Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice.
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 s...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-04-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3076437?pdf=render |
| _version_ | 1818127975428653056 |
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| author | Mike Kalogiannis Emily Hsu Jon T Willie Richard M Chemelli Yaz Y Kisanuki Masashi Yanagisawa Christopher S Leonard |
| author_facet | Mike Kalogiannis Emily Hsu Jon T Willie Richard M Chemelli Yaz Y Kisanuki Masashi Yanagisawa Christopher S Leonard |
| author_sort | Mike Kalogiannis |
| collection | DOAJ |
| description | 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, i.p.), but not a high dose (0.08 mg/kg, i.p.) of the cholinesterase inhibitor physostigmine increased the number of arrests but did not alter arrest lifetimes. The muscarinic antagonist atropine (0.5 mg/kg, i.p.) 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. |
| first_indexed | 2024-12-11T07:25:54Z |
| format | Article |
| id | doaj.art-d71b6efbd3824739b64c34d8ee10a411 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T07:25:54Z |
| publishDate | 2011-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-d71b6efbd3824739b64c34d8ee10a4112022-12-22T01:15:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-04-0164e1869710.1371/journal.pone.0018697Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice.Mike KalogiannisEmily HsuJon T WillieRichard M ChemelliYaz Y KisanukiMasashi YanagisawaChristopher S LeonardTo 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, i.p.), but not a high dose (0.08 mg/kg, i.p.) of the cholinesterase inhibitor physostigmine increased the number of arrests but did not alter arrest lifetimes. The muscarinic antagonist atropine (0.5 mg/kg, i.p.) 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.http://europepmc.org/articles/PMC3076437?pdf=render |
| spellingShingle | Mike Kalogiannis Emily Hsu Jon T Willie Richard M Chemelli Yaz Y Kisanuki Masashi Yanagisawa Christopher S Leonard Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. PLoS ONE |
| title | Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. |
| title_full | Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. |
| title_fullStr | Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. |
| title_full_unstemmed | Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. |
| title_short | Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. |
| title_sort | cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice |
| url | http://europepmc.org/articles/PMC3076437?pdf=render |
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