Hippocampal neurons' cytosolic and membrane-bound ribosomal transcript profiles are differentially regulated by learning and subsequent sleep.
Hippocampal neurons' cytosolic and membrane-bound ribosomal transcript profiles are differentially regulated by learning and subsequent sleep.
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DOI：
10.1073/pnas.2108534118
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发表时间：
2021-11-30
影响因子：
11.1
通讯作者：
Aton SJ
中科院分区：
文献类型：
--
作者：
Delorme J;Wang L;Kodoth V;Wang Y;Ma J;Jiang S;Aton SJ
睡眠不足会破坏海马体依赖记忆的巩固。为了了解这种效应的细胞学基础，我们量化了与翻译胞浆中的核糖体和不同海马神经元群体细胞膜上的核糖体相关的RNA。我们的分析表明，虽然睡眠不足(但不是学习)改变了细胞质中的大量核糖体转录，但学习对特征较差的膜结合核糖体的转录谱有显著影响。我们证明，学习后睡眠剥夺阻断了已经很小的学习驱动的胞质核糖体变化。它同时改变了兴奋性海马神经元和高度活跃的“engram”神经元中与膜结合的核糖体的代谢和生物合成过程相关的转录。总而言之，这些发现提供了对学习改变的细胞机制以及随后睡眠不足造成的破坏的洞察力。海马体对于将短暂的经历整合成持久的记忆是必不可少的。学习后睡眠促进了记忆的巩固，尽管潜在的细胞机制在很大程度上是未知的。我们对这个问题采取了一种公正的方法，使用了海马体介导的睡眠依赖记忆巩固(上下文恐惧记忆)的小鼠模型。由于突触的可塑性与神经元细胞膜(如受体)和胞浆(如细胞骨架元素)的变化有关，因此我们描述了学习和随后的睡眠或睡眠剥夺(SD)如何影响这些细胞隔室。翻译核糖体亲和纯化用于在不同的亚细胞室(胞浆和细胞膜)和不同的细胞群(整个海马区、Camk2a+神经元或具有磷酸化核糖体S6亚单位的高活性神经元[pS6+])中分析核糖体相关RNA。我们研究了作为睡眠与SD和先前学习(语境恐惧条件作用；cfc)的函数，记录档案是如何变化的。虽然睡眠不足改变了许多胞质核糖体转录本，但cfc几乎没有改变，cfc驱动的变化被随后的SD所阻断。与之形成鲜明对比的是，SD改变了几个膜结合核糖体(MB)的转录本，而学习改变了更多的转录本(包括长的非编码RNA[lncRNAs])。受cfc影响最大的细胞通路参与了结构重构。对睡眠小鼠和SD小鼠的CFC-MB转录谱的比较表明，在SD干扰的生物过程中，Camk2a+神经元的细胞代谢和高活性pS6+(推测为“engram”)神经元的蛋白质合成发生了变化。这些发现为学习如何影响海马神经元提供了洞察力，并表明SD对记忆巩固的影响是细胞类型和亚细胞室特有的。
Sleep loss disrupts consolidation of hippocampus-dependent memory. To understand the cellular basis for this effect, we quantified RNAs associated with translating ribosomes in cytosol and on cellular membranes of different hippocampal neuron populations. Our analysis suggests that while sleep loss (but not learning) alters numerous ribosomal transcripts in cytosol, learning has dramatic effects on transcript profiles for less–well-characterized membrane-bound ribosomes. We demonstrate that postlearning sleep deprivation occludes already minimal learning-driven changes on cytosolic ribosomes. It simultaneously alters transcripts associated with metabolic and biosynthetic processes in membrane-bound ribosomes in excitatory hippocampal neurons and highly active, putative “engram” neurons, respectively. Together, these findings provide insights into the cellular mechanisms altered by learning and their disruption by subsequent sleep loss. The hippocampus is essential for consolidating transient experiences into long-lasting memories. Memory consolidation is facilitated by postlearning sleep, although the underlying cellular mechanisms are largely unknown. We took an unbiased approach to this question by using a mouse model of hippocampally mediated, sleep-dependent memory consolidation (contextual fear memory). Because synaptic plasticity is associated with changes to both neuronal cell membranes (e.g., receptors) and cytosol (e.g., cytoskeletal elements), we characterized how these cell compartments are affected by learning and subsequent sleep or sleep deprivation (SD). Translating ribosome affinity purification was used to profile ribosome-associated RNAs in different subcellular compartments (cytosol and membrane) and in different cell populations (whole hippocampus, Camk2a+ neurons, or highly active neurons with phosphorylated ribosomal subunit S6 [pS6+]). We examined how transcript profiles change as a function of sleep versus SD and prior learning (contextual fear conditioning; CFC). While sleep loss altered many cytosolic ribosomal transcripts, CFC altered almost none, and CFC-driven changes were occluded by subsequent SD. In striking contrast, SD altered few transcripts on membrane-bound (MB) ribosomes, while learning altered many more (including long non-coding RNAs [lncRNAs]). The cellular pathways most affected by CFC were involved in structural remodeling. Comparisons of post-CFC MB transcript profiles between sleeping and SD mice implicated changes in cellular metabolism in Camk2a+ neurons and protein synthesis in highly active pS6+ (putative “engram”) neurons as biological processes disrupted by SD. These findings provide insights into how learning affects hippocampal neurons and suggest that the effects of SD on memory consolidation are cell type and subcellular compartment specific.
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影响因子：
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