Current models of sleep-wake regulation are ?neuron-centric?. However, there are astrocytes in the brain, and they outnumber neurons. A single astrocyte contacts hundreds of dendrites, and tens of thousands of synapses (Bushong et al., 2002, Halassa et al., 2007). The concept of a tripartite synapse has emerged where astrocytes actively control neuronal activity and synaptic transmission. We provided the first evidence that selectively activating astrocytes in the posterior hypothalamus increases both NREM and REM sleep in mice. This is the first time that optogenetic or DREDD activation of cells other than neurons has been shown to increase sleep. Most importantly, sleep was increased at night, the normal wake period in nocturnal mice. This indicates that astrocytes can impart a load that can induce sleep. What this means is that astrocytes can impart a load on neurons throughout the brain, thus providing for the first time an explanation for the waxing and waning of sleep. This will support the hypothesis of ?local use dependent sleep? throughout the brain. We will determine the gliotransmitter that is released, and also monitor the activity of adjacent sleep-wake neurons in response to optogenetic stimulation.
Aim 1 will use microdialysis to test the hypothesis that adenosine accumulates in response to optogenetic stimulation of ChR2-positive astroglia. We are focusing on adenosine based on the substantial evidence that it is released from astrocytes and its linkage with sleep. However, the other potential gliotransmitters will also be measured.
This aim will also use the adenosine A1 receptor antagonist, CPT, to block the sleep induced by optogenetic stimulation of astrocytes.
Aim 2 will test the hypothesis that in response to optogenetic stimulation of ChR2-positive astroglia the arousal neurons in the posterior hypothalamus are inhibited, and this is blocked by the adenosine A1 receptor antagonist.
This aim will also determine the site-specificity of the effect in mice by activating the ChR2-containing astrocytes in areas implicated in sleep-wake regulation (VLPO, basal forebrain, and dorsolateral pons). The overall impact of this project is that it mechanistically connects astrocytes, adenosine, A1 receptor, and local neuronal activity with sleep. Inclusion of astrocytes in circuit models will lead to better explanation of sleep homeostasis, which is something that current ?neuron-centric? models have failed to do.

Public Health Relevance

Current circuit models of sleep-wake regulation are ?neuron-centric?. However, there are astrocytes in the brain, and they outnumber neurons. The impact of including astrocytes in sleep models is that it better explains fundamental aspects of sleep-wake regulation, such as local- use dependent sleep and the waxing and waning of sleep. We are inspired by particle physicists who continually refine their models by using new technology to identify missing components. In neuroscience we must also apply new technology to better delineate network models.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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He, Janet
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Medical University of South Carolina
Schools of Medicine
United States
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Liu, Meng; Blanco-Centurion, Carlos; Shiromani, Priyattam J (2017) Rewiring brain circuits to block cataplexy in murine models of narcolepsy. Curr Opin Neurobiol 44:110-115
Shiromani, Priyattam J; Peever, John H (2017) New Neuroscience Tools That Are Identifying the Sleep-Wake Circuit. Sleep 40:
Blanco-Centurion, Carlos; Liu, Meng; Konadhode, Roda P et al. (2016) Optogenetic activation of melanin-concentrating hormone neurons increases non-rapid eye movement and rapid eye movement sleep during the night in rats. Eur J Neurosci 44:2846-2857