Optometry and Vision Sciences - Theses
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ItemReceptive field properties and dynamics in mammalian primary visual cortex( 2015)The functional properties and structure of receptive fields in primary visual cortical (V1) neurons represent how visual information is processed in the mammalian neocortex. Cortical receptive fields are diverse and highly dynamic to accommodate the constantly changing visual environment. The mechanisms behind the organisation of different types of receptive fields are still highly debated after David Hubel and Torsten Wiesel first described the fundamental properties of cortical receptive fields half a century ago. These pivotal discoveries were conducted in the classic animal models of vision research: cats and monkeys. In recent years, fuelled by the opportunities for genetic and molecular manipulation, mice have rapidly become a major model for studying cortical visual processing. It is essential to recognise the similarities and differences between mouse V1 and that of the well-established animal models. A major goal in this thesis is to compare the receptive field properties of mouse V1 (area 17) and cat V1 (area 17 and 18). Cortical neurons are largely composed of excitatory pyramidal cells and GABAergic inhibitory cells. Compared to excitatory neurons, the receptive field properties of inhibitory neurons are poorly understood due to the difficulty in identifying the diverse inhibitory subpopulations. In Chapter 4, by separating inhibitory and excitatory neurons based on their spike waveform shapes, I was able to examine the inhibitory receptive fields in both mouse and cat V1 and demonstrate differences in orientation selectivity and response linearity between these cell types in two species. In addition, I was also able to show that inhibitory cells were significantly over-represented in layer 1 of cat V1 and were less sensitive to low contrasts, as a population, compared to excitatory cells. Based on receptive field structures and response properties, V1 neurons are classified into simple cells and complex cells. Simple cells are thought to have spatially segregated ON and OFF subfields and are thus highly selective for the spatial phases of oriented edges. Complex cells have intermingled ON and OFF subfields and are largely phase-insensitive. Recent evidence reveals that some complex cells in cat and monkey V1 show increased phase sensitivity in their spiking activity as stimulus contrast is reduced, which suggests a shift towards a simple-like receptive field at low contrasts. By employing drifting sine-wave gratings (Chapter 5) and contrast-reversing gratings as visual stimuli (Chapter 6), I demonstrated the same effect in mouse V1 neurons. Furthermore, through intracellular recording I also observed contrast-dependent phase-sensitivity in the subthreshold membrane potentials of the cells as well as their spiking responses. This confirmed that the contrast-driven effect was a result of altered synaptic inputs and not the non-linear transformation from membrane potential to spike output.
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ItemWireless visual electrophysiology in conscious rats for preclinical drug testing( 2014)Aim: To develop a montage to measure electroretinogram (ERG) and visual evoked response without anaesthesia and apply to detect central penetrance for drug testing. Material and methods: Anaesthetised works were firstly undertaken to determine optimal electrode placements (3-month-old male Long-Evans rats, n = 6). Telemetry transmitters were implanted in rats (3-month-old male Long-Evans rats, n = 8), from which ERG and VEP in conscious rats are recorded. Using the telemetry montage, we investigated the effect commonly used laboratory anaesthetics (intramuscular ketamine:xylazine or inhalant isoflurane) has on visual electrophysiology. To test for central penetrance, rats (3-month-old male Long-Evans rats, n=8 each group) were implanted with telemetry transmitter and administered with either isoguvacine or muscimol. Both drugs are GABAa agonists, with the difference being muscimol readily crosses the blood-neural-barriers whereas isoguvacine does not. Therefore systemic administration of isoguvacine should return different ERG and VEP changes to local administration but the signal changes should be similar between local and systemic muscimol injections. The results of this experiment are compared to that of anaesthetised (3-month-old male Long-Evans rats, n=5 each group), conventional recordings to investigate anaesthesia confounds. Results: We show, for first time, wireless ERGs and VEPs are recordable in conscious rodents. Furthermore, the data indicates that the signals are stable for at least four weeks but commonly used laboratory anaesthesia alters waveform profiles. The GABAa agonists experiment suggests that the telemetry system is capable of detecting drug penetrance, however, the presence of anaesthesia confounds findings. Conclusion: We show that current conventional recording are confounded by anaesthesia and this novel system can potentially be used to detect drug penetrance. Moreover this system demonstrates potential for longitudinal studies, paving the way for neurodegenerative studies such as glaucoma in the future.
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ItemContrast processing in ageing and early glaucoma( 2014)A natural visual experience commonly requires an ability to differentiate objects of supra-threshold contrast (contrast discrimination) and to adjust to changes in contrast (contrast adaptation). While the loss of contrast sensitivity with glaucoma has been well documented in the literature, the effect of glaucoma on supra-threshold contrast processing is less studied. This thesis investigated the effects of early glaucoma on contrast discrimination and rapid contrast adaptation. Additionally, alterations in retinal and cortical responses to supra-threshold contrast stimuli with glaucoma were investigated using electrophysiology techniques. As age is a risk factor for glaucoma, this thesis also considered the effects of normal ageing on contrast processing. The results of this thesis suggest that glaucoma can result in supra-threshold contrast deficits, with patients having early glaucoma demonstrating a reduction in rapid contrast adaptation and poorer contrast discrimination. As ageing did not alter rapid contrast adaptation, the assessment of contrast adaptation might be a useful functional tool in early glaucoma, although further studies are required to develop this. Further studies are also required to consider the implications of supra-threshold contrast deficits with glaucoma on natural vision. The smaller cortical deficits relative to retinal deficits revealed with electrophysiological recordings suggest that post-retinal abnormalities are minimal in patients with early glaucoma. Hence, there is a possibility that the supra-threshold contrast deficits seen in early glaucoma in this thesis may mainly arise from retinal abnormalities. There is also the possibility that post-retinal compensation resulted in minimal cortical deficits in patients with early glaucoma. Further experiments involving patients with more advanced glaucoma may help to elucidate post-retinal contrast processing mechanisms with glaucoma. In older adults, elevated cortical responses in the presence of reduced retinal responses suggest the possibility of age-related reduction in cortical inhibition. Altogether, the results of this thesis provide further understanding of the mechanisms underlying supra-threshold contrast deficits in early glaucoma and ageing.
