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Further studies of the hypocretin/orexin system

English title Further studies of the hypocretin/orexin system
Applicant Mühlethaler Michel
Number 135708
Funding scheme Project funding (Div. I-III)
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.04.2011 - 30.09.2013
Approved amount 313'109.85
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Keywords (9)

hypocretin; arousal; narcolepsy; sleep; waking; neuropetide; cerebral cortex; orexin; hypocretin

Lay Summary (English)

Lead
Lay summary

Study of layer 6b, an orexin-sensitive layer in the cerebral cortex

This project represents the continuation of a program to understand the mechanisms by which the hypothalamic neuropeptide orexin influences sleep/wake states. Deficit in this neuropeptide is known to produce sleep disorder narcolepsy, an inability to maintain waking, in both animals and humans.

               Numerous studies, including from our laboratory, have suggested that orexin neurons exert their influence by their widespread excitatory projections upon the classical arousal systems that express noradrenaline, serotonin, acetylcholine and histamine as neurotransmitters. While this might indeed be partially true, it is noteworthy that lesioning experiments on these systems have failed to reproduce a narcoleptic phenotype.

                 Other projections of the orexin system might play a more fundamental role in this respect and we recently found that orexin exerts a powerful excitatory action on a thin cell layer at the bottom of the cortex, layer 6b. Given the pattern of connectivity of this seldom studied layer, we suggest that it could play a role as a diffuse cortical activating system.

                 Our goal, using a combination of techniques, is to study the neurons of layer 6b, their electrophysiological properties, their response to neurotransmitters, their morphological aspect, the transmitters they express, the extent of their projection. We will in particular focus on those cells which are sensitive to orexin. Our underlying hypothesis are first, that during the post natal days orexin could act like acetylcholine and promote synchronized activity and second, that in adult cortical networks, orexin could preserve some of this capacity and could contribute to cortical activation and the maintenance of the waking state.

            These studies are expected to shed light on the mechanisms by which sleep/wake states are regulated.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
120726 Further studies of the hypocretin/orexin system 01.04.2008 Project funding (Div. I-III)

Abstract

This research grant aims at addressing several issues related to the neurotransmitter hypocretin (also known as orexin), a brain neuropeptide notably involved in sleep-wake regulation and addictive behaviours. Lesion of this system is known to produce narcolepsy, a brain disease which can affect animals and humans and is characterized notably by an inability to maintain wakefulness. The themes covered in the proposal include the control of the cells that secrete this peptide in the hypothalamus and the action of the peptide on brain targets and in particular the cerebral cortex. Several techniques will be used and in particular molecular biology, electrophysiology and pharmacology.
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