Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits.
Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits.
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DOI：
10.1016/j.bbr.2016.04.027
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发表时间：
2016-07-15
影响因子：
2.7
通讯作者：
Obrietan K
中科院分区：
文献类型：
--
作者：
Price KH;Dziema H;Aten S;Loeser J;Norona FE;Hoyt K;Obrietan K
大量文献表明，生物钟定时的中断对情绪、记忆和复杂思维有着深远的影响。这个时间保持过程的中心是位于视交叉上核（SCN）内的主昼夜节律起搏器。值得注意的是，在中枢神经系统中，时钟计时并不局限于SCN，而是在广泛的细胞类型和大脑区域中检测到辅助振荡能力，包括作为复杂认知过程基础的前脑回路。这些观察结果提出了关于SCN和前脑振荡器之间的层次和功能关系的问题，以及相关的关于调制认知的潜在时钟门控突触电路的问题。在这里，我们利用了一个时钟敲除策略，其中选择性地删除兴奋性前脑神经元的基本昼夜节律计时基因Bmal1，而SCN时钟保持完整，以测试前脑时钟计时在学习，记忆，焦虑和行为绝望中的作用。有了这个模型系统，我们观察到了许多对依赖于校园的认知测量的影响。缺乏前脑Bmal 1的小鼠在巴恩斯迷宫中表现出习得和回忆的缺陷。值得注意的是，前脑Bmal1的缺失废除了一天中的时间依赖的新对象位置记忆。然而，Bmal 1的缺失并没有改变高架十字迷宫、旷场试验和悬尾试验的表现，表明这种表型特异性地损害认知，但不影响。这些数据共同表明，前脑时钟计时在塑造昼夜节律的学习和记忆检索效率方面发挥着关键作用。
A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day.