Cell-specific control of circadian gene expression: investigating the role of astrocyte clocks in neural function

生物钟根据环境昼夜循环来组织生理和行为。这些时钟产生大约24小时的节律，依靠一小组被称为时钟基因的基因来维持和协调生物体各个层面的昼夜节律活动。时钟基因的表达是普遍存在的，大多数哺乳动物细胞和组织在基因表达中表达昼夜节律。昼夜节律生物学的一个主要兴趣是确定所有这些细胞时钟所起的作用。在哺乳动物中，下丘脑的视交叉上核（SCN）是协调全身昼夜节律的主要生物钟的所在地。然而，在哺乳动物的大脑中，神经元和星形胶质细胞在时钟基因表达中都表现出昼夜节律。星形胶质细胞是哺乳动物大脑中最丰富的细胞类型，现在被认为是许多神经元反应的重要参与者。尽管神经元在昼夜节律的产生和协调中所起的作用已受到相当多的关注，但星形胶质细胞和昼夜节律在星形胶质细胞中所起的作用仍未被探索。星形胶质细胞功能缺陷导致神经网络失调和脑功能异常。此外，最近的证据表明，星形胶质细胞昼夜节律特性的破坏会损害其再摄取和释放各种递质的能力，这表明星形胶质细胞中的时钟参与神经元通信。我们假设星形胶质细胞的昼夜节律振荡是小鼠最佳神经元功能和基线行为所必需的。我们建议选择性地破坏星形胶质细胞中的分子钟，以分离和检查它们对哺乳动物脑功能的贡献。我们将利用现有的技术，并将它们结合起来，开发一种研究昼夜节律和复杂行为的新模型。

Circadian clocks organize physiology and behaviour in tune with the environmental day-night cycle. These clocks generate rhythms of approximately 24h and rely on a small set of genes, called clock genes, to sustain and coordinate circadian activity at all levels of the organism. Clock gene expression is ubiquitous and most mammalian cells and tissues express circadian rhythms in gene expression. A primary interest of circadian biology is to determine the role played by all these cellular clocks. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a primary circadian clock that coordinates circadian rhythms throughout the body. Within the mammalian brain, however, both neurons and astrocytes display circadian rhythms in clock gene expression. Astrocytes are the most abundant cell type of the mammalian brain and are now recognized as essential players in many neuronal responses. Whereas the role played by neurons in the generation and coordination of circadian rhythmicity has received considerable attention, the role played by astrocytes and the role played by circadian rhythms in astrocytes remain unexplored. Deficits in astrocytic functions lead to dysregulated neuronal networks and aberrant brain functions. In addition, recent evidence has shown that disruptions in the circadian properties of astrocytes impair their ability to reuptake and release various transmitters, suggesting that the clock in astrocytes participates in neuronal communication. We hypothesize that circadian oscillations in astrocytes are required for optimal neuronal function and baseline behaviour in mice. We propose to disrupt the molecular clock selectively in astrocytes to isolate and examine their contributions to mammalian brain functions. We will use already existing technologies and combine them to develop a novel model for the study of circadian rhythms and complex behaviours.