Project

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Glutamatergic mechanisms in sleep-wake homeostasis in health and disease - molecular brain imaging and pharmacogenetics

English title Glutamatergic mechanisms in sleep-wake homeostasis in health and disease - molecular brain imaging and pharmacogenetics
Applicant Landolt Hans-Peter
Number 135414
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurology, Psychiatry
Start/End 01.05.2011 - 30.09.2015
Approved amount 415'000.00
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All Disciplines (5)

Discipline
Neurology, Psychiatry
Neurophysiology and Brain Research
Pharmacology, Pharmacy
Genetics
Clinical Pharmacology

Keywords (13)

Sleep-wake regulation; Synaptic plasticity; Homeostasis; Brain imaging (PET, 1H-MRS, fMRI); Human genetics; mGluR5; Brain-derived neurotrophic factor (BDNF); Adenosine; Idiopathic hypersomnia; Major depressive disorder; Single nucleotide polymorphism; Vigilance; Mood

Lay Summary (English)

Lead
Lay summary
receptor, and other molecular markers of synaptic plasticity, play an important role in sleep homeostasis. All these molecules interact either directly or indirectly with metabotropic glutamate receptors of subtype 5 (mGluR5). This project aims to investigate whether (1) glutamatergic mechanisms in general, and mGluR5 in particular, are critically involved in sleep homeostasis, and (2) whether abnormalities in these mechanisms are associated with reduced vigilance and depressed mood in patients with idiopathic hypersomnia (iHS) and major depressive disorder (MDD). To address these questions, 2AThe unknown functions of sleep constitute one of the remaining frontiers in modern biomedical research. According to the principle of sleep homeostasis, elevated sleep need following sleep deprivation is counteracted by prolonged sleep duration and, especially, by enhanced sleep intensity. Recent data suggest that Homer 1a, brain-derived neurotrophic factor, adenosine deaminase, adenosine AThe project is conducted in close collaboration with clinical researchers and is expected to reveal insights into the pathophysio­logy of iHS and MDD. Ultimately, these insights may lead to novel targets to treat sleep-wake related disorders and hint towards the functions of sleep.. H-MRS), functional magnetic resonance imaging (fMRI), human genetics, selective pharmacology, EEG mapping, neurobehavioral testing and mood assessments will be employed1an integrative, multi-modal approach combining positron emission tomography (PET), magnetic resonance spectroscopy (
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A case-control field study on the relationships among type 2 diabetes, sleepiness, and habitual caffeine intake
Urry Emily, Jetter Alexander, Holst Sebastian C., Berger Wolfgang, Spinas Giatgen A., Langhans Wolfgang, Landolt Hans-Peter (2017), A case-control field study on the relationships among type 2 diabetes, sleepiness, and habitual caffeine intake, in J Psychopharm, 233.
Assessment of CYP1A2 enzyme activity in relation to type-2 diabetes and habitual caffeine intake
Urry Emily, Jetter Alexander, Landolt Hans-Peter (2016), Assessment of CYP1A2 enzyme activity in relation to type-2 diabetes and habitual caffeine intake, in Nutr Metab, e66.
Caffeine, the circadian clock, and sleep
(2015), Caffeine, the circadian clock, and sleep, in Science, 349(6254), 1289-1289.
Catechol-O-methyltransferase, dopamine, and sleep-wake regulation
(2015), Catechol-O-methyltransferase, dopamine, and sleep-wake regulation, in Sleep Medicine Reviews, 22, 47-53.
Sleep homeostasis, metabolism, and adenosine
Holst Sebastian C., Landolt Hans Peter (2015), Sleep homeostasis, metabolism, and adenosine, in Current Sleep Medicine Reports, 27.
Acute and chronic effects of sleep deprivation
