Objective
Summary: The appropriate regulation of sleep and wakefulness is a fundamental biological process that impacts human health, cognitive performance, and quality of life. However, the neural mechanisms regulating sleep/wake behavior and its associated circuits in the brain are largely unknown. Recent studies have illustrated the role of hypocretin/orexin (Hcrt) in sleep regulation, but the mechanisms that control the Hcrt system and subsequent changes in neural circuit function are still poorly described. I will take advantage of the larval zebrafish, a genetically and optically accessible model organism whose brain shares basic sleep-related structures with the human brain, in order to systematically investigate how and to what extent serotonergic (5-hydroxytrypamine, 5-HT) neurons of the dorsal raphe nucleus exert effects on sleep cycles via the Hcrt system and associated downstream circuitry. Furthermore, I will disambiguate whether 5-HT neurons affect sleep by direct influence on Hcrt neuron activity or by signalling downsteam on Hcrt target neurons. These analyses require a multidisciplinary approach possible only in zebrafish. First, I will use a novel bioluminescence-based method to investigate how drugs that target the 5-HT system, alter the activity of Hcrt and 5-HT neurons in freely behaving fish. Second, in order to verify a causal relationship between activity in 5-HT and Hcrt neurons and observed behavioral changes, I will activate the same neural populations with optogenetic methods while monitoring behavior in freely behaving fish. Third, I will use the same pharmacological and optogenetic approaches to visualize the direct effects of specific subpopulations of 5-HT and Hcrt neurons on activity throughout the whole brain with functional two-photon calcium imaging. The results of these experiments will provide invaluable insights into how specific neuromodulatory systems interact with each other in order to regulate neural circuits underlying sleep.
Call for proposal
FP7-PEOPLE-2012-IIF
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Funding Scheme
MC-IIF - International Incoming Fellowships (IIF)Coordinator
WC1E 6BT LONDON