Ciproxifan improves working memory through increased prefrontal cortex neural activity in sleep-restricted mice

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.