1. Retinal Development and Function
1a. Postnatal Development and Maturation of the Mouse Retina
The retina is composed of several layers of neurons which sense light and send visual signals to the brain so we can see. RGCs are the output neurons conveying visual information from the retina to the brain. RGCs have complex yet characteristic morphology that determines how they receive and transmit visual information. Misregulation of RGC development and synaptic function often leads to devastating vision losses in eye diseases. We showed that one of the neurotrophins, NT-3, regulates the postnatal development of dopaminergic neurons in the mouse retina (Yoshida et al., 2011). We also developed a new analytic tool to examine the visual-response properties of RGCs using a multi-electrode array recording system (Cantrell et al., 2010; Chen et al., 2014). Our studies on normal development of RGCs also laid the foundation for investigating their degeneration in response to the environmental changes and disease insults.
1b. Visual Signal Transformation from the Retina to the Brain
Visual signals travel from the retina through the optic nerve, which is composed of RGC axons to connect the eyes to the brain. In mice, more than 90% of RGCs project to the superior colliculus (SC), a midbrain structure involved in multimodal sensorimotor integration and eye movement. I have a long and successful collaboration with Jianhua Cang's laboratory to investigate the visual signal transformation from the retina to higher visual centers (e.g., Wang et al., 2009; Rangarajan, Lawhn-Heath et al., 2011; Zhao et al., 2013; Inayat et al, 2015; Shi et al. 2017). One highlight of our productive collaboration is the study of the progressive degeneration of superior collicular functions in glaucomatous mice (Chen, et al, 2015). We showed that SC neurons of mice with glaucoma had weakened responses to visual stimulation, and exhibited mismatched and irregular receptive field structure. These studies build the foundation which we use to better understand how visual system function is disrupted in glaucoma and how to best preserve vision for patients with eye diseases.
2. Retinal Degeneration in Glaucoma
2a. Establishing Mouse Models of Glaucoma to Examine RGC Degeneration
Glaucoma is a group of eye diseases, which is often associated with elevated eye pressures (also known as intraocular pressure, i.e. IOP). Elevated IOP results in RGC death, which leads to a permanent vision loss. All current treatments seek to lower or control IOP, and none of these treatments is curative. In other words, vision loss cannot be restored because RGC loss is irreversible. The greatest hurdle in developing therapies is our poor understanding of how RGCs degenerate and die in response to the insult of ocular hypertension. We published a series of papers to establish a mouse model of chronic IOP elevation, mimicking human tension-related glaucoma (Feng et al., 2013a; Feng et al., 2013b; Chen et al., 2015). We examined how different populations of RGCs respond to the disease insult and their underlying mechanisms (Feng et al.2013a; Chen et al., 2015; Puyang et al., 2016; Feng et al., 2017). Using transgenic lines expressing fluorescent proteins in RGCs, we demonstrated type-dependent RGC degeneration in mice with chronic IOP elevation (Feng et al., 2013; Chen et al., 2015; Feng et al., 2016). We further showed that BDNF protects RGCs in a type-specific manner against acute optic nerve injury (Feng et al., 2017) and chronic IOP elevation (Feng et al., 2016).
2b. Early Detection of Neural Damage by Non-Invasive Imaging Techniques
Early detection of glaucoma is difficult because glaucoma often does not have an obvious symptom or pain; and it is too late when there is irreversible and massive RGC death. Therefore, our goal is to establish a new biomarker for neural damage in early glaucoma. In the past six years, I have collaborated with Prof. Hao Zhang's team in the Department of Biomedical Engineering at Northwestern University on developing novel imaging techniques for better detection and management of glaucoma (Song et al., 2013; Chen et al., 2015; Yi et al., 2016). For example, most Optical Coherence Tomography (OCT) devices that use a near-infrared (NIR) light source are applied to monitor anatomical alterations of the retina in eye diseases. In glaucoma management, one of the main parameters is the thinning of the retinal nerve fiber layer formed by the RGC axons. However, the thinning of fiber layer often correlates with late-stage RGC death. Zhang’s team developed visible-light OCT (vis-OCT) which offers significantly improved spatial resolution and sensitivity compared to NIR-OCT. Using this tool, we are carrying out a series of experiments to establish a novel biomarker for early signs of RGC degeneration. We are also characterizing ultrastructural damage in RGCs and their axons prior to massive RGC loss in mouse models of glaucoma.