Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice.
Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice.
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DOI：
10.1016/j.biopsych.2016.03.1050
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发表时间：
2016-12-01
影响因子：
10.6
通讯作者：
Welsh DK
中科院分区：
文献类型：
--
作者：
Landgraf D;Long JE;Proulx CD;Barandas R;Malinow R;Welsh DK
重度抑郁症与昼夜节律紊乱有关。为了研究情绪障碍和生物钟中断之间的因果关系，以前的动物模型研究采用了光/暗操纵，时钟基因的全局突变或脑区病变。然而，光可以通过非昼夜机制影响情绪;时钟基因具有多效性，不依赖于时钟的功能;大脑病变不仅会破坏细胞的昼夜节律，还会破坏细胞并消除重要的神经元连接，包括光接收通路。因此，一个明确的因果关系的作用，功能生物钟在情绪调节尚未建立。我们将编码短发夹RNA的病毒载体立体定向注射到大脑的主昼夜节律起搏器，视交叉上核（SCN）中，以敲低必需时钟基因Bmal 1的表达。在这些SCN特异性Bmal 1敲低（SCN-Bmal 1-KD）小鼠中，SCN的昼夜节律大大减弱，而小鼠保持在标准的光/暗周期中，SCN神经元保持完整，神经元连接不受干扰，包括光输入。在习得性无助模式中，SCN-Bmal 1-KD小鼠的逃避速度较慢，甚至在暴露于无法逃避的压力之前。他们还花了更多的时间不动的尾部悬挂测试和更少的时间在明亮的部分，一个光明/黑暗的盒子。SCN-Bmal 1-KD小鼠还表现出更大的体重增加，异常的昼夜节律模式的皮质酮，和衰减的皮质酮增加应激反应。扰乱SCN昼夜节律足以引起小鼠的无助感、行为绝望和焦虑样行为，建立了SCN-Bmal 1-KD小鼠作为抑郁症的新动物模型。
Major depressive disorder is associated with disturbed circadian rhythms. To investigate the causal relationship between mood disorders and circadian clock disruption, previous studies in animal models have employed light/dark manipulations, global mutations of clock genes, or brain area lesions. However, light can impact mood by noncircadian mechanisms; clock genes have pleiotropic, clock-independent functions; and brain lesions not only disrupt cellular circadian rhythms but also destroy cells and eliminate important neuronal connections, including light reception pathways. Thus, a definitive causal role for functioning circadian clocks in mood regulation has not been established. We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain's master circadian pacemaker, the suprachiasmatic nucleus (SCN). In these SCN-specific Bmal1-knockdown (SCN-Bmal1-KD) mice, circadian rhythms were greatly attenuated in the SCN, while the mice were maintained in a standard light/dark cycle, SCN neurons remained intact, and neuronal connections were undisturbed, including photic inputs. In the learned helplessness paradigm, the SCN-Bmal1-KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN-Bmal1-KD mice also showed greater weight gain, an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress. Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair, and anxiety-like behavior in mice, establishing SCN-Bmal1-KD mice as a new animal model of depression.
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影响因子：
56.9
作者：
Dulcis, Davide;Jamshidi, Pouya;Spitzer, Nicholas C.
通讯作者：
Spitzer, Nicholas C.
DOI：
10.1073/pnas.0703615105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Gonzalez, M. M. C.;Aston-Jones, G.
通讯作者：
Aston-Jones, G.
影响因子：
5.3
作者：
Monje, Francisco J.;Cabatic, Maureen;Pollak, Daniela D.
通讯作者：
Pollak, Daniela D.
影响因子：
3.7
作者：
Landgraf D;Long J;Der-Avakian A;Streets M;Welsh DK
通讯作者：
Welsh DK
影响因子：
3.6
作者：
Gorka, Z;Moryl, E;Papp, M
通讯作者：
Papp, M