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Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors
Circadian clocks are autonomous oscillators driving daily rhythms in physiology and behavior. In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptiona...
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| Published in: | PLoS computational biology 2018-12, Vol.14 (12), p.e1006607-e1006607 |
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| creator | Tokuda, Isao T Ono, Daisuke Honma, Sato Honma, Ken-Ichi Herzel, Hanspeter |
| description | Circadian clocks are autonomous oscillators driving daily rhythms in physiology and behavior. In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptional feedbacks generate noisy oscillations. Coupling mediated by neuropeptides such as VIP and AVP lends precision and robustness to circadian rhythms. The detailed coupling mechanisms between SCN neurons are debated. We analyze organotypic SCN slices from neonatal and adult mice in wild-type and multiple knockout conditions. Different degrees of rhythmicity are quantified by pixel-level analysis of bioluminescence data. We use empirical orthogonal functions (EOFs) to characterize spatio-temporal patterns. Simulations of coupled stochastic single cell oscillators can reproduce the diversity of observed patterns. Our combination of data analysis and modeling provides deeper insight into the enormous complexity of the data: (1) Neonatal slices are typically stronger oscillators than adult slices pointing to developmental changes of coupling. (2) Wild-type slices are completely synchronized and exhibit specific spatio-temporal patterns of phases. (3) Some slices of Cry double knockouts obey impaired synchrony that can lead to co-existing rhythms ("splitting"). (4) The loss of VIP-coupling leads to desynchronized rhythms with few residual local clusters. Additional information was extracted from co-culturing slices with rhythmic neonatal wild-type SCNs. These co-culturing experiments were simulated using external forcing terms representing VIP and AVP signaling. The rescue of rhythmicity via co-culturing lead to surprising results, since a cocktail of AVP-antagonists improved synchrony. Our modeling suggests that these counter-intuitive observations are pointing to an antagonistic action of VIP and AVP coupling. Our systematic theoretical and experimental study shows that dual coupling mechanisms can explain the astonishing complexity of spatio-temporal patterns in SCN slices. |
| doi_str_mv | 10.1371/journal.pcbi.1006607 |
| format | article |
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In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptional feedbacks generate noisy oscillations. Coupling mediated by neuropeptides such as VIP and AVP lends precision and robustness to circadian rhythms. The detailed coupling mechanisms between SCN neurons are debated. We analyze organotypic SCN slices from neonatal and adult mice in wild-type and multiple knockout conditions. Different degrees of rhythmicity are quantified by pixel-level analysis of bioluminescence data. We use empirical orthogonal functions (EOFs) to characterize spatio-temporal patterns. Simulations of coupled stochastic single cell oscillators can reproduce the diversity of observed patterns. Our combination of data analysis and modeling provides deeper insight into the enormous complexity of the data: (1) Neonatal slices are typically stronger oscillators than adult slices pointing to developmental changes of coupling. (2) Wild-type slices are completely synchronized and exhibit specific spatio-temporal patterns of phases. (3) Some slices of Cry double knockouts obey impaired synchrony that can lead to co-existing rhythms ("splitting"). (4) The loss of VIP-coupling leads to desynchronized rhythms with few residual local clusters. Additional information was extracted from co-culturing slices with rhythmic neonatal wild-type SCNs. These co-culturing experiments were simulated using external forcing terms representing VIP and AVP signaling. The rescue of rhythmicity via co-culturing lead to surprising results, since a cocktail of AVP-antagonists improved synchrony. Our modeling suggests that these counter-intuitive observations are pointing to an antagonistic action of VIP and AVP coupling. Our systematic theoretical and experimental study shows that dual coupling mechanisms can explain the astonishing complexity of spatio-temporal patterns in SCN slices.