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• Journal article
  Unosson M, Brancaccio M, Hastings M, Johansen AM, Finkenstadt Bet al., 2021,

  A spatio-temporal model to reveal oscillator phenotypes in molecular clocks: Parameter estimation elucidates circadian gene transcription dynamics in single-cells

  , PLoS Computational Biology, Vol: 17, Pages: 1-19, ISSN: 1553-734X

  We propose a stochastic distributed delay model together with a Markov random field prior and a measurement model for bioluminescence-reporting to analyse spatio-temporal gene expression in intact networks of cells. The model describes the oscillating time evolution of molecular mRNA counts through a negative transcriptional-translational feedback loop encoded in a chemical Langevin equation with a probabilistic delay distribution. The model is extended spatially by means of a multiplicative random effects model with a first order Markov random field prior distribution. Our methodology effectively separates intrinsic molecular noise, measurement noise, and extrinsic noise and phenotypic variation driving cell heterogeneity, while being amenable to parameter identification and inference. Based on the single-cell model we propose a novel computational stability analysis that allows us to infer two key characteristics, namely the robustness of the oscillations, i.e. whether the reaction network exhibits sustained or damped oscillations, and the profile of the regulation, i.e. whether the inhibition occurs over time in a more distributed versus a more direct manner, which affects the cells’ ability to phase-shift to new schedules. We show how insight into the spatio-temporal characteristics of the circadian feedback loop in the suprachiasmatic nucleus (SCN) can be gained by applying the methodology to bioluminescence-reported expression of the circadian core clock gene Cry1 across mouse SCN tissue. We find that while (almost) all SCN neurons exhibit robust cell-autonomous oscillations, the parameters that are associated with the regulatory transcription profile give rise to a spatial division of the tissue between the central region whose oscillations are resilient to perturbation in the sense that they maintain a high degree of synchronicity, and the dorsal region which appears to phase shift in a more diversified way as a response to large perturbations and thus

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• Book chapter
  Brancaccio M, Hastings M, 2021,

  Circadian Timekeeping in the Suprachiasmatic Nucleus: Genes, Neurotransmitters, Neurons, and Astrocytes.

  , Neuroendocrine Clocks and Calendars, Publisher: Springer Nature, ISBN: 9783030556433

  This book explores how daily and seasonal rhythmicity is generated, how these rhythms are synchronised by our environment, and how they regulate the neuroendocrine systems that impact our physiology and behaviour.

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• Book
  Brancaccio M, 2021,

  Preface

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• Book
  , 2021,

  Circadian Clock in Brain Health and Disease

  , Publisher: Springer International Publishing, ISBN: 9783030811464
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• Journal article
  Brancaccio M, Wolfes AC, Ness N, 2021,

  Astrocyte Circadian Timekeeping in Brain Health and Neurodegeneration

  , CIRCADIAN CLOCK IN BRAIN HEALTH AND DISEASE, Vol: 1344, Pages: 87-110, ISSN: 0065-2598
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  • Citations: 4
• Journal article
  Patton AP, Edwards MD, Smyllie NJ, Hamnett R, Chesham JE, Brancaccio M, Maywood ES, Hastings MHet al., 2020,

  The VIP-VPAC2 neuropeptidergic axis is a cellular pacemaking hub of the suprachiasmatic nucleus circadian circuit

  , NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
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  • Citations: 31
• Journal article
  Calderazzo S, Brancaccio M, Finkenstadt B, 2019,

  Filtering and inference for stochastic oscillators with distributed delays

  , Bioinformatics, Vol: 35, Pages: 1380-1387, ISSN: 1367-4803

  MotivationThe time evolution of molecular species involved in biochemical reaction networks often arises from complex stochastic processes involving many species and reaction events. Inference for such systems is profoundly challenged by the relative sparseness of experimental data, as measurements are often limited to a small subset of the participating species measured at discrete time points. The need for model reduction can be realistically achieved for oscillatory dynamics resulting from negative translational and transcriptional feedback loops by the introduction of probabilistic time-delays. Although this approach yields a simplified model, inference is challenging and subject to ongoing research. The linear noise approximation (LNA) has recently been proposed to address such systems in stochastic form and will be exploited here.ResultsWe develop a novel filtering approach for the LNA in stochastic systems with distributed delays, which allows the parameter values and unobserved states of a stochastic negative feedback model to be inferred from univariate time-series data. The performance of the methods is tested for simulated data. Results are obtained for real data when the model is fitted to imaging data on Cry1, a key gene involved in the mammalian central circadian clock, observed via a luciferase reporter construct in a mouse suprachiasmatic nucleus.Availability and implementationProgrammes are written in MATLAB and Statistics Toolbox Release 2016 b, The MathWorks, Inc., Natick, Massachusetts, USA. Sample code and Cry1 data are available on GitHub https://github.com/scalderazzo/FLNADD.