Landolt Hans Peter, Sousek Alexandra, Holst Sebastian C. (2014), Acute and chronic effects of sleep deprivation, in Bassetti Claudio (ed.), Wiley, Regensburg, 49.
Adenosine, caffeine, and performance: from cognitive neuroscience of sleep to sleep pharmacogenetics
(2014), Adenosine, caffeine, and performance: from cognitive neuroscience of sleep to sleep pharmacogenetics, in Current Topics in Behavioral Neurosciences, 25, 331-366.
Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans
(2014), Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans, in Journal of Neuroscience, 34(2), 566-573.
Light modulation of human sleep depends on a polymorphism in the clock gene Period3
(2014), Light modulation of human sleep depends on a polymorphism in the clock gene Period3, in Behavioural Brain Research, 271, 23-29.
Sleep ability mediates individual differences in the vulnerability to sleep loss: Evidence from a PER3 polymorphism
(2014), Sleep ability mediates individual differences in the vulnerability to sleep loss: Evidence from a PER3 polymorphism, in Cortex, 52(1), 47-59.
The circadian regulation of sleep: Impact of a functional ADA-polymorphism and its association to working memory improvements
(2014), The circadian regulation of sleep: Impact of a functional ADA-polymorphism and its association to working memory improvements, in PLoS ONE, 9(12), e113734.
Time-on-task decrement in vigilance is modulated by inter-individual vulnerability to homeostatic sleep pressure manipulation
(2014), Time-on-task decrement in vigilance is modulated by inter-individual vulnerability to homeostatic sleep pressure manipulation, in Frontiers in Behavioral Neuroscience, 8(MAR), 59.
Effect of prolonged wakefulness on electroencephalographic oscillatory activity during sleep
(2013), Effect of prolonged wakefulness on electroencephalographic oscillatory activity during sleep, in Journal of Sleep Research, 23(3), 253-260.
Functional neuroimaging: Sedating medication effects
Landolt Hans Peter, Urry Emily (2013), Functional neuroimaging: Sedating medication effects, in Nofzinger Eric (ed.), Cambridge University Press, Cambridge, 396.
Genetic effects
Landolt Hans Peter (2013), Genetic effects, in Kushida Clete (ed.), Academic Press, Philadelphia, 251.
Genetic polymorphisms of DAT1 and COMT differentially associate with actigraphy-derived sleep-wake cycles in young adults
(2013), Genetic polymorphisms of DAT1 and COMT differentially associate with actigraphy-derived sleep-wake cycles in young adults, in Chronobiology International, 31(5), 705-714.
Increased Metabotropic Glutamate Receptor Subtype 5 Availability in Human Brain After One Night Without Sleep
Hefti Katharina, Holst Sebastian C., Sovago Judit, Bachmann Valerie, Buck Alfred, Ametamey Simon M., Scheidegger Milan, Berthold Thomas, Gomez-Mancilla Baltazar, Seifritz Erich, Landolt Hans-Peter (2013), Increased Metabotropic Glutamate Receptor Subtype 5 Availability in Human Brain After One Night Without Sleep, in BIOLOGICAL PSYCHIATRY, 73(2), 161-168.
Insights into behavioral vulnerability to differential sleep pressure and circadian phase from a functional ADA polymorphism
(2013), Insights into behavioral vulnerability to differential sleep pressure and circadian phase from a functional ADA polymorphism, in Journal of Biological Rhythms, 29(2), 119-130.
Psychomotor Vigilance Task demonstrates impaired vigilance in disorders with excessive daytime sleepiness
(2013), Psychomotor Vigilance Task demonstrates impaired vigilance in disorders with excessive daytime sleepiness, in Journal of Clinical Sleep Medicine, 10(9), 1019-1024.
Sleep deprivation increases dorsal nexus connectivity to the dorsolateral prefrontal cortex in humans
