Cerebral mGluR5 availability contributes to elevated sleep need and behavioral adjustment after sleep deprivation

Holst, Sebastian C.; Sousek, Alexandra; Hefti, Katharina; Saberi-Moghadam, Sohrab; Buck, Alfred; Ametamey, Simon M.; Scheidegger, Milan; Franken, Paul; Henning, A; Seifritz, Erich; Tafti, Mehdi; Landolt, Hans

doi:10.7554/elife.28751

Cited by 54 publications

(65 citation statements)

References 67 publications

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“…Based on immunocytochemistry, it was suggested that most rat GABAergic preoptic neurons that project to the histamine neurons in the posterior hypothalamus co-released galanin (66); indeed, galanin directly reduces the firing rate of histamine neurons (67). Activating optogenetically GABAergic (non-galanin) 13 terminals from the PO hypothalamus in the area where the histamine neurons are located induces NREM sleep (64). On the other hand, optogenetic activation of PO galanin neuron soma produced wakefulness (64); this result could be caused by other galanin neuron subtypes (68).…”

Section: Discussionmentioning

confidence: 99%

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Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

Ma¹,

Miracca²,

Yu³

et al. 2019

Preprint

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Sleep deprivation induces a characteristic rebound in NREM sleep accompanied by an immediate increase in the power of delta (0.5 -4 Hz) oscillations, proportional to the prior time awake. To test the idea that galanin neurons in the mouse lateral preoptic hypothalamus (LPO) regulate this sleep homeostasis, they were selectively genetically ablated. The baseline sleep architecture of LPO-DGal mice became heavily fragmented, their average core body temperature permanently increased (by about 2°C) and the diurnal variations in body temperature across the sleep-wake cycle also markedly increased. Additionally, LPO-DGal mice showed a striking spike in body temperature and increase in wakefulness at a time (ZT24) when control mice were experiencing the opposite -a decrease in body temperature and becoming maximally sleepy (start of "lights on"). After sleep deprivation sleep homeostasis was largely abolished in LPO-DGal mice: the characteristic increase in the delta power of NREM sleep following sleep deprivation was absent, suggesting that LPO galanin neurons track the time spent awake. Moreover, the amount of recovery sleep was substantially reduced over the following hours. We also found that the a2 adrenergic agonist dexmedetomidine, used for long-term sedation during intensive care, requires LPO galanin neurons to induce both the NREM-like state with increased delta power and the reduction in body temperature, characteristic features of this drug. This suggests that dexmedetomidine over-activates the natural sleep homeostasis pathway via galanin neurons. Collectively, the results emphasize that NREM sleep and the concurrent reduction in body temperature are entwined at the circuit level. 3 Significance Catching up on lost sleep (sleep homeostasis) is a common phenomenon in mammals, but there is no circuit explanation for how this occurs. We have discovered that galanin neurons in the hypothalamus are essential for sleep homeostasis as well as for the control of body temperature. This is the first time that a neuronal cell type has been identified that underlies sleep homeostasis. Moreover, we show that activation of these galanin neurons are also essential for the actions of the a2 adrenergic agonist dexmedetomidine, which induces both hypothermia together with powerful delta oscillations resembling NREM sleep. Thus, sleep homeostasis, temperature control and sedation by a2 adrenergic agonists can all be linked at the circuit level by hypothalamic galanin neurons.

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Section: Discussionmentioning

confidence: 99%

“…Widely expressed genes (e.g. Sik3, Adora1, clock, mGluR5, per3, reverba) have been found to modulate sleep homeostasis (9,(11)(12)(13)(14)(15)(16)(17). Astrocytes and skeletal muscle release messengers which can modulate the process (18,19).…”

Section: Introductionmentioning

confidence: 99%

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

Ma¹,

Miracca²,

Yu³

et al. 2019

Preprint

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“…We next assessed whether humans showed a similar heterogeneity in the response of δ power to SD. A total of 110 healthy human subjects from four published datasets who underwent wholenight SD amounting a sustained waking period of 40h (Bodenmann et al, 2009, Holst et al, 2017, Valomon et al, 2018, Weigend et al, 2019, were included in the analysis. Here we show only the aggregate results, but similar results were obtained in each study separately.…”

