Timothy J. Gawne - US grants

When a primate views the world it makes a saccadic eye movement, and at the end of this movement the eyes remain more-or-less fixed in position for typically a third of a second, whereupon a new saccadic eye movement is performed. At the end of each saccadic eye movement the different pieces of the images of different objects are brought into the receptive fields of different assemblages of neurons. The visual scene is cluttered, with many objects overlapping and occluding each other. The activity elicited by the appearance of new stimuli in the receptive fields of neurons propagates through a loose hierarchy of cortical visual areas with a particular time course. The coordinated activity of many neurons in the different cortical areas during this interval between saccades is presumably what gives rise to visual perception. A great deal has been learned about the pattern of connections between the various cortical visual areas, and about the single aspects of a visual stimulus for which the individual neurons in each area are most sensitive to. However, less is known about how the visual system deals with complex stimuli, and for what (if many) role the time-varying aspects of neurons in the visual system might play. This study will address these issues by recording from single neurons and pairs of neurons in several cortical visual areas (V1, V2, V4, and IT) of awake behaving rhesus monkeys, using both simple and more complex visual stimuli, exploring the responses of neurons to stimuli that are either flashed on or brought into the receptive fields of neurons via a saccade, and quantifying the variation over time of neuronal responses under these conditions. The results of this project should now only increase our basic understanding of how the brain works, but should also be valuable for such efforts as the design of visual prostheses, where knowledge of the principles of neuronal encoding is vital, and also in the clinical interpretation of visually evoked potentials, which could be improved by a more detailed knowledge of the time course of visual processing.

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Abstract Not Provided.

The sense of vision seems effortless, and intuitively visual perception seems like it should be simple. However, research has shown that visual scene analysis requires, in addition to the retinas and numerous brainstem nuclei, the use of about one-third of the cerebral cortex. This is because visual perception (as opposed to the mere image recording seen in a digital camera) means taking the pattern of light and dark from a 2D image and from it inferring the structure and properties of objects in the real 3D world. Vision is not a low-level process, but a higher cognitive process whose study has drawn the attention of a large fraction of the neuroscientists.
The rhesus monkey is the best available model of the human visual system. This project will involve recording from single V4 cortical neurons from behaving rhesus monkeys to multiple simultaneous visual stimuli. Visual cortical area V4 is a major cortical center for form perception. Unlike so-called "higher" cortical areas such as the inferotemporal (IT) cortex, neurons in V4 can be easily stimulated with simple geometric shapes. Unlike so-called "lower" areas such as V1 and V2, neurons in V4 have receptive fields large enough to encompass more than one discrete visual stimulus at a time. These properties mean that V4 is an ideal location to study how neurons in the visual system combine information from different parts of an image.
Neurons early in the visual system examine only a small part of an image (i.e., they have small receptive fields), but neurons in later areas of processing have much larger receptive fields. Neurons with large receptive fields cannot be simply summing their inputs, or the result would be objects that appear as just a large blur. Neurons must be processing their inputs in a manner other than averaging or summing. But what are the rules of this processing? Experimental and theoretical studies suggest that one set of rules is for a neuron to select only the inputs that by themselves would elicit the maximum response. A competing theory is that neurons should compute the weighted average of their inputs. This study aims to resolve this controversy, an aim that is of significant importance to the field of visual neuroscience, and potentially, of importance to computer vision.
While the focus of this project is on vision, in principal the results could apply to all of the cerebral cortex. Nature is conservative, and rarely creates a mechanism that is only used on just one location. Also, cerebral cortex is notable for it's relative homogeneity, i.e, the neural circuits in part of the cerebral cortex follow generally the same organization as the circuits on another place in cortex. Finally, the cerebral cortex is notable for the richness of reciprocal connections between different regions. Indeed, it is this richness of interconnections that makes the cerebral cortex so susceptible to seizures. A core part of how the cerebral cortex functions must be how a given region combines or selects from the richness of inputs available to it. As such, this study aims to explore not just the visual system but fundamental aspects of cortical function.

The broader impact of the research is to promote interdisciplinary teaching and training of both undergraduate and graduate students. There will be a focus on encouraging participation from members of underrepresented groups from several minority serving institutions in Alabama.

