Expression of clock genes in the master circadian pacemaker and peripheral clocks: relationships with neuroinflammatory conditions

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Mammalian behavior and physiology undergo daily rhythms that are coordinated by an endogenous circadian timing system. This system is organized in a hierarchical structure, in which a master pacemaker, located in the suprachiasmatic nucleus of the hypothalamus (SCN), regulates downstream oscillators in other brain areas and in peripheral tissues. At all levels of the circadian network, a chain of interwoven loops generates molecular oscillations of ‘clock genes’ at the cellular level, with cyclic gene expression in the various organs governing overt rhythms in behavior and physiology, The present thesis discusses the general structure of the circadian clockwork, and elaborates on mechanisms and neural networks underlying a major (and vital) endogenous biological rhythm, represented by the daily alternation of sleep and wakefulness. This introduces the experimental work aimed at the analysis of the impact of aging and sleep homeostatic mechanisms on the expression of clock genes in the central and peripheral components of the clock machinery. Aging is in the focus of the study since it represents a physiological condition which very frequently brings about alterations of biological rhythms, with a high burden and cost for the individual and the society. The molecular correlates of aging-related chronobiological disturbances are, however, still largely unexplored. In addition, the experimental work which is here presented focuses on the relationships between sleep-wake regulation and immune-related responses. Immunity is, like sleep, a vital function, and a variety of data increasingly suggest that these two functions could be inter-related, but the potential molecular crosstalk also represents a still largely unexplored domain.