Jia Yun-Fang, Song Ning-Ning, Mao Rong-Rong, Li Jin-Nan, Zhang Qiong, Huang Ying, Zhang Lei, Han Hui-Li, Ding Yu-Qiang, Xu Lin
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Disease, and Laboratory of Learning and Memory, Kunming Institute of Zoology, Chinese Academy of Sciences Kunming, China ; Kunming College of Life Science, University of Chinese Academy of Sciences Beijing, China.
Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, Tongji University School of Medicine Shanghai, China ; Department of Anatomy and Neurobiology, Tongji University School of Medicine Shanghai, China.
Front Behav Neurosci. 2014 Sep 23;8:325. doi: 10.3389/fnbeh.2014.00325. eCollection 2014.
Dysfunction of central serotonin (5-HT) system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT) in Pet1-Cre;Rosa26-DT receptor (DTR) mice. The central 5-HT-deficient mice showed reduced anxiety-like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides understanding the relationship between diabetes mellitus and psychiatric disorders.
中枢5-羟色胺（5-HT）系统功能障碍被认为是焦虑和抑郁的潜在机制之一，糖尿病与精神障碍之间的关联已因糖尿病患者中焦虑/抑郁的高患病率而受到关注。这促使我们在中枢5-HT缺乏的小鼠以及同时患有糖尿病的小鼠中研究这些行为。分别通过条件性敲除Tph2或Lmx1b来生成缺乏5-HT或中枢5-羟色胺能神经元的小鼠。通过在Pet1-Cre;Rosa26-DT受体（DTR）小鼠中给予白喉毒素（DT），实现中枢5-羟色胺能神经元和胰岛细胞的同时耗竭。中枢5-HT缺乏的小鼠表现出焦虑样行为减少，因为与对照组相比，它们在明暗箱试验中在亮箱中停留的时间更长且进入亮箱的频率更高；在高架十字迷宫试验中也观察到了类似结果。然而，它们在强迫游泳试验和悬尾试验中的不动时间没有差异，表明中枢5-HT缺乏的小鼠具有正常的抑郁样行为。正如预期的那样，经DT处理的Pet1-Cre;Rosa26-DTR小鼠同时缺乏中枢5-羟色胺能神经元和胰岛内分泌细胞，表现出几种典型的糖尿病症状。有趣的是，它们表现出焦虑样行为增加，但在强迫游泳试验和悬尾试验中的不动时间减少。此外，这些小鼠的海马神经发生显著增强。这些结果表明，中枢5-HT缺乏可能不足以在小鼠中诱导焦虑/抑郁样行为，而增强的海马神经发生可能导致5-HT缺乏的糖尿病小鼠出现抑郁样行为改变。我们目前的研究有助于理解糖尿病与精神障碍之间的关系。
