Sleep problems such as excessive daytime sleepiness and insomnia are common in the United States. They are found in many psychiatric and neurological disorders and cause deficits in attention, learning and memory. The cellular mechanism that makes animals sleepy and causes cognitive deficits in sleepy animals is unknown. Chemical signaling between glia and neurons (i.e. gliotransmission) may be an important part of this mechanism. Glial astrocytes are brain cells that are electrically silent (relative to neurons) and for many decades were thought to serve purely supportive functions in the brain (e.g. ion buffering). More recent findings indicate that astrocytes are important partner in synaptic neurotransmission. Astrocytes surround synapses and respond to neurotransmitters by secreting their own chemical messengers (gliotransmitters), which in turn regulate neuronal excitability and synaptic transmission. The role of gliotransmission in mammalian behavior is only now beginning to be explored. In mammals astrocytes are densely concentrated in brain regions critical for arousal, sleep and higher cognitive function. We hypothesize that gliotransmission in these regions mediates not only sleepiness, but cognitive deficits associated with sleep loss. We will test our hypothesis by quantitatively measuring sleep regulation in mice with an inducible (conditional) mutation that inhibits astrocytic gliotransmission in vivo. We will also use these mice test the role of gliotransmission in learning and attention deficits caused by sleep loss. In this revised application, we have added two new sets of experiments in response to initial review. First, we now address the role of regional gliotransmission within brain areas implicated in sleep regulation (e.g. the basal forebrain and pre-optic area of the hypothalamus) or memory (hippocampus). This is accomplished by regionally expressing transgenes in the brain in vivo. Second, we also have added a new cognitive task, which is sensitive to sleep loss, but never before examined with respect to gliotransmission (T-maze reference reversal). Our revised application now far exceeds our previous explorations of these phenomena. Our findings will thus provide new insights into the cellular basis of sleep need and the function of non-neuronal cells in animal behavior.

Public Health Relevance

Sleep disorders are associated with cognitive dysfunction, mood disorders and mental illness. Some sleep problems may be caused by abnormalities in sleep homeostasis a process that increases the need for sleep. The cellular mechanisms governing sleep homeostasis are unknown, but may involve chemical signaling from non-electrically excitable cells. Identifying the role of these cells in sleep will provide new insight into the cellular basis of sleepiness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH099544-01A1
Application #
8583611
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Vicentic, Aleksandra
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$524,755
Indirect Cost
$196,783
Name
University of Pennsylvania
Department
Neurosciences
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Frank, Marcos G (2013) Astroglial regulation of sleep homeostasis. Curr Opin Neurobiol 23:812-8
Watson, Adam J; Frank, Marcos G (2013) Astrocytes do the ""shuttle"". Sleep 36:1413-4