{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:22:29Z","timestamp":1792664549089,"version":"4.5.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["PRMRP:161864"],"award-info":[{"award-number":["PRMRP:161864"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS104612-01A1"],"award-info":[{"award-number":["R21NS104612-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS116546"],"award-info":[{"award-number":["R21NS116546"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Study Objectives<\/jats:title>\n                  <jats:p>Traumatic brain injury (TBI) can result in posttraumatic epilepsy (PTE) and sleep disturbances. We hypothesized that treatment with sleep aids after TBI can ameliorate PTE.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>CD-1 mice underwent controlled cortical impact (CCI), sham injury, or no craniotomy. Sham and CCI groups underwent a monthlong daily treatment with sleep aids including a dual orexin antagonist (DORA-22) or THIP (gaboxadol) or a respective vehicle starting on the day of CCI. We performed continuous EEG (electroencephalography) recordings at week 1 and months 1, 2, and 3 for ~1 week each time. Seizure analysis occurred at all-time points and sleep analysis occurred in week 1 and month-1\/2 in all groups. Subsets of CCI and sham groups were subjected to voltageclamp experiments in hippocampal slices to evaluate GABAergic synaptic inhibition.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>DORA-22 treatment suppressed seizures in month 1\u20133 recordings. TBI reduced the amplitude and frequency of miniature inhibitory synaptic currents (mIPSCs) in dentate granule cells and these changes were rescued by DORA-22 treatment. Sleep analysis showed that DORA-22 increased nonrapid eye movement (NREM) sleep during lights-off whereas THIP increased REM sleep during lights-on in week 1. Both treatments displayed subtle changes in time spent in NREM or REM at month-1\/2 as well. TBI not only increased normalized EEG delta power (N\u0394) at week-1 and month-1 but also resulted in the loss of the homeostatic diurnal oscillation of N\u0394, which was restored by DORA-22 but not THIP treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Dual orexin antagonists may have a therapeutic potential in suppressing PTE potentially by enhancing GABAergic inhibition and impacting sleep homeostatic drive.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/sleep\/zsac238","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T16:17:48Z","timestamp":1664295468000},"source":"Crossref","is-referenced-by-count":18,"title":["Dual orexin antagonist normalized sleep homeostatic drive, enhanced GABAergic inhibition, and suppressed seizures after traumatic brain injury"],"prefix":"10.1093","volume":"45","author":[{"given":"Sruthi R","family":"Konduru","sequence":"first","affiliation":[{"name":"Department of Neurology, Wayne State University , Detroit, MI , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse R","family":"Isaacson","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Wisconsin School of Medicine and Public Health , Madison, WI , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1814-5713","authenticated-orcid":false,"given":"Danny J","family":"Lasky","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Wisconsin School of Medicine and Public Health , Madison, WI , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Rock Bridge High School , Columbia, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan K","family":"Rao","sequence":"additional","affiliation":[{"name":"Rock Bridge High School , Columbia, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swati S","family":"Vattem","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Wisconsin School of Medicine and Public Health , Madison, WI , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie J","family":"Rewey","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Wisconsin School of Medicine and Public Health , Madison, WI , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4655-8777","authenticated-orcid":false,"given":"Mathew V","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Wisconsin School of Medicine and Public Health , Madison, WI , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama K","family":"Maganti","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Wisconsin School of Medicine and Public Health , Madison, WI , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"2023092721040705700_CIT0001","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/B978-0-444-52892-6.00001-5","article-title":"Epidemiology of traumatic brain injury","volume":"127","author":"Faul","year":"2015","journal-title":"Handb Clin Neurol."},{"issue":"7\u20138","key":"2023092721040705700_CIT0002","doi-asserted-by":"crossref","first-page":"767","DOI":"10.3109\/02699052.2013.793396","article-title":"Understanding the neuropsychiatric consequences associated with significant traumatic brain injury","volume":"27","author":"Bhalerao","year":"2013","journal-title":"Brain Inj."