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Pedunculopontine arousal system physiology - Implications for insomnia.

Garcia-Rill E, Luster B, Mahaffey S, Bisagno V, Urbano FJ - Sleep Sci (2015)

Bottom Line: This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of insomnia, mainly representing an overactive waking drive.We determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and channel types in PPN cells.We found three different PPN cell types that have one or both channels and may be active during waking only, REM sleep only, or both.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Neuroscience, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

ABSTRACT
We consider insomnia a disorder of waking rather than a disorder of sleep. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of insomnia, mainly representing an overactive waking drive. We determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and channel types in PPN cells. We found three different PPN cell types that have one or both channels and may be active during waking only, REM sleep only, or both. These discoveries point to a specific mechanism and novel therapeutic avenues for insomnia.

No MeSH data available.


Related in: MedlinePlus

PPN cells manifest gamma band activity through N- and P/Q-, N-only, and P/Q-only type Ca2+ channels. Top, N+P/Q). Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). Following superfusion with ω-CgTx for 10 min, oscillation amplitude was reduced (middle record, dark gray). Thereafter, ω-Aga was superfused for 10 min blocking the remaining oscillations (right record, light gray). Middle, N-only) Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). ω-Aga applied into the bath for 10 min caused no significant effect on the membrane oscillations (middle record, dark gray), that is, the oscillations are NOT reduced by ω-Aga. ω-CgTx was then superfused for 10 min, causing a complete blockade of the membrane oscillations (right record, light gray). Bottom, P/Q-only) Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). ω-CgTx was applied for 10 min causing no significant effect on the oscillations (middle record, dark gray), that is, the oscillations are NOT reduced by ω-CgTx. ω-Aga then was superfused for 10 min causing a complete blockade of the membrane oscillations (right record, light gray).
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f0005: PPN cells manifest gamma band activity through N- and P/Q-, N-only, and P/Q-only type Ca2+ channels. Top, N+P/Q). Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). Following superfusion with ω-CgTx for 10 min, oscillation amplitude was reduced (middle record, dark gray). Thereafter, ω-Aga was superfused for 10 min blocking the remaining oscillations (right record, light gray). Middle, N-only) Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). ω-Aga applied into the bath for 10 min caused no significant effect on the membrane oscillations (middle record, dark gray), that is, the oscillations are NOT reduced by ω-Aga. ω-CgTx was then superfused for 10 min, causing a complete blockade of the membrane oscillations (right record, light gray). Bottom, P/Q-only) Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). ω-CgTx was applied for 10 min causing no significant effect on the oscillations (middle record, dark gray), that is, the oscillations are NOT reduced by ω-CgTx. ω-Aga then was superfused for 10 min causing a complete blockade of the membrane oscillations (right record, light gray).

Mentions: We have breakthrough findings showing that in some PPN cells (50%), the N-type calcium channel blocker ω-conotoxin-GVIA (ω-CgTx) reduced gamma oscillation amplitude, while subsequent addition of the P/Q-type blocker ω-agatoxin-IVA (ω-Aga) blocked the remaining oscillations. Other PPN cells (20%) manifested gamma oscillations that were not significantly affected by the addition of ω-CgTx, however, ω-Aga blocked the remaining oscillations. In the rest of the cells (30%), ω-Aga had no effect on gamma oscillations, while ω-CgTx blocked them. Similar results were found during recordings of voltage-dependent calcium currents. These results confirm the presence of cells in the PPN that manifest gamma band oscillations through only N-type, only P/Q-type, and both N- and P/Q-type calcium channels [36,37]. This new cell type classification suggests that some PPN neurons fire only during REM sleep (“REM-on”, N-type only), only during waking (“Wake-on”, P/Q-type only), or during both waking and REM sleep (“Wake/REM-on”, N-type+P/Q-type) [36,37]. Fig. 1 shows the responses to depolarizing ramps in each of these cell types, with responses being mediated by both N- and P/Q-type calcium channels (partial block by each channel blocker), by N-type only (complete block by ω-CgTx), and by P/Q-type only (complete block by ω-Aga). Fig. 2 shows the distribution and main intracellular control pathways modulating the two channel types, and presumed in vivo firing patterns.


Pedunculopontine arousal system physiology - Implications for insomnia.

