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

English title Glutamatergic mechanisms in sleep-wake homeostasis - molecular brain imaging and pharmacogenetics
Applicant Landolt Hans-Peter
Number 163439
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 01.01.2016 - 30.09.2019
Approved amount 429'000.00
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All Disciplines (5)

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

Keywords (12)

Brain imaging (PET, 1H-MRS); Negative allosteric modulator (NAM); Human genetics; Neuronal plasticity; Sleep-wake regulation; FMRP; Fragile X Syndrome; Dipraglurant (ADX48621); Glutamate; Homeostasis; FMR1; mGluR5

Lay Summary (German)

Lead
Im vorliegenden Projekt untersuchen wir, ob die Verfügbarkeit von metabotropen Glutamat-Rezeptoren vom Subtyp-5 im Gehirn zum individuellen Schlafbedürfnis beiträgt.
Lay summary
Wir verbringen ungefähr einen Drittel unseres Lebens im Schlaf. Eine allgemein akzeptierte Antwort auf die Frage „Warum schlafen wir?“ liegt jedoch im Dunkeln. Dies ist gegenwärtig eine der brennendsten offenen Fragen der Neurowissenschaften und der medizinischen Forschung. Im vorliegenden Projekt werden glutamaterge Mechanismen der Schlaf-Wachregulation erforscht. Glutamat ist der wichtigste erregende Überträgerstoff im Gehirn und spielt eine herausragende Rolle bei der neuronalen Plastizität, die sowohl dem Lernen als auch dem Gedächtnis zugrunde liegt. Eine Störung glutamaterger Prozesse unterliegt bestimmten genetischen Formen der geistigen Behinderung wie z.B. dem Fragilen X Syndrom. Unsere früheren Studien zeigen, dass das Wachbleiben gesunder Probanden während einer Nacht zu einer erhöhten Verfügbarkeit von mGluR5 (metabotrope Glutamat-Rezeptoren vom Subtyp-5) im Gehirn führt. Weiter führende Analysen belegen, dass auch die physiologische Intensität des Tiefschlafs (gemessen durch die langsam-wellige Aktivität in den Hirnstromkurven [EEG]) mit der Dichte dieser Rezeptoren zusammen hängt. Im vorliegenden Projekt kombinieren wir Positron Emission Tomographie (PET), Magnetresonanz-Spektroskopie (1H-MRS), Humangenetik, selektive Pharmakologie, neurophysiologische Untersuchungen mittels EEG und Messungen der kognitiven Leistungsfähigkeit und der Stimmung zur Überprüfung der Hypothese, dass mGluR5 entscheidend an der Schlaf-Wach-Homöostase (d.h. Aufbau des Schlafdrucks im Wach, Abbau des Schlafdrucks im Schlaf) beteiligt sind. Es ist zu erwarten, dass diese Untersuchungen neue Zielstrukturen zur Behandlung von Schlaf-Wachstörungen hervor bringen könnten.
Direct link to Lay Summary Last update: 27.11.2015

