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Arya Zarrinbakhsh,1,2 Neeru Gupta,1– 6 Jessica Sinha,1 Xun Zhou,1,3 Shuo Chen,7 Haaris Mahmood Khan,4 Eduardo V Navajas,4 Mirza Faisal Beg,7 You Liang,8 Yeni Yucel1– 4,9– 11 1Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, Ontario, Canada; 2Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; 3Department of Ophthalmology and Vision Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; 4Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; 5Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; 6School of Population and Public Health, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; 7School of Engineering Science, Faculty of Applied Sciences, Simon Fraser University, Vancouver, British Columbia, Canada; 8Department of Mathematics, Faculty of Science, Toronto Metropolitan University, Toronto, Ontario, Canada; 9Department of Physics, Faculty of Science, Toronto Metropolitan University, Toronto, Ontario, Canada; 10Faculty of Engineering and Architectural Science, Toronto Metropolitan University, Toronto, Ontario, Canada; 11Institute of Biomedical Engineering, Science and Technology (iBEST), St. Michael’s Hospital, Toronto Metropolitan University, Toronto, Ontario, CanadaCorrespondence: Yeni Yucel, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, 30 Bond Street, Toronto, Ontario, M5B1W8, Canada, Tel +1 416 864 6060 extension 77594, Fax +1 416 864 5648, Email yeni.yucel@unityhealth.toPurpose: Microgravity-induced headward fluid shifts are one of the mechanisms implicated in spaceflight-associated eye conditions, including intraocular pressure (IOP) and retinal nerve fiber layer (RNFL) thickness changes. In this longitudinal study, we investigated IOP and RNFL thickness changes over time in a mouse model of microgravity-induced headward fluid shifts.Methods: The study involved 20 adult male B6(Cg)-Tyrc− 2J/J mice, randomly assigned to two groups: the hindlimb unloading (HU) mice, unloaded for 21 days followed by 14 days of release, and control mice kept under the same conditions except HU for 35 days. IOP and RNFL thickness in peripapillary and peripheral rings of right and left eyes were measured before and once a week after HU. Our analysis utilized mixed linear models to compare the estimated marginal means of IOP and RNFL thickness on each day with baseline values for each eye. Post hoc splined mixed linear models with a knot at day 14 were employed to assess the rate of IOP change in each segment.Results: IOP was significantly elevated in both eyes of the HU mice on day 14 compared to baseline. The splined analysis revealed a bilateral positive rate of IOP change up to day 14, followed by a negative rate of change thereafter. In contrast, control mice displayed no significant differences in IOP at any timepoint. RNFL thicknesses of right eye peripapillary and peripheral rings were reduced after 1 week and 2 weeks, respectively. In contrast, left eye RNFL thickness measurements did not show any significant change compared to baseline.Conclusion: The HU mouse model displays a distinct ocular phenotype that may be useful for understanding IOP and RNFL changes in microgravity and their relevance to Spaceflight-Associated Neuro-ocular Syndrome.Keywords: hindlimb unloading, spaceflight-associated neuro-ocular syndrome, intraocular pressure, optical coherence tomography, retinal nerve fiber layer, mouse