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
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.
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.
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.
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.
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.
Holst Sebastian C., Landolt Hans-Peter (2018), Sleep-Wake Neurochemistry, in
Sleep Medicine Clinics, 13(2), 137-146.
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.
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.