Sleep Homeostasis Modulates Hypocretin-Mediated Sleep-to-Wake Transitions

Carter, Matthew E.; Adamantidis, Antoine; Ohtsu, Hiroshi; Deisseroth, Karl; Lecea, Luı́s de

doi:10.1523/jneurosci.1205-09.2009

Cited by 223 publications

(174 citation statements)

References 65 publications

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“…On the basis of this model, the LC provides enough excitatory drive to the neocortex such that other arousal systems such as the histaminergic and cholinergic systems are not required to predict reliable sleep-to-wake transitions, although each of these structures may encode different components of arousal. This result is consistent with our previous results showing that Hcrt-mediated sleep-to-wake transitions occur in the absence of histaminergic signaling (25).…”

Section: Discussionsupporting

confidence: 94%

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Mechanism for Hypocretin-mediated sleep-to-wake transitions

Carter

Brill

Bonnavion³

et al. 2012

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

251

203

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Current models of sleep/wake regulation posit that Hypocretin (Hcrt)-expressing neurons in the lateral hypothalamus promote and stabilize wakefulness by projecting to subcortical arousal centers. However, the critical downstream effectors of Hcrt neurons are unknown. Here we use optogenetic, pharmacological, and computational tools to investigate the functional connectivity between Hcrt neurons and downstream noradrenergic neurons in the locus coeruleus (LC) during nonrapid eye movement (NREM) sleep. We found that photoinhibiting LC neurons during Hcrt stimulation blocked Hcrt-mediated sleep-to-wake transitions. In contrast, when LC neurons were optically stimulated to increase membrane excitability, concomitant photostimulation of Hcrt neurons significantly increased the probability of sleep-to-wake transitions compared with Hcrt stimulation alone. We also built a conductance-based computational model of Hcrt-LC circuitry that recapitulates our behavioral results using LC neurons as the main effectors of Hcrt signaling. These results establish the Hcrt-LC connection as a critical integrator-effector circuit that regulates NREM sleep/wake behavior during the inactive period. This coupling of distinct neuronal systems can be generalized to other hypothalamic integrator nuclei with downstream effector/output populations in the brain.ChR2 | norepinephrine | step function opsin T he neural basis of wakefulness and arousal is thought to depend on subcortical populations of "arousal-promoting" nuclei located in the hypothalamus and brainstem (1, 2). Neurons in the lateral hypothalamus that express hypocretins (Hcrts-also called "orexins"), a pair of neuropeptides produced from the same genetic precursor (3, 4), have been proposed to play a key role in stabilizing wake states by directly projecting throughout the brain to other arousal populations (1,5,6). Electrophysiological recordings of Hcrt neurons show that they are relatively silent during sleep compared with wakefulness, with phasic bursts of activity preceding transitions to wakefulness (7,8). Loss-of-function perturbation of the Hcrts or their receptors causes a narcolepsy phenotype (9-11). When centrally administered, the Hcrts increase the time spent awake and decrease nonrapid eye movement (NREM) and rapid eye movement (REM) sleep (12, 13).Although it is evident that Hcrts promote wakefulness and arousal, it is unknown which downstream structures are necessary and/or sufficient to mediate their effects. Hcrt neurons project diffusely throughout the brain (14), and it is possible that their effects on wakefulness are due to widespread, global postsynaptic targets. Alternatively, Hcrts may affect arousal primarily by projecting to key downstream arousal centers. An intriguing possibility is that Hcrt neurons affect wakefulness by projecting to the locus coeruleus (LC), a noradrenergic structure in the brainstem known to promote wakefulness and arousal (15, 16). Indeed, the LC receives the densest afferent projections from Hcrt neurons (14, 17). Application o...

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Section: Discussionsupporting

confidence: 94%

“…We genetically targeted Hcrt neurons by injecting lentiviral vectors expressing either Hcrt::ChR2-mCherry or Hcrt::mCherry into the Hcrt field. These viruses were previously shown to deliver optogenetic transgenes specifically and efficiently to Hcrt neurons (23,25). …”

mentioning

confidence: 99%

Mechanism for Hypocretin-mediated sleep-to-wake transitions

Carter

Brill

Bonnavion³

et al. 2012

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

251

203

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“…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 OX1R and histamine H1 receptors have normal sleep/wake behavior (9).…”

mentioning

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.

123

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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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“…Thus, orexin is an important factor in the regulation of wakefulness through connections with other arousal systems and sleep homeostasis [65] . Adequate sleep is necessary for memory consolidation but direct evidence is still rare.…”

Section: Hypothalamusmentioning

confidence: 99%

Optogenetics in neuroscience: what we gain from studies in mammals

Chen

Zeng

2012

Neurosci. Bull.

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Abstract:Optogenetics is a newly-introduced technology in the life sciences and is gaining increasing attention. It refers to the combination of optical technologies and genetic methods to control the activity of specific cell groups in living tissue, during which high-resolution spatial and temporal manipulation of cells is achieved. Optogenetics has been applied to numerous regions, including cerebral cortex, hippocampus, ventral tegmental area, nucleus accumbens, striatum, spinal cord, and retina, and has revealed new directions of research in neuroscience and the treatment of related diseases. Since optogenetic tools are controllable at high spatial and temporal resolution, we discuss its applications in these regions in detail and the recent understanding of higher brain functions, such as reward-seeking, learning and memory, and sleep.Further, the possibilities of improved utility of this newly-emerging technology are discussed. We intend to provide a paradigm of the latest advances in neuroscience using optogenetics.

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Sleep Homeostasis Modulates Hypocretin-Mediated Sleep-to-Wake Transitions

Cited by 223 publications

References 65 publications

Mechanism for Hypocretin-mediated sleep-to-wake transitions

Mechanism for Hypocretin-mediated sleep-to-wake transitions

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

Optogenetics in neuroscience: what we gain from studies in mammals

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