Bidirectional and context-dependent changes in theta and gamma oscillatory brain activity in noradrenergic cell-specificHypocretin/Orexin receptor 1-KO mice

Abstract

The neuromodulators noradrenaline (NA) and hypocretins (Hcrt) both have major, but distinct, roles in implementing the brain circuit processing modes that define wakefulness and waking behaviors. The A6 NA cell group in the locus coeruleus (LC-NA) receives dense projections from the Hcrt cells of the hypothalamus, and acts as critical mediator of Hcrt-induced arousal. The range of behaviors relying on the Hcrt-to-LC-NA neuronal connection however remains undefined.We generated a conditionally inactivated allele of Hcrtr1, the Hcrt receptor gene expressed by LC-NA cells, and used a Dbh-Cre transgene to create mice with NA-specific Hcrtr1 inactivation (Hcrtr1Dbh-CKO mice). Electrocortical activity (ECoG) of these mice was analyzed in distinct behavioral contexts, and contrasted to the one of Cre-less control littermates. While baseline waking was grossly normal albeit for enhanced activity in the slow-delta (δ) range, upon exposure to a novel environment, Hcrtr1 Dbh-CKO mice displayed (i) a slowing of the waking ECoG, with enhanced δ and inter-δ/θ band activity, (ii) blunting of the θ rhythm and fast-γ activity, while (iii) β and slow-γ activities were enhanced. Moreover, locomotor and ECoG responses to sleep deprivation (SD) were markedly reduced. Surprisingly, while deficits in manually-enforced wakefulness resembled those following cage change (CC), spontaneous dark phase waking, and after providing nest material, were enhanced in θ and fast-γ oscillatory activities. Our data suggest that Hcrtr1 Dbh-CKO mice are deficient in adaptive regulation of wakefulness in stressassociated conditions with electrocortical signs of decreased alertness and hippocampal θ activation. Furthermore, their waking θ and fast-γ ECoG power show concerted, but opposite, trends in stressful versus rewarding contexts. Finally, slow-wave-sleep (SWS) following SD and CC both showed a profound deficit in slow-δ activity, suggesting that Hcrt-to-NA signalling is critical in active waking to induce the homeostatic slow-δ rebound that characterizes ensuing SWS.not peer-reviewed)