Garcia-Rill E, Luster B, Mahaffey S, Bisagno V, Urbano FJ - Sleep Sci (2015)

PPN cells manifest gamma band activity through N- and P/Q-, N-only, and P/Q-only type Ca2+ channels. Top, N+P/Q). Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). Following superfusion with ω-CgTx for 10 min, oscillation amplitude was reduced (middle record, dark gray). Thereafter, ω-Aga was superfused for 10 min blocking the remaining oscillations (right record, light gray). Middle, N-only) Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). ω-Aga applied into the bath for 10 min caused no significant effect on the membrane oscillations (middle record, dark gray), that is, the oscillations are NOT reduced by ω-Aga. ω-CgTx was then superfused for 10 min, causing a complete blockade of the membrane oscillations (right record, light gray). Bottom, P/Q-only) Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). ω-CgTx was applied for 10 min causing no significant effect on the oscillations (middle record, dark gray), that is, the oscillations are NOT reduced by ω-CgTx. ω-Aga then was superfused for 10 min causing a complete blockade of the membrane oscillations (right record, light gray).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4608886&req=5

f0005: PPN cells manifest gamma band activity through N- and P/Q-, N-only, and P/Q-only type Ca2+ channels. Top, N+P/Q). Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). Following superfusion with ω-CgTx for 10 min, oscillation amplitude was reduced (middle record, dark gray). Thereafter, ω-Aga was superfused for 10 min blocking the remaining oscillations (right record, light gray). Middle, N-only) Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). ω-Aga applied into the bath for 10 min caused no significant effect on the membrane oscillations (middle record, dark gray), that is, the oscillations are NOT reduced by ω-Aga. ω-CgTx was then superfused for 10 min, causing a complete blockade of the membrane oscillations (right record, light gray). Bottom, P/Q-only) Membrane oscillations recorded during 1 s long ramps in the presence of synaptic blockers and tetrodotoxin (left record, black). ω-CgTx was applied for 10 min causing no significant effect on the oscillations (middle record, dark gray), that is, the oscillations are NOT reduced by ω-CgTx. ω-Aga then was superfused for 10 min causing a complete blockade of the membrane oscillations (right record, light gray).
Mentions: We have breakthrough findings showing that in some PPN cells (50%), the N-type calcium channel blocker ω-conotoxin-GVIA (ω-CgTx) reduced gamma oscillation amplitude, while subsequent addition of the P/Q-type blocker ω-agatoxin-IVA (ω-Aga) blocked the remaining oscillations. Other PPN cells (20%) manifested gamma oscillations that were not significantly affected by the addition of ω-CgTx, however, ω-Aga blocked the remaining oscillations. In the rest of the cells (30%), ω-Aga had no effect on gamma oscillations, while ω-CgTx blocked them. Similar results were found during recordings of voltage-dependent calcium currents. These results confirm the presence of cells in the PPN that manifest gamma band oscillations through only N-type, only P/Q-type, and both N- and P/Q-type calcium channels [36,37]. This new cell type classification suggests that some PPN neurons fire only during REM sleep (“REM-on”, N-type only), only during waking (“Wake-on”, P/Q-type only), or during both waking and REM sleep (“Wake/REM-on”, N-type+P/Q-type) [36,37]. Fig. 1 shows the responses to depolarizing ramps in each of these cell types, with responses being mediated by both N- and P/Q-type calcium channels (partial block by each channel blocker), by N-type only (complete block by ω-CgTx), and by P/Q-type only (complete block by ω-Aga). Fig. 2 shows the distribution and main intracellular control pathways modulating the two channel types, and presumed in vivo firing patterns.

Bottom Line: This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of insomnia, mainly representing an overactive waking drive.We determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and channel types in PPN cells.We found three different PPN cell types that have one or both channels and may be active during waking only, REM sleep only, or both.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Neuroscience, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

ABSTRACT
We consider insomnia a disorder of waking rather than a disorder of sleep. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of insomnia, mainly representing an overactive waking drive. We determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and channel types in PPN cells. We found three different PPN cell types that have one or both channels and may be active during waking only, REM sleep only, or both. These discoveries point to a specific mechanism and novel therapeutic avenues for insomnia.

No MeSH data available.


Related in: MedlinePlus