Oxygen Toxicity As A Factor In Retinal Degenerations: Genetic And Environmental Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$269,250.00
Summary
This project will explore the mechanisms underlying a group of blinding diseases called Retinitis Pigmentosa (RP). They are caused by the death or degneration of the light-receptive cells of the retina of the eye (photoreceptors). It is well established that many forms of RP are caused by genetic mutations but many cases (40-50%) occur 'sporadically', i.e. without a family history. Further there is growing evidence that the rate at which genetic forms of the disease progress is strongly influenc ....This project will explore the mechanisms underlying a group of blinding diseases called Retinitis Pigmentosa (RP). They are caused by the death or degneration of the light-receptive cells of the retina of the eye (photoreceptors). It is well established that many forms of RP are caused by genetic mutations but many cases (40-50%) occur 'sporadically', i.e. without a family history. Further there is growing evidence that the rate at which genetic forms of the disease progress is strongly influenced by environmental factors, particularly light and oxygen. To analyse how these environmental factors affect the stability of the retina, we will use a range of techniques (including gene array technology) to study the molecular events which link light or oxygen stress to photoreceptor death. The work will be done in mouse 'models' of the disease. It is increasingly well established that the rodent (rat and mouse) retina and human retina share a basic structure and functional detail. These models allow intensive investigation, with results which are directly applicable to human disease. Our principal emphasis will be on three aspects of these models: (1) the molecular mechanisms induced in the retina by light stress or oxygen stress; (2) the role of mitochondria (cellular organelles essential for both cell metabolism and cell stability; and (3) genes which regulate the vulnerability of photoreceptors to oxygen stress. RP has been recognised for nearly 100 years as a leading cause of blindness in young adults. It is usually diagnosed in the young adult as a failure of night vision, but the prognosis is grim (relentlessly progressive loss of vision), and there is still no effective treatment. The work proposed will contribute to our understanding of the basic mechanisms involved, and will explore some approaches to therapy for, or at least to mitigation of the blindness of RP.Read moreRead less
Effect Of Aging And Mitochondrial Dysfunction On The Optic Nerve Response To Pressure-induced Oxidative Stress
Funder
National Health and Medical Research Council
Funding Amount
$415,554.00
Summary
The risk of glaucoma, a potentially blinding disease of the optic nerve, increases exponentially with age, but the cellular mechanisms responsible are not known. We hypothesise that age-related changes in mitochondria, the energy producing part of the cell, render nerve cells prone to damage. This project will determine whether aging and mitochondrial impairment increase nerve damage and whether dietary moodifications that preserve mitochondria during aging, protect the optic nerve from damage
Using Contextual Effects To Test Theories Of Coding In Visual Cortex
Funder
National Health and Medical Research Council
Funding Amount
$200,500.00
Summary
The visual cortex is the main structure in the brain that processes the visual scene. Cells in the cortex respond selectively to features of the scene such as the orientation of objects, the direction they move and their brightness relative to the background. Cortical cells are arranged in a topographic map of visual space, so that nearby cells respond to light from nearby parts of the image. Recent advances have shown that cells talk to each other so a stimulus in one part of the visual field c ....The visual cortex is the main structure in the brain that processes the visual scene. Cells in the cortex respond selectively to features of the scene such as the orientation of objects, the direction they move and their brightness relative to the background. Cortical cells are arranged in a topographic map of visual space, so that nearby cells respond to light from nearby parts of the image. Recent advances have shown that cells talk to each other so a stimulus in one part of the visual field can influence the responses of cells looking at other regions. This communication between cells is important in guiding the brain to focus on areas of the visual scene that are most important, a process known as attention. An example would be that a mouse moving through the periphery of someone's vision would attract their attention away from objects elsewhere in the scene. This project is designed to study the way that cells in the visual cortex cooperate to guide attention. Attention is important because it reduces the need to process all the detail in the visual scene with the same level of accuracy, leaving more resources free to process what is important. Attention deficits are a problem for people with dyslexia, so understanding the physiological basis of attention is an important goal. As well as attention, the visual system has a range of other mechanisms to select important information from the visual scene. For example, visual adaptation tends to improve the ability to code changes in the visual scene at the expense of reducing the sensitivity of the system overall. This project will investigate the relationship between attentional and adaptive mechanisms in the visual cortex. We expect to establish the precise physiological mechanisms that drive adaptive and attentional mechanisms in the mammalian brain.Read moreRead less
Multidimensional Coding Of Visual Information In The Retina
Funder
National Health and Medical Research Council
Funding Amount
$359,431.00
Summary
Although both the retina and visual cortex are part of the central nervous system, the coding of visual information in the two laminar structures differs markedly in that all three dimensions of the cortical sheet are used to code multiple response axes but only one dimension of the retinal sheet. This project examines how visual response properties are mapped through the depth of the retina and this will provide a comparatively simple paradigm of complex information processing in the brain.