? DESCRIPTION (provided by applicant): During postnatal development when the eye is still growing, a mechanism commonly referred to as the emmetropization mechanism uses the eye's refractive error to regulate the growth of the scleral shell to match the axial length of the eye t the focal plane. When functioning properly, this mechanism ensures that images will be sharply focused on the retina. The problem, for over 40% of Americans and up to 96% of groups in East Asia, is that the eye becomes too long for its own optics and is thus myopic. In addition to the cost (over $14 billion annually in the United States) of eye exams, glasses, contact lenses, and refractive surgery, even low amounts of myopia raise the risk of developing blinding conditions. Thus, effective strategies to slow eye growth and reduce the prevalence of juvenile-onset myopia in children are needed. Various strategies (bifocal glasses and contact lenses, muscarinic antagonist eye drops, scleral reinforcement surgery) have been developed to control axial elongation and myopia with limited success. An important problem is that we do not have a solid understanding of the visual cue or cues that are used by the emmetropization mechanism to determine if the eye is too short (hyperopia) and should increase its growth rate to achieve emmetropia, or if the eye is becoming too long (myopia) and should slow the axial elongation rate to match the maturation of the optics. We have developed a new theory of how the retina does this based on the temporal characteristics of fluctuations of in-focus vs. out-of-focus images experienced by photoreceptors and the neurons to which they connect. This has led us to discover two stimuli that have powerful effects on refractive development in young tree shrews, a cone-dominated dichromatic mammal closely related to primates: (1) Ambient long wavelength (628 ± 10 nm) red light slows eye growth so that eyes remain hyperopic. We will test two hypotheses about the red-produced STOP signals that will not only improve our understanding of the emmetropization mechanism, but also will tell us if a form of this red stimulus has the potential to be developed as a method to slow myopia development in children. In specific aim 1 we will determine if the red light paradigm slows eye growth in juvenile tree shrews when used for as little as two hours per day and in older juvenile animals. In specific aim 2 we will determine if the red light paradigm can restrain the eye growth caused by wearing a minus lens, an established tool for inducing myopia in animals that may mimic human myopiagenic environments. We have also found (2) that ambient flickering short wavelength (464 ± 10 nm) blue light containing many temporal frequencies is strongly myopiagenic. Further, interactions of the red and blue is stimuli can negate the effects of the red light, producing myopia. In specific aim 3 we will examine the blue/red temporal interactions that stimulate myopia. These may identify components of artificial lighting that should be avoided. The data collected in the proposed grant will potentially lead to a further proposal as an RO1.

During postnatal development when the eye is still growing, an ?emmetropization mechanism? uses the eye?s refractive error to regulate the growth of the scleral shell to match the axial length of the eye to the focal plane. Despite this, in over 40% of Americans and up to 96% of groups in East Asia, the eye becomes too long for its own optics and is thus myopic. Even low amounts of myopia raise the risk of developing blinding conditions and refractive surgery does not change this. Thus, effective strategies to slow eye growth and reduce the prevalence of myopia are needed. Maintenance of emmetropia is a neglected area of research. Most myopic children emmetropize relatively normally, but then are unable to maintain emmetropia in the longer maintenance phase of emmetropia. Our research in tree shrews (cone-dominated dichromatic mammals closely related to primates) has shown that maintaining emmetropia is an active process throughout adolescence. Is the eye becoming too short (hyperopia) and should increase its growth rate to maintain emmetropia (retinal GO signals are needed), or is it becoming too long (myopia) and should slow the axial elongation rate to maintain emmetropia (retinal STOP signals are needed). An important problem is that we do not have a solid understanding of the visual cues used by the emmetropization mechanism to generate STOP signals that will prevent eyes from becoming too long. In tree shrews, we have discovered that exposure to narrow-band long wavelength (red) light (which only stimulates the long-wavelength sensitive, or LWS, cones) seems to generate STOP signals that slow growth during the maintenance phase of emmetropization. In specific aim 1, we will determine the optimal parameters for the red light to generate the maximum STOP signal with minimal exposure and learn if red-light STOP signals show non-linear summation, similar to other stimuli that generate STOP signals (myopic defocus or interrupted minus-lens wear). In specific aim 2, we will determine if the red light ?treatment? can produce consistent STOP signaling over a long period of time in the maintenance phase of emmetropization. We will also examine if the red light can counteract the myopiagenic effects of a minus lens in a paradigm similar to that used in myopia-control studies. In specific aim 3, we will use both analysis of retinal dopamine, and of gene expression in the retina and post-retinal signaling cascade, to determine if red-light STOP signals act via the same pathways as other STOP stimuli (such as recovery from induced myopia), or if the pathways are parallel and novel. The knowledge gained from this project will not only generate critical data on the operation of the emmetropization mechanism during the maintenance phase, but also may result in the development of red light as a novel anti-myopia therapy.