Hypocretin Deficiency in Narcolepsy With Cataplexy Is Associated With a Normal Body Core Temperature Modulation

Abstract

Narcolepsy with cataplexy (NC) is a sleep disorder caused by the loss of the hypothalamic neurons producing hypocretin. The clinical hallmarks of the disease are excessive daytime sleepiness, cataplexy, other rapid eye movement (REM) sleep phenomena, and a fragmented wake-sleep cycle. Experimental data suggest that the hypocretin system is involved primarily in the circadian timing of sleep and wakefulness but also in the control of other biological functions such as thermoregulation. The object of this study was to determine the effects of the hypocretin deficit and of the wake-sleep cycle fragmentation on body core temperature (BcT) modulation in a sample of drug-free NC patients under controlled conditions. Ten adult NC patients with low cerebrospinal fluid (CSF) hypocretin levels (9 men; age: 38 ± 12 yrs) were compared with 10 healthy control subjects (7 men; age: 44.9 ± 12 yrs). BcT and sleep-wake cycle were continuously monitored for 44 h from 12:00 h. During the study, subjects were allowed to sleep ad libitum, living in a temperature- and humidity-controlled room, lying in bed except when eating, in a light-dark schedule (dark [D] period: 23:00-07:00 h). Sleep structure was analyzed over the 24-h period, the light (L) and the D periods. The wake-sleep cycle fragmentation was determined by calculating the frame-shift index (number of 30-s sleep stage shifts occurring every 15 min) throughout the 44-h study. The analysis of BcT circadian rhythmicity was performed according to the single cosinor method. The time-course changes in BcT and in frame-shift index were compared between narcoleptics and controls by testing the time × group (controls versus NC subjects) interaction effect. The state-dependent analysis of BcT during D was performed by fitting a mixed model where the factors were wake-sleep phases (wake, NREM stages 1 and 2, slow-wave sleep, and REM sleep) and group. The results showed that NC patients slept significantly more than controls during the 24 h due to a higher representation of any sleep stage (p < .001) during L, whereas the total amount of night sleep and its architecture were comparable in the two groups. Wake-sleep fragmentation was higher (p < .001) in NC subjects especially during L. Despite these differences, mesor (24-h mean), amplitude, and acrophase (peak time) of BcT circadian rhythm were comparable in narcoleptics and controls, and no between-group differences were detected in the time-course changes and in the state-dependent modulation at night of BcT. These data indicate that the hypocretin deficit in drug-free NC patients and their altered wake-sleep cycle couple with an intact modulation of BcT.

A unified survival theory of the functioning of the hypocretinergic system

“…For example, as early as 1951, Anand and Brobeck (5,6) reported that a group of cells (which were later identified as hypocretinergic) within the lateral hypothalamus function as a comprehensive "feeding center"; bilateral lesions of these neurons result in the complete cessation of food consumption [see Nishino and Sakurai (119) and Adequate Survival Stimuli Activate the Hypocretinergic System]. There are also a plethora of recent studies, cited in the present text, that confirm that the responsible neurons in the lateral hypothalamus are hypocretinergic (30,60,62,119). Thus, during survival behaviors, there are hypocretinergically induced increases in arterial pressure, heart rate, and ventilation as well as a shift in blood flow from visceral to skeletal muscles in conjunction with cortical arousal; all of these survivalrelated responses are significantly lacking in preprohypocretin knockout and hypocretin neuron-ablated animals (14,83).…”

“…In this regard, decades of research have confirmed that neurons in the lateral hypothalamus are capable of controlling all of the critical components of survival behaviors (3,17,26,30,60,62,128). For example, as early as 1951, Anand and Brobeck (5,6) reported that a group of cells (which were later identified as hypocretinergic) within the lateral hypothalamus function as a comprehensive "feeding center"; bilateral lesions of these neurons result in the complete cessation of food consumption [see Nishino and Sakurai (119) and Adequate Survival Stimuli Activate the Hypocretinergic System].…”

Orexins and the cardiovascular events of awakening

“…Recordings of skin SNA in NT1 patients indicated a normal decrease during NREM sleep compared with wakefulness, 13 and data on ORX-ATX3 rats have not shown significant differences in the effect of sleep on tail skin temperature compared with wild-type rats. 45 Contrasting results were also obtained by studies of the 24-h profiles of core body temperature in NT1 patients [59][60][61] and by studies of sleep-related changes in core body temperature between NREM sleep and wakefulness in NT1 patients, ORX-ATX3 mice, and ORX-KO mice. [61][62][63] More recent experiments on ORX-ATX3 rats indicated that the integrity of orexin neurons is important for the full expression of cold defense responses, such as brown adipose tissue thermogenesis, behavioral activity, and tail skin vasoconstriction.…”

“…45 Contrasting results were also obtained by studies of the 24-h profiles of core body temperature in NT1 patients [59][60][61] and by studies of sleep-related changes in core body temperature between NREM sleep and wakefulness in NT1 patients, ORX-ATX3 mice, and ORX-KO mice. [61][62][63] More recent experiments on ORX-ATX3 rats indicated that the integrity of orexin neurons is important for the full expression of cold defense responses, such as brown adipose tissue thermogenesis, behavioral activity, and tail skin vasoconstriction. 64 Studies of thermoregulation in ORX-ATX3 mice and ORX-KO mice led to the conclusion that orexin neurons regulate body temperature through an orexin cotransmitter.…”

Challenges in the development of therapeutics for narcolepsy

“…Although a circadian rhythm of core body temperature ( T b ) was clearly evident in human narcoleptics (Grimaldi et al, 2010a), nighttime T b levels were elevated relative to controls (Mosko et al, 1983; Pollak and Wagner, 1994). Whether this is a cause or a consequence of disrupted nocturnal sleep in narcoleptics was unclear.…”