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• Journal article
  Hastings MH, Maywood ES, Brancaccio M, 2019,

  The mammalian circadian timing system and the suprachiasmatic nucleus as its pacemaker

  , Biology, Vol: 8, ISSN: 2079-7737

  The past twenty years have witnessed the most remarkable breakthroughs in our understanding of the molecular and cellular mechanisms that underpin circadian (approximately one day) time-keeping. Across model organisms in diverse taxa: cyanobacteria (Synechococcus), fungi (Neurospora), higher plants (Arabidopsis), insects (Drosophila) and mammals (mouse and humans), a common mechanistic motif of delayed negative feedback has emerged as the Deus exmachina for the cellular definition of ca. 24 h cycles. This review will consider, briefly, comparative circadian clock biology and will then focus on the mammalian circadian system, considering its molecular genetic basis, the properties of the suprachiasmatic nucleus (SCN) as the principal circadian clock in mammals and its role in synchronising a distributed peripheral circadian clock network. Finally, it will consider new directions in analysing the cell-autonomous and circuit-level SCN clockwork and will highlight the surprising discovery of a central role for SCN astrocytes as well as SCN neurons in controlling circadian behaviour.

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• Journal article
  Brancaccio M, Edwards MD, Patton AP, Smyllie NJ, Chesham JE, Maywood ES, Hastings MHet al., 2019,

  Cell-autonomous clock of astrocytes drives circadian behavior in mammals

  , Science, Vol: 363, Pages: 187-192, ISSN: 0036-8075

  Circadian (~24-hour) rhythms depend on intracellular transcription-translation negative feedback loops (TTFLs). How these self-sustained cellular clocks achieve multicellular integration and thereby direct daily rhythms of behavior in animals is largely obscure. The suprachiasmatic nucleus (SCN) is the fulcrum of this pathway from gene to cell to circuit to behavior in mammals. We describe cell type–specific, functionally distinct TTFLs in neurons and astrocytes of the SCN and show that, in the absence of other cellular clocks, the cell-autonomous astrocytic TTFL alone can drive molecular oscillations in the SCN and circadian behavior in mice. Astrocytic clocks achieve this by reinstating clock gene expression and circadian function of SCN neurons via glutamatergic signals. Our results demonstrate that astrocytes can autonomously initiate and sustain complex mammalian behavior.

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• Journal article
  Maywood ES, Elliott TS, Patton AP, Krogager TP, Chesham JE, Ernst RJ, Beranek V, Brancaccio M, Chin JW, Hastings MHet al., 2018,

  Translational switching of Cry1 protein expression confers reversible control of circadian behavior in arrhythmic Cry-deficient mice

  , Proceedings of the National Academy of Sciences of the United States of America, Vol: 115, Pages: E12388-E12397, ISSN: 0027-8424

  The suprachiasmatic nucleus (SCN) is the principal circadian clock of mammals, coordinating daily rhythms of physiology and behavior. Circadian timing pivots around self-sustaining transcriptional–translational negative feedback loops (TTFLs), whereby CLOCK and BMAL1 drive the expression of the negative regulators Period and Cryptochrome (Cry). Global deletion of Cry1 and Cry2 disables the TTFL, resulting in arrhythmicity in downstream behaviors. We used this highly tractable biology to further develop genetic code expansion (GCE) as a translational switch to achieve reversible control of a biologically relevant protein, Cry1, in the SCN. This employed an orthogonal aminoacyl-tRNA synthetase/tRNACUA pair delivered to the SCN by adeno-associated virus (AAV) vectors, allowing incorporation of a noncanonical amino acid (ncAA) into AAV-encoded Cry1 protein carrying an ectopic amber stop codon. Thus, translational readthrough and Cry1 expression were conditional on the supply of ncAA via culture medium or drinking water and were restricted to neurons by synapsin-dependent expression of aminoacyl tRNA-synthetase. Activation of Cry1 translation by ncAA in neurons of arrhythmic Cry-null SCN slices immediately and dose-dependently initiated TTFL circadian rhythms, which dissipated rapidly after ncAA withdrawal. Moreover, genetic activation of the TTFL in SCN neurons rapidly and reversibly initiated circadian behavior in otherwise arrhythmic Cry-null mice, with rhythm amplitude being determined by the number of transduced SCN neurons. Thus, Cry1 does not specify the development of circadian circuitry and competence but is essential for its labile and rapidly reversible activation. This demonstrates reversible control of mammalian behavior using GCE-based translational switching, a method of potentially broad neurobiological interest.

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