{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/21453"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/21453","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Cholinergic regulation of a mammalian circadian clock","abstract":"A cholinergic agonist, carbachol, has been shown to shift the phase of circadian rhythms in rodents when injected intracerebroventricularly. However, the site and receptor type mediating this action have been unknown. The suprachiasmatic nuclei (SCN), the primary circadian pacemaker in mammals, continue to show a circadian rhythm in neuronal activity in a hypothalamic brain slice. Using this in vitro preparation, we investigated the direct regulation of the SCN circadian pacemaker by cholinergics.","abstract_html":"A cholinergic agonist, carbachol, has been shown to shift the phase of circadian rhythms in rodents when injected intracerebroventricularly. However, the site and receptor type mediating this action have been unknown. The suprachiasmatic nuclei (SCN), the primary circadian pacemaker in mammals, continue to show a circadian rhythm in neuronal activity in a hypothalamic brain slice. Using this in vitro preparation, we investigated the direct regulation of the SCN circadian pacemaker by cholinergics.","abstract_has_math":false,"creators":["Liu, Chen"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Neuroscience","degree_department":null,"school":null,"contributors":["Gillette, Martha U."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-05-07T13:09:04Z","date_published":"2011-05-07T13:09:04Z","updated_at":"2026-07-22T22:25:18Z","subjects":["Biology, Neuroscience"],"languages":["eng"],"rights":["Copyright 1995 Liu, Chen"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["AAI9624419","(UMI)AAI9624419"],"render_values":[{"text":"AAI9624419","href":null,"code":true},{"text":"(UMI)AAI9624419","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/21453","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Gillette, Martha U."]},{"key":"dc:creator","label":"Author","values":["Liu, Chen"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2011-05-07T13:09:04Z","10000-01-01","1995"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Neuroscience"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biology, Neuroscience"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 1995 Liu, Chen"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["AAI9624419","(UMI)AAI9624419","http://hdl.handle.net/2142/21453"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["A cholinergic agonist, carbachol, has been shown to shift the phase of circadian rhythms in rodents when injected intracerebroventricularly. However, the site and receptor type mediating this action have been unknown. The suprachiasmatic nuclei (SCN), the primary circadian pacemaker in mammals, continue to show a circadian rhythm in neuronal activity in a hypothalamic brain slice. Using this in vitro preparation, we investigated the direct regulation of the SCN circadian pacemaker by cholinergics.","We found that the phase of the SCN activity rhythm was advanced by application of a microdrop of carbachol onto each SCN during the subjective night, but not day, with the largest phase advance of 6.5 hr induced at circadian time (CT) 18. The effect of carbachol at CT 18 was mimicked by acetylcholine and two muscarinic agonists, muscarine and McN-A-343 (MI selective), but not by nicotine, and was blocked by the muscarinic antagonists, atropine (0.1 $\\mu$M) and pirenzepine (1 $\\mu$M), not by a nicotinic antagonist. An M3-selective antagonist, 4-DAMP (1 $\\mu$M), partially blocked the carbachol effect. Whole cell current clamp study revealed that the majority of the SCN neurons which responded to carbachol showed a hyperpolarization and an increase in membrane conductance, which can be blocked by atropine. These results demonstrate that carbachol acts directly on the SCN to reset the phase of its activity rhythm during the subjective night, through a muscarinic receptor, possibly an M1 subtype.","Since the phase response relationship for carbachol is almost identical to that for a cGMP analog reported previously, we tested whether cGMP signaling pathway mediates cholinergic input to the SCN pacemaker. Both the guanylyl cyclase (GC) inhibitor, LY83583, and the protein kinase G (PKG) inhibitor, KT5823, blocked the carbachol-induced phase advance at CT 18. Assays of PKG activity and cGMP levels demonstrated that carbachol (100 $\\mu$M) increased PKG activity and cGMP concentration in the SCN