Optometry and Vision Sciences

Diabetic retinopathy (DR) is a significant cause of vision impairment worldwide, and it is projected to incur a rising global disease burden. Although the pathophysiology of diabetic retinopathy had been historically characterised as a vascular disease, there is a growing body of evidence to suggest that DR is also a process of retinal neurodegeneration. There is also evidence that functional changes occur to the retinal vasculature’s capacity to respond to physiological stimuli, before anatomical changes manifest. Additionally, there is evidence to suggest that neuronal dysfunction precedes anatomical evidence of neurodegeneration in both clinical and experimental studies of diabetes. These findings were examined in Chapter 2, and collectively suggest that functional deficits of both the vascular and neuronal retinal components may be key components of DR pathogenesis. Several research questions were proposed in this thesis in order to further understand vascular and neuronal interactions in the retina, at the earliest stages of diabetes. In order to model an early stage of diabetic disease, 4 weeks of hyperglycaemia was introduced to a cohort of dark Agouti laboratory rats using streptozotocin (STZ). Flickering light was used to stimulate neuronal driven vasodilation in the retina, and the autoregulatory capacity of retinal vasculature was challenged through inhalation of oxygen and carbon dioxide. Electroretinography was conducted to assess retinal function, and the scotopic threshold response (STR) was recorded during gas inhalation as a measure of inner retinal functional response to an autoregulatory challenge. A series of pilot studies were undertaken to optimise the parameters of flicker stimulation, gas delivery, retinal imaging and electroretinography. These materials and methods were described in Chapter 3. Flicker stimulation reliably produced vasodilation of inner retinal arteries and veins, although this response was not significantly affected by 4 weeks of STZ hyperglycaemia. Oxygen and carbon dioxide breathing introduced vasodilation and vasoconstriction of the inner retinal arteries and veins, respectively. The speed of venous vasoconstriction was reduced in STZ animals during oxygen breathing, and carbon dioxide breathing revealed a reduced arterial vasodilatory capacity in STZ animals. These findings were described and discussed in Chapter 4, and they indicate that, despite normal retinal neurovascular coupling, subtle autoregulatory deficits in the retinal vasculature are present at an early stage of diabetes. The oscillatory potentials and STR were found to be reduced after 4 weeks of hyperglycaemia, suggesting a manifest deficit of inner retinal function. Additionally, carbon dioxide breathing introduced an increase in the peak positive STR (pSTR) amplitude in both normal and STZ animals, whereas oxygen breathing resulted in a decrease of pSTR amplitude that was more significant in the STZ cohort. These findings were described and discussed in Chapter 5, and they seem to suggest that that relative inner retinal ischemia may be present early in the course of diabetes. Furthermore, this effect could be exacerbated by vasoconstrictive stimuli. The overall experimental findings suggest that neurovascular coupling is unaffected at an early stage of diabetes, despite findings of inner retinal dysfunction and subtle deficit of vascular autoregulation in the retina. This suggests, in addition to neuronal and vascular activity, that other physiological processes, likely mediated by glial cells, may be implicated in the modulation neurovascular interactions in the retina. These experimental findings and implications were discussed in Chapter 6, as well as study limitations and future directions of research.

This is the first study to simultaneously measure electroretinography, ocular blood flow, and oxygen tension during intraocular pressure elevation. By doing so it shows that changes in oxygen tension are more closely related to function than blood flow. Moreover, by comparing these parameters in young and older eyes this study shows that older eyes have less oxygen availability with higher intraocular pressure despite having similar function. This argues that older eyes use more oxygen to sustain normal function.

This thesis shows that hyperglycaemia makes retinal function and ocular blood flow more sensitive to acute intraocular pressure (IOP) elevation. Increased functional susceptibility was associated with a reduced capacity to upregulate endothelial nitric oxide synthase. Chronic IOP elevation (4 weeks) produced retinal dysfunction and exacerbated the susceptibility of ocular blood flow to IOP challenge in diabetic but not healthy rats. These data suggest that hyperglycaemia-induced blood flow anomalies may contribute to the functional susceptibility of the diabetic eye to IOP.

Glaucoma is an increasingly common sight threatening disease. Our understanding of the pathogenesis requires good models for disease risk factors. This thesis refines models of chronic intraocular pressure elevation in rats. Non-invasive assessment showed evidence of widespread retinal dysfunction. It is clear that dysfunction was not solely determined by intraocular pressure, but is associated with either ocular trauma or agent toxicity. Clear methodological recommendations are provided to minimise widespread damage and thus provide improved models for understanding glaucoma.

Optometry and Vision Sciences - Theses

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