</description><identifier>ISSN: 1553-7358</identifier><identifier>ISSN: 1553-734X</identifier><identifier>EISSN: 1553-7358</identifier><identifier>DOI: 10.1371/journal.pcbi.1006607</identifier><identifier>PMID: 30532130</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Arginine Vasopressin - metabolism ; Arginine Vasopressin - physiology ; Biological clocks ; Biology ; Biology and Life Sciences ; Bioluminescence ; Brain research ; Brain slice preparation ; Cell culture ; Circadian Clocks - physiology ; Circadian rhythm ; Circadian Rhythm - physiology ; Circadian rhythms ; Complexity ; Computer and Information Sciences ; Computer simulation ; Coupling ; Coupling factors ; Data analysis ; Empirical analysis ; Gene expression ; Mammals ; Medical research ; Medicine ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Modelling ; Neonates ; Neurons ; Neurons - physiology ; Neuropeptides ; Neuropeptides - metabolism ; Neurosciences ; Organs ; Orthogonal functions ; Oscillators ; Period Circadian Proteins - metabolism ; Physical Sciences ; Physiology ; Polypeptides ; Reporters ; Research and Analysis Methods ; Signal Transduction ; Stochasticity ; Suprachiasmatic nucleus ; Suprachiasmatic Nucleus - physiology ; Synchronization ; Transcription ; University graduates ; Vasoactive Intestinal Peptide - metabolism ; Vasoactive Intestinal Peptide - physiology</subject><ispartof>PLoS computational biology, 2018-12, Vol.14 (12), p.e1006607-e1006607</ispartof><rights>2018 Tokuda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Tokuda et al 2018 Tokuda et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-804f2de48dc32644842fd6f1138fc8df824eb96ccbd4bd44b36d3df59b0d334b3</citedby><cites>FETCH-LOGICAL-c592t-804f2de48dc32644842fd6f1138fc8df824eb96ccbd4bd44b36d3df59b0d334b3</cites><orcidid>0000-0001-6212-0022</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2250637447/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2250637447?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,37048,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30532130$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ayers, Joseph</contributor><creatorcontrib>Tokuda, Isao T</creatorcontrib><creatorcontrib>Ono, Daisuke</creatorcontrib><creatorcontrib>Honma, Sato</creatorcontrib><creatorcontrib>Honma, Ken-Ichi</creatorcontrib><creatorcontrib>Herzel, Hanspeter</creatorcontrib><title>Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors</title><title>PLoS computational biology</title><addtitle>PLoS Comput Biol</addtitle><description>Circadian clocks are autonomous oscillators driving daily rhythms in physiology and behavior. In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptional feedbacks generate noisy oscillations. Coupling mediated by neuropeptides such as VIP and AVP lends precision and robustness to circadian rhythms. The detailed coupling mechanisms between SCN neurons are debated. We analyze organotypic SCN slices from neonatal and adult mice in wild-type and multiple knockout conditions. Different degrees of rhythmicity are quantified by pixel-level analysis of bioluminescence data. We use empirical orthogonal functions (EOFs) to characterize spatio-temporal patterns. Simulations of coupled stochastic single cell oscillators can reproduce the diversity of observed patterns. Our combination of data analysis and modeling provides deeper insight into the enormous complexity of the data: (1) Neonatal slices are typically stronger oscillators than adult slices pointing to developmental changes of coupling. (2) Wild-type slices are completely synchronized and exhibit specific spatio-temporal patterns of phases. (3) Some slices of Cry double knockouts obey impaired synchrony that can lead to co-existing rhythms ("splitting"). (4) The loss of VIP-coupling leads to desynchronized rhythms with few residual local clusters. Additional information was extracted from co-culturing slices with rhythmic neonatal wild-type SCNs. These co-culturing experiments were simulated using external forcing terms representing VIP and AVP signaling. The rescue of rhythmicity via co-culturing lead to surprising results, since a cocktail of AVP-antagonists improved synchrony. Our modeling suggests that these counter-intuitive observations are pointing to an antagonistic action of VIP and AVP coupling. Our systematic theoretical and experimental study shows that dual coupling mechanisms can explain the astonishing complexity of spatio-temporal patterns in SCN slices.