Doctor of Philosophy, University of Cambridge (2017)
Master of Science, University of Bristol (2013)
Bachelor of Science, University Of Birmingham (2012)
Circadian (daily) rhythms pervade mammalian behaviour. They are generated by cell-autonomous, transcriptional/translational feedback loops (TTFL), active in all tissues. This distributed clock network is co-ordinated by the principal circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Its robust and accurate time-keeping arises from circuit-level interactions that bind its individual cellular clocks into a coherent time-keeper. Cells that express the neuropeptide vasoactive intestinal peptide (VIP) mediate retinal entrainment of the SCN, and in the absence of VIP, or its cognate receptor VPAC2, circadian behaviour is compromised because SCN cells cannot synchronise. The contributions to pacemaking of other cell types, including VPAC2-expressing target cells of VIP, are, however, not understood. We therefore employed intersectional genetics to manipulate the cell-autonomous TTFL of VPAC2-expressing cells. Measuring circadian behavioural and SCN rhythmicity in these temporally chimaeric male mice thus enabled us to determine the contribution of VPAC2-expressing cells (35% of SCN cells) to SCN time-keeping. Lengthening of the intrinsic TTFL period of VPAC2 cells by deletion of the CK1epsilonTau allele concomitantly lengthened the period of circadian behavioural rhythms. It also increased the variability of the circadian period of bioluminescent TTFL rhythms in SCN slices recorded ex vivo Abrogation of circadian competence in VPAC2 cells by deletion of Bmal1 severely disrupted circadian behavioural rhythms and compromised TTFL time-keeping in the corresponding SCN slices. Thus, VPAC2-expressing cells are a distinct, functionally powerful subset of the SCN circuit, contributing to computation of ensemble period and maintenance of circadian robustness. These findings extend our understanding of SCN circuit topology.SIGNIFICANCE STATEMENTCircadian (daily) rhythms govern our lives. They are co-ordinated by the brain's central clock, the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN works so well because of powerful interactions between its 20,000 cells. But SCN cells are very heterogeneous, and the specific time-keeping contributions of particular sub-groups are unknown. Using mice, we genetically manipulated the clock of cells expressing VPAC2, the receptor for an important SCN neuropeptide: VIP. Slowing down VPAC2 cellular clocks slowed down mouse behavioural rhythms. Stopping the clock of VPAC2 cells disrupted circadian behaviour and SCN rhythms. These findings extend the understanding of SCN circuitry by showing that VPAC2-expressing cells are a distinct, functionally powerful component of the SCN circuit, governing its period and robustness.
View details for DOI 10.1523/JNEUROSCI.2015-20.2020
View details for PubMedID 33234609
The hypothalamic suprachiasmatic nuclei (SCN) are the principal mammalian circadian timekeeper, co-ordinating organism-wide daily and seasonal rhythms. To achieve this, cell-autonomous circadian timing by the ~20,000 SCN cells is welded into a tight circuit-wide ensemble oscillation. This creates essential, network-level emergent properties of precise, high-amplitude oscillation with tightly defined ensemble period and phase. Although synchronised, regional cell groups exhibit differentially phased activity, creating stereotypical spatiotemporal circadian waves of cellular activation across the circuit. The cellular circuit pacemaking components that generate these critical emergent properties are unknown. Using intersectional genetics and real-time imaging, we show that SCN cells expressing vasoactive intestinal polypeptide (VIP) or its cognate receptor, VPAC2, are neurochemically and electrophysiologically distinct, but together they control de novo rhythmicity, setting ensemble period and phase with circuit-level spatiotemporal complexity. The VIP/VPAC2 cellular axis is therefore a neurochemically and topologically specific pacemaker hub that determines the emergent properties of the SCN timekeeper.
View details for DOI 10.1038/s41467-020-17110-x
View details for PubMedID 32636383
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
The suprachiasmatic nucleus (SCN) is the master circadian clock controlling daily behavior in mammals. It consists of a heterogeneous network of neurons, in which cell-autonomous molecular feedback loops determine the period and amplitude of circadian oscillations of individual cells. In contrast, circuit-level properties of coherence, synchrony, and ensemble period are determined by intercellular signals and are embodied in a circadian wave of gene expression that progresses daily across the SCN. How cell-autonomous and circuit-level mechanisms interact in timekeeping is poorly understood. To explore this interaction, we used intersectional genetics to create temporally chimeric mice with SCN containing dopamine 1a receptor (Drd1a) cells with an intrinsic period of 24 h alongside non-Drd1a cells with 20-h clocks. Recording of circadian behavior in vivo alongside cellular molecular pacemaking in SCN slices in vitro demonstrated that such chimeric circuits form robust and resilient circadian clocks. It also showed that the computation of ensemble period is nonlinear. Moreover, the chimeric circuit sustained a wave of gene expression comparable to that of nonchimeric SCN, demonstrating that this circuit-level property is independent of differences in cell-intrinsic periods. The relative dominance of 24-h Drd1a and 20-h non-Drd1a neurons in setting ensemble period could be switched by exposure to resonant or nonresonant 24-h or 20-h lighting cycles. The chimeric circuit therefore reveals unanticipated principles of circuit-level operation underlying the emergent plasticity, resilience, and robustness of the SCN clock. The spontaneous and light-driven flexibility of period observed in chimeric mice provides a new perspective on the concept of SCN pacemaker cells.
View details for DOI 10.1073/pnas.1511351113
View details for Web of Science ID 000372876400071
View details for PubMedID 26966234
View details for PubMedCentralID PMC4822582
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