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Further studies of the hypocretin/orexin system

Applicant Mühlethaler Michel
Number 120726
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 01.04.2008 - 31.03.2011
Approved amount 408'582.00
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Keywords (8)

sleep; orexin; circadian; wakefulness; hypocretin; addiction; stress; amygdala

Lay Summary (English)

Lead
Lay summary
The hypocretin/orexin (hcrt/orx) neurons are major players in the circuits of sleep and wakefulness. Alteration in the hcrt/orx system is indeed conductive to the sleep disorder narcolepsy in animals and humans. The goal of this request is to pursue the exploration of this system to better understand the mechanisms regulating the activity of hcrt/orx neurons as well as the way by which they act on target neurons. Three distinct projects are proposed to this effect: Project A will be carried on within the recently revealed context of a role of the hcrt/orx system in stress and addiction. Project B is concerned with the circadian control of hcrt/orx neurons. Project C will be concerned with the regulation of the activity of hcrt/orx neurons in vivo. These projects will be pursued using an approach coupling electrophysiology, pharmacology and the use of a new transgenic mouse model that, which allows us to selectively isolate mRNAs from hcrt/orx neurons.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
105825 Further in vitro studies on the hypocretin/orexin and melanin-concentrating hormone systems of the dorso-lateral hypothalamus 01.10.2004 Project funding (Div. I-III)
135708 Further studies of the hypocretin/orexin system 01.04.2011 Project funding (Div. I-III)

Abstract

The hypocretin/orexin (hcrt/orx) neurons are major players in the circuits of sleep and wakefulness. Alteration in the hcrt/orx system is indeed conductive to narcolepsy in animals and humans. The goal of this request is to pursue the exploration of this system to better understand the mechanisms regulating the activity of hcrt/orx neurons as well as the way by which they act on target neurons. Three distinct projects are proposed to this effect:Project A will be carried on within the recently revealed context of a role of the hcrt/orx system in stress and addiction. Two axes will be exploited. First, based on our published demonstration of the action of hcrt/orx on neurons of the central amygdala, we will test the hypothesis that hcrt/orx (and other hypothalamic peptides) could enhance a certain form of long-term potentiation (LTP) on these cells, thereby playing a role in fear conditioning and thus facilitating the storage of “emotional memories”. Second, we will explore the hypothesis that hcrt/orx neurons of the perifornical (PF) area have distinctive properties from those of the lateral hypothalamus (LH), as they are apparently involved in different domains, respectively sleep/wake regulation and stress/addiction. We will do so using an approach coupling electrophysiology, pharmacology and the use of a new transgenic mouse model (“PABP-mouse”) that was recently developed in collaboration, which allows us to selectively isolate mRNAs from hcrt/orx neurons.Project B is concerned with the circadian control of hcrt/orx neurons. In preliminary studies in young rat brain slices, we found that the responses of hcrt/orx neurons to a noradrenergic alpha-1 receptor agonist display a circadian rhythm. Based on these data, our hypothesis is that some properties of hcrt/orx neurons could be regulated in a circadian manner so as to promote or maintain states. Two related projects will be undertaken. First, using the PABP-mouse, we intend to explore the circadian expression of certain genes of hcrt/orx neurons. Second, based on the results obtained, we will study those gene products whose circadian rhythm is deemed relevant for the regulation of states by the hcrt/orx neurons. These studies will be performed using an electrophysiological and pharmacological approach in brain slices and in an explant preparation preserving the connectivity between the suprachiasmatic nucleus, the master brain clock, and the hcrt/orx neurons.Project C will be concerned with the regulation of the activity of hcrt/orx neurons in vivo. Our technical objective is to obtain long-term intracellular recordings from identified hcrt/orx neurons and be able to stimulate afferent modulatory pathways. Studying the noradrenergic input to these cells will be our principal goal, in order to settle a nagging question concerning the exact role of this input on hcrt/orx neurons.
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