The Mouse Sleep & Circadian Clinic Lausanne, University of Lausanne

Center for Integrative Genomics

Contact:
Paul Franken
Position:
M.E.R.-1 (Assistant Professor)
Address:
Genopode building, 1015
City:
Lausanne
Country:
Switzerland
Phone:
+41 21 692 3972
Fax:
+41 21 692 3965
Contact E-mail:
Research Domain
  • Basic Animal
Keywords
  • Genetics of Sleep
  • Pharmacology of Sleep
  • Sleep and Ageing
  • Sleep and Body Functions (Cardio-Respiratory, Thermoregulation/Metabolism, Endocrine)
  • Sleep Physiology-Neurophysiology in Animal
  • Light and Non-Classical Photoreception
  • Biological Rhythms

Laboratory description

We study the interaction between the two main processes that regulate sleep; i.e., homeostasis and circadian rhythms, at the behavioral, electrophysiological, molecular, and genetic levels. To gain inside into the molecular correlates of the homeostatic process and its interaction with the circadian process we combine forward, molecular, and reverse genetic approaches in the mouse. As a forward genetics approach we use QTL mapping in Recombinant Inbred strains and GWAS in outbred mice. To facilitate sleep phenotyping of large numbers of mice we helped develop and validate a novel non-invasive and high throughput method. For molecular genetic approaches we use transcriptome profiling of mRNA and micro-RNA transcripts in the brain under baseline and sleep deprivation conditions, in adrenalectomized mice, and after pharmacologically induced waking in various inbred strains of mice. Reverse genetic approaches are used in another line of research, which concerns our discovery that circadian clock genes not only keep track of time-of-day but also of time-spent-awake. We now investigate the mechanisms by which clock genes affect sleep homeostasis. The observation that the DNA binding of CLOCK, BMAL1, and NPAS2 both depends on intracellular energy charge and prior sleep-wake history is an exciting clue we are investigating using in vivo imaging techniques.

We use mathematical modeling approaches to quantify the complex non-linear relationship between changes in clock gene expression in the forebrain, sleep need, and the sleep-wake distribution.


Technical Capabilities and areas of expertise

Circadian rhythms, Sleep homeostasis, Metabolism, Clock genes, EEG, Locomotor activity, Temperature regulation, Mathematical modelling, Quantitative Genetics, In vivo and in vitro bio-luminescence and fluorescence imaging, Transcriptome profiling (mRNA, miRNA), DNA-binding (ChIP), GWAS.


Selected Publications in the 5 past years:

Cueni, Canepari, Emmenegger, Watanabe, Bond, Franken, Adelman, Lüthi (2008) T-type Ca2+ channels, SK2 channels and SERCAs gate sleep-related oscillations in thalamic dendrites. Nature Neurosci 11: 683-92
Wisor, Pasumarthi, Gerashchenko, Thompson, Pathak, Sancar, Franken, Lein, Kilduff (2008) Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel EEG differences among mouse strains. J Neurosci 28: 7193-201
Andretic, Franken, Tafti (2008) Genetics of Sleep. Annu Rev of Genet 42: 361-88
Franken*, Langmesser*, Feil, Emmenegger, Albrecht, Feil (2009) cGMP-dependent protein kinase type I is implicated in the regulation of the timing and quality of sleep and wakefulness. PLoS ONE 4: e4238
Hasan, Pradervand, Ahnaou, Drinkenburg, Tafti, Franken (2009) How to keep the brain awake? The complex molecular pharmacogenetics of wake promotion. Neuropsychpharmacology 34: 1625-40
Franken, Dijk (2009) Circadian clock genes and sleep homeostasis. Eur J Neurosci 29: 1820-9
Tsai, Hannibal, Hagiwara, Colas, Ruppert, Ruby, Heller, Bourgin*, Franken* (2009) Melanopsin as a sleep modulator: circadian gating of the direct effects of light on sleep and altered sleep homeostasis in Opn4−/− mice. PLoS Biol 7: e1000125
Mongrain, Hernandez, Pradervand, Dorsaz, Curie, Hagiawara, Gip, Heller, Franken (2010) Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis. Sleep 33: 1147-57
Vienne, Bettler, Tafti*, Franken* (2010) Differential effects of GABAB receptor subtypes, gamma-hydroxybutyric acid, and baclofen on EEG activity and sleep regulation. J Neurosci 30:14194-204
Astori, Wimmer, Prosser, Corti, Corsi, Liaudet, Volterra, Franken, Adelman, Lüthi (2011) The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus. PNAS 108:13823-8
Mongrain, La Spada, Curie, Franken (2011) Sleep Loss Reduces the DNA-Binding of BMAL1, CLOCK, and NPAS2 to Specific Clock Genes in the Mouse Cerebral Cortex. PLoS One 6: e26622
Hasan, Dauvilliers, Mongrain, Franken, Tafti (2012) Age-related changes in sleep in inbred mice are genotype dependent. Neurobiol Aging 33: 195.e13-26.
Mang, Franken (2012) Sleep and EEG Phenotyping in Mice. Curr Protoc Mouse Biol 2: 54-74
Vienne, Lecciso, Constantinescu, Schwartz, Franken, Heinzer, Tafti (2012) Differential effects of sodium oxybate and baclofen on EEG, sleep, neurobehavioral performance, and memory. Sleep 35: 1071-83
Hinard, Mikhail, Pradervand, Curie, Houtkooper, Auwerx, Franken, Tafti (2012) Sleep in a dish: key electrophysiological, molecular, and metabolic signatures of sleep and wakefulness revealed in primary cortical cultures. J Neurosci 32: 12506-17.
Wimmer, Astoria, Bond, Rovó, Chatton, Adelman, Franken, Lüthi (2012) Consolidation of sleep by strengthening thalamic rhythms through SK2 channel over-expression. J Neurosci. 32: 13917-28.
Gast, Müller, Lopez, Huber, Franken, Birchler, Fontana (2012) Anti-TNFα treatment blocks CD40-induced NREM sleep in a mouse model of sickness behavior syndrome. Brain Behav Immun S0889-1591(12)00466-7. 10.1016/j.bbi.2012.10.004.
Curie, Mongrain, Dorsaz, Mang, Emmenegger, Franken (2012) Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation. Sleep (in press)