</description><subject>Animals</subject><subject>Arginine Vasopressin - metabolism</subject><subject>Arginine Vasopressin - physiology</subject><subject>Biological clocks</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Bioluminescence</subject><subject>Brain research</subject><subject>Brain slice preparation</subject><subject>Cell culture</subject><subject>Circadian Clocks - physiology</subject><subject>Circadian rhythm</subject><subject>Circadian Rhythm - physiology</subject><subject>Circadian rhythms</subject><subject>Complexity</subject><subject>Computer and Information Sciences</subject><subject>Computer simulation</subject><subject>Coupling</subject><subject>Coupling factors</subject><subject>Data analysis</subject><subject>Empirical analysis</subject><subject>Gene expression</subject><subject>Mammals</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Modelling</subject><subject>Neonates</subject><subject>Neurons</subject><subject>Neurons - physiology</subject><subject>Neuropeptides</subject><subject>Neuropeptides - metabolism</subject><subject>Neurosciences</subject><subject>Organs</subject><subject>Orthogonal functions</subject><subject>Oscillators</subject><subject>Period Circadian Proteins - metabolism</subject><subject>Physical Sciences</subject><subject>Physiology</subject><subject>Polypeptides</subject><subject>Reporters</subject><subject>Research and Analysis Methods</subject><subject>Signal Transduction</subject><subject>Stochasticity</subject><subject>Suprachiasmatic nucleus</subject><subject>Suprachiasmatic Nucleus - physiology</subject><subject>Synchronization</subject><subject>Transcription</subject><subject>University graduates</subject><subject>Vasoactive Intestinal Peptide - metabolism</subject><subject>Vasoactive Intestinal Peptide - physiology</subject><issn>1553-7358</issn><issn>1553-734X</issn><issn>1553-7358</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptUk1v1DAQjRCIfsA_QGCJSy-72PFHkgtStWqhUgUH4Irl2OONV1k72AnV_vt6d9OqRUiWPB6_N34zfkXxjuAloRX5tAlT9KpfDrp1S4KxELh6UZwSzumiorx--SQ-Kc5S2mCcw0a8Lk4o5rQkFJ8Wv1ehgwhe71CwSLuolXHKo9jtxm6bkPNo7AD9WH1DLqF1-AvRg0Ht7pB2foQ49OpAHu8C0mEaeufXyCo9hpjeFK-s6hO8nffz4tf11c_V18Xt9y83q8vbheZNOS5qzGxpgNVG01IwVrPSGmEJobXVtbF1yaBthNatYXmxlgpDjeVNiw2l-XhefDjWHfqQ5DyaJMuSY0ErxqqMuDkiTFAbOUS3VXEng3LykAhxLVUcne5BUqhUWQlDoOZMAVeMYoYtMMWxbas61_o8vza1WzAa_BhV_6zo8xvvOplnJwXFRDR7MRdzgRj-TJBGuXVJQ98rD2HKuvPPkSyd4Az9-A_0_92xI0rHkFIE-yiGYLm3ywNL7u0iZ7tk2vunjTySHvxB7wH2M75x</recordid><startdate>20181201</startdate><enddate>20181201</enddate><creator>Tokuda, Isao T</creator><creator>Ono, Daisuke</creator><creator>Honma, Sato</creator><creator>Honma, Ken-Ichi</creator><creator>Herzel, Hanspeter</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QO</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AL</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>JQ2</scope><scope>K7-</scope><scope>K9.</scope><scope>LK8</scope><scope>M0N</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-6212-0022</orcidid></search><sort><creationdate>20181201</creationdate><title>Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors</title><author>Tokuda, Isao T ; Ono, Daisuke ; Honma, Sato ; Honma, Ken-Ichi ; Herzel, Hanspeter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-804f2de48dc32644842fd6f1138fc8df824eb96ccbd4bd44b36d3df59b0d334b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Arginine Vasopressin - metabolism</topic><topic>Arginine Vasopressin - physiology</topic><topic>Biological clocks</topic><topic>Biology</topic><topic>Biology and Life Sciences</topic><topic>Bioluminescence</topic><topic>Brain research</topic><topic>Brain slice preparation</topic><topic>Cell culture</topic><topic>Circadian Clocks - physiology</topic><topic>Circadian rhythm</topic><topic>Circadian Rhythm - physiology</topic><topic>Circadian rhythms</topic><topic>Complexity</topic><topic>Computer and Information Sciences</topic><topic>Computer simulation</topic><topic>Coupling</topic><topic>Coupling factors</topic><topic>Data analysis</topic><topic>Empirical analysis</topic><topic>Gene expression</topic><topic>Mammals</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Modelling</topic><topic>Neonates</topic><topic>Neurons</topic><topic>Neurons - physiology</topic><topic>Neuropeptides</topic><topic>Neuropeptides - metabolism</topic><topic>Neurosciences</topic><topic>Organs</topic><topic>Orthogonal functions</topic><topic>Oscillators</topic><topic>Period Circadian Proteins - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS computational biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tokuda, Isao T</au><au>Ono, Daisuke</au><au>Honma, Sato</au><au>Honma, Ken-Ichi</au><au>Herzel, Hanspeter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors</atitle><jtitle>PLoS computational biology</jtitle><addtitle>PLoS Comput Biol</addtitle><date>2018-12-01</date><risdate>2018</risdate><volume>14</volume><issue>12</issue><spage>e1006607</spage><epage>e1006607</epage><pages>e1006607-e1006607</pages><issn>1553-7358</issn><issn>1553-734X</issn><eissn>1553-7358</eissn><notes>new_version</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Current address: Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan</notes><notes>The authors have declared that no competing interests exist.