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep–wake cycle
Weigend Susanne, Holst Sebastian C, Treyer Valérie, O’Gorman Tuura Ruth L, Meier Josefine, Ametamey Simon M, Buck Alfred, Landolt Hans-Peter (2019), Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep–wake cycle, in Sleep, 42(11), 1-11.
Dynamic Metabolic Changes in the Human Thalamus at the Transition From Waking to Sleep - Insights From Simultaneous Functional MR Spectroscopy and Polysomnography
Lehmann Mick, Hock Andreas, Zoelch Niklaus, Landolt Hans-Peter, Seifritz Erich (2019), Dynamic Metabolic Changes in the Human Thalamus at the Transition From Waking to Sleep - Insights From Simultaneous Functional MR Spectroscopy and Polysomnography, in Frontiers in Neuroscience, 13, 1158.
Unraveling the genetic underpinnings of sleep deprivation-induced impairments in human cognition
Satterfield Brieann C., Stucky Benjamin, Landolt Hans-Peter, Van Dongen Hans P.A. (2019), Unraveling the genetic underpinnings of sleep deprivation-induced impairments in human cognition, in Progress in Brain Research, 246, 127-158.
Prolonged Waking and Recovery Sleep Affect the Serum MicroRNA Expression Profile in Humans
WeigendSusanne, HolstSebastian C., MeierJosefine, BrockMatthias, KohlerMalcolm, LandoltHans-Peter (2018), Prolonged Waking and Recovery Sleep Affect the Serum MicroRNA Expression Profile in Humans, in Clocks & Sleep, 1(1 ), 75-86.
Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men
Valomon Amandine, Holst Sebastian C., Borrello Alessandro, Weigend Susanne, Müller Thomas, Berger Wolfgang, Sommerauer Michael, Baumann Christian R., Landolt Hans-Peter (2018), Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men, in Neuropsychopharmacology, 43(7), 1599-1607.
Sleep-Wake Neurochemistry
Holst Sebastian C., Landolt Hans-Peter (2018), Sleep-Wake Neurochemistry, in Sleep Medicine Clinics, 13(2), 137-146.
Cerebral mGluR5 availability contributes to elevated sleep need and behavioral adjustment after sleep deprivation
Sebastian C Holst, Alexandra Sousek, Katharina Hefti, Sohrab Saberi-Moghadam, Alfred Buck, Simon M Ametamey, Milan Scheidegger, Paul Franken, Anke Henning, Erich Seifritz, Mehdi Tafti, Hans-Peter Landolt (2017), Cerebral mGluR5 availability contributes to elevated sleep need and behavioral adjustment after sleep deprivation, in eLife, 6, e28751.

Collaboration

Group / person Country
Types of collaboration
Prof. M. Tafti / Universität Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. P. Kaufmann & Prof. A. Buck / UniversitätsSpital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Ch. Baumann / UniversitätsSpital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. E. Seifritz / Psychiatrische Universitätsklinik Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. S. M. Ametamey / ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the Swiss Society of Sleep Research, Sleep Medicine and Chronobiology Talk given at a conference Big data in sleep science 27.06.2019 Fribourg, Switzerland Stucky Benjamin; Landolt Hans-Peter;
Meeting of the Association for the Science and Information on Coffee Talk given at a conference Keynote lecture: Coffee, caffeine, and sleep 17.09.2018 Portland, United States of America Landolt Hans-Peter;
Sleep & Health Zurich 2018 Talk given at a conference Who is vulnerable to sleep deprivation? 02.02.2018 Zurich, Switzerland Landolt Hans-Peter;
ESRS Sleep Science School Talk given at a conference Genetics of sleep phenotypes, EEG fingerprints, and sleep biomarkers 19.10.2017 Fréjus, France Münzing Susanne; Landolt Hans-Peter;
WorldSleep2017 Talk given at a conference Adenosine, glutamate, and sleep deprivation 09.10.2017 Prag, Czech Republic Landolt Hans-Peter;
Annual Meeting of the Neuroscience Center Zürich Talk given at a conference CRPP Sleep & Health - past, present, future 14.09.2017 Zürich, Switzerland Landolt Hans-Peter;
SLEEP 2017 Talk given at a conference A pharmacogenetic approach to dissect performance deficits resulting from sleep loss 05.06.2017 Boston, United States of America Landolt Hans-Peter;
Institutsseminar des Instituts für Luft- und Raumfahrtmedizin Individual talk Pharmacogenetic dissection of sleep-wake regulation in humans 09.05.2017 Köln, Germany Landolt Hans-Peter;
Swiss Canadian Innovation Day Talk given at a conference Sleep and Health 24.03.2017 Ottawa, Canada Landolt Hans-Peter;
Conférence Pharmacologie Talk given at a conference Pharmacogenetic dissection of sleep-wake functions in humans 24.01.2017 Fribourg, Switzerland Landolt Hans-Peter;
Bi-Annual Meeting of the International Pharmaco-EEG Society Talk given at a conference Elucidating mechanisms of sleep-wake regulation in humans with pharmaco-genetic tools 29.10.2016 Nijmegen, Netherlands Landolt Hans-Peter;
Von der Neurobiologie zur Psychiatrie Talk given at a conference Adenosin, Schlaf und Depression: neue genetische Erkenntnisse 17.06.2016 Freiburg, Germany Landolt Hans-Peter;
Mini-Spec Individual talk Neues aus der Schlafforschung 28.05.2016 Appenzell, Switzerland Landolt Hans-Peter;
CRPP Sleep & Health Retreat Talk given at a conference Key questions in sleep-wake pharmacology 05.02.2016 Zürich, Switzerland Landolt Hans-Peter;


