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

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.

Sleep Homeostasis Modulates Hypocretin-Mediated Sleep-to-Wake Transitions

“…environmental conditions strengthen synaptic connections onto Hcrt neurons, potentially increasing Hcrt neural activity and promoting arousal regardless of circadian time (Rao et al, 2007). Our study supports this hypothesis, demonstrating the sufficiency of Hcrt neurons to promote arousal throughout the entire light/dark period.…”

Staying awake puts pressure on brain arousal systems

“…In this issue of the JCI, Rao et al (14) have made an important contribution to our understanding of how the activity of the hypocretin wakefulness-promoting system changes during prolonged wakefulness. The authors postponed, for 2-4 hours, the normal sleep period in mice either by injecting the animals with the wake-promoting drug modafinil or by sleep depriving them using gentle handling.…”

Dopaminergic D1and D2Receptors Are Essential for the Arousal Effect of Modafinil

“…Modafinil acts differently from established psychostimulants (Lin et al, 1992) and possesses only minimal potential for abuse (Jasinski, 2000;DerocheGamonet et al, 2002;Rao et al, 2007). However, the mechanism of modafinil-induced wakefulness is controversial.…”