Doctor of Philosophy, University of Cambridge (2017)
Master of Science, University of Bristol (2013)
Bachelor of Science, University Of Birmingham (2012)
In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ?24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.
View details for DOI 10.1016/j.cell.2019.02.017
View details for Web of Science ID 000466843000011
View details for PubMedID 31030999
View details for PubMedCentralID PMC6506277
Establishing a functional neuronal circuit requires not only synapsing with the right cell type, but also targeting the right subcellular compartment. In this issue of Neuron, Tai etal. (2019) identify the cell adhesion molecule L1CAM as integral to the mechanism by which chandelier cells establish subcellular compartment-specific innervation of pyramidal neurons in the mammalian cerebral cortex.
View details for PubMedID 30998894
The suprachiasmatic nucleus (SCN) co-ordinates circadian behaviour and physiology in mammals. Its cell-autonomous circadian oscillations pivot around a well characterisedtranscriptional/translational feedback loop (TTFL), whilst the SCN circuit as a whole is synchronised to solar time by its retinorecipient cells that express and release vasoactive intestinal peptide (VIP). The cell-autonomous and circuit-level mechanisms whereby VIP synchronises the SCN are poorly understood. We show that SCN slices in organotypic culture demonstrate rapid and sustained circuit-level circadian responses to VIP that are mediated at a cell-autonomous level. This is accompanied by changes across a broad transcriptional network and by significant VIP-directed plasticity in the internal phasing of the cell-autonomous TTFL. Signalling via ERK1/2 and tuning by its negative regulator DUSP4 are critical elements of the VIP-directed circadian re-programming. In summary, we provide detailed mechanistic insight into VIP signal transduction in the SCN at the level of genes, cells and neural circuit.
View details for PubMedID 30710088