Self-organised

Title Date Place
24th Congress of the European Sleep Research Society (ESRS) 25.09.2018 Basel, Switzerland
Sleep & Health Zurich 2018 01.02.2018 Zürich, Switzerland

Knowledge transfer events



Self-organised

Title Date Place
Zurich Sleep 2018 06.12.2018 Zürich, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Sleep & Health Zurich 2018 German-speaking Switzerland 2018
Talks/events/exhibitions Aktuelle Herausforderungen in der Schlafforschung German-speaking Switzerland 2017
Talks/events/exhibitions Herausforderungen in der Schlaftherapie: Ein- und Ausblick German-speaking Switzerland 2017

Associated projects

Number Title Start Funding scheme
135414 Glutamatergic mechanisms in sleep-wake homeostasis in health and disease - molecular brain imaging and pharmacogenetics 01.05.2011 Project funding

Abstract

1. Background: With research supported by the current SNSF grant entitled “Glutamatergic mechanisms in sleep-wake homeostasis in health and disease - molecular brain imaging and pharmacogenetics”, we provided compelling evidence that sleep deprivation induces dynamic increases in the functional availability of metabotropic glutamate receptors of subtype 5 (mGluR5) in the living human brain. The function of mGluR5 is causally associated with the pathophysiology of fragile X syndrome (FXS), a leading inherited cause of intellectual disability and autism. FXS is caused by a massive expansion of (CGG) repeats in the fragile X mental retardation 1 gene (FMR1), which encodes fragile X mental retardation protein (FMRP). We found in healthy volunteers that the number of (CGG) repeats (odd vs. even) in FMR1 modulates the availability of mGluR5. Furthermore, mGluR5 availability and distinct behavioral and neurophysiological markers of sleep need and sleep intensity (referred to as sleep homeostasis) are tightly correlated. Interestingly, animal studies demonstrate that mGluR5 functionally interact with Homer1, a core molecular marker of sleep homeostasis. Our findings, thus, strongly suggest that mGluR5 availability and expression of FMRP may determine individual sleep need in humans.2. Specific Aims: These hypotheses will now be tested using multi-modal imaging with simultaneous positron emission tomography and proton magnetic resonance spectroscopy scanning of mGluR5 availability and metabolite levels (e.g., glutamate and glutamine) in the brain, as well as measuring the FMRP concentration in peripheral blood in baseline, during sleep deprivation and after recovery sleep. Established biomarkers of sleep homeostasis in electroencephalographic oscillations (number, amplitudes, slopes) in wakefulness and sleep will be quantified through algorithms established in our lab. The exact roles of mGluR5 in subjective and behavioral consequences of individual differences in sleep need will be assessed through investigation of a novel negative allosteric modulator of mGluR5 (dipraglurant).3. Specific Hypotheses: (1) mGluR5 and FMRP modulate wake-related neuronal plasticity and contribute to the homeostatic build-up of sleep need in wakefulness. (2) Selective, negative allosteric modulation of mGluR5 mimics a physiological attenuation in sleep pressure, including changes in subjective and neurobehavioral state. (3) The mGluR5 may provide a novel target system to improve sleep-wake disturbances and sleep-associated brain functions.4. Experimental Design and Methods: Complementary neurophysiological, imaging, genetic, neurocognitive, behavioral, and pharmacological methods will be employed (controlled, within-subject designs), to investigate whether the mGluR5/FMRP are molecular regulators of sleep-wake homeostasis in humans.5. Expected Value of the Proposed Project: We expect that the proposed integrative physiological studies in humans, including multi-modal molecular brain imaging and pharmacogenetics, will show causal relationships among mGluR5 function, homeostatic sleep-wake regulation, and sleep-wake related neuronal plasticity. Our interdisciplinary team brings together complementary expertise along a ‘molecule-to-human-to-medicine’ continuum, which may lead to novel insights into pathophysiological underpinnings of sleep-wake related disorders.
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