Highlights of PiezoSleep System From Recent Literature
PiezoSleepTM Tracks Sleep in Preclinical Drug Discovery for Narcolepsy and HIV related Sleep Disorders
PiezoSleepTM Tracks Sleep in Preclinical Drug Discovery for Narcolepsy and HIV related Sleep Disorders
A potential treatment for Narcolepsy Type 1 (NT1) has been reported by Orexia Therapeutics. NT1 is due to loss of orexin/hypocretin producing neurons and is characterized by excessive daytime sleepiness, sleep fragmentation, abnormal REM sleep, cataplexy, hypnagogic hallucinations and sleep paralysis. Researchers at Orexia Therapeutics identified small molecule orexin receptor 2 (OX2R) agonists that display equivalent potency to the natural orexin ligand in in vitro OX2R reporter assays. In vivo studies of OXR-849 and OXR-469 were conducted with wildtype and with ATAX mice, which lack orexin producing neurons and display a phenotype similar to human narcolepsy including fragmented sleep and cataplexy. The PiezoSleep system was used to record sleep and wake states in OX2R agonist and placebo treated mice. OX2R agonists dose-dependently promoted wake in both ATAX and wildtype mice. OX2R agonists consolidated wakefulness during the active period and reduced cataplexy bouts in ATAX mice. See details presented at the 2022 European Sleep Research Society Meeting: https://investors.centessa.com/events/event-details/european-sleep-research-society-meeting
Poor sleep health is a prevalent comorbid condition in individuals living with HIV, with common difficulties of falling asleep, maintaining sleep, or early morning awakening. Lack of sleep contributes to other comorbid conditions, further eroding the quality of life of people living with HIV. Johns Hopkins researchers demonstrated for the first time sleep deficits in a mouse model of HIV infection EcoHIV, using the PiezoSleep system to track sleep traits. Differences in the sleep architecture were identified in EcoHIV mice compared to wildtype mice over six day recordings. Sleep was found to be significantly reduced in EcoHIV mice during the first 3 hours of the subjective day (light onset), usually a period of higher sleep for nocturnal mice, under both 12hr light:dark conditions as well as in 24 hr dark conditions. Sleep was also more fragmented, with more frequent and shorter sleep periods compared to wildtype mice, while the total sleep time was the same. Based on evidence that cognitive impairments in HIV are due at least in part to glutamineric imbalance and immune dysfunction in the brain, investigators examined the effect of a brain penetrant glutamine antagonist, JHU083 on sleep deficits and behavior impairments in EcoHIV mice. JHU083 normalized the sleep differences at the light onset period, and partially reversed fragmented sleep in EcoHIV mice, as well as improved the behavioral phenotypes present in this mouse model. Investigators also analyzed biological pathway dysregulation in EcoHIV mice, and demonstrated normalization of pathway components by JHU083. Read more at https://pubmed.ncbi.nlm.nih.gov/35734753/
PiezoSleepTM provides a noninvasive method to assess sleep traits in mouse disease models with disordered sleep. Large numbers of animals can easily be recorded simultaneously, providing a larger sample size for statistical assessment. Automated sleep scoring and sleep analysis tools simplify evaluation of treatment effects on sleep characteristics for both primary and secondary sleep disorders for in vivo drug discovery.
Drug induced alterations in sleep patterns identified with the PiezoSleep system.
Researchers at the University of Texas investigated circadian and sleep altering effects of two drugs used to treat conditions with known circadian components; Verapamil is used to treat cluster headaches, which occur at roughly the same time of day for most patients, and Moricizine was previously used to treat arrhythmia, where cardiac events are known to occur more frequently in the morning.
Following identification of circadian effects of the drugs in vitro, the investigators used the PiezoSleepTM system to assess drug related changes in sleep patterns in mice, identifying alterations in the time of sleep onset, sleep bout-lengths, and in light vs dark period sleep. Verapamil, a calcium channel blocker used to treat cluster headaches, migraines, hypertension, and angina, altered the time of sleep, but not total sleep, in a sex specific manner in mice. Male mice treated with verapamil slept more in the light period; treated female mice slept more in the dark (active) period, with shorter average sleep bout durations. Verapamil reduced activity levels in both sexes, and reduced the free running period both in vitro and in vivo. In a separate study, Moricizine was found to increase the total amount of sleep in mice, particularly in the early dark period, when mice are usually most active. In vitro, Moricizine was found to lengthen the circadian cycle in a dose dependent manner.
