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 (20e40 ms) up and down movements.
Number of stimulations (2e4), and delay between 2 stimulations (100e200 ms) were randomized. Each
sequence of stimulation was also randomly administered (10e30 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) intertrial
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.