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The Temperature Dependence of Sleep

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Harding, Edward C., Franks, Nicholas P., Wisden, William·2019·Frontiers in Neuroscience
DOI 10.3389/fnins.2019.00336PMC PMC6491889
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Abstract

Mammals have evolved a range of behavioural and neurological mechanisms that coordinate cycles of thermoregulation and sleep. Whether diurnal or nocturnal, sleep onset and a reduction in core temperature occur together. Non-rapid eye movement (NREM) sleep episodes are also accompanied by core and brain cooling. Thermoregulatory behaviours, like nest building and curling up, accompany this circadian temperature decline in preparation for sleeping. This could be a matter of simply comfort as animals seek warmth to compensate for lower temperatures. However, in both humans and other mammals, direct skin warming can shorten sleep-latency and promote NREM sleep. We discuss the evidence that body cooling and sleep are more fundamentally connected and that thermoregulatory behaviours, prior to sleep, form warm microclimates that accelerate NREM directly through neuronal circuits. Paradoxically, this warmth might also induce vasodilation and body cooling. In this way, warmth seeking and nesting behaviour might enhance the circadian cycle by activating specific circuits that link NREM initiation to body cooling. We suggest that these circuits explain why NREM onset is most likely when core temperature is at its steepest rate of decline and why transitions to NREM are accompanied by a decrease in brain temperature. This connection may have implications for energy homeostasis and the function of sleep.

