212 results found
Yu X, Zhao G, Wang D, et al., 2022, A specific circuit in the midbrain detects stress and induces restorative sleep, Science, Vol: 377, Pages: 1-10, ISSN: 1095-9203
In mice, social defeat stress (SDS), an ethological model for psychosocial stress, induces sleep. Such sleep could enable resilience, but how stress promotes sleep is unclear. Activity - dependent tagging revealed a subset of ventral tegmental area GABA-somatostatin (VTAVgat-Sst) cells that sense stress and drive NREM and REM sleep via the lateral hypothalamus, andalso inhibit corticotropin-releasing factor (CRF) release in the paraventricular hypothalamus. Transient stress enhances the activity of VTA Vgat-Sst cells for several hours, allowing them to exert their sleep effects persistently. Lesioning of VTAVgat-Sst cells abolished SDS-induced sleep; without it, anxiety and corticosterone levels remained elevated after stress. Thus, aspecific circuit allows animals to restore mental and body functions via sleeping, potentially providing a refined route for treating anxiety disorders.
Miracca G, Anuncibay Soto B, Tossell K, et al., 2022, NMDA receptors in the lateral preoptic hypothalamus are essential for sustaining NREM and REM sleep, The Journal of Neuroscience, Vol: 42, Pages: 5389-5409, ISSN: 0270-6474
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, NMDA26 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 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). By contrast, fragmentation persisted under high sleeppressure produced by sleep deprivation - mice had a high propensity to sleep but woke up. By analyzing changes in delta 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.
Franks NP, Wisden W, 2021, The inescapable drive to sleep: Overlapping mechanisms of sleep and sedation, SCIENCE, Vol: 374, Pages: 556-559, ISSN: 0036-8075
Harding EC, Ba W, Zahir R, et al., 2021, Nitric oxide synthase neurons in the preoptic hypothalamus are NREM and REM sleep-active and lower body temperature, Frontiers in Neuroscience, Vol: 15, ISSN: 1662-453X
When mice are exposed to external warmth, nitric oxide synthase (NOS1) neurons in the median and medial preoptic (MnPO/MPO) hypothalamus induce sleep and concomitant body cooling. However, how these neurons regulate baseline sleep and body temperature is unknown. Using calcium photometry, we show that NOS1 neurons in MnPO/MPO are predominantly NREM and REM active, especially at the boundary of wake to NREM transitions, and in the later parts of REM bouts, with lower activity during wakefulness. In addition to releasing nitric oxide, NOS1 neurons in MnPO/MPO can release GABA, glutamate and peptides. We expressed tetanus-toxin light-chain in MnPO/MPO NOS1 cells to reduce vesicular release of transmitters. This induced changes in sleep structure: over 24 h, mice had less NREM sleep in their dark (active) phase, and more NREM sleep in their light (sleep) phase. REM sleep episodes in the dark phase were longer, and there were fewer REM transitions between other vigilance states. REM sleep had less theta power. Mice with synaptically blocked MnPO/MPO NOS1 neurons were also warmer than control mice at the dark-light transition (ZT0), as well as during the dark phase siesta (ZT16-20), where there is usually a body temperature dip. Also, at this siesta point of cooled body temperature, mice usually have more NREM, but mice with synaptically blocked MnPO/MPO NOS1 cells showed reduced NREM sleep at this time. Overall, MnPO/MPO NOS1 neurons promote both NREM and REM sleep and contribute to chronically lowering body temperature, particularly at transitions where the mice normally enter NREM sleep.
