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Garcia-Rill lab garciarilledgar@uams.edu

   Our work over the last 5 years addressed certain factors related to the developmental decrease in rapid eye movement (REM) sleep, which occurs in favor of additional waking time, and its relationship to developmental factors that may influence its potential role in brain development.  Specifically, we proposed theories for its occurrence and agree with the classic notion that REM sleep is, at least, a mechanism that may play a role in the maturation of thalamocortical pathways. The developmental decrease in REM sleep occurs gradually from birth until close to puberty in the human, and in other mammals it is brief and coincides with eye and ear opening and the beginning of massive exogenous activation. Therefore, the purported role for REM sleep may change to involve a number of other functions with age.  We generated findings showing that morphological and physiological properties as well as cholinergic, gamma amino-butyric acid (GABA), kainic acid (KA), n-methyl-d-aspartic acid (NMDA), noradrenergic and serotonergic synaptic inputs to mesopontine cholinergic neurons, as well as the degree of electrical coupling between mostly non-cholinergic mesopontine neurons and levels of the neuronal gap junction protein connexin 36, change dramatically during this critical period in development. A novel mechanism for sleep wake control based on well-known transmitter interactions as well as electrical coupling was described.  We hypothesize that a dysregulation of this process could result in life-long disturbances in arousal and REM sleep drive, leading to hypervigilance or hypovigilance such as that observed in a number of disorders that have a mostly postpubertal age of onset, e.g. schizophrenia, anxiety disorder, bipolar disorder, narcolepsy, etc.

   We recently described the presence of dye and electrical coupling in the RAS, specifically in the parfascicular (Pf), pedunculopontine nucleus (PPN) and subcoeruleus (SubC). We also found that the stimulant modafinil decreased the resistance of PPN and SubC neurons, in keeping with results in the cortex, reticular thalamus and inferior olive. The effects of modafinil were evident in the absence of changes in resting membrane potential or of changes in the amplitude of induced excitatory postsynaptic currents (EPSCs), and were blocked by low concentrations of the gap junction blocker mefloquine, also in the absence of changes in resting membrane potential or in the amplitude of induced EPSCs. This suggests that these compounds do not act indirectly by affecting voltage-sensitive channels such as potassium channels, but rather modulate electrical coupling via gap junctions. These findings in general suggest that increasing electrical coupling may promote states of synchronization of sleep-wake rhythms, thus controlling changes in state. The presence of coincident rhythmic inhibitory postsynaptic currents (IPSCs), especially during cholinergic receptor activation, suggests that a syncitium of inhibitory GABAergic neurons is present in the Pf, PPN and/or SubC, helps generate synchronous oscillations, i.e. ensemble activity. Electrical coupling appears to modulate oscillations in different cell types in each structure, suggesting a role for electrical coupling in sleep-wake control.


UAMS News Bureau, Office of Communications & Marketing, 4301 West Markham # 890, Little Rock, AR 72205-7199, www.uams.edu/newsbureau/

News Release, July 19, 2007 
Media Contacts:
Leslie W. Taylor, 501-686-8998, Wireless phone: 501-951-7260, leslie@uams.edu,    Andrea Peel, 501-686-8996, Wireless phone: 501-351-7903, andrea@uams.edu   

UAMS Researchers Identify Sleep-Wake Controls with Implications for Coma Patients and Those Under Anesthesia 

LITTLE ROCK - How do we wake up? How do we shift from restful sleep to dreaming? Researchers at the University of Arkansas for Medical Sciences (UAMS) have discovered a new brain mechanism that just might explain how we do that. This new mechanism also may help us understand how certain anesthetics put us to sleep and how certain stimulants wake us up.
   In their first published study on this topic, researchers in the UAMS Center for Translational Neuroscience found that some neurons in the reticular activating system, a region of the brain that controls sleep-wake states, are electrically coupled.
   "By finding methods for increasing the electrical coupling of these cells, we create a stronger pathway for potential sleep-wake control," said study author Edgar Garcia-Rill, Ph.D., a professor of neurobiology and developmental sciences in the UAMS College of Medicine and director of the Center for Translational Neuroscience.
   "The possible applications range from the ability to wake people up from anesthesia or put them to sleep more rapidly, to stimulating someone in a comatose state to awaken if there are enough of these cells left alive to join together," Garcia-Rill said.
  
