Release of Hypocretin (Orexin) during Waking and Sleep States

Kiyashchenko, Lyudmila I.; Mileykovskiy, Boris Y.; Maidment, Nigel T.; Lam, Hoa A.; Wu, Ming-Fung; John, Joshi; Peever, John H.; Siegel, Jerome M.

doi:10.1523/jneurosci.22-13-05282.2002

Cited by 309 publications

(211 citation statements)

References 39 publications

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“…In addition, unit recordings have revealed non-hypocretinergic neurons that increase their firing rate in conjunction with motor activity (Lee, et al, 2005). Although hypocretinergic neurons seem to be primarily involved in somatomotor activity (Kiyashchenko, et al, 2002, Lee, et al, 2005, Martins, et al, 2004, Mileykovskiy, et al, 2005, Torterolo, et al, 2001, our results suggest that additional, as-yetunidentified neurons in this region may also be involved in this function. The activity of these unidentified neurons decreased during QS, which is in agreement with electrophysiological studies (Alam, et al, 2002).…”

Section: Discussionmentioning

confidence: 46%

MCH-containing neurons in the hypothalamus of the cat: Searching for a role in the control of sleep and wakefulness

Torterolo

Sampogna²,

Morales

et al. 2006

Brain Research

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Neurons that utilize melanin-concentrating hormone (MCH) and others that employ hypocretin as neurotransmitter are located in the hypothalamus and project diffusely throughout the CNS, including areas that participate in the generation and maintenance of the states of sleep and wakefulness. In the present report, immunohistochemical methods were employed to examine the distribution of MCHergic and hypocretinergic neurons. In order to test the hypothesis that the MCHergic system is capable of influencing specific behavioral states, we studied Fos immunoreactivity in MCHcontaining neurons during 1) quiet wakefulness, 2) active wakefulness with motor activity, 3) active wakefulness without motor activity, 4) quiet sleep, and, 5) active sleep induced by carbachol (AScarbachol). We determined that MCHergic neuronal somata in the cat are intermingled with hypocretinergic neurons in the dorsal and lateral hypothalamus, principally in the tuberal and tuberomammillary regions; however, hypocretinergic neurons extended more in the anteriorposterior axis than MCHergic neurons. Axosomatic and axodendritic contacts were common between these neurons. In contrast to hypocretinergic neurons, which are known to be active during motor activity and AS-carbachol, Fos immunoreactivity was not observed in MCH-containing neurons in conjunction with any of the preceding behavioral conditions. Non-MCHergic, non-hypocretinergic neurons that expressed c-fos during active wakefulness with motor activity were intermingled with MCH and hypocretin-containing neurons, suggesting that these neurons are related to some aspect of motor function. Further studies are required to elucidate the functional sequela of the interactions between MCHergic and hypocretinergic neurons and the phenotype of the other neurons that were active during motor activity.

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Section: Discussionmentioning

confidence: 46%

MCH-containing neurons in the hypothalamus of the cat: Searching for a role in the control of sleep and wakefulness

Torterolo

Sampogna²,

Morales

et al. 2006

Brain Research

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“…Orexin-containing terminals are found on and around ARC POMC neurons Guan et al, 2001;Muroya et al, 2004), and the release of orexin is highest during active, awake periods (Kiyashchenko et al, 2002). Considering the appetite-suppressing influence of POMC neurons, their electrical inhibition by orexin, described here, may help to ensure that food seeking coincides with periods when the animal is most alert and active.…”

Section: Discussionmentioning

confidence: 88%

“…Considering the appetite-suppressing influence of POMC neurons, their electrical inhibition by orexin, described here, may help to ensure that food seeking coincides with periods when the animal is most alert and active. Conversely, during periods of rest and sleep, the reduced release of orexin (Kiyashchenko et al, 2002) may enhance the firing of POMC neurons, suppressing hunger to facilitate the induction and maintenance of sleep states.…”

Section: Discussionmentioning

confidence: 99%

Electrical Inhibition of Identified Anorexigenic POMC Neurons by Orexin/Hypocretin

Zubcevic²,

Ashcroft³

et al. 2007

J. Neurosci.

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Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) suppress appetite, and lack of POMC-derived peptides or electrical silencing of POMC neurons causes obesity. ARC POMC neurons are surrounded by nerve terminals containing the wakefulness-promoting peptides orexins/hypocretins, but whether orexin affects their electrical activity has not been tested directly. Here we identify living ARC POMC cells in mouse brain slices by targeted expression of green fluorescent protein. Using whole-cell patch-clamp recordings, we show that orexin suppresses the spontaneous action potential firing of these neurons. Orexin-induced inhibition involves membrane hyperpolarization, a decreased excitatory synaptic drive, and an increased frequency of GABAergic inputs. Our results suggest a reduction in the electrical activity of ARC POMC neurons, which is mediated by changes in presynaptic inputs, contributes to the appetite-enhancing action of orexins.

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“…Hcrt levels fluctuate with the sleep-wake cycle. Of relevance to this study is the finding that Hcrt levels may be significantly higher in the rat basal forebrain during REM sleep as compared with slow wave sleep (Kiyashchenko et al, 2002). The resultant activation of septohippocampal cholinergic neurons during REM sleep could explain the high levels of hippocampal ACh release that occur during REM sleep (Marrosu et al, 1995) when aminergic inputs are quiescent.…”

Section: Implications For Hippocampal Arousalmentioning

confidence: 88%

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

Wu¹,

Záborszky²,

Hajszán³

et al. 2004

J. Neurosci.

131

101

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Hypothalamic fibers containing the wake-promoting peptides, hypocretins (Hcrts) or orexins, provide a dense innervation to the medial septum-diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics. The MSDB, via its cholinergic and GABAergic projections to the hippocampus, controls the hippocampal theta rhythm and associated learning and memory functions. Neurons of the MSDB express very high levels of the Hcrt receptor 2, which is mutated in canine narcoleptics. In the present study, we investigated the electrophysiological effects of Hcrt peptides on septohippocampal cholinergic neurons that were identified in living brain slices of the MSDB using a selective fluorescent marker. Hcrt activation of septohippocampal cholinergic neurons was reversible, reproducible, and concentration dependent and mediated via a direct postsynaptic mechanism. Both Hcrt1 and Hcrt2 activated septohippocampal cholinergic neurons with similar EC 50 values. The Hcrt effect was dependent on external Na ϩ , reduced by external Ba 2ϩ , and also reduced in recordings with CsCl-containing electrodes, suggesting a dual underlying ionic mechanism that involved inhibition of a K ϩ current, presumably an inward rectifier, and a Na ϩ -dependent component. The Na ϩ component was dependent on internal Ca 2ϩ , blocked by replacing external Na ϩ with Li ϩ , and also blocked by bath-applied Ni 2ϩ and KB-R7943, suggesting involvement of the Na ϩ -Ca 2ϩ exchanger. Using double-immunolabeling studies at light and ultrastructural levels, we also provide definitive evidence for a hypocretin innervation of cholinergic neurons. Thus Hcrt effects within the septum should increase hippocampal acetylcholine release and thereby promote hippocampal arousal.

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Release of Hypocretin (Orexin) during Waking and Sleep States

Cited by 309 publications

References 39 publications

MCH-containing neurons in the hypothalamus of the cat: Searching for a role in the control of sleep and wakefulness

MCH-containing neurons in the hypothalamus of the cat: Searching for a role in the control of sleep and wakefulness

Electrical Inhibition of Identified Anorexigenic POMC Neurons by Orexin/Hypocretin

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

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