title: Age-related changes in photosensitive melanopsin-expressing retinal ganglion cells correlate with circadian rhythm impairments in sighted and blind rats.
abstract: The melanopsin system consists of intrinsically photosensitive retinal ganglion cells containing the photopigment melanopsin (mRGCs). These mRGCs mediate several non-image-forming visual functions, including light entrainment of circadian rhythms. Here we evaluate age-related alterations of the melanopsin system and circadian rhythms in P23H line 1 (P23H-1) rats, a rodent model of retinitis pigmentosa (RP). In homozygous P23H-1 rats and wild-type control rats from the same genetic background (Sprague-Dawley), body temperature and locomotor activity were continuously monitored at 10-min intervals for 7 days, once every 4-5 weeks, between 2 and 24 months of age, using a telemetry transmitter. The distribution and number of mRGCs were assessed in control rats at 12, 18, and 24 months of age and in P23H-1 rats aged 12, 18, 24, and 30 months by immunostaining whole-mount retinas with antibodies against melanopsin. The mean density of mRGCs in control rats showed no significant variations when evaluated at 12 and 18 months of age, and fell by approximately 56% between 18 and 24 months of age. Meanwhile, a significant decrease in the mean number of mRGCs was found in 18-month-old P23H-1 rats as compared to 18-month-old control rats (81% decrease). Parametric and non-parametric analyses of the records showed a gradual age-dependent weakening of body temperature and locomotor activity circadian rhythms robustness in both control and P23H-1 rats from 2 to 24 months of age. However, body temperature and locomotor activity circadian patterns were less robust throughout the experiment in P23H-1 as compared to control rats, with lower amplitude, weaker coupling strength to environmental zeitgebers and higher fragmentation of the rhythms. The present study shows that the degeneration of photoreceptors and inner retinal neurons, characteristic of RP, has age-related degenerative effects on the melanopsin system and is associated with weaker circadian patterns.
authors.affiliation: a Department of Physiology, Genetics and Microbiology , University of Alicante , Alicante , Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Lax
authors.affiliation: a Department of Physiology, Genetics and Microbiology , University of Alicante , Alicante , Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Esquiva
authors.affiliation: b Department of Physiology , University of Zaragoza , Zaragoza , Spain.|c Aragon Institute for Health Research (IIS Aragón) , Zaragoza , Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Fuentes-Broto
authors.affiliation: c Aragon Institute for Health Research (IIS Aragón) , Zaragoza , Spain.|d Department of Surgery , University of Zaragoza , Zaragoza , Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Segura
authors.affiliation: e Department of Applied Physics , University of Zaragoza , Zaragoza , Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez-Cano
authors.affiliation: a Department of Physiology, Genetics and Microbiology , University of Alicante , Alicante , Spain.|f Institute Ramón Margalef, University of Alicante , Alicante , Spain.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Cuenca
authors.affiliation: c Aragon Institute for Health Research (IIS Aragón) , Zaragoza , Spain.|g Department of Ophthalmology , Lozano Blesa University Hospital , Zaragoza , Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pinilla
mesh_terms: D000375:Aging; D000818:Animals; D001766:Blindness / Q000378:metabolism*; D002940:Circadian Rhythm / Q000502:physiology*; D004195:Disease Models, Animal; D008027:Light; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology; D017299:Rod Opsins / Q000378:metabolism*; D000099210:Melanopsin
chemical_list: D017299:Rod Opsins; D000099210:Melanopsin
keywords: Aging; P23H rat; neurodegenerative diseases; retinitis pigmentosa