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FIGURE 1 Sleep preparation is a thermoregulatory behaviour (A) shows typical nesting behaviour in four species. Mouse nesting (Mus musculus, C57Bl6/J), house cat (Felis catus) curling up, nest building in the chimpanzee (Pan troglodytes verus) and bedding (Homo sapiens). (B) Example of circadian temperature cycle over 6 days in a male C57Bl6/J mouse. (C) Average of transitions from the same mouse over 16 consecutive days 2 h before and after the light change. (D) Minimum temperature (n = 21) during light phase compared to minimum (n = 21) and maximum temperature (n = 16) in the dark phase, plotted as change from zero for a group of male C57Bl6/J mice. Data shown in (B–D) is from (Harding et al., unpublished). All images used with permission or copyright clearance. The nesting chimpanzee photo credit: Kathelijne Koops. The nesting cat photo credit: Isobel Harding, the sleeping human is available under CC0-1.0 universal and the nesting mouse is adapted from Deacon (2006).
FIGURE 1 Sleep preparation is a thermoregulatory behaviour (A) shows typical nesting behaviour in four species. Mouse nesting (Mus musculus, C57Bl6/J), house cat (Felis catus) curling up, nest building in the chimpanzee (Pan troglodytes verus) and bedding (Homo sapiens). (B) Example of circadian temperature cycle over 6 days in a male C57Bl6/J mouse. (C) Average of transitions from the same mouse over 16 consecutive days 2 h before and after the light change. (D) Minimum temperature (n = 21) during light phase compared to minimum (n = 21) and maximum temperature (n = 16) in the dark phase, plotted as change from zero for a group of male C57Bl6/J mice. Data shown in (B–D) is from (Harding et al., unpublished). All images used with permission or copyright clearance. The nesting chimpanzee photo credit: Kathelijne Koops. The nesting cat photo credit: Isobel Harding, the sleeping human is available under CC0-1.0 universal and the nesting mouse is adapted from Deacon (2006).CC BY · PubMed Central
FIGURE 2 Thermoregulation is important for human sleep. (A) Humans use bedding to form warm microclimates during sleep. These activate central hypothalamic mechanisms to induce sleep and peripheral vasodilation. (B) Distal-to-proximal gradient and core temperature decline predict sleep onset (adapted from Krauchi et al., 2000).
FIGURE 2 Thermoregulation is important for human sleep. (A) Humans use bedding to form warm microclimates during sleep. These activate central hypothalamic mechanisms to induce sleep and peripheral vasodilation. (B) Distal-to-proximal gradient and core temperature decline predict sleep onset (adapted from Krauchi et al., 2000).CC BY · PubMed Central
FIGURE 3 Sensory and homeostatic inputs that gate sleep. Sleep onset is determined by four competing inputs: the homeostatic drive to sleep and three permissive conditions that relate to sleep timing, the behavioural input, the circadian input and the autonomic input. Endocrine inputs are also a key part of each category. Ghrelin and leptin are important for sensing of hunger/satiety, respectively, while melatonin is a key component of the circadian rhythm. Adenosine and NO may form part of the homeostatic input. (Top - Factors promoting wakefulness) Circadian cues are permissive for wake and homeostatic pressure to sleep is low. Behavioural factors also promote wakefulness and autonomic inputs are not permissive for sleep. Wake promoting nuclei drive cortical and thalamic excitability, whilst inhibiting sleep-prompting areas such as PO and vPAG. Behavioural needs of food and reproduction overcome those of sleep and thermal comfort. Behavioural inputs are also wake-promoting and may integrate this information in the VTA. Hormonal inputs, such as ghrelin, are detected in the ARC and are sleep-permissive. Autonomic signals, such as ambient temperature, are relayed via the spinal cord and pass through the LPb to the PO for integration. Circuits detecting environmental warmth are not active, vasoconstriction dominates and BAT is active. AgRP neurons signal hunger and inhibit sleep. (Bottom – Factors promoting NREM sleep) Circadian cues are now permissive for sleep and homeostatic pressure to sleep is high. Behavioural factors also promote sleep and autonomic inputs are permissive for sleep. On seeking shelter and warmth and having eaten, sleep is permitted. Autonomic signals, such as ambient temperature, are relayed via the spine and pass through the LPb to the PO for integration. NOS1-glutamate neurons are activated by skin warmth and initiate both NREM and body cooling. Activation of vasodilatory and BAT downregulation circuits is via NOS1 projections to LPO GABAergic neurons or via direct projections to DMH and rRPA/RVLM. Behavioural inputs are now sleep promoting and may integrate this information in the VTA. Hormonal inputs, such as leptin, are detected in the ARC and are sleep permissive. POMC neurons detect satiety and are permissive for sleep. NO, nitric oxide; NOS1, nitric oxide synthase-1; PO, preoptic area; LPO, lateral preoptic area; vPAG, ventral periaqueductal grey; TMN, tuberomammillary nucleus; VTA, ventral tegmental area; ARC, arcuate nucleus; LPb, lateral parabrachial; LC, locus coeruleus; DR, dorsal raphe; BAT, brown adipose tissue; AgRP, agouti-related peptide; DMH, dorsal medial hypothalamus; rRPA, rostral raphe pallidus; RVLM, rostral ventrolateral medulla; POMC, pro-opiomelanocortin (Leshan et al., 2012; Eban-Rothschild et al., 2016; Weber and Dan, 2016; Yu et al., 2016; Goldstein et al., 2018; Harding et al., 2018; Yu et al., 2019).
