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

点击翻译按钮获取中文摘要

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.