Molecular neurobiology of circadian timing
Circadian rhythms are those daily cycles of physiology and behaviour that persist when organisms are isolated from the external world. They are expressed at all levels of life, from prokaryotic blue-green algae to higher plants and animals. Their biological role is to anticipate and thereby allow organisms to adapt to the solar day and night. In humans the cycle of sleep and wakefulness is the most obvious circadian rhythm, reflecting a profound alternation of brain states. Disruption of our circadian programme through shift work, old age and neurological disease is a significant and growing cause of chronic illness.
The principal circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, where individual neurons can operate as selfsustained circadian clocks. This same clock mechanism is also present in our major organ systems; heart, lungs, liver, kidney etc. The SCN maintains synchrony amongst these sub-ordinate clocks via its control over behaviour, neuroendocrine pathways and the autonomic nervous system. The genes responsible for encoding our circadian clockwork have recently been identified.
We are using real-time in vivo fluorescence and bioluminescence imaging, DNA microarrays, proteomic expression analyses and molecular genetic manipulations to understand how these "clock" genes and their protein products are able to assemble themselves into a 24h time-keeper, and how the central and peripheral timers together co-ordinate our metabolic and physiological rhythms. Through this approach we aim to provide a molecular genetic explanation for one of the most conserved and ancient forms of behaviour-circadian timing.
- Brancaccio M, Patton AP, Chesham JE, Maywood ES, Hastings MH. (2017)
Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling.
Neuron 93(6): 1420-1435. PMID: 28285822.
- Ernst RJ, Krogager TP, Maywood ES, Zanchi R, Beranek V, Elliott TS, Barry NP, Hastings MH & Chin JW. (2016)
Genetic code expansion in the mouse brain.
Nature Chemical Biology 12: 776-778.
- Patton AP, Chesham JE, Hastings MH. (2016)
Combined pharmacological and genetic manipulations unlock unprecedented temporal elasticity and reveal phase-specific modulation of the molecular circadian clock of the mouse suprachiasmatic nucleus.
Journal of Neuroscience 36: 9326-9341.
- Smyllie NJ, Pilorz V, Boyd J, Meng QJ, Saer B, Chesham JE, Maywood ES, Krogager TP, Spiller DG, Boot-Handford R, White MR, Hastings MH, Loudon AS. (2016)
Visualizing and Quantifying Intracellular Behavior and Abundance of the Core Circadian Clock Protein PERIOD2.
Current Biology 26: 1880-1886.
- Smyllie NJ, Chesham JE, Hamnett R, Maywood ES, Hastings MH. (2016)
Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus.
Proceeding of the National Academy of Sciences U S A 113(13): 3657-62.
- Edwards MD, Brancaccio M, Chesham JE, Maywood ES, Hastings MH. (2016)
Rhythmic expression of cryptochrome induces the circadian clock of arrhythmic suprachiasmatic nuclei through arginine vasopressin signaling.
Proceeding of the National Academy of Sciences U S A 113(10): 2732-7.
- Militi S, Maywood ES, Sandate CR, Chesham JE, Barnard AR, Parsons MJ, Vibert JL, Joynson GM, Partch CL, Hastings MH, Nolan PM. (2016)
Early doors (Edo) mutant mouse reveals the importance of period 2 (PER2) PAS domain structure for circadian pacemaking.
Proceeding of the National Academy of Sciences U S A 113(10): 2756-61.
- Parsons, M.J., Brancaccio. M., Sethi, S., Maywood, E.S., Satija, R., Edwards, J.K., Jagannath, A., Couch, Y., Finelli, M.J., Smyllie, N.J., Esapa, C., Butler, R., Barnard, A.R., Chesham, J.E., Saito, S., Joynson, G., Wells, S., Foster, RG., Oliver, P.L., Simon, M.N., Mallon, A-M., Hastings, M.H. and Nolan, P.M. (2015)
The regulatory factor ZFHX3 modifies circadian function in SCN via an AT motif-driven axis.
Cell 163(3): 607-621.
- Liz Maywood
- Johanna (Jo) Chesham
- Dhevahi Niranjan
- Marco Brancaccio
- Andrew Patton
- Ryan Hamnett
- Nicola Smyllie
- Emma Morris