Circadian rhythm and the cerebral circulation

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Circadian rhythms are oscillating biological processes that affect animal behavior (i.e. eating, sleeping), as well as major systems of the body (i.e. cardiovascular system). At the molecular level, circadian rhythms are driven by a core group of “clock genes” ” (i.e. Bmal1, CLOCK, Per and Cry) that evoke the rhythmic expression of target genes important for various physiological processes. Although the brain contains the central regulator of the body's circadian rhythm, evidence indicates that peripheral cells and tissues exhibit their own intrinsic circadian rhythm, driven by the same cohort of molecular “clock” genes.******As the computational core of the CNS, the brain exhibits a high level of metabolic activity, and is absolutely dependent upon a continuous supply of O2 and glucose, which are delivered by the cerebral circulation. Distribution of blood flow throughout the brain is regulated by a meshwork of small, myogenically active arteries and arterioles that can “autoregulate” or adjust their intraluminal diameter to maintain blood flow in the face of changing arterial pressure. Autoregulation is largely due to processes intrinsic to cerebral resistance arteries, and is critical for long-term neural activity. At present, it is completely unknown how circadian rhythms impact cerebrovascular function.******We hypothesize that the circadian clock machinery within the cerebral circulation regulates the cellular mechanisms underlying blood flow control. These effects may oscillate daily (i.e. exhibit a circadian rhythm), or manifest more slowly in the form of vascular remodeling.****Our proposed research will explore the regulation of cerebrovascular function at several levels of complexity, beginning with the impact of circadian rhythm on the cellular mechanisms governing contractility in cerebral resistance arteries. We will investigate the impact of light/dark cycle on pressure- and hormone-dependent contractile responses and endothelium-dependent regulation of myogenic tone, and examine how age and sex influence these processes. We will examine the time-dependent expression of molecular “clock” genes in cerebrovascular smooth muscle and endothelium and also investigate the potential diurnal expression of key molecules in the vascular wall important for myogenic contraction and endothelium-dependent vasodilation. We will also utilize a Bmal1 knockout mouse to examine how disruption of circadian rhythm affects cerebrovascular function, along with the mechanical properties of cerebral arteries.******Circadian-related changes in the molecular pathways and functional behavior of the cerebral circulation will provide new insights for the regulation of cerebral blood flow and brain activity. These studies will further serve as a paradigm to examine the effect of circadian rhythm on blood vessel properties within other vascular beds and its impact on tissue/organ function.***