</notes><abstract>Circadian clocks are autonomous oscillators driving daily rhythms in physiology and behavior. In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptional feedbacks generate noisy oscillations. Coupling mediated by neuropeptides such as VIP and AVP lends precision and robustness to circadian rhythms. The detailed coupling mechanisms between SCN neurons are debated. We analyze organotypic SCN slices from neonatal and adult mice in wild-type and multiple knockout conditions. Different degrees of rhythmicity are quantified by pixel-level analysis of bioluminescence data. We use empirical orthogonal functions (EOFs) to characterize spatio-temporal patterns. Simulations of coupled stochastic single cell oscillators can reproduce the diversity of observed patterns. Our combination of data analysis and modeling provides deeper insight into the enormous complexity of the data: (1) Neonatal slices are typically stronger oscillators than adult slices pointing to developmental changes of coupling. (2) Wild-type slices are completely synchronized and exhibit specific spatio-temporal patterns of phases. (3) Some slices of Cry double knockouts obey impaired synchrony that can lead to co-existing rhythms ("splitting"). (4) The loss of VIP-coupling leads to desynchronized rhythms with few residual local clusters. Additional information was extracted from co-culturing slices with rhythmic neonatal wild-type SCNs. These co-culturing experiments were simulated using external forcing terms representing VIP and AVP signaling. The rescue of rhythmicity via co-culturing lead to surprising results, since a cocktail of AVP-antagonists improved synchrony. Our modeling suggests that these counter-intuitive observations are pointing to an antagonistic action of VIP and AVP coupling. Our systematic theoretical and experimental study shows that dual coupling mechanisms can explain the astonishing complexity of spatio-temporal patterns in SCN slices.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30532130</pmid><doi>10.1371/journal.pcbi.1006607</doi><orcidid>https://orcid.org/0000-0001-6212-0022</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Arginine Vasopressin - metabolism Arginine Vasopressin - physiology Biological clocks Biology Biology and Life Sciences Bioluminescence Brain research Brain slice preparation Cell culture Circadian Clocks - physiology Circadian rhythm Circadian Rhythm - physiology Circadian rhythms Complexity Computer and Information Sciences Computer simulation Coupling Coupling factors Data analysis Empirical analysis Gene expression Mammals Medical research Medicine Mice Mice, Inbred C57BL Mice, Knockout Modelling Neonates Neurons Neurons - physiology Neuropeptides Neuropeptides - metabolism Neurosciences Organs Orthogonal functions Oscillators Period Circadian Proteins - metabolism Physical Sciences Physiology Polypeptides Reporters Research and Analysis Methods Signal Transduction Stochasticity Suprachiasmatic nucleus Suprachiasmatic Nucleus - physiology Synchronization Transcription University graduates Vasoactive Intestinal Peptide - metabolism Vasoactive Intestinal Peptide - physiology |
| title | Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T22%3A37%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Coherency%20of%20circadian%20rhythms%20in%20the%20SCN%20is%20governed%20by%20the%20interplay%20of%20two%20coupling%20factors&rft.jtitle=PLoS%20computational%20biology&rft.au=Tokuda,%20Isao%20T&rft.date=2018-12-01&rft.volume=14&rft.issue=12&rft.spage=e1006607&rft.epage=e1006607&rft.pages=e1006607-e1006607&rft.issn=1553-7358&rft.eissn=1553-7358&rft_id=info:doi/10.1371/journal.pcbi.1006607&rft_dat=%3Cproquest_plos_%3E2250637447%3C/proquest_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c592t-804f2de48dc32644842fd6f1138fc8df824eb96ccbd4bd44b36d3df59b0d334b3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2250637447&rft_id=info:pmid/30532130&rfr_iscdi=true |