Michael Hastings

Circadian clock circuits in the mammalian brain and Molecular genetic analysis of the neurobiology of tidal clocks in a marine crustacean
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Project 1: Circadian clock circuits in the mammalian brain.

Our lives are built around daily (circadian) cycles of behaviour and metabolism, the rhythm of sleep and wakefulness being the most pervasive. Well ordered circadian rhythms and sleep are a pre-requisite for both physical and mental health, such that disturbances of them are associated with many forms of illness, both metabolic (e.g. obesity and diabetes) and psychiatric (e.g. depression and schizophrenia).

The principal co-ordinator of circadian rhythms is the suprachiasmatic nucleus (SCN) of the hypothalamus: this is the dominant circadian clock of the brain, using a molecular genetic feedback loop that can define approx. 24h cycles indefinitely. But how does this cluster of 10,000 clock neurons send out timing signals to control the rest of the brain and body? This project will apply state-of-the-art neural reconstruction high-volume microscopy and virally based methods to track, reconstruct and then genetically manipulate circuits that convey SCN time signals to brain regions involved in circadian physiology and behaviour. It will exploit both in vivo (behavioural, physiological) and in vitro (organotypic brain slice techniques) approaches using genetically modified mice, including lines carrying constitutive and conditional, circadian and neurochemical genetic mutations, combined with bioluminescent and fluorescent imaging and optogenetic and chemogenetic manipulation alongside genetic code expansion to control circadian protein expression by translational switching.

The project will provide a sound training in systems and molecular neuroscience.  The successful candidate will work within a multidisciplinary research group with a strong international reputation in circadian clock neurobiology, and will also enjoy productive interactions with other research groups in the Neurobiology Division and wider LMB.

Recent first-author papers from previous graduate students of Hastings group:

  • Edwards et al. PNAS (2016).
  • Smyllie et al. PNAS (2016)
  • Smyllie et al. Current Biology (2016).

References

Patton AP, Hastings MH. (2018)
The suprachiasmatic nucleus.
Current Biology 28(15):R816-R822. doi: 10.1016/j.cub.2018.06.052. PMID:  30086310.

Hastings MH, Maywood ES, Brancaccio M. (2018)
Generation of circadian rhythms in the suprachiasmatic nucleus.
Nature Reviews Neuroscience 19(8):453-469. doi: 10.1038/s41583-018-0026-z. PMID:  29934559.

Krogager TP, Ernst RJ, Elliott TS, Calo L, Beránek V, Ciabatti E, Spillantini MG, Tripodi M, Hastings MH, Chin JW. (2018)
Labeling and identifying cell-specific proteomes in the mouse brain.
Nature Biotechnology 36(2):156-159. doi: 10.1038/nbt.4056. Epub 2017 Dec 18. PMID: 29251727.

Brancaccio M, Patton AP, Chesham JE, Maywood ES, Hastings MH. (2017)
Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling.
Neuron 93: 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. PMID: 27571478.


Project 2: Molecular genetic analysis of the neurobiology of tidal clocks in a marine crustacean.

Circadian (24 hour) body clocks are conserved amongst terrestrial organisms, adapting them to the daily solar cycle. A greater diversity and abundance of life, however, inhabits environments varying over tidal/lunar time. Work by our group and others has established a molecular/genetic paradigm for circadian timing, conserved across diverse taxa, involving delayed negative feedback by circadian proteins on expression of the circadian “clock genes” encoding them. In contrast, absolutely nothing is known of the molecular neurobiology of tidal clocks and the behavioural rhythms they drive. This rich neurobiological problem is virgin territory. We shall investigate tidal timing in the isopod crustacean Eurydice pulchra. An inhabitant of UK beaches, it emerges from the sand to feed on flood tides and re-burrows before the ebb carries it away. In the laboratory under constant environmental conditions, it exhibits beautiful circa-tidal activity cycles, with a period ranging between 11.5 and 13.5 hours. Activity is coincident with the predicted high water on the home beach and can be shifted by vibration (mimicking wave action). The underlying molecular neurobiology of this exquisitely precise behaviour is unknown.

This project will utilise sequencing and genomic analyses, homology cloning, RNAseq, behavioural analyses, protein expression and neurobiological analyses of Eurydice nervous system to characterise the molecular genetics behind this elusive clock. The Applicant will be well supported by resources and expertise of LMB and also by ongoing collaborations with Marine Biology groups (Webster, Wilcockson) and Drosophila neurogeneticists (Kyriacou). Candidates should have competence and interest in molecular genetics and neurobiology, including PCR, DNA cloning, genomic sequence analysis, immunohistochemistry and in situ hybridisation. We shall identify tidal genes and then examine their functions in cell culture and in vivo. Is the tidal clock a shorter cycle equivalent of the circadian feedback loop or is it something more exotic?  Our recently published work (see below) suggests that the tidal clock is altogether something different.

Recent first-author papers from previous PhD students in Hastings group:

  • Edwards et al. PNAS (2016).
  • Smyllie et al. PNAS (2016).
  • Smyllie et al. Current Biology (2016).

References

O’Neill JS, Lee KD, Zhang L, Feeney K, Webster SG, Blades MJ, Kyriacou CP, Hastings MH, Wilcockson DC. (2015)
Metabolic molecular markers of the tidal clock in the marine crustacean Eurydice pulchra.
Current Biology 25:(8):R326-7.  PMID: 25898100.

Zhang L, Hastings MH, Green EW, Tauber E, Sladek M, Webster SG, Kyriacou CP, Wilcockson DC. (2013)
Dissociation of Circadian and Circatidal Timekeeping in the Marine Crustacean Eurydice pulchra.
Current Biology 23(19):1863-73.  PMID: 24076244.

Wilcockson D & Zhang L (2008)
Circatidal clocks.
Current Biology 18: R753 - R755.

Hastings MH. (1981)
The entraining effect of turbulence on the circa-tidal activity rhythm and its semi-lunar modulation in Eurydice pulchra.
Journal of the marine biological Association, U.K.  61: 151-160.