A visual circuit uses complementary mechanisms to support transient and sustained pupil constriction

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usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="u8gjcL4oavOR3q1uQwedFGMX7LjPikTEt4Vr2wd0plAkPfTbdaTxzXVcCyb95OBe"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="u8gjcL4oavOR3q1uQwedFGMX7LjPikTEt4Vr2wd0plAkPfTbdaTxzXVcCyb95OBe"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="u8gjcL4oavOR3q1uQwedFGMX7LjPikTEt4Vr2wd0plAkPfTbdaTxzXVcCyb95OBe"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="u8gjcL4oavOR3q1uQwedFGMX7LjPikTEt4Vr2wd0plAkPfTbdaTxzXVcCyb95OBe"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="27669145"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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required-field-asterisk"> Name your collection: </label><input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label"> Choose a collection: </label><select id="collections-action-dialog-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 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'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="collections_button" data-ga-action="click" data-ga-label="add"> Add </button><button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="collections_button" data-ga-action="click" data-ga-label="cancel"> Cancel </button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" 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class="journal-actions-trigger trigger" ref="linksrc=journal_actions_btn" title="eLife" tabindex="0" aria-controls="full-view-journal" aria-expanded="false" aria-label="Toggle dropdown menu for journal eLife" data-pinger-ignore> Elife </button><div id="full-view-journal" class="journal-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for journal eLife"><div class="title">Actions</div><div class="content"><ul class="journal-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Elife%22%5Bjour%5D&sort=date&sort_order=desc" data-href="/?term=%22Elife%22%5Bjour%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_journal_name_link&journal_abbrev=Elife" data-ga-category="search" data-ga-action="journal_link" data-ga-label="Elife"> Search in PubMed </a></li><li><a class="search-in-nlm-catalog-link dropdown-block-link" ref ="linksrc=search_in_nlm_catalog_link" href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Elife%22%5BTitle+Abbreviation%5D" data-ga-category="search_catalog" data-ga-action="journal_link" data-ga-label="Elife"> Search in NLM Catalog </a></li><li><a class="add-to-search-link dropdown-block-link" ref ="linksrc=add_to_search_link" role="button" data-search-term='"Elife"[jour]' data-ga-category="search" data-ga-action="add_to_search" data-ga-label='"Elife"[jour]' href="#"> Add to Search </a></li></ul></div></div></div><span class="period">. </span><span class="cit">2016 Sep 26:5:e15392.</span> </div> <span class="citation-doi"> doi: 10.7554/eLife.15392. </span> </div> <h1 class="heading-title"> A visual circuit uses complementary mechanisms to support transient and sustained pupil constriction </h1> <div class="inline-authors"> <div class="authors"> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Keenan+WT&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="William Thomas Keenan">William Thomas Keenan</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biology, Johns Hopkins University, Baltimore, United States." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Rupp+AC&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Alan C Rupp">Alan C Rupp</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biology, Johns Hopkins University, Baltimore, United States." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Ross+RA&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Rachel A Ross">Rachel A Ross</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Psychiatry, Massachusetts General Hospital, Boston, United States." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Somasundaram+P&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Preethi Somasundaram">Preethi Somasundaram</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Marlyand, Baltimore, United States." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Hiriyanna+S&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Suja Hiriyanna">Suja Hiriyanna</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="National Eye Institute, National Institutes of Health, Bethesda, United States." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Wu+Z&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Zhijian Wu">Zhijian Wu</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="National Eye Institute, National Institutes of Health, Bethesda, United States." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Badea+TC&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Tudor C Badea">Tudor C Badea</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="National Eye Institute, National Institutes of Health, Bethesda, United States." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Robinson+PR&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Phyllis R Robinson">Phyllis R Robinson</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Marlyand, Baltimore, United States." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Lowell+BB&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Bradford B Lowell">Bradford B Lowell</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States." href="#full-view-affiliation-6" ref="linksrc=author_aff"> 6 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States." href="#full-view-affiliation-7" ref="linksrc=author_aff"> 7 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Program in Neuroscience, Harvard Medical School, Boston, United States." href="#full-view-affiliation-8" ref="linksrc=author_aff"> 8 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Hattar+SS&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Samer S Hattar">Samer S Hattar</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biology, Johns Hopkins University, Baltimore, United States." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Neuroscience, Johns Hopkins University, Baltimore, United States." href="#full-view-affiliation-9" ref="linksrc=author_aff"> 9 </a></sup></span> </div> </div> </div> <div class="short-article-details"> Affiliations <button class="more-details" id="toggle-authors" data-alt-text="Collapse" aria-controls="expanded-authors" aria-expanded="false" data-pinger-ignore data-fetch-url="/27669145/long-authors/" data-id-prefix=""> <span class="title"> Expand </span> </button> </div> <div class="extended-article-details" id="expanded-authors" aria-hidden="true"> <div class="expanded-authors" id="full-view-expanded-authors"> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="full-view-affiliation-1" id="full-view-affiliation-1" ><sup class="key">1</sup> Department of Biology, Johns Hopkins University, Baltimore, United States.</li> <li data-affiliation-id="full-view-affiliation-2" id="full-view-affiliation-2" ><sup class="key">2</sup> Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.</li> <li data-affiliation-id="full-view-affiliation-3" id="full-view-affiliation-3" ><sup class="key">3</sup> Department of Psychiatry, Massachusetts General Hospital, Boston, United States.</li> <li data-affiliation-id="full-view-affiliation-4" id="full-view-affiliation-4" ><sup class="key">4</sup> Department of Biological Sciences, University of Marlyand, Baltimore, United States.</li> <li data-affiliation-id="full-view-affiliation-5" id="full-view-affiliation-5" ><sup class="key">5</sup> National Eye Institute, National Institutes of Health, Bethesda, United States.</li> <li data-affiliation-id="full-view-affiliation-6" id="full-view-affiliation-6" ><sup class="key">6</sup> Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.</li> <li data-affiliation-id="full-view-affiliation-7" id="full-view-affiliation-7" ><sup class="key">7</sup> Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.</li> <li data-affiliation-id="full-view-affiliation-8" id="full-view-affiliation-8" ><sup class="key">8</sup> Program in Neuroscience, Harvard Medical School, Boston, United States.</li> <li data-affiliation-id="full-view-affiliation-9" id="full-view-affiliation-9" ><sup class="key">9</sup> Department of Neuroscience, Johns Hopkins University, Baltimore, United States.</li> </ul> </div> </div> </div> <ul class="identifiers" id="full-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">27669145</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" 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<span class="citation-journal"> Elife<span class="citation-separator">.</span> </span> <span class="date"> <time class="citation-year" datetime="2016">2016</time><span class="citation-separator">.</span> </span> </div> <div class="more-article-details-section with-display-settings"> <button class="more-article-details" id="toggle-article-details" data-alt-text="Hide details" ref="linksrc=toggle_article_details" aria-controls="full-article-details" aria-expanded="false" data-fetch-url="/27669145/long-authors/" data-id-prefix=""> <span class="title">Show details</span> </button> <div class="display-options" data-format-key="format" data-default-format-value="abstract" data-current-format-value="abstract" role="region"> <button class="trigger usa-button" title="Change format" data-ga-category="display_options" data-ga-action="display_options_dialog"> <span class="button-label">Display options</span> </button> <div class="dropdown" hidden> <div class="title"> Display options </div> <div 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</a></li></ul></div></div></div><span class="period">. </span><span class="cit">2016 Sep 26:5:e15392.</span> </div> <span class="citation-doi"> doi: 10.7554/eLife.15392. </span> </div> <div class="expanded-authors" id="short-view-expanded-authors"> <div class="authors"> <h3 class="title"> Authors </h3> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Keenan+WT&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="William Thomas Keenan">William Thomas Keenan</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biology, Johns Hopkins University, Baltimore, United States." