Effect of age and sex on neurodevelopment and neurodegeneration in the healthy eye: Longitudinal functional and structural study in the Long-Evans rat

Abstract

The processes involved in neurodevelopment and aging have not yet been fully discovered. This is especially challenging in premorbid or borderline situations of neurodegenerative diseases such as Alzheimer's or glaucoma. The retina, as part of the central nervous system, can be considered the easiest and most accessible neural structure that can be analyzed using non-invasive methods. Animal studies of neuroretinal tissue in situations of health and under controlled conditions allow the earliest sex- and aging-induced changes to be analyzed so as to differentiate them from the first signs occurring in manifested disease. This study evaluates differences by age and sex based on intraocular pressure (IOP) and neuroretinal function and structure in healthy young and adult rats before decline due to senescence. For this purpose, eighty-five healthy Long-Evans rats (31 males and 54 females) were analyzed in this 6-month longitudinal study running from childhood to adulthood. IOP was measured by tonometer (Tonolab; Tiolat Oy Helsinki, Finland), neuroretinal function was recorded by flash scotopic and light-adapted photopic negative response electroretinography (ERG) (Roland consult® RETIanimal ERG, Germany) at 4, 16 and 28 weeks of age; and structure was evaluated by in vivo optical coherence tomography (OCT) (Spectralis, Heidelberg® Engineering, Germany). Analyzing both sexes together, IOP was below 20 mmHg throughout the study; retina (R), retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thicknesses measured by OCT decreased over time; an increase in ERG signal was recorded at week 16; and no differences were found between right and left eyes. However, analyzing differences by sex revealed that males had higher IOP (even reaching ocular hypertension [>20 mmHg] by the end of the study [7 months of age]), exhibited greater neuroretinal thickness but higher structural percentage loss, and had worse dark- and light-adapted function as measured by ERG than females. This study concludes that age and sex influenced neurodevelopment and neurodegeneration. Different structural and functional degenerative patterns were observed by sex; these occurred earlier and more intensely in males than in age-matched females.

Keywords: Aging; Electroretinography; Neurodegeneration; Neurodevelopment; Optical coherence tomography; Retina; Sex.