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. 2019 Oct 21;42(11):zsz161.
doi: 10.1093/sleep/zsz161.

Dynamic Changes in Cerebral and Peripheral Markers of Glutamatergic Signaling Across the Human Sleep-Wake Cycle

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Free PMC article

Dynamic Changes in Cerebral and Peripheral Markers of Glutamatergic Signaling Across the Human Sleep-Wake Cycle

Susanne Weigend et al. Sleep. .
Free PMC article

Abstract

Sleep and brain glutamatergic signaling are homeostatically regulated. Recovery sleep following prolonged wakefulness restores efficient functioning of the brain, possibly by keeping glutamatergic signaling in a homeostatic range. Evidence in humans and mice suggested that metabotropic glutamate receptors of subtype-5 (mGluR5) contribute to the brain's coping mechanisms with sleep deprivation. Here, proton magnetic resonance spectroscopy in 31 healthy men was used to quantify the levels of glutamate (Glu), glutamate-to-glutamine ratio (GLX), and γ-amino-butyric-acid (GABA) in basal ganglia (BG) and dorsolateral prefrontal cortex on 3 consecutive days, after ~8 (baseline), ~32 (sleep deprivation), and ~8 hours (recovery sleep) of wakefulness. Simultaneously, mGluR5 availability was quantified with the novel radioligand for positron emission tomography, [18F]PSS232, and the blood levels of the mGluR5-regulated proteins, fragile X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF) were determined. The data revealed that GLX (p = 0.03) in BG (for Glu: p < 0.06) and the serum concentration of FMRP (p < 0.04) were increased after sleep loss. Other brain metabolites (GABA, N-acetyl-aspartate, choline, glutathione) and serum BDNF levels were not altered by sleep deprivation (pall > 0.6). By contrast, the night without sleep enhanced whole-brain, BG, and parietal cortex mGluR5 availability, which was normalized by recovery sleep (pall < 0.05). The findings provide convergent multimodal evidence that glutamatergic signaling is affected by sleep deprivation and recovery sleep. They support a role for mGluR5 and FMRP in sleep-wake regulation and warrant further studies to investigate their causality and relevance for regulating human sleep in health and disease. Clinical Trial Registration: www.clinicaltrials.gov (study identifier: NCT03813082).

Keywords: BDNF; FMRP; PET-MRS imaging; plasticity; sleep homeostasis.

Figures

Figure 1.
Figure 1.
Experimental protocol. After an adaptation and baseline night, participants underwent 40 hours of prolonged wakefulness followed by a recovery night. At baseline (BL), after sleep deprivation (TSD), and again after recovery sleep (RE), levels of mGluR5 were measured using positron emission tomography (PET) with [18F]PSS232 at the same circadian timepoint (blue dotted lines). Furthermore, distinct brain metabolites were measured with magnetic resonance spectroscopy (MRS). Blue box summarizes type of data collection and number of subjects at the imaging sessions in BL, TSD and RE conditions (blue dotted lines). Blood samples for the quantification of FMRP and BDNF levels were drawn at these timepoints. In addition, a cognitive test session was performed, consisting of vigilance (Psychomotor Vigilance Task [PVT]) [38], sleepiness (Karolinska Sleepiness Scale [KSS]) [39], tiredness symptoms (Tiredness Symptoms Scale [TSS]) [40], and affective state (Visual Analogue Scales [VAS]) [41] testing.
Figure 2.
Figure 2.
Effects of sleep deprivation and recovery sleep on endogenous brain metabolites in dorsolateral prefrontal cortex (dlPFC, left) and basal ganglia (BG, right). Magnetic resonance spectroscopy yielded levels of glutamate (Glu; A), glutamate/glutamine ratio (GLX; B) and γ-amino-butyric-acid (GABA; C) relative to creatine in baseline (BL, dark gray), sleep deprivation (TSD, blue) and recovery (RE, light gray) conditions. Bars represent means of arbitrary units (A.U.) ± standard error of the mean (SEM). Numbers on the bars indicate the number of contributing individuals. Black dots represent individual participants. Missing data points were caused by technical problems during 1H-MRS quantification. Data for Glu and GLX were acquired with PRESS and data for GABA with MEGAPRESS sequences. p-values: Benjamini-Hochberg corrected paired, t-tests.
Figure 3.
Figure 3.
Effects of sleep deprivation and recovery sleep on whole-brain metabotropic glutamate receptor subtype 5 (mGluR5) availability. (A) Global NonDisplaceable binding potential (BPND) after [18F]PSS232 uptake in human brain. Individual data points in baseline (BL, n = 22) and following total sleep deprivation (TSD, n = 20) and recovery sleep (RE, n = 18) are plotted. Connecting lines represent within-subjects changes from BL to TSD and from TSD to RE. The color code identifies individuals exhibiting an increase from BL to TSD (filled black circles) and individuals exhibiting a decrease from BL to TSD (filled red circles); filled gray circles: TSD condition missing. p-values: Tukey-Kramer corrected paired, t-tests following significant mixed-model ANOVA with the within-subject factor “condition” (F2,36 = 4.52, p < 0.02). (B) Box plots of relative changes in global mGluR5 availability from BL to TSD, TSD to RE, and BL to RE. Black dots represent individual participants. Asterisks indicate significant change scores: *p < 0.03, **p < 0.01 (Mann-Whitney U tests).
Figure 4.
Figure 4.
Regional differences in the effect of sleep deprivation and recovery sleep on metabotropic glutamate receptor subtype 5 (mGluR5) availability. Upper panel: NonDisplaceable binding potential (BPND) after [18F]PSS232 uptake in Caudate nucleus (A), amygdala (B) and parietal cortex (C). Individual data points in baseline (BL, n = 22) and following total sleep deprivation (TSD, n = 20) and recovery sleep (RE, n = 18) are plotted. Connecting lines represent within-subjects changes from BL to TSD and from TSD to RE. The color code identifies individuals exhibiting an increase from BL to TSD (filled black circles) and individuals exhibiting a decrease from BL to TSD (filled red circles); filled gray circles: TSD condition missing. p-values: Benjamini-Hochberg corrected paired, t-tests following significant mixed-model ANOVA with the within-subject factor “condition” (Caudate nucleus: F2,36 = 6.25, p < 0.01; amygdala: F2,36 = 5.54, p < 0.01; parietal cortex: F2,36 = 6.85, p < 0.01). Lower panel: Box plots of relative changes in mGluR5 availability in Caudate nucleus (A), amygdala (B), and parietal cortex (C) from BL to TSD, TSD to RE, and BL to RE. Black dots represent individual participants. Asterisks indicate significant change scores: *p < 0.03, **p < 0.01 (Mann-Whitney U tests).
Figure 5.
Figure 5.
Effects of sleep deprivation and recovery sleep on serum fragile X mental retardation protein (FMRP) levels. (A) Circulating FMRP concentration in human blood serum. Individual data points in baseline (BL, n = 24) and following total sleep deprivation (TSD, n = 27) and recovery sleep (RE, n = 26) are plotted. Connecting lines represent within-subjects changes from BL to TSD and from TSD to RE. The color code identifies individuals exhibiting an increase from BL to TSD (filled black circles) and individuals exhibiting a decrease from BL to TSD (filled red circles); filled gray circles: TSD condition missing. p-values: Tukey-Kramer corrected paired, t-tests following significant mixed-model ANOVA with the within-subject factor “condition” (F2,44 = 3.37, p < 0.05). (B) Box plots of relative changes in blood FMRP levels from BL to TSD, TSD to RE, and BL to RE. Black dots represent individual participants.

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