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Rupp+AC&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Alan C Rupp">Alan C Rupp</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biology, Johns Hopkins University, Baltimore, United States." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Ross+RA&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Rachel A Ross">Rachel A Ross</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Psychiatry, Massachusetts General Hospital, Boston, United States." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Somasundaram+P&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Preethi Somasundaram">Preethi Somasundaram</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Marlyand, Baltimore, United States." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Hiriyanna+S&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Suja Hiriyanna">Suja Hiriyanna</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="National Eye Institute, National Institutes of Health, Bethesda, United States." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Wu+Z&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Zhijian Wu">Zhijian Wu</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="National Eye Institute, National Institutes of Health, Bethesda, United States." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Badea+TC&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Tudor C Badea">Tudor C Badea</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="National Eye Institute, National Institutes of Health, Bethesda, United States." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Robinson+PR&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Phyllis R Robinson">Phyllis R Robinson</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Marlyand, Baltimore, United States." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Lowell+BB&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Bradford B Lowell">Bradford B Lowell</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States." href="#short-view-affiliation-6" ref="linksrc=author_aff"> 6 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States." href="#short-view-affiliation-7" ref="linksrc=author_aff"> 7 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Program in Neuroscience, Harvard Medical School, Boston, United States." href="#short-view-affiliation-8" ref="linksrc=author_aff"> 8 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Hattar+SS&cauthor_id=27669145" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Samer S Hattar">Samer S Hattar</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biology, Johns Hopkins University, Baltimore, United States." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Neuroscience, Johns Hopkins University, Baltimore, United States." href="#short-view-affiliation-9" ref="linksrc=author_aff"> 9 </a></sup></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> Department of Biology, Johns Hopkins University, Baltimore, United States.</li> <li data-affiliation-id="short-view-affiliation-2" id="short-view-affiliation-2" ><sup class="key">2</sup> Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.</li> <li data-affiliation-id="short-view-affiliation-3" id="short-view-affiliation-3" ><sup class="key">3</sup> Department of Psychiatry, Massachusetts General Hospital, Boston, United States.</li> <li data-affiliation-id="short-view-affiliation-4" id="short-view-affiliation-4" ><sup class="key">4</sup> Department of Biological Sciences, University of Marlyand, Baltimore, United States.</li> <li data-affiliation-id="short-view-affiliation-5" id="short-view-affiliation-5" ><sup class="key">5</sup> National Eye Institute, National Institutes of Health, Bethesda, United States.</li> <li data-affiliation-id="short-view-affiliation-6" id="short-view-affiliation-6" ><sup class="key">6</sup> Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.</li> <li data-affiliation-id="short-view-affiliation-7" id="short-view-affiliation-7" ><sup class="key">7</sup> Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.</li> <li data-affiliation-id="short-view-affiliation-8" id="short-view-affiliation-8" ><sup class="key">8</sup> Program in Neuroscience, Harvard Medical School, Boston, United States.</li> <li data-affiliation-id="short-view-affiliation-9" id="short-view-affiliation-9" ><sup class="key">9</sup> Department of Neuroscience, Johns Hopkins University, Baltimore, United States.</li> </ul> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">27669145</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC5079752&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5079752/" data-ga-category="full_text" data-ga-action="PMCID" > PMC5079752 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.7554/eLife.15392&id_type=DOI" href="https://doi.org/10.7554/elife.15392" data-ga-category="full_text" data-ga-action="DOI" > 10.7554/eLife.15392 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> </div> </header> <div class="actions-buttons inline"><div class="inner-wrap"><button class="full-text-links-button full-text-links-dialog-trigger" title="Open dialog with full text links" ref="linksrc=full_text_links"> Full text links </button><button class="citation-button citation-dialog-trigger" aria-label="Open dialog with citation text in different styles" 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id="inline-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div> <div class="abstract" id="abstract"> <h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> Rapid and stable control of pupil size in response to light is critical for vision, but the neural coding mechanisms remain unclear. Here, we investigated the neural basis of pupil control by monitoring pupil size across time while manipulating each photoreceptor input or neurotransmitter output of intrinsically photosensitive retinal ganglion cells (ipRGCs), a critical relay in the control of pupil size. We show that transient and sustained pupil responses are mediated by distinct photoreceptors and neurotransmitters. Transient responses utilize input from rod photoreceptors and output by the classical neurotransmitter glutamate, but adapt within minutes. In contrast, sustained responses are dominated by non-conventional signaling mechanisms: melanopsin phototransduction in ipRGCs and output by the neuropeptide PACAP, which provide stable pupil maintenance across the day. These results highlight a temporal switch in the coding mechanisms of a neural circuit to support proper behavioral dynamics. </p> </div> <p> <strong class="sub-title"> Keywords: </strong> ipRGC; melanopsin; mouse; neuropeptides; neuroscience; neurotransmitters; retinal circuitry; vision. </p> </div> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" ga_category="literature_resources" ga_action="disclaimer_link" ga_label="under_abstract">PubMed Disclaimer</a> </p> <div class="conflict-of-interest" id="conflict-of-interest"> <h2 class="title"> Conflict of interest statement </h2> <div class="statement"> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors declare that no competing interests exist.</p> </div> </div> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="figure-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/f3f3938a6aec/elife-15392-fig1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="736" data-image-height="664" data-image-alt="Figure 1." data-pmc-id="PMC5079752" data-figure-id="fig1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/6fde4fc8244a/elife-15392-fig1.gif" alt="Figure 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="736"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="664"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1.. The pupillary light response contains… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1.. The pupillary light response contains two phases: transient and sustained. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> )… </p></div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1.. The pupillary light response contains two phases: transient and sustained. </strong> <div class="figure-caption-contents">(<b>A</b>) Approximate light intensity ranges (lux) at different times of day. (<b>B</b>) Transient constriction in response to a 10 lux overhead stimulus (mean ± SD). Boxes contain representative pupil images at time 0 and 30 s. (<b>C</b>) Continued monitoring of pupil constriction from b for 60 min of continuous light at 5 min intervals with representative images. (<b>D</b>) Intensity-response curve for transient and sustained constriction (30 s and 60 min, respectively). Data fit with a sigmoidal curve (<i>n</i> = 5, mean ± SD). (<b>E</b>) Light intensity required for half-maximal constriction (EC<sub>50</sub>) determined for both transient and sustained phases of the PLR. EC<sub>50</sub> extracted from the sigmoidal curve fits for each mouse (points are individual mice, line is mean). Statistical significance determined with a student’s <i>t</i> test. (<b>F</b>) Half-life of PLR decay at 1, 10, and 100 lux. Statistical significance determined by main effect of light intensity from one-way ANOVA. See also Figure 1—figure supplement 1, Figure 1—figure supplement 2. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.003">http://dx.doi.org/10.7554/eLife.15392.003</ext-link></div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="figure-1figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/d93cc9586e0c/elife-15392-fig1-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="738" data-image-height="616" data-image-alt="Figure 1—figure supplement 1." data-pmc-id="PMC5079752" data-figure-id="fig1s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/cbba34904c53/elife-15392-fig1-figsupp1.gif" alt="Figure 1—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="738"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="616"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1—figure supplement 1.. Experimental setup and… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1—figure supplement 1.. Experimental setup and light stimulus details. