Circadian rhythm and the cerebral circulation

昼夜节律是影响动物行为(如进食、睡眠)以及身体主要系统(如心血管系统)的振荡生物过程。在分子水平上，昼夜节律是由一组核心的时钟基因(即BMal1、Clock、Per和Cry)驱动的，这些基因唤起了对各种生理过程重要的靶基因的节律性表达。尽管大脑包含了人体昼夜节律的中央调节器，但有证据表明，外周细胞和组织表现出自己固有的昼夜节律，由相同的分子时钟基因驱动。 作为中枢神经系统的计算核心，大脑表现出高度的代谢活动，并且绝对依赖于由大脑循环输送的氧气和葡萄糖的持续供应。血流在整个大脑中的分布是由一组微小的、具有肌源性活性的动脉和小动脉组成的网络来调节的，这些动脉和小动脉可以“自动调节”或调整其管腔内直径，以在动脉压力不断变化的情况下维持血液流动。自我调节在很大程度上是由于大脑阻力动脉固有的过程，对长期的神经活动至关重要。目前，昼夜节律如何影响脑血管功能尚不清楚。 我们假设，大脑循环中的生物钟机制调节着血流控制的细胞机制。这些影响可能每天振荡(即表现出昼夜节律)，或者以血管重塑的形式表现得更慢。 我们建议的研究将从昼夜节律对大脑阻力动脉收缩的细胞机制的影响开始，在几个复杂的水平上探索脑血管功能的调节。我们将研究明/暗周期对压力和激素依赖的收缩反应和内皮依赖的肌张力调节的影响，并研究年龄和性别如何影响这些过程。我们将研究分子时钟基因在脑血管平滑肌和血管内皮细胞中的时间依赖性表达，并研究血管壁上对肌源性收缩和内皮依赖性血管扩张至关重要的关键分子的潜在的昼夜表达。我们还将利用BMal1基因敲除小鼠来研究昼夜节律的中断如何影响脑血管功能，以及脑动脉的机械特性。 脑循环分子通路和功能行为的昼夜节律变化将为脑血流和脑活动的调节提供新的见解。这些研究将进一步作为研究昼夜节律对其他血管床内血管特性的影响及其对组织/器官功能的影响的范例。

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.