FIGURE 3 Sensory and homeostatic inputs that gate sleep. Sleep onset is determined by four competing inputs: the homeostatic drive to sleep and three permissive conditions that relate to sleep timing, the behavioural input, the circadian input and the autonomic input. Endocrine inputs are also a key part of each category. Ghrelin and leptin are important for sensing of hunger/satiety, respectively, while melatonin is a key component of the circadian rhythm. Adenosine and NO may form part of the homeostatic input. (Top - Factors promoting wakefulness) Circadian cues are permissive for wake and homeostatic pressure to sleep is low. Behavioural factors also promote wakefulness and autonomic inputs are not permissive for sleep. Wake promoting nuclei drive cortical and thalamic excitability, whilst inhibiting sleep-prompting areas such as PO and vPAG. Behavioural needs of food and reproduction overcome those of sleep and thermal comfort. Behavioural inputs are also wake-promoting and may integrate this information in the VTA. Hormonal inputs, such as ghrelin, are detected in the ARC and are sleep-permissive. Autonomic signals, such as ambient temperature, are relayed via the spinal cord and pass through the LPb to the PO for integration. Circuits detecting environmental warmth are not active, vasoconstriction dominates and BAT is active. AgRP neurons signal hunger and inhibit sleep. (Bottom – Factors promoting NREM sleep) Circadian cues are now permissive for sleep and homeostatic pressure to sleep is high. Behavioural factors also promote sleep and autonomic inputs are permissive for sleep. On seeking shelter and warmth and having eaten, sleep is permitted. Autonomic signals, such as ambient temperature, are relayed via the spine and pass through the LPb to the PO for integration. NOS1-glutamate neurons are activated by skin warmth and initiate both NREM and body cooling. Activation of vasodilatory and BAT downregulation circuits is via NOS1 projections to LPO GABAergic neurons or via direct projections to DMH and rRPA/RVLM. Behavioural inputs are now sleep promoting and may integrate this information in the VTA. Hormonal inputs, such as leptin, are detected in the ARC and are sleep permissive. POMC neurons detect satiety and are permissive for sleep. NO, nitric oxide; NOS1, nitric oxide synthase-1; PO, preoptic area; LPO, lateral preoptic area; vPAG, ventral periaqueductal grey; TMN, tuberomammillary nucleus; VTA, ventral tegmental area; ARC, arcuate nucleus; LPb, lateral parabrachial; LC, locus coeruleus; DR, dorsal raphe; BAT, brown adipose tissue; AgRP, agouti-related peptide; DMH, dorsal medial hypothalamus; rRPA, rostral raphe pallidus; RVLM, rostral ventrolateral medulla; POMC, pro-opiomelanocortin (Leshan et al., 2012; Eban-Rothschild et al., 2016; Weber and Dan, 2016; Yu et al., 2016; Goldstein et al., 2018; Harding et al., 2018; Yu et al., 2019).CC BY · PubMed Central
FIGURE 4 Signal integration in the preoptic hypothalamus. Warmth on the skin stimulates sensory inputs, through the LPb, to preoptic nitrergic-glutamatergic neurons that initiate simultaneous NREM and body cooling. This maybe through activation of separate GABAergic neurons for sleep and hypothermia in the MPO and LPO, but they may also activate galinergic-GABAergic neurons to initiate sleep and body cooling. The synaptic role of NO is unknown in these circuits but potential sites are labelled. NREM is initiated by inhibition of arousal nuclei, including the TMN and the LH. Others are likely to be involved. Body cooling is facilitated by activation of DMH and inhibition of rRPA neurons to induce vasodilation and downregulation of BAT thermogenesis. Inputs to the lateral parabrachial and the preoptic area are modulated by AgRP neuron-mediate inhibition from the arcuate. These detect hunger and put a break on NREM. Satiety induces activation of POMC neurons, that also express TRPV1, are permissive for NREM and induce local inhibition of AgRP neurons. Nitrergic-glutamate neurons may respond to leptin through the leptin Rb, as do AgRP and POMC neurons. They, or a separate local population, may also respond to changes in brain temperature through the TRPM2 ion channel. NO, nitric oxide; NOS1, nitric oxide synthase-1; PO, preoptic area; LPO, lateral preoptic area; vPAG, ventral periaqueductal grey; TMN, tuberomammillary nucleus; ARC, arcuate nucleus; LPb, lateral parabrachial; BAT, brown adipose tissue; AgRP, agouti-related peptide; POMC, pro-opiomelanocortin; DMH, dorsal medial hypothalamus; rRPA, rostral raphe pallidus; RVLM, rostral ventrolateral medulla; TRPM2, transient receptor potential cation channel; TRPV1, transient receptor potential cation channel vallinoid-1; GAL, Galanin (Leshan et al., 2012; Weber and Dan, 2016; Yu et al., 2016; Goldstein et al., 2018; Harding et al., 2018; Jeong et al., 2018; Tan and Knight, 2018; Yu et al., 2019).
FIGURE 4 Signal integration in the preoptic hypothalamus. Warmth on the skin stimulates sensory inputs, through the LPb, to preoptic nitrergic-glutamatergic neurons that initiate simultaneous NREM and body cooling. This maybe through activation of separate GABAergic neurons for sleep and hypothermia in the MPO and LPO, but they may also activate galinergic-GABAergic neurons to initiate sleep and body cooling. The synaptic role of NO is unknown in these circuits but potential sites are labelled. NREM is initiated by inhibition of arousal nuclei, including the TMN and the LH. Others are likely to be involved. Body cooling is facilitated by activation of DMH and inhibition of rRPA neurons to induce vasodilation and downregulation of BAT thermogenesis. Inputs to the lateral parabrachial and the preoptic area are modulated by AgRP neuron-mediate inhibition from the arcuate. These detect hunger and put a break on NREM. Satiety induces activation of POMC neurons, that also express TRPV1, are permissive for NREM and induce local inhibition of AgRP neurons. Nitrergic-glutamate neurons may respond to leptin through the leptin Rb, as do AgRP and POMC neurons. They, or a separate local population, may also respond to changes in brain temperature through the TRPM2 ion channel. NO, nitric oxide; NOS1, nitric oxide synthase-1; PO, preoptic area; LPO, lateral preoptic area; vPAG, ventral periaqueductal grey; TMN, tuberomammillary nucleus; ARC, arcuate nucleus; LPb, lateral parabrachial; BAT, brown adipose tissue; AgRP, agouti-related peptide; POMC, pro-opiomelanocortin; DMH, dorsal medial hypothalamus; rRPA, rostral raphe pallidus; RVLM, rostral ventrolateral medulla; TRPM2, transient receptor potential cation channel; TRPV1, transient receptor potential cation channel vallinoid-1; GAL, Galanin (Leshan et al., 2012; Weber and Dan, 2016; Yu et al., 2016; Goldstein et al., 2018; Harding et al., 2018; Jeong et al., 2018; Tan and Knight, 2018; Yu et al., 2019).CC BY · PubMed Central
