Circadian Structural Plasticity in Central Pacemakers

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SUMARY Circadian rhythms depend on the molecular transcription/translation negative feedback loop (TTL) operating in clock neurons, and on the network properties of these neurons. Among the properties that could be recruited by the circadian clock are changes in the identity of pre/post synaptic partners and/or strength of the connectivity between clock neurons, a property collectively termed as circadian structural plasticity. The central hypothesis for our parent Award is that circadian structural plasticity within the central circadian clock of mammals, located within the suprachiasmatic nucleus (SCN), is part of the time-encoding mechanism. An early-stage symptom of Alzheimer’s disease (AD) is the disruption of sleep and circadian rhythms. For this Supplement, we test the hypothesis that these symptoms may result in part from the disruption of circadian structural plasticity within the SCN. Specific aim 2D will assess the effect of AD on the expression of the clock gene PER2 through PER2-LUC reporting in ex vivo SCN slices from either AD or WT mice. This experiment will determine the effect of AD on the amplitude of the rhythm of clock gene expression and on the synchrony between cells within the SCN neuronal network. Specific aim 2E will examine the effect of AD on circadian structural remodeling in SCN VIPergic neurons, which are an essential component of the timekeeping mechanism, through virally mediated labeling of VIP neurons with synaptophysin-mCherry followed by ex vivo fluorescent reporting of circadian rhythms of retraction/extension of presynaptic fibers. Specific aims 2F and 2G will use serial blockface scanning electron microscopy to examine circadian plasticity at the ultrastructural level by examining synaptic structural changes (2F) and changes in astrocytic processes that ensheath neurons (2G). Our experiments test predictions of the hypothesis that disruptions of sleep and circadian rhythms that are characteristic of early stages of AD may emerge from the effect of the disease on key circadian plasticity changes within the master circadian clock. Elucidating the potential mechanisms behind these early symptoms of AD could open new opportunities to treat sleep and circadian disruptions in AD patients.