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Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep\/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach<\/jats:title><jats:p>Three 8\u2010week experiments were conducted with wild\u2010type and rTg4510 mice after age of onset of hyperarousal (4.5\u2009months): (1) Tau transgene suppression with doxycycline (200\u2009ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>); or (3) Active phase non\u2010NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX<jats:sub>2<\/jats:sub>) receptor antagonist MK\u20101064 (40\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and\/or immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Tau transgene suppression improved tauopathy and hippocampal\u2010dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX<jats:sub>2<\/jats:sub> receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX<jats:sub>2<\/jats:sub> receptor antagonism induced only short\u2010lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau\u2010 and sex\u2010dependent disruption of OX<jats:sub>2<\/jats:sub> receptor signalling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Pharmacologically reducing hyperarousal corrects tau\u2010induced sleep\/wake and cognitive deficits. Tauopathy causes sex\u2010dependent disruptions of OX<jats:sub>2<\/jats:sub> receptor signalling\/function, which may have implications for choice of hypnotic therapeutics in tauopathies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16212","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T06:05:28Z","timestamp":1691561128000},"page":"87-106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Orexin 2 receptor antagonism sex\u2010dependently improves sleep\/wakefulness and cognitive performance in tau transgenic mice"],"prefix":"10.1111","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0768-0582","authenticated-orcid":false,"given":"Ryan J.","family":"Keenan","sequence":"first","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health  Parkville Victoria Australia"},{"name":"Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Daykin","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health  Parkville Victoria Australia"},{"name":"Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Metha","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health  Parkville Victoria Australia"},{"name":"Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne  Parkville Victoria Australia"},{"name":"Department of Finance, Faculty of Business and Economics The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Cornthwaite\u2010Duncan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David K.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Central Clinical School Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyra","family":"Clarke","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Oberrauch","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health  Parkville Victoria Australia"},{"name":"Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddison","family":"Brian","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health  Parkville Victoria Australia"},{"name":"Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Stephenson","sequence":"additional","affiliation":[{"name":"Bruce Lefroy Centre Murdoch Children's Research Institute  Parkville Victoria Australia"},{"name":"Department of Paediatrics The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron J.","family":"Nowell","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology Monash Institute of Pharmaceutical Sciences  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Allocca","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health  Parkville Victoria Australia"},{"name":"Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne  Parkville Victoria Australia"},{"name":"Somnivore Inc. 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