慢性不可预知温和应激诱导的抑郁小鼠中央杏仁核和边缘前皮质神经网络的可塑性变化

doi:10.12122/j.issn.1673-4254.2024.11.04

摘要/Abstract

摘要：

目的探讨由慢性不可预知温和应激（CUMS）引起的抑郁症小鼠神经网络的可塑性变化与空间学习记忆调控之间的关系。方法采用随机数字表法将C57Thy1-YFP/GAD67-GFP小鼠分为对照组和CUMS组（n=15），对照组不做处理，CUMS组施加8周的应激以建立模型。利用糖水偏好实验、旷场实验和强迫游泳实验评估小鼠的抑郁水平，通过Morris水迷宫实验检测小鼠空间学习记忆能力的变化，采用膜片钳全细胞模式检测中央杏仁核（CeA）与边缘前皮质（PrL）脑区中不同亚群神经元动作电位发放模式的改变。结果与对照组相比，CUMS组小鼠的糖水偏好指数降低（P<0.01），其在旷场实验中的总运动距离、穿越格子数、进入中心区域次数、中心区域停留时间等各项指标均下降（P<0.01），在强迫游泳实验中的挣扎时间、游泳时间和爬行时间均降低（P<0.01），而静止时间增高（P<0.01），在定位实验中定位潜伏期和路径长度均增加（P<0.05），在空间探索实验中目标象限内路程占总路程百分比和游泳时间均降低（P<0.05），而目标区首次入口时间和对角象限内游泳时间均增长（P<0.01）。同时CUMS提高了CeA区谷氨酸能神经元和PrL区GABA能神经元的能障、绝对不应期和动作电位间距（P<0.05），降低了CeA区GABA能神经元和PrL区谷氨酸能神经元的能障、绝对不应期和动作电位间距（P<0.05）。结论 CUMS诱导的抑郁状态可能引起CeA和PrL区中兴奋性和抑制性神经元网络的可塑性变化，进而损伤了空间学习记忆能力。

关键词: 抑郁, 可塑性, 杏仁核, 内侧前额叶皮层

Abstract:

Objective To explore the relationship between alterations of neural network plasticity and spatial learning and memory functions in mouse models with depression-like behaviors. Methods C57Thy1-YFP/GAD67-GFP mice were randomized into control group (with no treatment) and chronic unpredictable mild stress (CUMS) group (n=15) subjected to CUMS for 8 weeks. Depression-like behaviors of the mice were assessed using sucrose preference test, open field test, and forced swimming test, and their spatial learning and memory abilities were evaluated using Morris water maze test. The changes in the firing patterns of different neuronal subtypes were detected in the central nucleus of the amygdala (CeA) and the prelimbic cortex (PrL) using whole-cell patch-clamp technique. Results Compared with the control mice, CUMS mice showed significantly decreased sucrose preference, total distance moved, number of grid-crossings, entries into the central area, and time spent in the central area in the open field test (P<0.01). In the forced swimming test, CUMS mice exhibited obviously shortened time of struggling, swimming, and climbing with increased immobility time. In Morris water maze test, CUMS mice showed significantly increased escape latency and path length, decreased percentage of distance and swimming time within the target quadrant, and increased first entry latency into the target zone and swimming time within the opposite quadrant. Exposure to CUMS resulted in significantly enhanced energy barrier and increased absolute refractory period and inter-spike interval of glutamatergic neurons in the CeA and GABAergic neurons in the PrL, while the opposite changes were observed in GABAergic neurons in the CeA and glutamatergic neurons in the PrL. Conclusion CUMS-induced depression may lead to plastic changes in the excitatory and inhibitory neuronal networks within the CeA and PrL to cause impairment of spatial learning and memory abilities in mice.

Key words: depression, neuroplasticity, amygdala, medial prefrontal cortex

刘冬播, 陈泽文, 王云, 李昕鹏, 赵彭玉, 郑浩贤. 慢性不可预知温和应激诱导的抑郁小鼠中央杏仁核和边缘前皮质神经网络的可塑性变化[J]. 南方医科大学学报, 2024, 44(11): 2082-2091.

Dongbo LIU, Zewen CHEN, Yun WANG, Xinpeng LI, Pengyu ZHAO, Haoxian ZHENG. Neuronal plasticity changes in the central amygdala and prelimbic cortex network in mice with chronic unpredictable mild stress-induced depression[J]. Journal of Southern Medical University, 2024, 44(11): 2082-2091.

图/表 7

图1 CUMS对小鼠糖水偏好的影响

Fig.1 Effect of chronic unpredictable mild stress (CUMS) on sucrose preference in mice. **P<0.01 vs control group.

图2 CUMS对小鼠旷场活动行为的影响

Fig.2 Effects of CUMS performance of the mice in open field test.A: Total distance moved.B: Number of crossing grid.C: Number of entries into the central area.D: Time spent in the central area.EPercentage of distance traveled in the central area.F Percentage of time spent in the central area. G Number of rearing. **P<0.01 vs control group.

图3 CUMS对小鼠强迫游泳行为的影响

Fig.3 Effects of CUMS on performance of the mice in forced swimming test. A: Struggling time. B: Swimming time. C: Immobility time. D: Climbing time. **P<0.01 vs control group.

图4 CUMS组和对照组小鼠在Morris水迷宫定位实验中的表现

Fig.4 Performance of CUMS and control mice for localization in Morris water maze test. A: Escape latency. B: Path length. C: Average swimming velocity. *P<0.05, **P<0.01, ***P<0.001 vs control group.

图5 CUMS组和对照组小鼠在Morris水迷宫空间探索实验中的表现

Fig.5 Performance of CUMS and control mice for spatial exploration in Morris water maze test. A: Swimming time. B: Percentage of distance within the target quadrant. C: First entry latency into target zone. TQ: Target quadrant. AQ: Adjacent quadrant. OQ: Opposite quadrant. IQ: Irrelevant quadrant. *P<0.05, **P<0.01 vs control group.

图6 CUMS对小鼠CeA区谷氨酸能和GABA能神经元动作电位发放模式的改变

Fig.6 Changes of action potential firing patterns of glutamatergic and GABAergic neurons in CeA region of CUMS mice. A: Waveforms of sequential action potentials of glutamatergic neurons in CUMS mice (solid line) and control mice (dotted line). B-D: Effects of CUMS on electrophysiological properties of glutamatergic neurons. E: Waveforms of sequential action potentials of GABAergic neurons in CUMS mice (solid line) and control mice (dotted line). F-H: Effects of CUMS on electrophysiological properties of GABAergic neurons. Vts: Threshold potential; Vr: Resting potential; ARP: Absolute refractory period; ISI: Inter-spike interval. *P<0.05, **P<0.01, ***P<0.001 vs control group.

图7 CUMS对小鼠PrL区谷氨酸能和GABA能神经元动作电位发放模式的改变

Fig.7 Changes of action potential firing patterns of glutamatergic and GABAergic neurons in PrL region of CUMS mice. A: Waveforms of sequential action potentials of glutamatergic neurons in CUMS mice (solid line) and control mice (dotted line). B-D: Effects of CUMS on electrophysiological properties of glutamatergic neurons. E: Waveforms of sequential action potentials of GABAergic neurons in CUMS mice (solid line) and control mice (dotted line). F-H: Effects of CUMS on electrophysiological properties of GABAergic neurons. *P<0.05, **P<0.01, ***P<0.001 vs control group.

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