Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours.
Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours.
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DOI：
10.1017/s1461145712000703
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Lu XY
中科院分区：
文献类型：
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作者：
Guo M;Huang TY;Garza JC;Chua SC;Lu XY
以往的研究表明，中枢神经系统中的瘦素及其受体(LepRb)在调节抑郁和焦虑相关行为方面发挥着重要作用。然而，LepRb在特定脑区调节不同情绪行为的生理功能仍有待确定。在这项研究中，我们使用一系列评估抑郁和焦虑相关行为的行为范式，研究了LepRb消融对成人海马区的行为影响。利用Cre/loxP定点重组系统，通过双侧立体定向将表达Cre重组酶的腺相关病毒(AAV-Cre)导入成年小鼠齿状回，实现了LepRb的靶向缺失。注射后2周检测到AAV-Cre介导的LepRb漂浮区的缺失。与此相一致，注射AAV-Cre的小鼠海马区内瘦素刺激的Akt磷酸化被减弱。注射AAV-CRE的小鼠在高架加迷宫、暗箱和旷场测试中表现出正常的运动活动和焦虑样行为，但在尾部悬吊、蔗糖偏好和习得性无助测试中表现出抑郁样行为。综上所述，这些数据表明，成年海马区LepRb基因的缺失足以引发类似抑郁的行为。我们的结果支持这样一种观点，即海马体中的瘦素信号可能对维持积极的情绪状态和积极应对压力至关重要。
Previous studies have demonstrated that leptin and its receptors (LepRb) in the central nervous system play an important role in regulating depression- and anxiety-related behaviors. However, the physiological functions of LepRb in specific brain regions for mediating different emotional behaviors remain to be defined. In this study, we examined the behavioral effects of LepRb ablation in the adult hippocampus using a series of behavioral paradigms for assessing depression- and anxiety-related behaviors. Targeted deletion of LepRb was achieved using the Cre/loxP site-specific recombination system through bilateral stereotaxic delivery of an adeno-associated virus expressing Cre-recombinase (AAV-Cre) into the dentate gyrus of adult mice homozygous for a floxed leptin receptor allele. AAV-Cre-mediated deletion of the floxed region of LepRb was detected 2 weeks after injection. In accordance with this, leptin-stimulated phophorylation of Akt was attenuated in the hippocampus of AAV-Cre injected mice. Mice injected with AAV-Cre displayed normal locomotor activity and anxiety-like behavior, as determined in the elevated plus maze, light dark box and open field tests, but showed increased depression-like behaviors in the tail suspension, sucrose preference and learned helplessness tests. Taken together, this data suggests that deletion of LepRb in the adult hippocampus is sufficient to induce depression-like behaviors. Our results support the view that leptin signaling in the hippocampus may be essential for maintaining positive mood states and active coping to stress.