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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 8

Occlusion of For-LTP in hypocretin/orexin neurons in mice repeatedly exposed to prolonged wakefulness.

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Occlusion of For-LTP in hypocretin/orexin neurons in mice repeatedly exp...
(A) LTP of mEPSC frequency is attenuated in mice chronically treated with modafinil compared with saline-treated mice. (B) Pooled data from all tested neurons recorded 30 minutes after the application of forskolin demonstrate that LTP of mEPSC frequency induced by forskolin (50 μM) is significantly attenuated in mice repeatedly treated with modafinil compared with control mice. *P < 0.05. (C) Time course shows that LTP of mEPSC amplitude exists in control mice but not in modafinil-treated mice. (D) Pooled data from all tested neurons recorded 30 minutes after the application of forskolin demonstrate that LTP of mEPSC amplitude is blocked in mice repeatedly treated with modafinil. *P < 0.05, Student’s t test. (E) Cumulative probability of mEPSC amplitude detected before (476 events) and 30 minutes after the treatment of forskolin (793 events) in control mice confirms a significant enhancement after the treatment (P < 0.001, Kolmogorov-Smirnov test). (F) Cumulative probability of mEPSC amplitude detected before (527 events) and 30 minutes after the treatment of forskolin (1,296 events) in modafinil-treated mice confirms that there was no significant change in the amplitude of mEPSC after the treatment with forskolin (P > 0.05, Kolmogorov-Smirnov test).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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