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> ) Environmental light… </p></div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1—figure supplement 1.. Experimental setup and light stimulus details. </strong> <div class="figure-caption-contents">(<b>A</b>) Environmental light intensity measured in lux across one day (April 2, 2015) in Baltimore, Maryland, USA. The light meter used is unable to measure light intensities below 1 lux, indicated with the gray box. Dotted lines refer to the meteorological sunrise and sunset. Data is fit with a hand-drawn curve for ease of visualization. (<b>B</b>) Mice are unanesthetized and restrained by hand under a light bulb with a broad spectrum similar to sunlight (<b>C</b>). Spectral power is normalized to the most highly represented wavelength in sunlight. Breaking down the fraction of light into 50 nm bins for each light source, the daylight bulbs are very similar to sunlight across all wavelengths (<b>D</b>), while incandescent bulbs lack short wavelengths and are enriched in long wavelengths. Pupils are continuously recorded in darkness and light using an infrared video camera. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.004">http://dx.doi.org/10.7554/eLife.15392.004</ext-link></div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="figure-1figure-supplement-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/791ce8ef6be1/elife-15392-fig1-figsupp2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="744" data-image-height="624" data-image-alt="Figure 1—figure supplement 2." data-pmc-id="PMC5079752" data-figure-id="fig1s2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/dd7991bc155e/elife-15392-fig1-figsupp2.gif" alt="Figure 1—figure supplement 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="744"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="624"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1—figure supplement 2.. Negative-feedback model of… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1—figure supplement 2.. Negative-feedback model of PLR decay. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> ) Diagram displaying how… </p></div> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1—figure supplement 2.. Negative-feedback model of PLR decay. </strong> <div class="figure-caption-contents">(<b>A</b>) Diagram displaying how the negative feedback model works (7 s light in example) (See Online Methods for step-by-step explanation). The model assumes that packets of light information are discrete and are relayed to the PLR circuit to result in pupil constriction at later timepoints. We determined the kinetics of light information relay using a 1-s light pulse-chase. Then, we simply modulate the relative light intensity reaching the retina based on assuming continuous 1-s packets of information. At each new 1-s interval, the model samples the assumed pupil sizes currently driven by each previous packet of light information, uses the maximum value as the current pupil size, and then reduces the stimulus intensity using that pupil size. We then use this new intensity to determine constriction caused at that time. This iterates every second. (<b>B</b>) Putative kinetics of feedback’s impact on PLR at several light intensities (0.0001, 0.001, 0.01, 0.1, 1, 10, 100, 1000, and 10,000 lux). (<b>C</b>) Magnitude of PLR decay caused by feedback as modeled with (<b>D</b>) EC<sub>50</sub>. Note that our model predicts minor PLR decay as a result of PLR feedback. (<b>E</b>) Experimental investigation of feedback’s role in PLR decay. Atropine was applied to the left eye to inhibit pupil constriction and thus feedback. No enhancement of sustained PLR of the right eye was observed (paired two-tailed t-test). <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.005">http://dx.doi.org/10.7554/eLife.15392.005</ext-link></div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="figure-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/8140adcbc207/elife-15392-fig2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="750" data-image-height="926" data-image-alt="Figure 2." data-pmc-id="PMC5079752" data-figure-id="fig2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/6756a832f6c8/elife-15392-fig2.gif" alt="Figure 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="750"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="926"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2.. Transient input to ipRGCs is… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2.. Transient input to ipRGCs is mediated by rods. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> ) Diagram of… </p></div> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2.. Transient input to ipRGCs is mediated by rods. </strong> <div class="figure-caption-contents">(<b>A</b>) Diagram of ipRGC behavioral circuit. (<b>B</b>) Intensity-response curves of the PLR in each of the photoreceptor mutant mouse lines (mean ± SD): wildtype (<i>n</i> = 6), Rod KO (<i>Gnat1<sup>-/-</sup> n</i> = 6), Melanopsin KO (<i>Opn4<sup>-/-</sup> n</i> = 8), and Cone KO (<i>Gnat2<sup>-/-</sup> n</i> = 7). Representative pupil images for each mouse line at 10 lux. (<b>C</b>) Gene schematic comparison of endogenous mouse M-cone allele and human red cone knock-in allele as well as the spectral sensitivity shift observed. Notice that cones are more sensitive to red light in Red cone KI line. (<b>D</b>) The PLR to red light (626-nm LED) is identical in mice with cones that are more sensitive to red light (Red cone KI, <i>n</i> = 6) compared to littermate WT (<i>n</i> = 5), mean ± SD. (<b>E</b>) Removing rod function abolishes the PLR in response to red light (626-nm LED), even in mice with cones with enhanced sensitivity to red light. WT <i>n</i> = 7, Red cone KI (<i>Opn1mw<sup>red</sup>) n</i> = 8, Rod KO (<i>Gnat1<sup>-/-</sup>)<sup>-</sup> n</i> = 8, Red cone KI; Rod KO (<i>Gnat1<sup>-/-</sup>; Opn1mw<sup>red</sup>) n</i> = 4. Light intensity is 14.3 log photons/cm<sup>2</sup>/s. (<b>F</b>) Intensity-response curves in mutant mice with each photoreceptor isolated (Rod-only: <i>Cnga3<sup>-/-</sup>; Opn4<sup>-/-</sup> n</i> = 6)(Cone-only: (<i>Gnat1<sup>-/-</sup>; Opn4<sup>-/-</sup> n</i> = 6)(Mel.-only: <i>Gnat1<sup>-/-</sup>; Gnat2<sup>-/-</sup> n</i> = 7) Data is mean ± SD, statistical significance determined using a one-way ANOVA with Sidak’s post-test. (right) Representative pupil images at 100 lux. (<b>G</b>) Kinetics of transient pupil constriction (100 lux) in mice with only rod, cone, or melanopsin function, same genotypes and number of animals as in <b>F</b>. Traces of individual mice are shown behind curve-fits. One-phase decays were fit to all except cone-only which was fit with a two-phase decay due to its rapid pupil decay within 30 s. Melanopsin-only kinetic fit was offset from 0 by 3 s to account for delay in constriction. See also Figure 2—figure supplements 1–5. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.006">http://dx.doi.org/10.7554/eLife.15392.006</ext-link></div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="4" data-label-slug="figure-2figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/bea35550404a/elife-15392-fig2-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-4" role="button" data-image-width="689" data-image-height="411" data-image-alt="Figure 2—figure supplement 1." data-pmc-id="PMC5079752" data-figure-id="fig2s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-4" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/64ef8d3e5c90/elife-15392-fig2-figsupp1.gif" alt="Figure 2—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="689"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="411"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2—figure supplement 1.. Dark-adapted pupil sizes… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2—figure supplement 1.. Dark-adapted pupil sizes of photoreceptor mutant mouse lines used. </p> </strong> <div class="figure-caption-contents"><p> Dark-adapted pupil… </p></div> </div> <figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2—figure supplement 1.. Dark-adapted pupil sizes of photoreceptor mutant mouse lines used. </strong> <div class="figure-caption-contents">Dark-adapted pupil sizes of all mouse lines used for photoreceptor investigation. Pupil size was recorded before light onset and pupil area (mm<sup>2</sup>) is reported. No statistical difference was found for any genotype compared to wildtype (p>0.05 for all comparisons). Statistical significance was determined by one-way ANOVA followed by Sidak’s post-test. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.007">http://dx.doi.org/10.7554/eLife.15392.007</ext-link></div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="5" data-label-slug="figure-2figure-supplement-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/1e2ce794fe4e/elife-15392-fig2-figsupp2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-5" role="button" data-image-width="716" data-image-height="641" data-image-alt="Figure 2—figure supplement 2." data-pmc-id="PMC5079752" data-figure-id="fig2s2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-5" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/113807dec085/elife-15392-fig2-figsupp2.gif" alt="Figure 2—figure supplement 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="716"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="641"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2—figure supplement 2.. Rods are required… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2—figure supplement 2.. Rods are required for the transient phase of the PLR. </p> </strong> <div class="figure-caption-contents"><p> (… </p></div> </div> <figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2—figure supplement 2.. Rods are required for the transient phase of the PLR. </strong> <div class="figure-caption-contents">(<b>A</b>) Diagram of the retina labeling the photoreceptors. For experiments in <b>B</b>–<b>D</b>, WT <i>n</i> = 14, <i>Opn4<sup>-/-</sup> n</i> = 8, <i>Cnga3<sup>-/-</sup> n</i> = 4, <i>Gnat2<sup>-/-</sup> n</i> = 7, Cone-DTA <i>n</i> = 7, <i>Gnat1<sup>-/-</sup> n</i> = 6, Rod-DTA <i>n</i> = 9. (<b>B</b>) Kinetics of rapid constriction in response to dim light (10 lux). Rod KO mice are the only photoreceptor mutants to display a deficit. Cone and Mel. KO mice are identical to wildtype. (<b>C</b>) Intensity-response curves of the PLR in each of the photoreceptor mutant mouse lines (mean ± SD). The bar on top of the figure denotes the estimated sensitivities of rods and cones. (<b>D</b>) Rod mutant animals are the only mutants that display a sensitivity (EC<sub>50</sub>) deficit compared to WT (p<0.0001). In fact, Cone-DTA mice are moderately more sensitive than WT (*p=0.011). Points indicate individual mice, line indicates mean. Statistical significance determined using a one-way ANOVA with Sidak’s post-test. