Imperial College London

DrMarcoBrancaccio

Faculty of MedicineDepartment of Brain Sciences

Lecturer in Dementia Research, UK DRI Group Leader
 
 
 
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Contact

 

+44 (0)20 7594 7907m.brancaccio

 
 
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Location

 

E517Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

23 results found

De Virgiliis F, Mueller F, Palmisano I, Chadwick JS, Luengo-Gutierrez L, Giarrizzo A, Yan Y, Danzi MC, Picon-Muñoz C, Zhou L, Kong G, Serger E, Hutson TH, Maldonado-Lasuncion I, Song Y, Scheiermann C, Brancaccio M, Di Giovanni Set al., 2023, The circadian clock time tunes axonal regeneration., Cell Metab, Vol: 35, Pages: 2153-2164.e4

Nerve injuries cause permanent neurological disability due to limited axonal regeneration. Injury-dependent and -independent mechanisms have provided important insight into neuronal regeneration, however, common denominators underpinning regeneration remain elusive. A comparative analysis of transcriptomic datasets associated with neuronal regenerative ability revealed circadian rhythms as the most significantly enriched pathway. Subsequently, we demonstrated that sensory neurons possess an endogenous clock and that their regenerative ability displays diurnal oscillations in a murine model of sciatic nerve injury. Consistently, transcriptomic analysis showed a time-of-day-dependent enrichment for processes associated with axonal regeneration and the circadian clock. Conditional deletion experiments demonstrated that Bmal1 is required for neuronal intrinsic circadian regeneration and target re-innervation. Lastly, lithium enhanced nerve regeneration in wild-type but not in clock-deficient mice. Together, these findings demonstrate that the molecular clock fine-tunes the regenerative ability of sensory neurons and propose compounds affecting clock pathways as a novel approach to nerve repair.

Journal article

Hastings MH, Brancaccio M, Gonzalez-Aponte MF, Herzog EDet al., 2023, Circadian rhythms and astrocytes: the good, the bad, and the ugly., Annual Review of Neuroscience, Vol: 46, Pages: 123-143, ISSN: 1545-4126

This review explores the interface between circadian timekeeping and the regulation of brain function by astrocytes. Although astrocytes regulate neuronal activity across many time domains, their cell-autonomous circadian clocks exert a particular role in controlling longer-term oscillations of brain function: the maintenance of sleep states and the circadian ordering of sleep and wakefulness. This is most evident in the central circadian pacemaker, the suprachiasmatic nucleus, where the molecular clock of astrocytes suffices to drive daily cycles of neuronal activity and behavior. In Alzheimer's disease, sleep impairments accompany cognitive decline. In mouse models of the disease, circadian disturbances accelerate astroglial activation and other brain pathologies, suggesting that daily functions in astrocytes protect neuronal homeostasis. In brain cancer, treatment in the morning has been associated with prolonged survival, and gliomas have daily rhythms in gene expression and drug sensitivity. Thus, circadian time is fast becoming critical to elucidating reciprocal astrocytic-neuronal interactions in health and disease. Expected final online publication date for the Annual Review of Neuroscience, Volume 46 is July 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Journal article

Brancaccio M, 2022, Glia-neuron interplay drivescircadian glycosphingolipid homeostasisand structural brain plasticity, NEURON, Vol: 110, Pages: 3058-3060, ISSN: 0896-6273

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

Journal article

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.

Book chapter

Brancaccio M, 2021, Preface

Book

, 2021, Circadian Clock in Brain Health and Disease, Publisher: Springer International Publishing, ISBN: 9783030811464

Book

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

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

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.

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.

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.

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.

Journal article

Hastings MH, Maywood ES, Brancaccio M, 2018, Generation of circadian rhythms in the suprachiasmatic nucleus, NATURE REVIEWS NEUROSCIENCE, Vol: 19, Pages: 453-469, ISSN: 1471-003X

Journal article

Brancaccio M, Patton AP, Chesham JE, Maywood ES, Hastings MHet al., 2017, Astrocytes control circadian timekeeping in the suprachiasmatic nucleus via glutamatergic signaling, Neuron, Vol: 93, Pages: 1420-1435.e5, ISSN: 0896-6273