Bosch Oliver G., Rihm Julia S., Scheidegger Milan, Landolt Hans-Peter, Staempfli Philipp, Brakowski Janis, Esposito Fabrizio, Rasch Bjoern, Seifritz Erich (2013), Sleep deprivation increases dorsal nexus connectivity to the dorsolateral prefrontal cortex in humans, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(48), 19597-19602.
Sleep habits, sleep quality and sleep medicine use of the swiss population results from a new survey in a representative sample
(2013), Sleep habits, sleep quality and sleep medicine use of the swiss population results from a new survey in a representative sample, in Therapeutische Umschau, 71(11), 637-646.
Functional ADA polymorphism increases sleep depth and reduces vigilant attention in humans.
Bachmann Valérie, Klaus Federica, Bodenmann Sereina, Schäfer Nikolaus, Brugger Peter, Huber Susanne, Berger Wolfgang, Landolt Hans-Peter (2012), Functional ADA polymorphism increases sleep depth and reduces vigilant attention in humans., in Cerebral cortex (New York, N.Y. : 1991), 22(4), 962-70.
Génétique du Sommeil Normal et des Rythmes Circadiens
Landolt Hans-Peter (2012), Génétique du Sommeil Normal et des Rythmes Circadiens, in Billiard Michel (ed.), Masson, Paris, 45-57.
Human Melatonin and Alerting Response to Blue-Enriched Light Depend on a Polymorphism in the Clock Gene PER3
Chellappa SL, Viola AU, Schmidt C, Bachmann V, Gabel V, Maire M, Reichert CF, Valomon A, Gotz T, Landolt HP, Cajochen C (2012), Human Melatonin and Alerting Response to Blue-Enriched Light Depend on a Polymorphism in the Clock Gene PER3, in JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 97(3), 433-437.
Polymorphisms of ADORA2A modulate psychomotor vigilance and the effects of caffeine on neurobehavioural performance and sleep EEG after sleep deprivation.
Bodenmann S, Hohoff C, Freitag C, Deckert J, Rétey J V, Bachmann V, Landolt H-P (2012), Polymorphisms of ADORA2A modulate psychomotor vigilance and the effects of caffeine on neurobehavioural performance and sleep EEG after sleep deprivation., in British journal of pharmacology, 165(6), 1904-13.
Reduced neurobehavioral impairment from sleep deprivation in older adults: contribution of adenosinergic mechanisms.
Landolt Hans-Peter, Rétey Julia V, Adam Martin (2012), Reduced neurobehavioral impairment from sleep deprivation in older adults: contribution of adenosinergic mechanisms., in Frontiers in neurology, 3, 62-62.
The BDNF Val66Met polymorphism modulates sleep intensity: EEG frequency- and state-specificity.
Bachmann Valérie, Klein Carina, Bodenmann Sereina, Schäfer Nikolaus, Berger Wolfgang, Brugger Peter, Landolt Hans-Peter (2012), The BDNF Val66Met polymorphism modulates sleep intensity: EEG frequency- and state-specificity., in Sleep, 35(3), 335-44.
Genetic determination of sleep EEG profiles in healthy humans.
Landolt Hans-Peter (2011), Genetic determination of sleep EEG profiles in healthy humans., in Progress in brain research, 193, 51-61.
Sleep homeostasis, adenosine, caffeine, and narcolepsy
(2011), Sleep homeostasis, adenosine, caffeine, and narcolepsy, in Baumann Christian (ed.), Springer, New York, 85-92.
Functional polymorphisms in dopaminergic genes modulate neurobehavioral and neurophysio-logical consequences of sleep deprivation
Holst Sebastian C., Müller Thomas, Valomon Amandine, Seebauer Britta, Berger Wolfgang, Landolt Hans-Peter, Functional polymorphisms in dopaminergic genes modulate neurobehavioral and neurophysio-logical consequences of sleep deprivation, in Sci Rep.
Genetics of sleep in healthy humans
Landolt Hans Peter, Djik Derk-Jan, Genetics of sleep in healthy humans, in Kryger Meir (ed.), Elsevier, Philadelphia.
Sleep pharmacogenetics: personalized sleep-wake therapy
Holst Sebastian C., Valomon Amandine, Landolt Hans Peter, Sleep pharmacogenetics: personalized sleep-wake therapy, in Annual Reviews in Pharmacology and Toxicology.