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.008">http://dx.doi.org/10.7554/eLife.15392.008</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="6" data-label-slug="figure-2figure-supplement-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/475da2a0edac/elife-15392-fig2-figsupp3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-6" role="button" data-image-width="648" data-image-height="425" data-image-alt="Figure 2—figure supplement 3." data-pmc-id="PMC5079752" data-figure-id="fig2s3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-6" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/d5f5e5e66e8f/elife-15392-fig2-figsupp3.gif" alt="Figure 2—figure supplement 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="648"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="425"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2—figure supplement 3.. Melanopsin is not… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2—figure supplement 3.. Melanopsin is not required for transient PLR in response to environmentally… </p> </strong> </div> <figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2—figure supplement 3.. Melanopsin is not required for transient PLR in response to environmentally relevant overhead light. </strong> <div class="figure-caption-contents">Transient PLR determined under 3 different experimental light conditions. (Left) Blue (474-nm) LED light presented to contralateral eye (1.9 × 10<sup>16</sup> photons/cm<sup>2</sup>/s). (Middle) White halogen light presented to contralateral eye (27.58 W/m<sup>2</sup>). (Right) 1000 lux white compact fluorescent light presented overhead to both eyes (4.4 W/m<sup>2</sup>). Line represents mean and points are individual mice. Statistical significance determined by one-way ANOVA followed by Sidak’s post-test. No difference observed when light presented overhead. Control (<i>Opn4<sup>+/-</sup>) n</i> = 7 and <i>Opn4<sup>-/-</sup> n</i> = 9. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.009">http://dx.doi.org/10.7554/eLife.15392.009</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="7" data-label-slug="figure-2figure-supplement-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/c3552f5510ea/elife-15392-fig2-figsupp4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-7" role="button" data-image-width="793" data-image-height="1039" data-image-alt="Figure 2—figure supplement 4." data-pmc-id="PMC5079752" data-figure-id="fig2s4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-7" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/76b25077b017/elife-15392-fig2-figsupp4.gif" alt="Figure 2—figure supplement 4." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="793"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1039"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2—figure supplement 4.. Rod input to… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2—figure supplement 4.. Rod input to the transient PLR is influenced by cones. </p> </strong> <div class="figure-caption-contents"><p> (… </p></div> </div> <figcaption id="figure-caption-7" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2—figure supplement 4.. Rod input to the transient PLR is influenced by cones. </strong> <div class="figure-caption-contents">(<b>A</b>) Cartoon representation of a cone and a diagram of its phototransduction cascade. Different aspects of this cascade are disrupted in the various ‘rod-only’ lines we use. (<b>B</b>) Multiple mouse lines with rods as the only functional photoreceptors. For the experiments in <b>C</b> and <b>D</b>: WT <i>n</i> = 6, Rod-only type 1 (RO1: <i>Cnga3<sup>-/-</sup>; Opn4<sup>-/-</sup>) n</i> = 6, Rod-only type 2 (RO2: <i>Gnat2<sup>-/-</sup>; Opn4<sup>-/-</sup>) n</i> = 8, Rod-only type 3 (RO3: Cone-DTA; <i>Opn4<sup>-/-</sup>) n</i> = 5. (<b>C</b>) Intensity-response curve of the PLR in all of the rod-only lines, which are all similar to wild-type at all light intensities (mean ± SD). At 1000 lux, only RO2s are statistically different from wildtype (p=0.006 by one-way ANOVA with Sidak‘s post-test). (<b>D</b>) Sensitivity (EC<sub>50</sub>) in each of the mutant lines. No statistical differences were observed between the mouse lines (compared to WT, RO1 p=0.956, RO2 p=0.340, RO3 p=0.141 using a one-way ANOVA with Sidak’s post-test), although the RO2 line had more variability and trended toward lower sensitivity. (<b>E</b> and <b>F</b>) Kinetic comparison of rod-only lines at dim (<b>E</b>) and bright (<b>F</b>) light intensities. RO1 and RO3 lines are identical to wildtype under both light intensities, however, RO2 mice display PLR decay within 30s. All statistics are one-way ANOVA with Sidak’s post-test, line indicates mean. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.010">http://dx.doi.org/10.7554/eLife.15392.010</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="8" data-label-slug="figure-2figure-supplement-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/6a4936f23048/elife-15392-fig2-figsupp5.jpg" itemprop="contentUrl" aria-describedby="figure-caption-8" role="button" data-image-width="677" data-image-height="409" data-image-alt="Figure 2—figure supplement 5." data-pmc-id="PMC5079752" data-figure-id="fig2s5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-8" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/cca91bcec455/elife-15392-fig2-figsupp5.gif" alt="Figure 2—figure supplement 5." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="677"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="409"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2—figure supplement 5.. Melanopsin can drive… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2—figure supplement 5.. Melanopsin can drive rapid constriction at high light intensities. </p> </strong> <div class="figure-caption-contents"><p> Multiple mouse… </p></div> </div> <figcaption id="figure-caption-8" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2—figure supplement 5.. Melanopsin can drive rapid constriction at high light intensities. </strong> <div class="figure-caption-contents">Multiple mouse lines with ipRGCs as the only functional photoreceptors (melanopsin-only) or a mouse line with cones as the only functional photoreceptors (cone-only) were tested. For the experiments in <b>A</b> and <b>B</b>: WT <i>n</i> = 9, Gnat1<sup>-/-</sup><i>n</i> = 10, Melanopsin-only type 1 (MO1: <i>Gnat1<sup>-/-</sup>; Cnga3<sup>-/-</sup>) n</i> = 7, Melanopsin-only type 2 (MO2: <i>Gnat1<sup>-/-</sup>; Gnat2<sup>-/-</sup>) n</i> = 9, Melanopsin-only type 3 (MO3: Rod-DTA; Cone-DTA) <i>n</i> = 6, Cone-only (<i>Gnat1<sup>-/-</sup>; Opn4<sup>-/-</sup>) n</i> = 6. (<b>A</b>) Intensity-response curve of the PLR in all of the melanopsin-only lines and in the cone-only mouse line (mean ± SD). (<b>B</b>) EC<sub>50</sub> in each of the lines. All mutant lines are less sensitive than WT (p<0.0001) by >2 log units. Cone-only mice are additionally less sensitive than Rod KO mice (p<0.0001), but no melanopsin-only line is significantly different from Rod KO (Compared to RKO: MO1 p=0.201, MO2 p=0.625, MO3 p=0.591). All statistics are one-way ANOVA with Sidak’s post-test, line indicates mean. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.011">http://dx.doi.org/10.7554/eLife.15392.011</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="9" data-label-slug="figure-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/378e05f53a65/elife-15392-fig3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-9" role="button" data-image-width="781" data-image-height="783" data-image-alt="Figure 3." data-pmc-id="PMC5079752" data-figure-id="fig3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-9" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/fff73721cab9/elife-15392-fig3.gif" alt="Figure 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="781"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="783"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3.. Glutamaterigic output provides precise and… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3.. Glutamaterigic output provides precise and rapid transient signaling. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> ) Diagram of… </p></div> </div> <figcaption id="figure-caption-9" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3.. Glutamaterigic output provides precise and rapid transient signaling. </strong> <div class="figure-caption-contents">(<b>A</b>) Diagram of ipRGC behavioral circuit. (<b>B</b>) Intensity-response curves of the PLR in each of the neurotransmitter mutant mouse lines (Wildtype <i>n</i> = 6) (ipRGC glu. KO: <i>Opn4<sup>Cre/+</sup> ; Slc17a6<sup>fl/fl</sup> n</i> = 4) (ipRGC PACAP KO: <i>Opn4<sup>Cre/+</sup> ;Adcyap1<sup>fl/-</sup> n</i> = 6)(mean ± SD). (<b>C</b>) Sensitivity (EC<sub>50</sub>) in each of the mutant lines. Statistical significance determined by one-way ANOVA with Sidak’s post-test. (<b>D</b>) Kinetics of transient pupil constriction (1000 lux) in mice lacking glutamatergic or PACAPergic neurotransmission. Traces of individual mice are shown behind one-phase decay curve-fits. Half-lives: Wildtype (1.1 s), ipRGC glu. KO (4.8 s), ipRGC PACAP KO (1.1 s). (<b>E</b>) Representative pupil images at 5 s and 30 s post-illumination (1000 lux). Figure 3—figure supplements 1–3. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.013">http://dx.doi.org/10.7554/eLife.15392.013</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="10" data-label-slug="figure-3figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/222c89c33fca/elife-15392-fig3-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-10" role="button" data-image-width="568" data-image-height="1020" data-image-alt="Figure 3—figure supplement 1." data-pmc-id="PMC5079752" data-figure-id="fig3s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-10" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/a96209161410/elife-15392-fig3-figsupp1.gif" alt="Figure 3—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="568"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1020"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3—figure supplement 1.. Dark-adapted pupil sizes… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3—figure supplement 1.. Dark-adapted pupil sizes of neurotransmitter mutant lines used. </p> </strong> <div class="figure-caption-contents"><p> Dark-adapted pupil sizes… </p></div> </div> <figcaption id="figure-caption-10" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3—figure supplement 1.. Dark-adapted pupil sizes of neurotransmitter mutant lines used. </strong> <div class="figure-caption-contents">Dark-adapted pupil sizes of all mouse lines used for neurotransmitter investigation. Pupil size was recorded before light onset and pupil area (mm<sup>2</sup>) is reported. ipRGC glutamate KO mice are the only line used which display a significant difference in dark-adapted pupil size suggesting that glutamatergic signaling is important for setting pupil size in darkness (p=0.0001). Statistical significance was determined by one-way ANOVA followed by Sidak’s post-test. