Network organization of the circadian clock

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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.