Collaboration

Group / person Country
Types of collaboration
University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Surrey Great Britain and Northern Ireland (Europe)
- Publication
McGill University Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Summa Symposium “The importance of sleep for mental and physical health” Talk given at a conference Sleep and neuronal plasticity: a pharmaco-genetic perspective 16.06.2015 Utrecht, Netherlands Landolt Hans-Peter;
Evaluation Symposium of Clinical Research Priority Program Sleep & Health, University of Zürich Talk given at a conference Sleep pharmacogenetics 16.03.2015 Zürich, Switzerland Holst Sebastian Camillo; Landolt Hans-Peter; Seifritz Erich;
15th Zürich Sleep Medicine Symposium Talk given at a conference Individuelle Koffeinsensibilität: Implikationen für eine personalisierte Schlafmedizin? 15.01.2015 Zürich, Switzerland Landolt Hans-Peter;
22nd Congress of the European Sleep Research Society (ESRS) Talk given at a conference A pharmacogenetic perspective on vigilance regulation during sleep deprivation 20.09.2014 Tallinn, Estonia Landolt Hans-Peter;
Purines 2014, International Conference on Nucleotides, Nucleosides and Nucleobases Talk given at a conference A human pharmacogenetic and brain imaging perspective on sleep homeostasis and neuronal plasticity 26.07.2014 Bonn, Germany Landolt Hans-Peter;
INSPIRE 2014 Talk given at a conference Sleep deprivation and pharmacotherapy 26.04.2014 Viareggio, Italy Landolt Hans-Peter; Sousek Alexandra;
Clinical Neurosciences Bern Talk given at a conference The pharmacogenetics of sleep‐wake drugs 24.01.2014 Bern, Switzerland Holst Sebastian Camillo; Landolt Hans-Peter;
5th Research Symposium of the Child Development Center Talk given at a conference Sleep and neuronal plasticity: a human pharmacogenetic perspective 21.01.2014 Au, Switzerland Landolt Hans-Peter; Holst Sebastian Camillo;
Le Congrès du Sommeil, Société Française de Recherche et Medicine du Sommeil Talk given at a conference Un petit café? – coffee, genetics and sleep deprivation 22.11.2013 Marseille, France Landolt Hans-Peter;
Centre de Recherche en Neurosciences de Lyon Individual talk What keeps the brain awake? The human pharmacogenetics of CNS stimulants 13.10.2013 Lyon, France Landolt Hans-Peter;
2nd Swiss Chronobiology Meeting Talk given at a conference Individual differences in the sleep EEG: Impact of genetic polymorphisms 05.09.2013 Fribourg, Switzerland Landolt Hans-Peter;
2nd Alpine Sleep Summer School (ASSS) Talk given at a conference Genetic determinants of sleep-wake regulation 26.08.2013 Ljubljana, Slovenia Landolt Hans-Peter;
2nd Alpine Sleep Summer School (ASSS) Talk given at a conference Neurochemistry of sleep-wake systems 26.08.2013 Ljubljana, Slovenia Landolt Hans-Peter;
SLEEP2013, 27th Meeting of the Associated Professional Sleep Societies (APSS) Talk given at a conference Effects of sleep loss on mGluR5 availability in the human brain: multi-modal imaging 02.06.2013 Baltimore, United States of America Landolt Hans-Peter;
Symposium System Neurophysiologie Talk given at a conference Sleep, genes, and vigilance 30.05.2013 Bern, Switzerland Landolt Hans-Peter;
Leiden Genetics Colloquium, Leiden Center for Translational Neuroscience Individual talk What keeps the brain awake? The human pharmacogenetics of CNS stimulants 07.05.2013 Leiden, Netherlands Landolt Hans-Peter;
McGill-ZNZ Network for the study of somnological and circadian bases of affective disorders Talk given at a conference A role for adenosine in the antidepressant effect of “wake therapy”? 12.03.2013 Zürich, Switzerland Landolt Hans-Peter;
20. Jahrestagung der DGSM Talk given at a conference Inter-individuelle Unterschiede beim Schlaf-Wachverhalten – neue Polymorphismen 06.12.2012 Berlin, Germany Landolt Hans-Peter;
Annual Meeting of the Dutch Society for Sleep-Wake Research Talk given at a conference Individual responses to sleep loss and countermeasures 23.11.2012 Groningen, Netherlands Landolt Hans-Peter;
21st Congress of the European Sleep Research Society Talk given at a conference Genes, sleep, and performance 04.09.2012 Paris, France Landolt Hans-Peter;
Bordeaux Région Aquitaine Initiative for Neurosciences (BRAIN) Individual talk Human sleep pharmaco-genetics 23.07.2012 Bordeaux, France Landolt Hans-Peter;
McGill-ZNZ Network for the study of somnological and circadian bases of affective disorders Talk given at a conference Pharmacogenetics and brain imaging at the interface of sleep and mood 14.06.2012 Montreal, Canada Landolt Hans-Peter;
Founding Symposium of the Zürich Center for interdisciplinary Sleep Research (ZiS) Talk given at a conference Genetics and pharmacogenetics of sleep and circadian pathways 11.04.2012 Zürich, Switzerland Landolt Hans-Peter;
P2T 2012 Congrès Talk given at a conference Genetics, adenosine and sleep-wake systems: how coffee keeps us awake 04.04.2012 Dijon, France, France Landolt Hans-Peter;
Lémanic Neuroscience Program Individual talk Human polymorphisms and their impact for sleep-wake pharmacology 19.03.2012 Lausanne, France Landolt Hans-Peter;
Le Congrès du Sommeil Talk given at a conference Privation de sommeil et vulnérabilité 25.11.2011 Strasbourg, France, France Landolt Hans-Peter;
Joint meeting of the Swiss Society of Sleep Research, Sleep Medicine and Chronobiology (SSSSC) and the Swiss Neurological Society Talk given at a conference Stimulants, wake promotion, and sleep depth 03.11.2011 St. Gallen, Switzerland Landolt Hans-Peter; Hefti Katharina;
1st Alpine Sleep Summer School Talk given at a conference Neurochemistry of sleep-wake systems 22.08.2011 Lugano, Switzerland Landolt Hans-Peter;
Narcolepsy: Medical needs and current therapies Talk given at a conference mGluR5 and sleep regulation in humans: A positron emission tomography study 07.07.2011 Novartis Institutes for Biomedical Research, Basel, Switzerland Landolt Hans-Peter;
Fédération Bordeaux Neurosciences Individual talk Sleep deprivation, stimulants, and performance 23.05.2011 Bordeaux, France, France Landolt Hans-Peter;


