Pharmacogenetic inhibition of the subcoeruleus region influences rem sleep and cataplexy in narcoleptic mice

Abstract

Introduction: Cataplexy -the sudden involuntary loss of skeletal muscle tone -is a defining feature of narcolepsy. The current study aimed to determine if cataplexy is influenced by direct manipulation of REM sleep circuitry. We did this by pharmacogenetically inhibiting the REM sleep centre, subcoeruleus (Sub-C). Methods:Inhibitory DREADD (hM4D-Gi) was bilaterally targeted to the Sub-C in hypocretin knockout mice (n=7). Intraperitoneal administration of clozapine-n-oxide was used to inhibit Sub-C cells expressing hM4D-Gi. Electrophysiological and behavioural criteria were used to characterize cataplexy and REM sleep.Results: Sub-C inhibition increased REM sleep and cataplexy amounts (p<0.05). Sub-C inhibition increased time spent in cataplexy amounts by increasing the number of cataplexy attacks (p<0.05). This intervention triggered increases in basal muscle tone during REM sleep, but had negligible effects on muscle tone during cataplexy (p>0.05).ii Conclusion: Pharmacogenetic manipulation of the Sub-C suggest that REM sleep and cataplexy are mediate by similar neural mechanism.iii