Answer. Very briefly, hypocretinergic neurons take in information about the circadian rhythm, energy metabolism, the limbic (emotional) system and many other variables in order to send out a coordinated signal to other waking systems, thus endowing the waking-sleep cycle with stability.

A. Optogenetics consists in converting neurons that are sensitive to a certain wavelength by introducing light-activated ion channels. This technology, which so far can only be used in animal models, allows genetically defined neurons and neural circuits to be manipulated with millisecond precision. This is truly revolutionary, because it allows us to understand and dissect the brain function at circuit level, something that was not previously possible. We were the first to use optogenetic techniques in vivo, and we chose the hypocretin system precisely to show that its stimulation in mice is sufficient to awaken the animals. This and other optogenetic experiments have established a causal relationship between the activity of the hypocretinergic system and control over the transitions of the waking states.

A. This is an area that we are still working on in several laboratories. We still do not fully understand the relationship between hypocretins and dopamine or reward circuits. There is a great deal of evidence to support the idea that hypocretins activate dopamine and increase the 'value' of a positive stimulus. However, direct stimulation of hypocretins appears to have a negative value, as the animals avoid contexts associated with Hcrt activity. We have also seen that persistent stimulation of Hcrt neurons triggers a stress response. To put it simply, we could say that the connection between Hcrt and dopamine would account for the small number of narcoleptic patients with problems of drug abuse, but of course there are many connections that we are not aware of and it is a very complex problem.

A. The future is really promising. In animal models it appears that the administration of Hcrt ligands rescues the narcoleptic phenotype without the need to regulate its release with precision. This means that it would be possible to treat narcolepsy efficiently with drugs. There are at least three molecules under development in the pharmaceutical industry that selectively bind to Hcrt receptors. It is difficult to give dates, but I am confident that within a decade we will have a selective drug treatment for type I narcolepsy.

Acknowledgement. Many thanks to Professor de Lecea for his answers; given the interest his presence arouses among us, we will definitely attend his conference in Madrid.