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Hypocretin (orexin) regulation of sleep-to-wake transitions.

de Lecea L, Huerta R - Front Pharmacol (2014)

Bottom Line: The hypocretin (Hcrt), also known as orexin, peptides are essential for arousal stability.Here we discuss background information about the interaction of Hcrt with other neuromodulators, including norepinephrine and acetylcholine probed with optogenetics.We conclude that Hcrt neurons integrate metabolic, circadian and limbic inputs and convey this information to a network of neuromodulators, each of which has a different role on the dynamic of sleep-to-wake transitions.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.

ABSTRACT
The hypocretin (Hcrt), also known as orexin, peptides are essential for arousal stability. Here we discuss background information about the interaction of Hcrt with other neuromodulators, including norepinephrine and acetylcholine probed with optogenetics. We conclude that Hcrt neurons integrate metabolic, circadian and limbic inputs and convey this information to a network of neuromodulators, each of which has a different role on the dynamic of sleep-to-wake transitions. This model may prove useful to predict the effects of orexin receptor antagonists in sleep disorders and other conditions.

No MeSH data available.


Related in: MedlinePlus

Time series of in silico conductance-based models of Hcrt and LC neurons. During sleep, both Hcrt and LC neurons are relatively quiescent. Once Hcrt neurons have integrated all of their inputs, including metabolic, circadian, and limbic states, they initiate a train of spikes (here mimicked by a virtual stimulation) that release glutamate and eventually Hcrt on post-synaptic neurons. This model is made of 40 neurons using the same conductance-based model published in (Carter et al., 2012). Excitability of Hcrt and LC neurons in this model was modified by using the Vt value -52 mV and is regulated by randomly selecting the Vt values centered at -52.0 mV using a Gaussian process with standard deviation of 1 mV. HCRT neurons are stimulated during 10 s with a 5 pA current as indicated by a blue straight line on the left hand side. Glutamate release elicits a slow depolarization on LC neurons, and cumulative release of Hcrt reaches a threshold that results in a train of spikes of LC neurons. Three maximal currents elicited by HCRT receptors into the LCs are used: 20, 25, and 30 pA. The delayed excitability of LC neurons is very sensitive by only modifying the peak current by 10%. The dotted blue line indicates when the HCRTs start to be stimulated. This model is a simplification because it ignores the effect of regulatory inhibitory neurons widely present in hypothalamic circuits. Further work should show the stabilization of the LCs by using GABAergic circuits.Carter et al. (2010) demonstrated that subtle stimulation of LC neurons, reaching 20 pulses in 5 s, deterministically results in an awakening.
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Figure 1: Time series of in silico conductance-based models of Hcrt and LC neurons. During sleep, both Hcrt and LC neurons are relatively quiescent. Once Hcrt neurons have integrated all of their inputs, including metabolic, circadian, and limbic states, they initiate a train of spikes (here mimicked by a virtual stimulation) that release glutamate and eventually Hcrt on post-synaptic neurons. This model is made of 40 neurons using the same conductance-based model published in (Carter et al., 2012). Excitability of Hcrt and LC neurons in this model was modified by using the Vt value -52 mV and is regulated by randomly selecting the Vt values centered at -52.0 mV using a Gaussian process with standard deviation of 1 mV. HCRT neurons are stimulated during 10 s with a 5 pA current as indicated by a blue straight line on the left hand side. Glutamate release elicits a slow depolarization on LC neurons, and cumulative release of Hcrt reaches a threshold that results in a train of spikes of LC neurons. Three maximal currents elicited by HCRT receptors into the LCs are used: 20, 25, and 30 pA. The delayed excitability of LC neurons is very sensitive by only modifying the peak current by 10%. The dotted blue line indicates when the HCRTs start to be stimulated. This model is a simplification because it ignores the effect of regulatory inhibitory neurons widely present in hypothalamic circuits. Further work should show the stabilization of the LCs by using GABAergic circuits.Carter et al. (2010) demonstrated that subtle stimulation of LC neurons, reaching 20 pulses in 5 s, deterministically results in an awakening.

Mentions: Peyron et al. (1998) described a broad distribution of Hcrt fibers throughout the brain. Very few Hcrt projections have been studied in detail. The LC receives a very dense network of Hcrt-immunopositive axon terminals, and the connectivity between Hcrt and LC neurons has been shown to be monosynaptic. Recently, Carter et al. (2012) have suggested a conductance-based computational model by which a short (> 10 s) period of phasic Hcrt activity enhances the excitability of post-synaptic LC neurons through conductances that elevate the concentration of intracellular calcium (Figure 1). Hcrt action on post-synaptic targets is remarkably slow (Burlet et al., 2002; Kohlmeier et al., 2008), lasting several seconds, a dynamic that is consistent with the wake latencies observed after optogenetic stimulation of Hcrt cells in vivo (Mileykovskiy et al., 2005). Release of Hcrt, either synaptic or extrasynaptic, increases the excitability of LC neurons. Since optogenetic studies have showed that only a few light pulses (~20) to LC neurons are sufficient to induce behavioral sleep-to-wake transitions, mild excitation of LC neurons by other afferents within ~10 s of Hcrt-enhanced excitability would reach the threshold of an awakening with high probability (Figure 1).


