Abstract
Purpose :
The 85% cone-dominant retina of the diurnal, long-lived, vision-dependent, 13-lined ground squirrels (13LGS) can withstand the seasonal hibernation-related microenvironmental alterations in the retina. This study explores the 13LGS’s evolved cellular and molecular coping mechanisms of reversible retinal stress and its age-related retinal abnormalities to identify novel pathways for targeted therapies in cone-based blinding conditions, including age-related macular degenerations (AMD).
Methods :
Eyes were collected from young adult (2-3yr-old) 13LGS at different physiological states: fully awake euthermia, dark-adapted torpor, and light-adapted post-torpor arousal (1-6-12-24 hr). Eyes were also collected from euthermic aged (5-7yr-old) animals. All retinas were assessed by immunohistochemistry (IHC) and gene expression analysis (qRT-PCR) for markers labeling the cones, macroglia, microglia, immune cells, and neurotrophic targets [n=4/state, both sexes]. All data are represented as Mean±SEM.
Results :
Relative to young adult 13LGS in the euthermic state, IHC of torpor and arousal states showed transient cellular changes akin to acute human AMD: RCA1+, IBA1+ amoeboid microglia; upregulated GFAP+ filaments in the inner retina; and inner retinal MANF+ immunoreactivity. The parallel molecular comparison of mRNA levels revealed 2-to-3-fold significant higher expression of CD68, IL33, RLBP-1, GFAP, MANF (immune/glial/neurotrophic), as well as CD86, IL-6, IFN-g, CXCL10, IL1b (proinflammatory). Notably mRNA levels in euthermic but aged 13LGS retinas resembled those of torpor and arousal young adults. In the later stages of young adult arousal from torpor, upregulation of IL4 and IL10 (anti-inflammatory/regenerative) suggested a reversal of retinal stress. Abnormal rosette-like whorls of Recoverin+/PNA+ photoreceptors were also seen near the optic nerve head of aged 13LGS retinas by IHC.
Conclusions :
Relative to the active euthermic state, hibernating 13LGS retina displays cellular and molecular stress markers that potentially starts to correct within 24 hr after hibernation exit. Similar stress markers and rosette-like photoreceptor whorls are also present in the aged euthermic 13LGS retinas. A clear understanding of the regulatory pathways orchestrating the spatiotemporal transitions between these pro- and anti-inflammatory phenotypes could suggest novel treatments in AMD.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.