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Wakefulness Promotion in the Hypothalamus: Proposing a Model


The abstract below is derived from a short paper summarizing various studies into the nature of sleep and wakefulness.  Crucially, these studies point to the hypothalamus acting as the control centre or ‘switch’ between the two states.  The abstract suggests that the Posterior Hypothalamus is responsible for wakefulness through Orexin (Hypocretin) neurons, whereas the Preoptic area of the Hypothalamus is responsible for sleep through GABAergic and galaninergic neurons.  Moreover, the abstract proposes that these two actions of the hypothalamus inhibit one another to create a stable sleeping and waking cycle.



What this means for the bigger picture?


With numerous links already drawn between Orexin (Hypocretin) and wakefulness this abstract narrows down the area of the brain in which such interactions take place.  When added to the existing body of knowledge, this research may help to combat sleep disorders such as insomnia and narcolepsy.  The studies mentioned in this abstract also point towards further research into models of action and inhibition between sleep and wake promoting areas of the brain.





The paper summarized a broad range of relevant scientific studies, however it was written back in 2001.  As such some of its findings and observations may have been updated due to developments after that point.



So what does this have to do with Modafinil?


One theory of how Modafinil acts is that it “induces expression in Orexinergic neurons.”[i] In essence, Modafinil may work by enhancing Orexin (Hypocretin) function.  This abstract offers further information on the subject by suggesting that Modafinil’s action may have an effect on the hypothalamus.  In particular Modafinil may alter the cycle of action and inhibition proposed in the abstract, which is especially interesting given alternative suggestions that Modafinil “may promote waking via the activation of the histaminergic system”[ii]



Further Reading


For more on brain structures in relation to sleep and wake cycles, have a look at this study on basal forebrain sites of action.


There’s also this study regarding how Orexins (Hypocretins) could potentially provide a “novel therapeutic approach to the treatment of narcolepsy.”


See below for the complete abstract with key findings in bold.

[i] Scammell TE, Estabrooke IV, Mccarthy MT, et al. “Hypothalamic arousal regions are activated during modafinil-induced wakefulness.” J Neurosci. 2000;20(22):8620-8.


[ii] Ishizuka T1, Sakamoto Y, Sakurai T, Yamatodani A, ‘Modafinil increases histamine release in the anterior hypothalamus of rats’ Neurosci Lett. 2003 Mar 20;339(2):143-6. Abstract available at



The sleep switch: hypothalamic control
of sleep and wakefulness
Saper CB, Chou TC, Scammell TE.
Dept of Neurology and Program in Neuroscience,
Harvard Medical School,
Beth Israel Deaconess Medical Center,
02215, Boston, MA, USA
Trends Neurosci 2001 Dec 1;24(12):726-31


More than 70 years ago, von Economo predicted a wake-promoting area in the posterior hypothalamus and a sleep-promoting region in the preoptic area. Recent studies have dramatically confirmed these predictions. The ventrolateral preoptic nucleus contains GABAergic and galaninergic neurons that are active during sleep and are necessary for normal sleep. The posterior lateral hypothalamus contains orexin/hypocretin neurons that are crucial for maintaining normal wakefulness. A model is proposed in which wake- and sleep-promoting neurons inhibit each other, which results in stable wakefulness and sleep. Disruption of wake- or sleep-promoting pathways results in behavioral state instability.