Christen Simon CSimon@uams.edu

Overview

        In humans, REM sleep time decreases from ~8 hours (50% of sleep time) in the newborn to ~1 hour (15% of sleep time) in the adult.  A similar decrease occurs in the rat at postnatal days 10-30.  We hypothesize that if this developmental decrease in REM sleep does not occur, a number of disorders may occur, which all have a common symptom of increased REM sleep drive and hypervigilance.  These disorders include schizophrenia, anxiety disorders, depression, and many sleep disorders.  Sensory inputs and changes in arousal activate the pedunculopontine (PPN) nucleus, which is part of the reticular activating system (RAS) and responsible for modulating arousal states, such as waking and REM sleep.  The PPN contains cholinergic, glutamatergic and GABAergic cells.  The PPN receives glutamatergic input from the mesopontine tegmentum.  In turn, glutamatergic and cholinergic efferents from the PPN ascend to the parafasicular (Pf) nucleus of the thalamus, which then sends glutamatergic efferents to the cortex.  Furthermore, cholinergic (and probably glutamatergic) efferents from the PPN descend to the Subcoeruleus (SubC).  The SubC also receives glutamatergic input from other nuclei in the mesopontine tegmentum.  This glutamatergic input modulates the cholinergic input from the PPN and affects the generation of PGO waves and REM sleep atonia.  My hypothesis is that there is a change in the response of PPN and SubC neurons to glutamate during the developmental decrease in REM sleep.  Disturbance of these developmental changes may lead to the disturbances of vigilance in the disorders previously mentioned.

My preliminary results reveal two novel findings, a) there may be a developmental change in the responses of PPN neurons to glutamate receptor agonists, and b) cells in the PPN appear to fire maximally at gamma band frequency and to exhibit gamma band subthreshold oscillations.  I will explore these new findings using whole-cell patch clamp and population activity recordings in the PPN and the SubC.  I hypothesize the following:  1) PPN cells will respond differentially to glutamate receptor agonists, indicating distinct populations of cells in the PPN are modulated by NMDA vs. kainic acid receptors.  Furthermore, there will be developmental changes in the responses of PPN and SubC neurons to glutamate receptor agonists.  2) Application of glutamate receptor agonists will induce gamma band activity in at least some PPN and SubC neurons and this activity will be correlated with the response of the population as a whole in these nuclei.

The information gathered from these experiments is critical for further understanding the role of glutamatergic inputs to the PPN and descending inputs to SubC, and how these inputs modulate signs of waking and REM sleep.  These studies represent novel ideas for sleep-wake control and may revolutionize how we 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 and hypervigilance.

Recent Studies

Study objectives: The pedunculopontine nucleus (PPN) is involved in the activated states of waking and paradoxical sleep, forming part of the reticular activating system (RAS). The studies described tested the hypothesis that PPN neurons are capable of generating gamma frequency activity.

Design: Whole-cell patch clamp recordings (immersion chamber) were conducted on 9-17 days old rat brainstem slices.

Measurements and Results: Regardless of cell type (I, II or III) or type of response to carbachol (excitation, inhibition, biphasic), almost all PPN neurons fired at gamma frequency when subjected to depolarizing steps (50 +/- 16 Hz, mean +/- SD). 

Conclusion: Gamma band activity appears to be a part of the intrinsic membrane properties of PPN neurons. Given sufficient excitation, the PPN may impart gamma band activation on its targets.

Figure 1. Gamma band activity in whole-cell recorded PPN cells. A) Increasing steps of current (increase of 30 pA per step, each step was 500 ms in duration) induced cells to fire action potentials at higher frequencies. This cell fired maximally at 54 Hz, which is within the gamma range.  B) Average first (■), middle (●) and end (▲) interspike interval during each current step.  The average maximal firing frequency was during the first interspike interval of the 180 pA current step, when cells fired at an average rate of 50 +/- 16 Hz.  During the middle and end interspike intervals, the cell firing rate decreased to low gamma frequency.  C) Graph showing the first, middle, and end firing frequencies of each cell type at the 180 pA current step.  Each cell type fired fastest during the beginning of the stimulus; type I (n = 17) cells fired significantly faster than type II (n = 16) or type III (n = 16) [p > 0.05].  The average (+/- SD) maximal firing frequency for type I, II, and III neurons were: 58 +/- 15 Hz, 45 +/- 15 Hz, and 46 +/- 16 Hz, respectively.  There was no significant difference in the firing frequencies of type I, II, or III PPN neurons during the middle and end interspike intervals.