},{"issue":"1","key":"2023092721040705700_CIT0003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1535-7511.2005.00083.x","article-title":"Posttraumatic epilepsy: a major problem in desperate need of major advances","volume":"6","author":"Garga","year":"2006","journal-title":"Epilepsy Curr."},{"key":"2023092721040705700_CIT0004","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1001\/archneur.1986.00520080019013","article-title":"Predicting posttraumatic epilepsy in penetrating head injury","volume":"43","author":"Weiss","year":"1986","journal-title":"Arch Neurol."},{"key":"2023092721040705700_CIT0005","doi-asserted-by":"crossref","first-page":"113946","DOI":"10.1016\/j.expneurol.2021.113946","article-title":"Contusion brain damage in mice for modelling of post-traumatic epilepsy with contralateral hippocampus sclerosis: comprehensive and longitudinal characterization of spontaneous seizures, neuropathology, and neuropsychiatric comorbidities","volume":"348","author":"Golub","year":"2022","journal-title":"Exp Neurol."},{"key":"2023092721040705700_CIT0006","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.expneurol.2008.10.005","article-title":"Posttraumatic epilepsy after controlled cortical impact injury in mice","volume":"215","author":"Hunt","year":"2009","journal-title":"Exp Neurol."},{"issue":"1","key":"2023092721040705700_CIT0007","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/epi4.12462","article-title":"Sleep-wake characteristics in a mouse model of severe traumatic brain injury: relation to posttraumatic epilepsy","volume":"6","author":"Konduru","year":"2021","journal-title":"Epilepsia Open."},{"issue":"7","key":"2023092721040705700_CIT0008","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/S1474-4422(15)00068-X","article-title":"Sleep-wake disturbances following traumatic brain injury","volume":"14","author":"Ouellet","year":"2015","journal-title":"Lancet Neurol."},{"issue":"Pt 7","key":"2023092721040705700_CIT0009","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1093\/brain\/awm109","article-title":"Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study","volume":"130","author":"Baumann","year":"2007","journal-title":"Brain."},{"issue":"5","key":"2023092721040705700_CIT0010","first-page":"zsx044","article-title":"Sleep-wake disturbances after traumatic brain injury: synthesis of human and animal studies","volume":"40","author":"Sandsmark","year":"2017","journal-title":"Sleep."},{"key":"2023092721040705700_CIT0011","doi-asserted-by":"crossref","first-page":"131","DOI":"10.2147\/NSS.S182158","article-title":"Impact of traumatic brain injury on sleep: an overview","volume":"11","author":"Aoun","year":"2019","journal-title":"Nat Sci Sleep."},{"issue":"5","key":"2023092721040705700_CIT0012","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1089\/neu.2014.3664","article-title":"Chronic decrease in wakefulness and disruption of sleep-wake behavior after experimental traumatic brain injury","volume":"32","author":"Skopin","year":"2015","journal-title":"J Neurotrauma."},{"issue":"5","key":"2023092721040705700_CIT0013","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1089\/neu.2018.5810","article-title":"Hypocretin mediates sleep and wake disturbances in a mouse model of traumatic brain injury","volume":"36","author":"Thomsay","year":"2019","journal-title":"J Neurotrauma."},{"key":"2023092721040705700_CIT0014","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/nrn3837","article-title":"The role of orexin in motivated behaviours","volume":"15","author":"Sakurai","year":"2014","journal-title":"Nat Rev Neursci"},{"issue":"8","key":"2023092721040705700_CIT0015","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.5664\/jcsm.7282","article-title":"An update on dual orexin receptor antagonists and their potential role in insomnia therapeutics","volume":"14","author":"Janto","year":"2018","journal-title":"J Clin Sleep Med."},{"issue":"12","key":"2023092721040705700_CIT0016","doi-asserted-by":"crossref","first-page":"5275","DOI":"10.1523\/JNEUROSCI.3200-12.2013","article-title":"Hypocretin\/orexin neurons contribute to hippocampus-dependent social memory and synaptic plasticity in mice","volume":"33","author":"Yang","year":"2013","journal-title":"J Neurosci."},{"key":"2023092721040705700_CIT0017","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.neuroscience.2004.05.012","article-title":"Orexins\/hypocretins cause sharp wave- and theta-related synaptic plasticity in the hippocampus via glutamatergic, gabaergic, noradrenergic, and cholinergic signaling","volume":"127","author":"Selbach","year":"2004","journal-title":"Neuroscience."},{"key":"2023092721040705700_CIT0018","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s12868-018-0445-9","article-title":"The effect of intracerebroventricular administration of orexin receptor type 2 antagonist on pentylenetetrazol-induced kindled seizures and anxiety in rats","volume":"19","author":"Asadi","year":"2018","journal-title":"BMC Neurosci."