These studies highlight the utility of the PiezoSleepTM system for efficiently investigating drug induced changes in sleep patterns without the need for surgery and EEG monitoring, facilitating higher powered studies with larger number of animals in drug screening studies, at lower cost.
Complete publications:
Clock-Modulating Activities of the Anti-Arrhythmic Drug Moricizine
The PiezoSleep system is used to evaluate SARM1 as a target for intervention in Traumatic Brain Injury
Sleep disruption is a common comorbidity of traumatic brain injury (TBI), chronically affecting approximately half of individuals who have had a mild, moderate or severe traumatic brain injury. Researchers at Uniformed Services University included the PiezoSleepTM system in a study to assess the potential of SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) as a target for therapeutic intervention following TBI. SARM1 initiates a programmed pathway that depletes energy stores and results in structural breakdown of axons following injury.
In this model of chronic TBI, atrophy of the corpus collosum, and behavior tests including sleep, were compared in TBI vs sham injured wild type (WT) and SAMR1 knock-out (KO) mice. Longitudinal MRI volumetric measurements of the corpus collosum in mice following TBI at 3 days (acute injury) and ten weeks (chronic stage), compared to baseline (pre-injury) measurements showed a higher level of atrophy in WT mice compared to SARM1 KO mice at ten weeks post-injury. In agreement with this observation, axons of SARM1 KO mice had less damage than axons of WT mice at ten weeks post-injury by multiple histological measures. Sleep studies at eight weeks post-injury identified reduced sleep in WT TBI mice compared to sham treated WT mice, whereas there was no statistical difference in percent sleep between TBI and sham treated SARM1 KO mice. Disrupted sleep in WT TBI mice occurred during the light period, or subjective night, for mice. Collectively, these results provide evidence for preservation of axon integrity and function following TBI when SARM1 is disabled, indicating SARM1 as a viable target for therapeutic intervention. Sleep monitoring indicates that sleep disruption is present in this chronic TBI mouse model, and may be a useful in vivo indicator of progressive disease. Sleep monitoring post-TBI over multiple weeks would be useful to identify when sleep disruption first appears and whether it continues, worsens, or changes over time. Noninvasive sleep tracking with PiezoSleepTM is ideal for longitudinal data collection in TBI models, where mice have already experienced brain trauma, with the added benefit of lower cost and automated data collection in multiple groups of mice.
Link to publication:
Mechanisms of homeostatic regulation of GABA type A receptors by accessory protein Shisa7, with observed differences in tonic inhibition in sleep and wake.
Researchers at the National Institute of Health investigated the role of Shisa7 in modulating tonic inhibition in the hippocampus using cultured hippocampal CA1 neurons, mouse hippocampal slices, and by comparing tonic current in sleep and wake states in Shisa7 Knockout (KO) and wild-type (WT) mice.
The results from this study provide evidence that PKA phosphorylation of Shisa7 promotes exocytosis of α5-GABAAR, thereby increasing tonic inhibition in the hippocampus via increased levels of α5-GABAAR at the extrasynaptic neuronal surface. Differences in tonic inhibition mediated by Shisa7 in sleep and wake states were investigated by measuring tonic current in hippocampal slices from WT and Shisa7 Knockout KO mice that had been in extended sleep or wake states (4 hours), monitored by the PiezoSleepTM system, at the time of sacrifice. Tonic current was found to be higher during wake than in sleep, and modulated by Shisa7, as observed by sleep vs wake differences in WT mice that were not present in Shisa7 KO mice.
Link to publication:
Activity- and sleep-dependent regulation of tonic inhibition by Shisa7
Research
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Lord, J. S., S. M. Gay, K. M. Harper, V. D. Nikolova, K. M. Smith, S. S. Moy and G. H. Diering, 2022. Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice. Mol Autism 131: 35.
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Burish, M.J., Han, C., Mawatari, K., Wirianto, M., Kim, E., Ono, K., Parakramaweera, R., Chen, Z., Yoo, S.H., 2021. The first-line cluster headache medication verapamil alters the circadian period and elicits sex-specific sleep changes in mice. Chronobiol Int, 1-12.