Key Publications of the Laboratory:

Franken, Dijk, Tobler, Borbély (1991) Sleep deprivation in rats: effects on EEG spectra, vigilance states, and cortical temperature, Am J Physiol 261: R198-208
Franken, Chollet, Tafti (2001) The homeostatic regulation of sleep need is under genetic control. J Neurosci 21: 2610-21
Ruby, Brennan, Xie, Cao, Franken, Heller, O’Hara (2002) The role of melanopsin in circadian responses to light. Science 298: 2211-3
Wisor, O’Hara, Terao, Selby, Kilduff, Sancar, Edgar, Franken (2002) A role for cryptochromes in sleep regulation. BMC Neurosci 3: 20
Dudley, Erbel-Sieler, Estill, Reick, Franken, Pitts, McKnight (2003) Altered Patterns of Sleep, Activity and Behavioral Adaptability in NPAS2-Deficient Mice. Science 301: 379-83
Tafti, Petit, Chollet, Neidhart, de Bilabao, Kiss, Wood, Franken (2003) Deficiency in short-chain fatty acid β-oxidation affects theta oscillations during sleep. Nature Genetics: 34: 320-5
Maret, Franken, Dauvilliers, Ghyselinck, Chambon, Tafti (2005) Retinoic acid signaling affects cortical synchrony during sleep. Science 310: 111-3
Franken, Dudley, Estill, Barakat, Thomason, O’Hara, McKnight (2006) The transcription factor NPAS2 affects the regulation and EEG of non-REM sleep: genotype and sex interactions. PNAS 103: 7118-23
Maret, Dorsaz, Gurcel, Pradervand, Petit, Pfister, Hagenbuchle, O’Hara, Franken, Tafti (2007) Homer1a is a core brain molecular correlate of sleep loss. PNAS 104: 20090-5
Cueni, Canepari, Emmenegger, Watanabe, Bond, Franken, Adelman, Lüthi (2008) T-type Ca2+ channels, SK2 channels and SERCAs gate sleep-related oscillations in thalamic dendrites. Nature Neurosci 11: 683-92
Andretic, Franken, Tafti (2008) Genetics of Sleep. Annu Rev of Genet 42: 361-88
Franken, Dijk (2009) Circadian clock genes and sleep homeostasis. Eur J Neurosci 29: 1820-9
Tsai, Hannibal, Hagiwara, Colas, Ruppert, Ruby, Heller, Bourgin*, Franken* (2009) Melanopsin as a sleep modulator: circadian gating of the direct effects of light on sleep and altered sleep homeostasis in Opn4−/− mice. PLoS Biol 7: e1000125
Mongrain, Hernandez, Pradervand, Dorsaz, Curie, Hagiawara, Gip, Heller, Franken (2010) Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis. Sleep 33: 1147-57
Curie, Mongrain, Dorsaz, Mang, Emmenegger, Franken (2012) Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation. Sleep (in press)


Current/Completed Grants (past 5 years):