Hypocretin (orexin) regulation of sleep-to-wake transitions.

de Lecea L, Huerta R - Front Pharmacol (2014)

Time series of in silico conductance-based models of Hcrt and LC neurons. During sleep, both Hcrt and LC neurons are relatively quiescent. Once Hcrt neurons have integrated all of their inputs, including metabolic, circadian, and limbic states, they initiate a train of spikes (here mimicked by a virtual stimulation) that release glutamate and eventually Hcrt on post-synaptic neurons. This model is made of 40 neurons using the same conductance-based model published in (Carter et al., 2012). Excitability of Hcrt and LC neurons in this model was modified by using the Vt value -52 mV and is regulated by randomly selecting the Vt values centered at -52.0 mV using a Gaussian process with standard deviation of 1 mV. HCRT neurons are stimulated during 10 s with a 5 pA current as indicated by a blue straight line on the left hand side. Glutamate release elicits a slow depolarization on LC neurons, and cumulative release of Hcrt reaches a threshold that results in a train of spikes of LC neurons. Three maximal currents elicited by HCRT receptors into the LCs are used: 20, 25, and 30 pA. The delayed excitability of LC neurons is very sensitive by only modifying the peak current by 10%. The dotted blue line indicates when the HCRTs start to be stimulated. This model is a simplification because it ignores the effect of regulatory inhibitory neurons widely present in hypothalamic circuits. Further work should show the stabilization of the LCs by using GABAergic circuits.Carter et al. (2010) demonstrated that subtle stimulation of LC neurons, reaching 20 pulses in 5 s, deterministically results in an awakening.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921570&req=5

Figure 1: Time series of in silico conductance-based models of Hcrt and LC neurons. During sleep, both Hcrt and LC neurons are relatively quiescent. Once Hcrt neurons have integrated all of their inputs, including metabolic, circadian, and limbic states, they initiate a train of spikes (here mimicked by a virtual stimulation) that release glutamate and eventually Hcrt on post-synaptic neurons. This model is made of 40 neurons using the same conductance-based model published in (Carter et al., 2012). Excitability of Hcrt and LC neurons in this model was modified by using the Vt value -52 mV and is regulated by randomly selecting the Vt values centered at -52.0 mV using a Gaussian process with standard deviation of 1 mV. HCRT neurons are stimulated during 10 s with a 5 pA current as indicated by a blue straight line on the left hand side. Glutamate release elicits a slow depolarization on LC neurons, and cumulative release of Hcrt reaches a threshold that results in a train of spikes of LC neurons. Three maximal currents elicited by HCRT receptors into the LCs are used: 20, 25, and 30 pA. The delayed excitability of LC neurons is very sensitive by only modifying the peak current by 10%. The dotted blue line indicates when the HCRTs start to be stimulated. This model is a simplification because it ignores the effect of regulatory inhibitory neurons widely present in hypothalamic circuits. Further work should show the stabilization of the LCs by using GABAergic circuits.Carter et al. (2010) demonstrated that subtle stimulation of LC neurons, reaching 20 pulses in 5 s, deterministically results in an awakening.
Mentions: Peyron et al. (1998) described a broad distribution of Hcrt fibers throughout the brain. Very few Hcrt projections have been studied in detail. The LC receives a very dense network of Hcrt-immunopositive axon terminals, and the connectivity between Hcrt and LC neurons has been shown to be monosynaptic. Recently, Carter et al. (2012) have suggested a conductance-based computational model by which a short (> 10 s) period of phasic Hcrt activity enhances the excitability of post-synaptic LC neurons through conductances that elevate the concentration of intracellular calcium (Figure 1). Hcrt action on post-synaptic targets is remarkably slow (Burlet et al., 2002; Kohlmeier et al., 2008), lasting several seconds, a dynamic that is consistent with the wake latencies observed after optogenetic stimulation of Hcrt cells in vivo (Mileykovskiy et al., 2005). Release of Hcrt, either synaptic or extrasynaptic, increases the excitability of LC neurons. Since optogenetic studies have showed that only a few light pulses (~20) to LC neurons are sufficient to induce behavioral sleep-to-wake transitions, mild excitation of LC neurons by other afferents within ~10 s of Hcrt-enhanced excitability would reach the threshold of an awakening with high probability (Figure 1).

Bottom Line: The hypocretin (Hcrt), also known as orexin, peptides are essential for arousal stability.Here we discuss background information about the interaction of Hcrt with other neuromodulators, including norepinephrine and acetylcholine probed with optogenetics.We conclude that Hcrt neurons integrate metabolic, circadian and limbic inputs and convey this information to a network of neuromodulators, each of which has a different role on the dynamic of sleep-to-wake transitions.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.

ABSTRACT
The hypocretin (Hcrt), also known as orexin, peptides are essential for arousal stability. Here we discuss background information about the interaction of Hcrt with other neuromodulators, including norepinephrine and acetylcholine probed with optogenetics. We conclude that Hcrt neurons integrate metabolic, circadian and limbic inputs and convey this information to a network of neuromodulators, each of which has a different role on the dynamic of sleep-to-wake transitions. This model may prove useful to predict the effects of orexin receptor antagonists in sleep disorders and other conditions.

No MeSH data available.


Related in: MedlinePlus