Sarah L. Pallas, Ph.D. - US grants

DESCRIPTION (Adapted from applicant's abstract): During visual system development, retinal afferents must not only find their correct topographic location within the target, but there must also be a correct numerical match between afferents and target, even though both are initially overproduced. This control process is critical in establishing visual receptive field properties and perceptual acuity. Studies outlined in this proposal will examine the control process, using the hamsters retinotectal system as an experimental model. Partial ablation of the superior colliculus in neonatal hamsters creates a population mismatch between retinal axons and the remaining target tissue, which serves to compress the visual field map but which leaves largely unaffected the receptive field properties of individual collicular neurons. The PI proposes that the conservation of receptive field properties is the result of activity-dependent preservation of convergence ratios between retinal axons and collicular neurons. Much of this conservation mechanism is not visually driven since the process occurs prior to eye opening. NMDA receptors are a potential component of the conservation mechanism. Through its role in coincidence detection the NMDA receptor may provide collicular neurons with the ability to recognize and select for competing retinal inputs with temporal activity patterns that fall within a specific time window (which translates into a window of visual space). The model predicts that the window varies in width between central and peripheral representations of the visual field. Such a mechanism would enable the preservation of visual response properties without interfering with the formation of a compressed retinal map. The goal of the proposed studies is to test the model by examining retinal map formation and the development of visual receptive field properties under conditions where activity of retinotectal axons is blocked, patterned visual input is disrupted and NMDA receptor function is antagonized. Potential variations in temporal requirements for activity-dependent cooperation with eccentricity will be examined by varying the interstimulus interval between two visual inputs and examining the effect of this variation on synaptic potentiation in neurons located throughout the superior colliculus. Because the proposed studies address questions not only of map formation but also of response property construction they uniquely begin to look for developmental control of complex functional capacities across visual areas of the CNS. These control mechanisms may protect against perinatal damage by allowing the visual system to compensate for damage to a target cell population without compromising visual function.

The connections between nerve cells in juvenile brain networks are flexible and can be shaped by the environment and experience. Network stability increases with age, producing both costs and benefits. Different species have evolved distinct patterns of plasticity reduction. This project compares developmental changes in visual system plasticity across several mammalian species. It will reveal how early sensory experience influences the way brain circuits are put together, and how ongoing sensory stimulation maintains the boundary between stability vs. flexibility of neural circuits. Because the genomes of many mammals have now been sequenced, it is possible to employ genetic manipulations that until recently were only feasible in mice. Comparative work is necessary to arrive at a more complete understanding of plasticity mechanisms and to determine whether animals with better vision and more reliance on visual perception for survival than mice (the current species of choice) might provide a better animal model for human visual development. Taken together, the results of the study will provide important mechanistic information about how and why the brain develops and changes with experience, and which animal models are the most relevant for biomedical research. Understanding the natural processes that control the boundary between plasticity and stability make it possible to manipulate that boundary for human benefit. Results from this study will also provide basic information about neural network plasticity which may be useful for designing drug and rehabilitative therapies to treat or repair diseases or injuries of visual pathways specifically, and brain pathways in general.

Visual experience during an early critical period is required for normal development of visual cortical (V1) structure and function in carnivores and non-human primates. Mice are now the preferred animal model for studies of visual pathway development and plasticity. Visual development and plasticity of mice differs from that of primates in both known and unknown ways that may have important consequences for the generalization of research findings to humans. Previous visual deprivation studies in hamsters and mice from the P.I.'s lab have shown that early visual experience is not required for normal developmental refinement of receptive fields in visual midbrain and visual cortex. Instead, vision is necessary only for the maintenance of normal function in visual midbrain (SC) and V1 of adults. The hypothesis to be tested in this study is that the degree to which a species' visual system development depends on visual experience is influenced by the extent to which vision is important in their ecological niche. The predicted outcome is that nocturnal species whose young stay in a burrow (such as mice) will be less dependent on vision to shape the development of their visual pathways than diurnal species whose young spend more time above ground. The timing and level of sensitivity to visual experience will be measured in several rodent species that differ in their daily activity patterns, nesting habits, and ecological niche. The rodent data will be compared to that from a carnivore species that has traditionally been used in studies of visual system development and plasticity.