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.014">http://dx.doi.org/10.7554/eLife.15392.014</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="11" data-label-slug="figure-3figure-supplement-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/e393d7e574a8/elife-15392-fig3-figsupp2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-11" role="button" data-image-width="696" data-image-height="142" data-image-alt="Figure 3—figure supplement 2." data-pmc-id="PMC5079752" data-figure-id="fig3s2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-11" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/f9813cc8ebeb/elife-15392-fig3-figsupp2.gif" alt="Figure 3—figure supplement 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="696"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="142"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3—figure supplement 2.. Description of conditional… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3—figure supplement 2.. Description of conditional PACAP allele. </p> </strong> <div class="figure-caption-contents"><p> Schematic of the conditional PACAP allele… </p></div> </div> <figcaption id="figure-caption-11" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3—figure supplement 2.. Description of conditional PACAP allele. </strong> <div class="figure-caption-contents">Schematic of the conditional PACAP allele (<i>Adcyap1<sup>lox</sup></i>). Boxes indicate exons (1–5). Grey indicates UTR while black indicates protein coding sequence. A single FRT site remains after removal of selection cassette. LoxP sites flank exon 2. Cre-mediated excision results in a frameshift and production of a truncated protein. See Materials and methods for further information of allele generation and confirmation. A more detailed description of the generation and use of the allele will appear in a manuscript that is in preparation (Ross and Lowell, unpublished). <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.015">http://dx.doi.org/10.7554/eLife.15392.015</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="12" data-label-slug="figure-3figure-supplement-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/f7c77a861a0e/elife-15392-fig3-figsupp3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-12" role="button" data-image-width="544" data-image-height="1034" data-image-alt="Figure 3—figure supplement 3." data-pmc-id="PMC5079752" data-figure-id="fig3s3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-12" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/aa2505558091/elife-15392-fig3-figsupp3.gif" alt="Figure 3—figure supplement 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="544"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1034"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3—figure supplement 3.. PACAP can drive… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3—figure supplement 3.. PACAP can drive significant constriction within 30s of high light onset. </p> </strong> </div> <figcaption id="figure-caption-12" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3—figure supplement 3.. PACAP can drive significant constriction within 30s of high light onset. </strong> <div class="figure-caption-contents">Transient constriction was monitored in neurotransmitter mutant mice under high light (5000 lux). Data from each mouse is shown with the mean (black bar). ipRGC glutamate KO mice (<i>Opn4<sup>Cre/+</sup> ; Slc17a6<sup>fl/fl</sup>: n</i> = 4) display a significant reduction in transient phase pupil constriction compared to wildtype (<i>n</i> = 6)(p<0.0001) while ipRGC PACAP KO (<i>Opn4<sup>Cre/+</sup>;Adcyap1<sup>fl/-</sup>: n</i> = 6) and PACAP KO (<i>n</i> = 4) mice are indistinguishable from wildtype (p>0.999). Statistical signficance determined via one-way ANOVA followed by Sidak’s post-test. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.016">http://dx.doi.org/10.7554/eLife.15392.016</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="13" data-label-slug="figure-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/8281a7235ee8/elife-15392-fig4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-13" role="button" data-image-width="737" data-image-height="931" data-image-alt="Figure 4." data-pmc-id="PMC5079752" data-figure-id="fig4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-13" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/78641945a497/elife-15392-fig4.gif" alt="Figure 4." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="737"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="931"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4.. Melanopsin/rod synergy supports PLR under… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4.. Melanopsin/rod synergy supports PLR under persistent conditions. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> ) Diagram of ipRGC… </p></div> </div> <figcaption id="figure-caption-13" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4.. Melanopsin/rod synergy supports PLR under persistent conditions. </strong> <div class="figure-caption-contents">(<b>A</b>) Diagram of ipRGC behavioral circuit. (<b>B</b>) Intensity-response curves for wildtype and melanopsin knockout mice (<i>Opn4<sup>-/-</sup></i>): transient (dotted lines for reference) and sustained (60 min: solid lines) (WT <i>n</i> = 6, <i>Opn4<sup>-/-</sup> n</i> = 12). (right) Representative pupil images under 1000 lux persistent light. (<b>C</b>) 60-min time course of pupil constriction under constant light (1000 lux). Data fit with a one-phase association curve (WT <i>n</i> = 5, <i>Opn4<sup>-/-</sup> n</i> = 7). (<b>D</b>) Sustained pupil constriction monitored every 5 min for 1 hr in melanopsin knockout mice (<i>Opn4<sup>Cre/Cre</sup></i>) expressing the G<sub>q</sub>-coupled DREADD (hM3D) specifically in ipRGCs (AAV2-hSyn-DIO-hM3D(G<sub>q</sub>)-mCherry). CNO injection IP (blue) caused robust constriction within 5–10 min that was sustained for 60 min, whereas PBS injection (black) did not. CNO data is fit with a one-phase association curve and PBS data is fit with a linear regression (<i>n</i> = 6, mean ± SD). (<b>E</b>) (top) Diagram showing viral eye injection in only one eye. (bottom) Confocal microscope images of an <i>Opn4<sup>Cre/Cre</sup></i>retina injected with AAV2-CMV-DIO-mRuby-P2A-Melanopsin-FLAG showing infection and expression (mRuby, top; anti-OPN4, bottom). Scale bar = 50 µm. (<b>F</b>) Successful rescue of pupil constriction by virally restored melanopsin expression in a single eye of adult mice (WT <i>n</i> = 6, Mel. KO <i>n</i> = 12, Mel.-Rescue <i>n</i> = 4). (right) Representative pupil images of Mel. KO and Mel.-Rescue mice at 1000 lux. (<b>G</b>) PLR intensity-response curves of Wildtype (<i>n</i> = 6), Mel.-only (Rod-DTA; Cone-DTA <i>n</i> = 8), Cone KO (<i>Cnga3<sup>-/-</sup>n</i> = 4), and Rod KO (Rod-DTA <i>n</i> = 5) mice (mean ± SD). Melanopsin is sufficient at high light (≥1000 lux), however, rods are required at lower light intensities. Cone KO mice are similar to wildtype. (top) Representative pupil images at 1000 lux. See also Figure 4—figure supplement 1–4. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.018">http://dx.doi.org/10.7554/eLife.15392.018</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="14" data-label-slug="figure-4figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/4f6d15f5950e/elife-15392-fig4-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-14" role="button" data-image-width="733" data-image-height="343" data-image-alt="Figure 4—figure supplement 1." data-pmc-id="PMC5079752" data-figure-id="fig4s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-14" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/6d500e8a90d1/elife-15392-fig4-figsupp1.gif" alt="Figure 4—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="733"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="343"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4—figure supplement 1.. Melanopsin is required… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4—figure supplement 1.. Melanopsin is required for sustained constriction across the day. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A… </b> </p></div> </div> <figcaption id="figure-caption-14" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4—figure supplement 1.. Melanopsin is required for sustained constriction across the day. </strong> <div class="figure-caption-contents">(<b>A</b>) Sustained constriction at 10,000 lux (WT <i>n</i> = 6, only 1 is plotted due to inability to see extremely small pupils in very bright light, Mel. KO n = 6). (<b>B</b>) Time course of pupil constriction under 12 hr of constant light corresponding to circadian day (room lighting = 350 lux) using wildtype (<i>n</i> = 3) and melanopsin knockout mice (<i>n</i> = 4) (line is smoothed mean). <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.019">http://dx.doi.org/10.7554/eLife.15392.019</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="15" data-label-slug="figure-4figure-supplement-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/3036da578e83/elife-15392-fig4-figsupp2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-15" role="button" data-image-width="765" data-image-height="619" data-image-alt="Figure 4—figure supplement 2." data-pmc-id="PMC5079752" data-figure-id="fig4s2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-15" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/2de9b4624153/elife-15392-fig4-figsupp2.gif" alt="Figure 4—figure supplement 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="765"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="619"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4—figure supplement 2.. Viral infection and… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4—figure supplement 2.. Viral infection and expression is specific to ipRGCs. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> )… </p></div> </div> <figcaption id="figure-caption-15" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4—figure supplement 2.. Viral infection and expression is specific to ipRGCs. </strong> <div class="figure-caption-contents">(<b>A</b>) Schematic of the method to activate exclusively ipRGCs using an exogenous GPCR (hM3D(G<sub>q</sub>)) and its ligand (CNO). (<b>B</b>) Confocal microscope image showing infection of ipRGCs observed by mCherry expression following administration of a Cre-dependent AAV injected into the vitreous of melanopsin-Cre knockout mice (<i>Opn4<sup>Cre/Cre</sup></i>). (<b>C–E</b>) Confirmation of ipRGC-specific expression of melanopsin from AAV-DIO-mRuby-P2A-Melanopsin-FLAG viral injections. <i>Opn4<sup>Cre/+</sup></i> mice were used to colocalize viral (<b>C</b>) mRuby with (<b>D</b>) endogenous and exogenous melanopsin expression. (<b>E</b>) We observe specific expression of mRuby in a significant portion of ipRGCs, although some ipRGCs lack mRuby staining, presumably due to lack of infectivity (arrows show mRuby-negative ipRGCs). Scale bars = 50 μm. (<b>F</b>) Quantification of fraction of ipRGCs (melanopsin-antibody) which are mRuby-positive. Quantification shown for three mice (A single 20x field was quantified for each mouse). Approximately 90% of melanopsin-positive cells express mRuby. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.020">http://dx.doi.org/10.7554/eLife.15392.020</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="16" data-label-slug="figure-4figure-supplement-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/116450e696b4/elife-15392-fig4-figsupp3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-16" role="button" data-image-width="742" data-image-height="648" data-image-alt="Figure 4—figure supplement 3." data-pmc-id="PMC5079752" data-figure-id="fig4s3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-16" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/494b2b54fffc/elife-15392-fig4-figsupp3.gif" alt="Figure 4—figure supplement 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="742"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="648"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4—figure supplement 3.. Rods, but not… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4—figure supplement 3.. Rods, but not cones, contribute to sustained PLR sensitivity. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A… </b> </p></div> </div> <figcaption id="figure-caption-16" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4—figure supplement 3.. Rods, but not cones, contribute to sustained PLR sensitivity. </strong> <div class="figure-caption-contents">(<b>A</b>) PLR intensity-response curves of wildtype and mice with only melanopsin phototransduction intact (‘melanopsin-only’: <i>Gnat1<sup>-/-</sup>; Gnat2<sup>-/-</sup> n</i> = 4, <i>Gnat1<sup>-/-</sup>; Cnga3<sup>-/-</sup> n</i> = 4, Rod-DTA; Cone-DTA <i>n</i> = 8) (mean ± SD). (<b>B</b>) Sustained PLR intensity-response curves of wildtype (<i>n</i> = 11) and rod mutant mice (<i>Gnat1<sup>-/-</sup> n</i> = 5, Rod-DTA <i>n</i> = 5) (mean ± SD). (<b>C</b>) Sustained PLR intensity-responses of wildtype and cone mutant mice (‘cone mutants’: <i>Gnat2<sup>-/-</sup> (n</i> = 4), <i>Cnga3<sup>-/-</sup></i>(n = 4), Cone-DTA (<i>n</i> = 4)). (<b>D</b>) Sustained EC<sub>50</sub> for wildtype and cone mutant, rod mutant and melanopsin-only mice (line = mean). All rod mutant and melanopsin-only mouse lines display significnt loss of sensitivity (p<0.0001). Two of three cone mutant mouse lines were not significantly different from wildtype (<i>Cnga3<sup>-/-</sup></i>p=0.57, Cone-DTA p>0.999), though <i>Gnat2<sup>-/-</sup></i> displayed a 0.69 log-unit decrease in sustained PLR EC<sub>50</sub> (<i>Gnat2<sup>-/-</sup>P</i> = 0.004). Additionally, all rod mutant lines were similar to their corresponding melanopsin-only line (p>0.706) while all cone mutant lines were significantly more sensitive than their corresponding melanopsin-only line (p≤0.0001). Statistical significance determined via one-way ANOVA with Sidak’s post-test. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.021">http://dx.doi.org/10.7554/eLife.15392.021</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="17" data-label-slug="figure-4figure-supplement-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/33fc019fd777/elife-15392-fig4-figsupp4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-17" role="button" data-image-width="758" data-image-height="795" data-image-alt="Figure 4—figure supplement 4." data-pmc-id="PMC5079752" data-figure-id="fig4s4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-17" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/a9803775a6f8/elife-15392-fig4-figsupp4.gif" alt="Figure 4—figure supplement 4." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="758"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="795"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4—figure supplement 4.. Rods drive the… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4—figure supplement 4.. Rods drive the residual sustained pupil constriction observed in the absence… </p> </strong> </div> <figcaption id="figure-caption-17" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4—figure supplement 4.. Rods drive the residual sustained pupil constriction observed in the absence of melanopsin. </strong> <div class="figure-caption-contents">(<b>A</b>) Sustained PLR dose-responses for wildtype (<i>n</i> = 11), melanopsin knockout (<i>Opn4<sup>-/-</sup>, n</i> = 12) and mice with only rod phototransduction intact (‘rod-only’: <i>Cnga3<sup>-/-</sup>; Opn4<sup>-/-</sup> n</i> = 4) (mean ± SD). (right) Scatter plot of 1000 lux sustained PLR. Melanopsin knockout and ‘rod-only’ mice not statistically different by one-way ANOVA with Sidak’s post-test (p=0.983) (line indicates mean). (<b>B</b>) Sustained PLR intensity-responses for wildtype (<i>n</i> = 11), melanopsin knockout (<i>Opn4<sup>-/-</sup> n</i> = 12) and mice with only cone phototransduction intact (‘cone-only’: <i>Opn4<sup>-/-</sup>; Gnat1<sup>-/-</sup>, n</i> = 6, mean ± SD). (right) Scatter plot of 1000 lux sustained PLR. Melanopsin knockout and ‘cone-only’ mice are statistically different by one-way ANOVA followed by Sidak’s post-test. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.022">http://dx.doi.org/10.7554/eLife.15392.022</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="18" data-label-slug="figure-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/6997414eb025/elife-15392-fig5.jpg" itemprop="contentUrl" aria-describedby="figure-caption-18" role="button" data-image-width="715" data-image-height="770" data-image-alt="Figure 5." data-pmc-id="PMC5079752" data-figure-id="fig5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-18" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/a60a4af1aa1b/elife-15392-fig5.gif" alt="Figure 5." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="715"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="770"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5.. PACAP is essential for the… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5.. PACAP is essential for the sustained PLR. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> ) Diagram of ipRGC… </p></div> </div> <figcaption id="figure-caption-18" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5.. PACAP is essential for the sustained PLR. </strong> <div class="figure-caption-contents">(<b>A</b>) Diagram of ipRGC behavioral circuit. (<b>B</b>) PLR intensity-response curves of sustained constriction in mice lacking glutamatergic or PACAPergic neurotransmission (WT <i>n</i> = 6, ipRGC glu. KO <i>n</i> = 4, ipRGC PACAP KO <i>n</i> = 6)(mean ± SD). Both mutants display deficits at 10, 100, and 1000 lux as compared to wildtype (wildtype v. ipRGC Glu. KO: 10 and 100 lux p<0.0001, 1000 lux p=0.0004 by two-way ANOVA with Sidak’s post-test)(wildtype v. ipRGC PACAP KO: 10, 100, and 1000 lux p<0.0001 by two-way ANOVA with Sidak’s post-test). (<b>C</b>) Representative pupil images of sustained constriction at 1000 lux. (<b>D</b>) Comparison of transient and sustained constriction under high light (1000 lux). ipRGC glu. KO mice (red) show an increase in pupil constriction with time whereas ipRGC PACAP KOs (blue) display a significant loss of constriction over time (ipRGC glu. KO transient v. sustained p<0.0001, ipRGC PACAP KO transient v. sustained p=0.0003, wildtype transient v. sustained p=0.9921 by one-way ANOVA with Sidak’s post-test). (<b>E</b>) Pupil constriction of neurotransmitter mutant mice after sustained 5000 lux light. Data from individual mice shown with mean (black bar). Statistical significance determined by one-way ANOVA with Sidak’s post-test. See also Figure 5—figure supplement 1. