Activity of dorsal raphe cells across the sleep–waking cycle and during cataplexy in narcoleptic dogs

Abstract

Cataplexy, a symptom associated with narcolepsy, represents a unique dissociation of behavioural states. During cataplectic attacks, awareness of the environment is maintained, as in waking, but muscle tone is lost, as in REM sleep. We have previously reported that, in the narcoleptic dog, noradrenergic cells of the locus coeruleus cease discharge during cataplexy. In the current study, we report on the activity of serotonergic cells of the dorsal raphe nucleus. The discharge patterns of serotonergic dorsal raphe cells across sleep-waking states did not differ from those of dorsal raphe and locus coeruleus cells recorded in normal rats, cats and monkeys, with tonic discharge in waking, reduced activity in non-REM sleep and cessation of activity in REM sleep. However, in contrast with locus coeruleus cells, dorsal raphe REM sleep-off neurones did not cease discharge during cataplexy. Instead, discharge continued at a level significantly higher than that seen in REM sleep and comparable to that seen in non-REM sleep. We also identified several cells in the dorsal raphe whose pattern of activity was the opposite of that of the presumed serotonergic cells. These cells were maximally active in REM sleep and minimally active in waking and increased activity during cataplexy. The difference between noradrenergic and serotonergic cell discharge profiles in cataplexy suggests different roles for these cell groups in the normal regulation of environmental awareness and muscle tone and in the pathophysiology of narcolepsy.

Serotonergic Regulation of the Orexin/Hypocretin Neurons through the 5-HT1AReceptor

“…In support of this idea, 5-HT precursor treatment induces drowsiness and reduces sleep latency (Ursin, 2002). On the other hand, the serotonergic DR neurons have their highest firing rate in waking, and this activity slows during SWS to almost complete cessation of firing during REM sleep (McGinty and Harper, 1976;Trulson and Jacobs, 1979;Wu et al, 2004). Neural activity of the DR is also closely linked to motor activity (Trulson et al, 1981;Lydic et al, 1984).…”

Behavioral State Instability in Orexin Knock-Out Mice

“…Although EEG theta activity and atonia occur in both cataplexy and REM sleep (Guilleminault et al, 1974;Mitler and Dement, 1977;Dyken et al, 1994;Willie et al, 2003), cataplexy is a distinct state, based on behavioral and physiologic criteria. In narcoleptic dogs, neurons of the LC, dorsal raphe, and tuberomammillary nucleus (TMN) fall silent during REM sleep, but, during cataplexy, the raphe and the TMN fire at moderate and high rates, respectively Wu et al, 2004). Cataplexy in orexin KO mice is immediately preceded by active wake with grooming, climbing, and ambulation and is immediately followed by an abrupt resumption of activity (Chemelli et al, 1999;Willie et al, 2003).…”

Pituitary Macrotumor Causing Narcolepsy‐Cataplexy in a Dachshund

“…Familial narcolepsy is caused by breed‐specific mutations in the hypocretin receptor 2 gene. This gene encodes the receptor for hypocretin found predominantly in the locus ceruleus and dorsal raphe nuclei, which in dogs are located in the pons and mesopontine junction, respectively 20. CSF hypocretin concentrations are normal in these dogs, and the abnormal receptor prevents ligand binding and activation of downstream pathways 1, 21.…”