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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Santa Cruz Electronic Theses and Dissertations (2014)

The retina extracts relevant features from the visual scene and transmits these features to the brain through separate pathways that will eventually result in the perception of sight. The retinal ganglion cells (RGCs) are the only retinal cell type to send an axonal projection to the brain. This indicates that the signals generated by the RGCs are the end result of retinal processing, and the features detected by the RGCs are all that will be transmitted to the brain about the visual environment. Each RGC type represents a unique pathway that detects specific visual features. RGCs of the same type tile the retina so that the entire visual field is sampled. Different types of RGCs overlap so that each pixel in the visual field gets sampled by each pathway. To understand the different retinal pathways and what gets sent to the brain, it is necessary to know what types of RGCs are in the retina. Current classifications have used morphologies and physiology to describe the different RGC types. It is estimated that 20 different types of RGCs are present in the mammalian retina. However, very little is known about how these morphological features affect functional properties due to the inability to perturb the morphology and observe changes in physiology in many mammals. In order to overcome this limitation, I utilized a large-scale multielectrode array (MEA) approach to record and characterize responses from hundreds of RGCs in the mouse retina. The mouse model is advantageous due to the ease of genetic manipulation, allowing me to disrupt morphology and relate the changes to function. I first characterized and classified RGCs in the wild-type retina to develop a reference for mutant comparisons. I was able to classify up to 8 types of RGCs along with functional properties of the classes, such as tiling arrangements of the RGC receptive fields (RFs). Using a mutant mouse that has defects in dendritic and cell body spacing, I show that the dendritic structure is important for RF tiling and direction selective responses thus showing how morphology affects function. Finally, I used a transgenic mouse, in which RGCs expressing a particular gene was ablated, to show that these eliminated RGCs were a distinct functional subset that responded to light offset. The work that I performed will contribute to a complete classification of RGCs by linking the morphological types to the functional types, as well as the genetic programs that establish their properties. This will be necessary to determine what features are detected by the retina and how they ultimately lead to behavior.

    Cover page: Functional Characterization of Retinal Ganglion Cells in the Wild-Type and Mutant Mouse
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2018)

    Background

    Activity in neurons drives afferent competition that is critical for the refinement of nascent neural circuits. In ferrets, when an eye is lost in early development, surviving retinogeniculate afferents from the spared eye spread across the thalamus in a manner that is dependent on spontaneous retinal activity. However, how this spontaneous activity, also known as retinal waves, might dynamically regulate afferent terminal targeting remains unknown.

    Methods

    We recorded retinal waves from retinae ex vivo using multi-electrode arrays. Retinae came from ferrets who were binocular or who had one eye surgically removed at birth. Linear mixed effects models were used to investigate the effects of early monocular enucleation on retinal wave activity.

    Results

    When an eye is removed at birth, spontaneous bursts of action potentials by retinal ganglion cells (RGCs) in the surviving eye are shorter in duration. The shortening of RGC burst duration results in decreased pairwise RGC correlations across the retina and is associated with the retinal wave-dependent spread of retinogeniculate afferents previously reported in enucleates.

    Conclusion

    Our findings show that removal of the competing eye modulates retinal waves and could underlie the dynamic regulation of competition-based refinement during retinogeniculate development.
      Cover page: Monocular enucleation alters retinal waves in the surviving eye
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2024)
      BACKGROUND: Yellow fever virus (YFV) infections are a major global disease concern with high mortality in humans, and as such it is critical to identify clinical correlates of disease severity. While nonstructural protein 1 (NS1) of the related dengue virus is implicated in contributing to vascular leak, little is known about the role of YFV NS1 in severe YF and mechanisms of vascular dysfunction in YFV infections. METHODS: Using serum samples from laboratory-confirmed YF patients with severe (n = 39) or non-severe (n = 18) disease in a well-defined hospital observational cohort in Brazil, plus samples from healthy uninfected controls (n = 11), we investigated factors associated with disease severity and endothelial dysfunction. FINDINGS: We found significantly increased levels of NS1, as well as syndecan-1, a marker of vascular leak, in serum from severe YF as compared to non-severe YF or control groups. We also showed that hyperpermeability of endothelial cell monolayers treated with serum from severe YF patients was significantly higher compared to non-severe YF and control groups, as measured by transendothelial electrical resistance (TEER). Further, we demonstrated that YFV NS1 induces shedding of syndecan-1 from the surface of human endothelial cells. Notably, YFV NS1 serum levels significantly correlated with syndecan-1 serum levels, TEER values, and signs of disease severity. Syndecan-1 levels also significantly correlated with clinical laboratory parameters of disease severity, viral load, hospitalization, and death. INTERPRETATION: This study provides further evidence for endothelial dysfunction as a mechanism of YF pathogenesis in humans and suggests serum quantification of YFV NS1 and syndecan-1 as valuable tools for disease diagnosis and/or prognosis. FUNDING: This work was supported by the US NIH and FAPESP.
        Cover page: Yellow fever disease severity and endothelial dysfunction are associated with elevated serum levels of viral NS1 protein and syndecan-1.
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