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ItemThalamocortical transformation of visual signals: role of geniculate orientation biases and intracortical circuits in orientation selectivity of striate cortical neurons( 2013)One of the fundamental questions in our understanding of the visual system is posed by various neurons along the afferent visual pathway, from eye to the brain, which differ in their response properties. While the neurons in the retina and the lateral geniculate nucleus (LGN) of cats and most mammals respond reasonably to diffuse patches of light, most primary visual cortical neurons (striate cortex) respond only to elongated stimuli of particular orientation. Hubel and Wiesel’s Nobel prize winning discovery of this orientation selective property of striate cortical neurons has opened up an enormous field for investigation. They proposed that striate cortical orientation selectivity arises from excitatory convergence of several non-oriented LGN afferents whose receptive fields are arranged along the long axis of the striate cell’s receptive field. The emergence of orientation-tuned responses among these striate cortical neurons from relatively poorly tuned thalamic neurons has been a topic that courted an intense debate. This comes from the findings of alternative models of orientation selectivity that have shown that the excitatory input from the LGN is almost circular, that the major excitatory drive comes from within the cortex and intracortical inhibition may have a role in the generation of orientation selectivity. These models claimed that inhibitory circuits within the visual cortex are required to sharpen the broadly tuned input from the LGN. One such model, called anisotropic LGN-driven recurrent model (ALD-R model), suggests an alternative scheme that exploits the orientation biases present in the responses of subcortical neurons, with the intracortical inhibitory and excitatory networks sharpening this broadly tuned subcortical inputs at the cortical level. Several experiments were designed in this study to test the predictions of the ALD-R model, including the role played by geniculate orientation biases and non-specific inhibition in the orientation tuning of cat striate cortical neurons. Firstly, the contribution of broadly tuned inhibition on geniculate orientation biases was tested using a novel electrical stimulation protocol within the LGN. The effect of this LGN electrical stimulation was also studied in the topographically corresponding striate cortical region. Our results showed that the non-specific inhibition brought about by electrical stimulation within the LGN resulted in significant sharpening of the LGN orientation biases as well as a mild broadening of the orientation selectivity of neurons in the corresponding striate cortical region. The effect of non-specific inhibition generated by this electrical stimulation paradigm was also compared with pharmacologically induced inhibition on geniculate relay cells and the results were comparable. These findings add support to the ALD-R model, where even non-specific inhibition acting on geniculate orientation biases could lead to sharper orientation tuning similar to those seen among striate cortical neurons. The dependence of striate cortical orientation preferences on LGN orientation biases was tested in the second experiment, where simultaneous paired extracellular recordings were performed from a geniculate cell and a cortical cell, which had overlapping receptive fields. The rationale behind this study is that a geniculocortical pair with matched orientation preferences would show higher coherence than a pair that has near orthogonal orientation preferences. The degree of coherence between the spikes from each neuronal pair was compared with the differences in optimal orientations exhibited by each geniculocortical pair. The results support the prediction of ALD-R model that orientation preferences of LGN neurons can predict the orientation preferences of striate neurons that they purportedly project to. The next experiment tested whether contrast invariance of orientation tuning, a property that is often pointed out as a drawback of Hubel and Wiesel’s model, is a subcortical property that gets transferred to striate cortical neurons. Extracellular responses of LGN neurons for varying stimulus contrasts were studied and their orientation sensitivities for the high and low contrast stimuli were compared. The results show that cat LGN neurons exhibit contrast invariance of orientation tuning and striate neurons could acquire this property from the geniculate excitatory inputs. Together, the results of the above studies substantiate the claims of ALD-R model where broad orientation selectivities present in geniculate inputs predict striate cortical orientation tuning and also other properties such as contrast invariance. The contribution of intracortical inhibition, especially those that are broadly tuned or non-specific is pivotal for the generation of orientation selectivity of striate cortical neurons.
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ItemAgeing effects on ocular blood flow, oxygen tension and function during IOP elevation( 2012)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.
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ItemFunctional correlates between the rat electroretinogram and visual evoked potential( 2012)The ERG and VEP are sequentially-activated responses, widely used for diagnosis of eye and brain diseases. Measuring both simultaneously provides additional information to help localise where in the visual pathway injury has occurred. This thesis shows how retinal information streams are encoded in the VEP. In addition, it shows that changes to ERG components can predict the amount of loss downstream in the retina. However, retinal loss may not predict VEP changes.
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ItemSusceptibility of the diabetic rat retina to intraocular pressure challenge( 2012)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.