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 #
5R01MH087592-08
Application #
9343044
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Vicentic, Aleksandra
Project Start
2010-06-10
Project End
2018-07-31
Budget Start
2017-08-05
Budget End
2018-07-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Yamaguchi, Hiroshi; Hopf, F Woodward; Li, Shi-Bin et al. (2018) In vivo cell type-specific CRISPR knockdown of dopamine beta hydroxylase reduces locus coeruleus evoked wakefulness. Nat Commun 9:5211
Giardino, William J; Eban-Rothschild, Ada; Christoffel, Daniel J et al. (2018) Parallel circuits from the bed nuclei of stria terminalis to the lateral hypothalamus drive opposing emotional states. Nat Neurosci 21:1084-1095
Yamaguchi, Hiroshi; de Lecea, Luis (2018) In vivo cell type-specific CRISPR gene editing for sleep research. J Neurosci Methods :
Tyree, Susan M; de Lecea, Luis (2017) Lateral Hypothalamic Control of the Ventral Tegmental Area: Reward Evaluation and the Driving of Motivated Behavior. Front Syst Neurosci 11:50
Eban-Rothschild, Ada; Giardino, William J; de Lecea, Luis (2017) To sleep or not to sleep: neuronal and ecological insights. Curr Opin Neurobiol 44:132-138
Fujita, Akie; Bonnavion, Patricia; Wilson, Miryam H et al. (2017) Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability. J Neurosci 37:9574-9592
Tyree, Susan M; de Lecea, Luis (2017) Optogenetic Investigation of Arousal Circuits. Int J Mol Sci 18:
He, Chao; Luo, Fenlan; Chen, Xingshu et al. (2016) Superficial Layer-Specific Histaminergic Modulation of Medial Entorhinal Cortex Required for Spatial Learning. Cereb Cortex 26:1590-1608
Eban-Rothschild, Ada; Rothschild, Gideon; Giardino, William J et al. (2016) VTA dopaminergic neurons regulate ethologically relevant sleep-wake behaviors. Nat Neurosci 19:1356-66
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

Showing the most recent 10 out of 27 publications