title: Ciproxifan improves working memory through increased prefrontal cortex neural activity in sleep-restricted mice.
abstract: Histamine receptor type 3 (H3) antagonists are promising awakening drugs for treatment of sleep disorders. However, few works have tried to identify their cognitive effects after sleep restriction and their impact on associated neural networks. To that aim, Bl/6J male mice were submitted to acute sleep restriction in a shaker apparatus that prevents sleep by transient (20-40 ms) up and down movements. Number of stimulations (2-4), and delay between 2 stimulations (100-200 ms) were randomized. Each sequence of stimulation was also randomly administered (10-30 s interval) for 20 consecutive hours during light (8 h) and dark (12 h) phases. Immediately after 20 h-sleep restriction, mice were injected with H3 antagonist (ciproxifan 3 mg/kg ip) and submitted 30-min later to a working memory (WM) task using spatial spontaneous alternation behaviour. After behavioural testing, brains were perfused for Fos immunohistochemistry to assess neuronal brain activation in the dorsal dentate gyrus (dDG) and the prefrontal cortex. Results showed that sleep restriction decreased slow wave sleep (from 35.8±1.4% to 9.2±2.7%, p<0.001) and was followed by sleep rebound (58.2±5.9%, p<0.05). Sleep restriction did not modify anxiety-like reactivity and significantly decreased WM at long (30 s) but not short (5 s) inter-trial intervals. Whereas sleep restriction failed to significantly modify immunopositive cells in vehicles, ciproxifan administration prevented WM deficits in sleep restricted mice through significant increases of Fos labelling in prelimbic, infralimbic and cingulate 2 cortex. In conclusion, ciproxifan at 3 mg/kg enhanced WM in sleep restricted mice through specific modulation of prefrontal cortex areas.
authors.affiliation: IRBA (Armed Biomedical Research Institute) BP73, F-91223 Bretigny-sur-Orge Cedex, France.
authors.forename: F
authors.initials: F
authors.lastname: Chauveau
authors.affiliation: IRBA (Armed Biomedical Research Institute) BP73, F-91223 Bretigny-sur-Orge Cedex, France.
authors.forename: K
authors.initials: K
authors.lastname: Laudereau
authors.affiliation: Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, France.
authors.forename: P A
authors.initials: PA
authors.lastname: Libourel
authors.affiliation: Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, France.
authors.forename: D
authors.initials: D
authors.lastname: Gervasoni
authors.affiliation: IRBA (Armed Biomedical Research Institute) BP73, F-91223 Bretigny-sur-Orge Cedex, France.
authors.forename: J
authors.initials: J
authors.lastname: Thomasson
authors.affiliation: IRBA (Armed Biomedical Research Institute) BP73, F-91223 Bretigny-sur-Orge Cedex, France.
authors.forename: B
authors.initials: B
authors.lastname: Poly
authors.affiliation: IRBA (Armed Biomedical Research Institute) BP73, F-91223 Bretigny-sur-Orge Cedex, France.
authors.forename: C
authors.initials: C
authors.lastname: Pierard
authors.affiliation: INCIA (Institute of Cognitive and Integrative Neurosciences of Aquitaine), UMR CNRS 5287, University of Bordeaux1, F-33400 Talence, France. Electronic address: daniel.beracochea@u-bordeaux1.fr.
authors.forename: D
authors.initials: D
authors.lastname: Beracochea
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D054828:Histamine H3 Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D008810:Mice, Inbred C57BL; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000494:pharmacology*; D010812:Physical Stimulation; D017286:Polysomnography; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D012892:Sleep Deprivation / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D054828:Histamine H3 Antagonists; D007093:Imidazoles; D018697:Nootropic Agents; D016760:Proto-Oncogene Proteins c-fos; C115705:ciproxifan
keywords: H3 antagonist; Hippocampus; Prefrontal cortex; Sleep restriction; Working memory