The goal of this proposal is to continue studying the development of functional circuits in the retina. Immature retinal neurons spontaneously generate correlated activity in the form of waves of action potentials that sweep across the retinal ganglion cell layer. These retinal waves occur during the developmental period when functional circuits within the retina are emerging and retinal projections to the brain are undergoing a tremendous amount of refinement. Recent discoveries indicate that light penetrating through the closed eyelids may also influence retinal firing patterns during development. In this renewal, we focus on two Aims that explore the impact of early vision on retinal activity and the potential roles it plays in development and early light guided behaviors. In the first Aim, we explore the mechanisms by which spontaneous activity modulates early light responses mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) during the first postnatal week. IpRGCs, which express the photopigment melanopsin, are the first photoreceptors that mature in the retina, and they therefore provide the earliest light-driven signals to the brain. We recently published that blockade of retinal waves increase the number of light responsive cells via an increase in gap junction coupling between ipRGCs and other retinal neurons. Here we explore the mechanisms underlying this activity-dependent modulation of coupling and its function in early light-guided behaviors. In the second Aim, we investigate how retinal waves interact with these emerging visual circuits of the retina during the second postnatal week, just prior to eye-opening. Specifically we will test the novel hypothesis that light stimulation alters the properties of retinal waves and determine whether this light modulation of waves is critical for refinement of retinofugal projections. Experiments are based on state-of-the art technologies that include volumetric two-photon imaging of genetically encoded calcium sensors. This work will address the principles that establish the mechanisms underlying spontaneous activity in developing circuits and the role these principles play in activity- dependent developmental processes. It will also elucidate the principles that govern the normal development of the human nervous system, thus making it possible to understand the origin of neurological birth defects and to devise strategies that enable the nervous system to regenerate functioning neural circuits after injury.
Retinal waves are highly correlated spontaneous firing patterns detected in the developing retina, and they provide a critical source of activity to drive the refinement of connections throughout the developing visual system. Recently, it was discovered that the developing retina exhibits some light sensitivity prior to maturation of rods and cone. Our work will determine how retinal waves interact with early light-sensitivity of the retina. A detailed understanding of the organizing principles that govern the normal development of retinal circuits will lead to understanding the origin of some neurological birth defects.
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