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.023">http://dx.doi.org/10.7554/eLife.15392.023</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="19" data-label-slug="figure-5figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/b4235abec872/elife-15392-fig5-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-19" role="button" data-image-width="704" data-image-height="873" data-image-alt="Figure 5—figure supplement 1." data-pmc-id="PMC5079752" data-figure-id="fig5s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-19" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/519b37c2d7eb/elife-15392-fig5-figsupp1.gif" alt="Figure 5—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="704"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="873"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5—figure supplement 1.. PACAP KO mice… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5—figure supplement 1.. PACAP KO mice display similar PLR phenotypes to ipRGC-specific PACAP KO… </p> </strong> </div> <figcaption id="figure-caption-19" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5—figure supplement 1.. PACAP KO mice display similar PLR phenotypes to ipRGC-specific PACAP KO mice. </strong> <div class="figure-caption-contents">(<b>A</b>) Intensity-response curves of the transient PLR (30s light) in each of the neurotransmitter mutant mouse lines (Wildtype <i>n</i> = 6)(ipRGC glu. KO: <i>Opn4<sup>Cre/+</sup> ; Slc17a6<sup>fl/fl</sup> n</i> = 4)(PACAP KO: <i>Adcyap1<sup>-/-</sup> n</i> = 4)(mean ± SD). (<b>B</b>) Sensitivity (EC<sub>50</sub>) in each of the mutant lines. Statistical significance determined by one-way ANOVA with Sidak’s post-test. (<b>C</b>) Comparison of transient and sustained (60 min. light) constriction under high light (1000 lux). ipRGC glu. KO mice (red) show an increase in pupil constriction with time whereas PACAP KOs (blue) display a significant loss of constriction over time. (<b>D</b>) PLR intensity-response curves of sustained constriction in mice lacking glutamatergic or PACAPergic neurotransmission (WT <i>n</i> = 6, ipRGC glu. KO <i>n</i> = 4, PACAP KO <i>n</i> = 4)(mean ± SD). Both mutants display similar deficits until 1000 lux where PACAP KO mice show a further deficit (PACAP KO v. ipRGC Glu. KO: p=0.0019 by one-way ANOVA with Sidak’s post-test). (right) Representative pupil images of sustained constriction at 1000 lux. (<b>E</b>) Pupil constriction of neurotransmitter mutant mice after sustained 5000 lux light. Data from individual mice shown with mean (black bar). Statistical significance determined by one-way ANOVA with Sidak’s post-test. (<b>F</b>) 60-min. time course of pupil constriction under constant light (1000 lux). Data fit with a one-phase association curve (WT <i>n</i> = 5, PACAP KO <i>n</i> = 4). (mean ± SD). <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.024">http://dx.doi.org/10.7554/eLife.15392.024</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="20" data-label-slug="figure-6"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/91cbae895bdd/elife-15392-fig6.jpg" itemprop="contentUrl" aria-describedby="figure-caption-20" role="button" data-image-width="797" data-image-height="955" data-image-alt="Figure 6." data-pmc-id="PMC5079752" data-figure-id="fig6"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-20" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/09c6398a80d0/elife-15392-fig6.gif" alt="Figure 6." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="797"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="955"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 6.. Model of ipRGC circuit transitions. </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 6.. Model of ipRGC circuit transitions. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> and <b> B </b> ) Heat maps of… </p></div> </div> <figcaption id="figure-caption-20" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 6.. Model of ipRGC circuit transitions. </strong> <div class="figure-caption-contents">(<b>A</b> and <b>B</b>) Heat maps of (<b>A</b>) transient and (<b>B</b>) sustained PLR as duration and intensity vary. Night, dawn/dusk, and daytime light intensities indicated by ticks on right side of plot. (top) Heat maps of individual photoreceptor contributions (grayscale). Black represents no contribution and degree of white represents increasing contribution. Each photoreceptor contribution heat map is a combination of necessity (individual photoreceptor transduction knockouts) and sufficiency (‘photoreceptor-only’) heat maps (for example: Input Contribution<sub>rod</sub> = Max(Necessity<sub>rod</sub>, Sufficiency<sub>rod</sub>)). (middle) Rod (red), cone (green), melanopsin (blue) contributions are combined into a single heat map. (bottom) Color combination guide for reference when viewing heat map. (<b>C</b> and <b>D</b>) Same as above for neurotransmitter contributions to transient (<b>C</b>) and sustained (<b>D</b>) ipRGC signaling. Glutamatergic contribution is in green and PACAPergic contribution is in blue. See the Materials and methods section for details on heat map generation. Note that the axes are the same for the individual and combined heatmaps. See also Figure 6—figure supplement 1. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.026">http://dx.doi.org/10.7554/eLife.15392.026</ext-link></div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="21" data-label-slug="figure-6figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/cf4de9904399/elife-15392-fig6-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-21" role="button" data-image-width="740" data-image-height="289" data-image-alt="Figure 6—figure supplement 1." data-pmc-id="PMC5079752" data-figure-id="fig6s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-21" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e8c/5079752/431a9416e300/elife-15392-fig6-figsupp1.gif" alt="Figure 6—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="740"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="289"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 6—figure supplement 1.. Necessity/Sufficiency heat maps… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 6—figure supplement 1.. Necessity/Sufficiency heat maps for photoreceptor input to pupil constriction. </p> </strong> <div class="figure-caption-contents"><p> Heat maps… </p></div> </div> <figcaption id="figure-caption-21" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 6—figure supplement 1.. Necessity/Sufficiency heat maps for photoreceptor input to pupil constriction. </strong> <div class="figure-caption-contents">Heat maps of necessity and sufficiency of each input (top: rods, cones, melanopsin) as stimulus duration and intensity vary. The necessity/sufficiency heat maps for a particular component were subsequently used to generate a photoreceptor contribution heat map (See Figure 6). Black indicates no necessity/sufficiency and white indicates full necessity/sufficiency. <b>DOI:</b> <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.7554/eLife.15392.027">http://dx.doi.org/10.7554/eLife.15392.027</ext-link></div> </figcaption> </figure> </div> <div class="see-all actions-bar"> <button class="show-more" aria-controls="slides-container" data-ga-category="figure" data-ga-action="show_all"> All figures (22) </button> </div>  <div class="pswp figures-dialog" id="figures-dialog" tabindex="-1" role="dialog" aria-hidden="true" data-image-gallery-uid="article-figures" aria-label="Figures Dialog">  <div class="pswp__bg"></div>  <div class="pswp__scroll-wrap">  <div class="pswp__container"> <div class="pswp__item"></div> <div class="pswp__item"></div> <div class="pswp__item"></div> </div>  <div class="pswp__ui pswp__ui--hidden"> <div class="pswp__top-bar">  <div class="pswp__counter"></div> <button class="pswp__button pswp__button--close" title="Close (Esc)"></button> <button class="pswp__button pswp__button--share" title="Share"></button> <button class="pswp__button pswp__button--fs" title="Toggle fullscreen"></button> <button class="pswp__button pswp__button--zoom" title="Zoom in/out"></button>   <div class="pswp__preloader"> <div class="pswp__preloader__icn"> <div class="pswp__preloader__cut"> <div class="pswp__preloader__donut"></div> </div> </div> </div> </div> <div class="pswp__share-modal pswp__share-modal--hidden pswp__single-tap"> <div class="pswp__share-tooltip"></div> </div> <button class="pswp__button pswp__button--arrow--left" title="Previous (arrow left)"> </button> <button class="pswp__button pswp__button--arrow--right" title="Next (arrow right)"> </button> <div class="pswp__caption"> <div class="pswp__caption__center"></div> </div> </div> </div> </div> <div class="figure-dialog-caption"> <div class="figure-caption-link-container"> <a class="figure-caption-link" href="#">See this image and copyright information in PMC</a> </div> <div class="figure-caption-center" data-expand-title="click to show full caption" data-collapse-title="click to hide full caption"> </div> <button class="figure-caption-toggle-btn" aria-label="show full caption" data-expand-text="show full caption" data-collapse-text="hide full caption">  </button> </div> </div> <div class="similar-articles" id="similar"> <h2 class="title"> Similar articles </h2> <ul class="articles-list" id="similar-articles-list"> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/25497360/" ref="article_id=25497360&linksrc=similar_articles_link&ordinalpos=1" data-ga-category="similar_article" data-ga-action="25497360" data-ga-label=""> Temporal characteristics of melanopsin inputs to the human pupil light reflex. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Joyce DS, Feigl B, Cao D, Zele AJ.</span> <span class="docsum-authors short-authors">Joyce DS, et al.</span> <span class="docsum-journal-citation full-journal-citation">Vision Res. 2015 Feb;107:58-66. doi: 10.1016/j.visres.2014.12.001. 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href="https://www.ncbi.nlm.nih.gov/mesh?term=Research+Support%2C+N.I.H.%2C+Extramural" data-ga-category="search_mesh" data-ga-action="pub_type_link" data-ga-label="Research Support, N.I.H., Extramural"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Research Support, N.I.H., Extramural"[pt]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Research Support, N.I.H., Extramural"[pt]" href="#"> Add to Search </a></li></ul></div></div></div></li></ul> </div> <div id="mesh-terms" class="mesh-terms keywords-section"> <h2 class="title"> MeSH terms </h2> <ul class="keywords-list"><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Glutamic Acid / metabolism" tabindex="0" aria-controls="keyword-actions-mesh-terms-0" aria-expanded="false" data-pinger-ignore> Glutamic Acid / metabolism </button><div id="keyword-actions-mesh-terms-0" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Glutamic Acid / metabolism"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Glutamic+Acid%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Glutamic+Acid%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Glutamic Acid/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Glutamic Acid / metabolism"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Glutamic+Acid" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Glutamic Acid / metabolism"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Glutamic Acid/metabolism"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Glutamic Acid/metabolism"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Light*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-1" aria-expanded="false" data-pinger-ignore> Light* </button><div