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Research Articles, Systems/Circuits

NMDA Receptors in the Lateral Preoptic Hypothalamus Are Essential for Sustaining NREM and REM Sleep

Giulia Miracca, Berta Anuncibay-Soto, Kyoko Tossell, Raquel Yustos, Alexei L. Vyssotski, Nicholas P. Franks and William Wisden
Journal of Neuroscience 6 July 2022, 42 (27) 5389-5409; DOI: https://doi.org/10.1523/JNEUROSCI.0350-21.2022
Giulia Miracca
1Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom
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Berta Anuncibay-Soto
1Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom
2UK Dementia Research Institute, Imperial College London, London SW7 2AZ, United Kingdom
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Kyoko Tossell
1Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom
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Raquel Yustos
1Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom
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Alexei L. Vyssotski
3Institute of Neuroinformatics, University of Zürich/Eidgenössische Technische Hochschule Zürich, Zürich CH-8057, Switzerland
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Nicholas P. Franks
1Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom
2UK Dementia Research Institute, Imperial College London, London SW7 2AZ, United Kingdom
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William Wisden
1Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom
2UK Dementia Research Institute, Imperial College London, London SW7 2AZ, United Kingdom
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Abstract

The lateral preoptic (LPO) hypothalamus is a center for NREM and REM sleep induction and NREM sleep homeostasis. Although LPO is needed for NREM sleep, we found that calcium signals were, surprisingly, highest in REM sleep. Furthermore, and equally surprising, NMDA receptors in LPO were the main drivers of excitation. Deleting the NMDA receptor GluN1 subunit from LPO abolished calcium signals in all cells and produced insomnia. Mice of both sexes had highly fragmented NREM sleep-wake patterns and could not generate conventionally classified REM sleep. The sleep phenotype produced by deleting NMDA receptors depended on where in the hypothalamus the receptors were deleted. Deleting receptors from the anterior hypothalamic area (AHA) did not influence sleep-wake states. The sleep fragmentation originated from NMDA receptors on GABA neurons in LPO. Sleep fragmentation could be transiently overcome with sleeping medication (zolpidem) or sedatives (dexmedetomidine; Dex). By contrast, fragmentation persisted under high sleep pressure produced by sleep deprivation (SD), mice had a high propensity to sleep but woke up. By analyzing changes in δ power, sleep homeostasis (also referred to as “sleep drive”) remained intact after NMDA receptor ablation. We suggest NMDA glutamate receptor activation stabilizes firing of sleep-on neurons and that mechanisms of sleep maintenance differ from that of the sleep drive itself.

SIGNIFICANCE STATEMENT Insomnia is a common affliction. Most insomniacs feel that they do not get enough sleep, but in fact, often have good amounts of sleep. Their sleep, however, is fragmented, and sufferers wake up feeling unrefreshed. It is unknown how sleep is maintained once initiated. We find that in mice, NMDA-type glutamate receptors in the hypothalamus are the main drivers of excitation and are required for a range of sleep properties: they are, in fact, needed for both sustained NREM sleep periods, and REM sleep generation. When NMDA receptors are selectively reduced from inhibitory preoptic (PO) neurons, mice have normal total amounts of sleep but high sleep-wake fragmentation, providing a model for studying intractable insomnia.

  • hypothalamus
  • NMDA receptor
  • NREM
  • preoptic
  • REM
  • sleep

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The Journal of Neuroscience: 42 (27)
Journal of Neuroscience
Vol. 42, Issue 27
6 Jul 2022
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NMDA Receptors in the Lateral Preoptic Hypothalamus Are Essential for Sustaining NREM and REM Sleep
Giulia Miracca, Berta Anuncibay-Soto, Kyoko Tossell, Raquel Yustos, Alexei L. Vyssotski, Nicholas P. Franks, William Wisden
Journal of Neuroscience 6 July 2022, 42 (27) 5389-5409; DOI: 10.1523/JNEUROSCI.0350-21.2022

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NMDA Receptors in the Lateral Preoptic Hypothalamus Are Essential for Sustaining NREM and REM Sleep
Giulia Miracca, Berta Anuncibay-Soto, Kyoko Tossell, Raquel Yustos, Alexei L. Vyssotski, Nicholas P. Franks, William Wisden
Journal of Neuroscience 6 July 2022, 42 (27) 5389-5409; DOI: 10.1523/JNEUROSCI.0350-21.2022
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Keywords

  • hypothalamus
  • NMDA receptor
  • NREM
  • preoptic
  • REM
  • sleep

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