The study, "Evidence for Electrical Coupling in the SubCoeruleus (SubC) Nucleus," documenting this cellular new mechanism, was published in the April issue of the Journal of Neurophysiology (http://jn.physiology.org/). In June, the research team presented additional findings at the annual meeting of the Associated for Professional Sleep Societies in Minneapolis.
   The researchers found that neurons in the SubCoeruleus nucleus, a part of the brain believed to control the phase of deep sleep known as rapid-eye-movement (REM) sleep, joined in a way that allowed them to transmit electrical activity across the cells. The activity occurred spontaneously or could be induced by chemical agents that induce REM sleep. 
   The research article was accompanied by an editorial that called the finding "seminal" in the field of sleep-wake research. The editorial was written by peers Matthew Ennis of the Department of Anatomy and Neurobiology at the University of Tennessee Health Center in Memphis and Subimal Datta of the Department of Psychiatry and Behavioral Neuroscience at the Boston University School of Medicine.
   "The findings of [the researchers] provide novel and exciting avenues for understanding sleep-wake control as well as for the treatment of sleep and arousal disorders," wrote Ennis and Datta in the editorial.
   Lead author of the study was David S. Heister, a graduate student pursuing a combined medical and doctoral degree in the Department of Neurobiology and Developmental Sciences of the UAMS Graduate School and UAMS College of Medicine.
   Joining Heister and Garcia-Rill are Abdallah Hayar, Ph.D., and Amanda Charlesworth, Ph.D., UAMS faculty members in the Department of Neurobiology and Developmental Sciences and researchers in the Center for Translational Neuroscience; Charlotte Yates, Ph.D., from the Department of Physical Therapy at the University of Central Arkansas; and former UAMS faculty member Yi-Hong Zhou, Ph.D., of the University of California-Irvine.
   The researchers pointed to earlier work with animal models showing that stimulation of a specific region of the brain, the reticular activating system, produced electrical activity similar to that seen during waking and REM sleep. In studying the SubCoeruleus section of the brain, the researchers detected the presence of electrical coupling of cells similar to the kind that showed an ability to switch between the REM and waking state. The presence of electrical coupling between these cells offers a potential pathway for substances that could regulate the sleep-wake control, Garcia-Rill said.
  
The electroencephalogram, or EEG, of the waking brain shows fast rhythms of 10-50 cycles per second, while the sleeping brain cycles at frequencies below 10 per second.  Electrical coupling would allow many cells to fire together, generating a rhythm that is transmitted to other parts of the brain to induce changes in sleep-wake states. In collaboration with the chemical transmitters that control the firing rates in individual cells, the two mechanisms could generate any of the frequencies seen in the EEG. Some anesthetics are known to block gap junctions, the channels by which electrical coupling takes place, while some stimulants increase electrical coupling.
Garcia-Rill helped establish the UAMS Center for Translational Neuroscience in 2003 as a division of the Department of Neurobiology and Developmental Sciences supported by a Center of Biomedical Research Excellence award from the national Center for Research Resources at the National Institutes of Health. It is one of the few facilities in the nation devoted to quickly moving new treatments from basic scientific research to developing new treatments for patients in the clinic. The CTN is part of the Jackson T. Stephens Spine & Neuroscience Institute.  The Center for Translational Neuroscience also has a Community Research and Education Core Facility that works to bring clinical treatments to the medical and lay community.
   UAMS is the state's only comprehensive academic health center, with five colleges, a graduate school, a medical center, six centers of excellence and a statewide network of regional centers. UAMS has
2,435 students and 714 medical residents. It is one of the state's largest public employers with about 9,400 employees, including nearly 1,000 physicians who provide medical care to patients at UAMS, Arkansas Children's Hospital, the VA Medical Center and UAMS' Area Health Education Centers throughout the state. UAMS and its affiliates have an economic impact in Arkansas of $5 billion a year. For more information, visit www.uams.edu.