},{"issue":"2","key":"2023092721040705700_CIT0019","doi-asserted-by":"crossref","first-page":"357","DOI":"10.5665\/sleep.5444","article-title":"Orexin receptor antagonism improves sleep and reduces seizures in kcna1-null mice","volume":"39","author":"Roundtree","year":"2016","journal-title":"Sleep."},{"issue":"2","key":"2023092721040705700_CIT0020","first-page":"383","article-title":"Suvorexant, a dual orexin receptor antagonist, protected seizure through interaction with GABAA and glutamate receptors","volume":"19","author":"Razavi","year":"2020","journal-title":"Iran J Pharm Res."},{"issue":"2","key":"2023092721040705700_CIT0021","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1177\/1535759721989674","article-title":"Untangling a web: basic mechanisms of the complex interactions between sleep, circadian rhythms, and epilepsy","volume":"21","author":"Maganti","year":"2021","journal-title":"Epilepsy Curr."},{"key":"2023092721040705700_CIT0022","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1038\/s41467-020-16915-0","article-title":"Rapid fast-delta decay following prolonged wakefulness marks a phase of wake-inertia in NREM sleep","volume":"11","author":"Hubbard","year":"2020","journal-title":"Nat Commun."},{"key":"2023092721040705700_CIT0023","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s40478-021-01165-y","article-title":"In-depth characterization of a mouse model of post-traumatic epilepsy for biomarker and drug discovery","volume":"9","author":"Di Sapia","year":"2021","journal-title":"Acta Neuropathol Commun."},{"issue":"5","key":"2023092721040705700_CIT0024","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1002\/ana.26208","article-title":"Sleep deprivation exacerbates seizures and diminishes GABAergic tonic inhibitioN","volume":"90","author":"Konduru","year":"2021","journal-title":"Ann Neurol."},{"issue":"2","key":"2023092721040705700_CIT0025","first-page":"23","article-title":"Pediatric epilepsy mechanisms: expanding the paradigm of excitation\/inhibition imbalance","volume":"6","author":"Shao","year":"2019","journal-title":"Children (Basel)."},{"issue":"5","key":"2023092721040705700_CIT0026","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1152\/jn.00232.2012","article-title":"Seizures as imbalanced up states: excitatory and inhibitory conductances during seizure-like events","volume":"109","author":"\u017diburkus","year":"2013","journal-title":"J Neurophysiol."},{"issue":"252","key":"2023092721040705700_CIT0027","first-page":"3","article-title":"Decrease in tonic inhibition contributes to increase in dentate semilunar granule cell excitability after brain injury","volume":"32","author":"Gupta","year":"2012","journal-title":"J Neurosci."},{"key":"2023092721040705700_CIT0028","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3389\/fncel.2013.00089","article-title":"Neural circuit mechanisms of post-traumatic epilepsy","volume":"7","author":"Hunt","year":"2013","journal-title":"Front Cell Neurosci."},{"key":"2023092721040705700_CIT0029","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.5664\/jcsm.5.2S.S6","article-title":"Regulation and functional correlates of slow wave sleep","volume":"5","author":"Dijk","year":"2009","journal-title":"J Clin Sleep Med."},{"key":"2023092721040705700_CIT0030","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.neuroscience.2011.08.033","article-title":"Aging-related alterations in orexin\/hypocretin modulation of septo-hippocampal amino acid neurotransmission","volume":"195","author":"Stanley","year":"2011","journal-title":"Neuroscience."},{"key":"2023092721040705700_CIT0031","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.pbb.2015.01.006","article-title":"Hippocampal orexin receptors inactivation reduces PTZ induced seizures of male rats","volume":"130","author":"Goudarzi","year":"2015","journal-title":"Pharmacol Biochem Behav."},{"issue":"3","key":"2023092721040705700_CIT0032","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.nbd.2010.03.012","article-title":"Increase of GABAA receptor-mediated tonic inhibition in dentate granule cells after traumatic brain injury","volume":"38","author":"Mtchedlishvilli","year":"2010","journal-title":"Neurobiol Dis."},{"key":"2023092721040705700_CIT0033","first-page":"R650","article-title":"Time course of EEG power density during long sleep in humans","volume":"258","author":"Dijk","year":"1009","journal-title":"Am J Physiol."},{"issue":"1","key":"2023092721040705700_CIT0034","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neuron.2013.12.025","article-title":"Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration","volume":"81","author":"Tononi","year":"2014","journal-title":"Neuron."},{"key":"2023092721040705700_CIT0035","doi-asserted-by":"crossref","first-page":"S16","DOI":"10.5664\/jcsm.5.2S.S16","article-title":"Slow wave homeostasis and synaptic plasticity","volume":"5","author":"Tononi","year":"2009","journal-title":"J Clin Sleep Med."