Network organization of the circadian clock

位于下丘脑的生物钟调节着生理和行为的日常节奏。了解这个时钟是如何运作的是我研究项目的长期目标。我们知道，视交叉上核（SCN）中的生物钟包含许多特殊的细胞类型，每种细胞类型都有特定的作用。这些不同的细胞群一起形成了一个有凝聚力的生物钟。时间生物学中两个相关且重要的问题是：“这些细胞群是如何联网形成一个有凝聚力的时钟的？”以及“这些网络是如何被经验修改的？”本建议的目标是首先阐明生物钟的网络特性，然后确定这些网络是如何通过经验修改的。***目的1将研究胃泌素释放肽（GRP）细胞和血管活性肠多肽（VIP）在昼夜节律网络中的作用。SCN接收视网膜输入到两个不同的细胞群，由它们的肽能表型定义：GRP和VIP细胞。这些肽已被证明足以重置生物钟，但由于一些遗传模型的并发症，围绕其必要性的证据不太清楚。我们将使用一套互补的神经科学技术来探索这些不同的神经肽及其细胞对SCN网络的作用，包括药理学，转基因和合成生物学方法。***目的2将研究昼夜节律网络的可塑性。昼夜节律钟的周期由照明历史改变。我们认为这些变化反映了昼夜神经网络的重新布线。虽然网络的实际重新布线是不可能观察到的，但重新布线所需的细胞机制的表达是可以量化的。因此，我们假设与突触可塑性相关的蛋白质将通过改变生物钟周期的治疗而上调。此外，我们将使用神经网络建模来研究各种细胞参数如何影响昼夜节律网络。***最后，目标#3将研究经验导致与行为节律性恶化相关的生物钟可塑性变化的机制（例如，振幅下降、行为模式碎片化、昼夜节律阶段变异性增加）。具体来说，我们将验证这样一种假设：扰乱节律性的经历是通过生物钟的神经炎症（小胶质细胞浸润）来实现的，从而导致生物钟的网络中断。意义：昼夜节律系统对于理解大脑如何调节复杂行为是容易处理的。描述构成SCN组织基础的网络特性将提高我们对调节循环行为的基本过程的理解。********

A circadian clock located in the hypothalamus regulates daily rhythms of physiology and behaviour. Understanding how this clock functions is the long term goal of my research program. We know that the circadian clock in the suprachiasmatic nucleus (SCN) contains a number of specialized cell types, each of which performs a specific role. Together, these different cell populations form a cohesive circadian clock. Two related and important questions in chronobiology are “How are these cell populations networked together to form a cohesive clock?” and “How are these networks modified by experience?” The goal of the present proposal is to first elucidate network properties of the circadian clock, and then to determine how these networks are modified by experience.***Objective #1 will examine the role of gastrin releasing peptide (GRP) cells and vasoactive intestinal polypeptide (VIP) in the circadian network. The SCN receives retinal input to two distinct cell populations defined by their peptidergic phenotypes: GRP and VIP cells. These peptides have been shown to be sufficient to reset the clock, but evidence around their necessity is less clear due to complications with some genetic models. We will use a set of complimentary neuroscientific techniques to probe the role these distinct neuropeptides and their cells make to SCN networking, including pharmacology, transgenic and synthetic biological approaches. ***Objective #2 will examine plasticity in the circadian network. The period of the circadian clock is modified by lighting history. We believe that these changes reflect rewiring of the circadian neural networks. While actual rewiring of the network is impossible to observe, the expression of cellular machinery necessary for rewiring can be quantified. Thus, we hypothesize that proteins associated with synaptic plasticity will be up-regulated by treatments that alter the period of the circadian clock. Moreover, we will use neural network modeling to investigate how various cellular parameters may influence the circadian network. ***Finally, Objective #3 will examine the mechanisms by which experience can lead to plastic changes of the circadian clock associated with deterioration of behavioural rhythmicity (e.g., decreased amplitude, fragmentation of behavioural patterns, increased variability of circadian phase). Specifically, we will test the hypothesis that experiences that disrupt rhythmicity do so through neuroinflammation (microglia infiltration) of the circadian clock, leading to a disrupted networking in the circadian clock.***Significance: The circadian system is tractable for understanding how the brain regulates complex behaviour. Delineating the network properties that underlie the organization of the SCN will improve our understanding of the fundamental processes that regulate cyclic behaviour.********