{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:51:29Z","timestamp":1787014289357,"version":"build-2736575974"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["P30 EY001583"],"award-info":[{"award-number":["P30 EY001583"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K08 NS120595"],"award-info":[{"award-number":["K08 NS120595"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["headachejournal.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Headache"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The aim of this study was to determine the photoreceptor basis of light avoidance in mice and assess the effect of CGRP sensitization on this behavior.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Prior studies have suggested that photophobia is mediated by a subset of retinal ganglion cells (RGCs) that contain melanopsin, making them intrinsically photosensitive (ipRGCs). These cells also receive extrinsic input from cones, which can also mediate light sensitivity. Here, we examined how spectral targeting of melanopsin or specific cone types in mice produces light avoidance and whether sensitizing mice with calcitonin gene\u2010related peptide (CGRP) amplifies the avoidance response to ipRGC stimulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Light avoidance behavior was measured in a two\u2010zone chamber illuminated by narrow\u2010band light\u2010emitting diodes (LEDs) targeting photopic opsins: 365\u2009nm (ultraviolet [UV]; rodent S\u2010cone), 460\u2009nm (blue; melanopsin), and 630\u2009nm (red; human L\u2010cone). In a non\u2010targeted assay, we assessed the degree of light avoidance in wild\u2010type (WT) C57BL\/6J mice to varying contrasts (0.05 to 1.00) of the blue and red LEDs. In a targeted assay, mice were exposed to zones with differing relative contrast levels (0.50, 0.75, or 1.00) for the targeted photoreceptor(s). This was assessed in transgenic mice with: (1) human L\u2010cone cone knock\u2010in (HLCKI) or (2) adult\u2010onset ablation of M1 ipRGCs (Opn4\n                      <jats:sup>aDTA<\/jats:sup>\n                      <jats:italic>).<\/jats:italic>\n                      Mice were studied without intervention or following chronic intermittent administration of CGRP with either peripheral CGRP or vehicle (Veh) administration every\u2010other\u2010day for 9\u2009days. A primary measure (mean +\/\u2212 SEM) was the asymptote value (AV) of chamber preference.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      WT mice showed greater light avoidance with increasing light contrast. HLCKI mice avoided zones with high melanopsin (1.00: 0.52\u2009\u00b1\u20090.08;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200918) and L\u2010cone (1.00: 0.30\u2009\u00b1\u20090.11;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200915) stimulation but showed a preference for the zone with higher S\u2010cone (1.00: \u22120.35\u2009\u00b1\u20090.06;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200916) stimulation. These effects were contrast\u2010dependent. The addition of S\u2010cone stimulation reduced the aversive effect of melanopsin (0.10\u2009\u00b1\u20090.12;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200914) or L\u2010cone (\u22120.19\u2009\u00b1\u20090.10;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200915) contrast. Ablation of ipRGCs in HLCKI x Opn4\n                      <jats:sup>\n                        aDT\n                        <jats:italic>A<\/jats:italic>\n                      <\/jats:sup>\n                      mice eliminated both avoidance of melanopsin stimulation and the preference for S\u2010cone stimulation, as compared to controls. Nine days of chronic intermittent administration of CGRP led to significantly increased avoidance of melanopsin stimulation (0.58\u2009\u00b1\u20090.08,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200921) as compared to Veh administration (0.26\u2009\u00b1\u20090.09,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200922) (\n                      <jats:italic>F<\/jats:italic>\n                      (1, 41) =\u20095.70,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.022).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings support a key role for the ipRGCs in the production of photophobia. This aversive response to light stems from integrated ipRGC signals that combine excitatory intrinsic melanopsin and extrinsic L\u2010cone inputs and are opposed by extrinsic, inhibitory S\u2010cone input. Chronic elevation of CGRP levels in migraine may amplify ipRGC signals, leading to photophobia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.70018","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T11:59:46Z","timestamp":1765799986000},"page":"132-143","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Amplifying and ameliorating light avoidance in mice with photoreceptor targeting and calcitonin gene\u2010related peptide sensitization"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9750-2434","authenticated-orcid":false,"given":"Eric A.","family":"Kaiser","sequence":"first","affiliation":[{"name":"Department of Neurology University of Pennsylvania  Philadelphia Pennsylvania 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