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Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons
Yan Rao, … , Tamas L. Horvath, Xiao-Bing Gao
Yan Rao, … , Tamas L. Horvath, Xiao-Bing Gao
Published December 3, 2007
Citation Information: J Clin Invest. 2007;117(12):4022-4033. https://doi.org/10.1172/JCI32829.
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Research Article

Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons

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Abstract

Sleep is a natural process that preserves energy, facilitates development, and restores the nervous system in higher animals. Sleep loss resulting from physiological and pathological conditions exerts tremendous pressure on neuronal circuitry responsible for sleep-wake regulation. It is not yet clear how acute and chronic sleep loss modify neuronal activities and lead to adaptive changes in animals. Here, we show that acute and chronic prolonged wakefulness in mice induced by modafinil treatment produced long-term potentiation (LTP) of glutamatergic synapses on hypocretin/orexin neurons in the lateral hypothalamus, a well-established arousal/wake-promoting center. A similar potentiation of synaptic strength at glutamatergic synapses on hypocretin/orexin neurons was also seen when mice were sleep deprived for 4 hours by gentle handling. Blockade of dopamine D1 receptors attenuated prolonged wakefulness and synaptic plasticity in these neurons, suggesting that modafinil functions through activation of the dopamine system. Also, activation of the cAMP pathway was not able to further induce LTP at glutamatergic synapses in brain slices from mice treated with modafinil. These results indicate that synaptic plasticity due to prolonged wakefulness occurs in circuits responsible for arousal and may contribute to changes in the brain and body of animals experiencing sleep loss.

Authors

Yan Rao, Zhong-Wu Liu, Erzsebet Borok, Rebecca L. Rabenstein, Marya Shanabrough, Min Lu, Marina R. Picciotto, Tamas L. Horvath, Xiao-Bing Gao

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Figure 1

LTP of excitatory synapses on hypocretin/orexin neurons following an acute exposure to prolonged wakefulness.

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LTP of excitatory synapses on hypocretin/orexin neurons following an acu...
(A) Modafinil (100 mg/kg) induces a long-lasting increment of locomotor activity in mice. Each point represents averaged beam breaks within a block of 5 minutes from all animals in each group during our experiments. The arrow indicates injection of modafinil or saline. (B) Sample traces of mEPSCs recorded in hypocretin/orexin neurons from saline- and modafinil-treated mice. (C) Mean frequency of mEPSCs recorded in hypocretin/orexin neurons 0, 1, and 2 hours after the injection of saline or modafinil. *P < 0.05, Student’s t test. (D–F) Cumulative probability of the amplitude of mEPSCs recorded in all neurons from saline- and modafinil-treated mice 0, 1, and 2 hours after the injection. (D) Saline, 1,518 events; modafinil, 1,557 events. (E) Saline, 4,510 events; modafinil, 2,753 events. (F) Saline, 3,250 events; modafinil, 3,942 events. (G and H) Relative contributions of AMPARs and NMDARs on evoked EPSCs recorded in hypocretin/orexin neurons from mice treated with saline and modafinil. (G) Sample traces of evoked EPSCs carried by AMPARs and NMDARs in hypocretin/orexin neurons from mice treated with saline (left) and modafinil (right). (H) Pooled data of the AMPAR/NMDAR ratio from all neurons in saline- (n = 10) or modafinil-treated mice (n = 10) 1 hour after the injection. *P < 0.05, Student’s t test.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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