Section: Distinct δ Sub-bands Are Present In the Human Brain Followinmentioning

confidence: 99%

“…All subjects signed informed consent and were compensated financially for participating. For more details see previous publications (Bodenmann et al, 2009, Holst et al, 2017, Valomon et al, 2018, Weigend et al, 2019. Some subjects were removed across 5 studies for signal artifacts, which made time-course analysis of spectral bands difficult.…”

Section: Study Participantsmentioning

confidence: 99%

Reassessing the validity of slow-wave dynamics as a proxy for NREM sleep homeostasis

Hubbard

Gent

Hoekstra

et al. 2019

Preprint

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Sleep-wake driven changes in NREM sleep (NREMS) EEG delta (δ: ~0.75-4.5Hz) power are widely used as proxy for a sleep homeostatic process. We noted frequency increases in δ-waves in sleep-deprived (SD) mice, prompting us to re-evaluate how slow-wave characteristics relate to prior sleep-wake history. We discovered two types of δ-waves; one responding to SD with high initial power and fast, discontinuous decay (δ2: ~2.5-3.5Hz) and another unrelated to time-spentawake with slow, linear decays (δ1: ~0.75-1.75Hz). Human experiments confirmed this δ-band heterogeneity. Similar to SD, silencing of centromedial thalamus neurons boosted δ2-waves, specifically. δ2-dynamics paralleled that of temperature, muscle tone, heart-rate, and neuronal UP/DOWN state lengths, all reverting to characteristic NREMS levels within the first recovery hour. Thus, prolonged waking seems to necessitate a physiological recalibration before typical NREMS can be reinstated. These short-lasting δ2-dynamics challenge accepted models of sleep regulation and function based on the merged δ-band as sleep-need proxy.

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“…In humans, mGluR5 show high expression in brain regions regulating sleep (Hefti et al, 2013) and their functional availability was increased after prolonged wakefulness (Hefti et al, 2013). Furthermore, increased mGluR5 availability correlated with behavioral and neurophysiological markers of elevated sleep need, including self-rated sleepiness, unintended sleep during prolonged wakefulness, as well as SWA and slow (< 1 Hz) oscillatory activity in the NREM sleep EEG (Hefti et al, 2013;Holst et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep-wake cycle

Weigend

Holst

Treyer

et al. 2018

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Both sleep and glutamatergic signaling in the brain are tightly controlled and homeostatically regulated. Sleep homeostasis is reliably reflected by predictable changes in brain electrical activity in waking and sleep, yet the underlying molecular mechanisms remain elusive.Current hypotheses posit that recovery sleep following prolonged waking restores efficient functioning of the brain, for example by keeping glutamatergic signaling in a homeostatic range. We recently provided evidence in humans and mice that metabotropic glutamate receptors of subtype-5 (mGluR5) contribute to the brain's coping mechanisms with sleep deprivation. Here we combined in 31 healthy men, proton magnetic resonance spectroscopy to measure the levels of glutamate (Glu), GLX (glutamate-to-glutamine ratio) and GABA (γamino-butyric-acid) in basal ganglia (BG) and dorsolateral prefrontal cortex, simultaneous positron emission tomography to quantify mGluR5 availability with the novel radioligand, [ 18 F]PSS232, and quantification in blood plasma of the mGluR5-regulated proteins, fragile-X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF). All measurements were conducted at the same circadian time in baseline, following sleep deprivation and after recovery sleep. We found that Glu and GLX in BG (p all < 0.01), but not in prefrontal cortex, and the plasma concentration of FMRP (p < 0.02), were increased after sleep loss and tended to normalize following recovery sleep (p all < 0.1). Furthermore, a night without sleep enhanced whole-brain and striatal mGluR5 availability and was normalized by recovery sleep (p all < 0.05). By contrast, other brain metabolites and plasma BDNF levels were not altered. The findings demonstrate convergent changes in distinct markers of glutamatergic signaling across prolonged wakefulness and recovery sleep in humans. They warrant further studies to elucidate the underlying mechanisms that link the homeostatic regulation of sleep and glutamatergic system activity in health and disease.

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Cerebral mGluR5 availability contributes to elevated sleep need and behavioral adjustment after sleep deprivation

Cited by 54 publications

References 67 publications

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

Reassessing the validity of slow-wave dynamics as a proxy for NREM sleep homeostasis

Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep-wake cycle

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