The neuronal underpinnings of the sleep/wake cycle and the possible functions of sleep in cognition remain to be fully characterized. Neuromodulators such as dopamine (DA), norepinephrine (NE) and acetylcholine (ACh) have been implicated in arousal in numerous behavioral settings. Work from many laboratories, including ours, has demonstrated that the neuropeptide Hypocretin (Hcrt), also known as orexin, is essential for arousal stability, possibly by orchestrating the activity of these neuromodulators however, the neuronal mechanisms underlying this coordination are still unknown. Here, we will use transgenic, anatomical, electrophysiological, chemo and optogenetic approaches to test functional connectivity between neuronal circuits associated with sleep to wake transitions. In the first aim, we will study which hypothalamic inhibitory circuits are sensitive t external factors that affect arousal and sleep, such as acute stress and metabolic challenges, and whether these factors induce sleep by inhibiting Hcrt neurons.
In aim 2 we will test the hypothesis is that DA, NE, Ach have different and specific roles on the dynamic of sleep and wakefulness and that their functional connectivity with Hcrt is critical for a healthy sleep/wake cycle. The necessity of DA or ACh transmission for Hcrt-mediated awakenings will be interrogated by photoinhibition of the neuromodulators with simultaneous photostimulation of Hcrt.
In aim 3, we will test whether manipulation of individual arousal circuits during sleep has consequences on the consolidation of different types of memories. Together, these experiments will significantly increase our understanding of how Hcrt neurotransmission is modulated by external factors and how Hcrt neurons integrate and transmit this information into effector systems. Our experiments will also shed light into the mechanisms that underlie memory consolidation during sleep, with consequences in cognitive performance.

Public Health Relevance

We will use state-of-the art methods to interrogate the neuronal underpinnings of sleep to wake transitions. A first goal will determine how external factors that impact the quality of sleep such as stress and metabolic imbalances, affect specific neuronal circuits. A second set of experiments will determine how particular neuronal circuits are connected to affect the dynamic of sleep and wakefulness. We will also investigate how manipulations to individual transmitter systems during sleep affect consolidation of different types of memories.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH087592-07
Application #
9105427
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Vicentic, Aleksandra
Project Start
2009-12-01
Project End
2018-07-31
Budget Start
2016-09-01
Budget End
2017-07-31
Support Year
7
Fiscal Year
2016
Total Cost
$407,694
Indirect Cost
$157,694
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Sorooshyari, Siamak; Huerta, Ramón; de Lecea, Luis (2015) A Framework for Quantitative Modeling of Neural Circuits Involved in Sleep-to-Wake Transition. Front Neurol 6:32
Bonnavion, Patricia; Jackson, Alexander C; Carter, Matthew E et al. (2015) Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses. Nat Commun 6:6266
de Lecea, Luis (2015) Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Curr Top Behav Neurosci 25:367-78
Mosqueiro, Thiago; de Lecea, Luis; Huerta, Ramon (2014) Control of sleep-to-wake transitions via fast aminoacid and slow neuropeptide transmission. New J Phys 16:
Irmak, Simal Ozen; de Lecea, Luis (2014) Basal forebrain cholinergic modulation of sleep transitions. Sleep 37:1941-51
Giardino, William J; de Lecea, Luis (2014) Hypocretin (orexin) neuromodulation of stress and reward pathways. Curr Opin Neurobiol 29:103-8
Rolls, A; Makam, M; Kroeger, D et al. (2013) Sleep to forget: interference of fear memories during sleep. Mol Psychiatry 18:1166-70
Touriño, Clara; Eban-Rothschild, Ada; de Lecea, Luis (2013) Optogenetics in psychiatric diseases. Curr Opin Neurobiol 23:430-5
Carter, Matthew E; Brill, Julia; Bonnavion, Patricia et al. (2012) Mechanism for Hypocretin-mediated sleep-to-wake transitions. Proc Natl Acad Sci U S A 109:E2635-44
de Lecea, Luis; Carter, Matthew E; Adamantidis, Antoine (2012) Shining light on wakefulness and arousal. Biol Psychiatry 71:1046-52

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