Pires RC, Macdonald W, Edge CJ, et al., 2021, Xenon prevents neuroinflammation in a novel model of blast traumatic brain injury in rats, European Society for Anaesthesiology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 947-947, ISSN: 0003-2999
Pires RC, Mohamed-Ali N, Aldhoun J, et al., 2021, Moderate hypothermia combined with xenon, but not hypothermia alone, reduces secondary injury development after traumatic brain injury in rats, ropean Society for Anaesthesiology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 946-946, ISSN: 0003-2999
Yu X, Ba W, Zhao G, et al., 2021, Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior, Molecular Psychiatry, Vol: 26, Pages: 5213-5228, ISSN: 1359-4184
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Campos-Pires R, Onggradito H, Ujvari E, et al., 2021, The noble gas xenon is neuroprotective and promotes beneficial neuroinflammation following severe neurotrauma in rats, 38th National Neurotrauma Symposium, Publisher: Mary Ann Liebert, Pages: A114-A114, ISSN: 0897-7151
Harding EC, Ba W, Zahir R, et al., 2021, Nitric oxide synthase neurons in the preoptic hypothalamus are sleep-active and contribute to regulating NREM and REM sleep and lowering body temperature, Publisher: Cold Spring Harbor Laboratory
When mice are exposed to external warmth, nitric oxide synthase (NOS1) neurons in the median and medial preoptic (MnPO/MPO) hypothalamus induce sleep and concomitant body cooling. However, how these neurons regulate baseline sleep and body temperature is unknown. Using calcium photometry, we show that NOS1 neurons in MnPO/MPO are predominantly NREM active. This is the first instance of a predominantly NREM-active population in the PO area, or to our knowledge, elsewhere in the brain. In addition to releasing nitric oxide, NOS1 neurons in MnPO/MPO can release GABA, glutamate and peptides. We expressed tetanus-toxin light-chain in MnPO/MPO NOS1 cells to reduce vesicular release of transmitters. This induced changes in sleep structure: over 24 hours, mice had less NREM sleep in their dark (active) phase, and more NREM sleep in their light (sleep) phase. REM sleep episodes in the dark phase were longer, and there were fewer REM transitions between other vigilance states. REM sleep had less theta power. Mice with synaptically blocked MnPO/MPO NOS1 neurons were also warmer. In particular, mice were warmer than control mice at the dark-light transition (ZT0), as well as during the dark phase siesta (ZT16-20), where there is usually a body temperature dip. Also, at this siesta point of cooled body temperature, mice usually have more NREM, but mice with synaptically blocked MnPO/MPO NOS1 cells showed reduced NREM sleep at this time. Overall, MnPO/MPO NOS1 neurons promote both NREM and REM sleep and contribute to chronically lowering body temperature, particularly at transitions where the mice normally enter NREM sleep.
Campos-Pires R, Onggradito H, Ujvari E, et al., 2021, Xenon is neuroprotective and promotes beneficial early neuroinflammation in a rat model of severe traumatic brain injury, Society for Neuroscience
Campos-Pires R, Onggradito H, Ujvari E, et al., 2021, Xenon is neuroprotective and promotes beneficial early neuroinflammation in a rat model of severe traumatic brain injury, Society for Neuroscience
Yu X, Franks NP, Wisden W, 2021, Brain Clocks, Sleep, and Mood, CIRCADIAN CLOCK IN BRAIN HEALTH AND DISEASE, Vol: 1344, Pages: 71-86, ISSN: 0065-2598
Campos-Pires R, Onggradito H, Ujvari E, et al., 2020, Xenon treatment after severe traumatic brain injury improves locomotor outcome, reduces acute neuronal loss and enhances early beneficial neuroinflammation: a randomized, blinded, controlled animal study, Critical Care (UK), Vol: 24, Pages: 1-18, ISSN: 1364-8535
BackgroundTraumatic brain injury (TBI) is a major cause of morbidity and mortality, but there are no clinically proven treatments that specifically target neuronal loss and secondary injury development following TBI. In this study, we evaluate the effect of xenon treatment on functional outcome, lesion volume, neuronal loss and neuroinflammation after severe TBI in rats.MethodsYoung adult male Sprague Dawley rats were subjected to controlled cortical impact (CCI) brain trauma or sham surgery followed by treatment with either 50% xenon:25% oxygen balance nitrogen, or control gas 75% nitrogen:25% oxygen. Locomotor function was assessed using Catwalk-XT automated gait analysis at baseline and 24 h after injury. Histological outcomes were assessed following perfusion fixation at 15 min or 24 h after injury or sham procedure.ResultsXenon treatment reduced lesion volume, reduced early locomotor deficits, and attenuated neuronal loss in clinically relevant cortical and subcortical areas. Xenon treatment resulted in significant increases in Iba1-positive microglia and GFAP-positive reactive astrocytes that was associated with neuronal preservation.ConclusionsOur findings demonstrate that xenon improves functional outcome and reduces neuronal loss after brain trauma in rats. Neuronal preservation was associated with a xenon-induced enhancement of microglial cell numbers and astrocyte activation, consistent with a role for early beneficial neuroinflammation in xenon’s neuroprotective effect. These findings suggest that xenon may be a first-line clinical treatment for brain trauma.
