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Kylie Chew, Jordan Renna, David McNeill, Shih-Kuo Chen, Haiqing Zhao, David Berson, Samer Hattar; ipRGCs regulate the development of the circadian pacemaker and vision. Invest. Ophthalmol. Vis. Sci. 2013;54(15):402. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Light is required for many physiological processes including image formation as well as synchronization of circadian rhythms to a 24-hour cycle. Intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for adjusting the approximate 24-hour period of the circadian pacemaker to exactly 24 hours. The synchronization of the circadian clock to the solar day (photoentrainment) and image formation utilize distinct central neuronal pathways. This anatomical segregation has led to the notion that postnatal refinement of vision and circadian clock setting require separate processes. Here we show that eliminating ipRGCs during early development affects both the canonical properties of the circadian pacemaker and vision.
We expressed diphtheria toxin A subunit under the melanopsin promoter to ablate ipRGCs in early postnatal development.
Opn4DTA/DTA mice exhibit a circadian period that is significantly longer than either wild type or mice in which ipRGCs are ablated only in adulthood. Mice raised in constant darkness also free-run with a significantly longer period, which is rescued upon exposure to light, even in adulthood. These results indicate, contrary to previous dogma that the circadian pacemaker develops independent of environmental input; light is critical for the pacemaker’s maturation. Initially as a control, we examined the central projections of conventional retinal ganglion cells (RGCs) to the dorsal lateral geniculate nucleus (dLGN) in Opn4DTA/DTA mice. We were surprised that Opn4DTA/DTA mice have severe deficits in the segregation of contralateral and ipsilateral RGC central projections to the dLGN. Consistent with these findings, Opn4DTA/DTA mice have visual acuity defects as measured by two distinct behavioral tasks. To identify the subtype(s) of ipRGCs that mediate the refinement of the circadian clock and vision, we utilized a mouse in which there are only 200 ipRGCs of the M1 subtype, which only project to circadian centers. These animals exhibit normal circadian photoentrainment with a normal circadian period, and surprisingly, normal segregation of RGC projections to the dLGN and normal visual acuity.
We find that only 200 M1 ipRGCs that project to circadian centers are sufficient for the maturation of not only the circadian pacemaker, but also the refinement of image forming circuits.
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