title: An EEG Investigation of Sleep Homeostasis in Healthy and CLN5 Batten Disease Affected Sheep.
abstract: Sheep have large brains with human-like anatomy, making them a useful species for studying brain function. Sleep homeostasis has not been studied in sheep. Here, we establish correlates of sleep homeostasis in sheep through a sleep deprivation experiment. We then use these correlates to elucidate the nature of sleep deficits in a naturally occurring ovine model of neuronal ceroid lipofuscinosis (NCL, Batten disease) caused by a mutation in CLN5 In humans, mutations in this gene lead to cortical atrophy and blindness, as well as sleep abnormalities. We recorded electroencephalograms (EEGs) from unaffected and early stage CLN5(-/-) (homozygous, affected) sheep over 3 consecutive days, the second day being the sleep deprivation day. In unaffected sheep, sleep deprivation led to increased EEG delta (0.5-4 Hz) power during non-rapid eye movement (NREM) sleep, increased time spent in the NREM sleep state, and increased NREM sleep bout length. CLN5(-/-) sheep showed comparable increases in time spent in NREM sleep and NREM sleep bout duration, verifying the presence of increased sleep pressure in both groups. Importantly, CLN5(-/-) sheep did not show the increase in NREM sleep delta power seen in unaffected sheep. This divergent delta power response is consistent with the known cortical degeneration in CLN5(-/-) sheep. We conclude that, whereas sleep homeostasis is present in CLN5(-/-) sheep, underlying CLN5(-/-) disease processes prevent its full expression, even at early stages. Such deficits may contribute to early abnormalities seen in sheep and patients and warrant further study.
  
  
  
  Sleep abnormalities pervade most neurological diseases, including the neuronal ceroid lipofuscinoses (NCLs). Here, we show that, in an ovine model of a variant late-infantile NCL, there is abnormal expression of sleep homeostasis. Whereas some sleep pressure correlates respond to sleep deprivation, the strongest electroencephalogram (EEG) correlate of sleep pressure, non-REM delta power, failed to increase. This highlights the relevance of sleep deficits in this disease, in which the drive for sleep exists but the underlying disease prevents its full expression. Sleep abnormalities could contribute to early disease symptoms such as behavioral disorder and cognitive decline. Our study also shows sleep homeostatic EEG correlates in sheep, opening up new opportunities for studying sleep in a large social mammal with complex human-like brain neuroanatomy.
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
authors.forename: Nicholas
authors.identifier: 0000-0001-9336-6180
authors.initials: N
authors.lastname: Perentos
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
authors.forename: Amadeu Q
authors.identifier: 0000-0001-8227-351X
authors.initials: AQ
authors.lastname: Martins
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
authors.forename: Robin J M
authors.identifier: 0000-0002-6380-2014
authors.initials: RJ
authors.lastname: Cumming
authors.affiliation: Department of Molecular Biosciences, Faculty of Agricultural and Life Sciences, Lincoln University, Lincoln 7647, New Zealand, and.
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Mitchell
authors.affiliation: Department of Molecular Biosciences, Faculty of Agricultural and Life Sciences, Lincoln University, Lincoln 7647, New Zealand, and.
authors.forename: David N
authors.initials: DN
authors.lastname: Palmer
authors.affiliation: Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawiak
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom, ajm41@cam.ac.uk.
authors.forename: A Jennifer
authors.identifier: 0000-0003-0181-6346
authors.initials: AJ
authors.lastname: Morton
mesh_terms: D000818:Animals; D001921:Brain / Q000503:physiopathology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D006706:Homeostasis; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000503:physiopathology*; D012016:Reference Values; D012756:Sheep; D012892:Sleep Deprivation / Q000503:physiopathology*; D012894:Sleep Stages
chemical_list: D008565:Membrane Proteins
keywords: EEG; neuronal ceroid lipofuscinosis; sheep; sleep deprivation; sleep homeostasis; thalamus