Orexin/Hypocretin and Histamine: Distinct Roles in the Control of Wakefulness Demonstrated Using Knock-Out Mouse Models

Anaclet, Christelle; Parmentier, Régis; Ouk, Koliane; Guidon, Gérard; Buda, C; Sastre, Jean-Pierre; Akaoka, H.; Sergeeva, Olga A.; Yanagisawa, Masashi; Ohtsu, Hiroshi; Franco, Patricia; Haas, Helmut L.; Lin, Jian‐Sheng

doi:10.1523/jneurosci.2604-09.2009

Cited by 197 publications

(188 citation statements)

References 54 publications

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“…Furthermore, mice with histamine deficiency also fail to exhibit prolonged sleep latencies during CC manipulation (25). This latter result indicates an orexinergic influence of arousal under these circumstances because the histamine system subserves much of the orexin-induced arousal (26). Further studies are required to determine the role of these neuromodulators in supporting arousal.…”

Section: Discussionmentioning

confidence: 99%

Behavioral and biochemical dissociation of arousal and homeostatic sleep need influenced by prior wakeful experience in mice

Suzuki

Sinton²,

Greene

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Sleep is regulated by homeostatic mechanisms, and the low-frequency power in the electroencephalogram (delta power) during nonrapid eye movement sleep reflects homeostatic sleep need. Additionally, sleep is limited by circadian and environmentally influenced arousal. Little is known, however, about the underlying neural substrates for sleep homeostasis and arousal and about the potential link between them. Here, we subjected C57BL/6 mice to 6 h of sleep deprivation using two different methods: gentle handling and continual cage change. Both groups were deprived of sleep to a similar extent (>99%), and, as expected, the delta power increase during recovery sleep was quantitatively similar in both groups. However, in a multiple sleep latency test, the cage change group showed significantly longer sleep latencies than the gentle handling group, indicating that the cage change group had a higher level of arousal despite the similar sleep loss. To investigate the possible biochemical correlates of these behavioral changes, we screened for arousal-related and sleep needrelated phosphoprotein markers from the diencephalon. We found that the abundance of highly phosphorylated forms of dynamin 1, a presynaptic neuronal protein, was associated with sleep latency in the multiple sleep latency test. In contrast, the abundance of highly phosphorylated forms of N-myc downstream regulated gene 2, a glial protein, was increased in parallel with delta power. The changes of these protein species disappeared after 2 h of recovery sleep. These results suggest that homeostatic sleep need and arousal can be dissociated behaviorally and biochemically and that phosphorylated N-myc downstream regulated gene 2 and dynamin 1 may serve as markers of homeostatic sleep need and arousal, respectively. phosphoproteomics | two-dimensional difference gel electrophoresis S leep-wakefulness is continuously regulated by circadian and homeostatic mechanisms. In addition, multiple factors affect the level of arousal, including emotional, environmental, and physiological influences (1). During non-rapid eye movement (NREM) sleep, the homeostatic sleep need is correlated with the power in the delta wave band (i.e., 1-4 Hz) in the electroencephalogram (EEG). Delta power is augmented in proportion to previous wakefulness time and is dissipated during sleep. These findings imply that homeostatic sleep need is regulated by the durations of prior sleep and wakefulness (2). On the other hand, the level of arousal is inversely related to the likelihood of falling asleep and can be measured in terms of the sleep latency in the multiple sleep latency test (MSLT) (3). Because prolonged waking increases sleep need in addition to lowering the level of arousal, sleep latency often varies inversely with EEG delta power expressed during sleep (3). However, the level of arousal can be affected independently of time spent awake (for example, with stressful or exciting experiences during waking), implying that, under conditions of identical sleep deprivation time, the s...

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Section: Discussionmentioning

confidence: 99%

Behavioral and biochemical dissociation of arousal and homeostatic sleep need influenced by prior wakeful experience in mice

Suzuki

Sinton²,

Greene

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…TMN neurons appear to play an essential role in promoting wakefulness as inactivation of the TMN region of cats with muscimol potently increases sleep (17), and mice lacking histamine have less wakefulness at the beginning of the dark period (18,19). Orexins excite TMN neurons (6,7), and microdialysis of orexin-A near the TMN increases wakefulness and induces release of histamine in the cortex (5).…”