slice. The increase in cGMP was blocked by 1 $\\mu$M atropine, indicating the involvement of a muscarinic receptor. Together, these data revealed a specific pathway of cholinergic regulation of the SCN clock through a muscarinic receptor and the GC/cGMP/PKG signaling pathway.","Made available in DSpace on 2011-05-07T13:09:04Z (GMT). No. of bitstreams: 2 license.txt: 4922 bytes, checksum: 910b249b4beec47e7ab768910c8f966f (MD5) 9624419.pdf: 4197123 bytes, checksum: 461c4ffcf09aebde438006e25eb0a9bb (MD5) Previous issue date: 1995","Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding (hding2@illinois.edu) on 2011-05-07T14:50:53Z Item is restricted indefinitely.","Restriction data tranferred 2014-07-01T11:23:18-05:00 Original Data Group with Access UIUC Users [automated] Release Date: none Reason: ETDs are only available to UIUC Users without author permission","ETDs are only available to UIUC Users without author permission","U of I Only"]},{"key":"dc:title","label":"Title","values":["Cholinergic regulation of a mammalian circadian clock"]}]}],"canonical_facts":{"dc:contributor":["Gillette, Martha U."],"dc:creator":["Liu, Chen"],"dc:date":["2011-05-07T13:09:04Z","10000-01-01","1995"],"dc:description":["A cholinergic agonist, carbachol, has been shown to shift the phase of circadian rhythms in rodents when injected intracerebroventricularly. However, the site and receptor type mediating this action have been unknown. The suprachiasmatic nuclei (SCN), the primary circadian pacemaker in mammals, continue to show a circadian rhythm in neuronal activity in a hypothalamic brain slice. Using this in vitro preparation, we investigated the direct regulation of the SCN circadian pacemaker by cholinergics.","We found that the phase of the SCN activity rhythm was advanced by application of a microdrop of carbachol onto each SCN during the subjective night, but not day, with the largest phase advance of 6.5 hr induced at circadian time (CT) 18. The effect of carbachol at CT 18 was mimicked by acetylcholine and two muscarinic agonists, muscarine and McN-A-343 (MI selective), but not by nicotine, and was blocked by the muscarinic antagonists, atropine (0.1 $\\mu$M) and pirenzepine (1 $\\mu$M), not by a nicotinic antagonist. An M3-selective antagonist, 4-DAMP (1 $\\mu$M), partially blocked the carbachol effect. Whole cell current clamp study revealed that the majority of the SCN neurons which responded to carbachol showed a hyperpolarization and an increase in membrane conductance, which can be blocked by atropine. These results demonstrate that carbachol acts directly on the SCN to reset the phase of its activity rhythm during the subjective night, through a muscarinic receptor, possibly an M1 subtype.","Since the phase response relationship for carbachol is almost identical to that for a cGMP analog reported previously, we tested whether cGMP signaling pathway mediates cholinergic input to the SCN pacemaker. Both the guanylyl cyclase (GC) inhibitor, LY83583, and the protein kinase G (PKG) inhibitor, KT5823, blocked the carbachol-induced phase advance at CT 18. Assays of PKG activity and cGMP levels demonstrated that carbachol (100 $\\mu$M) increased PKG activity and cGMP concentration in the SCN slice. The increase in cGMP was blocked by 1 $\\mu$M atropine, indicating the involvement of a muscarinic receptor. Together, these data revealed a specific pathway of cholinergic regulation of the SCN clock through a muscarinic receptor and the GC/cGMP/PKG signaling pathway.","Made available in DSpace on 2011-05-07T13:09:04Z (GMT). No. of bitstreams: 2 license.txt: 4922 bytes, checksum: 910b249b4beec47e7ab768910c8f966f (MD5) 9624419.pdf: 4197123 bytes, checksum: 461c4ffcf09aebde438006e25eb0a9bb (MD5) Previous issue date: 1995","Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding (hding2@illinois.edu) on 2011-05-07T14:50:53Z Item is restricted indefinitely.","Restriction data tranferred 2014-07-01T11:23:18-05:00 Original Data Group with Access UIUC Users [automated] Release Date: none Reason: ETDs are only available to UIUC Users without author permission","ETDs are only available to UIUC Users without author permission","U of I Only"],"dc:identifier":["AAI9624419","(UMI)AAI9624419","http://hdl.handle.net/2142/21453"],"dc:language":["eng"],"dc:rights":["Copyright 1995 Liu, Chen"],"dc:subject":["Biology, Neuroscience"],"dc:title":["Cholinergic regulation of a mammalian circadian clock"],"dc:type":["text"],"thesis:degree_discipline":["Neuroscience"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:18Z"}