Miracca G, Soto BA, Tossell K, et al., 2020, Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep
<jats:title>SUMMARY</jats:title><jats:p>The preoptic hypothalamus regulates both NREM and REM sleep. We found that calcium levels in mouse lateral preoptic (LPO) neurons were highest during REM. Deleting the core GluN1 subunit of NMDA receptors from LPO neurons abolished calcium signals during all vigilance states, and the excitatory drive onto LPO neurons was reduced. Mice had less NREM sleep and were incapable of generating conventionally classified REM sleep episodes: cortical theta oscillations were greatly reduced but muscle atonia was maintained. Additionally, mice lacking NMDA receptors in LPO neurons had highly fragmented sleep-wake patterns. The fragmentation persisted even under high sleep pressure produced by sleep deprivation. Nevertheless, the sleep homeostasis process remained intact, with an increase in EEG delta power. The sedative dexmedetomidine and sleeping medication zolpidem could transiently restore consolidated sleep. High sleep-wake fragmentation, but not sleep loss, was also produced by selective GluN1 knock-down in GABAergic LPO neurons. We suggest that NMDA glutamate receptor signalling stabilizes the firing of “GABAergic NREM sleep-on” neurons and is also essential for the theta rhythm in REM sleep.</jats:p>
Lignos L, Nollet M, Wisden W, et al., 2020, Does sleep deprivation cause stress in mice? A comparison of gentle handling versus novel object presentation sleep deprivation methods, 25th Congress of the European-Sleep-Research-Society (ESRS), Publisher: WILEY, Pages: 195-196, ISSN: 0962-1105
Tossell K, Yu X, Soto BA, et al., 2020, Sleep deprivation triggers somatostatin neurons in prefrontal cortex to initiate nesting and sleep via the preoptic and lateral hypothalamus, Publisher: bioRxiv
Animals undertake specific behaviors before sleep. Little is known about whether these innate behaviors, such as nest building, are actually an intrinsic part of the sleep-inducing circuitry. We found, using activity-tagging genetics, that mouse prefrontal cortex (PFC) somatostatin/GABAergic (SOM/GABA) neurons, which become activated during sleep deprivation, induce nest building when opto-activated. These tagged neurons induce sustained global NREM sleep if their activation is prolonged metabotropically. Sleep-deprivation-tagged PFC SOM/GABA neurons have long-range projections to the lateral preoptic (LPO) and lateral hypothalamus (LH). Local activation of tagged PFC SOM/GABA terminals in LPO and the LH induced nesting and NREM sleep respectively. Our findings provide a circuit link for how the PFC responds to sleep deprivation by coordinating sleep preparatory behavior and subsequent sleep.