Experimental Validation Of A Clinical Indicator Of Utricular Function.
Funder
National Health and Medical Research Council
Funding Amount
$198,689.00
Summary
The vestibular system is responsible for our sense of balance, it is located in the inner ear and is responsible for maintaining posture and helping an organism to make appropriate eye movements when the head moves. Damage to the vestibular system by disease or accident is extremely debilitating for a patient. A chief goal of our research program is to develop simple tests of the vestibular system that can be used in the clinic to diagnose vestibular disorders. Most present clinical tests only t ....The vestibular system is responsible for our sense of balance, it is located in the inner ear and is responsible for maintaining posture and helping an organism to make appropriate eye movements when the head moves. Damage to the vestibular system by disease or accident is extremely debilitating for a patient. A chief goal of our research program is to develop simple tests of the vestibular system that can be used in the clinic to diagnose vestibular disorders. Most present clinical tests only test the part of the vestibular system that responds to angular rotations (the semicircular canals). There are few good tests that can reliably diagnose problems concerned with sensed position (the otoliths). Recent evidence from human studies has shown that by delivering small electrical currents (galvanic stimulation) via electrodes located on the surface of the skin behind the ears, a characteristic pattern of eye movement occurs. Our hypothesis is that the distinctive pattern of eye movement produced is a result of otolith stimulation. The aim of this project is to determine exactly how these small currents produce the eye movements and if these eye movements are in fact mediated by the otoliths. To determine the physiology that underlies these types of responses we are unable to conduct these experiments in humans. Our present program will therefore use both behavioural and physiological experiments on guinea pigs to test our hypotheses about galvanic stimulation and otolith function. The significance of this work lies in that it will lead to a new way of evaluating the function of the gravity sensing part of the human vestibular system which appear to be uniquely important for patients with balance problems.Read moreRead less
Electroretinogram Recordings Of Human Scotopic Dark Adaptation Following Intense Bleaching Exposures
Funder
National Health and Medical Research Council
Funding Amount
$272,250.00
Summary
After a human subject has been exposed to intense illumination, it can take many minutes for the eye to regain full sensitivity, as one experiences (for example) when entering a dark cave after being out on a bright sunny beach. This project will investigate the processes that occur in the cells of retina lining the back of the eye, that prevent the instantaneous recovery of vision following intense illumination. Electrical recordings will be made from the eyes of normal individuals, using new t ....After a human subject has been exposed to intense illumination, it can take many minutes for the eye to regain full sensitivity, as one experiences (for example) when entering a dark cave after being out on a bright sunny beach. This project will investigate the processes that occur in the cells of retina lining the back of the eye, that prevent the instantaneous recovery of vision following intense illumination. Electrical recordings will be made from the eyes of normal individuals, using new techniques that allow the activity of different types of nerve cell in the retina to be monitored. The study will determine how it is that events in the light-detector cells of the eye (the rod and cone photoreceptors) influence the activity of subsequent nerve cells in the visual system, and how these events contribute to the poor vision that one experiences following bright lights.Read moreRead less
Behavioural And Physiological Tests Of Clinical Indicators Of Vestibular Function.
