OREXIN/HYPOCRETIN KNOCKOUT IMPAIRS ADULT MOUSE VISUAL PERCEPTION AND PROCESSING, AND DISRUPTS DEVELOPMENT OF THE CORTICAL SUBPLATE

Lateral hypothalamic orexin/hypocretin circuits are required for stable consciousness: loss of orexin signals causes narcolepsy in humans, dogs and mice. While orexins activate deep cortical layers in mouse primary visual cortex (V1), their role for vision remains underexplored. On a behavioral/perceptual level, orexin knockout (KO) mice had normal visual acuity, but worse orientation discrimination, needing a larger angle difference to discriminate square wave patterns. This may suggest disrupted visual signal processing. Indeed, in V1 of anaesthetized orexin KO mice, typical peaks of visually evoked potentials (VEP) were delayed compared to WT-controls. Using the oddball paradigm, in which a stimulus is presented frequently (redundant context) or rarely (oddball context), we observed impaired context-dependent V1-modulation in orexin KO: in WT, VEP-waveforms were context-modulated 68ms after stimulus onset, but delayed to 104ms in orexin KOs. In addition, enhancement of fast gamma power (>80Hz) by the oddball context was smaller in amplitude and vanished faster in V1 of KO compared to WT-mice. Furthermore, orexin KO disrupted development of the cortical subplate and layer (L) 6: The number of complexin 3-positive subplate cells was increased in mouse V1 between postnatal days 8-21, while L6 thickness was increased at day 8, but reduced at 21-35 days. In addition, using whole-cell patch-clamp electrophysiology, we observed a 50% reduction in the amplitude of glutamatergic AMPA-receptor mediated currents in L4 to L2/3 V1-circuits. Together our data show that loss of orexin peptides affects visual circuits on anatomical and local circuit level, and causes deficits in visual processing and perception.