Promotion of Wakefulness and Energy Expenditure by Orexin-A in the Ventrolateral Preoptic Area

Mavanji, Vijayakumar; Perez‐Leighton, Claudio E.; Kotz, Catherine M.; Billington, Charles J.; Parthasarathy, Sairam; Sinton, Christopher M.; Teske, Jennifer A.

doi:10.5665/sleep.4970

Cited by 47 publications

(91 citation statements)

References 83 publications

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“…In addition, while cataplexy was observed in some O/A3 mice during the dark phase in other experiments, we did not observe any cataplexy in the O/A3 mice during TWAA testing, perhaps due to the absence of total loss of orexin neurons in these mice at the time of testing. Increased TWAA performance after OXA treatment is not likely due to increased orexin-induced arousal, as all tests were performed at least 24 h after the last orexin injection, and the OXA waking effect lasts only 2 h post injection in rats [53,54]. …”

Section: Discussionmentioning

confidence: 99%

Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice

Mavanji

Butterick

Duffy

et al. 2017

Neurobiology of Learning and Memory

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Orexin A is produced in neurons of the lateral, perifornical and dorsomedial regions of the lateral hypothalamic area, which then project widely throughout the central nervous system to regulate arousal state, sleep-wake architecture, energy homeostasis and cognitive processes. Disruption of orexin signaling leads to sleep disturbances and increased body mass index, but recent studies also indicate that orexin neuron activation improves learning and memory. We hypothesized that hippocampal orexin receptor activation improves memory. To test this idea, we obtained orexin/ataxin-3 (O/A3) mice, which become deficient in orexin neurons by about 12 weeks of age. We first measured hippocampal orexin receptor 1 (OX1R) gene expression and protein levels, then tested acquisition and consolidation of two-way active avoidance (TWAA) memory, a hippocampal-dependent learning and memory task. Finally, we determined if exogenous intra-hippocampal OXA treatment could reverse cognitive impairment (as determined by TWAA) in OA/3 mice. We showed that OX1R mRNA expression and protein levels were significantly elevated in O/A3 mice, indicating the potential for preserved orexin responsiveness. The O/A3 mice were significantly impaired in TWAA memory vs. control mice, but OXA treatment (both acute and chronic) reversed these memory deficits. These results demonstrate that orexin plays an important role in hippocampal-dependent consolidation of two-way active avoidance memory, and orexin replacement can rescue the cognitive impairment.

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Section: Discussionmentioning

confidence: 99%

Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice

Mavanji

Butterick

Duffy

et al. 2017

Neurobiology of Learning and Memory

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“…The ventrolateral preoptic area (VLPO), involved in sleep‐to‐wake transitions , receives orexin projections and contains both orexin receptors . Orexin‐A injection into VLPO decreases sleep and increases time spent awake, physical activity, and total EE due to increases in several components of total EE . Orexin receptor blockade reduces the behavioral effects due to orexin‐A injections but also reduces basal EE (total and several components) .…”

Section: Introductionmentioning

confidence: 99%

Partial Sleep Deprivation Reduces the Efficacy of Orexin‐A to Stimulate Physical Activity and Energy Expenditure

DePorter

Coborn

Teske

2017

Obesity

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Objective: Sufficient sleep is required for weight maintenance. Sleep deprivation due to noise exposure stimulates weight gain by increasing hyperphagia and reducing energy expenditure (EE). Yet the mechanistic basis underlying the weight gain response is unclear. Orexin-A promotes arousal and negative energy balance, and orexin terminals project to the ventrolateral preoptic area (VLPO), which is involved in sleep-to-wake transitions. To determine whether sleep deprivation reduces orexin function in VLPO and to test the hypothesis that sleep deprivation would attenuate the orexin-A-stimulated increase in arousal, physical activity (PA), and EE. Methods: Electroencephalogram, electromyogram, distance traveled, and EE were determined in male Sprague-Dawley rats following orexin-A injections into VLPO both before and after acute (12-h) and chronic (8 h/d, 9 d) sleep deprivation by noise exposure. Results: Orexin-A in the VLPO significantly increased arousal, PA, total EE, and PA-related EE and reduced sleep and respiratory quotient before sleep deprivation. In contrast to after acute sleep deprivation in which orexin-A failed to stimulate EE during PA only, orexin-A failed to significantly increase arousal, PA, fat oxidation, total EE, and PA-related EE after chronic sleep deprivation. Conclusions: Sleep deprivation may reduce sensitivity to endogenous stimuli that enhance EE due to PA and thus stimulate weight gain.

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“…For instance, people with narcolepsy often have lower levels of orexins in cerebrospinal fluid (21). This suggests that the inhibition of orexin receptors in human may contribute to the alleviation of insomnia (22). Indeed, an effective smallmolecule antagonist of orexin receptors termed Suvorexant (23) was approved by the FDA for the treatment of insomnia in 2014 (24).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Characteristics of Porcine Orexin 2 Receptor and Mutants

et al. 2020

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Promotion of Wakefulness and Energy Expenditure by Orexin-A in the Ventrolateral Preoptic Area

Abstract: These data show the ventrolateral preoptic area is a site of action for orexin-A, which may promote negative energy balance by modulating sleep/wakefulness and stimulating spontaneous physical activity and energy expenditure.

Cited by 47 publications

References 83 publications

Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice

Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice

Partial Sleep Deprivation Reduces the Efficacy of Orexin‐A to Stimulate Physical Activity and Energy Expenditure

Pharmacological Characteristics of Porcine Orexin 2 Receptor and Mutants

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