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Amplifying and ameliorating light avoidance in mice with photoreceptor targeting and calcitonin gene‐related peptide sensitization.

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Title:	Amplifying and ameliorating light avoidance in mice with photoreceptor targeting and calcitonin gene‐related peptide sensitization.
Authors:	Kaiser, Eric A. (AUTHOR), Cavanah, Audrey (AUTHOR), Aguirre, Geoffrey K. (AUTHOR), Jensen, Frances E. (AUTHOR)
Source:	Headache: The Journal of Head & Face Pain. Jan2026, Vol. 66 Issue 1, p132-143. 12p.
Subjects:	Biological models, Light, Vision disorders, Research funding, Data analysis, Two-way analysis of variance, Visual pigments, Avoidance conditioning, Mann Whitney U Test, Mice, Neuropeptides, Animal experimentation, Statistics, Analysis of variance, Photoreceptors, Data analysis software, Retinal ganglion cells
Geographic Terms:	Pennsylvania
Abstract:	Objective: 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. Background: 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‐related peptide (CGRP) amplifies the avoidance response to ipRGC stimulation. Methods: Light avoidance behavior was measured in a two‐zone chamber illuminated by narrow‐band light‐emitting diodes (LEDs) targeting photopic opsins: 365 nm (ultraviolet [UV]; rodent S‐cone), 460 nm (blue; melanopsin), and 630 nm (red; human L‐cone). In a non‐targeted assay, we assessed the degree of light avoidance in wild‐type (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‐cone cone knock‐in (HLCKI) or (2) adult‐onset ablation of M1 ipRGCs (Opn4aDTA). Mice were studied without intervention or following chronic intermittent administration of CGRP with either peripheral CGRP or vehicle (Veh) administration every‐other‐day for 9 days. A primary measure (mean +/− SEM) was the asymptote value (AV) of chamber preference. Results: WT mice showed greater light avoidance with increasing light contrast. HLCKI mice avoided zones with high melanopsin (1.00: 0.52 ± 0.08; n = 18) and L‐cone (1.00: 0.30 ± 0.11; n = 15) stimulation but showed a preference for the zone with higher S‐cone (1.00: −0.35 ± 0.06; n = 16) stimulation. These effects were contrast‐dependent. The addition of S‐cone stimulation reduced the aversive effect of melanopsin (0.10 ± 0.12; n = 14) or L‐cone (−0.19 ± 0.10; n = 15) contrast. Ablation of ipRGCs in HLCKI x Opn4aDTA mice eliminated both avoidance of melanopsin stimulation and the preference for S‐cone stimulation, as compared to controls. Nine days of chronic intermittent administration of CGRP led to significantly increased avoidance of melanopsin stimulation (0.58 ± 0.08, n = 21) as compared to Veh administration (0.26 ± 0.09, n = 22) (F (1, 41) = 5.70, p = 0.022). Conclusions: 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‐cone inputs and are opposed by extrinsic, inhibitory S‐cone input. Chronic elevation of CGRP levels in migraine may amplify ipRGC signals, leading to photophobia. Plain Language Summary: To better understand light sensitivity, a common symptom associated with migraine, we studied which cells in the eye produce the signals that cause mice to avoid light. We found that mice avoided blue and red light but preferred ultraviolet (UV) light, which is a result of a special cell type (intrinsically photosensitive retinal ganglion cells [ipRGCs]) in the eye that processes these light signals. We also found that mice who were repeatedly exposed to calcitonin gene‐related peptide (CGRP), a key nervous system messenger in migraine, increased their avoidance of blue light, which may model what happens in people with chronic migraine who experience light sensitivity. [ABSTRACT FROM AUTHOR]
	Copyright of Headache: The Journal of Head & Face Pain is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database:	Psychology and Behavioral Sciences Collection

Description
Abstract:	Objective: 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. Background: 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‐related peptide (CGRP) amplifies the avoidance response to ipRGC stimulation. Methods: Light avoidance behavior was measured in a two‐zone chamber illuminated by narrow‐band light‐emitting diodes (LEDs) targeting photopic opsins: 365 nm (ultraviolet [UV]; rodent S‐cone), 460 nm (blue; melanopsin), and 630 nm (red; human L‐cone). In a non‐targeted assay, we assessed the degree of light avoidance in wild‐type (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‐cone cone knock‐in (HLCKI) or (2) adult‐onset ablation of M1 ipRGCs (Opn4aDTA). Mice were studied without intervention or following chronic intermittent administration of CGRP with either peripheral CGRP or vehicle (Veh) administration every‐other‐day for 9 days. A primary measure (mean +/− SEM) was the asymptote value (AV) of chamber preference. Results: WT mice showed greater light avoidance with increasing light contrast. HLCKI mice avoided zones with high melanopsin (1.00: 0.52 ± 0.08; n = 18) and L‐cone (1.00: 0.30 ± 0.11; n = 15) stimulation but showed a preference for the zone with higher S‐cone (1.00: −0.35 ± 0.06; n = 16) stimulation. These effects were contrast‐dependent. The addition of S‐cone stimulation reduced the aversive effect of melanopsin (0.10 ± 0.12; n = 14) or L‐cone (−0.19 ± 0.10; n = 15) contrast. Ablation of ipRGCs in HLCKI x Opn4aDTA mice eliminated both avoidance of melanopsin stimulation and the preference for S‐cone stimulation, as compared to controls. Nine days of chronic intermittent administration of CGRP led to significantly increased avoidance of melanopsin stimulation (0.58 ± 0.08, n = 21) as compared to Veh administration (0.26 ± 0.09, n = 22) (F (1, 41) = 5.70, p = 0.022). Conclusions: 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‐cone inputs and are opposed by extrinsic, inhibitory S‐cone input. Chronic elevation of CGRP levels in migraine may amplify ipRGC signals, leading to photophobia. Plain Language Summary: To better understand light sensitivity, a common symptom associated with migraine, we studied which cells in the eye produce the signals that cause mice to avoid light. We found that mice avoided blue and red light but preferred ultraviolet (UV) light, which is a result of a special cell type (intrinsically photosensitive retinal ganglion cells [ipRGCs]) in the eye that processes these light signals. We also found that mice who were repeatedly exposed to calcitonin gene‐related peptide (CGRP), a key nervous system messenger in migraine, increased their avoidance of blue light, which may model what happens in people with chronic migraine who experience light sensitivity. [ABSTRACT FROM AUTHOR]
ISSN:	00178748
DOI:	10.1111/head.70018