Campos-Pires R, Mohamed-Ali N, Franks N, et al., 2020, Hypothermia combined with xenon reduces secondary injury development and enhances neuroprotection by preventing neuronal cell loss in a rat model of traumatic brain injury, European Journal of Anaesthesia vol e37, Pages: 300-300
Harding EC, Franks NP, Wisden W, 2020, Sleep and thermoregulation, Current Opinion in Physiology, Vol: 15, Pages: 7-13, ISSN: 2468-8673
Nollet M, Wisden W, Franks N, 2020, Sleep deprivation and stress - a reciprocal relationship, Interface Focus, Vol: 10, Pages: 1-11, ISSN: 2042-8901
Sleep is highly conserved across evolution, suggesting vital biological functions that are yet to be fully understood. Animals and humans experiencing partial sleep restriction usually exhibit detrimental physiological responses, while total and prolonged sleep loss could lead to death. The perturbation of sleep homeostasis is usually accompanied by an increase of the hypothalamic-pituitary-adrenal (HPA) axis, leading to a rise of circulating level of stress hormones (e.g., cortisol in humans, corticosterone in rodents). Such hormones follow a circadian release pattern under undisturbed conditions and participate in the regulation of sleep. The investigation of the consequences of sleep deprivation, from molecular changes to behavioural alterations, has been used to study the fundamental functions of sleep. However, the reciprocal relationship between sleep and the activity of the HPA axis is problematic when investigating sleep using traditional sleep-deprivation protocols that can induce stress per se. This is especially true in studies using rodents in which sleep deprivation is achieved by exogenous, and potentially stressful, sensory-motor stimulations that can undoubtedly confuse their conclusions. While more research is needed to explore the mechanisms underlying sleep loss and health, avoiding stress as a confounding factor in sleep-deprivation studies is therefore crucial. This review examines the evidence of the intricate links between sleep and stress in the context of experimental sleep deprivation, and proposes a more sophisticated research framework for sleep-deprivation procedures that could benefit from recent progress in biotechnological tools for precise neuromodulation, such as chemogenetics and optogenetics, as well as improved automated real-time sleep scoring algorithms.
Wisden W, Franks NP, 2020, The stillness of sleep., Scienc, Vol: 367, Pages: 366-367, ISSN: 1095-9203
Hsieh B, Harding E, Wisden W, et al., 2019, A miniature neural recording device to investigate sleep and temperature regulation in mice, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 1-4
Sleep is an important and ubiquitous process that,despite decades of research, a large part of its underlyingbiological circuity still remain elusive. To conduct research inthis field, many devices capable of recording neural signalssuch as LFP and EEG have been developed. However, most ofthese devices are unsuitable for sleep studies in mice, the mostcommonly used animals, due to their size and weight. Thus, thispaper presents a novel 4 channel, compact ( 2.1cm by 1.7cm )and lightweight ( 3.6g ) neural-logging device that can recordfor 3 days on just two 0.6g zinc air 312 batteries. Instead ofthe typical solution of using multiple platforms, the presenteddevice integrates high resolution EEG, EMG and temperaturerecordings into one platform. The onboard BLE module allowsthe device to be controlled wirelessly as well as stream data in realtime, enabling researchers to check the progress of the recordingwith minimal animal disturbance. The device demonstrates itsability to accurately record EEG and temperature data throughthe long 24 hour in-vivo recordings conducted. The obtainedEEG data could be easily sleep scored and the temperaturesvalues were all within expected physiological range.