The suprachiasmatic nucleus (SCN) of the hypothalamus orchestrates daily rhythms of physiology and behavior in mammals. Its circadian (∼24 hr) oscillations of gene expression and electrical activity are generated intrinsically and can persist indefinitely in temporal isolation. This robust and resilient timekeeping is generally regarded as a product of the intrinsic connectivity of its neurons. Here we show that neurons constitute only one “half” of the SCN clock, the one metabolically active during circadian daytime. In contrast, SCN astrocytes are active during circadian nighttime, when they suppress the activity of SCN neurons by regulating extracellular glutamate levels. This glutamatergic gliotransmission is sensed by neurons of the dorsal SCN via specific pre-synaptic NMDA receptor assemblies containing NR2C subunits. Remarkably, somatic genetic re-programming of intracellular clocks in SCN astrocytes was capable of remodeling circadian behavioral rhythms in adult mice. Thus, SCN circuit-level timekeeping arises from interdependent and mutually supportive astrocytic-neuronal signaling.

Journal article

Feeney KA, Putker M, Brancaccio M, O'Neill JSet al., 2016, In-depth characterization of firefly luciferase as a reporter of circadian gene expression in mammalian cells, Journal of Biological Rhythms, Vol: 31, Pages: 540-550, ISSN: 0748-7304

Firefly luciferase (Fluc) is frequently used to report circadian gene expression rhythms in mammalian cells and tissues. During longitudinal assays it is generally assumed that enzymatic substrates are in saturating excess, such that total bioluminescence is directly proportional to Fluc protein level. To test this assumption, we compared the enzyme kinetics of purified luciferase with its activity in mammalian cells. We found that Fluc activity in solution has a lower Michaelis constant (Km) for luciferin, lower temperature dependence, and lower catalytic half-life than Fluc in cells. In consequence, extracellular luciferin concentration significantly affects the apparent circadian amplitude and phase of the widely used PER2::LUC reporter in cultured fibroblasts, but not in SCN, and we suggest that this arises from differences in plasma membrane luciferin transporter activity. We found that at very high concentrations (>1 mM), luciferin lengthens circadian period, in both fibroblasts and organotypic SCN slices. We conclude that the amplitude and phase of circadian gene expression inferred from bioluminescence recordings should be treated with some caution, and we suggest that optimal luciferin concentration should be determined empirically for each luciferase reporter and cell type.

Journal article

Edwards MD, Brancaccio M, Chesham JE, Maywood ES, Hastings MHet al., 2016, Rhythmic expression of cryptochrome induces the circadian clock of arrhythmic suprachiasmatic nuclei through arginine vasopressin signaling, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 2732-2737, ISSN: 0027-8424

Circadian rhythms in mammals are coordinated by the suprachiasmatic nucleus (SCN). SCN neurons define circadian time using transcriptional/posttranslational feedback loops (TTFL) in which expression of Cryptochrome (Cry) and Period (Per) genes is inhibited by their protein products. Loss of Cry1 and Cry2 stops the SCN clock, whereas individual deletions accelerate and decelerate it, respectively. At the circuit level, neuronal interactions synchronize cellular TTFLs, creating a spatiotemporal wave of gene expression across the SCN that is lost in Cry1/2-deficient SCN. To interrogate the properties of CRY proteins required for circadian function, we expressed CRY in SCN of Cry-deficient mice using adeno-associated virus (AAV). Expression of CRY1::EGFP or CRY2::EGFP under a minimal Cry1 promoter was circadian and rapidly induced PER2-dependent bioluminescence rhythms in previously arrhythmic Cry1/2-deficient SCN, with periods appropriate to each isoform. CRY1::EGFP appropriately lengthened the behavioral period in Cry1-deficient mice. Thus, determination of specific circadian periods reflects properties of the respective proteins, independently of their phase of expression. Phase of CRY1::EGFP expression was critical, however, because constitutive or phase-delayed promoters failed to sustain coherent rhythms. At the circuit level, CRY1::EGFP induced the spatiotemporal wave of PER2 expression in Cry1/2-deficient SCN. This was dependent on the neuropeptide arginine vasopressin (AVP) because it was prevented by pharmacological blockade of AVP receptors. Thus, our genetic complementation assay reveals acute, protein-specific induction of cell-autonomous and network-level circadian rhythmicity in SCN never previously exposed to CRY. Specifically, Cry expression must be circadian and appropriately phased to support rhythms, and AVP receptor signaling is required to impose circuit-level circadian function.

