Defining Roles of Perivascular Retinal Neurons by Integrating Visual Stimuli and Vascular Tones
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PROJECT SUMMARY/ABSTRACT Retinal neurons wire to circuits to transmit processed light stimulations into electrical signals before passing them onto the brain. Beyond interneurons, retinal ganglion cells (RGCs) also interact with nearby non-neuronal cells, such as glial cells, vessels, and circulating microglia, forming a microenvironment. Beyond the traditional view of presynaptic inputs, how the local microenvironment modulates RGC signal processing remains largely unknown. Given the compact space within the inner retina, my central hypothesis is that specific RGC subsets may selectively interact with nearby non-neuronal cells, such as vascular endothelial cells, which may modulate neuronal signal processing. Primarily in the retina, light stimuli are not the only sensory stimuli; other modulations, such as temperature, ocular or vascular pressures, and neurochemical stimulation, may also have specific impacts on RGC signal processing. Notably, the RGCs can extract different types of stimuli and optimize information processing to efficiently send integrated information to the brain. My preliminary data demonstrated that beyond the traditional inputs from presynaptic interneurons (bipolar cells and amacrine cells), one group of RGCs is located near the blood vessels with perivascular endfeet. These perivascular RGCs also express Piezo2 - a mechanosensitive channel. Thus, they may be the primary neurons in the retina that not only respond to light stimuli but also to mechanical stimulations. The innovation of this study is to study how mechanosensitive channels affect the light response of some perivascular RGCs. Additionally, I propose exploring the role of Piezo2 in modulating perivascular RGCs between normal conditions and optic neuropathy models. This proposal aims to study the interaction of perivascular RGCs with blood vessels via mechanosensitive channels. I will use electrophysiology, pharmacology, genetics, viral tools, single-cell sequencing, and in vivo imaging to achieve these goals. In Aim 1, I will study how Piezo2 channels affect the visual function of the perivascular RGCs. In Aim 2, I will investigate the neuroprotection role of perivascular RGCs in different retinal diseases mediated by Piezo2. At my independent laboratory (Aim 3), I will establish an intraocular imaging platform to enhance the findings using non-invasive, real-time in vivo imaging. The proposed work is significant since results from this study may uncover novel neurovascular protective mechanisms against degeneration and lead to new strategies for intervention. My long-term goal is to understand the visual circuit assembly in the retina at single-neuron type resolution to establish a roadmap to understand how the retina's visual features are detected and interpreted by the brain. Additional training obtained during this award in visual system development (with Dr. Xin Duan), mechanosensitive channel (with Dr. Yuh Nung Jan), and retinal disease (with Dr. Yang Hu). Combined with my predoctoral training in electrophysiology and visual guided behaviors (with Dr. Yifeng Zhang), these expertises will provide a solid foundation for an independent research career.
