qOMR - Visual Acuity and Contrast Sensitivity

Hardware features

• Calibrated 4 screen environment for presenting the virtual stimulation cylinder
• Elevated central platform for placing the unrestrained animal
• Top and bottom mirrors to create the illusion of infinite depth for optimized stimulation
• IR-camera for automated head tracking independent of coat color
• Adjustable IR-illumination
• Anti-reflective (and protective) shields for the screens
• Filter set for scotopic measurements

Software features

• Video-based real-time tracking of head movement is used for both:
  1. Continuous automated position-adjustment of the virtual cylinder to the animal´s head position.
  2. Evaluation of head movement synchronous to the stimulation for a quantitative measure of the optomotor response. This analysis is fully automated.
• Batch run option with multiple stimulation protocols.
• Example for real-time tracking:

Applications

General application areas:

• Characterization of vision
• Screening for vision defects
• Tracking of disease progression and recovery
• Phenotyping of new breed lines
• Quantification of treatment response

Characterisation or preclinical testing in relevant disease models, for example:

• Glaucoma
• Retinal degeneration
• Diabetes
• Aging
• Restoration of vision

Investigation of various aspects of vision in mice and other rodents:

• Visual acuity
• Contrast sensitivity
• Spectral sensitivity
• Temporal sensitivity

Advantages

• Simple, robust, and non-invasive test to examine vision in rodents
• Fully automated measurement and analysis: no manual positioning of the stimulus, no specially trained experimenter required, time and cost effective, and unbiased
• As a reflex, optomotor response measurements do not require animal training
• Freely behaving animals, no surgery, no fixation
• Flexible, user-friendly experimental design and data handling.

Publications

Studying Optic Neuropathies

Gan et al. (1) demonstrate the involvement of the Slit-Robo signaling pathway in retinal ganglion cell degeneration and its neuroprotective potential. In a chronic optic neuropathy model, the reduction of SRGAP2 (Slit-Robo GTPase-activating protein 2) increased retinal ganglion cell survival. The qOMR test revealed reduced visual performance in wildtype mice of the optic nerve crush model, while retinal function was partially restored in Srgap2+/- mice.

Studying Eye Development

Cole et al. (2) characterized the defects in retinal structure and vision during postnatal development in Pax6 small-eye mice. The homeobox gene PAX6 plays a pivotal role in ocular development, and this study demonstrates that its haploinsufficiency leads to a steady, age-dependent decline in visual acuity. Impressively, longitudinal qOMR measurements from day 15 up to day 120 beautifully described this visual decline.

Studying Stem Cell-Based Therapeutic Interventions in Rats

The group around Akon Higuchi (3) from Wenzhou Medical University investigated the efficacy of various types of stem cells in treating retinal degeneration in a rat model. Each stem cell line administered exhibited a beneficial effect on qOMR testing, consistent with the results of electroretinography evaluation. However, the treatment effect proved to be transient, with human induced pluripotent stem cell-derived retinal pigment epithelium (hiPSC-derived RPC) cells demonstrating the most promising therapeutic potential.

Studying Genome Editing and Gene Therapeutic Interventions

The homology-independent targeted integration (HITI) method represents a promising gene-editing technique for therapeutically correcting mutations. In their study, Onishi et al. (4) introduced an efficient workflow for this technique, targeting the rhodopsin gene in a mouse model of retinitis pigmentosa. They successfully suppressed the degeneration of photoreceptor cells. Interestingly, the therapeutic effect was only evident in the left eye, as only this eye had received the active HITI treatment.

Liu et al. (5), in their report published in JBC, explored an alternative tool for in vivo genome editing, namely adenine base editors (ABE). Using this technique, they targeted splice sites of Peroxidasin in mouse embryos. The resulting homozygous offspring recapitulated the corresponding human disease phenotype, as evidenced by the abolished visual performance of these mice in qOMR testing.

(1) Gan, Yi-Jing, Ying Cao, Zu-Hui Zhang, Jing Zhang, Gang Chen, Ling-Qin Dong, Tong Li, Mei-Xiao Shen, Jia Qu, und Zai-Long Chi. “Srgap2 Suppression Ameliorates Retinal Ganglion Cell Degeneration in Mice”. Neural Regeneration Research 18, Nr. 10 (2023): 2307. https://doi.org/10.4103/1673-5374.369122.

(2) Cole, James D., John A. McDaniel, Joelle Nilak, Ashley Ban, Carlos Rodriguez, Zuhaad Hameed, Marta Grannonico, u. a. “Characterization of Neural Damage and Neuroinflammation in Pax6 Small-Eye Mice”. Experimental Eye Research 238 (Januar 2024): 109723. https://doi.org/10.1016/j.exer.2023.109723.

