glutamatergic neurons in the medial prefrontal cortex (mPFC) in the antidepressant effects of esketamine. Methods A total of 150 male C57BL/6J mice were randomly divided into 15 groups (n=10). The mice subjected to the chronic restraint stress (CRS), and those exhibiting depressive-like behaviors following CRS received either esketamine or saline treatment, and subsequent behavioral changes were evaluated. Depressive-like behaviors were assessed using tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT). The changes in neuronal activity within the mPFC were examined using c-Fos immunofluorescence staining. To explore the underlying mechanism, chemogenetic approaches were employed to specifically modulate the activity of mPFC glutamatergic neurons and examine how these manipulations influenced the effect of esketamine on behaviors of the mice. Results Compared with saline-treated CRS mice, the mice with esketamine treatment showed significantly reduced immobility time in TST and FST and increased sucrose preference rate. Immunofluorescence staining revealed significantly increased expression of c-Fos in glutamatergic neurons in esketamine-treated mice. Chemogenetic activation of mPFC glutamatergic neurons (hM3Dq group) significantly decreased immobility time of the mice in the TST and FST and increased their sucrose preference as compared with the mice in mCherry group (P<0.01), while inhibition of the mPFC glutamatergic neurons (hM4Di group) produced no significant effect. Among the mice treated with esketamine, those in hM4Di group exhibited significantly increased immobility time in TST and FST and decreased sucrose preference compared with those in mCherry group, while the mice in hM3Dq group showed no such changes. Conclusion Esketamine produces antidepressant effects in mice with CRS by activating glutamatergic neurons in the mPFC.

Key words: esketamine, depression, medial prefrontal cortex, glutamatergic neurons

张倬宁, 郝新宇, 曹福羊, 郭永馨, 郭舒婷, 蔡辰, 米卫东, 仝黎. 艾司氯胺酮通过激活小鼠mPFC区谷氨酸能神经元发挥抗抑郁样作用[J]. 南方医科大学学报, 2026, 46(3): 489-496.

Zhuoning ZHANG, Xinyu HAO, Fuyang CAO, Yongxin GUO, Shuting GUO, Chen CAI, Weidong MI, Li TONG. Esketamine alleviates depression-like behaviors in mice with chronic restraint stress by activating glutamatergic neurons in the medial prefrontal cortex[J]. Journal of Southern Medical University, 2026, 46(3): 489-496.

图/表 4

图1 艾司氯胺酮对CRS模型小鼠抑郁样行为的影响

Fig.1 Effects of esketamine on depressive-like behaviors in mice with chronic restraint stress (CRS) (n=40). A: Flowchart showing the establishment of CRS models in mice and the schedule of behavioral tests. B: Tail Suspension Test (TST), Forced Swim Test (FST) and Sucrose Preference Test (SPT) of the mice for assessing depressive-like behaviors of the mice. C: Immobility time of the mice in TST and FST and sucrose preference in SPT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

图2 艾司氯胺酮抗抑郁样行为中mPFC区谷氨酸能神经元活性的变化

Fig.2 Esketamine activates CaMKII subtype glutamatergic neurons in the medial prefrontal cortex (mPFC) of CRS mice (n=15). A: Procedure of modeling and tissue collection. B: Representative images of c-Fos immunofluorescence staining and glutamatergic neurons in the mPFC. C: Statistical analysis of c-Fos neurons co-localized with glutamatergic neurons in the mPFC of the mice. **P<0.01, ****P<0.0001.

图3 化学遗传学调控mPFC区谷氨酸能神经元活性对CRS模型小鼠抑郁样行为的影响

Fig.3 Effect of chemogenetic regulation of glutamatergic neuron activity in the mPFC on depressive-like behaviors of CRS mice (n=15). A: Illustration of virus injection and a coronal brain section showing virus expression in the mPFC. B: Expression of chemogenetic virus in the glutamatergic neurons. The mPFC was co-labeled with mCherry red fluorescence, Glu green immunofluorescence, and DAPI blue fluorescence. C: Procedure of virus injection and behavioral tests. D: Immobility time of the mice in TST/FST and sucrose preference in the SPT. **P<0.01, ***P<0.001, ****P<0.0001.

图4 探索艾司氯胺酮是否通过激活mPFC区谷氨酸神经元发挥抗抑郁作用

Fig.4 Esketamine alleviates depressive-like behaviors of the mice by activating CaMKIIα glutamatergic neurons in the mPFC (n=40). A: Illustration of a virus injection and a coronal brain section demonstrating virus expression in the mPFC. B: Expression of chemogenetic virus in the glutamatergic neurons. C: Procedure of virus injection and behavioral tests. D: Immobility time in the TST/FST and the sucrose preference in the SPT. **P<0.01, ***P<0.001, ****P<0.0001.

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艾司氯胺酮通过激活小鼠mPFC区谷氨酸能神经元发挥抗抑郁样作用

Esketamine alleviates depression-like behaviors in mice with chronic restraint stress by activating glutamatergic neurons in the medial prefrontal cortex

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