Citation: Semo M, Coffey P, Gias C, Vugler A. Retrograde melanopsin signaling increases with age in retinal degenerate mice lacking rods and the majority of cones. Invest Ophthalmol Vis Sci. PURPOSE. Following on from reports of retrograde retinal signaling in mice, we sought to investigate the influence of age and retinal location on this phenomenon using mice that lack rods and the majority of cones. METHODS. We used functional anatomy for c-fos (Fos) and tyrosine hydroxylase (TH) to measure

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... ight-driven activation of dopamine neurons along a dorsal-ventral transect in C3H/ He wild-type and rodless-coneless rd/rd cl (rdcl) mice aged 3, 5, and >14 months. A parallel series of retinae from 3-month-old mice was also stained for cone opsins and melanopsin. RESULTS . Analysis by confocal microscopy revealed light-driven Fos activation in TH cells residing in the middorsal retina of the youngest rdcl mice. This region was largely devoid of residual cones but contained a large number of intrinsically photosensitive retinal ganglion cells (ipRGCs) and the highest density of melanopsin neurites. With advancing age, there was a paradoxical increase in retrograde signaling from~3% Fos-positive (Fosþ) TH cells at 3 months to~36% in rdcl mice >14 months. This increased activation occurred in more central and peripheral retinal regions. CONCLUSIONS. Our data provide new insights into the anatomy and plasticity of retrograde melanopsin signaling in mice with severe rod/cone dystrophy. The increased retrograde signaling we detect may result from either an increased potency of melanopsin signaling with advancing age and/or postsynaptic modification to dopaminergic neurons.