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An interview with Professor Luis de Lecea on the occasion of the Spanish Narcolepsy Association meeting for patients and doctors (European Narcolepsy Day. Madrid, 2019)

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Prof. Luis de Lecea Professor Luis de Lecea (b. Barcelona, 1965) is full professor in the Department of Psychiatry and Behavioral Sciences at Stanford University, California (USA). He graduated in Biology from the Universitat de Barcelona in 1987 and obtained a PhD from the same university in 1991. He was a post-doctoral fellow in Molecular Neurobiology at the Scripps Research Institute (San Diego) in 1996. A few months into his stay at the laboratory he discovered hypocretins. He is one of the most cited researchers in the field of sleep research and has received several international awards such as the NARSAD Distinguished Investigator Grant and Outstanding Investigator of the Sleep Research Society. Professor de Lecea will participate in this year's Annual Meeting of the Spanish Narcolepsy Association on March 16 (Caixa Fórum, Madrid) with a conference for patients and doctors entitled ‘To sleep or not to sleep. How the brain controls sleep’.
Question. The Spanish Narcolepsy Association appreciates your presence in Madrid despite all your commitments and the intense work you carry out in your laboratory. There are many questions we want to ask you, and we are going to start with the most basic one. In the last two decades you have published numerous articles on hypocretins and the hypocretinergic system, the main function of which would be to maintain a state of wakefulness. Could you sum up for us the function of the hypocretin neurons that you and your group discovered in 1998?
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.

Q. You pioneered the use of optogenetics in the study of sleep (2007), a technique that activates neurons with a pulse of laser light. Could you briefly explain what this technique consists in and what fundamental contribution it has made to research on narcolepsy?
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.

Q. Another important function of hypocretins is their projection into regions of the brain – through the neurotransmitter dopamine – thereby performing their role as neuromodulators. Does the link between hypocretins and dopamine explain why patients with narcolepsy have fewer addictions? To what extent does stress exert an influence?
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.

Q. Narcolepsy with cataplexy is a disease that has been known since the late nineteenth century and was treated with different drugs throughout the twentieth century prior to the discovery of hypocretins. Two decades have now passed and we are still using the same drugs. Why are we still without hypocretins for our patients? Are the functions of these peptides in other neural systems still unknown? Is it a question of lack of economic resources? What are the alternatives for the future?
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.
Dra. Rosa Peraita Adrados
Unidad de Sueño y Epilepsia-Neurofisiología Clínica. Hospital Universitario Gregorio Marañón. Universidad Complutense de Madrid (UCM). Madrid, España.
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