Funder
National Health and Medical Research Council
Funding Amount
$205,500.00
Summary
Part of the inner ear is responsible for our sense of balance and for maintaining clear vision and stable posture. Recurring vertigo attacks and persistent imbalance can disrupt the most productive years of patients' lives and balance-related falls account for more the half of accidental deaths in the elderly. Despite this most doctors find dizziness difficult to diagnose and impossible to treat, so specialist Balance Disorders Clinics see many patients a year but still have very long waiting ti ....Part of the inner ear is responsible for our sense of balance and for maintaining clear vision and stable posture. Recurring vertigo attacks and persistent imbalance can disrupt the most productive years of patients' lives and balance-related falls account for more the half of accidental deaths in the elderly. Despite this most doctors find dizziness difficult to diagnose and impossible to treat, so specialist Balance Disorders Clinics see many patients a year but still have very long waiting times. There is then clearly a major need to improve the understanding and the treatment of dizzy patients and improvement will come about through scientific understanding of vestibular dysfunction, and technological realization of improvements in the assessment and treatment of patients. This project seeks to identify whether 3 simple new indicators of balance function are valid, using tests on guinea pigs to understand the way in which they work.Read moreRead less
Oculomotor Tests Of Otolith Function Using Human Centrifugation
Funder
National Health and Medical Research Council
Funding Amount
$284,450.00
Summary
The effects of dysfunction of the balance system of the inner ear (the vestibular system) can range from mild brief episodes of dizziness to almost complete incapacitation: where the patient feels unstable, their posture is unstable, their vision is unstable. In order to guide appropriate treatment and rehabilitation, diagnostic tests are needed to identify whether the dysfunction is due to a brain problem or a problem in the inner ear, and if an ear problem - which part of the inner ear system ....The effects of dysfunction of the balance system of the inner ear (the vestibular system) can range from mild brief episodes of dizziness to almost complete incapacitation: where the patient feels unstable, their posture is unstable, their vision is unstable. In order to guide appropriate treatment and rehabilitation, diagnostic tests are needed to identify whether the dysfunction is due to a brain problem or a problem in the inner ear, and if an ear problem - which part of the inner ear system is affected. By combining basic research with clinically feasible methods my colleagues and I have, with NH and MRC support, developed some of the most widely used clinical tests of balance function available today (see Halmagyi, Cremer and Curthoys 2003 for a review). In this Project I seek to continue the development of a test of part of the balance system (the utricular macula) for which there are few acceptable tests. I will do that by using the unique facilities available at Sydney University and RPA Hospital, presenting controlled stimuli (linear accelerations) to healthy human subjects and patients with known vestibular losses, and measuring precisely their eye movement responses to these stimuli using computerized image processing techniques. The experiments will test an hypothesis about how part of the vestibular system, the utricular macula, works and controls eye movements. One eye movement response, rolling of the eye around the line of sight (called ocular torsion) during maintained roll head-tilts (to the patients left or right) may be due to the joint activation of two regions of the balance receptors: the utricular and saccular maculae. As a result of a recent direct test we have managed to conduct on two normal subjects, we think that hypothesis should be thoroughly re-tested on subjects and patients with known vestibular losses and in doing so provide new understanding of otolith function which may lead to new clinical tests.Read moreRead less
Role Of Cortico-cortical Connections In Mediating Cerebral Cortex Plasticity: Visual Cortex Model
Funder
National Health and Medical Research Council
Funding Amount
$362,500.00
Summary
In mammals injury to the retina not only affects the neurones within the eye but also induces changes in the other parts of the brain, particularly in the visual cortex. It has been found that after retinal injury cells in the visual cortex, normally receiving an input from the injured part of the retina, now receive an input from adjacent normal retina ( ectopic receptive field ). All mammals with well developed vision have a large number of separate visual cortical areas (more than 30 in prima ....In mammals injury to the retina not only affects the neurones within the eye but also induces changes in the other parts of the brain, particularly in the visual cortex. It has been found that after retinal injury cells in the visual cortex, normally receiving an input from the injured part of the retina, now receive an input from adjacent normal retina ( ectopic receptive field ). All mammals with well developed vision have a large number of separate visual cortical areas (more than 30 in primates). These areas are arranged in a hierarchy in which it is thought that as features of the visual stimuli become more complex they are discriminated in the areas higher in the hierarchy. These higher-order areas also project back to lower-order areas. This feedback activity from the higher areas can be reversibly abolished by cooling a given area to about 10oC and then rewarming it back to its normal temperature. We will try to determine if in cats (animals with well developed vision) following damage to a small region of the retina the feedback activity from higher visual cortical areas affects the ectopic receptive fields in the lower visual cortical areas. Another possibility is that the ectopic receptive field apparent following retinal damage might depend on horizontal connections within the particular cortical area, running from normal cortex to the area of cortex affected by the lesion. We propose to test this idea by blocking reversibly (with chemical agents) transmission of these horizontal fibres and determining the characteristics of neurones in the area affected by the lesion. Understanding the role of feedback and horizontal cortico-cortical connections in establishing new ectopic receptive fields following spatially delineated damage to the retina will help us to understand the mechanisms underlying perceptual distortions and visual hallucinations which occur following retinal traumas or some age-related retinal degenerations.Read moreRead less