The pedunculopontine nucleus (PPN) helps control sleep-wake rhythms and modulates posture and locomotion. The proposed research will address three functional aspects (ascending, local and descending) of the PPN, the cholinergic arm of the Reticular Activating System (RAS). From 10-30 days postnatally there is a dramatic decrease in the percent of REM sleep in the rat. A hypothesis was proposed suggesting that disturbances in the developmental decrease in REM sleep, a return to a neonatal state of REM sleep drive, could lead to a number of disorders characterized by increased REM sleep drive. We tracked changes in ascending and descending projections from the PPN, along with developmental changes in neurochemical systems modulating the PPN. We found that certain neurotransmitters could be responsible for modulating the developmental decrease in REM sleep, reported new interactions between identified cell types, and proposed a push-pull model for PPN modulation of posture and locomotion. We also discovered the presence of electrical coupling in the PPN as well as in an ascending and a descending target of the PPN. Preliminary evidence suggests that changes in electrical coupling parallel the developmental decrease in REM sleep. This newly discovered mechanism will be explored using a) whole-cell patch clamp and intracellular sharp electrode recordings, b) pharmacological manipulation to induce and block electrical coupling, and c) measures of connexin-36 mRNA expression and protein levels before and during the developmental decrease in REM sleep (7-30 days), in 1) the parafascicular nucleus (Pf), an ascending target of the PPN, 2) the PPN itself, and 3) the SubCoeruleus (SubC) nucleus, a descending target of the PPN implicated in the generation of REM sleep. The discovery of electrical coupling in these RAS nuclei is critical given that recent findings suggest that the stimulant modafinil exercises its effects by increasing electrical coupling. Conversely, a number of anesthetics are known to decrease electrical coupling. The mechanistic characterization proposed represents a new paradigm for sleep-wake control and may revolutionize how we think about sleep-wake control, reveal how electrical coupling interacts with known transmitter inputs in the RAS to modulate sleep-wake states, and how we may develop new therapeutic strategies for the treatment of a number of devastating disorders that have as a common symptom the manifestation of increased REM sleep drive. In fact, by ignoring the role of electrical coupling we will fail to understand this system. We discovered the presence of electrical coupling, by which nerve cells can communicate directly through pores called gap junctions, in the part of the brain that controls sleep-wake cycles, the reticular activating system (RAS). We demonstrated the presence of electrical coupling using recordings from pairs of neurons. This finding helps explain the actions of some anesthetics, which are known to block gap junctions, and of a new stimulant, modafinil, which is now known to increase electrical coupling. This novel mechanism may promote ensemble activity in large numbers of neurons to promote rhythms during waking, and the absence of such activity may lead to sleep. We propose a series of detailed studies to investigate the organization (which cells are coupled, which are not), the control (which transmitter systems activate, which inhibit), and the modulation (which agents can increase vs decrease coupling) of this mechanism. The mechanistic characterization proposed represents a new paradigm for sleep-wake control and may revolutionize how we think about sleep-wake control, reveal how electrical coupling interacts with known transmitter inputs in the RAS to modulate sleep-wake states, and how we may develop new therapeutic strategies for the treatment of a number of devastating disorders that have as a common symptom the manifestation of increased REM sleep drive. In fact, by ignoring the role of electrical coupling we will fail to understand this system.

Public Health Relevance

We discovered the presence of electrical coupling, by which nerve cells can communicate directly through pores called gap junctions, in the part of the brain that controls sleep-wake cycles, the reticular activating system (RAS). We demonstrated the presence of electrical coupling using recordings from pairs of neurons. This finding helps explain the actions of some anesthetics, which are known to block gap junctions, and of a new stimulant, modafinil, which is now known to increase electrical coupling. This novel mechanism may promote ensemble activity in large numbers of neurons to promote rhythms during waking, and the absence of such activity may lead to sleep. We propose a series of detailed studies to investigate the organization (which cells are coupled, which are not), the control (which transmitter systems activate, which inhibit), and the modulation (which agents can increase vs decrease coupling) of this mechanism. The mechanistic characterization proposed represents a new paradigm for sleep-wake control and may revolutionize how we think about sleep-wake control, reveal how electrical coupling interacts with known transmitter inputs in the RAS to modulate sleep-wake states, and how we may develop new therapeutic strategies for the treatment of a number of devastating disorders that have as a common symptom the manifestation of increased REM sleep drive. In fact, by ignoring the role of electrical coupling we will fail to understand this system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020246-26
Application #
8316295
Study Section
Special Emphasis Panel (ZRG1-IFCN-L (02))
Program Officer
He, Janet
Project Start
1984-03-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
26
Fiscal Year
2012
Total Cost
$310,844
Indirect Cost
$96,469
Name
University of Arkansas for Medical Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Hyde, James; MacNicol, Melanie; Odle, Angela et al. (2014) The use of three-dimensional printing to produce in vitro slice chambers. J Neurosci Methods 238:82-7
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Garcia-Rill, Edgar; Kezunovic, Nebojsa; Hyde, James et al. (2013) Coherence and frequency in the reticular activating system (RAS). Sleep Med Rev 17:227-38
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Hyde, James; Kezunovic, Nebojsa; Urbano, Francisco J et al. (2013) Visualization of fast calcium oscillations in the parafascicular nucleus. Pflugers Arch 465:1327-40
Hyde, James; Kezunovic, Nebojsa; Urbano, Francisco J et al. (2013) Spatiotemporal properties of high-speed calcium oscillations in the pedunculopontine nucleus. J Appl Physiol (1985) 115:1402-14
Simon, Christen; Hayar, Abdallah; Garcia-Rill, Edgar (2012) Developmental changes in glutamatergic fast synaptic neurotransmission in the dorsal subcoeruleus nucleus. Sleep 35:407-17
Urbano, Francisco J; Kezunovic, Nebojsa; Hyde, James et al. (2012) Gamma band activity in the reticular activating system. Front Neurol 3:6
Kezunovic, Nebojsa; Hyde, James; Simon, Christen et al. (2012) Gamma band activity in the developing parafascicular nucleus. J Neurophysiol 107:772-84

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