2004 -2008 Research grant of the National Institutes of Health (MH067752), ‘Non-circadian role for clock-genes in sleep homeostasis’ (PI); 4 years; US$ 1’700’000
2006 -2009 Research grant of the Swiss National Science Foundation (111974), ‘Redox-potential at the interface between sleep homeostasis and circadian rhythmicity’ (PI); 3 years; CHF 377’000
2006 – 2009 Eumorphia Secondary phenotyping (co-PI); 3 years
2008 – 2009 Novartis Research Fellowship, for Thomas Curie, post-doc, 1-year salary (PI)
2009 – 2011 Marie Curie IEF Fellowship, for Thomas Curie, post-doc, 2-year salary (PI)
2009 – 2012 Research grant of the Swiss National Science Foundation (125323), ‘Mice with conditional knockouts of orexin receptors in specific neuronal populations involved in the regulation of sleep and arousal’ (co-PI); 3 years; CHF 370’000
2010 – 2013 Research grant of the Swiss National Science Foundation (130825), ‘Sleep homeostasis, clock-genes, and glucocorticoid signaling’ (PI); 3 years; CHF 375’000
2011 – 2014 Sinergia grant of the Swiss National Science Foundation (136201), ‘A systems genetics approach towards identification of metabolic pathways controlling glycemia, sleep, and aging’ (PI and coordinator; Thorens UNIL, Auwerx EPFL, Xenarios SIB/Vital-IT); 3 years; CHF 1’600’000
2012 – 2014 Educational grant of the Swiss National Science Foundation (CRAGI2_139936), Agora ‘State of the Art – Science and Art in Practice’ (co-PI); 2 years; CHF 100’000
2012 – 2015 Research grant of the Swiss National Science Foundation (144282), ‘Genetic dissection of orexin signaling in neuronal networks involved in the regulation of the waking state and goal-directed behaviors’ (co-PI); 3 years; CHF 411’600


Other laboratory Members

Title:  MSc

Name:  Shanaz Diessler

Position:  Ph.D. student

Email:  Shanaz.Diessler at unil.ch

Name:  Yann Emmenegger

Position:  murine sleep technologist

Email:  Yann.Emmenegger at unil.ch

Title:  MSc

Name:  Ralf Wimmer

Position:  Ph.D. student

Email:  Ralf.Wimmer at unil.ch

Title:  PhD

Name:  Thomas Curie

Position:  Post-doctoral fellow

Email:  Thomas.Curie at unil.ch

Title:  MSc

Name:  Francesco La Spada

Position:  Ph.D. student

Email:  Francesco.LaSpada at unil.ch

Title:  MSc

Name:  Géraldine Morgane Mang

Position:  Ph.D. student

Email:  geraldine.mang at unil.ch


Collaborations

Title:  PhD MD

Name:  Bo Gao

Position:  Research Associate

Institution:  Inselspital Bern

Title:  PhD

Name:  Valérie Mongrain

Position:  Professor

Institution:  University of Montreal

Title:  PhD

Name:  Bruce O'Hara

Position:  Professor

Institution:  University of Kentucky

Title:  PhD MD

Name:  Johan Auwerx

Position:  Profesor

Institution:  EPFL (ETH Lausanne)

Title:  PhD

Name:  Ioannis Xenarios

Position:  Professor

Institution:  Swiss Institute of Bioinformatics

Title:  PhD

Name:  Bernard Thorens

Position:  Professor

Institution:  University of Lausanne

Title:  PhD

Name:  Anne Vassalli

Position:  Research Associate

Institution:  University of Lausanne

Title:  PhD MD

Name:  Jonathan Flint

Position:  Professor

Institution:  University of Oxford

Title:  PhD

Name:  Patrice Bourgin

Position:  Professor

Institution:  University of Strasbourg

Title:  PhD

Name:  Jérôme Nicod

Position:  Post-doctoral fellow

Institution:  University of Oxford

Title:  PhD

Name:  Ueli Schibler

Position:  Professor

Institution:  University of Geneva

Title:  PhD

Name:  Mehdi Tafti

Position:  Professor

Institution:  University of Lausanne

Title:  MD

Name:  Adriano Fontana

Position:  Professor

Institution:  University of Zürich

Title:  PhD

Name:  Urs Albrecht

Position:  Professor

Institution:  University of Fribourg


Past Members

Title:  PhD

Name:  Stephanie Maret

Position:  Senior Post-doctoral fellow

Email:  stephaniemaret at yahoo.com

Title:  PhD

Name:  Valérie Mongrain

Position:  Assistant Professor

Email:  valerie.mongrain at umontreal.ca

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