Fernandes Freitas Martins, Mónica Maria; (2024) Vision-dependent avoidance behaviours as a non-invasive assessment of visual function in mice. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The development of therapies for retinal degeneration relies heavily on mouse models. Here, I seek to translate a recently described visual stimulus-induced spontaneous behaviour into use as a low-severity test of vision, to determine retinal (dys)function and treatment effect and to understand the biology underpinning these stereotyped behaviours. Using wild-type (C57BL/6J) mice I first established a standardised framework where the impact of intra- and inter-animal variability and organisation of test sessions was assessed. On each session a mouse was placed in an arena that contained a refuge and stimuli presented, either a moving black disc of constant size (Sweep) or a rapidly expanding black disc (Loom). As expected, mice usually ran to refuge (escape) upon Loom stimulus, or briefly ceased moving (freezing) upon Sweep stimulus. This set of experiments allowed me to establish an optimized protocol and further perform a cross-sectional study of response against strain, age, and sex where behaviour responses were remarkably consistent. The longitudinal study revealed a consistent response profile across ages, with a decrease in escape responses to the loom stimuli in older (1 year) mice, whilst the strain study showed that whilst some strains exhibit reduced exploratory behaviours the type of response was maintained across strains. Next, I sought to explore some of the biology underlying these innate behaviours, by comparing responses both in non-degenerative animals that lack functioning rod or cone photoreceptors and/or melanopsin-sensitive cells and in models of progressive photoreceptor degeneration. My findings revealed an important role of intact rod function in mediating effective avoidance behaviours. This discovery resonates with the observed heightened responses at scotopic light levels in wild-type (C57BL/6J) mice, as well as with evolutionary principles. Further, I sought to examine how vision-dependent avoidance behaviours might be implemented alongside other modes of visual assessment as means of assessing therapeutic rescue. The variability observed in therapeutic rescue, even within individual animals, posed challenges in interpreting the Loom and Sweep data. The consistency of the data reported under this thesis suggest that vision-dependent avoidance behaviours could be a reliable and robust method to assess visual function in mice.

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