Journal article

Parsons MJ, Brancaccio M, Sethi S, Maywood ES, Satija R, Edwards JK, Jagannath A, Couch Y, Finelli MJ, Smyllie NJ, Esapa C, Butler R, Barnard AR, Chesham JE, Saito S, Joynson G, Wells S, Foster RG, Oliver PL, Simon MM, Mallon A-M, Hastings MH, Nolan PMet al., 2015, The regulatory factor ZFHX3 modifies circadian function in SCN via an AT motif-driven axis, Cell, Vol: 162, Pages: 607-621, ISSN: 0092-8674

We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3Sci), which accelerates circadian locomotor rhythms in mice. ZFHX3 regulates transcription via direct interaction with predicted AT motifs in target genes. The mutant protein has a decreased ability to activate consensus AT motifs in vitro. Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3Sci/+ SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed. Moreover, mutant ZFHX3 had a decreased ability to activate AT motifs in the promoters of these neuropeptide genes. Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3Sci/+ SCN slices. In conclusion, by cloning Zfhx3Sci, we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.

Journal article

Brancaccio M, Enoki R, Mazuski CN, Jones J, Evans JA, Azzi Aet al., 2014, Network-Mediated Encoding of Circadian Time: The Suprachiasmatic Nucleus (SCN) from Genes to Neurons to Circuits, and Back, JOURNAL OF NEUROSCIENCE, Vol: 34, Pages: 15192-15199, ISSN: 0270-6474

Journal article

Hastings MH, Brancaccio M, Maywood ES, 2014, Circadian pacemaking in cells and circuits of the suprachiasmatic nucleus, Journal of Neuroendocrinology, Vol: 26, Pages: 2-10, ISSN: 0953-8194

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker of the brain. It co‐ordinates the daily rhythms of sleep and wakefulness, as well as physiology and behaviour, that set the tempo to our lives. Disturbance of this daily pattern, most acutely with jet‐lag but more insidiously with rotational shift‐work, can have severely deleterious effects for mental function and long‐term health. The present review considers recent developments in our understanding of the properties of the SCN that make it a robust circadian time‐keeper. It first focuses on the intracellular transcriptional/ translational feedback loops (TTFL) that constitute the cellular clockwork of the SCN neurone. Daily timing by these loops pivots around the negative regulation of the Period (Per) and Cryptochrome (Cry) genes by their protein products. The period of the circadian cycle is set by the relative stability of Per and Cry proteins, and this can be controlled by both genetic and pharmacological interventions. It then considers the function of these feedback loops in the context of cytosolic signalling by cAMP and intracellular calcium ([Ca2+]i), which are both outputs from, and inputs to, the TTFL, as well as the critical role of vasoactive intestinal peptide (VIP) signalling in synchronising cellular clocks across the SCN. Synchronisation by VIP in the SCN is paracrine, operating over an unconventionally long time frame (i.e. 24 h) and wide spatial domain, mediated via the cytosolic pathways upstream of the TTFL. Finally, we show how intersectional pharmacogenetics can be used to control G‐protein‐coupled signalling in individual SCN neurones, and how manipulation of Gq/[Ca2+]i‐signalling in VIP neurones can re‐programme the circuit‐level encoding of circadian time. Circadian pacemaking in the SCN therefore provides an unrivalled context in which to understand how a complex, adaptive behaviour can be organised by the dynamic activity of a relatively few gene

Journal article

Maywood ES, Drynan L, Chesham JE, Edwards MD, Dardente H, Fustin J-M, Hazlerigg DG, O'Neill JS, Codner GF, Smyllie NJ, Brancaccio M, Hastings MHet al., 2013, Analysis of core circadian feedback loop in suprachiasmatic nucleus of <i>mCry1</i>-<i>luc</i> transgenic reporter mouse, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 9547-9552, ISSN: 0027-8424

Journal article

Brancaccio M, Maywood ES, Chesham JE, Loudon ASI, Hastings MHet al., 2013, A Gq-Ca<SUP>2+</SUP> Axis Controls Circuit-Level Encoding of Circadian Time in the Suprachiasmatic Nucleus, NEURON, Vol: 78, Pages: 714-728, ISSN: 0896-6273

Journal article

Brancaccio M, Pivetta C, Granzotto M, Filippis C, Mallamaci Aet al., 2010, <i>Emx2</i> and <i>Foxg1</i> Inhibit Gliogenesis and Promote Neuronogenesis, STEM CELLS, Vol: 28, Pages: 1206-1218, ISSN: 1066-5099

Journal article

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