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Author Notes:

E-mail: chris_leonard@nymc.edu

Conceived and designed the experiments: MK EH JW RC YK MY CL.

Performed the experiments: MK EH.

Analyzed the data: MK EH CL.

Contributed reagents/ materials/ analysis tools: MK JW RC YK MY CL.

Wrote the paper: MK EH JW RC YK MY CL.

The authors have declared that no competing interests exist.

Subject:

Research Funding:

Research was supported by USPHS grants NS27881 and HL64150 from the National Institutes of Health (NIH) (http://www.nih.gov/).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • PONTINE RETICULAR-FORMATION
  • EYE-MOVEMENT SLEEP
  • REM-SLEEP
  • CANINE NARCOLEPSY
  • ACETYLCHOLINE TURNOVER
  • GABAERGIC NEURONS
  • RAT-BRAIN
  • CATAPLEXY
  • WAKEFULNESS
  • MECHANISMS

Cholinergic Modulation of Narcoleptic Attacks in Double Orexin Receptor Knockout Mice

Journal Title:

PLoS ONE

Volume:

Volume 6, Number 4

Publisher:

, Pages e18697-e18697

Type of Work:

Article | Final Publisher PDF

Abstract:

To investigate how cholinergic systems regulate aspects of the sleep disorder narcolepsy, we video-monitored mice lacking both orexin (hypocretin) receptors (double knockout; DKO mice) while pharmacologically altering cholinergic transmission. Spontaneous behavioral arrests in DKO mice were highly similar to those reported in orexin-deficient mice and were never observed in wild-type (WT) mice. A survival analysis revealed that arrest lifetimes were exponentially distributed indicating that random, Markovian processes determine arrest lifetime. Low doses (0.01, 0.03 mg/kg, IP), but not a high dose (0.08 mg/kg, IP) of the cholinesterase inhibitor physostigmine increased the number of arrests but did not alter arrest lifetimes. The muscarinic antagonist atropine (0.5 mg/kg, IP) decreased the number of arrests, also without altering arrest lifetimes. To determine if muscarinic transmission in pontine areas linked to REM sleep control also influences behavioral arrests, we microinjected neostigmine (50 nl, 62.5 μM) or neostigmine + atropine (62.5 μM and 111 μM respectively) into the nucleus pontis oralis and caudalis. Neostigmine increased the number of arrests in DKO mice without altering arrest lifetimes but did not provoke arrests in WT mice. Co-injection of atropine abolished this effect. Collectively, our findings establish that behavioral arrests in DKO mice are similar to those in orexin deficient mice and that arrests have exponentially distributed lifetimes. We also show, for the first time in a rodent narcolepsy model, that cholinergic systems can regulate arrest dynamics. Since perturbations of muscarinic transmission altered arrest frequency but not lifetime, our findings suggest cholinergic systems influence arrest initiation without influencing circuits that determine arrest duration.

Copyright information:

© 2011 Kalogiannis et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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