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Saber, M., Giordano, K.R., Hur, Y., Ortiz, J.B., Morrison, H., Godbout, J.P., Murphy, S.M., Lifshitz, J., Rowe, R.K., 2020. Acute peripheral inflammation and post-traumatic sleep differ between sexes after experimental diffuse brain injury. The European journal of neuroscience 52, 2791-2814.
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Robinson-Junker, A., O’Hara, B., Durkes, A., Gaskill, B., 2019. Sleeping through anything: The effects of unpredictable disruptions on mouse sleep, healing, and affect. PloS one 14, e0210620.
Phillips, S., Xiong, H., Donohue, KD, O’Hara, BF., Lonstein, JS., Yan, L., 2019. Too sad to sleep? Sleep patterns in a rodent SAD model analyzed by the piezoelectric system. Society for Neuroscience Meeting, Chicago, 2019.
Paulose, J.K., Wang, C., O’Hara, B.F., Cassone, V.M., 2019. The effects of aging on sleep parameters in a healthy, melatonin-competent mouse model. Nature and science of sleep 11, 113-121.
Onos, K.D., Uyar, A., Keezer, K.J., Jackson, H.M., Preuss, C., Acklin, C.J., O’Rourke, R., Buchanan, R., Cossette, T.L., Sukoff Rizzo, S.J., Soto, I., Carter, G.W., Howell, G.R., 2019. Enhancing face validity of mouse models of Alzheimer’s disease with natural genetic variation. PLoS Genet 15, e1008155.
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Huffman, D., Ajwad, AA., Wang, J., Murphy MP., O’Hara, BF., Duncan, MJ., 2019. Feasibility of dynamic sleep enhancement in a mouse model of Alzheimer’s disease. Society for Neuroscience Meeting, Chicago, 2019
Hou T, W.C.J.S., O’Hara BF, Gong MC and Guo Z 2019. Active Time-Restricted Feeding Improved Sleep-Wake Cycle in db/db Mice. Front. Neurosci. 13.
Holth, J.K., Fritschi, S.K., Wang, C., Pedersen, N.P., Cirrito, J.R., Mahan, T.E., Finn, M.B., Manis, M., Geerling, J.C., Fuller, P.M., Lucey, B.P., Holtzman, D.M., 2019. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363, 880-884.
Guerriero, R., Harrison, DA., Shaw, P., O’Hara, BF., 2019. Investigation novel-sleep related genes in Drosophila melanogaster: A follow up on KOMP2 identified genes in Mus musculus. Society for Neuroscience Meeting, Chicago, 2019.
Goodwin, L.O., Splinter, E., Davis, T.L., Urban, R., He, H., Braun, R.E., Chesler, E.J., Kumar, V., van Min, M., Ndukum, J., Philip, V.M., Reinholdt, L.G., Svenson, K., White, J.K., Sasner, M., Lutz, C., Murray, S.A., 2019. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. Genome Res 29, 494-505.
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Duncan, M., Askarov E., Baker, A., Beechem, I., Gillis, BD., Salisbury, F., Guerriero, R., O’Hara, BF., Bachstetter, AD., Murphy, MP., 2019. The effects of fragmentation of the daily sleep-wake rhythm on amyloid-beta levels and neuroinflammation in the 3X Tg-AD mouse model of Alzheimer’s disease. Society for Neuroscience Meeting, Chicago, 2019.
Rowe, R.K., Harrison, J.L., Zhang, H., Bachstetter, A.D., Hesson, D.P., O’Hara, B.F., Greene, M.I., Lifshitz, J., 2018. Novel TNF receptor-1 inhibitors identified as potential therapeutic candidates for traumatic brain injury. J Neuroinflammation 15, 154.
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Harrison, J.L., Rowe, R.K., Ellis, T.W., Yee, N.S., O’Hara, B.F., Adelson, P.D., Lifshitz, J., 2015. Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse. Brain Behav Immun 47, 131-140.
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Development
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Klefot, J. M., Murphy, J. L., Donohue, K. D., O’Hara, B. F., Lhamon, M. E., & Bewley, J. M. (2016). Development of a noninvasive system for monitoring dairy cattle sleep. J Dairy Sci, 99(10), 8477-8485. doi:10.3168/jds.2015-10695
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