Tuning arousal with optogenetic modulation of locus coeruleus neurons

Carter, Matthew E.; Yizhar, Ofer; Chikahisa, Sachiko; Nguyen, Hieu Pham Trung; Adamantidis, Antoine; Nishino, Seiji; Deisseroth, Karl; Lecea, Luı́s de

doi:10.1038/nn.2682

Cited by 809 publications

(794 citation statements)

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“…We genetically targeted optogenetic transgenes to LC neurons by stereotaxically injecting a Cre recombinase-dependent adeno-associated virus (AAV) into knock-in mice selectively expressing Cre in tyrosine hydroxylase neurons (TH::IRES-Cre mice) (26). AAV vectors contained either eNpHR3.0-eYFP or eYFP and were previously shown to specifically deliver transgenes to >98% of tyrosine hydroxylase-positive neurons in the LC (24). We simultaneously delivered non-Cre-dependent lentiviral vectors carrying either Hcrt::ChR2-mCherry or Hcrt::mCherry sequences into the Hcrt field.…”

Section: Resultsmentioning

confidence: 99%

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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.

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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: Resultsmentioning

confidence: 99%

“…We previously used viral approaches to deliver genetically encoded optogenetic transgenes to Hcrt (23) and LC (24) neurons to study the effects of stimulation or inhibition on wakefulness with high spatial and temporal precision. Because Hcrt and LC neural populations are located in distinct brain regions (Fig.…”

mentioning

confidence: 99%

Mechanism for Hypocretin-mediated sleep-to-wake transitions

Carter

Brill

Bonnavion³

et al. 2012

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

Self Cite

240

203

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“…73 On the other hand, the increased discharge of locus coeruleus neurons that occurs during wakefulness 66 appears sufficient to cause awakening, and may be necessary for the normal duration of the wakefulness episodes. 74 The neurons of the locus coeruleus project to 32 and inhibit 75 neurons of the hypothalamic ventrolateral preoptic nucleus, which, as discussed above, is a key structure for NREM sleep. 31 In turn, neurons of the ventrolateral preoptic nucleus send inhibitory projections to the locus coeruleus.…”

Section: Integration Of the Neural And Cardiovascular Events Of Awakementioning

confidence: 98%

Orexins and the cardiovascular events of awakening

Silvani

2017

Temperature

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This brief review aims to provide an updated account of the cardiovascular events of awakening, proposing a testable conceptual framework that links these events with the neural control of sleep and the autonomic nervous system, with focus on the hypothalamic orexin (hypocretin) neurons. Awakening from non-rapid-eye-movement sleep entails coordinated changes in brain and cardiovascular activity: the neural "flip-flop" switch that governs state transitions becomes biased toward the ascending arousal systems, arterial blood pressure and heart rate rise toward waking values, and distal skin temperature falls. Arterial blood pressure and skin temperature are sensed by baroreceptors and thermoreceptors and may positively feedback on the brain wake-sleep switch, thus contributing to sharpen, coordinate, and stabilize awakening. These effects may be enhanced by the hypothalamic orexin neurons, which may modulate the changes in blood pressure, heart rate, and skin temperature upon awakening, while biasing the wake-sleep switch toward wakefulness through direct neural projections. A deeper understanding of the cardiovascular events of awakening and of their links with skin temperature and the wake-sleep neural switch may lead to better treatments options for patients with narcolepsy type 1, who lack the orexin neurons.

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“…Drugs which increase noradrenergic release, such as tricyclic antidepressants suppress cataplexy in humans, dogs and mice [41]. Surprisingly, prolonged optogenetic stimulation of the LC in mice caused behavioural arrests similar to cataplexy [42].…”

Section: Section 163-monoaminergic Mechanisms In Cataplexymentioning

confidence: 99%

Pharmacogenetic inhibition of the subcoeruleus region influences rem sleep and cataplexy in narcoleptic mice

2013

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Introduction: Cataplexy -the sudden involuntary loss of skeletal muscle tone -is a defining feature of narcolepsy. The current study aimed to determine if cataplexy is influenced by direct manipulation of REM sleep circuitry. We did this by pharmacogenetically inhibiting the REM sleep centre, subcoeruleus (Sub-C). Methods:Inhibitory DREADD (hM4D-Gi) was bilaterally targeted to the Sub-C in hypocretin knockout mice (n=7). Intraperitoneal administration of clozapine-n-oxide was used to inhibit Sub-C cells expressing hM4D-Gi. Electrophysiological and behavioural criteria were used to characterize cataplexy and REM sleep.Results: Sub-C inhibition increased REM sleep and cataplexy amounts (p<0.05). Sub-C inhibition increased time spent in cataplexy amounts by increasing the number of cataplexy attacks (p<0.05). This intervention triggered increases in basal muscle tone during REM sleep, but had negligible effects on muscle tone during cataplexy (p>0.05).ii Conclusion: Pharmacogenetic manipulation of the Sub-C suggest that REM sleep and cataplexy are mediate by similar neural mechanism.iii

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Tuning arousal with optogenetic modulation of locus coeruleus neurons

Cited by 809 publications

References 50 publications

Mechanism for Hypocretin-mediated sleep-to-wake transitions

Mechanism for Hypocretin-mediated sleep-to-wake transitions

Orexins and the cardiovascular events of awakening

Pharmacogenetic inhibition of the subcoeruleus region influences rem sleep and cataplexy in narcoleptic mice

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