(3) Liu, Qian, Jun Liu, Minmei Guo, Tzu-Cheng Sung, Ting Wang, Tao Yu, Zeyu Tian, Guoping Fan, Wencan Wu, und Akon Higuchi. “Comparison of Retinal Degeneration Treatment with Four Types of Different Mesenchymal Stem Cells, Human Induced Pluripotent Stem Cells and RPE Cells in a Rat Retinal Degeneration Model”. Journal of Translational Medicine 21, Nr. 1 (14. Dezember 2023): 910. https://doi.org/10.1186/s12967-023-04785-1.

(4) Onishi, Akishi, Yuji Tsunekawa, Michiko Mandai, Aiko Ishimaru, Yoko Ohigashi, Junki Sho, Kazushi Yasuda, u. a. “Efficient Workflow for Validating Homology-Independent Targeted Integration-Mediated Gene Insertion in Rod Photoreceptor Cells to Treat Dominant-Negative Mutations Causing Retinitis Pigmentosa”, 9. November 2023. https://doi.org/10.1101/2023.11.08.566127.

(5) Liu, Yuanyuan, Qing Li, Tong Yan, Haoran Chen, Jiahua Wang, Yingyi Wang, Yeqin Yang, u. a. “Adenine Base Editor–Mediated Splicing Remodeling Activates Noncanonical Splice Sites”. Journal of Biological Chemistry 299, Nr. 12 (Dezember 2023): 105442. https://doi.org/10.1016/j.jbc.2023.105442.

***

Publications by year:

Kretschmer V, Schneider S, Matthiessen PA, Reichert D, Hotaling N, Glasßer G, Lieberwirth I, Bharti K, De Cegli R, Conte I, Nandrot EF, May-Simera HL. Deletion of IFT20 exclusively in the RPE ablates primary cilia and leads to retinal degeneration. PLoS Biol. 2023 Dec 4;21(12):e3002402. doi: 10.1371/journal.pbio.3002402. Epub ahead of print. PMID: 38048369.

Liu Y, Li Q, Yan T, Chen H, Wang J, Wang Y, Yang Y, Xiang L, Chi Z, Ren K, Lin B, Lin G, Li J, Liu Y, Gu F. Adenine base editor-mediated splicing remodeling activates non-canonical splice sites. J Biol Chem. 2023 Nov 8:105442. doi: 10.1016/j.jbc.2023.105442. Epub ahead of print. PMID: 37949222.

Huh, C.Y.L., Leinonen, H., Nakayama, T., Tomasello, J.R., … & Gandhi, S.P. (2022). Retinoid therapy restores eye-specific cortical responses in adult mice with retinal degeneration. Current Biology.

Suh, S., Choi, E. H., Leinonen, H., Foik, A. T., Newby, G. A., Yeh, W. H., … & Palczewski, K. (2020). Restoration of visual function in adult mice with an inherited retinal disease via adenine base editing. Nature biomedical engineering, 1-10.

Lees, R. N., Akbar, A. F., & Badea, T. C. (2020). Retinal Ganglion Cell defects cause decision shifts in visually evoked defense responses. Journal of Neurophysiology 124:5,1530-1549

Chan, K., Hoon, M., Pattnaik, B. R., Ver Hoeve, J. N., Wahlgren, B., Gloe, S., … & Jansen, E. (2020). Induced Retinal Functional Alterations and Second-Order Neuron Plasticity in C57BL/6J Mice. Investigative Ophthalmology & Visual Science, 61(2), 17-17.

Thomson, B. R., Grannonico, M., Liu, F., Liu, M., Mendapara, P., Xu, Y., … & Quaggin, S. E. (2020). Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma. Translational Vision Science & Technology, 9(4), 16-16.

Kretschmer, V., Patnaik, S. R., Kretschmer, F., Chawda, M. M., Hernandez-Hernandez, V., & May-Simera, H. L. (2019). Progressive characterization of visual phenotype in Bardet-Biedl syndrome mutant mice. Investigative ophthalmology & visual science, 60(4), 1132-1143.

Wang, X., Zhao, L., Zhang, J., Fariss, R. N., Ma, W., Kretschmer, F., … & Gan, W. B. (2016). Requirement for microglia for the maintenance of synaptic function and integrity in the mature retina. Journal of Neuroscience, 36(9), 2827-2842.

Kretschmer, F., Tariq, M., Chatila, W., Wu, B., & Badea, T. C. (2017). Comparison of optomotor and optokinetic reflexes in mice. Journal of neurophysiology, 118(1), 300-316.

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