id="keyword-actions-mesh-terms-major-1" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Light*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Light%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Light%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Light"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Light*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Light" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Light*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Light"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Light"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Neurotransmitter Agents / metabolism" tabindex="0" aria-controls="keyword-actions-mesh-terms-2" aria-expanded="false" data-pinger-ignore> Neurotransmitter Agents / metabolism </button><div id="keyword-actions-mesh-terms-2" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Neurotransmitter Agents / metabolism"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Neurotransmitter+Agents%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Neurotransmitter+Agents%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Neurotransmitter Agents/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Neurotransmitter Agents / metabolism"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Neurotransmitter+Agents" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Neurotransmitter Agents / metabolism"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Neurotransmitter Agents/metabolism"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Neurotransmitter Agents/metabolism"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Photoreceptor Cells / physiology*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-3" aria-expanded="false" data-pinger-ignore> Photoreceptor Cells / physiology* </button><div id="keyword-actions-mesh-terms-major-3" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Photoreceptor Cells / physiology*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Photoreceptor+Cells%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Photoreceptor+Cells%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Photoreceptor Cells/physiology"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Photoreceptor Cells / physiology*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Photoreceptor+Cells" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Photoreceptor Cells / physiology*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Photoreceptor Cells/physiology"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Photoreceptor Cells/physiology"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Photoreceptor Cells / radiation effects*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-4" aria-expanded="false" data-pinger-ignore> Photoreceptor Cells / radiation effects* </button><div id="keyword-actions-mesh-terms-major-4" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Photoreceptor Cells / radiation effects*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Photoreceptor+Cells%2Fradiation+effects%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Photoreceptor+Cells%2Fradiation+effects%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Photoreceptor Cells/radiation effects"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Photoreceptor Cells / radiation effects*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Photoreceptor+Cells" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Photoreceptor Cells / radiation effects*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Photoreceptor Cells/radiation effects"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Photoreceptor Cells/radiation effects"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism" tabindex="0" aria-controls="keyword-actions-mesh-terms-5" aria-expanded="false" data-pinger-ignore> Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism </button><div id="keyword-actions-mesh-terms-5" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Pituitary+Adenylate+Cyclase-Activating+Polypeptide%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Pituitary+Adenylate+Cyclase-Activating+Polypeptide%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Pituitary+Adenylate+Cyclase-Activating+Polypeptide" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Pupil / physiology*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-6" aria-expanded="false" data-pinger-ignore> Pupil / physiology* </button><div id="keyword-actions-mesh-terms-major-6" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Pupil / physiology*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Pupil%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Pupil%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Pupil/physiology"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Pupil / physiology*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Pupil" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Pupil / physiology*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Pupil/physiology"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Pupil/physiology"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Retinal Ganglion Cells / physiology*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-7" aria-expanded="false" data-pinger-ignore> Retinal Ganglion Cells / physiology* </button><div id="keyword-actions-mesh-terms-major-7" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Retinal Ganglion Cells / physiology*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Retinal+Ganglion+Cells%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Retinal+Ganglion+Cells%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Retinal Ganglion Cells/physiology"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Retinal Ganglion Cells / physiology*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Retinal+Ganglion+Cells" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Retinal Ganglion Cells / physiology*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Retinal Ganglion Cells/physiology"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Retinal Ganglion Cells/physiology"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Retinal Ganglion Cells / radiation effects*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-8" aria-expanded="false" data-pinger-ignore> Retinal Ganglion Cells / radiation effects* </button><div id="keyword-actions-mesh-terms-major-8" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Retinal Ganglion Cells / radiation effects*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Retinal+Ganglion+Cells%2Fradiation+effects%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Retinal+Ganglion+Cells%2Fradiation+effects%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Retinal Ganglion Cells/radiation effects"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Retinal Ganglion Cells / radiation effects*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Retinal+Ganglion+Cells" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Retinal Ganglion Cells / radiation effects*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Retinal Ganglion Cells/radiation effects"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Retinal Ganglion Cells/radiation effects"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li></ul> </div> <div id="substances" class="substances keywords-section"> <h2 class="title"> Substances </h2> <ul class="keywords-list"><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Neurotransmitter Agents" tabindex="0" aria-controls="keyword-actions-substances-0" aria-expanded="false" data-pinger-ignore> Neurotransmitter Agents </button><div id="keyword-actions-substances-0" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Neurotransmitter Agents"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Neurotransmitter+Agents%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22Neurotransmitter+Agents%22%5Bnm%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&keyword="Neurotransmitter Agents"[nm]" data-ga-category="search" data-ga-action="substance" data-ga-label="Neurotransmitter Agents"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=%22Neurotransmitter+Agents%22" data-ga-category="search_mesh" data-ga-action="substance_link" data-ga-label="Neurotransmitter Agents"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Neurotransmitter Agents"[nm]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Neurotransmitter Agents"[nm]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Pituitary Adenylate Cyclase-Activating Polypeptide" tabindex="0" aria-controls="keyword-actions-substances-1" aria-expanded="false" data-pinger-ignore> Pituitary Adenylate Cyclase-Activating Polypeptide </button><div id="keyword-actions-substances-1" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Pituitary Adenylate Cyclase-Activating Polypeptide"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Pituitary+Adenylate+Cyclase-Activating+Polypeptide%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22Pituitary+Adenylate+Cyclase-Activating+Polypeptide%22%5Bnm%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&keyword="Pituitary Adenylate Cyclase-Activating Polypeptide"[nm]" data-ga-category="search" data-ga-action="substance" data-ga-label="Pituitary Adenylate Cyclase-Activating Polypeptide"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=%22Pituitary+Adenylate+Cyclase-Activating+Polypeptide%22" data-ga-category="search_mesh" data-ga-action="substance_link" data-ga-label="Pituitary Adenylate Cyclase-Activating Polypeptide"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Pituitary Adenylate Cyclase-Activating Polypeptide"[nm]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Pituitary Adenylate Cyclase-Activating Polypeptide"[nm]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Glutamic Acid" tabindex="0" aria-controls="keyword-actions-substances-2" aria-expanded="false" data-pinger-ignore> Glutamic Acid </button><div id="keyword-actions-substances-2" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Glutamic Acid"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Glutamic+Acid%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22Glutamic+Acid%22%5Bnm%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&keyword="Glutamic Acid"[nm]" data-ga-category="search" data-ga-action="substance" data-ga-label="Glutamic Acid"> Search in 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A visual circuit uses complementary mechanisms to support transient and sustained pupil constriction - PubMed