FIGURE 5 State transitions at different core temperatures. Sleep, anaesthesia and torpor sit on a continuum of decreasing core temperature that directly influences EEG power. On average NREM bouts are cooler than those of wake whilst brain temperature during REM is warmer. A representative example of NREM EEG at approximately 37°C is shown in green. Sedatives and anaesthetics induces delta oscillations in the EEG but also hypothermia. Dexmedetomidine (DEX; 100 μg/kg IP) induces sustained sedation but the power of the delta oscillations is suppressed. The example is shown in blue, 2 h after injection with core temperature at approximately 26°C. If the same dose of DEX is given to animal in a warm chamber then the power of the delta oscillations recovers. The example is shown in red 2 h after injection with a core temperature at 34°C. Some mammals use daily torpor to save energy during times of food scarcity. On average these are between 15 and 20°C but can range between 10 and 30°C. At approximately 21°C states of torpor may generate a sleep debt that results in recovery sleep on rewarming to 37°C. Artificial hypothermia, sometimes known as synthetic torpor, can be induced by 5-AMP (0.5 g/kg IP). This also induces delta oscillations that are suppressed by hypothermia. The example is shown in blue, 1.5 h after injection with core temperature at approximately 23°C. Below approximately 10°C the EEG is isoelectric and no oscillation can be discerned. Hibernators have periods have interbout euthermia with normal EEG power and wake-NREM and wake-REM transitions are detected. Example species are labelled with the temperature that they have been observed in for either daily torpor or hibernation. This reflects ambient environmental conditions important for EEG measurements but is not a strict hierarchy. EEG examples are from (Harding et al., unpublished) except for the hibernation example which is adapted from Frerichs et al. (1994). IP, intraperitoneal; 5-AMP, adenosine monophosphate. Djungarian hamster (Phodopus sungorus), Golden-mantled ground squirrel (Callospermophilus lateralis), Fat-tailed dwarf lemur (Cheirogaleus medius), Arctic ground squirrel (Urocitellus parryii). Data adapted from Frerichs et al. (1994); Ruf and Geiser (2015), and Vyazovskiy et al. (2017).
FIGURE 5 State transitions at different core temperatures. Sleep, anaesthesia and torpor sit on a continuum of decreasing core temperature that directly influences EEG power. On average NREM bouts are cooler than those of wake whilst brain temperature during REM is warmer. A representative example of NREM EEG at approximately 37°C is shown in green. Sedatives and anaesthetics induces delta oscillations in the EEG but also hypothermia. Dexmedetomidine (DEX; 100 μg/kg IP) induces sustained sedation but the power of the delta oscillations is suppressed. The example is shown in blue, 2 h after injection with core temperature at approximately 26°C. If the same dose of DEX is given to animal in a warm chamber then the power of the delta oscillations recovers. The example is shown in red 2 h after injection with a core temperature at 34°C. Some mammals use daily torpor to save energy during times of food scarcity. On average these are between 15 and 20°C but can range between 10 and 30°C. At approximately 21°C states of torpor may generate a sleep debt that results in recovery sleep on rewarming to 37°C. Artificial hypothermia, sometimes known as synthetic torpor, can be induced by 5-AMP (0.5 g/kg IP). This also induces delta oscillations that are suppressed by hypothermia. The example is shown in blue, 1.5 h after injection with core temperature at approximately 23°C. Below approximately 10°C the EEG is isoelectric and no oscillation can be discerned. Hibernators have periods have interbout euthermia with normal EEG power and wake-NREM and wake-REM transitions are detected. Example species are labelled with the temperature that they have been observed in for either daily torpor or hibernation. This reflects ambient environmental conditions important for EEG measurements but is not a strict hierarchy. EEG examples are from (Harding et al., unpublished) except for the hibernation example which is adapted from Frerichs et al. (1994). IP, intraperitoneal; 5-AMP, adenosine monophosphate. Djungarian hamster (Phodopus sungorus), Golden-mantled ground squirrel (Callospermophilus lateralis), Fat-tailed dwarf lemur (Cheirogaleus medius), Arctic ground squirrel (Urocitellus parryii). Data adapted from Frerichs et al. (1994); Ruf and Geiser (2015), and Vyazovskiy et al. (2017).CC BY · PubMed Central

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  1. Ma, 2019, Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the alpha2 adrenergic agonist dexmedetomidine., bioRxiv, 10.1101/565747 · DOI

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Metadata

Authors
Harding, E. C., Franks, N. P., & Wisden, W.
Affiliations
  • Imperial College London (GB)
  • UK Dementia Research Institute (GB)
Corresponding author
  • Franks, Nicholas P.
  • Wisden, William
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2019-04-24
Volume
13
Pages
336-336
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2019.00336
PMC
PMC6491889
OpenAlex
W2940903564
Cited by
261
References
159
Citations by year
2026: 53 · 2025: 48 · 2024: 40 · 2023: 38 · 2022: 30 · 2021: 28 · 2020: 17 · 2019: 7
FWCI
2.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
Wellcome Trust
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
Keywords
sleep, thermoregulation, core body temperature, brain cooling, circadian rhythm, behavioral thermoregulation, nest building, skin warming, sleep latency, vasodilation, energy homeostasis, sleep function

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