Sensory experience remodels genome architecture in neural circuit to drive motor learning
Sensory experience remodels genome architecture in neural circuit to drive motor learning
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DOI：
10.1038/s41586-019-1190-7
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发表时间：
2019-05-30
期刊：
影响因子：
64.8
通讯作者：
Bonni, Azad
中科院分区：
文献类型：
--
作者：
Yamada, Tomoko;Yang, Yue;Bonni, Azad
神经元活动依赖性转录将感觉体验与大脑的适应性反应（包括学习和记忆）结合起来。活性依赖性基因表达的机制，包括表观基因组的改变已经被表征（1-8）。然而，是否感觉经验重塑染色质结构在体内诱导神经代码转换和学习和记忆的成人大脑中的根本问题仍然有待解决。在这里，我们使用在体内钙成像，光遗传学和药理学的方法来表明，颗粒神经元激活小脑蚓部的前背侧在延迟触觉惊吓学习模式在小鼠中具有至关重要的作用。值得注意的是，使用大规模的转录组和染色质分析，我们表明，运动学习相关的颗粒神经元回路的激活重组神经元染色质，包括通过长距离增强子-启动子和转录活性区室相互作用来编排不同的颗粒神经元基因表达模块。在成年小鼠中，前背小脑蚓部颗粒神经元中的染色质结构调节剂粘附素的条件性CRISPR敲除破坏了增强子-启动子相互作用、活性依赖性转录和运动学习。这些发现定义了感觉体验模式、染色质结构和大脑中的神经回路编码如何驱动运动学习。
Neuronal-activity-dependent transcription couples sensory experience to adaptive responses of the brain including learning and memory. Mechanisms of activity-dependent gene expression including alterations of the epigenome have been characterized(1-8). However, the fundamental question of whether sensory experience remodels chromatin architecture in the adult brain in vivo to induce neural code transformations and learning and memory remains to be addressed. Here we use in vivo calcium imaging, optogenetics and pharmacological approaches to show that granule neuron activation in the anterior dorsal cerebellar vermis has a crucial role in a delay tactile startle learning paradigm in mice. Of note, using large-scale transcriptome and chromatin profiling, we show that activation of the motor-learning-linked granule neuron circuit reorganizes neuronal chromatin including through long-distance enhancer-promoter and transcriptionally active compartment interactions to orchestrate distinct granule neuron gene expression modules. Conditional CRISPR knockout of the chromatin architecture regulator cohesin in anterior dorsal cerebellar vermis granule neurons in adult mice disrupts enhancer-promoter interactions, activity-dependent transcription and motor learning. These findings define how sensory experience patterns chromatin architecture and neural circuit coding in the brain to drive motor learning.