Koziakova M, Harris K, Edge C, et al., 2019, Noble gas neuroprotection: Xenon and argon protect against hypoxic-ischaemic injury in rat hippocampus in vitro via distinct mechanisms, British Journal of Anaesthesia, Vol: 123, Pages: 601-609, ISSN: 1471-6771
BackgroundNoble gases may provide novel treatments for neurological injuries such as ischaemic and traumatic brain injury. Few studies have evaluated the complete series of noble gases under identical conditions in the same model.MethodsWe used an in vitro model of hypoxia–ischaemia to evaluate the neuroprotective properties of the series of noble gases, helium, neon, argon, krypton, and xenon. Organotypic hippocampal brain slices from mice were subjected to oxygen-glucose deprivation, and injury was quantified using propidium iodide fluorescence.ResultsBoth xenon and argon were equally effective neuroprotectants, with 0.5 atm of xenon or argon reducing injury by 96% (P<0.0001), whereas helium, neon, and krypton were devoid of any protective effect. Neuroprotection by xenon, but not argon, was reversed by elevated glycine.ConclusionsXenon and argon are equally effective as neuroprotectants against hypoxia–ischaemia in vitro, with both gases preventing injury development. Although xenon's neuroprotective effect may be mediated by inhibition of the N-methyl-d-aspartate receptor at the glycine site, argon acts via a different mechanism. These findings may have important implications for their clinical use as neuroprotectants.
Ma Y, Miracca G, Yu X, et al., 2019, Galanin Neurons Unite Sleep Homeostasis and α2-Adrenergic Sedation., Current biology : CB, Vol: 29, Pages: 3315-3322.e3, ISSN: 0960-9822
Our urge to sleep increases with time spent awake, until sleep becomes inescapable. The sleep following sleep deprivation is longer and deeper, with an increased power of delta (0.5-4 Hz) oscillations, a phenomenon termed sleep homeostasis [1-4]. Although widely expressed genes regulate sleep homeostasis [1, 4-10] and the process is tracked by somnogens and phosphorylation [1, 3, 7, 11-14], at the circuit level sleep homeostasis has remained mysterious. Previously, we found that sedation induced with α2-adrenergic agonists (e.g., dexmedetomidine) and sleep homeostasis both depend on the preoptic (PO) hypothalamus [15, 16]. Dexmedetomidine, increasingly used for long-term sedation in intensive care units , induces a non-rapid-eye-movement (NREM)-like sleep but with undesirable hypothermia [18, 19]. Within the PO, various neuronal subtypes (e.g., GABA/galanin and glutamate/NOS1) induce NREM sleep [20-22] and concomitant body cooling [21, 22]. This could be because NREM sleep's restorative effects depend on lower body temperature [23, 24]. Here, we show that mice with lesioned PO galanin neurons have reduced sleep homeostasis: in the recovery sleep following sleep deprivation there is a diminished increase in delta power, and the mice catch up little on lost sleep. Furthermore, dexmedetomidine cannot induce high-power delta oscillations or sustained hypothermia. Some hours after dexmedetomidine administration to wild-type mice there is a rebound in delta power when they enter normal NREM sleep, reminiscent of emergence from torpor. This delta rebound is reduced in mice lacking PO galanin neurons. Thus, sleep homeostasis and dexmedetomidine-induced sedation require PO galanin neurons and likely share common mechanisms.
Campos-Pires R, Mohamed-Ali N, Balaet M, et al., 2019, Xenon prevents early neuronal loss and neuroinflammation in a rat model of traumatic brain injury, BJA Research Forum / Anaesthetic Research Society, Publisher: Elsevier, Pages: e508-e509, ISSN: 0007-0912
Yu X, Ma Y, Harding EC, et al., 2019, Corrigendum: Genetic lesioning of histamine neurons increases sleep-wake fragmentation and reveals their contribution to modafinil-induced wakefulness., Sleep, Vol: 42
Campos-Pires R, Hirnet T, Valeo F, et al., 2019, XENON PREVENTS NEURODEGENERATION AND LATE-ONSET COGNITIVE IMPAIRMENT, AND IMPROVES SURVIVAL AFTER TRAUMATIC BRAIN INJURY IN MICE, 37th Annual National Neurotrauma Symposium, Publisher: MARY ANN LIEBERT, INC, Pages: A47-A47, ISSN: 0897-7151
Campos-Pires R, Yonis A, Pau A, et al., 2019, Delayed xenon treatment prevents injury development following blast-neurotrauma in vitro, 37th Annual National Neurotrauma Symposium, Publisher: Mary Ann Liebert, Pages: A40-A41, ISSN: 0897-7151
