The hypocretins, also known as orexins, are two neuropeptide transmitters produced exclusively by a few thousand neurons in the hypothalamus. Studies in mice, dogs and humans have shown that loss-of- function of the hypocretin system results in narcolepsy/cataplexy. We have recently shown that optical stimulation of genetically defined Hcrt neurons using the light activated cation channel, Channelrhodopsin 2 (ChR2) increases the probability of sleep-to-wake transitions. However, the role of Hcrt neurons in awake animals is still poorly understood. Here, we will use optogenetic manipulation of Hcrt neurons to test whether phasic activity of these neurons during wakefulness is sufficient to stabilize arousal. First, we will introduce ChR2 in Hcrt neurons using a lentivirus and we will use different photostimulation patterns to manipulate Hcrt neuronal activity during wakefulness to test whether sustained activity extends waking. We will monitor photostimulation-induced changes in Hcrt release by microdialysis. We will also monitor locomotor activity, anxiety, feeding, behavior and sleep/wake parameters. To determine the mechanism by which Hcrt induces wakefulness, we will optogenetically stimulate three of the main postsynaptic targets of the Hcrt system: noradrenergic neurons in the locus coeruleus, dopaminergic neurons in the ventral tegmental area, and cholinergic neurons in the basal forebrain. In a third specific aim, we will seek evidence demonstrating that blocking phasic activity during a few minutes under the appropriate conditions is sufficient to induce cataplexy in wild-type mice. Unlike pharmacological studies, optogenetics offers unprecedented millisecond scale temporal resolution, which allows vigilance state-specific analysis of neurotransmitter function in species with unconsolidated sleep such as rodents. Our data will expand the use of state-of-the-art optogenetic methods in sleep studies and will provide mechanistic models on how the hypocretinergic system stabilizes arousal. These experiments may also lead to new and enhanced treatments for narcolepsy, insomnia and other sleep disorders.
Our data will expand the use of state-of-the-art optogenetic methods in sleep studies and will provide mechanistic models on how the hypocretinergic system stabilizes arousal. These experiments may also lead to new and enhanced treatments for narcolepsy, insomnia and other sleep disorders.
|Tyree, Susan M; de Lecea, Luis (2017) Lateral Hypothalamic Control of the Ventral Tegmental Area: Reward Evaluation and the Driving of Motivated Behavior. Front Syst Neurosci 11:50|
|Eban-Rothschild, Ada; Giardino, William J; de Lecea, Luis (2017) To sleep or not to sleep: neuronal and ecological insights. Curr Opin Neurobiol 44:132-138|
|Tyree, Susan M; de Lecea, Luis (2017) Optogenetic Investigation of Arousal Circuits. Int J Mol Sci 18:|
|Fujita, Akie; Bonnavion, Patricia; Wilson, Miryam H et al. (2017) Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability. J Neurosci 37:9574-9592|
|He, Chao; Luo, Fenlan; Chen, Xingshu et al. (2016) Superficial Layer-Specific Histaminergic Modulation of Medial Entorhinal Cortex Required for Spatial Learning. Cereb Cortex 26:1590-1608|
|Eban-Rothschild, Ada; Rothschild, Gideon; Giardino, William J et al. (2016) VTA dopaminergic neurons regulate ethologically relevant sleep-wake behaviors. Nat Neurosci 19:1356-66|
|Bonnavion, Patricia; Jackson, Alexander C; Carter, Matthew E et al. (2015) Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses. Nat Commun 6:6266|
|de Lecea, Luis (2015) Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Curr Top Behav Neurosci 25:367-78|
|Sorooshyari, Siamak; Huerta, Ramón; de Lecea, Luis (2015) A Framework for Quantitative Modeling of Neural Circuits Involved in Sleep-to-Wake Transition. Front Neurol 6:32|
|Irmak, Simal Ozen; de Lecea, Luis (2014) Basal forebrain cholinergic modulation of sleep transitions. Sleep 37:1941-51|
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