Section: Discussionmentioning

confidence: 99%

Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice

Mochizuki¹,

Arrigoni²,

Marcus

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

124

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Narcolepsy is caused by a loss of orexin/hypocretin signaling, resulting in chronic sleepiness, fragmented non-rapid eye movement sleep, and cataplexy. To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase. Mice lacking OX2R signaling had poor maintenance of wakefulness indicative of sleepiness and fragmented sleep and lacked any electrophysiological response to orexin-A in the wake-promoting neurons of the tuberomammillary nucleus. These defects were completely recovered by crossing them with mice that express Cre in the female germline, thus globally deleting the transcription-disrupter cassette. Then, by using an adeno-associated viral vector coding for Cre recombinase, we found that focal restoration of OX2R in neurons of the tuberomammillary nucleus and adjacent parts of the posterior hypothalamus completely rescued the sleepiness of these mice, but their fragmented sleep was unimproved. These observations demonstrate that the tuberomammillary region plays an essential role in the wakepromoting effects of orexins, but orexins must stabilize sleep through other targets.arcolepsy is caused by a selective loss of the hypothalamic neurons producing the orexin (i.e., hypocretin) neuropeptides and is one of the most common causes of chronic sleepiness (1). In humans and mice, loss of orexin signaling results in unstable sleep/wake states, with poor maintenance of wakefulness, fragmented sleep, and intrusions into wakefulness of elements of rapid eye movement (REM) sleep, including brief episodes of paralysis known as cataplexy. The orexin neuropeptides strongly excite many brain regions that regulate sleep/wake behavior, yet the key pathways through which orexins stabilize wakefulness and sleep remain unknown.Orexins act through two receptors, OX1R and OX2R (also known as HCRTR1 and HCRTR2), and the OX2R seems to play a critical role in the maintenance of wakefulness. Mice constitutively lacking OX2R are unable to maintain long bouts of wakefulness and can fall asleep rapidly (2). In addition, an OX2R antagonist strongly promotes sleep, whereas an OX1R antagonist has no effect (3).Although it is clear that OX2R signaling is necessary for the normal maintenance of wakefulness, the anatomic sites through which this occurs remain unknown. OX2R is expressed in many wake-promoting brain regions, including the histaminergic neurons of the tuberomammillary nucleus (TMN), other monoaminergic regions, cholinergic systems, and forebrain regions, including the thalamus and cortex (4). Several researchers have hypothesized that the TMN is a key site because orexin-A excites the TMN neurons and infusion of orexin-A near this region promotes wakefulness (5-7). However, this perspective is controversial as optogenetic activation of the orexin neurons promotes arousal in mice lacking histamine (8), and mice lacking both OX1...

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“…In addition, the effect of orexin on arousal was not observed in histamine 1 receptor knock-out (H1 Ϫ/Ϫ ) mice (Huang et al, 2001). However, histidine decarboxylase knock-out (HDC Ϫ/Ϫ ) mice, H1 Ϫ/Ϫ mice, and OX1R Ϫ/ Ϫ;H1 Ϫ/Ϫ double knock-out mice did not show severe narcoleptic phenotypes (Anaclet et al, 2009;Hondo et al, 2010), suggesting that downstream pathways of OX2R, other than the histaminergic system, are critical for the regulation of sleep/wakefulness.…”

Section: Physiological Significance Of Orexininduced Activation Of Ormentioning

confidence: 98%

Orexin Directly Excites Orexin Neurons through Orexin 2 Receptor

Yamanaka¹,

Tabuchi²,

Tsunematsu³

et al. 2010

J. Neurosci.

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Orexin neurons (hypocretin neurons) have a critical role in the regulation of sleep/wakefulness, especially in the maintenance of arousal. Here, we revealed that orexin neurons are directly and indirectly activated by orexin via the orexin 2 receptor (OX2R). Orexin B (1 M) induced depolarization in orexin neurons, which was still observed in the presence of TTX (1 M), AP-5 (50 M), and CNQX (20 M). In addition, orexin B induced inward currents in the presence of TTX, suggesting a direct activation of orexin neurons. Although orexin B application induced depolarization in orexin neurons of OX1R knock-out mice at comparable levels to wild-type mice, the observation that orexin B failed to depolarize orexin neurons in the OX2R knock-out mice suggested that OX2R was a primary receptor for this response. Moreover, immunoelectron microscopic analyses revealed direct contacts among orexin neurons, which exhibited structural similarities to the glutamatergic synapses. Together, these results suggest that orexin neurons form a positive-feedback circuit through indirect and direct pathways, which results in the preservation of the orexin neuron network at a high activity level and/or for a longer period. Therefore, the activation of orexin neurons through OX2R might have an important role in the maintenance of arousal.

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Orexin/Hypocretin and Histamine: Distinct Roles in the Control of Wakefulness Demonstrated Using Knock-Out Mouse Models

Cited by 197 publications

References 54 publications

Behavioral and biochemical dissociation of arousal and homeostatic sleep need influenced by prior wakeful experience in mice

Behavioral and biochemical dissociation of arousal and homeostatic sleep need influenced by prior wakeful experience in mice

Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice

Orexin Directly Excites Orexin Neurons through Orexin 2 Receptor

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