Campos-Pires R, Mohamed-Ali N, Balaet M, et al., 2019, XENON REDUCES SECONDARY INJURY, PREVENTS NEURONAL LOSS AND NEUROINFLAMMATION IN A RAT MODEL OF TRAUMATIC BRAIN INJURY, 37th Annual National Neurotrauma Symposium, Publisher: MARY ANN LIEBERT, INC, Pages: A116-A116, ISSN: 0897-7151
Campos-Pires R, Hirnet T, Valeo F, et al., 2019, Xenon improves long-term cognitive function, reduces neuronal loss and chronic neuroinflammation, and improves survival after traumatic brain injury in mice, British Journal of Anaesthesia, Vol: 123, Pages: 60-73, ISSN: 1471-6771
Background.Xenon is a noble gas with neuroprotective properties. We previously showed that xenon improves short and long-term outcomes in young adult mice after controlled cortical impact (CCI). This is a follow-up study investigating xenon’s effect on very long-term outcome and survival. Methods.C57BL/6N (n=72) young adult male mice received single CCI or sham surgery and were treated with either xenon (75%Xe:25%O2) or control gas (75% N2:25%O2). The outcomes used were: 1) 24-hour lesion volume and neurological outcome score; 2)contextual fear-conditioning at 2 weeks and 20 months; 3) corpus callosum white matter quantification; 4) immunohistological assessment of neuroinflammation and neuronal loss; 5) long-term survival. Results.Xenon treatment significantly reduced secondary injury development (p<0.05), improved short-term vestibulomotor function (p<0.01),and prevented development of very late-onset traumatic brain injury (TBI)-related memory deficits. Xenon treatment reducedwhite matter loss in the contralateral corpus callosum and neuronal loss in the contralateral hippocampal CA1 andDG areas at 20 months. Xenon’s long-term neuroprotective effects were associated with a significant (p<0.05) reduction in neuroinflammation in multiple brain areas involved in associative memory, including reduction in reactive astrogliosis and microglial cell proliferation. Survival was improved significantly (p<0.05) in xenon-treated animals, compared to untreated animals up to 12 months after injury.Conclusions.These results show that xenon treatment after TBI results in very long-term improvements in clinically relevant outcomes and survival. Our findings support the idea that xenon treatment shortly after TBI may have long-term benefits in the treatment of brain trauma patients.
Yu X, Ba W, Zhao G, et al., 2019, Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior
Abstract The ventral tegmental area (VTA), an important source of dopamine, regulates goal- and reward-directed and social behaviors, wakefulness and sleep. Hyperactivation of dopamine neurons generates behavioral pathologies. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Lesioning or chemogenetically inhibiting VTA GABAergic (VTA Vgat ) neurons generated persistent wakefulness with mania-like qualities: locomotor activity was increased; sensitivity to D-amphetamine was heightened; immobility times decreased on the tail suspension and forced swim tests; and sucrose preference increased. Furthermore, after sleep deprivation, mice with lesioned VTA Vgat neurons did not catch up on the lost NREM sleep, even though they were starting from an already highly sleep-deprived baseline, suggesting that the sleep homeostasis process was bypassed. The mania-like behaviors, including the sleep loss, were reversed by the mood-stabilizing drug valproate, and re-emerged when valproate treatment was stopped. Lithium salts, however, had no effect. The mania like-behaviors partially depended on dopamine, because giving D1/D2/D3 receptor antagonists partially restored the behaviors, but also on VTA Vgat projections to the lateral hypothalamus (LH). Optically or chemogenetically inhibiting VTA Vgat terminals in the LH elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. VTA Vgat neurons are centrally positioned to help set an animal’s (and human’s) level of mental and physical activity. Inputs that inhibit VTA Vgat neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival. Taken to the extreme, however, decreased or failed inhibition from VTA Vgat neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).
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