Self-organised

Title Date Place
Symposium "Light: potent modulator of fundamental processes in biology and medicine” 30.01.2015 Zürich, Switzerland
Symposium of Clinical Research Priority Program Sleep & Health 15.01.2015 Zürich, Switzerland
Symposium "A role for mGluR in sleep-associated brain functions?” 02.06.2013 Baltimore, United States of America
Symposium of the McGill-ZNZ Network for the study of somnological and circadian bases of affective disorders 13.03.2013 Zürich, Switzerland
Symposium "(R)evolutions in sleep-wake pharmacology" 31.01.2013 Zürich, Switzerland
Annual Meeting of the Swiss Society for Sleep Research, Sleep Medicine and Chronobiology 11.04.2012 Zürich, Switzerland
Founding Symposium of the Zürich Center for interdisciplinary Sleep Research (ZiS) 11.04.2012 Zürich, Switzerland
Joint Meeting of the Swiss Society of Sleep Research, Sleep Medicine and Chronobiology (SSSSC) and the Swiss Neurological Society 03.11.2011 St. Gallen, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
PharmaDavos Talk 05.02.2015 Davos, Switzerland Landolt Hans-Peter;
Pharmazeutische Gesellschaft Zürich Talk 11.12.2014 Zürich, Switzerland Landolt Hans-Peter;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Annual Symposium of Clinical Research Priority Program Sleep & Health International 2015
Talks/events/exhibitions Gsundheit im Chilegass German-speaking Switzerland 2015
Talks/events/exhibitions Rotary Club Reusstal German-speaking Switzerland 2015
Other activities BrainFair German-speaking Switzerland 2012
Media relations: radio, television Quarks & Co. Westdeutscher Rundfunk International 2012