},{"key":"2023092721040705700_CIT0036","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3389\/fneur.2013.00143","article-title":"Sleep-dependent synaptic down-selection (I): modeling the benefits of sleep on memory consolidation and integration","volume":"4","author":"Nere","year":"2013","journal-title":"Front Neurol."},{"issue":"4","key":"2023092721040705700_CIT0037","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1093\/brain\/awx017","article-title":"Altered sleep homeostasis correlates with cognitive impairment in patients with focal epilepsy","volume":"140","author":"Boly","year":"2017","journal-title":"Brain."},{"key":"2023092721040705700_CIT0038","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.nbscr.2016.03.001","article-title":"Hypocretinergic and cholinergic contributions to sleep-wake disturbances in a mouse model of traumatic brain injury","volume":"2","author":"Thomasy","year":"2016","journal-title":"Neurobiol Sleep Circadian Rhythms."},{"key":"2023092721040705700_CIT0039","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1523\/JNEUROSCI.3019-14.2015","article-title":"Evidence for consolidation of neuronal assemblies after seizures in humans","volume":"35","author":"Bower","year":"2015","journal-title":"J Neurosci."},{"issue":"3","key":"2023092721040705700_CIT0040","first-page":"zsz241","article-title":"The dual orexinergic receptor antagonist DORA-22 improves the sleep disruption and memory impairment produced by a rodent insomnia model","volume":"43","author":"Gamble","year":"2020","journal-title":"Sleep."},{"key":"2023092721040705700_CIT0041","doi-asserted-by":"crossref","first-page":"217","DOI":"10.2147\/NSS.S330939","article-title":"Overnight delta dynamics associated with daytime psychomotor performance in adults with insomnia and healthy controls","volume":"14","author":"Lunsford-Avery","year":"2022","journal-title":"Nat Sci Sleep."},{"issue":"4","key":"2023092721040705700_CIT0042","doi-asserted-by":"crossref","first-page":"e00322","DOI":"10.1002\/prp2.322","article-title":"Anticonvulsive evaluation of THIP in the murine pentylenetetrazole kindling model: lack of anticonvulsive effect of THIP despite functional \u03b4-subunit-containing GABAA receptors in dentate gyrus granule cells","volume":"5","author":"Simonsen","year":"2017","journal-title":"Pharmacol Res Perspect."},{"issue":"5","key":"2023092721040705700_CIT0043","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.neuropharm.2004.12.015","article-title":"The GABAA receptor agonist THIP alters the EEG in waking and sleep of mice","volume":"48","author":"Vyazovskiy","year":"2005","journal-title":"Neuropharmacology."},{"key":"2023092721040705700_CIT0044","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/1471-2202-15-109","article-title":"Differential sleep-promoting effects of dual orexin receptor antagonists and GABAA receptor modulators","volume":"15","author":"Gotter","year":"2014","journal-title":"BMC Neurosci."},{"key":"2023092721040705700_CIT0045","doi-asserted-by":"crossref","first-page":"146","DOI":"10.3389\/fncir.2013.00146","article-title":"Acutely increasing \u03b4GABA(A) receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus","volume":"7","author":"Whissell","year":"2013","journal-title":"Front Neural Circuits."},{"issue":"6","key":"2023092721040705700_CIT0046","doi-asserted-by":"crossref","first-page":"zsz302","DOI":"10.1093\/sleep\/zsz302","article-title":"Dual orexin receptor antagonists increase sleep and cataplexy in wild type mice","volume":"43","author":"Mahoney","year":"2020","journal-title":"Sleep."},{"key":"2023092721040705700_CIT0047","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.trci.2019.01.003","article-title":"Effects of the dual orexin receptor antagonist DORA-22 on sleep in 5XFAD mice","volume":"5","author":"Duncan","year":"2019","journal-title":"Alzheimers Dement (N Y)."}],"container-title":["SLEEP"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/sleep\/advance-article-pdf\/doi\/10.1093\/sleep\/zsac238\/46750065\/zsac238.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/sleep\/article-pdf\/45\/12\/zsac238\/47762482\/zsac238.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/sleep\/article-pdf\/45\/12\/zsac238\/47762482\/zsac238.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T21:35:44Z","timestamp":1695850544000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/sleep\/article\/doi\/10.1093\/sleep\/zsac238\/6723634"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,27]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,9,27]]},"published-print":{"date-parts":[[2022,12,12]]}},"URL":"https:\/\/doi.org\/10.1093\/sleep\/zsac238","relation":{},"ISSN":["0161-8105","1550-9109"],"issn-type":[{"value":"0161-8105","type":"print"},{"value":"1550-9109","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,1]]},"published":{"date-parts":[[2022,9,27]]},"article-number":"zsac238"}}