1. Retinal Development and Function.

    Retinal ganglion cells (RGCs) have complex yet characteristic dendritic morphology that determine how they receive and transmit visual information. Misregulation of RGC development and synaptic function leads to devastating vision losses in eye diseases. The maturation of RGC structure and function is stringently regulated, but the underlying molecular and cellular mechanisms are largely unknown. It is thus critical to understand how RGCs regulate their structure and make functional connections in normal development. My previous studies in Dr. Dave Copenhagen's laboratory at UCSF showed that BDNF and NT-3, the survival factors of neurons, modulate RGC dendritic maturation during postnatal development (Liu et al., 2007; Liu  et al., 2009).

Built on these studies, my own laboratory continues to examine changes of RGC functional properties during normal development and when neurotrophin signaling is disrupted. We developed an innovative analytic tool to examine RGC spatiotemporal visual responses with multi-electrode array recordings (Cantrell et al., 2010). We have examined the maturation of direction- and orientation-selectivity of RGCs (Chen et al., 2014) and further showed that NT-3 regulates the development of RGC light-response properties (Cantrell et al., 2010) as well as of dopaminergic neurons in the mouse retina (Yoshida et al., 2011). Combining mouse genetics with novel imaging and physiological techniques, scientists have made great progress on understanding RGC types and their light response properties. It builds the foundation for us to further investigate the type-specific degeneration and death of RGCs in response to the environmental changes and disease insults.

2. Retinal Degeneration in Experimental Glaucoma.

    Glaucoma, one of the most common causes of blindness in the United States, is characterized by progressive RGC death and vision loss. Currently, all treatments for glaucoma seek to lower or control intraocular pressure (IOP), because high IOP is the known risk factor. None of these treatments is curative. The biggest hurdle in developing better therapies for direct neuroprotection is our poor understanding of how an RGC degenerates and dies with disease progression. Our research on RGC development and maturation provides unique and innovative tools to characterize the structural and functional alteration of RGCs in experimental glaucoma, which is much needed to advance the field.

    We induced chronic ocular hypertension by focal laser illumination and injection of polystyrene microbeads and IOP elevation could last up to six months. We have demonstrated RGC degeneration and vision loss with disease progression (Rangarajan et al., 2010; Feng et al., 2013a, 2013b; Thomson et al., 2014; Chen et al., 2015). For example, using the non-centered spike-triggered covariance (STC-NC) analysis to classify RGC into different subtypes (Cantrell et al., 2010), we are one of the first to show that the functional degeneration of RGCs is subtype-dependent (Chen et al., 2015). These studies have been well received and highly cited by the research field.

3. Functional studies of the mouse higher visual centers

  We have been collaborating with Dr. Cang's laboratory to investigate the development and function of mouse higher visual centers. In mice, more than 70% of RGCs project to the superior colliculus (SC), a midbrain structure involved in multimodal sensorimotor integration, saccade generation, and body movement. We have performed a series of morphological and functional studies of the mouse SC to better understand the visual signal transformation and its underlying mechanisms (Wang et al., 2009; Wang, Sarnaik, et al., 2010; Sarnaik, et al., 2014). We have also compared SC response properties with those in dLGN as well as in retina (Zhao et al., 2013).

  One highlight of our productive collaboration is the study of the progressive degeneration of superior collicular functions in mice with sustained ocular hypertension (Chen, et al, 2015). We showed that SC neurons of mice with ocular hypertension had weakened responses to visual stimulation, and exhibited mismatched ON and OFF subfields and irregular receptive field structure, suggesting that the ON and OFF pathways from the retina to the SC were disrupted. Our study provides a foundation to investigate the mechanisms underlying the progressive vision loss in experimental glaucoma.

Research Summary