Awards

Title Year
Borbély-Hess Award 2015
Best Presentation Award 2014
ZIHP Award 2014
Best Free Communication Award 2011

Associated projects

Number Title Start Funding scheme
130499 Development of mouse models for emotional-cognitive states in depression: meeting the need for face, aetiological and construct validity 01.05.2010 Project funding
163439 Glutamatergic mechanisms in sleep-wake homeostasis - molecular brain imaging and pharmacogenetics 01.01.2016 Project funding
120377 Pharmacogenetic and brain imaging studies of human sleep to elucidate molecular mechanisms underlying sleep-wake homeostasis 01.05.2008 Project funding
107874 Adenosine A1 and A2A receptors: studies to elucidate their roles in the regulation of human sleep, vigilance and mood 01.05.2005 Project funding

Abstract

1. Background: The unknown function(s) of sleep constitute one of the remaining frontiers in today’s biomedical research. The homeostatic facet of sleep-wake regulation is the most important aspect of sleep in relation to its function. According to this principle, elevated sleep need following sleep deprivation is counteracted by prolonged sleep duration and, especially, by enhanced sleep intensity. A highly predictable and reliable marker of sleep intensity is electroencephalographic (EEG) slow-wave activity (SWA) in non-rapid-eye-movement sleep. Accumulating evidence indicates that the changes in SWA are causally linked to local synaptic processes reflecting the duration and quality of prior wakefulness. Recent research of us and others strongly suggests that Homer 1a, brain-derived neurotrophic factor, adenosine deaminase, adenosine A2A receptor, and other molecular markers of synaptic plasticity, play an important role in sleep homeostasis. All these molecules interact either directly or indirectly with the metabotropic glutamate receptor subtype 5 (mGluR5). Thus, we will investigate whether (1) glutamatergic mechanisms in general, and mGluR5 in particular, are critically involved in sleep homeostasis, and (2) whether abnormalities in these mechanisms are associated with reduced vigilance and depressed mood in patients with idiopathic hypersomnia (iHS) and major depressive disorder (MDD).2. Specific Aims: (1) To elucidate the roles for mGluR5 and glutamine / glutamate in sleep-wake regulation and disease-related disturbances of vigilance and mood. (2) To provide the rationale for a potential novel strategy to pharmacologically treat disturbed sleep, vigilance and mood in neurological and psychiatric disorders. (3) To gain further insights into the genetic influences on sleep-wake homeostasis in humans.3. Working Hypotheses: (1) Glutamatergic mechanisms reflecting plastic synaptic processes contribute to the homeostatic build-up of sleep need during wakefulness in genetically characterized persons. (2) Selective, negative allosteric modulation of mGluR5 attenuates EEG markers of sleep homeostasis similarly to the adenosine receptor antagonist caffeine. (3) Disturbed glutamatergic mechanisms contribute to reduced vigilance and impaired mood in patients with iHS and MDD.4. Experimental Design and Methods: An integrative, multi-modal approach combining positron emission tomography (PET), magnetic resonance spectroscopy (1H-MRS), functional magnetic resonance imaging (fMRI), human genetics, selective pharmacology, EEG mapping, neurobehavioral testing and mood assessments will be employed.5. Expected Value of the Proposed Project: The proposed studies aim at elucidating a specific role for glutamatergic mechanisms in linking sleep homeostasis with plastic synaptic processes occurring during wakefulness. In collaboration with clinical researchers, the project aims to reveal pathophysio¬logical underpinnings of iHS and MDD. Ultimately, these insights may lead to novel targets to treat sleep-wake related disorders and hint towards the function(s) of sleep.
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