The display of patterned spontaneous activity is an emergent property of the immature nervous system that is thought to mediate synaptic competition and instruct self- organization in many developing neural circuits. In the visual system, isolated (in vitro) preparations of developing retina exhibit propagating electrical activiy amongst neighboring retinal ganglion cells (RGCs), termed 'retinal waves'. Since RGCs relay visual information to higher order structures in the central nervous system, retinal waves are thought to play a key role in activity-dependent refinement of topographic neural maps in the superior colliculus (SC), lateral geniculate nucleus (LGN), and visual cortex (VCtx). However, the role of retinal waves in neural circuit development remains remarkably controversial, in part because their existence has never been demonstrated in vivo. Previous work using extracellular microelectrode recording techniques in vivo demonstrated limited and local correlated spiking between pairs of embryonic rat RGCs, but no assessment of wave activity has been undertaken in vivo, likely because of the methodological challenges associated with recording from a large cohort of RGCs in neonatal animals. In this proposal, we use a highly novel imaging approach to examine and characterize spontaneous activity throughout the visual neuraxis, including RGCs, the SC and VCtx, in neonatal mice in vivo. We seek to establish whether traveling waves of spontaneous activity occur in awake, behaving neonatal mice, and examine the spatiotemporal properties of waves throughout the developing visual system during the first two weeks after birth. Our preliminary data indicates that spontaneous retinal waves are present for at least a week of development in vivo and exhibit a similar profile of spatiotemporal properties as those described previously in vitro. Moreover, retinal waves generate matched activity patterns in the midbrain and visual cortex. Given the remarkable fidelity of retinal waves during the period prior to eye opening in mice we report here in vivo, together with previous work demonstrating that spontaneous waves within macaque retina are present in vitro before birth, it seems likely that the visual system experiences patterned activation by retinal waves for a substantial gestational period during human fetal development that may be crucial for shaping the functional maturation of neural circuits before the onset of sensory experience. In all, these experiments are designed to investigate the properties and role of patterned spontaneous activity in vivo in the development of neural circuits in the mammalian visual system.

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We are interested in understanding how complex brain circuits develop. We focus on the visual system, as its function is relatively well understood and it is especially important to human behavior. We are particularly interested in understanding the mechanisms leading to the devastating visual deficits associated with the emergence of Amblyopia and Strabismus during development. Our experiments also have the potential to help develop techniques to restore visual function following eye trauma or disease, such as glaucoma or age related macular degeneration.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (SPC)
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Steinmetz, Michael A
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Yale University
Schools of Medicine
New Haven
United States
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